Handbook of Psychocardiology PDF
Handbook of Psychocardiology PDF
Handbook of Psychocardiology PDF
Alvarenga
Don Byrne
Editors
Handbook of
Psychocardiology
1 3Reference
Handbook of Psychocardiology
Marlies E. Alvarenga • Don Byrne
Editors
Handbook of
Psychocardiology
The phrase “hearts and minds” rolls off the tongue with ease and a conviction that the
two are faithfully linked. Risk factors for heart, stroke, and vascular disease have
deeply rooted social and behavioral determinants. People with depression or other
major psychiatric illness are more likely to develop cardiovascular disease either de
novo or as a consequence of the treatment they receive. People with acute cardiac
disease are faced with the possibility of mortality or future disability and it is no
surprise this carries a significant psychological burden. This is a complex two-way
relationship.
Our knowledge of psychocardiology is increasing rapidly as new tools become
available and the new biology including imaging, omics, and other techniques are
applied to help unravel the links between brain function, the autonomic nervous
system, and the circulation. This book is very timely in addressing a fast moving
field where there are significant challenges for the future.
The burden of cardiovascular disease is increasing worldwide associated with
development, the stresses associated with globalization, and the socioeconomic
gradients that occur. Obesity is on the rise and its metabolic consequences including
diabetes are closely related to behavior and to future cardiac and vascular diseases. In
developed economies, increasing longevity is giving rise to concerns about the
future burden of dementia. About half of dementia is vascular in origin and the
risk factors for the other half overlap closely with the classical cardiovascular risk
factors.
These and many other subjects are dealt with in this book. Professor Byrne and
Dr. Alvarenga have made significant contributions to the field themselves and they
have assembled an impressive list of authors to produce a comprehensive resource
for all those interested in the field.
The book provides a firm basis for the development of the science of cardiac
psychology in the opening section, providing a historical perspective, an outline of
the causes, pathophysiology, and role of tobacco smoking, alcohol, and other
lifestyle aspects. This is followed by an account of the psychopathology associated
with cardiovascular disease, including depression, anxiety, and stress as well as
psychoses and more specific and contemporary issues such as posttraumatic stress,
occupational stress, and the stress associated with cardiac disease itself and its
various remedies, particularly surgery. Special populations are particularly
v
vi Foreword
susceptible to both cardiovascular disease and depression, and there are chapters on
indigenous populations, refugees, the poor, and the homeless. These well-known
social determinants of cardiovascular disease are most likely linked by stress,
depression, and associated factors. Controversies on personality and propensity to
develop heart disease are the subject of other chapters of the book. Finally, there is an
ambitious attempt to explain these associations through the neurobiology of psy-
chology and of cardiovascular disease.
This is a comprehensive examination of a complex but important issue, and the
editors have not shirked any of the innate, social, psychological, or biomedical
factors involved. It will no doubt find a place as a valuable resource for all those
interested in the field, crossing disciplinary boundaries and stimulating new work in
the area.
Garry Jennings
Melbourne, Australia
Preface
vii
viii Preface
and their own particular visions for psychocardiology. And from our own experi-
ence, where scholarly writing has often taken precedence over relaxation, we
confidently predict that their contributions to the Handbook were so often done
“out of hours.” We are sincerely grateful to them for this – and it is on such willingly
shared wisdom that the Handbook’s value to cardiac psychology will ultimately
stand.
Volume 1
xi
xii Contents
Volume 2
Marlies E. Alvarenga
Monash Cardiovascular Research Centre
Monash Health and Department of Medicine
(SCS at Monash)
Monash University
Melbourne, VIC, Australia
xvii
xviii About the Editors
Don Byrne
ANU Medical School
Australian National University
Canberra, ACT, Australia
xix
xx List of Contributors
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Poets, Philosophers, and Other Wise People . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Stress, Distress, and the Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Psychocardiology Now . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Abstract
The term Psychocardiology has achieved prominence quite recently to describe both
a field of research and an approach to clinical practice, though the evidence upon
which this is based is not at all new. Systematic research linking the heart and the
mind has a far longer history – its origins in medical science can be found more than
a century ago in, for example, the work of the psychoanalytic movement. And from
a more cardiologic space, the speculations of the eminent physician Sir William
Osler clearly foreshadowed moves to link personality with diseases of the heart
when he said of the person at risk of angina, that . . . It is not the delicate neurotic
person who is prone to angina, but the robust, the vigorous in mind and body, the
keen and ambitious man, the indicator of whose engines is always at full speed
D. Byrne (*)
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
ANU Medical School, Research School of Psychology, Australian National University, Acton,
Canberra, ACT, Australia
e-mail: [email protected]
M.E. Alvarenga
MonashHEART, Monash Cardiovascular Research Centre, Monash Health and Department of
Medicine (SCS at Monash), Monash University, Melbourne, VIC, Australia
e-mail: [email protected]
ahead. This chapter traces the origins of thought linking the heart and mind,
commencing with the place of the heart in literature and religion, and ending with
a hypothesis that subjective perceptions of cardiovascular activation arising from
sympathetic arousal account for the compelling belief among person-kind that
diseases of the heart are inextricably linked to afflictions of the mind.
Keywords
Heart disease • Psychogenic heart disease • Aetiology of heart disease •
Psychocardiology • Mental illness • Cardiovascular disease
Introduction
The heart can quite accurately be called the driving organ of the human body. Its
regular cycle of systole and diastole pumps life-sustaining blood through the arterial
circulation to the rest of the body and then picks up waste materials through the
venous circulation as blood returns to the heart, taking advantage of the cleansing
capacity of the kidneys along its way. We have some conscious perception of this
fundamental and continuous biological process through such physical sensations as
the heartbeat – a regular pulsation felt in the left thoracic region of the body, clearly
evident at rest on palpation or auscultation, and even more clearly apparent to us
during such activities as strong physical exercise, when neither finger tips nor
stethoscope is necessary to alert us to the constant action of the heart. The same
conscious perception, of course, accompanies the myriad forms of psychological
arousal – but more of that later. And while we can feel this action, we do not – and
need not – consciously will it to happen. This is well taken care of – in the healthy
individual at least – by the close interface between the cardiovascular system and
both the central and peripheral nervous systems. The force of life is provided for us
through a well-understood set of biological activities, deeply intricate in their indi-
vidual functions but, at the same time, relatively clear-cut in mechanistic overview.
Of course that understanding of the functions of the cardiovascular system was not
always so. Fleming’s (1996) A Short History of Cardiology nicely explains the develop-
ment of knowledge on the functions and actions of the heart from around 1700 to the
mid-twentieth century, and Granger’s (1998) paper on advances in cardiovascular
physiology during the last century tracks the major biomedical milestones in this essential
piece of medical history. The focus of these excellent works – and others as well – has
however been clearly on biomedicine. And if we venture back further – or indeed if we
just look in parallel with these major biomedical landmarks, at how person-kind has
viewed the human heart throughout history – we see a somewhat more elaborate,
divergent, and quintessentially poetic view of this organ so central to our existence.
We say this because in works of poetry, religion, and philosophy, or simply in
folk wisdom, the heart has been identified unambiguously as the seat of human
consciousness – the origin of our motives and emotions, indeed of our moral
characters, whether good or bad. And references to the heart in this role abound
in countless works of (nontechnical) literature.
Psychogenesis and Heart Disease Now: The Thinking Heart in Action 5
In 1819 the romantic poet John Keats wrote, in his Ode to a Nightingale:
Keats spoke here of the bittersweet emotion he felt on hearing the beauty of the
nightingale’s song but reminded in doing so of the frailty and insignificance of
human life – whether his own or of person-kind in general, we do not know. But it
was his heart in which he located the felt and identifiable emotion and not his
rational thinking self – no mention was made of the role of his cognitive persona.
Much will be made in this Handbook of the nexus between the heart and three of
the most prominent of the more psychopathological emotions – anxiety, depression,
and anger. This is not surprising since there is now unequivocal evidence from
many sound and instructive scientific studies – epidemiological, clinical, and
psychobiological alike – to causally link the continued experience of one or other
of these emotions with the genesis of cardiovascular pathology and ultimately of
cardiovascular disease (CVD). Even so, this now widely accepted scientific evi-
dence is predated by a more poetic recognition that the heart is the true locus of the
experienced emotion. Anxiety is said not just to reside in the heart but also to have
deleterious consequences (An anxious heart weighs a man down – Proverbs, 12:25),
and the angry heart too does not escape note (Be not quick in your spirit to become
angry for anger lodges in the heart of fools – Ecclesiastes 7:9). But it is probably the
sad and anguished heart that has attracted most attention from poets and those of
like mind. Keats again, in 1820, highlights the heart in its anguish:
On the other hand, Emily Brontë (perhaps 20 years later but undated) spoke in a
brief poem of the sad and weary heart (from What Use is it to Slumber Here). And
of course William Shakespeare’s archetypal depressive, Hamlet Prince of Den-
mark, in what must be one of the most recited and quoted reflections on the sad –
and possibly suicidal – heart, said:
To die, to sleep—
No more—and by a sleep to say we end
The heartache and the thousand natural shocks
That flesh is heir to (Hamlet, Act 1, Scene 3).
But a plethora of other emotions and motives have also been linked to the heart
through the pens of both well-known and lesser known commentators. The heart
has been said to drive courage (The brave, impetuous heart . . . Matthew Arnold,
from Empedocles on Etna, 1852) and moral purity (Blessed are the pure in heart . . .
6 D. Byrne and M.E. Alvarenga
Matthew 5:8) but also to be the seat of evil (The heart is deceitful above all things,
and desperately wicked . . .Jeremiah 17:9). Both joy (A laugh, to be joyous, must
flow from a joyous heart . . . Thomas Carlyle, 1795–1881) and anguish (I groan in
anguish of heart . . . Psalm 38:8) have been attributed to the heart, as have both love
(Keep love in your heart . . . Oscar Wilde, 1854–1900) and hope (Walk on, walk on
with hope in your heart . . . from Rodgers and Hammerstein’s 1945 musical
Carousel). Kindness (The larger heart, the kindlier hand . . . from Alfred Lord
Tennyson’s Ring Out Wild Bells, 1850) and generosity (If you haven’t got any
charity in your heart, you have the worst kind of heart trouble . . . Bob Hope,
1903–2003) have both also been ascribed to the heart.
A commonly used Internet thesaurus provides many synonyms for the term
lightheartedness (http://www.thesaurus.com/browse/lightheartedness), all of them
equating to a state of care-free happiness. And to be lighthearted appears to be
advantageous – an old Irish proverb is reported to promise that . . .A light heart lives
long, a saying repeated in Shakespeare’s Loves Labours Lost. Some among us are
said (we hope) to be big hearted (generous, benevolent, or charitable), but others
regrettably show the antithetical quality of being mean hearted. To be coldhearted
implies a lack of empathy or feeling, while being hard-hearted is to be unkind,
merciless, or pitiless. And in passing here, it is worth noting here that one of the
really seminal scientific papers linking emotional experience to cardiovascular
mortality, published by C Murray Parkes and his colleagues in 1969, was titled
Broken Heart: A Statistical Study of Increased Mortality Among Widowers, the
term brokenhearted being commonly used to describe the anguish of bereavement.
Thus, the question central to the introduction to this Handbook is why should the
heart have been linked so consistently to emotions and motives in times before the
emergence of persuasive scientific evidence on the biological operation of the
cardiovascular system? Does the heart really think, does it feel, and does it drive
our observable behaviors in ways which characterize our unique identities as
individuals?
In the light of empirical evidence accumulating over the past half century or more,
the answer is now rather more straightforward – evidence emerging from the
interface of psychology, neuroscience, and cardiovascular physiology makes it
abundantly clear that the emotional lives of person-kind and the psychological
forces which drive us and form our motivations have their origins in and are largely
regulated by the central nervous system.
The issue of the psychobiological mechanisms linking the heart with the mind
therefore presents itself to us for consideration. Much of the evidence documenting
these mechanisms will be presented in considerable detail in many of the substan-
tive chapters making up this Handbook and we do not intend to foreshadow or
predetermine the substance of those chapters – they will speak for themselves with
good authority. The nature of these mechanisms does, however, also have a strong
Psychogenesis and Heart Disease Now: The Thinking Heart in Action 7
cogent attempts to fit the experience of love into a clear neurobiological framework
of autonomic arousal (Porges 1998, 2003), but little in the way of systematic and
persuasive psychophysiological evidence has been provided to document this. And
so perhaps, just for the time being, we must leave love to the poets.
In a recent and comprehensive review of the relevant literature, Appelhans and
Luecken (2006) cogently argued that HRV might lay at the foundation of emotional
regulation and, by extension, might provide a cogent biological mechanism through
which subjective perceptions of cardiovascular activity may be causally linked to
the experience of recognized and identifiable emotions. However, a broad perusal
of the literature on the nature and functions of emotional regulation suggests that
the area is typically defined and investigated as a global construct (Krohne
et al. 2002; Mauss et al. 2007). And the psychobiological evidence to date does
not provide a sustainable foundation for claims of any simple direction of causality
– either that the experience of any particular emotion leads to a consistent and
recognizable pattern of cardiovascular activation, or that identifiable and differen-
tiable profiles of cardiac activity are interpreted to be uniquely linked to the
subjective experience of specific emotional states.
The absence of causal evidence linking emotional experience and cardiovascular
activity, one way or the other, presents an obvious barrier to a more complete
understanding either of the feeling heart or of the thinking heart – but not a fatal
one. Models driving further investigations in the area must – and almost certainly
will – incorporate elements of cognition and the individual interpretation of per-
ceived cardiovascular activity, along with the more traditional and objective mea-
sures of stimulus (events arising in the psychosocial environment) and response
(cardiovascular activity itself). And though this will require complex and sophisti-
cated research designs, and perhaps novel and creative approaches to measurement,
it will in our view have the potential to advance the field of understanding
significantly.
So where has this story lead us thus far? The functions of the heart and of the
central and peripheral nervous systems – the mind, in more purely psychological
terms – are intricately and inextricably linked. The evidence is abundantly clear on
this point. But the heart does not – in and of itself – think or feel or cause us to act in
one way or another. Rather, it reflects these cognitions and emotions and motives
more or less faithfully, and in ways which are open to the subjective perceptions of
the individual – and to the unique meanings which these perceptions give rise to in
any among us. The heart can therefore be claimed to be a relatively accurate
barometer of the nature and intensity of those psychological events – cognitions,
emotions, and motivations – which in past times were believed to emanate directly
from that organ itself. The linking psychobiological mechanisms remain to be fully
clarified in the laboratory, though the rate and volume of the emergent published
evidence are conspicuously apparent in progressive reviews of the literature – and
much of this evidence will be expertly presented and reviewed in the remaining
chapters of this Handbook. And of course the translation of evidence to clinical
practice will not be forgotten.
10 D. Byrne and M.E. Alvarenga
Psychocardiology Now
While the heart/mind nexus has been acknowledged for many decades now (Koch
2013) and seriously investigated employing a multitude of research paradigms and
methodologies, from those focusing largely on the psychosocial correlates of
cardiovascular events through to those more concerned with these events them-
selves – and including diagnosed pathological events as well as those within the
more normal domain of cardiovascular physiology – the origins of the term
psychocardiology are obscure and its provenance is not easily attributed. In quite
recent times, however, the use of the term has been seen more and more frequently
in the scientific literature. A very systematic consideration of the evidence
supporting the heart/mind nexus, and using the term psychocardiology in the title
of the resulting publication, appeared less than a decade ago (Jordan et al. 2007). At
around the same time, the inaugural Heart and Mind: Psychogenic Cardiovascular
Disease Conference was convened by Australia’s Baker IDI Heart and Diabetes
Institute in 2008, and psychocardiology became an identifying catchphrase for this
continuing series of meetings. And in a slightly more clinically oriented context, the
term was proposed independently both by Koch (2013) and Halaris (2013) to
delineate an emerging clinical field where the interface between cardiology, psy-
chiatry, and psychology assumed a unique and integrated importance in addressing
the effective management of the alarmingly large number of people in so many
populations worldwide either with conspicuous CVD or at risk of manifesting this
in the near future. A clearer recognition over time of the importance of the role
played by depression in the genesis and course of CVD was certainly one driver of
this movement (Halaris 2013), but it is equally apparent from a now overwhelming
body of published evidence spanning a hundred years or more that
psychocardiology delineates a far broader field of knowledge and clinical practice.
Conclusion
The Handbook of Psychocardiology has therefore taken as its mission, the presenta-
tion of this evidence, coupled with critical and expert commentary evaluating its
worth and significance, in objectively establishing the nature of the heart/mind nexus
as we now know it. It has undertaken this task fully recognizing the theoretical and
empirical breadth of that evidence – from the psychosocial to the molecular biolog-
ical, from the findings of the cardiovascular laboratory to those of population
epidemiology, from studies of psychobiological causality to those from the realm
of clinical management, and from the individual disciplinary perspectives of cardi-
ology to those of psychology and psychiatry. And moreover – and probably most
importantly – the Handbook takes as axiomatic the view that psychocardiology
reflects above all the need for blurred and porous disciplinary boundaries and for
disciplinary integration rather than jealously guarded territories in fully addressing
the challenges of cardiovascular disease in the twenty-first century.
Psychogenesis and Heart Disease Now: The Thinking Heart in Action 11
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Cardiac Psychology: Ancient and Modern
History
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Heart as Both a Prime Mover and a Mirror of the Emotions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Heart Upstaged by the Brain: Mind and Soul Made Flesh in the Brain . . . . . . . . . . . . . . . . . . . 14
Autonomic Innervation of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Heart Rate in Psychological Measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
“Heart on Your Sleeve”: The Heart in Language . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Psychosomatic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
“Triggered” Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Abstract
Ideas linking the heart to the brain exist in ancient and of course modern texts. In
antiquity, the brain was not given its due! The London physician and neuroanat-
omist Thomas Willis changed this, correctly attributing the source of emotions
to the brain. Contemporary research does establish the existence, and autonomic
nervous system mechanisms, of cardiac responses to emotion. Further, it docu-
ments the phenomenon of “triggered” heart disease, when the autonomic ner-
vous control of the heart goes awry, producing heart disease of sudden onset,
precipitated by acute emotional upheaval.
M. Esler (*)
Human Neurotransmitter Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC,
Australia
e-mail: [email protected]
R. Schwarz
Baker IDI Heart and Diabetes Institute, Fitzroy, VIC, Australia
e-mail: [email protected]
Keywords
Mental stress • Autonomic nervous system • Psychosomatic heart disease •
Depressive illness • Panic disorder • “Triggered” heart attacks
Introduction
Ideas linking the heart to the brain and emotions exist in ancient and of course
modern texts. For Aristotle (Hamilton and Richards 1982; Zimmer 2004), the eyes
and ears were connected not to the brain but to blood vessels, which carried
perceptions to the heart. In his dialogues, Timaeus (Hamilton and Richards 1982;
Zimmer 2004), Plato located the “vital soul” in the heart. The heart was a distrib-
utor of the vital spirit and seat of the soul. In the heart, Herophilus and Erasistratus
described the blood turning red as it was imbued with vital spirit (Hamilton and
Richards 1982; Zimmer 2004). Vital spirit was distributed through arteries to the
body, including to the brain where, acting as a pump, the brain distributed it as a
liquor through the nerves. The vital soul was “endowed with courage and passion
and loves contention,” Plato wrote (Hamilton and Richards 1982; Zimmer 2004).
Along with the blood, the vital soul’s passions flowed out of the heart, exciting the
body into action. The superior soul, in his spiritual anatomy, had the brain at its
apex; the lower souls were the liver and heart. Plato ascribed no physical site to the
immortal soul, but early Christian Church fathers did. Although having no physical
dimension, its faculties resided in the ventricles of the brain (Zimmer 2004).
For Aristotle (Hamilton and Richards 1982; Zimmer 2004), the heart had centrality,
governing all sensations, movements, and emotions, through heat generation and
distribution through blood vessels; the brain was secondary, in that it “tempers the
heat and seething of the heart.” An explicit ancient “psychocardiology” reference
was attributed to Philistion of Locri, in Plato’s dialogue, Timaeus (Hamilton and
Richards 1982): “As a means of relief from the leaping heart when the passion is
excited . . . from the action of fire they (the engendered sons of God) contrived and
implanted the form of the lung – soft and bloodless . . .” (Hamilton and Richards
1982).
The Heart Upstaged by the Brain: Mind and Soul Made Flesh
in the Brain
the anatomy of the healthy brain, of the “brain of brutes” (sufferers of insanity or
mental defect), and by his clinical observations on those of his patients whom on
their death came to anatomical dissection, he banished the soul, and the source of
emotions, from the heart to the brain (Zimmer 2004). The biography of Willis and
his pivotal contributions are recounted in the book of Carl Zimmer, Soul Made
Flesh (Zimmer 2004).
The studies of the anatomist, Vesalius, and the physician and experimenter, Harvey
(Hamilton and Richards 1982), established that, above all, the heart is a pump,
although a responsive pump, responding to physical needs and to emotion. The
extrinsic regulation of the heart is primarily via the autonomic nervous system, by
way of its vagal and sympathetic nervous system innervation, supplemented by
adrenal medullary secretion of adrenaline. Heart rate and cardiac output reflexly
increase with exercise, to distribute the oxygen needed to sustain the physical work
of muscles, and additionally both are augmented by emotions in the fight or flight
response, to facilitate engagement or escape at times of threat. Reflex heart rate
slowing driven by the cardiac vagus occurs in “vasovagal” hypotension and syn-
cope, triggered by prolonged standing, pain, or anxiety (Vaddadi et al. 2010).
Autonomic control of the heart in humans can be studied through the use of
pharmacological autonomic blockade, of the vagus nerve with atropine (Julius
et al. 1971), and of the cardiac sympathetic nerves, with beta-adrenergic blockade
(Julius and Esler 1975; Esler et al. 1977), allowing investigation of the influence of
the autonomic nervous system on heart rate, cardiac output, and left ventricular
contractility. The release of the neurotransmitter, noradrenaline, from the sympa-
thetic nerves of the human heart has been measured with isotope dilution method-
ology (Esler et al. 1984), to quantify cardiac sympathetic nervous activity at rest,
during exercise (Hasking et al. 1988), and during laboratory mental stress responses
(Esler et al. 1989, 1995) and in patients with anxiety and depression (Alvarenga
et al. 2006; Barton et al. 2007).
English language of the present day (Collins Dictionary 2001) captures both the
ancient concepts of the heart as the center of vitality and passions and contemporary
ideas encompassed in the various constructs of psychocardiology. Common par-
lance considers the heart as the seat of life, emotions, love, courage, tenderness, and
pity. Your heart can be “on your sleeve,” “in your mouth,” or “in your boots.” You
may “lose your heart” (by being in love) or be “heartbroken” (with grief or despair).
Doing something “heart and soul” (i.e., absolutely) is an expression which would
have conveyed meaning for the ancients.
There has been a recent strong resurgence of support for the idea, often in the past
banished to the realm of medical folklore, that mental stress and psychological
illness is a cause of cardiovascular disease (Table 1). This acceptance, however, has
been in the face of a high level of skepticism, very explicitly illustrated in the
deliberations of a panel charged with reviewing the topic for an Australian national
health body on which one of us served. The opening address of the chair included
the opinion, “there is no evidence that stress causes heart disease, nor will there ever
be.” The authors, who are a cardiologist and a psychiatrist, here aim to correct the
chairman’s error.
War has been a fertile field for the development of psychosomatic heart disease,
with identification and nomenclature being dependent on the era and the level of
sophistication in the psychiatric formulation. Soldiers heart, irritable heart, shell
shock, and combat exhaustion are wartime disorders which have morphed post-
DSM III into the rubric of post-traumatic stress disorder. In civilian life, the
contemporary evidence supporting the existence of psychosomatic (psychogenic)
cardiovascular disease (Table 1) is perhaps strongest for the acute precipitation
(“triggering”) of the cardiac events (Rozanski et al. 1999) of myocardial infarction,
It has always seemed plausible that short-term mental stress can act as an immediate
precipitant (“trigger”) for the development of abnormal heart rhythm and sudden
death in patients with existing heart disease. For many years this claimed relation of
acute mental stress to heart attacks was largely based on individual anecdotes, such
as the celebrated case of the famous eighteenth-century English surgeon, John
Hunter, who wrote that he was at the mercy of any scoundrel who aggravated
him and then proved the point by dying suddenly in the middle of a stormy meeting
18 M. Esler and R. Schwarz
of the board of his hospital. Some people are predisposed through genetic flaws to
heart risk at times of mental stress, such as those with inherited variants of the long
QT interval syndrome, in whom abnormal ion transport in cardiac myocytes causes
electrical instability of the heart muscle (Zipes 1991).
In recent years systematic evidence has been gathered at times of disasters,
including war, missile attacks on civilians, and earthquakes, which also strongly
supports the proposition of a mental stress-heart attack link. Research linking
mental stress to sudden death is often disputed because of disagreement over
what constitutes a stress and whether stress can be accurately measured. Evidence
that rates of sudden, non-traumatic death are markedly increased during earth-
quakes, the 1994 Los Angeles earthquake providing a very telling example (Leor
et al. 1996), is free of this criticism, as here no finessing is needed in the psycho-
logical measurement of stress. During an earthquake, no doubt everyone is terrified.
Are heart attacks during community disasters a special case only or of more general
relevance? In individual personal life, “emotional earthquakes” do occur. In his
clinical practice, the cardiologist author has seen heart attacks in his patients
triggered by armed robbery, assaults, and even a racehorse winning by a “nose.”
Additionally, cardiac events during panic attacks are an explicit instance of trig-
gering (Mansour et al. 1998).
The biological mechanisms by which acute mental stress triggers heart attacks
are clear (Rozanski et al. 1999) (Fig. 1). First, this occurs almost exclusively in
those with existing atherosclerotic coronary artery narrowing, although this may
have been clinically silent and unrecognized. In the presence of coronary artery
stenosis and myocardial ischemia, the preferential activation of the sympathetic
nervous outflow to the heart with acute mental stress (Esler et al. 1989) can cause
Fig. 1 “Triggering” of myocardial infarction and sudden death. Sympathetic nervous activation
with acute mental stress (accompanied by vagal withdrawal) can act as a “trigger” for clinical
presentation of previously silent coronary artery disease. The blood pressure surge with mental
stress can lead to fissuring or rupturing of an atherosclerotic plaque, coronary artery thrombosis,
myocardial infarction, and sudden death. In the presence of coronary artery stenosis, sympathetic
activation and vagal withdrawal can induce lethal ventricular arrhythmias. Catecholamine activa-
tion of platelets is thrombogenic. High levels of activation of the cardiac sympathetic nerves can
cause coronary artery spasm, perhaps via neuropeptide Y release
Cardiac Psychology: Ancient and Modern History 19
Conclusion
Sudden cardiac death is the most significant and challenging problem in contem-
porary cardiology. So often coronary atherosclerosis is clinically silent and
undetected, to become catastrophically evident when an unstable atherosclerotic
plaque fissures or ruptures, leading to coronary thrombosis, myocardial infarction,
and a lethal ventricular arrhythmia. An acute physical stressor, commonly extreme
exercise, or acute mental stress is the usual trigger. To counter the sudden cardiac
death nemesis, recent coronary artery imaging research aims to detect subcritical
but clinically silent coronary artery stenosis and unstable coronary atherosclerotic
plaques. Delineating the biological mediators of heart risk in an acute mental stress
would provide a potential target for prevention, to inhibit platelet activation and
block excessive cardiovascular stimulation by the sympathetic nervous system and
adrenaline.
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Fundamentals of Cardiology for the
Non-Cardiologist
Contents
Basic Anatomy of the Human Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Basic Embryology of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Basic Physiology of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Cardiac Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Normal Electrical Conduction System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Heart Rate Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Cardiovascular Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Disorders of the Coronary Arteries: Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Disorders of the Electrical Conduction System: Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Cardiomyopathy and Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
Abstract
Awareness of the fundamentals of cardiac anatomy, physiology and various
disease states is essential to clinicians managing a patient with cardiac pathol-
ogy. This chapter summarizes the key aspects of cardiac structure and function,
as well as providing an overview of the broad range of cardiac pathology.
B. Xu (*) • M. Stokes
MonashHeart, Monash Medical Centre, Clayton, VIC, Australia
e-mail: [email protected]; [email protected]
I. Meredith
MonashHeart, Monash Medical Centre, Clayton, VIC, Australia
Southern Clinical School, Monash Cardiovascular Research Centre, Monash University,
Melbourne, VIC, Australia
e-mail: [email protected]; [email protected]
The chapter discusses the various presentations of cardiac disease and the
clinical assessment that is performed. Diseases discussed include those of
cardiac rhythm, vessels, valves, and muscle as well as congenital heart disease.
The various modalities of investigation and basic principles of management are
also reviewed.
Keywords
Atrial fibrillation (AF) • Bradyarrhythmias • Bundle of His • Cardiology • Basic
anatomy of • Basic embryology of • Cardiac cycle • Cardiovascular disorders.
see Cardiovascular disorders • Heart rate regulation • Normal electrical conduc-
tion system • Cardiovascular disorders • Arrhythmias • Cardiomyopathy and
heart failure • Congenital heart disease • Ischemic heart disease • Valvular heart
disease • Congenital heart disease • Contractility • Coronary artery disease
(CAD) • Diastole • Endocardium • Epicardium • Heart block • Heart failure
with preserved ejection fraction (HF-PEF) • Heart failure with reduced ejection
fraction (HF-REF) • Left atrial appendage • Myocardium • Non-ST-elevation
myocardial infarction (NSTEMI) • Patent foramen ovale (PFO) • Percutaneous
coronary intervention (PCI) • Permanent pacemaker (PPM) • Primary foramen •
Secondary foramen • Secondary septum • ST-elevation myocardial infarction
(STEMI) • Systole • Tachyarrhythmias • Torsades de pointes • Transcatheter
aortic valve replacement (TAVR) • Unstable angina (UA) • Valvular heart
disease
Cardiology is the branch of medicine which deals with the comprehensive assess-
ment, diagnosis, and management of patients with diseases and disorders of the
heart. Within the specialty of cardiology, adult cardiologists deal with patients with
cardiovascular disorders in the adult age group, including elderly patients, while
pediatric cardiologists treat patients with cardiovascular disorders in the pediatric
age group, including newborns. There are further subspecialty areas of practice
within cardiology, broadly divided into interventional cardiology, noninvasive
cardiology, and electrophysiology. Firstly, interventional cardiologists use percu-
taneous techniques to diagnose and manage patients with coronary artery disease
and other structural heart problems. Percutaneous coronary intervention refers to a
number of techniques that are used to treat significant atherosclerotic lesions in
coronary arteries. Congenital heart defects such as patent foramen ovale and atrial
septal defect can also be closed percutaneously. Recent advances in percutaneous
transcatheter aortic valve replacement (TAVR) have revolutionized the treatment
of patients with severe symptomatic aortic stenosis, who were previously deemed
inoperable. Secondly, noninvasive cardiologists specialize in the diagnosis and
assessment of patients with cardiac problems by employing multimodality cardiac
imaging techniques, including echocardiography, multi-detector computed tomog-
raphy (MDCT), and cardiac magnetic resonance imaging (CMR). These cardiac
imaging techniques help guide diagnosis and the selection and delivery of appro-
priate interventional treatment options for the appropriate patients. Thirdly, cardiac
Fundamentals of Cardiology for the Non-Cardiologist 23
electrophysiologists deal with rhythm disorders of the heart. They specialize in the
implantation of cardiac devices, such as permanent pacemakers (PPMs) to treat
bradyarrhythmias, implantable cardioverter defibrillators (ICDs) to prevent ven-
tricular fibrillation and sustain ventricular tachycardia, and cardiac resynchro-
nization therapy (CRT) in appropriate patients with severe symptomatic
congestive cardiac failure. Electrophysiologists also employ complex techniques
to diagnose and treat rhythm disorders of the heart.
The purpose of this chapter is to provide readers with a general overview of
cardiology. It will begin with an overview of the anatomy, embryology, and
physiology of the human heart, followed by a focused and clinically relevant
discussion of common cardiovascular disorders.
The heart is located in the thoracic cavity. It works as an efficient muscular pump as
a result of the coordinated function of the four cardiac chambers. The atria (the left
and right atria) are smaller and superiorly located. The ventricles (the left and right
ventricles) are larger and inferiorly located (Fig. 1). The heart is slightly rotated
toward the left in the thoracic cavity, such that the right ventricle is the most
anterior cardiac chamber. The left ventricular wall thickness is approximately
twice that of the right ventricle. This is because the left ventricle is required to
pump blood through the entire body in the systemic circulation. In comparison, the
right ventricle pumps blood through the lungs in the pulmonary circulation. Under
Fig. 1 Normal structure of the heart showing the four cardiac chambers (apical four-chamber
view on transthoracic echocardiography). Abbreviations: LA left atrium, LV left ventricle, RA right
atrium, RV right ventricle
24 B. Xu et al.
Fig. 2 Transthoracic echocardiography depicting the four cardiac valves, in parasternal short-axis
(a), parasternal long-axis (b), and parasternal short-axis (mitral valve level) (c) views. During
diastole, mitral valve opening gives rise to a characteristic “fish-mouth” appearance (c). Abbrevi-
ations: TV tricuspid valve, AV aortic valve, PV pulmonary valve, MV mitral valve
Fig. 3 Coronary angiogram demonstrating the left coronary system in the right anterior oblique
caudal projection (a) and the right coronary artery in the left anterior oblique cranial projection (b).
Abbreviations: LM left main trunk, LAD left anterior descending artery, LCx left circumflex artery,
RCA right coronary artery
artery (Fig. 3). The dominance of the coronary arterial circulation is determined by
which artery (either the left circumflex artery or the right coronary artery) that gives
rise to the posterior descending artery branch which resides in the posterior
interventricular groove. Disorders of the coronary arteries are broadly known as
coronary artery disease. The commonest cause of coronary artery disease is
atherosclerosis.
The primitive common atrial chamber arises from the expansion of the caudal
region of the simple tube (Oostra and Moorman 2009). It subsequently divides into
the two atrial chambers by the formation of a crescentic ridge (primary septum)
(Oostra and Moorman 2009; Preeta et al. 2012). The area between the leading edge
of the developing primary septum and the endocardial cushions is known as the
primary foramen (Oostra and Moorman 2009). The primary foramen becomes
progressively smaller in size, as the primary septum grows toward the endocardial
cushions. Eventually, the primary foramen closes as a result of fusion of the primary
septum with the endocardial cushions (Oostra and Moorman 2009). Subsequently,
multiple small fenestrations develop at the superior aspect of the primary septum to
form the secondary communication between the developing atria known as the
secondary foramen (ostium secundum) (Oostra and Moorman 2009; Preeta
et al. 2012). Next, an infolding of the atrial roof grows down along the right atrial
side of the primary septum. This infolding of the atrial roof is known as the
secondary septum (Oostra and Moorman 2009; Preeta et al. 2012). The secondary
septum develops to lie over the secondary foramen, except for a small area inferi-
orly. The area of the primary septum which is exposed on the right atrial side, not
covered by the secondary septum, is the fossa ovalis (Oostra and Moorman 2009;
Preeta et al. 2012). A flap-like valve called the foramen ovale is created between the
two atria (Oostra and Moorman 2009; Preeta et al. 2012). The foramen ovale
functions as a one-way valve to allow only right-to-left blood flow between the
two atria in utero. Shortly after birth, this defect is permanently fused in most people.
Persistence of this communication between the atria is known as a patent foramen
ovale (PFO). PFO is a common congenital heart lesion occurring in 30 % of the
general population. It is commonly an incidental finding of no major clinical
significance. However, for certain patients, it can be associated with ischemic stroke
by facilitating the passage of paradoxical embolus from the right-sided cardiac
chambers to the systemic circulation. In these situations, the PFO required could
be closed percutaneously by interventional cardiologists. PFO closure has also been
advocated by some as an effective treatment for migraine. However, this claim has
not been supported by results from recent randomized trial data (Ailani 2014).
Ventricular septation continues after the primary atrial septum is formed. It
results from the complex process of growth and remodeling of trabecular sheets,
expansion of the ventricular chambers, and the fusion of several tissues to form the
membranous and the muscular interventricular septum (Watanabe and Wikenheiser
2015; Oostra and Moorman 2009; Preeta et al. 2012).
Cardiac Cycle
In a standard cardiac cycle, there are two phases that allow blood to transition
through the heart’s four chambers. Systole refers to the phase of contraction, while
diastole refers to the phase of relaxation (Guyton and Hall 2000). The two atria and
Fundamentals of Cardiology for the Non-Cardiologist 27
the two ventricles alternatively contract and relax, providing the environment to
force blood from areas of higher pressure to areas of lower pressure. When blood is
flowing from the atria to the ventricles, the tricuspid and mitral valves are open to
allow this movement. Similarly, during ventricular systole, when blood is flowing
from the right ventricle to the lungs and from the left ventricle to the systemic
circulation, the pulmonary and aortic valves, respectively, open.
Cardiac output refers to the volume of blood which is ejected from the left
ventricle into the aorta each minute (Guyton and Hall 2000). It equals the stroke
volume (the volume of blood ejected by the left ventricle with each contraction)
multiplied by the heart rate (the number of heartbeats per minute) (Guyton and Hall
2000). In a healthy heart, stroke volume is regulated by the following three factors:
1. Preload – the degree of stretch in the heart before it contracts. The effect of
volume on myocardial stretch is explained by the Frank-Starling mechanism.
The Frank-Starling law dictates that the volume of blood ejected by the ventri-
cles during systole is dependent upon the volume of blood present in the
ventricles at the end of diastole. With increased myocardial fiber length at the
end of diastole (with higher volume), the strength of cardiac contraction and
consequently stroke volume and cardiac output will be higher. This principle
applies for the healthy human heart but not in hearts with disorders of
contraction.
2. Contractility – this refers to the strength of myocardial contraction at any given
preload. With stimulation of the sympathetic division of the autonomic nervous
system and the presence of the hormones adrenaline and noradrenaline, cardiac
muscle fiber contraction is more forceful which will increase stroke volume.
Drugs which increase ventricular contractility are classified as inotropes.
3. Afterload – this refers to the resistance that needs to be overcome for the
ventricles to eject their volume of blood. In disease states where there is
increased resistance to be overcome (e.g., hypertension or valve stenosis), left
ventricular wall stress is increased, which, if significant, may reduce stroke
volume and cardiac output.
The heart has its own intrinsic electrical conduction system. In the normal physi-
ological state, the dominant electrical impulse is generated from the sinoatrial node
(SA node) within the right atrium. This electrical signal, traveling through the
atrium, corresponds to the P wave on ECG. Before reaching the ventricles, the
electrical impulse has to pass through the atrioventricular node (AV node). At the
AV node, the electrical impulse is delayed. This corresponds to the PR interval on
ECG. From the AV node, the electrical impulse is conducted through specialized
conduction tissue known as the bundle of His, which is composed of the left and
right bundle branches. Subsequently, the electrical signal reaches the distal ventri-
cles directly via the Purkinje fibers. This process of ventricular muscle
28 B. Xu et al.
Variations in heart rate can affect the cardiac output. This can occur in various
physiologic states. The most important regulation of heart rate occurs via the
autonomic nervous system and its eventual modulation of the SA node (Guyton
and Hall 2000). The hormones adrenaline and noradrenaline which are released
from the adrenal medullae also affect heart rate regulation and, consequently,
cardiac output. A cardiovascular regulation center is located in the medulla
oblongata of the brain stem (Guyton and Hall 2000). Sensory impulses monitoring
movements, blood chemistry, and blood pressure feed into this center. Other brain
centers also provide input, including the limbic system. This cardiovascular center
modulates output by increasing or decreasing the nerve impulse activity via the
sympathetic and parasympathetic components of the autonomic nervous system.
Sympathetic fibers extend from the medulla oblongata to the spinal cord and
leave the spinal cord at the thoracic level (Guyton and Hall 2000). These fibers then
innervate the SA node, the AV node, and the myocardium via efferent cardiac
accelerator nerves. Sympathetic effect on heart rate is mediated at the muscle level
by the neurohormone, noradrenaline. Parasympathetic nerve impulses reach the
heart via the right and left vagus nerves (Guyton and Hall 2000). These fibers then
innervate the SA node, the AV node, and the atrial myocardium. The parasympa-
thetic nerve fibers release acetylcholine at these sites, resulting in reduction in heart
rate.
Cardiovascular Disorders
Fig. 4 A clinical classification of patients presenting with chest pain. Refer to the text for details.
Abbreviations: STEMI ST-elevation myocardial infarction, NSTE-ACS non-ST-elevation acute
coronary syndrome, NSTEMI non-ST-elevation myocardial infarction
disease. Patients with coronary artery disease who have an acute disease presenta-
tion are said to have an acute coronary syndrome. The spectrum of acute coronary
syndrome consists of unstable angina (UA), non-ST-elevation myocardial infarc-
tion (NSTEMI), and ST-elevation myocardial infarction (STEMI). The differenti-
ation between these entities is based on ECG and serum biomarker measurements
(Fig. 4). On history, patients with an acute coronary syndrome usually have
prolonged typical chest pain symptoms or an accelerating pattern of chest pain
symptoms that occur on minimal exertion or at rest. UA is not associated with any
cardiac biomarker rise. STEMI is associated with persistent ST segment elevation
in two or more contiguous ECG leads. NSTEMI is associated with serum cardiac
biomarker evidence of myocardial necrosis but without ST segment elevation on
ECG.
Ischemic heart disease is the commonest cause of mortality worldwide. The risk
factors for ischemic heart disease include hypertension, smoking, dyslipidemia,
diabetes mellitus, and obesity. Chronic renal disease and chronic inflammatory
conditions such as rheumatoid arthritis are increasingly recognized as also being
risk factors for ischemic heart disease. The general pathophysiological principles of
ischemic heart disease revolve around the development of atheromatous plaques
30 B. Xu et al.
coronary artery disease, it has been shown that patients can be effectively managed
by optimal medical therapy.
Typical medical therapy of patients with coronary artery disease includes
antiplatelet agents (aspirin and another antiplatelet agent such as clopidogrel or
ticagrelor), a high-dose lipid-lowering agent (such as a statin), an angiotensin-
converting enzyme inhibitor, and a beta-blocker. Lifestyle measures that are of
vital importance in the management of coronary artery disease include weight
reduction, smoking cessation, and healthy dietary habits (Estruch et al. 2013).
Coronary artery disease should not be viewed as a localized disease affecting the
coronary arteries, but rather it should be managed as part of a systemic
pro-inflammatory atherosclerotic milieu in patients with predisposing cardiovascu-
lar risk factors. Therefore, regardless of whether an interventional strategy is
pursued (PCI or CABG), ongoing lifestyle measures and optimal medical therapy
are of the utmost importance. Addressing the risk factors for coronary artery disease
and achieving compliance with optimal medical therapy reduce the progression of
atherosclerotic plaque and the risk of further acute coronary syndromes.
Fig. 6 Emergency percutaneous coronary intervention with angioplasty and stenting to a critical
mid-left anterior descending (LAD) artery lesion for a 58-year-old patient presenting with an
anterior ST-elevation myocardial infarction. Coronary angiogram demonstrating the severe
mid-LAD lesion prior to stenting (anterior-posterior cranial projection) (a), fluoroscopy demon-
strating the stent deployed at the site of the severe mid-LAD lesion (anterior-posterior cranial
projection) (b), coronary angiogram demonstrating the successful treatment of the severe
mid-LAD lesion by angioplasty and stent deployment (anterior-posterior cranial projection) (c),
final angiogram after coronary guidewire removal demonstrating excellent final angiographic
result (left anterior oblique cranial projection)
signal conduction delay at a level below the AV node indicates more advanced
conduction disease and is more often pathological, compared to conduction delay at
or above the level of the AV node. First-degree heart block is defined as a prolonged
PR interval that is greater than 200 ms. Isolated first-degree heart block is generally
asymptomatic and can usually be managed conservatively. However, first-degree
heart block may occur as part of more advanced conduction system disease (e.g., as
part of tri-fascicular block). Second-degree heart block is divided further into
Mobitz type 1 and Mobitz type 2. In Mobitz type 1 heart block, there is progressive
prolongation of the PR interval with each subsequent heartbeat, until a P wave is not
Fundamentals of Cardiology for the Non-Cardiologist 33
followed by a QRS complex, and the cycle resumes. Conduction delay in Mobitz
type 1 heart block usually occurs within the AV node, above the level of the bundle
of His. Mobitz type 1 heart block can be a normal physiological phenomenon,
especially as a result of increased vagal tone during sleep. Mobitz type 1 heart block
is generally not associated with syncope. Mobitz type 2 heart block occurs when a P
wave is not followed by a QRS complex following a pattern (e.g., 3:1 Mobitz type
2 heart block refers to the situation when for every three P waves, there is only one
conducted QRS complex). Mobitz type 2 heart block generally indicates conduc-
tion disease below the level of the AV node. In symptomatic patients with
pre-syncope or syncope, without a reversible cause (such as beta-blocker medica-
tion), treatment with permanent pacing is generally indicated. In third-degree heart
block, there is no electrical signal conduction from the atria to the ventricles,
causing a phenomenon known as AV dissociation. In these situations, ventricular
depolarization relies on the function of other pacemaker cells located within deeper
parts of the conduction system, below the level of the AV node. These pacemaker
cells generate a slow junctional or ventricular “escape” rhythm, usually at rates of
30–40 beats per minute. Patients with third-degree heart block can present with
syncope. Permanent pacing is strongly indicated for all patients with third-degree
heart block, unless there is a clear reversible cause or contraindication to permanent
pacing (e.g., active systemic sepsis).
Tachyarrhythmias
Tachycardia is defined as a pulse rate greater than 100 beats per minute. Tachyar-
rhythmias can be broadly divided into those arising from above the ventricular level
(supraventricular) and those arising from within the ventricle (ventricular). Supra-
ventricular tachyarrhythmias are generally associated with a narrow QRS complex
and are generally benign. Ventricular tachyarrhythmias are generally associated
with a broad QRS complex and are often associated with hemodynamic instability
and/or cardiac arrest. Supraventricular tachyarrhythmias include arrhythmias asso-
ciated with accessory conduction pathways such as in the Wolff-Parkinson-White
syndrome, junctional tachycardia, atrial tachycardia, atrial flutter, and atrial fibril-
lation. Generally, these rhythm disorders can be treated with medications. In certain
situations, electrophysiological ablation procedures can be performed to ablate the
pathways predisposing to these rhythm disorders.
Ventricular tachyarrhythmias include ventricular tachycardia and ventricular
fibrillation. Ventricular tachycardia can result from myocardial ischemia, underly-
ing cardiomyopathy, or acquired and congenital causes of prolonged QT interval in
patients with a structurally normal heart. Prolonged QT interval can predispose to a
specific form of polymorphic ventricular tachycardia known as torsades de pointes
(Fig. 7). Ventricular fibrillation most commonly results from myocardial ischemia.
Pulseless ventricular tachycardia and ventricular fibrillation should be treated
emergently by electrical cardioversion (defibrillation). Ventricular tachyarrhyth-
mias resulting from myocardial ischemia should be treated by revascularization,
restoring blood supply to regions of ischemic myocardium. There are specialized
pharmacological treatment options for ventricular tachyarrhythmias. In certain
34 B. Xu et al.
Fig. 7 Rhythm strip demonstrating a run of torsades de pointes, a form of polymorphic ventric-
ular tachycardia (arrows point to the commencement and termination of the polymorphic ventric-
ular tachycardia)
Atrial Fibrillation
Atrial fibrillation (AF) is an increasingly common problem in the aging population.
It is the commonest type of arrhythmia encountered in clinical practice. AF is
associated with an increased risk for the development of congestive cardiac failure.
It is also associated with a twofold increase in risk for all-cause mortality and
fivefold increased risk for stroke (Roger et al. 2012). AF is a supraventricular
tachyarrhythmia characterized by an irregularly irregular ventricular rhythm and
baseline fibrillatory waves (Fig. 8). Common cardiac abnormalities associated with
AF include hypertensive heart disease with left ventricular hypertrophy, ischemic
heart disease, and valvular heart disease such as mitral valve disease. Sleep-
disordered breathing and obesity are being increasingly recognized as risk factors
for AF. Temporary precipitants for AF include sepsis, excessive alcohol intake, and
hyperthyroidism. Patients with AF can present with palpitations, dyspnea, fatigue,
and decreased exercise tolerance. Many patients with AF do not have any subjec-
tive symptoms.
The clinical classification of AF includes several categories based on the time
course: (1) paroxysmal, if the AF episode terminates spontaneously within 7 days of
onset; (2) persistent, if the AF episode lasts for 7 days or longer; and (3) permanent,
long-standing AF persisting for more than 1 year, which is refractory to cardiover-
sion. The key management decisions for patients with AF include choosing a
management strategy aimed at either rhythm control (attempting to achieve and
maintain sinus rhythm) or rate control (controlling the ventricular rate response and
accepting the patient’s rhythm being AF), followed by an assessment of the
individual patient’s thromboembolic and stroke risk. In AF, thrombus can
Fundamentals of Cardiology for the Non-Cardiologist 35
commonly form in an atrial structure known as the left atrial appendage, which is
continuous with the left atrium (Fig. 9). Dislodgment of thrombus from the left
atrial appendage can cause systemic embolic phenomena, including stroke. The
decision to pursue a rhythm- or rate-control strategy depends on the individual
patient’s clinical situation. Generally, for a young patient with new-onset AF,
attempts are made to pursue rhythm control as these patients often do not tolerate
AF well. In comparison, for an elderly patient with multiple comorbidities and
dilated left atrium, the rate-control strategy may be reasonable. It has been shown
that there are no mortality differences between pursuing either a rhythm-control or
36 B. Xu et al.
rate-control strategy (Wyse et al. 2002). Validated assessment tools which guide
the clinical assessment to individual patient’s thromboembolic risk associated
with AF are the CHADS2 score and the more recently updated CHA2DS2-VASc
score. For patients with a CHA2DS2-VASc score of 1, an oral anticoagulant
should be considered (Camm et al. 2012). Until recently, warfarin has been the
gold-standard and mainstay anticoagulation therapy for patients with non-valvular
AF. There are now novel oral anticoagulants which could be used for patients with
non-valvular AF: rivaroxaban, apixaban, and dabigatran (Xu and Whitbourn
2012). One major advantage of these novel anticoagulants is that they do not
require regular monitoring blood tests. However, at this stage, there are no com-
mercially available reversal agents for these agents in the event of life-threatening
hemorrhage.
Table 2 Clinical conditions associated with heart failure with reduced ejection fraction
Common Myocardial ischemia/ischemic heart disease (approximately 50 % of new
cases)
Hypertension
Less Idiopathic dilated cardiomyopathy
common Familial dilated cardiomyopathy
Uncommon Valvular heart disease
Alcohol-associated cardiomyopathy
Inflammatory cardiomyopathy (i.e., post-viral myocarditis)
Peripartum cardiomyopathy
Drug induced (i.e., anthracyclines, cyclophosphamide, paclitaxel)
Thyroid dysfunction
Chronic arrhythmia
Rare Sarcoidosis
Inherited muscle disorders (i.e., muscular dystrophy, Friedreich’s ataxia)
Fig. 10 The HeartWare ventricular assist device. The smaller centrifugal pump contains a single
moving impeller part. The pump is implanted in the pericardial space. The driveline connects the
pump to a power source externally (Adapted with permission from HeartWare: http://www.
heartware.com)
Valvular heart disease (VHD) may present with breathlessness, fatigue, syncope, as
well as chest pain and palpitations. VHD encompasses a wide range of valvular
pathologies in different clinical settings. Suspicion for VHD should be raised in the
presence of dyspnea and other relevant clinical findings such as a cardiac murmur
or clinical findings suggestive of heart failure. A patient’s age and epidemiological
profile provide useful information regarding potential etiology. Degenerative or
calcific valvular disorders (e.g., severe calcific aortic stenosis) are much more
common in the older population (Vahanian et al. 2012). Younger patients with
valvular lesions are much more likely to have a primary valvular abnormality (e.g.,
mitral valve prolapse, congenitally bicuspid aortic valve) (Vahanian et al. 2012).
Transthoracic echocardiography is the gold-standard first-line investigation for
the assessment of the etiology of a cardiac murmur and of the severity of the
associated valvular pathology. See Table 5 for a summary of the clinical profiles
of patients with common valvular pathologies.
Identification of a significant valvular lesion requires assessment by a cardiolo-
gist. Management of valvular disease depends upon a number of factors including
the etiology of the valvular lesion, its severity, and the patient’s symptoms related
to the lesion (Vahanian et al. 2012). Monitoring with serial transthoracic echocar-
diograms and clinical review is appropriate for most valvular lesions in the mild to
moderate severity range. Once a valvular lesion is graded as severe and the patient
develops symptoms consistent with valvular dysfunction, consideration for valve
repair and/or replacement must be considered.
Medical therapy has some role in the management of VHD by providing relief of
pulmonary congestion (with diuretics), reducing afterload and ventricular
Fundamentals of Cardiology for the Non-Cardiologist 41
Congenital heart disease consists of a broad range of disorders that may affect heart
structure and function (Elliott et al. 2012). These conditions are present from birth
but can progress in their severity through life and may not present clinically until
late in adulthood. Congenital heart disorders vary significantly in their presentation,
consequences, and prognosis. Congenital heart disease may be diagnosed prenatally
via ultrasound which may allow for early planning for the appropriateness of
closure of defects such as ventricular septal defects, atrial septal defects, or patent
ductus arteriosus. Timing of an intervention to close a defect is an important
consideration in congenital disease, weighing the risks and hemodynamic and
clinical consequences of the defect with the risks of intervention which include
surgery or percutaneous treatments.
In certain situations, prompt treatment is required to sustain life in the early
postnatal period. For instance, in D-transposition of the great vessels, there is
ventriculo-arterial discordance. In this condition, deoxygenated blood from the
venous system enters the right side of the heart. Instead of then traveling through
the lungs, the right ventricle is connected to the aorta, and deoxygenated blood
travels out through the systemic circulation. Blood which has been oxygenated
travels into the left ventricle; however, it is then pumped back through the lungs
through the main pulmonary artery because of this ventriculo-arterial discordance.
Infants born with this condition often have other heart defects such as an atrial
septal defect, ventricular septal defect, or patent ductus arteriosus which all allow
some mixing of blood and therefore some oxygenated blood within the systemic
circulation. Without the presence of an interatrial or interventricular shunt, there is
42 B. Xu et al.
a lack of oxygenated blood supplying the systemic circulation, and these infants
require an early intervention to sustain life.
A number of congenital heart conditions represent abnormal communications
between different heart chambers or vessels and are included in this group of
disorders (e.g., atrial septal defects, ventricular septal defects, and patent ductus
arteriosus). Some congenital heart conditions may require long-term follow-up for
complications. For instance, a bicuspid aortic valve commonly leads to the devel-
opment of aortic stenosis or regurgitation. Diseases of the great vessels (e.g.,
coarctation of the aorta and truncus arteriosus) are often repaired surgically at a
young age but can present later in life with complications associated with the
original condition (e.g., re-coarctation). There are a number of other congenital
heart diseases which are due to abnormal formation of a part of the heart’s structure.
These include tricuspid atresia and hypoplastic left heart syndrome, which both
usually require early surgical treatments to sustain life.
There is now a growing population of surviving adults who underwent surgical
or percutaneous corrective procedures of a congenital cardiac condition at a young
age. These patients are often at risk of late complications and may present many
years later as an adult with dyspnea, fatigue, palpitations, syncope, or poor effort
tolerance. Unfortunately, a significant proportion of patients with congenital heart
disease are often lost to follow-up during the transition from pediatric to adult
cardiology clinics. To appropriately manage a patient with congenital heart disease,
it is important for the clinician to be aware of the patient’s original primary
diagnosis and the details of surgical and/or percutaneous procedures performed.
Conclusion
This chapter has summarized the fundamentals of cardiac anatomy, physiology and
pathology. For those involved in the management of cardiac patients, it provides an
overview of the various clinical presentations, investigations and management
strategies. The chapter provides an overview of the various sub-specialities within
cardiology including interventional cardiology, electrophysiology, heart failure,
congenital heart disease and cardiac imaging.
Glossary
Afterload The resistance the ventricles need to overcome to eject the volume of
blood.
Anatomy The study of the structures of the human body. This chapter focuses on
the anatomy of the heart.
Bradyarrhythmias Rhythm disorders of the heart with a heart rate less than
60 beats per minute.
Cardiac cycle The cardiac cycle consists of systole, the phase of contraction, and
diastole, the phase of relaxation.
Cardiac output The volume of blood ejected from the left ventricle each minute.
It can be derived by multiplying stroke volume with heart rate, the number of
heartbeats per minute.
Contractility The intrinsic contractile ability of the cardiac muscle.
Coronary angiography An invasive interventional cardiology technique com-
monly performed via femoral or radial arterial access, in which the lumen of
the coronary arteries is visualized in detail using special contrast and fluoroscopy
X-ray equipment. Coronary angiography provides the basis for percutaneous
coronary intervention, in which special guidewires, angioplasty balloons, and
stents are used to treat significant coronary artery lesions.
Coronary arteries Arteries which provide blood supply to the heart muscle.
Coronary artery disease Disease of the coronary arteries. The commonest cause
of coronary artery disease is atherosclerosis, the buildup of cholesterol-rich
inflammatory material, resulting in progressive narrowing of the coronary
arteries.
Echocardiography The study of the human heart by ultrasound. It is a useful
noninvasive imaging technique that provides detailed assessment of the struc-
ture, function, and physiology of the human heart.
Embryology The study of the development of the human body during fetal
life. This chapter briefly discusses the fetal development of the human heart.
Heart failure A complex clinical syndrome characterized by cardiac disorders
that lead to impairment of the ability of the ventricles to fill (diastolic heart
failure) or eject blood (systolic heart failure).
Physiology The study of the normal function of human organs. This chapter
provides an overview of the function of the human heart in health (physiology)
and in common disease states (pathophysiology).
Preload The degree of stretch in the heart before contraction.
Stroke volume The volume of blood ejected by the left ventricle with each
contraction.
Tachyarrhythmias Rhythm disorders of the heart with a heart rate greater than
100 beats per minute.
Valvular heart disease Disorders affecting the heart valves. They consist of a
wide range of pathologies in different clinical settings. Common symptoms of
valvular heart disease include dyspnea, pre-syncope, and fatigue.
44 B. Xu et al.
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Epidemiology of Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Gathering the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Observational Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Randomized Controlled Clinical Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Blood Pressure and Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Multifactorial Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Strategies for Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Future Challenges for Cardiovascular Disease Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
Abstract
Noncommunicable diseases such as cardiovascular diseases and cancers are key
threats to maintaining health and well-being in the twenty-first century. In 2008,
30 % of global deaths were due to cardiovascular disease, a mortality burden felt
by countries across the income/development spectrum. The middle of the twen-
tieth century saw the advent of epidemiological studies which have made
significant advances in understanding the factors driving cardiovascular disease
risk. Studies such as the Seven Countries Study gathered data from across the
globe on clinical and lifestyle factors and their relationship to rates of cardio-
vascular disease. Other landmark studies such as the Framingham Study set the
Keywords
Cardiovascular risk • Prevention • Risk factors • Epidemiology • Blood pressure •
Lipids
Introduction
Since early civilization, mankind has faced the coming and going of major threats to
human health and well-being. Environmental threats including famine, communicable
diseases, and human conflict underpinned the major challenges to survival for most of
the first 2,000 years of human civilization. The industrial revolution and advances in
technology, urbanization, wealth, and communication have fueled the epidemiological
transition (Fig. 1) to a state where new epidemics and major threats to life emerged.
Noncommunicable diseases such as cardiovascular diseases and cancers are now the
key threats to maintaining health and well-being in the twenty-first century.
This chapter will examine how information has been gathered to identify the key
factors underpinning the cardiovascular disease epidemic of the twentieth century.
It will also examine how prevention and treatment strategies have been developed
and implemented and what challenges low- to middle-income countries face to
avoid a repeat of the epidemic which at its peak in the mid-1960s claimed over
20,000 lives per year in the USA alone.
Cardiovascular disease epidemiology had its roots in the observation from autop-
sies conducted on young soldiers killed in combat during the First and Second
World Wars that many, even in their early 20s, had developed atherosclerotic
plaques (Meade 2001; Rosenthal 1934). At that time, in the 1930s and 1940s,
coronary heart disease was starting to emerge as a significant cause of death in
Epidemiology of Cardiovascular Disease 47
industrialized Western countries such as the USA. Infant mortality rates had
subsided due to improvement in sanitation systems and clean water provision in
more densely populated areas. Disparities among cardiovascular disease rates in
countries at similar stages of industrialization sparked the interest of Ancel Keys to
establish the Seven Countries Study in the 1950s (Keys 1970). The aim of the Seven
Countries Study was to gather data from across the globe on clinical and lifestyle
factors to examine the association of these factors with the rates of cardiovascular
disease.
Observational Epidemiology
Commencing in the 1950s and involving population cohorts in the USA, Japan,
Italy, Yugoslavia, Finland, the Netherlands, and Greece, the Seven Countries Study
was one of the first to examine the association between major clinical and lifestyle
factors and the risk of cardiovascular disease (Keys 1970). Importantly, it
also identified clinical factors and modifiable lifestyle behaviors associated with
cardiovascular risk factors, which have been the substrate of decades of research
into whether modulating these risk factors influenced cardiovascular disease
outcome.
The Framingham Study (Dawber 1980) is another early and well-known epide-
miological study examining risk factors for cardiovascular disease. Baseline data
collection commenced in 1950, and the original population sample consisted of
5,127 male and female residents of the small town of Framingham, Massachusetts,
USA, aged 30–59 years old and free of coronary heart disease. The Framingham
Study has contributed key information about the epidemiology of cardiovascular
48 C. Reid and A. Owen
Cigarette Smoking
The association between cigarette smoking and cardiovascular disease was
observed in the Seven Countries Study (Keys et al. 1984) and also in a number
of other population-based studies around the world. The British Doctors’ Study
(Doll and Peto 1976) undertaken by Sir Richard Doll in the UK, the Whitehall
Study (Reid et al. 1976), and the Honolulu Heart Study (Kagan et al. 1975) are
just a sample of the numerous studies which have supported the association
between cigarette smoking and cardiovascular diseases, particularly coronary
heart disease and stroke. Bradford-Hill’s rules of causality require reversal of a
risk factor to reduce the incidence of the outcome, and observational study data
support this for cigarette smoking. While estimates of the time required vary,
smokers who give up smoking have been shown to revert to coronary heart
disease rates similar to nonsmokers (Cook et al. 1986; Gordon et al. 1974).
Despite there being no randomized trial evidence available for smoking cessa-
tion, the overwhelming body of evidence for the association between cigarette
smoking and coronary disease and the benefit of cessation has led to major
public health campaigns and health policy changes to reduce prevalence. The
World Health Organization has been instrumental in driving global efforts to
combat smoking through its Framework Convention on Tobacco Control. In
some countries, control measures include a ban on tobacco advertising, smoke-
free workplace policies, and more recently plain tobacco packaging laws, which
have been introduced in Australia and New Zealand (Zacher et al. 2014). The
impact of these research findings and their translation to policy initiatives have
led to a reduction in cigarette smoking rates in a number of countries over the
past decades (Fig. 2).
Epidemiology of Cardiovascular Disease 49
50
Australia
45
% of population aged y+ who are daily smokers
Japan
40 Netherlands
35 Sweden
UK
30
USA
25
20
15
10
0
1980 1989/90 2001 2010
Diabetes
Diabetes is a disease characterized by chronic dysregulation of glucose homeosta-
sis. Since the middle of the last century, there has been a substantial increase in
diabetes prevalence, driven by a growing and aging population, urbanization, and
increasing prevalence of obesity and physical inactivity. Research suggests that the
burden of diabetes will continue to grow: the prevalence for all age groups
worldwide was estimated to be 2.8 % in 2000 and is projected to rise to 4.4 % in
2030 (Wild et al. 2004).
Diabetes was established as a cardiovascular disease risk factor by early obser-
vational studies. Recent analysis of data from Framingham has shown that over the
past half-century, the proportion of cardiovascular disease attributable to diabetes
has increased from 5.4 to 8.9 % in this cohort (Fox et al. 2007). Globally, the
INTERHEART study found diabetes accounted for 10 % of the population attrib-
utable risk of MI (Yusuf et al. 2004).
Dietary Intake
Dietary intake of excess calories and increased saturated fats is strongly associated
with the development of obesity, elevated blood cholesterol, and diabetes. Obesity
and diabetes are reaching epidemic proportions across the globe in both high-
income and low- to middle-income countries. The Ni-Hon-San study was an
early observation of the role of a changing diet on cardiovascular disease.
50 C. Reid and A. Owen
a Japan
70
Hawaii
Age-adjusted prevalence of CHD/ 60 California
50
40
30
20
10
0
Normal Borderline High
Blood Pressure categories
b
70 Japan
Hawaii
Age-adjusted prevalence of CHD/
60
California
50
40
30
20
10
0
<220 220-259 ≥260
Serum cholesterol (mg/dl)
Fig. 3 Blood pressure (a) and serum cholesterol levels (b) in Japanese populations lining in Japan,
Hawaii and California
It examined people migrating from Japan (a country with one of the lowest rates of
cardiovascular disease) to Honolulu and San Francisco (the USA having a very high
rate of cardiovascular disease). The Japanese migrants had increasing exposure to
dietary fat and cholesterol intake and a “Western diet.” As exposure increased, so
did blood pressure and cholesterol levels, levels of obesity and diabetes, and also
rates of coronary artery disease (Fig. 3) (Marmot et al. 1975).
Epidemiology of Cardiovascular Disease 51
Dietary fat content has been a focus of much research activity, and the work of
Ancel Keys was an early driver of this. Keys’ eponymous equation quantified the
effect of saturated and polyunsaturated fats on plasma cholesterol (Fetcher
et al. 1967). Understanding of the effect of dietary fats on cardiovascular disease
and its risk factors has evolved and expanded and continues to be an active area of
research. It is now known that some unsaturated fats, such as the long-chain
polyunsaturated omega-3 fats found in fish and seafood, are cardioprotective.
Conversely, trans fats produced by partial hydrogenation of vegetable oils have,
on a per calorie basis, the strongest relationship with cardiovascular disease of any
macronutrient (Mozaffarian et al. 2006).
Another dietary factor related to a major cardiovascular disease risk factor is
sodium chloride (salt) intake. Salt intake is directly related to blood pressure, and it
is estimated that a population-wide reduction of salt intake by 6 g/day could reduce
rates of stroke by 24 % and coronary heart disease by 18 % (He and MacGregor
2003).
Obesity
Rates of obesity have been growing worldwide, fueled by increasingly sedentary
lifestyles and increases in dietary energy density. The World Health Organization
estimates that in 2008, 35 % of adults worldwide were overweight, and 10 % of men
and 14 % of women were obese (Organisation 2013). There is considerable
geographic variation in levels of obesity, but it remains a major global health
challenge. Obesity is associated with development of cardiovascular risk factors,
including hypertension, dyslipidemia, and diabetes. It is likely a combination of
these strong associations between obesity, blood pressure, plasma lipids, and
glucose homeostasis, in addition to the evolution toward a more sedentary lifestyle
and energy-dense diet, which confounded early studies looking at associations
between body mass index (BMI) and cardiovascular disease. A recent analysis
pooling data from 97 cohort studies (collectively 1.8 million participants) found
that risk of coronary heart disease was 27 % higher for each 5 kg/m2 increment in
BMI (Lu et al. 2014). Elevations in blood pressure, cholesterol, and glucose
accounted for around half of that increased risk, so this suggests that addressing
excess body weight itself remains a critical issue.
Socioeconomic Status
Significant regional disparities in cardiovascular mortality in Scotland, which had one
of the highest coronary heart disease death rates in the world in the 1980s, led Hugh
Tunstall-Pedoe and colleagues to undertake a series of studies which clearly identified
socioeconomic factors, particularly unemployment and housing tenure, as being asso-
ciated with cardiovascular morbidity and mortality. More socioeconomically disad-
vantaged groups had greater risk factor levels, including smoking, poor diet, and heavy
alcohol consumption, but even after accounting for these factors, socioeconomic status
remained a significant risk factor for cardiovascular disease (Smith et al. 1990).
Alcohol Intake
Alcohol intake illustrates an interesting case in the evolution of our understanding of
behavioral risk factors for cardiovascular disease. Early epidemiological studies such
as two occupational cohort studies conducted in Chicago in the 1970s (Dyer et al. 1981)
were just two of the many early cohort studies noting that heavy alcohol consumption
was associated with increased rates of cardiovascular disease. Over the following
decades, studies of alcohol consumption and cardiovascular disease suggested the
existence of a J-shaped association, such that low-moderate alcohol consumers had
lower rates of cardiovascular disease than nondrinkers (Ronksley et al. 2011). Emerg-
ing evidence from INTERHEART suggests that this association may differ between
geographic regions, and low-moderate alcohol consumption may not offer the same
cardiovascular benefit in South Asian populations (Leong et al. 2014).
2003 position paper on evidence supporting the role of chronic stressors and
coronary heart disease. Chronic stressors with varying degrees of evidence for a
link with coronary disease include chronic work stress and job strain, effort-reward
imbalance, organizational injustice, and social isolation and lack of support. Acute
mental stresses included bereavement and acute emotional responses, job loss,
sporting events, and natural disasters (Colquhoun et al. 2013b).
Depression is an important independent risk factor for first and recurrent coro-
nary heart disease events. The prevalence of depression is particularly high in
patients with coronary disease, and it has a significant impact on the patient’s
quality of life and adherence to therapy and an independent effect on prognosis
(Colquhoun et al. 2013a). The previously mentioned INTERHEART study
included 11,119 patients with MI from 52 countries reported that perceived stress
and depression together accounted for 32.5 % of the population attributable risk
(PAR) for coronary heart disease (Yusuf et al. 2004). Together, these factors were
as important as smoking and more important than diabetes (PAR, 9.9 %) and
hypertension (PAR, 17.9 %) as risk factors. Rates of major depressive disorder of
around 15 % have been reported in patients after myocardial infarction or coronary
artery bypass grafting.
The relationship between blood pressure, changes in blood pressure, and subse-
quent cardiovascular disease events has been one of the most intensively researched
areas of clinical medicine over the past 50 years. Again, leading from the observa-
tional epidemiological studies both within and between populations, a near-linear
relationship has been demonstrated between levels of blood pressure and the risk of
stroke and coronary heart disease (Fig. 4) (Lewington et al. 2002). This has been
paralleled with major therapeutic developments targeted toward the mechanisms
underlying the development of high blood pressure. Broadly, these include
targeting the central nervous system, the renin-angiotensin system, the arterial
vascular system, and homeostasis. Clinical trials, starting with the early Veterans
Administration Trial (Veterans Administration Cooperation Study on
54 C. Reid and A. Owen
IHD mortality
years years
16 16
40–49
40–49
years
8 8 years
4 4
2 2
1 1
Fig. 4 Levels of systolic and diastolic blood pressure and age-related risk of Ischaemic Heart
Disease
CCB denotes calcium channel blocker; ACE-i, angiotensin-converting enzyme inhibitors; ARB,
angiotensin receptor blocker; thiazide, thiazide or thiazide-like diuretics. Blood pressure values
are systolic/diastolic blood pressure in mmHg
the globe. Therapeutic development led to the use of bile acid sequestrants,
nicotinic acid, and finally statins to effectively lower blood lipid levels and also
reduce fatal and nonfatal coronary event rates. Starting with the Coronary Drug
Project in the 1960s in patients with existing coronary heart disease (Friedman
et al. 1983), secondary prevention was firmly established, and trials such as the
West of Scotland Primary Prevention Study (Shepherd et al. 1995), the 4S Study
(The Scandinavian Simvastatin Survival Study Group 1994), and the LIPID study
(The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study
Group 1998) have demonstrated the value of lowering of LDL cholesterol in
patients with high and “normal cholesterol” levels. As with blood pressure, guide-
line development for the control of elevated blood lipids and cardiovascular disease
prevention has thrived backed by a myriad of cholesterol-lowering trials in various
populations (Psaty and Weiss 2014).
Novel targets, such as the trialing of HDL-raising drugs (Verma and Figueredo
2014), suppression of inflammation (Everett et al. 2010), and renal denervation of
sympathetic nerves (Krum et al. 2014), are examples of new therapeutic interven-
tions in recent years to refine and improve the control of these two major risk factors
that have been strongly associated with disease prevalence and incidence.
56 C. Reid and A. Owen
Multifactorial Risk
The Multiple Risk Factor Intervention Trial was one of the key trials to demonstrate
interrelationships between coronary heart disease risk factors (Neaton and Wentworth
1992). This trial (conducted in men only, in the 1980s) showed that those individuals
who had even mild elevations of multiple risk factors were at greater risk of coronary
disease than those who had larger elevations of single factors. This observation led to a
field of epidemiological research in modeling and risk prediction that has tried to
better identify those individuals who may benefit most from targeted intervention.
Models derived from the Framingham cohort study (Dawber 1980) are among the
most widely adopted for use to estimate risk of developing coronary disease.
Controversy still exists on the role of absolute risk assessment for targeting
interventions for individuals (D’Agostino Sr. et al. 2013). Age is the most dominant
risk factor for coronary heart disease, and when risk thresholds are recommended
(e.g., a 10 % 5 year Framingham risk), then the majority of individuals over the age
of 65 years and virtually all of those over the age of 70 years would be targeted for
preventive interventions irrespective of the individuals’ blood pressure or blood
lipid levels. Unfortunately most of the evidence derived for the benefits of blood
pressure lowering and cholesterol lowering have arisen from clinical trials in
middle-aged populations, and with global aging populations, the need for further
evidence directly relevant to the elderly is an imperative.
Genetics
The Framingham Offspring Study (which as the name suggests, recruited offspring of
participants from the original Framingham Study) showed that having a parent with
premature cardiovascular disease more than doubled the risk of developing cardio-
vascular disease (Lloyd-Jones et al. 2004). For some time it had been established that
there were Mendelian disorders associated with development of severe and premature
cardiovascular disease, such as familial hypercholesterolemia (caused by mutations in
the LDL receptor gene or Apo B gene, leading to substantially elevated circulating
LDL cholesterol levels), and mutations in ion channel genes (notably of sodium,
calcium, and potassium channels) leading to cardiac rhythm disorders. However the
widespread association with family history suggested that genetic effects on cardio-
vascular disease extended beyond these relatively rare gene variants.
The increasing accessibility of genetic analysis for application in epidemiolog-
ical studies is driving a new wave of research looking at common gene variants and
risk of cardiovascular disease. These include gene variants which have been found
to be associated with cardiovascular events (e.g., APOE polymorphisms), as well as
gene variants associated with the development of cardiovascular risk factors such as
hypertension, high cholesterol or triglyceride levels, or low HDL levels. Addition-
ally, gene variants have been identified which influence the response to commonly
used cardiovascular drugs, fueling the quest for “personalized medicine” in cardio-
vascular disease prevention and treatment.
Epidemiology of Cardiovascular Disease 57
Another growing area of genetic research is the interaction between genes and
environment/behavior. For example, in a Han Chinese population, it was recently
shown that possession of a single nucleotide polymorphism in the rs671 allele of the
acetaldehyde dehydrogenase 2 gene was associated with a greater risk of hyperten-
sion and adverse lipid profiles only in those who drank alcohol (Wang et al. 2013).
This highlights the complexity of genetics and genomics in cardiovascular disease
epidemiology.
Inflammation
A link between acute infection and heart disease, e.g., myocarditis, pericarditis, and
endocarditis, has been long established. Over the past half-century, epidemiological
studies have revealed associations between lower-grade systemic inflammation and
cardiovascular disease. In 1974, Friedman and colleagues published results from
the Kaiser-Permanente case-control study showing that a previous (>1 year prior)
elevated white cell count was strongly associated with the risk of having an MI
(Friedman et al. 1974). Evolution of the understanding of the pathophysiological
processes underpinning development of atherosclerotic plaques has highlighted the
role of inflammation in development of atherosclerotic cardiovascular disease, and
epidemiological studies are revealing associations between biomarkers of inflam-
mation, obesity, insulin resistance, and cardiovascular disease risk factors. A recent
example is severe periodontal disease (gum bleeding) which has been found to be
associated with increased systolic blood pressure (Tsakos et al. 2010) and risk of
atherosclerotic disease (Dietrich et al. 2013).
Aspirin and related salicylate compounds were used as antipyretic and pain-
relieving agents in the nineteenth century. In the latter half of the twentieth century,
the discovery that aspirin’s anti-inflammatory activity was related to inhibition of
prostaglandin synthesis earned Vane, Samuelsson, and Bergstrom a Nobel Prize in
Medicine (Bishopric 2013). In addition, as understanding of the pathophysiology of
cardiovascular disease evolved, aspirin’s ability to inhibit platelet aggregation
prompted a series of clinical trials confirming aspirin’s role in secondary prevention
of cardiovascular disease (Antiplatelet Triallists Collaboration 1994). More recent
studies have focused on the role of aspirin for primary prevention; aspirin confers
benefits but also increased bleeding risks, and consideration of this balance of risk
to benefit should be applied to the use of aspirin in the primary prevention setting
(ASPREE Study Group 2013).
70
Age-adjusted coronary heart disease mortality rate
60
(per 10,000 person -years)
50
40
30
20
≥6.3
10
5.7-6.3
5.2-5.7
0
4.7-5.2
<118 Cholesterol quintile
118-124 <4.7
125-131 (mmol/l)
132-141
≥142
Systolic BP quintile
(mmHg)
Fig. 5 Interaction between blood pressure and cholesterol levels on age adjusted coronary heart
disease mortality rates
CHD
/ Stroke
Social Status Empowerment
Blood Pressure,
Cholesterol, Diabetes,
Renal Disease
Genetic Susceptibility
Income Education
and treatments for blood pressure and lipids, were being offset by increases in
obesity and diabetes which were strongly related to upstream factors influencing
social status (Hotchkiss et al. 2014).
Conclusion
Cardiovascular disease remains the major cause of global burden of disease and will
continue to do so for many years to come. While great progress has been made in
understanding the etiology, treatment, and prevention of the disease at both the
individual and community level, future initiatives in population-wide prevention
strategies and reducing social disadvantage for both developed and developing
countries remain at the forefront of tackling the second cardiovascular disease
epidemic across the world.
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Cardiovascular Risk Factors: Role
of Lifestyle
Gautam Vaddadi
Contents
The Role of Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Potassium, Vitamins, and Fiber . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Fruit and Vegetables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Fish . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Soft Drinks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Mediterranean Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
Physical Activity, Inactivity, and Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Body Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
Obesity Paradox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Abstract
Cardiovascular disease (CVD) is the leading cause of death and disability in the
developed world. Lifestyle factors are thought to account for up to 90 % of
attributable risk of myocardial infarction worldwide. Smoking, dyslipidemia,
hypertension, diabetes, abdominal obesity, consumption of fruits and vegetables,
psychosocial factors, and physical activity are the key components of this risk.
Interventions to reduce risk such as exercise, smoking cessation, and dietary
change are valuable in lowering CVD risk at any age; however, instituting the
“right” lifestyle choices from childhood or even from conception is likely to
G. Vaddadi (*)
Department of Cardiology, The Alfred Hospital, Melbourne, VIC, Australia
e-mail: [email protected]
have the greatest impact on reducing the long-term burden of disease. The
“sitting time” is now recognized to add to the risk of CVD, even in people
who are physically active at other times. Sitting more than 10 h per day increases
all-cause mortality. TV watching is a strong predictor of CVD risk and is more
profound than “screen time” which may include video games. This may relate to
increased snacking and poor dietary choices when watching TV. If we are to
reduce CVD, a paradigm shift is needed in how our “Western” society operates.
Fundamental changes are needed in infrastructure, travel, use of cars, work
patterns, food industry, and education from birth to grave.
Keywords
Cardiovascular • Myocardial infarction • Hypertension • Obesity • Sitting
Cardiovascular disease (CVD) is the leading cause of death and disability in the
developed world (Murray and Lopez 2013). Globally it is thought to account for
17.3 million deaths annually (Laslett et al. 2012) and includes the following
common conditions:
In the Framingham Heart Study, the lifetime risk of developing coronary heart
disease at age 40 years was 42.4 % for men and 24.9 % for women (Lloyd-Jones
et al. 1999). Lifetime risk continues to remain high at age 70 being 1 in 3 for men
and 1 in 4 for women. In the developed world, the burden of ischemic heart disease
has escalated by 29 % between 1990 and 2010 with 55 % of this increase being
accounted for by a combination of population growth and aging (Moran
et al. 2014). The World Health Organization states that “Coronary heart disease
(CHD) is now the leading cause of death worldwide; it is on the rise and has become
a true pandemic that respects no borders.”
A healthy lifestyle is essential to the prevention of CVD, the leading cause of
morbidity and mortality worldwide. Preventative lifestyle measures can modify
many of the risk factors for CVD. In the INTERHEART population study, poten-
tially modifiable risk factors for myocardial infarction were assessed in 52 coun-
tries. Ninety percent of the attributable risk of a myocardial infarct worldwide in
both sexes and all age groups was potentially modifiable, including smoking,
dyslipidemia, hypertension, diabetes, abdominal obesity, psychosocial factors,
daily consumption of fruits and vegetables, regular alcohol consumption, and
physical activity (Yusuf et al. 2004). Prevention begins at a young age, ideally
during pregnancy, and is lifelong. Sadly much of our focus on prevention of CVD
begins in middle age and beyond. Evidence is accruing that the risk of CVD starts at
a very young age. Exposure to risk factors in utero has also been demonstrated to
Cardiovascular Risk Factors: Role of Lifestyle 67
play a role as was seen in the offspring of women who were pregnant during the
Dutch famine of the Second World War (Eriksson et al. 1999; Forsen et al. 1999).
Risk factor intervention does result in reduced CVD event rates. In recent times
there has been a steady decline in mortality from CHD in developed countries only
in part attributable to therapeutic advances such as pharmaceuticals and coronary
intervention (stents and bypass surgery). Changes in risk factors account for
approximately half of this effect (Capewell 1999; Perk et al. 2012). It is widely
believed that lifestyle interventions at a population level would take decades to
result in an impact on CVD event rates, but in fact a large body of data supports the
idea that lifestyle interventions such as smoking cessation and dietary change (more
fruit and vegetables, less meat/animal fat) can result in rapid changes (months to a
few years) to CVD event rates in a population (Capewell and O’Flaherty 2011).
Therefore lifestyle interventions could potentially play a huge role in reducing the
burden of CVD globally, especially if these interventions are applied
throughout life.
The mantra “you are what you eat” is apt. Dietary factors are being increasingly
demonstrated to play a major role in the development of the modifiable risk factors
for CVD. Dietary changes at a population level have been demonstrated to have a
rapid impact on CVD events and mortality (Capewell and O’Flaherty 2011).
A balanced healthy diet should contain the following:
• Saturated fat <10 % of total energy intake. Fat intake replaced by poly- and
monounsaturated fats.
• Trans-unsaturated fats at an absolute minimum. Ideally these should not be
present in processed food.
• <5 g of salt per day (Recent data from the PURE sodium study (O’Donnell
et al. 2014) suggests that current guidelines advocating very low salt intake for
the general population of 1.5 g/day are not beneficial and that targeting the 3–4 g/
day zone is reasonable).
• 30–45 g of fiber per day from fruits, whole grains, and vegetables.
• Two to three serves of fruits per day.
• Two to three serves of vegetables per day.
• Fish 1–2 /week (oily fish such as salmon preferred).
• Alcohol limited to two standard drinks per day for men and one for women.
Fat
It has been recognized for over 50 years that replacing saturated fats in the diet with
polyunsaturated fats reduces serum cholesterol. However the impact of saturated fat
intake on the occurrence of CVD remains controversial. Evidence from a broad
68 G. Vaddadi
range of studies supports the notion that replacing 1 % of energy from saturated fats
with polyunsaturated fats reduces risk of CHD by 2–3 % (Astrup et al. 2011). The
same has not been shown for replacement of saturated fat with carbohydrate or
monounsaturated fats.
Unsaturated fats are by and large the “good fats.” Polyunsaturated fats (PUFAs)
will lower LDL cholesterol levels when they are used to replace saturated fat in the
diet. PUFAs can be divided into two main subgroups, n-6 fatty acids which are
principally sourced from plants and n-3 fatty acids which are usually found in oily
fish. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are members
of the n-3 family of PUFAs and have been shown to reduce CHD mortality
(He et al. 2004) which is thought to perhaps represent an anti-arrhythmic effect.
Interestingly “trans” fats which are also unsaturated have been demonstrated to
increase cholesterol and decrease HDL. These are geometric isomers of the good fats,
essentially mirror images. But this small difference results in subtle alterations in
physical properties which has deadly consequences for human health. A meta-analysis
has shown that a higher trans-fat intake of just 2 % of daily energy expenditure is
associated with a 23 % increased risk of CHD (Mensink and Katan 1990; Michels and
Sacks 1995; Mozaffarian et al. 2006). Trans fats are commonly found in fried and
baked food produced commercially. Intake should be virtually zero.
Salt
High sodium intake has been strongly linked to increased blood pressure, argu-
ably one of the most significant modifiable risk factors for CVD. There is
currently great controversy in establishing what the right sodium intake is for
the general healthy population. Current guidelines advocate a maximum of 2.3 g/
day sodium intake (National Heart Foundation of Australia), and a level of 1.5 g/
day is a goal sodium intake set by the American Heart Association (He and
MacGregor 2001; He et al. 2013). The PURE sodium study (O’Donnell
et al. 2014), the largest study to investigate the links between sodium and health
outcomes, has cast doubt on these recommendations. It has shown that virtually
no population anywhere in the world reaches current targets for sodium intake.
Furthermore, in a healthy population, only those individuals consuming more
than 5 g/day of sodium, which is very high, had an adverse effect on blood
pressure and cardiovascular outcomes. This new research is likely to result in a
significant shift in the guidelines for salt intake as it applies to the healthy general
population. It should be noted that patients with hypertension and the elderly may
still benefit from much lower sodium intakes more in line with current guidelines.
Processed food is thought to account for approximately 75 % of our sodium
intake. All guidelines for the prevention of CVD strongly advocate minimal
intake of processed food of all types.
Cardiovascular Risk Factors: Role of Lifestyle 69
Potassium is primarily sourced from fruit and vegetables, the classic example being
bananas. A high potassium intake will result in increased sodium excretion in the
urine in order to maintain cationic balance. High potassium intake has been shown
to reduce stroke risk by up to 40 % (He and MacGregor 2001).
Vitamins A, E, B6, folic acid, and B12 have no convincing data that can support
their use in the prevention of CVD (Perk et al. 2012).
Diets high in dietary fiber confer a reduced CHD risk by mechanisms that are not
clear. Fiber has a beneficial effect on lipid levels and lowers glucose levels in the
postprandial state, thus potentially reducing the deleterious effects of high insulin levels.
The American Heart Association recommends a minimum of 25 g of fiber per day.
Diets that are rich in fresh fruit and vegetables confer a reduced risk of CVD. Most
of our data comes from prospective cohort studies which may be confounded by the
fact that people who eat a lot of fruit and vegetables are often different from people
who don’t in other ways such as smoking, saturated fat intake, and physical activity.
Attempts have been made to correct for these biases statistically, and a meta-
analysis has demonstrated a 4 % decrease in CHD risk and 5 % decrease in stroke
risk for each additional serving of fruit and vegetables per day (Dauchet et al. 2004,
2005, 2006).
Fruits and vegetables could be beneficial for a variety of reasons including being
a major source of fiber. They are high in potassium and thus can help lower sodium
intake and blood pressure. This was demonstrated in the DASH trial which showed
that the marked reduction in blood pressure in the intervention arm could be
attributed to the high consumption of fresh fruit and vegetables (Appel
et al. 1997; Greenland 2001; Sacks et al. 2001).
Fish
Fish is high in n-3 polyunsaturated fatty acids which is thought to be why fish
confers cardiovascular protection. Eating fish at least once a week reduces the risk
of CHD by 15 % (He et al. 2004). It has been estimated that a modest increase in fish
intake among the general population could result in a 36 % reduction in CHD
mortality and a 17 % reduction in all-cause mortality (Mozaffarian and Rimm
2006). European guidelines recommend two serves of fish per week, one serve
being oily fish.
70 G. Vaddadi
Fig. 1 Cumulative 25-year coronary heart disease (CHD) mortality rates in different cohorts of
the Seven Countries Study, according to baseline quartiles of total cholesterol level, adjusted for
age, smoking, and blood pressure
Soft Drinks
In the USA, sugar-based soft drinks account for a large proportion of daily calorie
intake. In children and adolescents, 10–15 % of calorie intake may be sourced from
these products (Perk et al. 2012). Regular consumption of sugar-sweetened drinks
(one to two serves/day) has been associated with a 35 % higher risk of CHD in
women when compared with one serve/month even when adjusted for other
unhealthy lifestyle factors. Regular soft drink consumption has been linked to
obesity and type 2 diabetes. Soft drinks that are artificially sweetened have not
been associated with CHD (Fung et al. 2009).
Mediterranean Diet
Aerobic exercise has been shown to decrease CVD in healthy subjects, people with
risk factors, and those patients with underlying CHD (Perk et al. 2012). Aerobic
exercise has a plethora of positive effects including reducing blood pressure,
improving glycemic control, and slowing the onset of type 2 diabetes and enhances
coronary blood flow and the microcirculation within the heart which may protect
the heart from damage during myocardial infarction. In a study of 55,137 adults,
leisure running reduced all-cause mortality by 30 % and cardiovascular mortality
risk by 45 % over 15 years of follow-up when compared to non-runners (Lee
et al. 2014). In contrast sedentary activities such as car riding and TV watching
(Stamatakis et al. 2013) increase CVD risk starting in childhood (Smith et al. 2014).
Playing computer games and other “active” screen-based activities may not have
the same negative effect on CVD risk, perhaps due to the association between poor
“snacking habits” and TV watching (Ouwens et al. 2012). A recently published
32-year longitudinal British study has shown that TV watching time in childhood
tracks into adulthood, suggesting that we should place an increased emphasis on
early lifestyle interventions to reduce risky behavioral choices (Smith et al. 2014).
Increasing levels of occupation and leisure-time physical activity are inversely
associated with most of the CVD risk factors and are also independently related
to a reduced risk of MI (Held et al. 2012). Strenuous occupation-related physical
activity was, however, not significantly associated with decreased risk. These
relationships are consistent in both sexes and across the young and elderly (Held
et al. 2012). Globally there is an increasing use of technology associated with a
more sedentary lifestyle such as the television and car. The INTERHEART study
has shown an adverse relationship between ownership of a car and TV with CVD
risk across all economic and geographic regions. Furthermore, ownership of a car or
TV is an independent risk factor for MI (Held et al. 2012). Excessive hours lying
down per day is associated with increased all-cause and cardiovascular mortality;
this effect persists in an ameliorated form in those individuals who are otherwise
physically active (Holtermann et al. 2014).
Sitting is an activity many of us do in abundance, driving cars, taking the train, at
our desks at work, and in restaurants, to name but a few. An increasing body of
evidence supports the notion that sitting time is increasing our risk of CVD, even
among those who are physically active during their leisure time (Owen et al. 2010;
van Uffelen et al. 2010; Gardiner et al. 2011). A recent Danish study has shown that
excessive sitting time, >10 h per day, is associated with increased all-cause
mortality, compared with individuals who sit <6 h per day (Bjork Petersen
et al. 2014). The effect is particularly stark among physically inactive adults who
have a high sitting time. This evidence supports the need for fundamental lifestyle
changes at work, at home, and at all levels of operation within our society.
The positive effects of exercise seem to extend across both sexes and in all age
groups including the elderly. In the EU it has been estimated that <50 % of people
72 G. Vaddadi
Alcohol
Body Weight
Body fat content, in particular abdominal fat and visceral adipose tissue (fat around
the organs), is now well recognized as a significant contributor to CVD risk. Being
overweight and obese are both associated with an increased risk of CVD death
(Haslam and James 2005). There is a progressive linear relationship between
all-cause mortality and degree of obesity (body mass index (BMI)). A BMI of
between 20 and 25 kg/m2 is associated with the lowest mortality. At 30–35 kg/m2,
Cardiovascular Risk Factors: Role of Lifestyle 73
Obesity Paradox
It is intriguing to note that patients who are overweight or obese appear to have a
better prognosis when they have established coronary artery disease than patients
with CHD and a normal BMI (Lavie et al. 2009a, b; Hastie et al. 2010). The reasons
for this are less than clear and are at odds with the clear deleterious effect of
increasing BMI on health outcomes for the general population.
Conclusions
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Cardiovascular Risk Factors: Role of Lifestyle 77
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Smoking and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
Determinants of the Onset of Smoking Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Stress and Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Exposure to Psychosocial Stress and Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
Traumatic Stress, Stress-Related Mood Disorders, and Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Smoking in Potentially Stress-Prone Occupational Populations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
Stress and Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Overview of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Stress and Smoking Onset in Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Stress and Adolescent Smoking (Onset or Current Behavior) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Anxiety, Depression, and Adolescent Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Stress and Adolescent Smoking Prevention and Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
Abstract
Smoking is an acknowledged – and significant – risk factor for cardiovascular
disease (CVD). Research into the causes of smoking behavior is extensive, but
few would disagree that smoking is a discretionary human behavior acquired
through the operation of a combination of well-understood psychological
D. Byrne (*)
The Medical School, The Australian National University, Canberra, ACT, Australia
e-mail: [email protected]
J. Mazanov
School of Business, UNSW-Canberra, Canberra, ACT, Australia
e-mail: [email protected]
mechanisms. This chapter considered the role of psychological stress in its many
forms – and including psychological illness – in the genesis of smoking behav-
ior. While the evidence is both widespread and various, the collective view is
that stress plays a very clear role in the maintenance of smoking behavior, and in
the frequency of tobacco consumption, in well-established adult smokers. More
than this, however, there is growing evidence that psychological distress expe-
rienced in adolescence is causally related to the onset of smoking behavior in
that age group. Public health programs to prevent smoking onset among adoles-
cents – as part of continuing efforts to lower the incidence of CVD in adults –
must therefore include components of stress reduction and management in
addressing this crucial issue.
Keywords
Cigarette smoking • CVD risk • Stress • Emotional distress • Adolescence
Introduction
The negative health consequences of cigarette smoking are now established beyond
any reasonable doubt. Smoking has been consistently, convincingly, and causally
related to a host of cardiovascular, peripheral vascular, and cerebrovascular diseases,
and this assertion has clear epidemiological support (Tanuseputro et al. 2003: Lloyd-
Jones et al. 2006; Erhardt 2009). It holds across genders and cultures (Kurian and
Cardarelli 2007) and for passive as well as active smoking (Whincup et al. 2004).
Moreover, CVD risk among smokers decreases with smoking cessation (Wannamethee
et al. 2005). And well-understood pathophysiological mechanisms are available to
explain the links between smoking and CVD risk (Ambrose and Barua 2004).
In the large majority of cases, CVD becomes manifest in middle or late adult-
hood, though cigarette smoking has its origins firmly in early to middle adoles-
cence. Despite this recognition, and the consequent application of a multitude of
smoking prevention programs targeted at early and middle adolescents (Byrne and
Mazanov 2005), rates of smoking behavior remain high in this crucial develop-
mental stage. Large numbers in developed countries report themselves to be regular
smokers, and females do so at rates generally greater than do males. Moreover,
adults continue to smoke in large numbers and across national and cultural bound-
aries (Ng et al. 2014). The problem is therefore obvious, and a substantial and
ongoing research effort remains directed at both the determinants of smoking onset
and the drivers of that behavior once it has been established. And an emerging
research effort has recently been focused on the most effective means of preventing
smoking behavior among adolescents or of the usefulness of smoking cessation
strategies in adults once the behavior has been established.
Smoking and Cardiovascular Risk: Role of Stress in the Genesis of Smoking. . . 81
Examination of the research linking stress and smoking behavior must be viewed in
the context of three important caveats. First, research into stress and smoking has
largely been empirically driven and is often lacking in a clear theoretical founda-
tion. Second, definitions and conceptualizations of stress have historically been
challenged. And third, Nesbitt’s paradox (Nesbitt 1973), in which . . . smoking
generates physiological and psychological changes which are normally incompat-
ible . . . (as stated by Parrott 1998), poses a perplexing discord between anecdotal
and clinical reports of smoking and stress reduction, on the one hand, and relevant
theory and empirical evidence on the other.
82 D. Byrne and J. Mazanov
Nonetheless, the popular view that smoking reduces stress, and that smoking
behavior is therefore reinforced through its stress-reducing properties, prevails in
the lay literature. An Internet search using the term stress and smoking yields an
abundance of sites, the large majority offering either folk wisdom (typically some
statement that stress promotes smoking behavior) or various intervention packages,
evidence-based or otherwise, to assist with stress management during smoking
cessation. There is a relatively small scientific literature, and even then often
indirect, documenting associations between stress and smoking. The hypothesized
relationship was first canvassed three decades ago (Schachter et al. 1977), but few
studies since have directly addressed the fundamental issues either of whether stress
causes (or contributes to) the onset of smoking behavior or whether, among those
who have already commenced smoking, stress simply increases the frequency of
cigarette consumption.
Much of the evidence addressing the latter issue is largely indirect, and it is also
mostly focused on the adult population of smokers (Spigner et al. 2005), not
surprisingly since it is the adult population in which the greatest numbers of regular
smokers are to be found. This evidence can best be captured under the four
groupings of: (a) cumulative exposure to psychosocial stress and smoking,
(b) sufferers of stress-related psychiatric disorders and smoking, (c) stress and
smoking in high occupational risk populations, and (d) stress and its impact on
attempts at smoking cessation.
The relationship between psychosocial stress and smoking behavior – and the
issue of why those experiencing stress should turn to cigarette smoking – lies at
the heart of Nesbitt’s paradox. Nonetheless, it is clear from the evidence that
among regular adult smokers at least, the experience of stress corresponds to an
increase in tobacco consumption rates (Michal et al. 2013). This is seen broadly
across age groups, from adolescents (Fields et al. 2009), young adults (Conrad
et al. 2013; Tavolacci et al. 2013), and adults in both the mid (Ng and Jeffery
2003; Slopen et al. 2012) and later years (Choi and Dinitto 2011). And the
relationship appears also to hold for tobacco craving (Childs and de Wit 2010;
Saladin et al. 2012). While psychosocial stress generally has been clearly associ-
ated with cigarette use, stress arising from more specific sources, for example,
unemployment (De Vogli and Santinello 2014), the aftermath of the September
11 terrorist attacks (Vlahov et al. 2002), and perceived racial discrimination
Purnell et al. 2012), also manifests the relationship. Alarmingly, psychosocial
stress has been associated with smoking behavior in both pregnant women
(Varescon et al. 2013) and young mothers (Hauge et al. 2012; Sperlich
et al. 2013). The evidence, collectively, therefore confirms the general link
between stress and smoking behavior.
Smoking and Cardiovascular Risk: Role of Stress in the Genesis of Smoking. . . 83
The use of mood disorders as a proxy index of stress has not provided unam-
biguous support for the view that stress and smoking are linked in anything but a
coincidental manner, but the evidence is sufficiently persuasive to warrant further
investigation. While the evidence is strongest for PTSD as a predictor of smoking
status, it is confounded in at least one study by the coexistence of depression.
cigarette consumption and to relapse into smoking among those who had previously
quit (Falba et al. 2005). Occupational stress is therefore clearly associated with
smoking behavior. Interestingly, stress specific to the workplace has been found to
impede smoking cessation attempts (Yasin et al. 2012), and workplace smoking
bans, conversely, result in the experience of further stress (Azagaba and Sharaf
2012). But whether this evidence extends to a causal influence on work stress on
smoking onset or is limited to some covariation between work stress and smoking
behavior among already established smokers remains to be confirmed by prospec-
tive investigation.
The evidence is sufficiently consistent now that, in line with both anecdote and
observation, stress has been generally linked with smoking in adult smokers in a
range of empirical investigations. The bulk of this evidence, however, comes from
studies inferring stress either from the presence of diagnosed psychological dys-
function or membership of an occupational group assumed to be stressful. Few
studies have reported covariations of smoking behavior with naturalistic
86 D. Byrne and J. Mazanov
The theme of this chapter rests on the view that the primary theoretical objection to
a causal link between stress and smoking onset in adolescence lies with (1973)
Nesbitt’s paradox. This aside, however, the past decade has seen a great deal of
evidence linking stress with smoking behavior in adolescence. Most of this evi-
dence falls within the three broad categories of: (a) stress and either current
smoking behavior or smoking onset, (b) smoking in adolescents suffering from a
psychological disorder linked with stress, or (c) stress as an impediment to smoking
prevention strategies in adolescents. These are now considered in turn.
The experience of high levels of stress, often in association with poor mobilization
of effective coping skills, has consistently been associated with current smoking
behavior in adolescents. Siqueira et al. (2000) examined 954 patients aged between
12 and 21 attending an urban multidisciplinary clinic; 25 % were current smokers
and this was clearly related to both high levels of experienced stress and the use of
negative coping strategies. The nature of the reported stressors was broadly based
but those involving the family were prominent. Family stress was also found to be a
correlate of both adolescent smoking behavior and daily smoking levels in a large
population sample (Miller and Volk 2002).
A study of normal secondary school adolescents (Karatzias et al. 2001) looked
both at experimental smoking (having tried smoking) and the maintenance of
established smoking behavior. School stress was the best predictor of experimental
smoking, but the maintenance of the behavior, once established, was better
predicted by poor quality of school life. While this study was essentially retrospec-
tive, the finding that (school) stress predicted experimental smoking but not
smoking maintenance hints at the possible link between stress and smoking onset.
A large population study (van den Breen et al. 2004) further reinforced the
importance of school stress, reporting associations between stress in the school
context and both initiation and progression of smoking among adolescents. High
levels of stress predicted progression along a trajectory of smoking in school-aged
adolescents (Hunt 2005). And findings such as these have gone beyond Western
samples of adolescents, with similar results recently reported from samples of
adolescents in China (Unger et al. 2001; Li et al. 2003; Liu 2003).
Smoking and Cardiovascular Risk: Role of Stress in the Genesis of Smoking. . . 87
for adolescent girls (Byrne and Mazanov 2003). Results indicated a broad range of
stressor categories (Byrne et al. 2007) as precursors to adolescent smoking, partic-
ularly among girls. The breadth of stressors associated with smoking attests to the
complex nature of adolescent stress. Examination of intention to smoke in this same
cohort revealed that dimensions of stress usefully predicted adolescents’ indicated
intention to be smokers (or nonsmokers) at some time into the future (Mazanov and
Byrne 2002). Intention to smoke is a contentious outcome variable, however, since
it is not perfectly correlated with the actual behavioral outcome, though it is often
used as a variable of convenience where a true prospective methodology is not
feasible. Droomers et al. (2005) extended the reasoning to the broader psychosocial
contexts in which adolescents live, linking smoking to the stress of low socioeco-
nomic class, though findings such as these are prone to a range of interpretations.
But two particular sources of adolescent stress have emerged from the recent
literature as worthy of further attention. First, gender differences in relation to stress
and smoking are clearly evident (Koval et al. 2000). Female gender has also been
associated with smoking rates, with girls tending to have higher rates of smoking
than boys, at least in Western samples (Byrne and Reinhart 1998). Adolescent girls
also appear to experience higher levels of stress than boys (Byrne et al. 2007). The
possibility that these issues may be linked (Croghan et al. 2006) cannot be
overlooked. One pathway which may explain the link is that of pubertal timing.
Early puberty in girls has been associated with the experience of stress (Simon
et al. 2003) and with both having tried smoking (Simon et al. 2003) and early
initiation and greater frequency of smoking (Dick et al. 2000). The potential to
understand high smoking rates in adolescent girls through the mechanism of stress
associated with early puberty deserves further exploration.
And second, as societies around the world become more multiethnic, adolescents
in minority groups are experiencing racial discrimination and stress arising from
that (Fisher et al. 2000). Early evidence is emerging that stress from this source is
associated with adolescent smoking. Guthrie et al. (2002) looked at racial discrim-
ination among African-American adolescent girls and reported a clear association
between the experience of discrimination and smoking. Controlling for levels of
stress arising from discrimination significantly reduced the size of the relationship
between discrimination and smoking, underscoring the importance of stress in
understanding the link. Udry et al. (2003) extended this reasoning to adolescents
of mixed race origins, associating elevated risk of smoking in mixed race adoles-
cents to stress arising from this situation. This potential link between stress and
adolescent smoking also requires vigorous examination.
adolescents or cessation of smoking among those who have already acquired the
behavior. As with the adult literature, there is emerging evidence that stress exerts
an influence on the ease with which adolescents are either able to resist the behavior
or give it up once acquired.
Common practice in the field of adolescent smoking cessation consistently
involves the teaching of stress management as an integral component of interven-
tion (Singleton and Pope 2000; O’Connell et al. 2004). Indeed, a study of smoking
cessation interventions (Turner et al. 2004) actually found that stress predicted
attendance at cessation sessions; those with high reported stress were less likely to
attend than those with low stress. And stress posed a significant barrier to smoking
cessation in another sample interviewed on their likelihood of quitting smoking
(Amos et al. 2006). A small qualitative study of young female smokers (Gilbert
2005) advocated that smoking cessation programs should be targeted to the needs of
young people and that the common belief that smoking leads to stress relief should
for a focus for such programs.
Unlike the adult literature, however, few studies have examined stress (or mental
health status) in relation to actual outcomes in smoking cessation programs. Horn
et al. (2004) studied a relatively small sample of rural adolescents either undergoing
a purpose-designed program to quit smoking or offered a brief, single intervention.
The cessation program was modestly successful, but the coexistence of depression
or anxiety reduced the effectiveness of cessation outcomes. On that basis these
authors recommended the inclusion of coping and stress management skills into
smoking cessation programs for adolescents.
The literature on smoking prevention in adolescents is, unfortunately, not
encouraging (Bruvold 1993), and there has been little to systematically link stress
with the achievement of prevention. Byrne and Mazanov (2005) did present data
evaluating an extensive smoking prevention program in a large sample of
Australian adolescents which does bear on the role of stress. Three approaches to
smoking prevention based respectively on the health consequences of smoking, the
fitness consequences of smoking, and resistance to peer pressure were trialed in a
1-year prospective study. While the intervention program focusing on the health
consequences of smoking was most effective in reducing smoking onset immedi-
ately following intervention, 1-year follow-up demonstrated that resistance to peer
pressure based on stress management was a more effective long-term prevention
strategy.
Conclusions
The evidence relating adolescent smoking to stress then is broadly persuasive but
not absolutely clear-cut. Much of the support has been implied from studies of
established adult smokers and focused on the apparent stress-reducing properties of
smoking behavior. And Nesbitt’s (1973 paradox remains a thorny theoretical issue.
Yet the empirical evidence continues to support a link between stress and adoles-
cent smoking, and some evidence (Byrne and Mazanov 1999, 2003, 2005) suggests
Smoking and Cardiovascular Risk: Role of Stress in the Genesis of Smoking. . . 91
that this link may be causal. Prospective evidence restricts the link largely to girls
but associations still remain evident in boys. And interestingly, there is little
evidence that stress influences smoking behavior over time in adolescents once
the behavior has been established (Mazanov and Byrne 2006). But the best evi-
dence on whether stress relates causally to the onset of adolescent smoking will
finally rest with intervention studies, and there is now sufficient of that evidence to
indicate that stress management should be a prominent component of all new
programs focusing on the prevention of smoking behavior among school-aged
adolescents.
Acknowledgment Portions of this chapter are based on revisions of an earlier publication by the
present authors (Personality, stress and the determination of smoking behaviour in adolescents, in
G.J. Boyle, G. Matthews and D.H. Salkofske (Eds) (2008) The Sage Handbook of Personality
Theory and Assessment. Los Angeles: Sage Publications Inc. (Chapter 34, pp 698–719). Used with
the publisher’s permission.
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Smoking and Cardiovascular Risk: Role
of Personality in Adolescent Smoking
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
Personality and Adolescent Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Association Versus Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Onset Versus Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
The Role of Model Personality in Adolescent Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Association Versus Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Onset Versus Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Additional Thoughts on Adolescent Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Smoking and the “Risky” Personality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Smoking Beliefs/Knowledge . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Association Versus Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Onset Versus Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
The Role of Smoking Beliefs and Knowledge in Adolescent Smoking . . . . . . . . . . . . . . . . . . . 106
Self-Esteem/Self-Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Association Versus Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Onset Versus Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
The Role of Self-Esteem/Self-Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Locus of Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Religiosity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Association Versus Causality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
J. Mazanov (*)
School of Business, UNSW-Canberra, Canberra, ACT, Australia
e-mail: [email protected]
D. Byrne
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
ANU Medical School, Research School of Psychology, Australian National University, Canberra,
ACT, Australia
e-mail: [email protected]
Abstract
Work to mitigate the increased risk of cardiovascular disease (CVD) brought
about by cigarette smoking compels primary and secondary prevention activity
among adolescents. Personality plays a prominent role among the variables
associated with adolescent onset and maintenance of smoking. The role of per-
sonality in adolescent smoking is examined by contrasting results from research
exploring association versus causality and then evidence from studies examining
onset versus maintenance in relation to models of personality, risk, smoking
beliefs/knowledge, self-esteem/self-efficacy, locus of control, and religiosity.
Analysis using the two comparisons demonstrates the need for research in the
area to consider dynamical approaches to explain changes in adolescent smoking
behavior more deeply. For example, advances in the mathematical sophistication
of adolescent smoking research make it possible to understand how changes in
knowledge about the health consequences of smoking influence the onset or
maintenance of smoking among adolescents. The development of more dynamical
explanations of adolescent behavior may prove valuable explanations of behavior
among adults trying to quit smoking to reduce the risk of CVD.
Keywords
Adolescent • Smoking • Personality • Causation • Behavior Change
Introduction
The link between tobacco smoking and increased risk of cardiovascular disease
(CVD) (among a plethora of other diseases) means primary and secondary preven-
tion of adolescent smoking has a direct effect on primary and secondary prevention
of CVD. Primary prevention seeks to preserve the naturally abstinent state of
adolescents through to their adult life. Secondary prevention recognizes that ado-
lescence is a time of experimentation with a range of behaviours including sub-
stance use, and therefore seeks to eliminate the behaviour before harms arising from
an increased relative risk of CVD become established. The effort to develop
intervention programs to promote the aims of primary and secondary prevention
has therefore focused on smoking onset and maintenance among adolescents.
These efforts have demonstrated the determinants of adolescent smoking onset
and maintenance to be both complex and diverse. Tyas and Pederson’s (1998) four
category typology of variables that influence onset of smoking (sociodemographic,
environmental, behavioural and personal influences) can be usefully deployed to
gain some insight into the complexity and diversity of adolescent smoking onset
Smoking and Cardiovascular Risk: Role of Personality in Adolescent Smoking 101
As noted above, the role of personality in adolescent smoking is both broad and
complex. The volume of psychosocial variables associated with adolescent
smoking behavior makes it impossible to include a comprehensive account of the
entire spectrum (Mazanov and Byrne 2002). This makes the choice of variables for
inclusion a difficult task, with some important variables necessarily omitted. This
review examines some personality constructs more consistently related to adoles-
cent smoking over time relative to others.
For this review, adolescence has been extended to include the teenage years and
early twenties. From a sociological point of view, Western democratic societies
tend to define adulthood as the voting age or the age at which a person can hold an
elected seat in parliament, usually 18 years. However, experimentation with health
risk behaviors characteristic of adolescence also occurs in the early twenties (when
around 5 % of lifetime smokers initiate; Choi et al. 2001). This may be correlated
with emerging evidence from neuroscience about the developing adolescent brain
and the rapid evolution in how that developing brain interprets and understands risk-
taking behavior (e.g., Pharo et al. 2011). For example, evidence suggests that there is
a fundamental change in the way health risks are interpreted in the mid- to late 20s
(Brook et al. 2008; Mahalik et al. 2013). The period of growth leading up to
stabilization is characterized by a rapid evolution in both what is understood to be
risky behavior and how often adolescents engage in risky behavior (Mazanov and
Byrne 2006b; Morrell et al. 2010). For these reasons, results outside the traditional
boundary of adolescence (18 years) are considered.
Each personality construct is considered two ways. The first is a contrast of factors
influencing onset and those which influence maintenance. The second contrast of
association versus causality is aimed at exploring how results from cross-sectional and
longitudinal research vary and their implications for primary and secondary prevention.
Models
This short review demonstrates the range of possible relationships that can emerge
from models of personality and adolescent smoking. Any survey of the “model”
literature is likely to find a mixture of results that declare ascendancy of one
variable over another. Importantly, this discussion shows such variables need to
104 J. Mazanov and D. Byrne
Risk
There is a clear relationship between the way adolescents deal with “risk” in its
many forms and smoking behavior. At a basic level, a number of studies correlate
“risk” with smoking behavior (smoking status or number of cigarettes smoked)
cross-sectionally (e.g., Doran et al. 2011) and longitudinally (Adalbjarnardottir and
Rafnsson 2002; Brook et al. 2004; Malmberg et al. 2013). That is, there is an
indication that “risk” and smoking behaviors have some kind of systematic rela-
tionship. Confirmation of the systematic relationship has come from studies spe-
cifically looking at what causes adolescents to start smoking. Some authors have
found compelling statistical evidence risk as independently influential (Botvin
et al. 2001), whereas others have found that risk influences smoking behavior in
concert with other psychosocial variables (Wills et al. 2007).
The relationship between “risk” and onset of adolescent smoking is variable, with
some research focusing on risk as the most central variable for prevention (Burt
et al. 2000) and others finding no relationship (Mazanov and Byrne 2006a).
Smoking and Cardiovascular Risk: Role of Personality in Adolescent Smoking 105
Audrain-McGovern et al. (2004) show that early onset is characteristic of those with
a higher sensation seeking. White et al. (2002) analysis showed that disinhibition
(part of the sensation-seeking domain) was the key for identifying different trajec-
tories in onset. Rebelliousness appears to be correlated with transitions in adoles-
cent smoking behavior in terms of onset and escalation from first cigarette to
monthly and to daily smoking; by comparison, thrill seeking diminishes in the
transition from monthly to daily smoking (Bricker et al. 2009). Other work on
rebelliousness shows the construct has little influence at onset but predicts mainte-
nance (Otten et al. 2011b). Importantly, these studies indicate risk as being equally
important for maintenance as it is for onset.
One important aspect of research into adolescent smoking and risk is the way in
which adolescents view the potentially negative impact smoking will have on their
life. Arnett (2000) and Borland (1997) report an “optimistic bias,” where adolescent
consistently underestimates the consequences smoking may have for them (e.g.,
breaking addiction). This has a significant impact on their decision-making ability
when it comes to making rational cost-benefit trade-offs described by theories of
health decision-making. Halpern-Felsher et al. (2004) note that adolescents tend to
minimize future risk, trading off future cost against immediate benefit. How this
plays out in the context of onset or maintenance of adolescent smoking must be
considered next to the result that perceptions of risk tend to evolve very rapidly as
the adolescent progresses toward adulthood (presumably with age and experience)
(see Mazanov and Byrne 2006b).
Based on the reliability of the results over time and across studies, the way
adolescents deal with risk clearly influences smoking onset and maintenance.
This result has emerged from the application of more mathematically sophisticated
models (e.g., analyzing growth trajectories) to understanding the role of risk in
adolescent smoking. The next phase is disentangling the causal sequence to a finer
level detail, perhaps through judicious application of neuroscience.
Smoking Beliefs/Knowledge
demonstrated facts about the consequences of smoking (Glied 2003) with little
success (Evans 2001). This failure brings into question whether beliefs or knowl-
edge are associated with smoking behavior in the way theory suggests.
There is evidence adolescents are very knowledgeable about the health conse-
quences of smoking (Tilleczek and Hine 2006), smokers more than nonsmokers
(Mazanov and Byrne 2007). What is less clear is whether this information influ-
ences beliefs or smoking behavior. There is some evidence that beliefs and knowl-
edge predict smoking behavior cross-sectionally (Hines et al. 1999; Islam and
Johnson 2005) and cross-culturally (Karimy et al. 2013; Steptoe et al. 2002; Yang
et al. 2013). However, the association varies across gender, sometimes more
important for boys than girls (Nebot et al. 2005) and vice versa (Epstein
et al. 2003). Perceived health risk also appears to be more important to the
intentions of adolescent smokers than never smokers (Brown et al. 2010). Some
suggest that this variable association may be a function of interactions with other
variables (e.g., mood, perceived social benefits, and avoidance self-efficacy; Ford
et al. 2013) or psychometry (Panter and Reeve 2002). More importantly, there is
evidence that beliefs and knowledge are causally irrelevant (Sperber et al. 2001),
suggesting a more systematic examination of beliefs and knowledge is needed in
terms of association and causality.
currently uses a range of single (e.g., Brown et al. 2010; Yang et al. 2013) and
multiple item measures (e.g., Mazanov and Byrne 2007) unique to each study.
Smoking expectancy scales that incorporate health consequences of smoking offer
one way of achieving consistency across studies (e.g., Hine et al. 2007). With a
robust and consistent measure in place, attention can refocus on the reliability of the
relationship. If a reliable relationship is found, further work on the role beliefs and
knowledge play in onset or maintenance is needed, especially for education-based
intervention or prevention programs.
Self-Esteem/Self-Efficacy
Locus of Control
The belief that one has control over one’s behavior is seen as central to health
behavior (Steptoe and Wardle 2001), especially in the context of self-efficacy
(refusal skills; Stuart et al. 1994). There has been a generally replicated result
that adolescent smokers have an external locus of control (e.g., Abdollahia and
Talib 2014; Ludtke and Schneider 1996). One significant study by Steptoe and
Wardle (2001), involving 7115 university students (age range 18–30) across 18 -
European countries, showed external locus of control was unrelated to smoking.
Locus of control was found to be nonsignificant across adolescent nonsmokers,
triers, and regular smokers (Tang and Loke 2013).
An important change in locus of control research has been the shift from Rotter’s
(1966) single internal-external continuum to facet locus of control (internality,
chance, and powerful others). Some studies show all three influence for smoking
behavior (Bennett et al. 1997) and others only for specific facets (e.g., extremely
high chance orientation only; Steptoe and Wardle 2001). There has been little work
on the role of locus of control in how smoking behavior changes. Stephens
et al. (2004) suggest readiness to change smoking behavior is unrelated to locus
of control. Presson et al. (2002) indicate an internal locus of control has some
protective effect against uptake.
In terms of association, locus of control seems to have a relatively strong
relationship with smoking behavior. Whether locus of control remains as a viable
predictor in the context of onset or maintenance is something future research needs
to address.
Religiosity
Religion has been used as the conduit for a range of substance use interventions,
notably in relation to alcohol (e.g., Alcoholics Anonymous and Evangelical Prot-
estantism; Sarafino 2006). This has seen research into the role religion might play in
protecting adolescents from smoking. A review of the role of religiosity in sub-
stance abuse noted the dominance of research from the United States, problems
with non-standardized measurement of religious engagement, and the need for
more longitudinal research (Chitwood et al. 2008). Fortunately, these issues are
being systematically addressed with respect to adolescent smoking.
110 J. Mazanov and D. Byrne
There was some evidence religion or personal morality was protective against onset
(Amey et al. 1996). Timberlake et al. (2006) report religiosity was the only
protective factor that overcame genetic effects. An interesting take on this relation-
ship was that a strong “private” sense of religion protected adolescents from
experimenting with cigarettes and the public demonstration of their religion
protected them from regular smoking (Nonnemaker et al. 2003). That is, if religious
adolescents take up smoking, their religion may retard progression to regular
smoking. This contention is supported by religiosity mitigating the rate of growth
in smoking over time (Mason and Spoth 2011; Spears et al. 2010; Wills et al. 2003)
and possibly more so for boys (Van den Bree et al. 2004). This suggests differential
processes are at work.
Religiosity has some role to play in adolescent smoking; exactly what that role may
be is open to debate. More research is needed in a wider range of religious contexts;
most research focuses on Judeo-Christian faiths with research in Islamic contexts a
rare exception and other religions almost absent (e.g., Sikh). Such research needs
designs that establish whether the correlation is psychological in nature or a
spurious relationship. Establishing this result provides guidance on whether reli-
gion may be viable as a basis for prevention or intervention programs.
Smoking and Cardiovascular Risk: Role of Personality in Adolescent Smoking 111
Conclusions
Given the central role of smoking increasing the relative risk of CVD, the ongoing
interest in the role of personality in adolescent smoking is justifiably growing. The
increasing mathematical sophistication of adolescent smoking research is demon-
strating the importance of examining causality more thoroughly. While research
examining differences provides descriptive evidence of how categories of smoking
differ, it is the exploration of causality that enables an understanding of the
processes that lead to those differences (e.g., Bricker et al. 2009); that is, an
understanding of why those categories of smoking differ and an ability to predict
the first tobacco smoking experience or accelerations in tobacco smoking.
Researchers may find it valuable to consider the dynamical nature of both depen-
dent and independent variables, that is, exploring how adolescent smoking behavior
changes over time as a function of how personality changes over adolescence.
Methodological experimentation in adolescent smoking research may lead to the
development of models and techniques that help combat CVD by promoting adult
smoking cessation. For example, the mathematical models that describe onset and
maintenance in adolescence may be directly applicable to explaining the psycho-
social foundations of cessation among adults. With the potential to drive primary
and secondary prevention among adolescents and adults, research examining
change in behavior over time needs to accelerate to generate a new understanding
of the role of personality in adolescent smoking onset and maintenance.
Acknowledgments Portions of this chapter are based on revisions of an earlier publication by the
present authors (Personality, stress and the determination of smoking behaviour in adolescents, in
G.J. Boyle, G. Matthews and D.H. Salkofske (Eds) (2008) The Sage Handbook of Personality
Theory and Assessment. Los Angeles: Sage Publications Inc. (Chapter 34, pp 698-719). Used with
the publisher’s permission.
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Alcohol and Cardiovascular Risk
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
The J-Shaped Curve: Is Alcohol Cardioprotective? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Risk of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Risk of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Risk of Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Risk of Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
Individuals with Preexisting Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Choice of Alcoholic Beverage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Pattern of Consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Risks Associated with Excessive Alcohol Consumption, Drinking to Intoxication, and
Alcohol Dependence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Confounding Factors and the Limitations of Evidence from Observational Studies . . . . . . . . . 128
The “Sick Quitter” Hypothesis: The Misclassification of Ex-Drinkers as Abstainers . . . . 128
Lifetime Abstainers May Differ from Drinkers in Ways Other than Just Alcohol
Consumption: Moderate Alcohol Consumption as a Marker of Optimal
Social Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
Limitations of Methodology: Measuring and Classifying Alcohol Consumption
in Observational Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Pathophysiological Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Alcohol and Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Other Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Public Health Implications: Should Safer Drinking Guidelines Be Altered? . . . . . . . . . . . . . . . . . 133
Clinical Implications and Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Abstract
Alcohol is a psychoactive substance that has a considerable impact on the
physical and mental health of individuals. While there is clear evidence for a
wide range of harms associated with alcohol consumption, research has also
been conducted into the potential positive effects, including cardiovascular
effects. The results of many of these studies are suggestive of a J-shaped
association between low levels of regular alcohol intake and a reduction in
cardiovascular risk – particularly coronary heart disease risk. This is an associ-
ation that appears to be affected both by the level and the pattern of alcohol
consumption. However, most of this research has consisted of observational and
population-based studies, with inherent methodological limitations and difficul-
ties controlling for confounding factors. Consequently, there is still insufficient
evidence to suggest a causal relationship between alcohol consumption and a
reduction in cardiovascular risk. On a population level, the putative benefits of
alcohol intake are more salient for some individuals compared to others – such as
older adults with other cardiovascular risk factors. On the other hand, negative
health effects can arise from even low levels of alcohol intake. Thus, the
provision of advice regarding alcohol consumption needs to be individualized
and is best undertaken within a clinical context.
Keywords
Alcohol • Alcohol drinking • Cardiovascular • Cardiovascular risk • Coronary
disease
Introduction
Alcohol is a psychoactive substance that has a significant impact on the health and
well-being of individuals and communities. Alcohol consumption contributed to
5.1 % of the global burden of disease and injury and up to 3.3 million deaths
worldwide in 2012 (WHO 2014). Alcohol is also a component cause of over
200 different types of disease and injury (WHO 2014). It has also been implicated
as a source of far-reaching intangible and tangible harms to others. For instance, a
recent Australian study estimated that heavy drinkers cost people around them more
than $14 billion in out-of-pocket costs and up to an additional $6 billion in
intangible costs (Laslett et al. 2010) – more than doubling previous estimates
(Collins and Lapsley 2008). On the other hand, individuals often cite positive social
and mental health benefits of alcohol, and moderate alcohol use is considered part
of the social norm and lifestyle in many cultures and countries.
One potential benefit of alcohol that has been studied extensively is that of
cardiovascular disease risk reduction. Substantial research has gone into under-
standing the association between cardiovascular disease and alcohol consumption,
with such research focusing on a number of key areas. Investigators have sought to
Alcohol and Cardiovascular Risk 121
Epidemiological and observational studies over the past three decades have
suggested that light to moderate alcohol consumption is associated with a reduced
risk of cardiovascular disease (Corrao et al. 2000; Di Castelnuovo et al. 2010;
Klatsky 2010; Marmot and Brunner 1991; Ronksley et al. 2011) (see Table 1). The
majority of these studies have reported a J-shaped curve, with light to moderate
drinking being associated with lower risk than complete abstinence and heavy
drinking placing an individual at highest risk (O’Keefe et al. 2007; Rimm
et al. 1999; Ronksley et al. 2011). Estimates of the cardiovascular mortality risk
reduction conferred by light to moderate alcohol consumption range from 20 % to
30 % (Di Castelnuovo et al. 2006; Rimm et al. 1999; Ronksley et al. 2011).
The cardioprotective association of low to moderate alcohol consumption
appears to be strongest for coronary artery disease (CAD), and it appears that the
majority of cardiovascular mortality risk reduction is attributable to the effect of
alcohol on CAD (Mukamal et al. 2010; Ronksley et al. 2011). Ronksley and
colleagues’ recent systematic review and meta-analysis included 84 studies of the
impact of alcohol on cardiovascular risk (Ronksley et al. 2011) and is the most
complete meta-analysis of this subject to date, sampling over one million people.
They found a pooled estimate of relative risk for all-cause mortality in all drinkers
compared to nondrinkers of 0.87 (95 % CI of 0.83–0.92); for cardiovascular
mortality, alcohol consumption was associated with a relative risk of about 0.75
(95 % CI 0.70–0.80 (Ronksley et al. 2011). This association was similar for incident
coronary artery disease (RR 0.71 (0.66–0.77)) and coronary artery disease mortality
(RR 0.75 (0.68–0.81)) (Ronksley et al. 2011). When dose relationships were
analyzed, they confirmed a J-shaped relationship between alcohol intake and
cardiovascular intake (Ronksley et al. 2011), which was later graphically
represented in Thompson’s discussion of the topic (Thompson 2013) as below
(see Figure 1). A dose-response analysis suggested that the lowest risk of CAD
mortality occurred with one to two drinks per day (Ronksley et al. 2011).
Another meta-analysis of 44 studies looked at the relationship between
alcohol consumption and ischemic heart disease (IHD) and attempted to
quantify a dose-response relationship stratified by sex and by IHD outcome
122 S. Arunogiri and D. Lubman
(Roerecke and Rehm 2012). This meta-analysis provided useful information as the
authors completely excluded any studies that included former drinkers and only
included lifetime abstainers (Roerecke and Rehm 2012). They found an overall
cardioprotective effect of alcohol on IHD risk and found a J-shaped curve relation-
ship between alcohol intake and IHD morbidity and mortality in men, with reduced
morbidity in women (Roerecke and Rehm 2012). In their dose-response analysis,
the lowest point of the J-curve (the point at which there was lowest IHD risk) was at
an alcohol intake of 31 g/day for men and 11 g/day for women (Roerecke and Rehm
2012). Thompson’s recent review reconstructed these findings from Roerecke and
Rehm, as demonstrated below (Thompson 2013, see Fig. 1) and summarized in
Table 1.
In conclusion, there is strong evidence for a J-shaped relationship between
alcohol intake and a number of cardiovascular outcomes. Whether this association
is a causal relationship, however, remains to be proven.
Alcohol and Cardiovascular Risk 123
1.4
0.6
0.4
0.2
0
0 < 2.5 2.5–14.9 15–29.9 30–60 >60
Alcohol intake (g/day)
Fig. 1 Meta-analysis showing the J-shaped relationship between alcohol intake and cardiovas-
cular mortality (Redrawn from data in Ronksley et al. 2011, Thompson 2013)
Risk of Hypertension
Both experimental and observational studies show that the more people drink, the
higher their risk of hypertension (Parry et al. 2011; Patra et al. 2010; Taylor
et al. 2009). A meta-analysis of 12 cohort studies found a linear dose-response
relationship between alcohol consumption and hypertension, particularly in men
(Taylor et al. 2009). Adopting the Heart and Stroke Foundation definition of
hypertension as a blood pressure of over 140/90 mmHg, men who drank 50 g or
more of alcohol daily (>5 standard drinks) had a relative risk of 1.57 for hyper-
tension, rising to a relative risk of 2.47 at 100 g per day (ten standard drinks) (Taylor
et al. 2009). For women, there was a modest protective effect for consumption
levels of less than 5 g per day (<0.5 standard drinks); however, above this level,
there was a linear relationship of alcohol intake with hypertension risk, to a relative
risk of 1.81 at 50 g per day and 2.81 at 100 g per day (Taylor et al. 2009). These
estimates are summarized in Table 1.
Risk of Stroke
Stroke can be classified as ischemic stroke or hemorrhagic stroke. Alcohol has been
demonstrated to elevate the risk of hemorrhagic stroke by contributing to hyper-
tension (Ohsawa and Tanno 2013). Some studies have suggested an almost linear
relationship between increasing doses of alcohol consumption and increasing risk
of hemorrhagic stroke, particularly in men (Patra et al. 2010). Hypertension also
124 S. Arunogiri and D. Lubman
Risk of Arrhythmias
Acute alcohol consumption has been associated with an increased risk of paroxys-
mal atrial arrhythmias such as atrial fibrillation via a number of pathophysiological
pathways (Sheikh et al. 2014). So-called holiday heart syndrome was described in
the 1970s as a consequence of excessive alcohol consumption during a vacation
resulting in presentations with atrial fibrillation (Fauchier 2003; Sheikh et al. 2014).
It is unclear what level of consumption results in the development of these
arrhythmias.
Heavy drinking occasions have also been associated with a lower threshold for
ventricular fibrillation (Costanzo et al. 2010b; Rehm et al. 2003) and have been
associated with other ventricular arrhythmias (Fauchier 2003).
Risk of Cardiomyopathy
Alcohol has been shown to have a detrimental effect on cardiac muscle structure
and function (Goncalves et al. 2014), and long-term alcohol consumption can lead
to a recognized and specific form of cardiomyopathy known as alcoholic cardio-
myopathy. This is a non-ischemic form of dilated cardiomyopathy, characterized by
an increase in myocardial mass, dilatation of the ventricles, and wall thinning
(Piano 2002). While the exact amount and duration of consumption leading to
cardiomyopathy has been hard to determine, data appear to suggest that levels of
alcohol consumption of greater than 7–15 standard drinks per day for more than
5–15 years are associated with cardiomyopathy (Piano and Phillips 2014). The
interaction between alcohol and myocardial injury is moderated by a range of
Alcohol and Cardiovascular Risk 125
While the initial studies of the impact of alcohol on cardiovascular risk focused on
healthy individuals with no baseline disease, evidence has since begun to emerge
showing that alcohol may have a cardioprotective role even in individuals with
cardiovascular disease.
A 2010 meta-analysis by Costanzo and colleagues examined eight published
prospective observational studies of 16, 351 patients with a history of cardiovas-
cular disease (specifically, a history of coronary heart disease, acute myocardial
infarction, or stroke) (Costanzo et al. 2010a). The relationship between cardiovas-
cular mortality and alcohol consumption in this cohort found a J-shaped curve, with
maximal effects in the range of 5–10 g/day of alcohol; this effect held even when
former drinkers were excluded from the reference category (Costanzo et al. 2010a).
Most studies included in this meta-analysis only administered alcohol intake
questionnaires late (over 2 months) after the index cardiovascular event, as authors
sought to get an accurate representation of individuals’ real intake of alcohol prior
to the event (Costanzo et al. 2010a). The authors also conducted a second meta-
analysis on this cohort for all-cause mortality and found a J-shaped relationship
between alcohol consumption and all-cause mortality in individuals with
preexisting cardiovascular disease – maximal protective effects were, again, in
the range of 5–10 g/day of alcohol (Costanzo et al. 2010a). In both analyses, the
protective effect held for levels of alcohol consumption up to 25 g/day. It is worth
noting that the greatest benefit derived was thus at a level of less than one standard
drink of alcohol per day, with some benefit up to 2.5 standard drinks per day
(Costanzo et al. 2010a).
One consideration in individuals with preexisting cardiovascular disease is the
risk of interactions between alcohol and cardiac medications. Alcohol may poten-
tially interact with antiplatelet and oral anticoagulant drugs. For instance,
alcohol consumption in combination with aspirin can raise the risk of gastrointes-
tinal bleeding in an additive fashion (Costanzo et al. 2010b). The effect of
alcohol on the induction of the cytochrome P-450 enzyme system in the liver
can result in the breakdown of particular medications being sped up, thereby
decreasing the concentration of these medications – this may play some role in
the metabolism of anticoagulant drugs such as warfarin and clopidogrel (Costanzo
et al. 2010b).
126 S. Arunogiri and D. Lubman
It was once believed that red wine was responsible for many of the cardioprotective
effects of alcohol (Grønbæk et al. 2000). This assumption arose from the concept of
the “French paradox” – the low cardiovascular disease and ischemic heart disease
mortality rate observed in French men, despite a diet high in saturated fat, was
attributed to the consumption of red wine (Renaud and de Lorgeril 1992). Com-
pounds in red wine, including polyphenols (such as resveratrol) and flavonoids,
were found to have a protective effect on endothelial function, platelet aggregation,
and low-density lipoprotein oxidation (Di Castelnuovo et al. 2010; Karatzi
et al. 2004).
However, large prospective studies have since found that the beneficial effects of
low to moderate alcohol consumption are not dependent on the type of alcoholic
beverage consumed or properties of the beverage but, rather, due to alcohol itself
(Mukamal et al. 2003; Rimm et al. 1996). Some studies have also demonstrated that
moderate-consumption wine drinkers may have healthier diets in comparison to
nondrinkers and heavy drinkers, which may further contribute to lowered cardio-
vascular risk (Hansel et al. 2012).
Pattern of Consumption
alcohol consumed over a week was almost the same in both countries (281.7 g in
Ireland, 254.6 g in France), but when the pattern of consumption was compared
between countries, 9.4 % of the Belfast cohort reported binge drinking compared to
0.5 % in the French sample – men in Belfast appeared to consume the total volume
over 1–2 days, whereas men in France reported consumption over the course of the
week (Ruidavets et al. 2010). The prevalence of binge drinking was thus almost
20 times higher in Ireland than in France, and this was associated with a doubling of
risk of ischemic heart disease for binge drinkers (hazard ratio of 1.97, 95 % CI
1.21–3.22) compared to regular drinkers (Ruidavets et al. 2010).
Other earlier studies that have found a protective effect for daily light to
moderate drinking have found no such protective effect, or even detrimental effects,
for individuals who report occasional heavy drinking even if their usual pattern was
moderate consumption (Rehm et al. 2003). In addition, evidence is emerging
linking infrequent consumption with high-volume drinking occasions (Naimi
et al. 2013). A recent study showed that of a group of individuals who reported
low average consumption overall, those who drank less frequently were more likely
to drink at higher levels associated with increased risk (Naimi et al. 2013). Thus,
any protective effects of low average consumption may be reversed or nullified by
this pattern of binge drinking (Naimi et al. 2013).
There are some problems with the literature in this area. Variability in the
definition of irregular heavy drinking occasions, and in the methods used to identify
or report relative risk estimates, results in significant levels of heterogeneity in
meta-analyses of existing studies (Roerecke and Rehm 2010). However, on bal-
ance, the overall consensus from the literature is that any putative cardioprotective
effect of alcohol consumption is strongly influenced by the pattern and volume of
consumption.
This evidence for increased cardiovascular risk with heavy alcohol consumption
needs to be taken in the context of the significant burden of morbidity and mortality
from other causes arising from binge drinking and from long-term heavy consump-
tion. A thorough discussion of such harms falls beyond the scope of this chapter.
Briefly, short-term harms from drinking to intoxication include intentional and
unintentional injury (such as road traffic accidents, falls, or drowning), violence,
and elevated risk of suicide (WHO 2011). Long-term harms include the risk of a
number of cancers, pancreatitis, liver cirrhosis, fetal alcohol syndrome, alcohol-
related brain injury, and alcohol dependence (Corrao et al. 2000; Costanzo
et al. 2010a; Parry et al. 2011; Rehm et al. 2009).
All studies investigating the relationship between alcohol and cardiovascular risk
are observational in nature, and thus subject to a number of limitations. Firstly, they
are unable to prove direct causation between variables of interest. Secondly, such
studies need to adequately account for a range of confounding factors that may play
a role in the association being investigated. In the case of alcohol and cardiovas-
cular risk, there are myriad confounding factors that may not be able to be
adequately assessed and controlled for, including social, cultural, and economic
variables. Finally, the literature in this field has often come under criticism for the
heterogeneity prevalent in the definitions used and the measurement of variables in
different studies. This leads to inherent difficulties in consolidating evidence for
meta-analyses.
In this section, some of the limitations of this evidence and proposed challenges
to the classical “J-shaped” relationship between alcohol consumption and cardio-
vascular risk will be examined.
Many of the prospective studies in this field classify “former drinkers,” who have
decreased or terminated their drinking, as abstainers. However, many individuals
may decrease or terminate their alcohol consumption as they age due to illness or
increasing medication use – that is, they would be considered “sick quitters”
(Shaper et al. 1988). These individuals may thus be at increased risk of developing
cardiovascular disease by virtue of their ill health rather than their reduction in
alcohol use. Shaper and colleagues suggested that including these people in the
“abstainer” comparison group resulted in a systematic misclassification error in
studies, which would bias findings toward an overestimation of protective effects
and an underestimation of detrimental effects of alcohol consumption (Roerecke
and Rehm 2011; Shaper et al. 1988). This misclassification can arise from a range of
Alcohol and Cardiovascular Risk 129
errors in studies, from the actual inclusion of former drinkers in the abstainer
category to inconsistencies in the assessment and measurement of alcohol intake
(Fillmore et al. 2007).
The impact of this misclassification has been tested in a number of meta-
analyses that sought to remove former drinkers and “sick quitters” from the
reference group. Fillmore and colleagues’ meta-analysis was rigorous and
attempted to address a number of errors in classification, which resulted in only a
small number of studies for analysis (Fillmore et al. 2006). In the final seven studies
analyzed, the evidence failed to confirm a J-shaped relationship between alcohol
consumption and cardiovascular events (Fillmore et al. 2006).
A more recent meta-analysis compared differences in ischemic heart disease
morbidity and mortality risk between former drinkers and long-term abstainers and
found that former drinkers had a significantly elevated risk of ischemic heart
disease mortality compared to long-term abstainers (Roerecke and Rehm 2011).
These authors went on to conduct a meta-analysis excluding former drinkers from
the reference category. While they found a trend to cardioprotective association
between low to moderate alcohol consumption and a number of ischemic heart
disease outcomes for both sexes, they stated that all models of the analysis showed a
significant level of unexplained heterogeneity (Roerecke and Rehm 2012). Thus,
while their results supported a cardioprotective effect of moderate alcohol con-
sumption, the authors highlighted that these findings were subject to inconsistencies
in the studies themselves, including lack of control for a variety of confounding
factors (Roerecke and Rehm 2012).
Finally, Ronksley and colleagues attempted to analyze the relationship between
alcohol intake and a number of cardiovascular outcomes (Ronksley et al. 2011).
Their results suggested that “former drinkers” had a significantly higher risk of
cardiovascular mortality in comparison to “current drinkers” (Ronksley et al. 2011).
However, they found that removing “former drinkers” from the reference category
did not make a “substantive difference” to the risk reduction estimates for mortality
or incident disease. Other authors have criticized these findings, feeling that studies
of inadequate rigor or statistical quality were included in the analysis (Stockwell
et al. 2012).
In summary, a number of meta-analyses have tried to study the impact of the
“sick quitter” effect, but their endeavors have been limited by the quantity and
quality of the studies conducted to date.
When studying an association between a risk factor and an outcome, the only
difference between the two groups being examined should ideally be the presence
or absence of the risk factor. Therefore, in this field, comparison and reference
groups should only differ in their level of alcohol consumption, with adjustments
130 S. Arunogiri and D. Lubman
made to account for all other variables. In particular, it is crucial that confounding
factors that may play a role in the outcome of interest are adjusted for.
However, there is growing evidence that there are a range of lifestyle factors that
are independently associated with an elevated risk of cardiovascular disease that
may occur more frequently in nondrinkers or lifetime abstainers; that is, light and
moderate drinkers have healthier lifestyles (Fekjaer 2013). For instance, Hansel and
colleagues found that moderate male drinkers were more likely than lifetime
abstainers to have characteristics associated with lower cardiovascular risk –
including lower BMI, heart rate, pulse pressure, fasting glucose, fasting triglycer-
ides, stress, and depression scores and better subjective health status, respiratory
function, social status, and physical activity (Hansel et al. 2010). Many of these
factors are not causally associated with alcohol consumption. The authors’ analysis
suggested that moderate and low drinkers had better health status than never-
drinkers (Hansel et al. 2010).
Other studies support these conclusions (Hansel et al. 2012). Naimi and col-
leagues conducted a US-based telephone survey to assess the prevalence of a range
of cardiovascular risk factors in moderate drinkers versus never-drinkers (Naimi
et al. 2005). These included factors such as health access, behavioral factors, social
factors, comorbid health conditions, and demographic factors (Naimi et al. 2005).
They found that 90 % of the risk factors they assessed were significantly more
prevalent among nondrinkers (Naimi et al. 2005).
Of note, many studies do not comprehensively or adequately account for these
factors. Many studies adjust for one or two factors, such as age or “socioeconomic
status”; however, residual confounding can still occur in such studies (Hansel
et al. 2012). Indeed, in one of the few studies to assess the impact of alcohol
consumption in tandem with physical activity, it was found that low physical
activity played a greater role in increasing cardiovascular risk than heavy drinking
(Soedamah-Muthu et al. 2013).
Thus, it may be possible that moderate alcohol consumption does not cause
cardioprotection but rather occurs in tandem with other healthy behaviors within
healthy individuals. While moderate drinkers may have a lower risk of cardiovas-
cular disease, whether this lowering of risk is due to alcohol remains to be seen.
Studies that demonstrate a peak cardioprotective effect at one to two standard
drinks per day may actually reflect that other beneficial factors possibly peak at
or around these levels of alcohol consumption (Fekjaer 2013). As some authors
have suggested, “moderate alcohol consumption may represent a marker of higher
socioeconomic status, superior health status and lower cardiovascular risk” (Hansel
et al. 2010).
A common limitation of the majority of the existing literature in this field is the use of
self-report measures of alcohol consumption. While self-report drinking measures
Alcohol and Cardiovascular Risk 131
have been shown to have reasonable reliability for most research purposes (Del Boca
and Darkes 2003), there are particular aspects of research in this area that may impact
on their validity, for example, the role of social context (Del Boca and Darkes 2003).
This includes factors such as the assessment setting (a treatment facility, versus a
household survey) and the immediate interpersonal situation – research or treatment
staff, other staff, family members, and bystanders (Del Boca and Darkes 2003) – as
well as the perceived social or cultural norms within the population. This is partic-
ularly salient in this area of research – for instance, a measure of consumption within
a treatment setting, shortly after an individual has suffered a cardiac event, may result
in a response influenced by the social desirability and expectation, leading to a level
of response bias (Del Boca and Darkes 2003).
In addition, most of the epidemiological studies in this field have only col-
lected measures of alcohol at baseline. For example, none of the cohort studies
included in one large systematic review of binge consumption assessed alcohol
more than once at baseline (Roerecke and Rehm 2010). This can lead to a
fundamental misclassification of the status of individuals (as drinkers versus
nondrinkers) when considering exposure to alcohol and not accounting for
changes in the level of consumption over time (Hansel et al. 2012). Furthermore,
few studies incorporate an assessment of instances of heavier consumption or a
measure of patterns of consumption, and may thus be misclassifying individuals
who usually drink at low to moderate levels but also have frequent binge or
heavier alcohol intake (Hall 2012; Roerecke and Rehm 2012). Finally, substantial
variability in both the measures used, and in the reporting of relative risk esti-
mates, also contributes to heterogeneity between studies in this area and limits
the ability to consolidate data for meta-analysis (Roerecke and Rehm 2010)
(Figs. 1 and 2).
Pathophysiological Mechanisms
1.0 1.0
relative risk
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0 0
ne
r
nal .99 .99 .99 ne
r
na
l
.99 .99 .99
i tai
sta a sio −1 1
− 2 3
− 3 5
s a sio − 11 − 23 −35
ab Oc
c 2.5 12 24 ea
b
Oc
c 2.5 12 24
ti me t im
L ife if e
Alcohol intake (g/day) L Alcohol intake (g/day)
1.0 1.0
relative risk
0.8 0.8
0.6 0.6
0.4 0.4
0.2 0.2
0 0
er al 9 9 9 r
na
l
.99 9 9
in n .9 .9 .9 ine 3.9 5.9
sta sio − 11 23 35 ta as
io
−1
1
−2 −3
ab cc
a
2.5 2− 24
− bs cc 2.5 12 24
e O 1 ea O
e tim e tim
Lif Alcohol intake (g/day) Lif Alcohol intake (g/day)
Fig. 2 Relationship between alcohol intake and IHD morbidity and mortality, stratified by gender
(Redrawn from Roerecke and Rehm 2012, Thompson 2013)
for 2–4 drinks a day, and 0.14 mmol/L for 4 drinks a day (Brien et al. 2011). This
study concluded that consumption of 30 g of alcohol per day (three standard drinks)
would increase HDL-C by about 8.3 % (Brien et al. 2011). This effect appeared to
be particularly strong in men, in sedentary patients, or in individuals with a low
baseline HDL-C (Brien et al. 2011; Rimm et al. 1999).
While there is strong evidence for this relationship between changes in alcohol
consumption and HDL-C concentration, it remains unclear whether this translates
into a direct reduction in cardiovascular risk. For instance, the Russian population
has an average high consumption of alcohol and also has a higher average HDL-C
compared to other countries, but has higher age-adjusted rates of cardiovascular
disease (O’Keefe et al. 2007). Other studies have also found that the impact of
alcohol on the risk of mortality from coronary heart disease is not affected by
adjusting for HDL-C (Magnus et al. 2011). Conversely, some studies suggest that
pharmacologically increasing HDL-C does not affect vascular risk in patients at
high risk for coronary events (Costanzo et al. 2010b).
Alcohol and Cardiovascular Risk 133
• CRP
• IL-6
Thus the direct effect of alcohol on increasing HDL-C should not be considered
to entirely account for any cardioprotective role of alcohol – this effect is believed
to account for approximately 50 % of the reduced CHD risk (Criqui and Ringel
1994; Gaziano et al. 1993).
Other Mechanisms
Alcohol is the third largest risk factor for disease and disability worldwide (WHO
2014). In 2012, about 3.3 million deaths (or 5.9 % of all global deaths) were
attributable to alcohol consumption, with alcohol contributing to 5.1 % of the
global burden of disease and injury (WHO 2014). Globally, alcohol contributes to
14 % of all cardiovascular and diabetes-related deaths (WHO 2011). Analyses in
134 S. Arunogiri and D. Lubman
Conclusions
Decades of research have been conducted on the links between alcohol consump-
tion and the risk of cardiovascular disease. The literature contributes to our under-
standing in a number of key areas. Firstly, there appears to be an association
between low to moderate levels of alcohol consumption and lower levels of
cardiovascular disease. This is particularly true of risk reduction for ischemic
heart disease. However, there are a wide range of confounding factors and meth-
odological limitations that apply to the existing literature, which means that this
association cannot be considered to be causal in nature. Secondly, excessive alcohol
136 S. Arunogiri and D. Lubman
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Part II
Stress, Psychopathology, and Cardiovascular
Disease
Stress: Concepts, Models, and Measures
Contents
Introduction Theories, Definitions, and Concepts of Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
The Stress Concept and the Development of Understanding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
The Cannon-Selye Tradition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Perception, Cognition, and Psychological Appraisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Tend-and-Befriend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
The Conservation of Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
The Psychobiology of Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Measuring Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Physiological Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Self-Report Life Event Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Daily Hassles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Theoretical Models for How Stress Affects Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Coping with Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Coping Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Stress and its Linkage to CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Abstract
Most people harbor some perception of the word “stress.” When one hears someone
mention that they are “under a lot of stress,” one has a certain idea of what they mean
and experience. Indeed, the word “stress” infuses everyday conversations, providing
a term with rich subtexts that explain innumerable problems, ailments, and illnesses
of unknown origins. Links between hypertension and stress have for many years
constituted the archetypical example of the causal relation between physiological
(or clinical) and psychological phenomena. Stressors, both mental and environmen-
tal, are today readily identified and reproduced, and one of the most active areas in
psychosomatic research has been the investigation of cardiovascular reactivity to
mental stress. This chapter addresses the development of various concepts of stress
ranging from those of the ancient Greeks to today, as well as how to operationalize
and measure stress. Furthermore, the chapter describes models of stress development
and how to understand the role of stress in association with health. In this regard, the
chapter also focuses on the role of coping and coping resources that influence the
stress-health relationship. At the end of the chapter, stress is demonstrably linked to
the development of coronary heart disease (CHD).
Keywords
Cannon, Walter • Conservation of Resources (COR) model • Coronary heart
disease (CHD) • Diathesis-stress model • Family Heart Study • Galenus, Clau-
dius • General adaptation syndrome (GAS) • Hardiness • Hassles Scale • Hypo-
thalamic-pituitary-adrenal (HPA) cortical axis • Osler, William • Perceived Stress
Scale (PSS) • Psychological stress • Resilience • Schedule of Recent Experiences
(SRE) • Self-esteem • Selye • Sense of coherence (SOC) • Social Readjustment
Rating Scale (SRRS) • Social support • Stockholm Female Coronary Risk Study •
Stress • Cannon-Selye tradition • Coping resources • Definition • Perception,
cognition, and psychological appraisal • Physiological measures • Psychobiology
of stress • Risk factors • Self-report life event scales • Stress-exposure model •
Stress-generation model • Tend-and-befriend • Tend-and-befriend • Uplifts Scale
Stress is a physical or emotional response to strain, and the human behavior it gives
rise to has puzzled researchers for more than a thousand years. The first extant
reports of stress’s behavioral impact are most commonly traced to the Roman
medical doctor Claudius Galenus (129–200AD) (often referred to as Galen in
modern texts). A young woman experiencing various inexplicable physical disease
symptoms made an appointment with Galen, who examined the woman and found
no physical cause for the symptoms she described. During this examination, a person
standing nearby began to talk about a young and stunning dancer named Phylades
that he had seen dancing on one of the city’s stages. At the mention of this dancer’s
name, the young woman’s pulse suddenly became rapid and uneven. Galen uttered
Stress: Concepts, Models, and Measures 145
the name of several other dancers, without any observable effect. From this, Galen
surmised that the young woman’s unease was directly attributable to her uncon-
scious love for the dancer Phylades. Though earlier descriptions exist of both the
psychological implications for physical conditions, and the physical impact on
psychological states, Galen’s observation represents the first known observation of
a stressful emotional state’s impact on and cause of alternations in physical health.
In modern times, some of the earliest and best descriptions of the same stem from
Sir William Osler’s studies on the impact of psychological strains on the human
heart, and as we will soon see, from Walter Cannon’s well-known studies of
psychological and physiological disequilibrium.
But what then is stress? How is it defined? What is the uniquely modern concept
of stress, and how did we get there? How is the phenomenon best described? And,
importantly, how can it be measured?
Stress is often defined as the physical and psychological result of internal or external
pressures. Research has linked stress to more diseases than any other biopsycholog-
ical factor. In particular, stress has been connected to the development of CHD.
Researchers have been studying stress and its impact on psychological and physical
health for several decades. Contributions to the understanding of stress have come
from basic neuroscience and biology, as well as from psychology, epidemiology,
sociology, and anthropology (Monroe 2008). This broad and multilevel mandate for
stress research has given rise to diverse approaches and much debate over the most
appropriate ways to define, conceptualize, and measure life stress. Separate research
traditions have emphasized different facets of the general topic of stress. One
common characteristic of all such definitions is the focus on environmental circum-
stances and on conditions that threaten, challenge, exceed, or harm the psychological
or biological capacities of the individual (Grant et al. 2004). In this sense, all
definitions of stress include an environmental component. These definitions differ,
however, in the degree to which they emphasize physiological and psychological
processes that occur in response to the environmental stressors (Grant et al. 2003).
Research has identified stress as a precursor for the development of other risk
factors, particularly hypertension and lipid levels. In recent years, researchers have
questioned whether stress is caused by a uniform kind of strain, whether stressors are
all the same, and finally, whether stress has the same consequences for both sexes
(Weidner et al. 1997, 2001; Taylor et al. 2000).
The term “stress” is loosely borrowed from the field of physics. Humans, it is
thought, are in some ways analogous to physical objects like metals that resist
moderate outside forces but lose their resiliency at a certain point of greater pressure.
146 U.K. Moksnes and G.A. Espnes
Cannon (1932) was likely the first modern stress researcher to apply the concept of
stress to humans in these physical terms, and he was principally concerned with the
effects on organisms of cold temperatures, a lack of oxygen, and other environmental
stressors. Cannon proposed that when an organism perceives a threatening stimulus,
the organism’s emotional and physiological homeostasis is rapidly aroused and
motivated via the sympathetic nervous and endocrine systems (Fleming
et al. 1984). This physiological activation results in a fight-or-flight response,
which means that the organism either mobilizes to attack the threat or, alternatively,
to flee. In this view, stress is a threat response directly related to survival and
adaptation. Cannon concluded that while organisms might be capable of withstand-
ing initial and low levels of stressors, prolonged exposure to severe stressors leads to
the breakdown of biological systems (Fleming et al. 1984; Taylor et al. 2000).
Alongside Cannon whose work he followed, Selye (1974) is also a prominent person
in stress research. Like Cannon, Selye’s basic understanding of stress was oriented
toward the threat to an organism’s homeostasis, but focused to a greater degree than
Cannon on a person’s emotional and physiological response to stressors, which refer to
the environmental conditions that elicit stress. Selye also employed the word strain to
describe the individual’s emotional and physiological reactions to stress. Significantly,
he also suggested that stress is not necessarily a negative factor to be avoided; in fact, a
distinction can be made between positive stress (eustress) and negative stress (distress).
In either case, the demand for coping resources is the same (Selye 1974, 1979).
Selye’s contributions to stress research included a concept of stress and a model
for how the body defends itself in stressful situations. According to Selye (1982,
p. 22), stress represents the nonspecific result of any demand upon the body. The
notion of a “nonspecific” response derives from the claim that all stressors, regard-
less of type, produce essentially the same pattern of physiological responses, namely,
an enlarged adrenal cortex, shrinking of the thymus and lymph glands, and ulcera-
tion of the stomach and duodenum. Over time, with repeated or prolonged exposure
to stress, the system experiences wear and tear. Based on these observations, Selye
(1956) developed his concept of the general adaptation syndrome (GAS).
The GAS consists of three stages: the alarm stage, the resistance stage, and the
exhaustion stage (Selye 1956, 1974, 1979, 1982). The alarm reaction refers to the
fight-or-flight response, in which case the organism is mobilized to meet the threat.
During the alarm stage, the body’s defenses against a stressor are mobilized through
activation of the sympathetic nervous system. In the second, resistance stage, the
physiological reactions of the alarm stage mobilize energy in order to adapt to or
overcome the stressor and obtain homeostasis. The length of this stage depends on the
severity of the stressor and the adaptive capacity of the organism. If the organism can
adapt, the resistance stage will continue for a long time. However, continuous stress
will cause neurological and hormonal changes, which pose risks for the development
of various diseases including peptide ulcers, ulcerative colitis, hypertension, and
cardiovascular disease. The third stage, that of exhaustion, is the result of long-
lasting resistance that has sapped the body’s energy reservoir, resulting in breakdown.
This collapse often results in death. Presumably, this only occurs when the threats
persist or are repeated often enough to overwhelm the organism’s ability to resist.
Stress: Concepts, Models, and Measures 147
This theory implies, first of all, the cumulative nature of the effects of stress. That
is, damage produced by stressors accumulates over time. Secondly, these effects are
involved in serious pathology when they overwhelm one’s ability to cope. Finally,
stress may be additive – because the body responds similarly to different threats, an
individual’s reaction to a threat will be augmented by his or her exposure to previous
threats.
Selye has been criticized on two levels. Firstly, a wealth of data challenge the
notion that humans react uniformly to stress. The manner in which individuals
respond to challenges in their environment can be understood as a function of
their personality, constitution, perceptions, and the context in which stressors
occur. Secondly, Selye has been criticized for employing somewhat illogical deduc-
tive reasoning; he depicted stress in terms of outcome, such that an organism could
be seen as under stress only during a phase of the general adaptation sequence
(Brannon and Feist 2007).
A third view of stress emphasizes the cognitive appraisal of a stressful situation and
deems the mediating role of psychological processes between environmental events
and the organism’s response more important than the stressful event itself (Fleming
et al. 1984; Monroe 2008). Implied here is the view that stress is not the product of an
imbalance between objective demands and response capacity, but rather of the
perception of these factors. In addition, the consequences of failing to cope are
perceived by the individual as important. Thus, stress is here described as the
subjective experience of pressure, implying an evaluation of the outcome of a
cognitive process. This view focuses on the degree and type of the challenge, threat,
harm, or loss, as well as on the individual’s perceived abilities to cope with such
stressors (Lazarus and Folkman 1984). The most widely accepted definition of
stress, the transactional definition offered by Lazarus and Folkman (1984), accords
with this focus on subjective experience: “Psychological stress involves a particular
relationship between the person and the environment that is appraised by the person
as taxing or exceeding his or her resources and endangering his or her well-being”
(p. 19). Accordingly, stress is subjective by nature, as it involves an appraisal of
individual experiences.
Lazarus and Folkman (1984) recognized that people use different types of
appraisal in their assessments of a situation. The individual initially appraises the
event itself – this is the primary appraisal – and identifies the event as (1) irrelevant,
(2) benign positive, or (3) stressful. In the course of a primary appraisal of stressful
circumstances, a secondary appraisal is initiated whereby an individual assesses their
own coping abilities and resources, i.e., whether they will be sufficient to meet the
harm, threat, or challenge of an event. Ultimately, the subjective experience of stress
is a balance between primary and secondary appraisals. The third type of appraisal is
reappraisal, which is necessitated by the fact that appraisals change constantly as
new information becomes available. Reappraisal does not always result in more
148 U.K. Moksnes and G.A. Espnes
Tend-and-Befriend
In spite of the fact that the human stress response has often been characterized as one
of fight-or-flight, Taylor et al. (2000) have proposed a theory that constitutes a
biobehavioral alternative to the fight-or-flight response. Taylor et al. (2000) maintain
that as a result of gender differences in the stress response, human female responses
are better characterized by a pattern termed “tend-and-befriend.” Tending involves
nurturing activities designed to protect the self and offspring that promote safety and
reduce distress, and befriending is the creation and maintenance of social networks.
Stress: Concepts, Models, and Measures 149
Perceived threat or
challenge
Stress
response
(strain)
Autonomic Subjective
hyperarousal distress
(physiological) (experiential)
Many of the prominent stress theories have been criticized for not addressing the
positive aspects of stress. One exception is the Conservation of Resources (COR)
model introduced by Hobfoll (1989), which encompasses several theories of stress,
but also extends these theories by employing a resource perspective. Hobfoll (1989)
presented this stress model as an attempt to bridge the gap between environmental
and cognitive viewpoints. The model’s basic tenet is that individuals strive to retain,
protect, and build valued resources, the potential or actual loss of which is threaten-
ing. These resources are those objects, personal characteristics, conditions, or ener-
gies that are valued by the individual or that serve as the means for attaining these
objects, personal characteristics, conditions, or energies (Hobfoll 1989). According
to this model, stress occurs when resources are lost or threatened. Therefore, when
confronted with stressors, individuals will strive to minimize net loss of these
resources, and when not stressed, individuals will develop resource surpluses in
150 U.K. Moksnes and G.A. Espnes
order to offset the possibility of future loss. The COR model expands upon previous
stress models by not only describing what individuals do when confronted with
stress but in the absence of threats, as well.
The model of stress and strain is derived from material technology. Though these
phenomena have been recognized for more than two millennia, we have developed
the theoretical concepts from the description of what goes on when a metal bar
gives in under the weight of heavy strain. As shown earlier in the chapter, this
strain/stress concept was eagerly adopted in the early twentieth century by phys-
iological and psychological researchers who focused on what happens when
straining situations like diseases or other damages are imposed on the body.
Therefore, the signs of stress that we have thus far demonstrated are a mixture of
physiological (biological) and psychological symptoms. But the term stress is now
more often employed to describe situations on an individual level, or even on the
social level, rather than to merely describe challenging situations to the body
(Caltabiano et al. 2008).
Everyone experiences stressful situations in their day-to-day lives. Examples
might include an exam, a near accident, an actual accident, etc. What is clear
in the experience of stress is the fact that it is not only a psychological experi-
ence; rather, in stressful situations, one’s whole system (all the component
physiological and psychological systems) is activated in order to alert the
whole organism and allow for the allocation of resources to the part of
the organism most capable of addressing the situation. A stressful situation
activates the whole range of our biological systems and prepares the body for
problem solving, a process often referred to as the physiological arousal.
The table below describes the most evident physiological symptoms of bodily
arousal that prepare the body and allocate resources during a stressful situation
(Table 1).
Measuring Stress
Given the breadth of the concept of stress and the differing views as to its nature, it is
no surprise that a variety of measurement approaches exist. Methodology surround-
ing the measurement of stress has long been controversial, and this applies just as
strongly to the case of adolescent studies as it does to the more widely researched
area of adult stress. There are some basic ways to assess stress: one can assess
physical arousal, survey or interview individuals as to their life events, or assess the
daily hassles that people experience (Monroe 2008).
Physiological Measures
The vast majority of human life stress studies have assessed recent major events in
the lives of individuals. Since the late 1950s and early 1960s, researchers have
developed a number of self-report instruments to measure stress. Though the relative
merits of interview versus inventory (self-report) approaches have been debated in
the case of both adult and adolescent groups, the use of inventories clearly saves both
152 U.K. Moksnes and G.A. Espnes
time and labor and increases the respondents’ anonymity (Byrne et al. 2007; Grant
et al. 2004). A further strength of the life event inventories as measures of stressor
load is illustrated by the fact that the items included on the instruments represent a
fairly wide range of stressful events. Such scales assign to each event a value that
reflects its stressor intensity (Monroe 2008). The earliest and best known of these
self-report procedures is the Schedule of Recent Experiences (SRE) developed by
Hawkins, Davies, and Holmes (1957) and the Social Readjustment Rating Scale
(SRRS) by Thomas H. Holmes and Richard Rahe (1967; Dohrenwend 2006). These
and other derivative self-report checklists include a range of relatively common life
experiences that assumedly assess varying degrees of adjustment or implicit life
stress. The SRRS, for instance, consists of a list of 43 life events arranged in rank
order from the most to the least stressful. The SRRS does not assess whether the
changes have been positive or negative, welcomed or unwelcomed, expected or
unexpected. Vague or ambiguous items reduce the precision of an instrument and the
likelihood of its correlation with other variables (Monroe 2008). As presented by
Byrne et al. (2007), the self-report debate also raises the issue of whether to focus on
stimulus versus process or response approaches to the measurement of stress. In line
with such a debate, the SRRS and other life event inventories have been criticized for
their inclusion of life events that may be confounded with measures of illness.
Alternative checklists for the assessment of life events have also been developed.
The Perceived Stress Scale (PSS) (Cohen et al. 1983) emphasizes an individual’s
perception of events. The PSS is a 14-item scale that assesses three components of
stress – daily hassles, major events, and changes in coping resources – and attempts
to measure the degree to which individuals appraise situations as “unpredictable,
uncontrollable, and overloading.”
A considerable body of research has directly compared life event checklist
measures with interview-based measures. Although the procedures across different
studies vary with regard to the specific life event checklist and interview method
used, findings consistently point to significant differences in the respective informa-
tion obtained by the two methods. Interviews are designed to elicit details of what
actually happened in order to furnish narratives that can be then rated by trained
investigators according to severity and other important characteristics. More gener-
ally, reviews of the life event literature nearly unanimously conclude that interview-
based measures represent the current gold standard for assessing life stress
(Dohrenwend 2006; Gorman 1993; Hammen 2005; Kessler 1997; Mazure 1998;
Paykel 2001).
Checklist measures of life events are, by contrast, the traditional and dominant
procedure for collecting data and are also the method most frequently employed for
assessing stressors affecting children and adolescents. Though the checklists vary
with regard to their respective width and depth, the general checklists are all similar,
as they present respondents with a sample of negative and, in some cases, positive
events that are representative of stressful experiences in childhood and adolescence.
Researchers have made some advances in the development and refinement of general
stressor checklists for adolescents (Bagley 1993; Cheng 1997; Compas et al. 1987;
Masten et al. 1994; Newcomb et al. 1981; Swearingen and Cohen 1985; Yeaworth,
Stress: Concepts, Models, and Measures 153
York, Hussey, Ingle, and Goodwin 1980), but less progress in the development of
checklists for children (for a review, see Grant et al. 2004). Measures for adolescents
have ranged from 39 to more than 200 items, the latter of only limited use in large
sample studies of adolescent stress and health. Other stressor checklists used for
stress measurement in younger age groups have been derived from existing inven-
tories of adult stressors. However, this approach is unsuccessful because it indirectly
equates stressors common in adult life with those central to adolescence, leaving
unmeasured certain important areas of adolescent stress.
Researchers typically develop specialized stressor checklists with two related
issues in mind: the need for measures specific to particular populations and the
need for measures specific to certain types of events. With some notable exceptions,
measures of cumulative life stressors have been hitherto largely based on European
and American middle-class samples. These measures have drawn criticism for
ignoring items pertinent to individuals of other ethnic and social groups, particularly
those living in disadvantaged urban communities (Grant et al. 2004).
Daily Hassles
Many of the life events assessed by psychological instruments are rare in occur-
rence and spread out over the life span. Most inventories attempt to assess stressful
life events with traditional checklists that consist of relatively broad life event
categories, such as those in the SRRS. However, some more recent investigators
have employed checklists that assess “daily hassles” or those stresses that result
from minor incidents in everyday life (Caltabiano et al. 2008; Monroe 2008).
These ongoing stressors that are a constant feature of our lives may be just as – if
not more – damaging to our health than those major life events that occur with less
frequency. As a consequence, Richard Lazarus and his associates developed the
original Hassles Scale, which consists of 117 items ranging from the merely
annoying, irritating, or frustrating ways in which people feel hassled to more
major problems and difficulties (Kanner et al. 1981). The subjects indicate which
hassles occurred in the past month and identify each event as “somewhat,”
“moderately,” or “extremely” severe. A companion inventory called the Uplifts
Scale was designed on the basis that desirable experiences make hassles more
bearable and thereby reduce their impact on health (Brannon and Feist 2007;
Monroe 2008). Administered along with the Hassles Scale, the Uplifts Scale
provides a list of events that might make a person feel good. In addition to
checking hassles or uplifts from the past month, respondents also rate the degree
of each on a three-point scale. This second assessment is consistent with Lazarus’
view that an individual’s perception of their stress is more crucial than the
objective event itself.
Three common aspects arise in the debate regarding the appropriate methods for
life stress measurement. The first concerns memory and the ability of individuals to
recall life events (Grant et al. 2004). Somewhat surprisingly, with the proper
structuring of questioning, individuals can remember reasonably well. The second
154 U.K. Moksnes and G.A. Espnes
issue of debate relates to the formal definition of a life event. Monroe (2008)
suggests that individuals quite often interpret life event descriptors in highly per-
sonal ways and that this is a major problem of self-report checklists. Thirdly,
research participants draw upon a number of additional sources of background and
contextual information when recalling and evaluating stressors. Recognition of these
aspects brings into focus just how readily stress measures are influenced by extra-
neous information or confounded by subjective bias.
It is a widely held notion that stressful and negative life events play an important role
in the development of many psychological and physical problems. Researchers have
proposed various models to explain how stress may lead to negative health outcomes
in the lives of all people, including adolescents.
The stress-exposure model conceptualizes stress as causing maladaptive behavior
and negative health outcomes by arguing that a preponderance of stressful life events
or perhaps one major stressful life event (e.g., death of a family member) could
precede and contribute to an individual becoming depressed or exhibiting maladap-
tive behavior (Hankin Mermelstein and Roesch 2007). In this regard, stress-
exposure models highlight the environmental context of an individual’s life and
more specifically the effects that stressful environments can have on the lives of
young people and adults. Coping resources may be overwhelmed by the experience
of multiple changes in close proximity, thus causing the internalization of symptoms
or the maladaptation of behavior (Graber and Sontag 2009; Rudolph 2002). In
essence, the experience of stressful events and their timing, as well as the increased
likelihood that certain events will occur, are the critical factors predicting negative
health outcomes in this model.
The stress-generation model focuses on a greater awareness of the complex and
reciprocal relation between stress and maladaptive behavior and emotions (Cole
et al. 2006). Influenced by the salience of interpersonal vulnerabilities and pre-
cipitants in depression, it is employed specifically in relation to depression. That
is, while the traditional stress-exposure model very much remains an important focus
of research, increasing consideration has also been given to a complimentary and
similarly important process, whereby depression-prone individuals are not simply
passive respondents to stressful events in their lives, but active agents in the creation
of depressogenic life stressors (Hammen 2006).
The diathesis-stress model postulates that major transitions or negative events
interact with prior vulnerabilities to psychopathology and result in increased prob-
lems or poor outcomes in the face of stressors (Graber and Sontag 2009). According
to this model, individuals with certain negative prior vulnerabilities (e.g., poor
emotion regulation skills, depressogenic cognitive styles, genetic markers) are
disproportionately – or even exclusively – likely to be affected when they experience
stressful life events (Hankin and Abrahamson 2001).
Stress: Concepts, Models, and Measures 155
The manner in which individuals respond to and deal with stress contributes
crucially to stress’ impact on their physical, emotional, and psychological well-
being. Lazarus and Folkman (1984) provide an oft-used definition of coping as
“constantly changing cognitive and behavioral efforts to manage specific external
and/or internal demands that are appraised as taxing or exceeding the resources of
the person” (1984, p. 141). Coping is thus understood as an ongoing process that
responds dynamically to the changing demands of a stressful encounter or event.
These efforts can be both action oriented and intrapsychic; they seek to manage,
tolerate, reduce, or minimize the demands of a stressful situation (Lazarus and
Launier 1978, see Taylor and Stanton 2007). As a dynamic transactional process
with the environment, the coping process is therefore substantially influenced by an
individual’s subjective appraisal of the stressful situation.
According to Lazarus and Folkman (1984), coping can serve two main functions:
coping can change or alienate the problem that has given rise to the experience of
stress or it can regulate the emotional response to that problem. Problem-focused
coping aims to reduce the demands of a stressful situation by recourse to action, e.g.,
to quit one’s job, learn new skills, or seek help from a professional. Individuals tend
to employ problem-focused approaches when they believe the necessary resources
are available. Emotional-focused coping focuses on changing one’s own emotional
response to a stressful situation, either emotionally or cognitively, and is often used
in situations in which individuals believe they do not possess the adequate resources
to meet the demands of the stressor. Examples of emotional-focused coping strate-
gies include seeking emotional support from friends and family and engaging in
activities that distract or suppress/refuse one’s attention, e.g., drinking alcohol, being
physically active, or watching a movie. Cognitive approaches emphasize and
involve redefinition of the manner in which individuals think about stressful situa-
tions. Examples are illustrated by such statements as: “now that I’ve got this chronic
disease, I must try to think positively” or “now that I’ve lost my job, I realize that I
can find one that I really like” (Lazarus 1999; Lazarus and Folkman 1984; Taylor and
Stanton 2007).
Coping Resources
assistance and obligations. Research has demonstrated that during periods of stress,
social support can reduce the likelihood of psychological problems like depression
or anxiety and promote psychological adjustment to a broad array of chronically
stressful conditions (Taylor and Stanton 2007). Social support can influence the
stress response in several different ways. In one broad type of instance, a social
support network might allow a stressed individual to gain confidence in his or her
ability to handle stressful situations; thus, when experiencing stress in the future, this
individual might appraise the stressor as less threatening than one would who
possessed fewer coping resources.
Resilience is defined as the achievement of a relatively good outcome despite the
experience of situations known to carry significant risks for the development of
psychopathology (Luthar et al. 2000). Resilience is thus not the mere absence of risk,
but rather the presence of protective factors or processes that buffer the effects of
adversity. This protection may be the result of individual factors, environmental
factors, or interplay between the two. Much of the interest in resilience research is
related to the potentially modifiable nature of resilience factors. Studies have found
that resilience is a significant predictor of mental health and an effective stress buffer
in relation to psychiatric symptoms (Friborg et al. 2006; Hjemdal et al. 2006).
Self-esteem encompasses an individual’s set of thoughts and feelings about his or
her own worth and importance (Rosenberg 1965), referring to one’s “global” or
“general” self-worth. Decades of theory and research have underscored the impor-
tance of self-esteem by demonstrably linking its positive role in relation to psycho-
logical health and well-being. Furthermore, many consider low self-esteem an
important factor in relation to symptoms of depression (Orth et al. 2009; Sowislo
and Orth 2013). Particularly, when faced with stressful events, individuals with low
self-esteem are seen to possess fewer coping resources and are therefore more
vulnerable to the development of psychological symptoms, whereas those with
high self-esteem are buffered against this effect. According to Orth et al. (2009),
“following stressful events, protective factors such as high self-esteem may prevent
the outcome of depressive symptoms by decreasing the negative impact of
depressogenic thoughts on the affective, cognitive, behavioural, and physiological
symptoms of depression” (p. 308). However, previous research that has tested the
moderating effect of self-esteem has yielded inconsistent results, highlighting the
urgent need for further investigation on this issue (Abela et al. 2006; Orth
et al. 2009).
Sense of coherence (SOC) is a concept introduced by Aaron Antonovsky (1987)
and denotes the tendency of individuals to see their world as comprehensible,
manageable, and meaningful. A strong SOC has been related to the possession of
internal resources like optimism and self-efficacy (Lindström and Eriksson 2010).
Moreover, a strong SOC is found to be associated with positive perceived health
(Eriksson and Lindström 2006; Honkinen et al. 2005), and strongly negatively
related to psychological symptoms (Buddeberg-Fischer et al. 2001; Skirka 2000).
In stressful situations, researchers have identified SOC’s moderating role with
respect to negative health outcomes. For individuals with a strong SOC, it is
postulated that they will harbor a general confidence in the availability of resources
Stress: Concepts, Models, and Measures 157
to meet the demands posed by stressful situations and will thus consider a stressor as
more a challenge than a threat. Such confidence increases the likelihood of positive
coping expectancies, which consequently prevent stress from turning into potentially
harmful tension (Antonovsky 1987). Adults with high SOC appear to cope better
under stress than people with a low SOC (Eriksson and Lindström 2006; Gana 2001;
Jorgensen et al. 1999; Richardson and Ratner 2005). However, few and inconsistent
findings of the stress-moderating role of SOC have been located in the case of
adolescent populations (Nielsen and Hansson 2007; Torsheim et al. 2001).
Hardiness, a concept introduced by Kobasa (1979), represents a personality
characteristic that significantly affects the relationship between stress and health.
Hardiness is characterized by three interrelated attitudes: (1) Control refers to an
individual’s belief that they can influence events in their lives – that is, a sense of
personal control. (2) Commitment designates an individual’s sense of purpose or
involvement in the events, activities, and social relationships in their lives. (3) Chal-
lenge refers to an individual’s tendency to view changes as incentives or opportuni-
ties for growth, rather than as threats to security. Thus, hardy people believe they
exercise control over their experiences, are committed, and perceive changing
environments as challenging opportunities for growth. Studies have shown that
hardy individuals remain healthier in the face of stress (Delahaij et al. 2010).
Though stress and coronary heart diseases will be given more attention in a subse-
quent chapter, we will nevertheless conclude this discussion by addressing the link
between stress and CHD development. The Stockholm Female Coronary Risk Study
demonstrated that women who had suffered an episode of CHD exhibited lower
heart rate responses to mental stress than their male counterparts (Weidner
et al. 2001). In summation of another Swedish study, stress is the main risk factor
for the development of CHD in women, and women suffer more problems with
home-based stress – that is, stress from within the family – than do men (Balog
et al. 2003). These results are supported by the findings of the Family Heart Study
(USA), which demonstrated that females experience less job strain from working
outside the house than do homemakers and men (Weidner et al. 1997; Ferris
et al. 2005) and from studies on burnout (Kinnunen et al. 2006).
A variety of strain situations appear to contribute to stress’s role in the production
of CHD, including factors marked by membership in a disadvantaged social class,
socioeconomic status, or low occupational class. It was suggested above that such
stressors may exercise the same effect on CHD development in both males and
females (Brezinka and Kittel 1995; Wamela et al. 2001), but more recently there
have been indications of differences, as well (e.g., Mobley et al. 2004). Lawlor
et al. (2005), in their examination of socioeconomic position through the life course
and its association with CHD development in women, illustrate that neither cigarette
smoking nor other adult risk factors can fully explain the elevated CHD risk in
females from adverse socioeconomic positions. Indeed, it is important to note, as one
158 U.K. Moksnes and G.A. Espnes
Conclusions
This chapter has demonstrated the wide range of studies on stress and stress
development and on the health consequences of stress. Investigators continue to
research better ways of tuning the definition and operationalization of stress in order
to more accurately measure stress levels and its impact on human health. Though the
stress concept is understood as one of the most potent pathogenic neuro-
biopsychological conditions – certainly, it is the most researched – there still exist
several mysteries related to its impact on health development. One such mystery
concerns the different ways that stress develops and variously impacts health across
the two sexes. Though we have noticed differences in stress’ paths, processes, and
impacts, these are far from thoroughly mapped. The clear differences in the manner
in which males and females develop and cope with stress may have a large influence
on our understanding of stress, its pathogenic character, and its operationalization
and measurement. At the moment, it seems stress research must address a number of
new complex research questions in order to more fully understand stress’s impact on
human health.
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Stress and Cardiovascular Reactivity
Anna C. Phillips
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Evidence Linking Stress Reactivity to Cardiovascular Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
Stress Exposures and Acute Cardiovascular Events: The Triggering Hypothesis . . . . . . . . . . . . 165
Mediators of Cardiovascular Reactivity and Health Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Cardiovascular Reactivity and Psychological Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
Self-Reported Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
Addictions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
Abstract
The response of the cardiovascular system to stressful situations has long been
considered to have implications for health outcomes. Both exaggerated and
diminished cardiovascular reactivity to acute psychological stressors have seri-
ous consequences for health. This chapter will compare and discuss research on
both high and low cardiovascular responses to psychological stress. Exaggerated
reactions are associated with the development of hypertension, markers of
systemic atherosclerosis, and cardiovascular disease. Blunted or low reactivity
is related to depression, obesity, and a range of addictions. It has been proposed
that an interaction between genetics and the environment contributes to individ-
Keywords
Acute stress • Blood pressure • Cardiovascular disease • Heart rate • Life events •
Stress • Reactivity
Introduction
confirm the contention that exaggerated stress reactions signal poor future cardio-
vascular health (see, e.g., Chida and Steptoe 2010; Treiber et al. 2003). More
recently, exaggerated cardiovascular responses to acute stress have also been
shown to relate to an increased risk of 16-year cardiovascular disease mortality
(Carroll et al. 2012).
The associations described above have emerged implicating high reactivity in the
etiology of cardiovascular disease. However, acute stress and how we react to it
may trigger acute cardiovascular events. A number of epidemiological studies
indicate that environmental stressors such as earthquakes, terror attacks, and even
the stress associated with watching key soccer matches are associated with
increased hospital admissions and mortality from acute cardiovascular events
(Carroll et al. 2002). The physiological mechanisms that may account for this
link are poorly understood. However, it is likely that elevated levels of hematocrit
(the percentage volume of blood that is occupied by red blood cells) and blood
viscosity would increase the shear stress on vulnerable atherosclerotic plaques,
thereby increasing the likelihood of rupture; acute cardiovascular events, particu-
larly heart attacks, are often the result of plaque rupture and coagulation. Increases
in hematocrit or decreases in its converse, plasma volume, have frequently been
found with acute psychological stress exposure (see, e.g., de Boer et al. 2006). This
suggests that acute psychological stress provokes a “prothrombotic” state and
increases the risk of a clot forming in vulnerable individuals precipitating a
heart attack or stroke. What is missing is concerted evidence that those who show
higher-magnitude reactions in these prothrombotic markers are at particular risk of
suffering a cardiovascular event. Thus, there are indications that greater reactivity
may constitute a risk for both the development and aggravation of inflammatory
disease.
mold our stress response systems to respond in a certain way later in life, which may
have long-term implications for health.
Depression
Obesity
The reactivity hypothesis has also been considered in the context of physical health
problems such as obesity. Obesity is a fast-growing epidemic in Western countries
(WHO 1997) with adverse health consequences. Abdominal adiposity has also been
linked with psychological distress, and it has been argued that an increased vulner-
ability to stress in the abdominally obese may be manifest as physiological hyper-
reactivity. The impact of stress on the neuroendocrine system is thought to promote
abdominal fat deposition (Bjorntorp 1996), and it has been suggested that obesity,
and especially central adiposity, will be associated with exaggerated cardiovascular
reactions to stress (Waldstein et al. 1999). The question arises as to whether obesity
and exaggerated cardiovascular reactivity to acute stress are positively related or
whether they are independent risk factors for cardiovascular pathology. A few mainly
small-scale studies have attempted to address this issue with mixed results (see, e.g.,
Davis et al. 1999; Waldstein et al. 1999). In the largest study to date, body mass index
was not significantly related to cardiovascular reactivity in 225 middle-aged public
servants, although waist-hip ratio, a measure of abdominal adiposity, was positively
associated with diastolic reactivity (Steptoe and Wardle 2005). In contrast, greater
fatness was related to a blunted vasodilatation response to mental stress in 48 healthy
young men (Hamer et al. 2007). Further, recently, adiposity was unrelated to cardio-
vascular or neuroendocrine stress reactivity in a sample of 67 women, although those
with larger waists had a greater increase in plasma leptin to stress (Brydon 2011).
It is difficult to draw firm, confident conclusions from the results of these studies,
particularly given that most samples were small and poorly representative of the
general population and few adjusted for potential confounding variables, including
baseline cardiovascular levels. The most consistent result appears to be a positive
association between systemic resistance reactivity, as reflected by DBP and/or total
peripheral resistance, and abdominal adiposity, although not all studies report this.
The West of Scotland Twenty-07 dataset was exploited to explore the association
between cardiovascular reactivity and adiposity, both cross-sectionally and pro-
spectively (Carroll et al. 2008). In this study, there was a significant negative
association between body mass index and HR reactivity. Obese participants also
exhibited much smaller HR reactions to stress than their non-obese counterparts.
These associations were independent of age cohort, sex, occupational group,
smoking, antihypertensive medication status, baseline cardiovascular levels, and
depression. BMI was measured again 5 years later and, as might be expected, had
significantly increased. In fully adjusted analyses with obesity at the fourth follow-
up as the dependent variable and obesity at the third follow-up as a covariate, lower
HR reactivity was associated with an increased risk of becoming obese over the
5 years between follow-ups. More recently, these cross-sectional findings have been
Stress and Cardiovascular Reactivity 169
replicated in the Dutch Famine Birth Cohort study and also emerged for cortisol
(Phillips et al. 2012). The findings across these two studies seem to mainly hold for
HR stress reactivity and not so much for BP stress reactivity. Sympathetic nervous
system blockade studies indicate that cardiac reactivity in the context of mental
stress reflects β-adrenergic activation (Sherwood et al. 1986; Winzer et al. 1999).
Indeed, indices of cardiac reactivity seem to be more sensitive than blood pressure
reactivity to β-adrenergic blockade (Sherwood et al. 1986; Winzer et al. 1999),
suggesting that cardiac reactivity reflects β-adrenergic activation to a greater extent
than blood pressure reactivity. This could explain why the present associations
mainly obtain for HR reactivity and hardly for blood pressure reactivity.
There is some other evidence that whereas the obese have elevated sympathetic
tone in the resting state, their sympathetic nervous system may be less responsive to
stimulation. For example, after ingestion of a meal, there is a postprandial sympa-
thetic nervous system response as reflected by higher plasma norepinephrine
concentrations and an increased low- to high-frequency ratio in the heart rate
variability spectrum (Tentolouris et al. 2003; Welle et al. 1981). However, this
effect has been observed to be much smaller in obese as opposed to lean individuals
(Tentolouris et al. 2003). Further, obesity is associated with a state of leptin
resistance in humans, and hyperleptinemia is related to lower sympathetic nervous
system activity in obese individuals (Quilliot et al. 2008), whereas circulating leptin
has been shown to relate to acute stress-induced increases in heart rate in non-obese
humans (Brydon et al. 2008). Thus, it is possible that obese individuals become
resistant to the sympatho-activating effects of leptin, resulting in blunted reactivity.
In sum, these studies suggest that it is low not high cardiac and cortisol reactivity
that is related to adiposity. Indeed, low reactivity, possibly by reflecting generally
blunted sympathetic nervous system response to acute challenge, may even be a
risk marker for developing obesity.
Self-Reported Health
given four response options: excellent, good, fair, and poor. Self-reported health at
the time of stress reactivity measurement was positively associated with blood
pressure reactions to the acute stress task such that participants who reported
relatively excellent or good health had larger SBP and DBP reactions than those
who reported poor or only fair health (Phillips et al. 2009). Prospective analyses
showed that cardiovascular reactivity also predicted the change in health status
5 years later for DBP and HR reactivity. These positive associations indicate that
participants exhibiting relatively higher cardiovascular reactivity had better self-
reported health 5 years later, independent of their earlier self-reported health. Thus,
as with obesity, it was low reactivity that was associated with the poorer health
outcomes, even following adjustment for a range of confounders. Supporting cross-
sectional data has also been provided from the Dutch Famine Birth Cohort study.
Those with large cardiovascular reactions to acute psychological stress reported
better health than those with small reactions; the same held true for cortisol
reactivity (De Rooij and Roseboom 2010).
Self-reported health is likely to be a function of numerous factors and to depend
on the integrity of multiple biological systems, not simply the subjective impact of
occult or manifest cardiovascular disease. One system that would appear to be
critical in this context is the immune system. Indeed, it has been proposed that what
we experience as illness, sickness, and pain is, at least in part, determined by
feedback from the immune system to the central nervous system (Maier and
Watkins 1998). Further, the acute stress-induced immuno-enhancement hypothesis
proposes that acute stress upregulates various aspects of immunity and that this has
functional implications for host defense (Dhabhar 2002). However, what about
individual differences in reactivity to acute stress? The acute stress-induced
immuno-enhancement hypothesis would imply that it would be the most reactive
that would reap the greatest immunological dividend. We now have provisional
evidence that this might be the case; greater blood pressure reactions toward the end
of an acute stress task were characteristic of individuals who mounted a better
antibody response to two influenza strains (Phillips et al. 2009). In sum, it would
appear that whereas high reactivity contributes to and exacerbates inflammatory
cardiovascular disease, low reactivity may compromise immunity and our ability to
fight infectious disease and as such be the maladaptive response.
Addictions
their impact on physiological reactivity, and their health consequences are part of the
expanded sense of reactivity and health discussed in this chapter.
There is emerging evidence that low or blunted cortisol and cardiovascular
reactivity is characteristic of those with substance dependencies and may indeed
be a general marker for risk of addiction (Lovallo 2006). For example, although the
act of smoking per se is associated with increases in cardiovascular activity
(Pomerleau et al. 1983), habitual smokers have been found to show diminished
cardiovascular (Girdler et al. 1997; Phillips et al. 2009; Roy et al. 1994; Sheffield
et al. 1997; Straneva et al. 2000) reactions to acute psychological stress. It is
unlikely that these effects reflect temporary abstinence during stress testing and
its effects on stress task engagement (Girdler et al. 1997). In addition, cardiovas-
cular and cortisol hypo-responsiveness has been found to predict relapse among
smokers who have recently quit smoking (al’Absi 2006; al’Absi et al. 2005). Thus,
low reactivity not only characterizes those addicted to smoking; it may also be a
risk marker of some prognostic significance (Glahn et al. 2007; Lovallo 2006).
Those addicted to alcohol have also been found to exhibit blunted cardiovascular
and cortisol stress reactivity (Lovallo et al. 2000; Panknin et al. 2002). In addition,
relatively low reactivity would appear to be a characteristic of nonalcoholics with a
family history of alcoholism (Sorocco et al. 2006), and offspring of parents addicted
to alcohol or drugs showed a blunted cortisol response to stress and were more
likely to experiment with cigarettes and marijuana (Moss et al. 1999). The data
suggest that blunted reactivity may not only be a characteristic of those with a
dependency but it may actually predate the addiction and signal risk of future
addiction. Accordingly, in low reactivity, we may have a marker of motivational
dysregulation linked to inherited risk of a wide range of addictions (Lovallo 2006).
Thus, it is not only high physiological reactivity that can be a risk marker for poor
health outcomes; low reactivity would also seem to be implicated.
Further, it is not only substance addictions which appear to correlate with blunted
cardiovascular reactivity. Exercise-dependent women, identified through a question-
naire regarding exercise behaviors, showed blunted cardiac and cortisol reactions to a
mental arithmetic stress task (Heaney et al. 2011). In a similar study in our laboratory,
we also showed that young women with symptoms of bulimia in the disordered
eating group showed blunted cortisol, cardiac output, heart rate, and stroke volume
reactions to the acute stress compared to controls (Ginty et al. 2011). These effects
could not be accounted for in terms of group differences in stress task performance or
cardiorespiratory fitness nor comorbid bulimia or exercise dependence, respectively.
These results offer further support for the hypothesis that blunted stress reactivity
may be a peripheral marker of a central motivational dysregulation in the brain.
Clinical Implications
Conclusion
We have seen that both high and low reactivity are bad for the health depending on
the health outcome in question. This could be conceptualized as either an inverted
U model of cardiovascular reactivity to stress or a model of continuous positive
associations between reactivity and some health outcomes and continuous negative
associations between reactivity and other health outcomes. These two models are
shown in Fig. 1. The data presented also suggest that the original cardiovascular
reactivity hypothesis might be revised to include prediction of pathology from both
ends of the continuum of cardiovascular response. This new perspective on reac-
tivity may allow us to expand our conceptual model of how departures from normal
physiological response patterns can predict risk for poorer health outcomes. Low, as
well as high, reactivity may be bad for our health.
Stress and Cardiovascular Reactivity 173
Reactivity Health
Bad for CVD
outcomes
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Depression and Cardiovascular Disease:
Psychobiological Mechanisms
Contents
Evidence Linking Depression with an Increased Risk of Developing Heart Disease . . . . . . . . 180
Evidence for Increased Risk of Death After a Myocardial Infarction . . . . . . . . . . . . . . . . . . . . . . . . 181
Possible Mechanisms for Increased Risk of Developing Heart Disease and Death
Post- myocardial Infarction, in Those with Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Behavioral and Lifestyle Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182
Platelet Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Autoimmune and Inflammatory Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Effect of Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
Abstract
Both major depression and cardiovascular disease are leading causes of burden
of disease worldwide. Major depression is common in those suffering cardio-
vascular disease, and likewise cardiovascular disease is common in those suf-
fering major depression. This chapter aims to look at the association between the
two and the underlying biological mechanisms that link them. There now is vast
evidence indicating that major depression is a risk factor for the development of
coronary heart disease. The mechanisms involved are numerous and certainly
multifactorial. These include behavioral and lifestyle factors, the sympathetic
nervous system, platelet function, and the autoimmune and inflammatory sys-
tems. Of importance is that major depression increases the mortality in those
suffering coronary heart disease. Until recently it was thought that this increased
mortality could be explained by the increased co-occurrence of classical cardiac
risk factors such as hypertension, diabetes, smoking, and dyslipidemia. It has
now been shown that major depression is itself an independent risk factor. There
is obvious need to understand the neurobiological mechanisms underpinning
both of these disease processes. This would hopefully aid the development of
better treatments of these diseases.
Keywords
Cardiovascular disease • Depression • Myocardial infarction • Platelet function •
Sympathetic nervous system
Major depression is the third leading cause of disease burden worldwide and is
predicted to be the leading cause by 2030 (Chavez et al. 2012). Cardiovascular
disease is a prominent concern for people, and therefore it is important to identify
causal mechanisms so that prevention and treatment strategies can be developed
(Newson et al. 2010). The lifetime prevalence of depression is in the order of 17 %.
Major depression is highly prevalent in cardiac patients, with 20–40 % of patients
meeting criteria for major depressive disorder (Celano and Huffman 2011). When
physical illness and depression occur together, the overall outcome for both dis-
eases is worse.
Depression and coronary artery disease are conditions that both significantly
decrease quality of life for the patient and impose a significant economic burden on
society (Zellweger et al. 2004). Health- care costs are higher and health-related
quality of life is lower in depressed patients in coronary artery disease (Summers
et al. 2010), and thus the adequate treatment of both condition is important not only
from a clinical but also from a service provision perspective. The possible mech-
anisms for increased risk of developing heart disease, in those with depression, are
varied and complicated.
subjects suffering major depression had an overall relative risk of 1.64 for devel-
oping ischemic heart disease compared to nondepressed subjects (Katon
et al. 2004). Also the prevalence rates of major depressive disorders in various
cardiac conditions are significantly higher than the frequencies that can be expected
in a healthy population (Kapfhammer 2011). The relative risk of developing
coronary heart disease is proportional to the severity of the depression. Atheroscle-
rosis, the underlying process leading to vascular events, has been associated with
depression. Participants in a study who screened positive on the American Health
Association depression protocol had a 55 % greater risk of cardiac events than those
who screened negative (Elderon et al. 2011). A meta-analysis of studies published
between 1945 and 1985 on psychosocial predictors of coronary artery disease
concluded that depression is the main psychosocial risk factor for cardiovascular
disease (Serrano et al. 2011).
Depression increases the risk of cardiac mortality and morbidity in patients with
coronary heart disease. Major depression in patients with existing ischemic heart
disease confers a relative risk between 1.5 and 2.5 for cardiac morbidity and
mortality (Lett et al. 2004). Patients with major depression are at greater cardiac
risk of cardiac death in the first few months after a myocardial infarction
(Ziegelstein et al. 2000), and in fact much of the mortality risk appears to be in
the first 6 months post-myocardial infarction (Jiang et al. 2002). The impact of
major depression on mortality in ischemic heart disease seems to be at least
equivalent to that of left ventricular dysfunction (Frasure-Smith et al. 1993). It
has been shown in men assessed 2 months after acute coronary syndrome that major
depression is a prognostic factor for a major adverse cardiac event over 2 years. The
mortality risk in patients with ischemic heart disease appears to be proportionate to
the severity of the depression. Depression sustained after acute coronary syndrome
is also associated with worse cardiac outcomes (Zuidersma et al. 2011). Among
survivors of acute myocardial infarction, up to 20 % meet diagnostic criteria for
major depression, the presence of which carries a fivefold increase risk of cardiac
death within 6 months (Lange-Asschenfeldt and Lederbogen 2011). It has been
shown that affective disorders are differentially associated with poorer post-cardiac
surgery outcomes independent of cardiac surgery morbidity risk factors. Similar
findings of high mortality in subjects with unstable angina and comorbid major
depression have been shown (Srinivasan 2011). Major depression is common
following an episode of unstable angina, with rates of 35–45 %, is associated
with an increased risk of major cardiac events during the following year, and has
been found to increase the risk of cardiac death more than fourfold (Lespérance
et al. 2000).
182 A.K. Dhar et al.
Various candidate mechanisms might explain how depression increases the risk for
coronary artery disease and subsequent cardiac mortality and morbidity. Some of
these include behavioral and lifestyle factors, the sympathetic nervous system,
platelet function, and autoimmune and inflammatory mechanisms.
been shown to have higher mean noradrenaline spillover compared to those without
secondary panic disorder.
It has also been shown that sympathetic nervous activity is regionalized in that in
depressed patients cardiac and total sympathetic activity is raised while muscle
sympathetic activity is not. It is suggested that reduced removal of noradrenaline
from the sympathetic synapse after its release in the heart, subsequently augmenting
the sympathetic neural signal, could be an important causal factor in generating
cardiac risk (Barton et al. 2007).
Platelet Function
(Kop and Gottdiener 2005). It has been postulated that inflammation causes an
increase in atherosclerosis thus increasing cardiac risk (Frasure-Smith and
Lespérance 2005).
Effect of Treatment
Depression is present in one of five outpatients with coronary heart disease and in
one in three outpatients with congestive heart failure, yet the majority of cases are
not recognized or appropriately treated (Whooley 2006). Optimizing treatment for
depression cannot only cause significant reduction in depressive symptoms but also
improve cardiac prognosis (Davidson et al. 2010). Pharmacological and
non-pharmacological treatments are known to improve depressive symptoms in
patients with coronary artery disease. Selective serotonin reuptake inhibitors
(SSRIs) are the class of drug of choice for treatment of those with major depression
and comorbid coronary artery disease. This is primarily due to the better tolerability
and absence of significant cardiovascular side effects (Zellweger et al. 2004).
The sertraline antidepressant heart attack randomized trial (SADHART) indi-
cated that sertraline improved depressive symptoms and did not adversely affect
cardiac function. Treatment with sertraline in depressed post-acute coronary syn-
drome patients is associated with reductions in platelet/endothelial activation, and a
trend toward a reduction in morbidity and mortality among the sertraline treated
patients was observed. SADHART demonstrated safety of sertraline post-acute
myocardial infarction along with a decrease in overall mortality, infarction, stroke,
unstable angina, and congestive cardiac failure.
Following SSRI treatment, sympathetic nervous activity in patients with major
depressive disorder is significantly reduced (Carney et al. 1999). A recent meta-
analysis of SSRI medications in patients with depression and coronary heart disease
showed a greater decrease in depressive symptoms and also a possible improvement
in coronary heart disease prognosis (Pizzi et al. 2011). The ENRICHD trial showed
that antidepressant treatment of depression improved prognosis for MI patients
(Berkman et al. 2003).
In the platelet sub-study of the SADHART trial, patients who had suffered a
myocardial infarction and had comorbid depression treated with sertraline showed
less activation of platelets and endothelial cells (Serebruany et al. 2003), even when
anticoagulants were accounted for. Also of importance was the fact that this
sub-study showed that there were no adverse events regarding bleeding, with the
use of sertraline. This again indicates that sertraline is a safe and effective drug.
Although sertraline has been shown to be a safe and effective drug, this cannot
be said for all patients and for all SSRIs, as it has been shown that there may be an
SSRI-induced vagally mediated inflammation. It has also been indicated that
treatment with the SSRI paroxetine can possibly cause mildly abnormal LDL
(low-density lipoprotein) levels (Lara et al. 2003).
Non-pharmacological therapy such as aerobic exercise has been shown not only
to improve depression but also cardiovascular health. Psychological treatment of
Depression and Cardiovascular Disease: Psychobiological Mechanisms 185
Conclusions
A definitive mortality study is unlikely to be ever done due to its cost and
complexity. We therefore need to be guided by the current evidence to guide us
in a choice of therapy that will minimize risk for individuals. The SADHART trials
have shown that sertraline is a safe and effective drug in treating major depression
in those with comorbid ischemic heart disease. Sertraline has also been shown to be
possibly protective in post- acute myocardial infarction patients.
The present findings underscore the need to consider depression as a common
and modifiable risk factor for coronary heart disease events (Brown et al. 2011).
Interdisciplinary management of these patients would optimize treatment for both
major depression and the ischemic heart disease. Screening for depression in
patients with cardiac disease should be instituted on a routine basis. The 2010
Global Burden of Disease study which estimated the premature mortality and
disability of all major diseases and injuries indicated that it is now appropriate to
186 A.K. Dhar et al.
consider major depression as a risk factor for coronary heart disease (Charlson
et al. 2011). The links between depression and cardiovascular disease have now
been well established. Further work is warranted in sympathetics and how SSRI
treatment modifies cardiac risk.
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Stress, Depression, and Cardiovascular Risk
in Children
Contents
Introduction: The Evidence for CVD Risk Markers in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192
Depression, Distress, and CVD Risk in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
Illness Prevention and Health Promotion in Children . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
The LOOK Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
Stress, Depression, and the Presence of CVD Risk Markers in Children: Evidence from
the LOOK Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206
Abstract
The effective prevention of cardiovascular disease (CVD) lies with the identifi-
cation and modification of risk markers known to be causally associated with
clinical events of CVD – and the evidence would support the view that the earlier
this can take place, the more effective CVD prevention will be. Thus, intervention
programs targeting such things as diet and obesity, cigarette smoking, and
D. Byrne (*)
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
ANU Medical School, Research School of Psychology, Australian National University, Acton,
Canberra, ACT, Australia
e-mail: [email protected]
L. Olive
Research School of Psychology, The Australian National University, Canberra, ACT, Australia
e-mail: [email protected]
R. Telford
Centre for Research and Action in Public Health, University of Canberra, Bruce, ACT, Australia
e-mail: [email protected]
Keywords
CVD risk • Children • Stress • Depression • Cardiorespiratory fitness • Physical
activity • Early intervention • CVD prevention
elevated blood lipids (Ayer and Sholler 2012; Daniels 2001; May et al. 2012; Reed
et al. 2007; Twisk et al. 1997), higher than normal blood pressure (Ayer and Sholler
2012; May et al. 2012; Reed et al. 2007), both type 1 and type 2 diabetes
(Morrison et al. 2012; Schnell et al. 2013; Velasquez-Mieyer et al. 2005), and low
physical activity and fitness (Froberg and Andersen 2005) are evident to an appar-
ently increasing degree in children. And there is good evidence that multiple risk
factors for CVD predict premature atherosclerosis in children and young adults
(Berensen et al. 1998).
Moreover, there is growing evidence that the early appearance of CVD risk
factors is linked to an equally early appearance of coronary atherosclerosis in
children and young adolescents (Daniels 2001), with the consequent expectation
that this will translate directly into a risk for clinical CVD in relatively early
adulthood. A novel study by McMahan et al. (2005) used both blood and tissue
samples obtained at postmortem examination from more than 2,500 young people
15–34 years old who had died from non-CVD causes, to assess the link between
CVD risk factors and atherosclerotic lesions. Postmortem measures of blood lipids,
body mass index, hypertension (estimated by examining the intimal thickness of
small renal arteries), and smoking (estimated from serum thiocyanate levels) were
strongly related to the presence of atherosclerotic lesions likely to endow future risk
of clinical CVD. There can be no doubt, therefore, that the development of CVD risk
in adulthood is firmly founded in childhood, leading Daniels et al. (2011) to
foreshadow the issue of CVD prevention and to conclude that “. . . the development
of CVD has its origins in families and . . .. approaches to prevention must be directed
at the developing child and adolescent and the family environment . . .” (p 1683).
Cardiovascular disease risk is, not surprisingly, a widely researched area in medicine.
One of the most novel and thought provoking and arguably one of the most useful
accumulations of evidence coming out of the past decade or so has been that
documenting the causal role of depression as a CVD risk factor. It is well established
that depression, often of clinical intensity, is a common consequence of a clinical
episode of CVD (Williams 2011). Consistent medical opinion now recommends
routine screening for depression among those with identified clinical CVD
(Colquhoun et al. 2013; Lichtman et al. 2008) to ensure effective intervention against
the possible exacerbation of coronary pathology. Moreover, there is now both exten-
sive and quite persuasive evidence that the existence of clinical depression is causally
related to an elevated risk of a clinical CVD event and to a less favorable prognosis
when such an event has occurred (Barth et al. 2004; Celano and Huffman 2011; Hare
et al. 2013; Zellweger et al. 2004). This link appears to hold for “. . . several decades
after the onset of clinical depression . . .” (Ford et al. 1998, p. 1422). Among the
elderly, the presence of depression increases the risk of CVD mortality by between
40 % and 60 % relative to those free from depression (Ariyo et al. 2000). Conversely –
and interestingly – the experience of positive effect seems to protect against the future
194 D. Byrne et al.
childhood health and health promotion. There seem, however, to be two principal
difficulties in solidifying this case into accepted practice. First, the evidence required
to persuasively argue the case necessarily involves very long-term prospective
studies, with large cohorts of children adequately screened for CVD risk at intake,
and then followed through to early adulthood and beyond. Studies such as these are
methodologically difficult and expensive to undertake, and with the possible excep-
tions of the Framingham study in the USA, the Young Finns study in Finland, and
the HUNT study in Norway, the evidence is presently sparse. And second, both the
risk targets themselves, and the approaches taken to achieving CVD risk interven-
tions, are frequently fragmented and oftentimes more intuitively than empirically or
theoretically driven. They are therefore difficult to enshrine into the accepted
wisdom of clinical public health practice.
The evidence becomes even more difficult to marshal into a persuasive argument
for early intervention when it rests with the psychological attributes of a young
population. Studies overviewed earlier in this chapter establish beyond reasonable
doubt that many known risk factors for CVD in adulthood are established in
childhood. And it follows from this that the foundation for clinical events of CVD
in adulthood can be traced back, at least in part, to the development of CVD risk
among children. There is, moreover, some evidence that this line of potential
causality holds for the (psychological) risk factor of depression (Ford et al. 1998).
The evidence also notes the growing problem of depression (and other psychological
distress more generally) in children and begs the question of whether depression
experienced in childhood might go on to form the basis for an elevated risk of CVD
somewhat later in adulthood. The elements of a coherent research question, posed
within the context that risk factors for future CVD have some foundation in
childhood, therefore present themselves for consideration. Both depression and
stress in adulthood constitute known risks for CVD, and there are likely plausible
biological mechanisms that may link these psychological risk factors with CVD risk
markers. Given that depression and stress are clearly evident among children, the
question logically arises as to whether childhood depression and stress also consti-
tute identifiable – and early – risks for future CVD (Low et al 2009). And by
extension, could the effective prevention of depression and stress in childhood
have a noticeable effect on rates of CVD later in adulthood?
Interventions based on the worthy objective of promoting future health or of
reducing the incidence of future illness are now relatively commonplace. But the
practice of health promotion over the past decade and a half has become increasingly
dependent on the availability of sound evidence, both epidemiological and clinical,
to guide the targets of health-promoting interventions and the forms they take
(Nutbeam 1999; Green 2000; Juneau et al. 2011). The difficulty with the risk
sequence just proposed – that psychological distress in children may influence the
later development of CVD in adults – is that it does not yet have sufficient targeted
evidence to justify the development and implementation of intervention strategies
based solely on the view that psychological distress experienced by children will
place them at greater risk of CVD sometime later in life. This chapter now goes on to
look at a recent and significant study which may provide that evidence.
Stress, Depression, and Cardiovascular Risk in Children 197
Measures
experiences relevant to children. Children reported their stressor experience for the
last 12 months on a 5-point Likert scale, ranging from 1 (This didn’t happen to me) to
5 (It made me very upset). While the literature on life events has expressed general
concern regarding the 12-month time frame for recall, Turner and Wheaton (1995)
consider this to be the standard in studies of the kind reported here. Individual item
scores thus spanned the range of 1–5, while the full-scale score spanned 50–250.
Based on data from the LOOK cohort, the CSQ has strong internal reliability and
both construct and predictive validity, as a measure of stressor experience in
children.
Physical Activity
A sedentary lifestyle has long been considered to endow elevated risk for CVD in
adults (Manson et al. 2004) – the childhood origins of this lifestyle pattern were
therefore fully explored in the LOOK study. New Lifestyles pedometers (Lee’s Sum-
mit, MO, USA) were used to measure the number of steps per day taken by children,
since the validity of this measure has been established in children of this age group
(Beets et al. 2005). Children wore pedometers on their hip for seven consecutive days,
though measurements taken on the first day were excluded to account for the potential
influence of the novelty of wearing a pedometer and because the sampling period did
not form a complete day. While the simple metric of steps/day provided an indication
of physical activity, a physical activity index was also calculated using best linear
unbiased predictor (BLUPS) to maximize the use of data. A more detailed description
of this measure has been previously described (Telford et al. 2009).
Table 1 Changes in children’s profiles for stress and depression over time (from intake to
follow-up)
% of children with a % of children with an % of children remaining
decrease in stress/ increase in stress/ stable in stress/
depression scores over depression scores over depression scores over
Scale 4 years 4 years 4 years
Stress full- 71.5 % 26.0 % 2.5 %
scale
change
Depression 61.5 % 28.5 % 9.0 %
full-scale
change
Stress levels at both intake and follow-up closely approximated a normal distri-
bution – levels of depression at both time points were somewhat skewed toward low
depression, but this was expected in a measure which was oriented toward a clinical
state (Byrne et al. 2011), though it was clear that even at that young age, some
children (7–8 years old) showed signs of experiencing troubling levels of both stress
and depression. Equally importantly, however, there was change in psychological
state over time – between intake and follow-up 4 years later – and this change can be
seen in Table 1.
Encouragingly, the majority of children decreased in both stress and depression
scores over the 4-year follow-up period – but more than a quarter in each case
showed an increase in these scores. There is no obvious explanation for this pattern
of change in either stress or depression. What was evident, however, was that
depression appeared to follow stress – as stress levels fluctuated over time, so did
levels of depression. Stress levels at intake were significantly related to depression
levels at follow-up in both boys (r = 0.25, p < 0.01) and girls (r = 0.27, p < 0.01)
providing evidence that stress in young children predicts depression some 4 years
later. At follow-up, levels of stress and depression were strongly related (r = 0.72,
p < 0.001 in boys and r = 0.61, p < 0.001 in girls).
A comprehensive risk assessment both at intake and at follow-up 4 years later
established CVD risk marker profiles for the samples at both points in time. Table 2
shows percents of each sample already, at this young age, who manifested elevated
levels of metabolic risk markers, assessed according to standard published criteria
for blood lipids (Daniels and Greer 2008; Kavey et al. 2003) and HOMA-IR
(Tresaco et al. 2005).
Levels of LDL-C indicating CVD risk appeared to be higher at intake than at
follow-up, but the reverse was quite apparent for levels of HOMA-IR, where children
4 years into the study had very noticeably higher levels of insulin resistance – or more
accurately in this age group, insulin sensitivity – than was evident at intake.
Risk profiles based on assessments of physical activity (PA), cardiorespiratory
fitness (CRF), and body mass index (BMI – as a proxy for %BF) can be seen in
Table 3.
Stress, Depression, and Cardiovascular Risk in Children 201
Table 2 Percentage of children with elevated metabolic risk profiles at intake and at follow-up
% of children with elevated risk % of children with elevated risk marker
Risk marker marker level at intake level at follow-up
LDL-C >3.36 mmol/L
Boys 14.7 % 11.1 %
Girls 17.0 % 9.4 %
HDL-C <0.9 mmol/L
Boys 1.0 % 1.7 %
Girls 1.1 % 2.3 %
TG >4.52 mmol/L
Boys 0.0 % 0.0 %
Girls 0.0 % 0.4 %
HOMA-IR 3.00a
Boys 1% 17 %
Girls 3% 36 %
a
Using the formula fFasting INS ðmULÞ fasting Glucose ðmmol=LÞg=22:5
Physical activity decreased quite markedly over the course of the follow-up, with
70 % of both boys and girls at follow-up showing less than optimal levels of daily
activity. Although children of the LOOK cohort were measured with lower CRF at
follow-up relative to the Australian normative group from Catley and Tomkins (2013),
children’s CRF increased over the course of follow-up as would be developmentally
expected – this was more evident for boys than for girls. Levels of obesity assessed by
BMI showed a slightly increasing trend over 4 years, but something approaching 25 %
of children in the sample overall showed evidence of obesity when judged according
to BMI – but bearing in mind the concerns posed by Telford et al. (2014) regarding the
capacity of the BMI to reflect adiposity in children.
Not surprisingly, gender differences in risk marker profiles were evident, even in
samples of quite young children. Boys had significantly higher HDL-C levels than
did girls at both time points, but this was not evident for LDL-C. Neither gender nor
time differences, however, were evident in triglyceride levels. Insulin resistance
increased significantly over time for both boys and girls, but the increase was
more marked for girls, and girls generally had a higher insulin resistance (HOMA-
IR) level than did boys. Boys were significantly more physically active than girls at
both intake and follow-up – levels of PA declined with age through to follow-up, but
the PA of boys declined at a greater rate than that of girls. Boys did, however, show
significantly better levels of CRF than did girls at both time points. At both intake
and follow-up, girls had a significantly greater %BF than boys. Over time, however,
%BF for girls remained stable, while for boys it increased.
But as with the experience of childhood stress and depression, levels of CVD risk
markers also fluctuated over the time course of the data collection, and these may be
seen in Table 4.
Fluctuations were not, however, consistent either across time or gender. Levels of
HDL-D, TG, and HOMA-IR all rose over the 4-year follow-up period and for both
202 D. Byrne et al.
Table 3 Percentage of children with elevated risk profiles based on fitness measures at intake and
at follow-up
% of children with elevated risk % of children with elevated risk
Risk marker marker level at intake marker level at follow-up
PA measured here <13,000 steps/day for boys; <11,000 steps/day for girls
as steps/day
Boys 58 % 70 %
Girls 63 % 70 %
CRFa Low/very low Low/very low
Boys 1% 14 %
Girls 2% 5%
BMIb Overweight/obese Overweight/obese
Boys 20 % 23 %
Girls 24 % 26 %
a
Currently there are no universally accepted recommendations for health-related levels of fitness.
Our 20-m shuttle run data was compared to normative data for Australian children (see Catley and
Tomkinson 2013), where children with fitness in the lowest 40th percentile were classified as having
low to very low fitness. Note that these data are not criterion referenced and do not indicate whether
children in the lowest 40th percentile have unhealthy cardiovascular fitness or increased metabolic
risk. However, previous Australian evidence has linked low CRF in childhood with increased
metabolic risk in adulthood (Dwyer et al. 2009)
b
Due to inconsistencies in different measurement methods of classifying developing children and
no agreed upon cutoff for %BF, children were classified for the purposes of this comparison
according to their BMI, to assist a comparison of the body composition of this cohort with those
of other studies, notwithstanding the limitations associated with BMI in children (see Cole
et al. 2000; Telford and Cunningham 2008; Telford et al. 2014)
boys and girls. The same was noted for both CRF and %BF, with both boys and girls
showing higher levels of CRF as would be expected with development and higher
levels of %BF over the 4-year time span – by contrast, both boys and girls appeared
to have noticeably lower levels of PA at follow-up than at intake.
Table 4 Changes in children’s risk profiles for LDL-C, HDL-C, TG, HOMA-IR, CRF, %BF, and
PA over time (from intake to follow-up), reported separately for gender
% of children with no
Risk % of children decreasing % of children increasing change in risk level over
marker in risk level over 4 years in risk level over 4 years 4 years
LDL-C
Boys 59.2 % 39.0 % 1.8 %
Girls 66.0 % 1.3 % 32.7 %
HDL-C
Boys 59.6 % 38.6 % 1.8 %
Girls 54.6 % 43.7 % 1.7 %
TG
Boys 30.7 % 67.9 % 1.4 %
Girls 54.6 % 43.7 % 1.7 %
HOMA-IR
Boys 9.2 % 85.3 % 5.5 %
Girls 4.2 % 95.4 % 0.4 %
CRFa
Boys 90.1 % 9.1 % 0.8 %
Girls 92.8 % 6.8 % 0.4 %
%BF
Boys 35.3 % 64.7 % 0.0 %
Girls 49.4 % 50.6 % 0.0 %
PAa
Boys 8.5 % 91.5 % 0.0 %
Girls 20.3 % 79.7 % 0.0 %
a
Note that an increase in physical activity and CRF confers a decrease in risk level
• Percent Body Fat (%BF) – adjusted for height, physical activity, and gender
• Cardiorespiratory Fitness (CRF) – adjusted for height and gender
• Physical Activity (PA) – adjusted for %BF and gender
• HOMA-Insulin Resistance (IR) – adjusted for %BF, PA, and gender
• Low-Density Lipoprotein (LDL)-C – adjusted for %BF, PA, and gender
• High-Density Lipoprotein (HDL)-C – adjusted for %BF, PA, and gender
• Triglycerides (TGs) – adjusted for %BF, PA, and gender (Table 6)
204 D. Byrne et al.
Table 5 Retrospective and prospective relationships between psychological state (stress and
depression) and CVD risk markers unadjusted for possible intervening factors
Psychological Stress and Stress (intake)
state CVD and CVD Depression and Depression (intake)
markers markers CVD markers and CVD markers
CVD risk marker (intake only) (follow-up) (intake only) (follow-up)
Percent body fat X X X X
(%BF)
Cardiorespiratory ¸ ¸ ¸ ¸
fitness (CRF)
Physical activity ? ¸ ¸ ¸
(PA)
Insulin resistance X ¸ X ?
HOMA-IR
Low-density X X X X
lipoprotein
cholesterol
(LDL-C)
High-density X X X X
lipoprotein
cholesterol
(HDL-C)
Triglycerides X X X X
(TGs)
¸ Statistically significant relationship ( p < 0.05)
X Statistically nonsignificant relationship ( p > 0.05)
? Statistical trend (0.05 < p < 0.1)
Table 6 Retrospective and prospective relationships between psychological state (stress and
depression) and CVD risk markers adjusted for possible intervening factors
Psychological Stress and Stress (intake) Depression
state CVD and CVD Depression and (intake) and CVD
markers markers CVD markers markers (follow-
CVD risk marker (intake only) (follow-up) (intake only) up)
Percent body fat X X X X
(%BF)
Cardiorespiratory ¸ ¸ ¸ X
fitness (CRF)
Physical activity X ¸ X ¸
(PA)
Insulin resistance X ¸ X X
HOMA-IR
Low-density X X X X
lipoprotein
cholesterol
(LDL-C)
High-density X X X X
lipoprotein
cholesterol
(HDL-C)
Triglycerides X X X X
(TGs)
¸ Statistically significant relationship ( p < 0.05)
X Statistically nonsignificant relationship ( p > 0.05)
? Statistical trend (0.05 < p < 0.1)
from the particular perspective of this book, for the health of the cardiovascular
system remains somewhat open. Much of the evidence reviewed earlier suggests this
to be the case and to recite Daniels et al. (2011): “. . . the development of CVD has its
origins in families and . . .. approaches to prevention must be directed at the
developing child and adolescent and the family environment . . .” (p 1683). The
evidence arising thus far from the LOOK study indicates a somewhat more cautious
conclusion. Longitudinal associations between stress and depression in 7–8-year-old
children and CVD risk profiles 4 years later, unadjusted for possible interrelation-
ships between the very variables contributing to those risk profiles, would suggest
that both stress and depression statistically predict measures of cardiovascular
fitness. Psychological state in 7–8-year-olds does not, however, predict levels of
metabolic risk markers 4 years later (with the exception of insulin resistance). The
links between stress and insulin resistance offer one potentially very useful insight
into how a psychological state may influence the future development of CVD.
The capacity for increased stress to elevate blood sugar levels in children – possibly
maintained over adolescence and into adulthood – marks a possible pathway which
bears closer examination in further studies (and will be taken up in chapter
“▶ Nonlinear Analyses of Data in Cardiovascular Physiology and
Epidemiology” of the current Handbook).
206 D. Byrne et al.
When analyses were adjusted for potentially confounding covariates, the strengths of
predictive associations were overall truncated, but remained for CRF, and PA, and (again
to some extent) for insulin resistance – further underscoring the possible importance of
this latter metabolic variable in foreshadowing CVD risk in children.
Conclusion
Would results such as this justify a concerted program of preventive intervention for
stress and depression in young children, with a view to preventing CVD in adult-
hood? On this basis alone, the evidence is too weak to recommend a step such as this.
But given that the mood in the public and preventive health arena is now right for the
introduction of comprehensive programs of CVD prevention in children, targeting a
broad range of potential CVD risk markers for future adult disease (e.g., fitness and
exercise, weight and diet, smoking, and alcohol use), there is every reason to
incorporate psychological interventions into such comprehensive programs of
CVD prevention. The proof will ultimately be in the results of an appropriately
well-designed and resourced trial to achieve this.
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Childhood Stress, Emotional Distress,
and Cardiovascular Function
in Adolescents
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 214
Emotional Distress and Cardiovascular Function in Adolescence: A Review
of the Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Depression, Psychosocial Stress, and Arterial Stiffness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Depression, Psychosocial Stress, and Endothelial Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
The LOOK Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
L. Olive (*)
Research School of Psychology, The Australian National University, Canberra, ACT, Australia
e-mail: [email protected]
D. Byrne
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
e-mail: [email protected]
R. Telford
Research Institute of Sport and Exercise, University of Canberra, Bruce, Canberra, ACT, Australia
e-mail: [email protected]
W. Abhayaratna
ANU Medical School, College of Medicine, Biology and Environment, Australian National
University, Garran, Canberra, ACT, Australia
Academic Unit of Internal Medicine, Canberra Hospital, Garran, Canberra, ACT, Australia
e-mail: [email protected]
R. Telford
Centre for Research and Action in Public Health, University of Canberra, Bruce, Canberra, ACT,
Australia
e-mail: [email protected]
Stress, Depression, and CVD Risk Profiles in Adolescence: Evidence from the
LOOK Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
Effects of Changes in Psychological State (Stress and Depression) on
Cardiovascular Function and Risk Marker Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Abstract
Associations between depression, chronic stress, and cardiovascular disease
(CVD) are often reported in the literature, suggesting that individuals with poor
psychological health are at a higher risk for developing CVD and CVD-related
mortality. Much of the research in this area has been carried out among adult
populations, but there is growing evidence that the origins of these relationships
occur at a much younger age. In the current chapter, the childhood and adolescent
literature is reviewed with a focus on the effects of depression and psychosocial
stress on a set of intermediary markers for CVD, namely, endothelial function and
arterial stiffness. Findings arising from the adolescent phase of the Lifestyle of
Our Kids (LOOK) study, a collaborative longitudinal study, are presented. From
these findings, it is clear that children as young as 12 years old are already
experiencing stress and depressive symptoms and more so in less fit and fatter
children. Although we did not uncover any direct impact of psychological health
on cardiovascular function, given the risks associated with low fitness and obesity,
depression and psychosocial stress in childhood and adolescence may be exerting
an early impact on the risk of developing CVD in later life.
Keywords
Emotional distress • Cardiovascular function, adolescence • Lifestyle of our
Kids (LOOK) study • Psychosocial stress • Depression • Pulse wave velocity
(PWV) • Cardiorespiratory fitness (CRF)
Introduction
The experience of adversity, chronic ongoing stress, and emotional distress during
childhood and adolescence is associated with a number of risk markers for cardio-
vascular disease (CVD; Low et al. 2009; Tomfohr et al. 2011) and with an increased
risk of developing CVD later in life (Dong et al. 2004; Korkeila et al. 2010).
Ongoing chronic psychological stress and clinical depression have been linked to
dysregulation of the stress response (Lopez-Duran et al. 2009), and it is this
dysregulation which is thought to play a causal role in the relationship between
dysfunctional psychological states and CVD (Grippo and Johnson 2009). The
precise mechanisms underlying these relationships are not well understood but
likely include both direct biological mechanisms across multiple interacting sys-
tems (e.g., neuroendocrine changes, autonomic and cardiovascular dysregulation,
and immune alterations) and indirect pathways mediated through behavioral,
Childhood Stress, Emotional Distress, and Cardiovascular Function in. . . 215
associations have also been shown to extend to younger apparently healthy adults
with no established cardiovascular risk (Vlachopoulos et al. 2006). A review of the
most current research literature undertaken with younger populations is
presented here.
Among adolescents, significant associations between depressive symptoms and
arterial stiffness, as measured by pulse wave velocity (PWV), were documented
among 157 healthy boys and girls in the United States after adjustments for a
number of established confounders (Dietz and Matthews 2011). Sub-analyses in
this study, which separated adolescents based on depression severity (moderate
vs. severe), indicated that more severe depressive symptoms were associated with
higher PWV (where higher PWV is indicative of greater arterial stiffness) com-
pared to moderate symptoms. This is suggestive of a dose-response relationship
between impaired arterial function and depression. Similarly, Su et al. (2014) found
that in healthy adolescents and young adults, those exposed to a moderate/severe
level of adverse events during the first 18 years of life had higher PWV compared to
those not exposed. Studies like these are important for progressing our understand-
ing of the earliest stages of CVD and therefore facilitating preventive medical
strategies in children and adolescents.
What is evident from searching the literature on the effects of psychological
health on arterial stiffness, however, is the need for more research and, specifically,
well-developed longitudinal studies that can increase the current evidence base in
this area. It is a similar case for studies investigating the effects of psychological
distress on endothelial function.
Cardio-
vascular
Health Bone
Family
Health
Influence
Psychological
Academic Health
Success
Nutrition
Metabolic
Health
Pedagogy
Physical
Activity
Motor
Fitness Performance
& Control
The current and previous chapters focus purposely on the effect of psychological
health on cardiovascular health outcomes measured in the LOOK study. For
findings relating to the childhood phase of the study, the reader is referred to
chapter “▶ Stress, Depression, and Cardiovascular Risk in Children.”
In this chapter, we focus on the transition from childhood to adolescence. Firstly,
we address the changes in stress and depression during this period and, secondly,
Childhood Stress, Emotional Distress, and Cardiovascular Function in. . . 219
the relationships of these psychological variables with our two prognostic measures
of cardiovascular health, namely, endothelial function and arterial stiffness.
Measures
Emotional Distress
Cardiovascular Function
Endothelial Function
Endothelial dysfunction is commonly described as the “inability of the artery to
sufficiently dilate in response to an appropriate endothelial stimulus” and is an early
predictor of CVD (Heitzer et al. 2001; Lerman and Zeiher 2005). In the LOOK
study, endothelial function was assessed noninvasively using the EndoPAT 2000
(Itamar). The EndoPAT device captures a beat-to-beat plethysmographic recording
of the finger arterial pulse wave amplitude (PWA) with pneumatic probes and has
demonstrated reliability and validity as a measure of endothelial function among
adolescents (Selamet Tierney et al. 2009). EndoPAT measures have also been used
in accurately identifying the early stages of atherosclerosis (e.g., Bonetti
et al. 2004). The EndoPAT examination involves three phases: (1) the baseline
phase, which is recorded for 5 min; (2) the occlusion phase, where a blood pressure
cuff is inflated to suprasystolic pressure for 5 min; and (3) the reactive hyperemia
(RHI) phase, which occurs after the cuff is released and the signal is recorded for
5 min. “Reactive hyperemia is considered an important hemodynamic response to a
220 L. Olive et al.
period of ischemia. Reactive hyperemia increases blood flow and thereby the
delivery of oxygen and removal of metabolic products. After cuff deflation
(phase 3), the pulse amplitude of a healthy individual will rise rapidly, whereas a
low response is observed in individuals with endothelial dysfunction.”
Arterial Stiffness
Pulse wave velocity (PWV), a measure of arterial stiffness, was assessed noninva-
sively using the SphygmoCor system (AtCor Medical, Sydney, Australia).
Electrocardiogram-gated carotid and femoral waveforms were recorded using
applanation tonometry. Carotid-femoral path length was measured as the difference
between the surface distances joining (i) the suprasternal notch, the umbilicus, and
the femoral pulse and (ii) the suprasternal notch and the carotid pulse. Carotid-
femoral transit time was estimated in 8–10 sequential femoral and carotid wave-
forms as the average time difference between the onset of the femoral and carotid
waveforms. Pulse wave velocity was calculated as the carotid-femoral path length
divided by the carotid-femoral transit time.
Blood Pressures
Supine brachial blood pressure (BP) was determined using an automated
oscillometric Omron 7051T. The average of two measurements made at 1-min
intervals was recorded.
Metabolic Health
With a focus on the transition from childhood into adolescence, firstly, we inves-
tigated the effect of psychosocial stress and depression on the two prognostically
significant markers of CVD we have discussed, namely, endothelial function and
Childhood Stress, Emotional Distress, and Cardiovascular Function in. . . 221
the measure of arterial stiffness, pulse wave velocity (PWV). However, given we
have already reported the effects of physical activity, cardiorespiratory fitness
(CRF), and percent body fat on blood-borne CVD factors (Telford et al. 2014),
we have taken the opportunity to investigate the effects of psychosocial stress and
depression on physical activity, CRF, and percent body fat. For this part of our
study, measures were taken in grade 6 (11–13 years) and grade 10 (15–17 years).
Some 520 children (265 boys and 255 girls) completed all measures in grade 6, with
263 children (125 boys and 138 girls) completing all measures at follow-up 4 years
later. The natural attrition from a longitudinal study such as this is not likely to
affect relationships between our variables of interest, but it is pertinent to report that
the primary reason for attrition between intake and follow-up was movement of
families out of location, or absence on the day of testing.
Table 1 shows the characteristics of the participants at baseline (grade 6) of the
current investigation and 4 years later at follow-up (grade 10). The first thing we
observed was the change in psychological state during the important developmental
period spanning grade 6 (11–13 years) to grade 10 (15–17 years). Increases in both
222 L. Olive et al.
Table 2 Changes in children’s profiles for stress and depression from childhood to adolescence
% with a decrease in % with an increase in % remaining stable in
Scale stress/depression stress/depression stress/depression
Stress full 38.4 % 57.9 % 3.7 %
scale
Depression 17.9 % 76 % 6.1 %
full scale
a small but nonsignificant decrease over this period, which was again observed for
both boys and girls. As indicated in Table 1, boys were found to be significantly
more active than girls, a gender difference that has been maintained from early
childhood (Telford et al. 2013). Finally, a significant increase in percent body fat
was observed for girls, but in contrast, a significant decrease was observed among
boys. Given the differences found between boys and girls on these factors, it was
important to take gender into account when analyzing the effect of stress and
depression on these candidate variables for the combined cohort.
During the period of transition between late childhood and adolescence, our data
did not reveal any effects of stress and depression on our two measures of cardio-
vascular function for our cohort. When investigating longitudinal effects of stress
and depression on arterial stiffness, changes in depression and stress between grade
6 and grade 10 had no effect on change in arterial stiffness. Furthermore, cross-
sectional relationships at age 10 indicated that psychosocial stress and depression
had no significant effect on endothelial function or arterial stiffness at this late
adolescent phase in the LOOK cohort.
On the other hand, we found that changes in depression over this time period
were significantly associated with changes in CRF and percent body fat but not
physical activity. Increases in depressive symptoms were associated with a decrease
in CRF and an increase in percent body fat. These associations were found both
before and after adjusting for potentially confounding variables (CRF adjusted for
gender and height; and physical activity adjusted for percent body fat and gender).
However, we found no evidence of any effect of psychosocial stress on CRF,
physical activity, or percent body fat.
Taken together, findings arising from the adolescent phase of the LOOK study
indicate children as young as 12 years old are already experiencing stress and
depressive symptoms and more so in less fit and fatter children. We did not uncover
any direct impact of stress and depression on cardiovascular function, but we are
careful to point out that our tools of measurement may not have been sufficiently
sensitive. Considering the relationships between depression and percent body fat;
together with our previously published findings in this cohort of the impact of
changes in (1) percent body fat on other risk factors such as cholesterol (Telford
et al. 2014) and (2) cross-sectional relationships between physical activity and
percent body fat with blood and other risk factors for CVD (Sakuragi et al. 2009),
it does remain that depression and psychosocial stress in childhood and adolescence
may well be implicated in the risk of developing CVD in later life.
Indeed this premise is supported by previous publications outlined above. There
are a number of plausible reasons our data were not in agreement with any direct
effect of psychological factors on cardiovascular function, including differences in
measurement tools utilized to capture psychological disturbance. Most notably, the
224 L. Olive et al.
LOOK study relied on self-reports from children. Future studies would benefit from
using more detailed clinical interviews in capturing the level of distress and
symptom patterns to better discriminate between children who are experiencing
low mood versus those who are suffering clinical levels of depression. This level of
data collection presents its own set of logistical difficulties in large-scale research
projects such as LOOK, and detailed interviews were not viable in this particular
study. Furthermore, our participants were younger than those of previous studies.
This may have impacted on their understanding and ability to report on changes in
their psychological state and also on the progression of subclinical CVD markers,
such as arterial stiffness and endothelial function. Their young age may have
contributed to a greater uniformity and low incidence of any cardiovascular dys-
function, which again would tend to offset findings of any relationships between
their psychology and cardiovascular health.
Further to this observation, although our LOOK study data provided evidence of
increasing stress and depression as the children moved into adolescence, the level
of symptoms experienced for the majority of participants fell in what could be
characterized as a “psychologically healthy” range. We suggest that the level of
symptoms of stress and depression experienced by our cohort was, in general, not
severe enough to have a direct impact on cardiovascular function. The underlying
strength of the LOOK study lies in its longitudinal design and projection through to
stages during adulthood where cardiovascular disease will, unfortunately, become
evident. At this stage, we will be in a position to better interpret the symptoms
shown in childhood and adolescence in terms of their real risk of CVD.
Conclusion
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Bereavement and the Risk
of Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Bereavement and Risk of Mortality for the Surviving Spouse . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
Predictors of Increased Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Psychological Risk Factors During Bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Anger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Behavioral Changes in Bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
Biological Changes in Bereavement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Immune and Inflammatory Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 236
Prothrombotic State . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
Heart Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 238
R. Bartrop (*)
Discipline of Psychiatry, Sydney Medical School-Northern, St Leonards, University of Sydney,
Sydney, NSW, Australia
Department of Mental Health, Blacktown-Mt Druitt Clinical School, School of Medicine, Western
Sydney University, Sydney, NSW, Australia
e-mail: [email protected]; [email protected]
T. Buckley
Sydney Nursing School, University of Sydney, Sydney, NSW, Australia
Department of Cardiology, Royal North Shore Hospital, Sydney Medical School, University of
Sydney, Sydney, NSW, Australia
e-mail: [email protected]
G.H. Tofler
Department of Cardiology, Royal North Shore Hospital, Sydney Medical School, University of
Sydney, Sydney, NSW, Australia
e-mail: [email protected]
Abstract
“The doctor died unexpectedly at home. His wife of 45 years passed away 4 days previ-
ously. He was known for his professional, surgical expertise, and his compassionate care
for patients and their families.” From a notice in a local paper.
The death of a loved one has long been known to convey an adverse health
risk, including increased cardiac events, although the mechanisms remain uncer-
tain. While the mortality risk appears to be greatest in the initial weeks following
bereavement, it remains significantly elevated during the first 6 months. Despite
the difficulties conducting studies at this time, early bereavement has been
associated with neuroendocrine activation, hemodynamic and prothrombotic
changes, altered sleep, and immune imbalance, all of which may contribute to
increased cardiovascular risk. Further research, based on an understanding of the
underlying mechanisms and identified physiological changes, is required to
pursue the goal of reducing health risk during this major life stress.
Keywords
Bereavement • Neuroendocrine • Sleep • Immune • Prothrombotic • Heart rate •
Cardiovascular risk
Introduction
The death of a loved one is a ubiquitous and often highly stressful event, requiring the
bereaved to frequently make significant mental and social adjustments (Stroebe
et al. 2007). The mainstream media and even scientific literature still describes “death
from a broken heart” affecting the spouse following the bereavement. Well-conducted
epidemiological studies reveal an increased mortality risk for the surviving spouse,
although some of this risk has been critically debated as an association rather than
caused by the bereavement (Buckley et al. 2010). The response to bereavement,
commonly referred to as grief, persists for varying periods ranging potentially from
several weeks where the death is seen as a release from unbearable misery, to much
longer periods of months and, for some, even years of chronic psychological distress.
Bereavement can be further complicated for a surviving spouse, when that person is
often required to deal with simultaneous disruption to their home life, financial insecu-
rity, and limitation of past activities (Stroebe et al. 2007). In addition to the material
changes, there may be social isolation further impacting on cardiovascular health in the
longer term (Bunker et al. 2003). The death of a child has been rated to be more severe
than spousal bereavement (Goodenough et al. 2004; Miyabayashi and Yasuda 2007).
Bereavement and the Risk of Cardiovascular Disease 231
In recent years emotional stress has been strongly associated with accelerated
atherosclerosis and cardiovascular disease (CVD) events. In the case-control
INTERHEART study, which included 11,119 cases of acute myocardial infarction
(AMI) from 52 countries, perceived life event stressors and depressive illnesses
together accounted for 32.5 % of the population attributable risk (PAR) for coro-
nary heart disease (CHD), with a similar PAR to smoking and greater than hyper-
tension (PAR 17.9 %) and diabetes (PAR 9.9 %) (Yusuf et al. 2004). The role of
behavioral variables in CVD has long been suspected. An Australian National Heart
Foundation position statement (Bunker et al. 2003) found that acutely stressful life
events could trigger CVD events but that the relevant researchers were unable to
quantify their magnitude. Since then, further publications have supported the link
between acute stressors and CVD (Glozier et al. 2013). Acute psychological
stressors might trigger an AMI, via a surge in heart rate and blood pressure resulting
in increased myocardial oxygen demand and possible plaque disruption, vasocon-
striction, and a prothrombotic effect (Tofler et al. 2012).
Protection during times of peak risk of myocardial infarction requires innovative
preventative measures (Tofler and Muller 2006). However, the absence of insight
into the appropriate strategies during this known risk period has not led to trans-
latable measures in clinical practice.
This paper will discuss the evidence for increased CVD risk during the early
bereavement period, in order to identify risk factors in those who are vulnerable.
Additionally, the potential mechanisms of such risk need to be built into a putative
representation by which grief stressors may trigger acute CVD events to inform
future research directions.
Fig. 1 Relative risk of AMI following bereavement (Adapted from Mostovsky et al. 2014)
bias from environmental influences, and common lifestyles, accidents, age, ethnic-
ity, and education (Manor and Eisenbach 2003; Martikainen and Valkonen 1996).
The greatest mortality risk period for a surviving spouse appears to be the
immediate weeks following bereavement, although the risk remains elevated for
the first 6 months (Christakis and Iwashyna 2003; Hart et al. 2007). In the Renfrew/
Paisley Study, bereaved spouses had a relative risk of 1.27 compared to married
individuals, with the risk of death from CVD or CHD highest in the first 6 months
(RR 1.21 or 1.31, respectively), even after adjustment for known cardiac risk
factors (Hart et al. 2007). On the other hand, in one study of women aged
<70 years who had survived 4 years after bereavement, their subsequent hazard
ratio was reduced to 0.64 (Lichtenstein et al. 1998).
Among 1,985 subjects with symptoms suggestive of acute myocardial infarction
(MI) enrolled in the Myocardial Infarction Onset Study (MIOS), 270 (13.6 %) had
experienced a bereavement (close relative or friend) in the prior 6 months, includ-
ing 19 within 1 day prior to their MI. Comparing the frequency of bereavements in
the days preceding the onset of MI symptoms to its expected frequency using self-
matched control data by using a crossover design, the incidence rate of MI onset
was elevated 21.1-fold (95 % CI 13.1–34.1) within 1 day of the bereavement and
declined steadily on each subsequent day (Mostofsky et al. 2012) (Fig. 1). The
relative risk was fourfold increased for the first month and remained elevated for the
first 3 months after bereavement. Since angiographic data were not routinely
available in this population, some of the early cardiac events, especially in the
Bereavement and the Risk of Cardiovascular Disease 233
first day, were possibly due to Takotsubo stress cardiomyopathy rather than coro-
nary thrombosis (Glozier et al. 2013; Lindsay et al. 2010; Mostofsky et al. 2012).
Because of the greater longevity for women than men, spousal bereavement is
frequently a female phenomenon. However, men may be more at risk following
spousal death, especially in the initial 6 months (Manor and Eisenbach 2003). In
that study, increased risk was present across all age groups, although younger men
(<54 years) and older men (>75 years) are possibly most at risk. Among bereaved
women, increased mortality risk is also seen across all age groups, although those
aged <75 years may be most at risk of CHD-related death following death of a
spouse (Lichtenstein et al. 1998). Although an unexpected death might be expected
to result in a greater risk for the surviving spouse than an expected death, this has
not been consistently reported (Christakis and Iwashyna 2003) and remains an
important question for further study. Reduced social support has been linked to
an increased risk of CVD (Bunker et al. 2003). In one study, women with families
of one to three children had a lower risk than those with either no children or more
than three, suggesting that having no children resulted in less support, while more
than three may have added to the pressures of the grief and subsequent mortality
risk (Manor and Eisenbach 2003).
Depression
Symptoms of depression usually decline after the first few months of bereavement,
but in some bereaved, the symptoms remain unresolved at 6 months (Buckley
et al. 2009; Maciejewski et al. 2007). Both major depression and depressive symp-
toms in the absence of the constellation of diverse symptoms of major depression are
associated with increased CVD risk (Rozanski et al. 1999; Lichtman et al. 2008).
Although their relative contribution requires further elucidation, several potential
mechanisms have been proposed for the increased CVD risk during depression.
These include both behavioral risk factors, including medication nonadherence,
increased smoking and physical inactivity and direct biological mechanisms, such
as hypothalamic–pituitary–adrenal axis dysfunction, inflammatory and prothrombotic
234 R. Bartrop et al.
changes, dietary factors, low omega-3 fatty acid levels, and reduced heart rate
variability enhancing arrhythmogenic risks (Rozanski et al. 1999; Steptoe et al. 2006).
Anxiety
As with depressive features, anxiety symptoms usually peak early and decline after
the first few months of bereavement (Gerra et al. 2003; Buckley et al. 2009;
Maciejewski et al. 2007). A link between anxiety and increased risk of sudden
cardiac death has been suggested (Rozanski et al. 1999). While anxiety as a CVD
risk factor has not been studied as extensively as other psychosocial factors, a 2-year
follow-up study of 33,999 male health professionals in the United States aged
42–77 years and initially free of diagnosed disease, revealed the age-related relative
risk of fatal CVD was threefold greater for those having the highest levels of phobic
anxiety, compared with those with the lowest levels (Kawachi et al. 1994).
In the MIOS study of patients interviewed after MI, 5 % reported anxiety
symptoms above the 75th percentile on a standardized scale in the 2-h prior to
symptom onset (Mittleman et al. 1995). Using the case-crossover methodology,
when this time period was compared to a control period 24–26 h earlier, the relative
risk was 1.6 (95 % confidence intervals (CI) 1.1–2.2). Additional evidence also
indicates that higher symptoms of anxiety are associated with poorer outcome in
patients with prior cardiac disease (Benninghoven et al. 2006). Increased sympa-
thetic activation predisposing to life-threatening arrhythmias has been proposed as
a likely pathway for the increased cardiac risk during states of increased anxiety, in
addition to adverse behavioral risk factors (Rogowski et al. 2007).
Anger
Elevated anger symptoms due to frustration are not uncommon during bereavement
with one study suggesting a peak in anger at 5 months after loss (Maciejewski
et al. 2007). In the MIOS study, 39 (2.4 %) patients with MI reported anger 5 on a
7-point scale within 2 h of onset of MI symptoms. The relative risk was 4.0 (95 %
confidence intervals 1.9–9.4) compared to the same 2 h period the day before the MI
(Mittleman et al. 1995). An association between acute anger and MI was also
reported in a Swedish study of 700 patients (Moller et al. 1999), with a relative
risk of 9.0 (95 % CI 4.4–18.2) within 1 h after an episode of anger. Proposed
mechanisms include sympathetic activation resulting in increased heart rate and
blood pressure, prolonged vasoconstriction aggravating endothelial dysfunction,
and a prothrombotic state (Tofler et al. 2012; Mostovsky et al. 2014).
300
6.00
250
5.00
200
150 4.00
100 3.00
bereaved control bereaved control
*p<0.05
Fig. 2 Cortisol levels and self-reported hours of sleep (Adapted from Buckley et al. 2009).
Morning blood cortisol levels and self-reported hours of sleep in bereaved participants at
2 weeks (entry) and 6 months compared to non-bereaved controls in the Cardiovascular Health
in Bereavement Study.
particularly among widowed men make them more susceptible to CVD. In the
Sydney-based Cardiovascular Health in Bereavement Study (CARBER 1) study,
early bereaved subjects reported reduced appetite as well as lower cholesterol levels
(Buckley et al. 2009). Increased alcohol consumption has also been reported in
bereavement, particularly among men (Stroebe et al. 2007). Mor et al. (1986)
reported in a sample of mainly bereaved spouses that 6 % reported increased use
of alcohol and 18 % reported use of antianxiety medications. In the CARBER
1 study, 19 % of bereaved participants increased their alcohol intake in the first
2 weeks of bereavement with men more likely to increase their consumption than
women (Buckley et al. 2009). However, the complex relationship between alcohol
consumption and CVD risk warrants further investigation (Baer et al. 2002).
Altered sleep patterns in bereavement have been reported by several research
groups including the CARBER 1 study (Buckley et al. 2009) (Fig. 2). While
sleep disturbance in bereavement can become chronic and debilitating for some
individuals, it returns to pre-bereavement levels for most with uncomplicated grief
(Richardson et al. 2003). Disturbed sleep patterns are a prominent feature of
depressive symptomatology, affecting more than 80 % of people experiencing
such an illness (Armitage and Hoffmann 2001). Preservation of normal sleep has
been associated with less depression in bereavement (Armitage and Hoffmann
2001). Reduced sleep time as a sequel to an increased hypothalamic–pituitar-
y–adrenal axis stress reaction may exacerbate depressive symptoms, since a strong
bidirectional relationship between sleep and depression has been previously
suggested (Riemann et al. 2001). In view of reported links between sleep loss and
inflammatory activation (Irwin et al. 2006) and increased CVD risk (Taylor
236 R. Bartrop et al.
Cortisol
Immune changes have been well described in bereavement. The first study to report
immune changes found reduced lymphocyte responses to mitogenic stimulation at
2 and 8 weeks of bereavement (Bartrop et al. 1977). Since then, changes such as
altered T-cell subpopulations and natural killer (NK) cell activity have been
reported during bereavement (Goodkin et al. 1996; Irwin et al. 1988; Linn
et al. 1984), although it remains unclear what role, if any, these changes contribute
toward CVD risk. Altered T-cell responses have been reported by Bartrop
et al. (1977) at intervals following bereavement and by Schleifer et al. (1983) at
1 month following such a loss and at 12 but not 6 months following loss of a close
friend or partner in homosexual men participating in a longitudinal study of HIV-1
infection (Goodkin et al. 1996).
While reduced T-lymphocyte proliferation has been described in bereavement,
the absolute number of lymphocytes is not consistently altered (Gerra et al. 2003;
Irwin et al. 1988; Spratt and Denney 1991). One study of bereaved parents showed
subtle changes in lymphocyte subpopulations, with Spratt suggesting that parental
response to the death of a child may differ in physiological response to other
bereaved adult groups (Spratt and Denney 1991). An association between reduced
natural killer (NK) cell activity and bereavement has also been reported (Gerra
et al. 2003; Irwin et al. 1988). Higher depression scores have been associated with
an array of changes in inflammatory parameters including an absolute loss of
suppressor/cytotoxic cells and an increase in the ratio of T helper to T suppressor/
cytotoxic cells in bereaved women and, in some studies, lower immunoglobulin-M
levels at 4–6 weeks following loss and reduced lymphocyte response (Irwin
et al. 1988; Linn et al. 1984).
Bereavement and the Risk of Cardiovascular Disease 237
120
70,00
110
65,00
100 60,00
bereaved control bereaved control
*p<0.05 *p<0.05
Fig. 3 Von Willebrand factor levels and 24 h average heart rate in bereaved subjects versus
non-bereaved controls (Adapted from Buckley et al. 2011, 2012a). vWF-ag levels and 24-h
average HR in bereaved participants at 2 weeks (entry) and 6 months compared to non-bereaved
controls in the Cardiovascular Health in Bereavement Study
Prothrombotic State
Increased levels of von Willebrand factor (vWF) and increased platelet activation
have been observed in early bereavement by our research group, with both changes
resolving 6 months later (Buckley et al. 2012) (Fig. 3). Von Willebrand factor, a
major haemostatic regulatory molecule synthesized by endothelium and involved in
platelet aggregation, has previously been associated in other studies with
posttraumatic stress (von Kanel et al. 2008) and clinical depression (Morel-Kopp
et al. 2009). Increased platelet activation may also contribute toward CVD risk
(Wang et al. 2007). One approach to prevention of CVD for those at increased risk
in bereavement could be the prescribing for short-term use of antithrombotic
medications, such as aspirin, in the early weeks of bereavement, as has previously
proposed for other transient periods of increased risk (Tofler and Muller 2006).
Heart Rate
Both acute and chronic psychological stressors have been associated with increased
heart rates (HR). For instance, symptoms of anxiety were associated with raised HR
during exposure to laboratory-induced stress (Cumming et al. 2007) and during
times of mental stress in air force cadets (Falaschi et al. 2003). Likewise, symptoms
of anger have been associated with increases in HR (Fredrickson et al. 2000).
Twenty-four-hour monitoring carried out in the CARBER 1 study revealed
higher HR in the acutely bereaved compared with a non-bereaved reference
group, whereas at 6 months, HR in the bereaved had fallen to non-bereaved levels
(Buckley et al. 2012a) (Fig. 3). Higher HR was also associated with higher levels of
anxiety and cortisol, suggesting that elevated HR in bereavement is mediated by the
hypothalamo-pituitary-adrenal axis activation. In another study of ten bereaved
individuals assessed between 2 and 24 months following loss, the bereaved indi-
viduals had a higher resting HR, measured over a 5-min interval, compared to both
a depressed group and a nondepressed control group (O’Connor et al. 2002).
Elevated HR in bereavement may be a significant contributor to CVD risk in
early bereavement since higher HR has been linked to coronary artery plaque
Bereavement and the Risk of Cardiovascular Disease 239
rupture and CVD events (Heidland and Strauer 2001). In that study of patients with
existing heart disease, an increase of five beats per minute in a 24-h assessment, as
seen in the acutely bereaved participants in the Sydney-based CARBER study,
increased the risk of new coronary events by 14 %, after controlling for other risk
factors. Lower heart rates recorded during that study in those taking HR-lowering
medications, while not surprising, suggested to our research group that these
medications could be cardioprotective during early bereavement, especially in
those at increased CVD risk (Buckley et al. 2012a). Higher heart rates have been
linked to greater cardiovascular risk and mortality (Kizilbash et al. 2008) and
coronary artery plaque rupture (Heidland and Strauer 2001).
Blood Pressure
Discussion
Bereavement, a unique and ubiquitous psychological stressor where acute mood
symptoms of depression, anxiety, and anger may last for time periods extending
over several weeks or months, has been associated with increased morbidity and
mortality, most notably in surviving spouses. CVD events account for a substantial
proportion of such increased deaths during early bereavement. The risk is highest in
the early weeks of bereavement and continues for the first 6 months among all ages
and both genders. Our research and the work of others indicate that risk is elevated
irrespective of whether the death is expected or not, although social support at the
time of death appears to have a protective effect for the surviving spouse.
Recent advances have led to a greater understanding of the physiological
mechanisms of acute coronary events and activities that might promote such
acute changes. As a corollary, these data might provide new directions for future
physiological evaluations during bereavement. It is now accepted that most, but not
all, acute coronary occlusions occur as the result of rupture of an unstable athero-
sclerotic plaque and superimposed thrombus formation. But it is also known that
myocardial necrosis may occur secondary to coronary vasospasm, with or without
thrombus formation (Kloner 2006). Takotsubo stress cardiomyopathy may also
have similarities in presentation to acute myocardial infarction (AMI), although
without significant coronary stenosis or thrombosis (Wittstein et al. 2005).
A representation of the mechanisms by which bereavement may trigger MI and
sudden cardiac death has been proposed (Fig. 4). Evidence suggests that increased
heart rate and blood pressure, reduced heart rate variability, and prothrombotic
and inflammatory change may contribute but there remains a need for further
prospective longitudinal evaluations. While immune imbalance has been widely
reported during bereavement, future work is also needed to establish if these
changes are associated with CVD events. Nonetheless, the data are compelling
for a link between bereavement and increased cardiovascular risk, and evidence
supports potential mechanisms for the increased risk. Characterization of the
biological changes in bereavement is an important step toward identifying those
most at risk and provide encouragement to clinicians to monitor such individuals
more closely, particularly in the early weeks of bereavement. Since the loss of a
loved one is a universal experience, consideration should also be given to poten-
tial interventions to reduce cardiac risk, although large international collaborative
studies may be required to evaluate their effectiveness. Our research group
believes that the early bereavement period may be susceptible to increased cardiac
protection, particularly if risk factors such as elevated heart rate and blood
pressure, or increased procoagulant factors, are found to be elevated in
prospective evaluations.
Bereavement and the Risk of Cardiovascular Disease 241
Fig. 4 Representation of how bereavement may trigger Acute Myocardial Infarction and Sudden
Cardiac Death (Adapted from Tofler et al. 2012)
Conclusion
with longer-term follow-up data are required before such therapies could be
recommended broadly.
Since the work of Bartrop et al. (1977), studies have shown downregulation in
T-cell function as well as mobilization of inflammatory cells. These temporary
fluctuations have not yet been clearly shown to be related to increased cardiac risk.
Thus it is premature to consider interventions that promote immune function except
where certain inflammatory disorders are known to have a substratum of immune
suppression (Miller and Cohen 2001). Even though the significance of the immu-
nopathology is unclear, scope exists to minimize infections by appropriate hygiene
for the bereaved individual and initiating efforts to avoid contracting respiratory
infections. Hemodynamic and prothrombotic changes in early bereavement raise
the possibility that therapies that impact on these changes may reduce CVD risk; an
ongoing study (CARBER 2) is currently evaluating this hypothesis using low-dose
beta-blocker and aspirin.
Where possible, clinicians should also make themselves aware of and influence
potentially adverse behavioral changes in the early- or medium-term periods of
bereavement such as increases in tobacco and alcohol intake, as well as poor dietary
choices. Although the focus before bereavement is naturally directed toward the ill
or dying person, the health and welfare of bereaved survivors should be of great
concern to health care professionals, family, and friends.
Much has been achieved since predictions that there would soon be evidence of
physiological correlates of health risk in early bereavement. Now that evidence for
increased CVD risk is present in bereavement, it is time to consider and test
preventative interventions aimed at reducing the health risk during this significant
and universal period of exposure to a major life stressor. The key message,
however, is one of hope for a satisfactory passage through what is, after all, a
natural process and one that mankind will all have to navigate.
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Contents
Anxiety and Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249
DSM-V . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Prevalence of Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Anxiety and Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Anxiety Syndromes and Increased Cardiac Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Anxiety and Long QT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Heart Rate Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Ventricular Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255
Sympathetic Nervous System Activation in Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 256
Panic Disorder and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 258
Abstract
Anxiety disorders tend to be highly prevalent in heart disease, particularly
amongst patients recovering from acute cardiac events. Yet, the role of anxiety
in heart disease has not received as much attention in the literature as has
depression. Epidemiologic studies indicate that there is an increased risk of
Keywords
Anxiety • Heart disease • Psychogenic heart disease • Explanatory models •
Psychobiology
The link between the mind and heart is not an entirely new proposition; it has in fact
been a long-standing philosophical argument until the reductionist medical model
of health ultimately led to research and treatment of mental and physical diseases
being carried out separately by psychological and medical disciplines. Indeed, it
was Descartes who initially proposed dualism as an explanation for how mental and
physical processes were independent of one another (Descartes 1649). Yet this
philosophical proposition cannot deny both anecdotal and empirical accounts that
the body and mind work collaboratively rather than autonomously and that the
relationship between these systems appears to be bidirectional.
The recognition that emotions might be regulated as much by the heart as they are
by the mind supports an integrative approach between these seemingly unrelated
entities. The pioneering psychologist William James was of the clear view that our
emotions generally, and anxiety in particular, were little more than self-reports of
our subjective perceptions of the somatic changes occurring during the flight/fight
response (James 1892). And since the cardiovascular system figures too promi-
nently in that most basic of all systemic biological phenomena, it is not surprising
that the heart has been tied so closely to the experience of anxiety.
The epistemology of the heart and mind link is indeed more than a philosophical
argument that explores how mental processes have the capacity to influence the
manifestation of physical phenomena and vice versa; it also raises the challenge of
exploring precise mechanisms linking the body and mind. Pathophysiologic
Anxiety and Cardiovascular Disease: Epidemiology and Proposed Mechanisms 249
Anxiety
DSM-V
Anxiety is ubiquitous by nature, and its severity and prevalence can significantly
fluctuate over time, to a point where an individual might not meet clinical criteria
for an anxiety disorder but where anxiety and chronic worry might nonetheless be
evident. This can pose as a challenge when researching the role of this condition in
heart disease, particularly as subclinical levels of anxiety have also been found to be
linked to an increased risk of developing coronary heart disease (Rozanski
et al. 1999). Thus, further understanding of how anxiety may impact heart disease
risk may be enhanced by studies also including subclinical measures of anxiety. In
addition, anxiety is a more persistent disorder than depression and historically a
harder disorder to treat effectively; therefore, it could be argued that the role of this
condition in the pathogenesis of heart disease might require a novel research
approach to effectively elucidate the anxiety–heart disease link.
Prevalence of Anxiety
It has been estimated that anxiety disorders constitute the most prevalent psychiat-
ric diseases in the west, with the highest lifetime prevalence estimates ranging from
around 14 % to 29 % (Kessler et al. 2005). An anxiety disorder can be described as
“an umbrella term” which can manifest in various distinct forms such as panic
disorder, generalized anxiety disorder, obsessive compulsive disorder,
posttraumatic stress disorder, and various phobias (APA 2000), and while distinct,
these disorders have comparable cognitive, neurobiological, and behavioral com-
ponents both at the clinical and subclinical levels (Moser and De Jong 2006).
Anxiety disorders more often than not tend to be comorbid with other psychiatric
and physical diseases (Cameron 2007). Anxiety is highly prevalent in heart disease,
particularly among patients recovering from acute cardiac events (Kubzansky and
Arthur 2004) and in older adults suffering from heart disease (El-Gabalawy
et al. 2013). A survey of general practitioners published in the British Journal of
Cardiology in 2006 unveiled that rates of anxiety (30 %) were higher than for
depression (20 %) following myocardial infarction (Thornton et al. 2006). In
patients with unstable angina and myocardial infarction, rates of anxiety appeared
persistent 1 year after their acute cardiac event (Grace et al. 2004).
Anxiety also appears to precipitate heart disease. A meta-analysis of 20 studies
found that the presence of anxiety at baseline was associated with a 26 % increase in
risk of onset of heart disease (95 % CI, 1.15–1.38) and 48 % increase in cardiac
death (95 % CI, 1.14–1.92) in a nonpsychiatric sample over a mean follow-up
period of 11.2 years (Roest et al. 2010). Janszky et al. (2010) in a longitudinal study
spanning 37 years found that men diagnosed with anxiety, but not depression, were
more than twice as likely to develop coronary heart disease (CHD) compared with a
non-anxious matched sample. This appears to be supported by Rothenbacher et al.’s
(2007) earlier finding that in patients with coronary heart disease undergoing
cardiac rehabilitation, anxiety is a stronger predictor of long-term prognosis of
Anxiety and Cardiovascular Disease: Epidemiology and Proposed Mechanisms 251
relapse than depression. Anxiety has also been linked with an increased risk of
ventricular arrhythmias (Wilkinson et al. 1998), carotid atherosclerosis (Paterniti
et al. 2001), nonfatal myocardial infarction, and sudden cardiac death (Kawachi
et al. 1994, 1996).
Stress is closely related to the development and maintenance of anxiety and its
complications (Black and Garbutt 2002), and it has been associated with the risk
and the occurrence of cardiac disease (Mosovich et al. 2008). Rosengren
et al. (2004) reported that in the first-time myocardial infarction cohort of males
and females, across different countries, there had been a high prevalence of stressful
events in the 12 months preceding the acute cardiac event compared to a control
group. Patients experiencing ventricular fibrillation, without previous cardiac
pathology, have also described significantly greater incidence of severe to moderate
stressful events in the 6–24 months preceding their acute cardiac event (Lane
et al. 2005). Systematic evidence has been gathered at times of natural and
man-made disasters, which strongly support the link between stress and heart
disease (Leor et al. 1996; Meisel et al. 1991). Forty-eight hours after the 2001
Nisqually earthquake in Washington, USA, there was a significant increase in the
number of cardiac deaths ( p = 0.02) when compared to the number of cardiac
deaths at the same time in previous years (Gold et al. 2007). Earlier, Leor
et al. (1996) also reported an increase in mortality from cardiac causes as a result
of the 1994 Los Angeles earthquake. Sudden cardiac death related to atherosclerotic
cardiovascular disease increased from a daily average of 4.6 2.1 in the preceding
week to 24 on the day of the earthquake (z = 4.41, p < 0.001). During the six days
after the earthquake, their results showed a drop in the number of sudden cardiac
deaths to below baseline (Leor et al. 1996) (Fig. 1).
The effects of emotional stress in heart disease arising from “excitation” have
also been researched with the 2006 Football World Cup in Germany showing a
spike in incidences of cardiac emergencies having a positive correlation with the
national team playing at the tournament (Mendenhall et al. 2008). The research
team calculated incidence ratios for the 7 days of matches played by the German
team and the 24 days of matches not involving the German team as a control. They
then calculated incidence ratios for subgroups of patients, according to their final
diagnosis. Their results showed a significant increase in the incidence of acute
coronary syndrome and symptomatic cardiac arrhythmia when the German team
played as opposed to when they did not play at the tournament. The fans’ anguish
over whether their team would win the match was also evident with spikes in
cardiac events observed when the national team played with perceived good teams
as opposed to when they played with perceived poorer teams. These studies did not
examine preexisting levels of anxiety in their sample nor did they seem to account
for other potential sources of cardiac risk, such as spectators being sleep deprived,
252 M.E. Alvarenga and D. Byrne
Fig. 1 Daily numbers of Sudden Deaths Related to Atherosclerotic Cardiovascular Disease from
January 10 through 23, 1994
70 2003
5 6 2005
2006
60
Cardiovascular Events (no./day)
50 2
1
40 4
3 8
30
20
7
10
0
May 1 May 15 June1 June15 July 1 July 15 July 30
Fig. 2 Daily Cardiovascular Events in the Study Population from May 1 to July 31 in 2003, 2005,
and 2006
diet during World Cup matches, or whether medication had been neglected due to
preoccupation with World Cup match (Fig. 2).
A satisfactory definition of stress can of course be a complex matter, but it
cannot be denied that in a significant manner sudden stress incorporates a strong
element of acute anxiety.
Anxiety and Cardiovascular Disease: Epidemiology and Proposed Mechanisms 253
Most research investigating the role of anxiety in heart disease has predominantly
assessed symptom levels, and no differentiation has been made between different
types of anxiety disorders making up the research samples.
Batelaan et al. (2014) undertook a study examining the differential impact of
panic, phobia, and worry on a 3-year onset of nonfatal cardiovascular disease and
found that generalized anxiety disorder (GAD) was strongly associated with
nonfatal cardiovascular disease. Hammel et al. (2011) showed that GAD patients
displayed lower inter-beat heart rate and lower heart rate variability, indicating that
the worry type of anxiety disorders appears to substantially increase risk of cardio-
vascular disease through decreased parasympathetic activity and increased sympa-
thetic response. Martens et al. (2010) found the presence of GAD increased the risk
for subsequent major cardiac events between 61 % and 74 %, even after adjusting
for comorbid depression, indices of cardiac function, medication, and physical
inactivity. These findings are in keeping with previous research examining the
impact of worry on coronary heart disease (Kubzansky et al. 1997) and cardiovas-
cular mortality (Phillips et al. 2009).
Phobic disorders do not appear to be associated with increased risk of cardio-
vascular disease (Batelaan et al. 2014) as found in previous studies (Albert
et al. 2005; Haines et al. 1987; Kawachi et al. 1994) investigating this association
in men. However, Brennan et al. (2009) found an association between phobic
anxiety and higher serum concentrations of leptin and inflammatory markers in
254 M.E. Alvarenga and D. Byrne
women with diabetes which indicates that there might be marked gender differ-
ences in the way anxiety impacts cardiovascular disease.
Panic-type anxiety (panic disorder, posttraumatic stress disorder) has been
associated with increased cardiovascular disease risk (Alvarenga et al. 2006;
Coughlin 2011; Esler et al. 2004b; Gomez-Caminero et al. 2005; Walters
et al. 2008). Coryell et al. (1986) had earlier conducted a longitudinal study over
12 years and found that men with panic disorder were twice as likely to die from
cardiovascular disease and suicide. Several small studies have also found a link
between panic disorder and coronary artery disease and worry and coronary artery
disease (Frasure-Smith et al. 1995; Herrmann et al. 2000; Moser and Dracup 1996).
The prevalence of panic disorder in patients with coronary artery disease (CAD) has
been estimated to lie between 10 % and 50 % (Fleet et al. 2000). In some instances
this association may represent the secondary development of panic disorder in
people with existing cardiac disease. Longitudinal studies, however, do show that
panic anxiety acts also as an antecedent risk factor for CVD (Coryell et al. 1986;
Kawachi et al. 1996). Panic disorder sufferers are exposed to a range of cardiac
complications which can occur, including triggered cardiac arrhythmias, recurrent
emergency room attendances with angina and electrocardiographic changes of
ischemia, and coronary artery spasm, in some cases complicated by coronary
thrombosis (Mansour et al. 1998; Esler 1998; Goldstein et al. 2002). Indeed,
panic anxiety has been proposed as a better predictor of coronary artery disease
than depression (Zafar et al. 2010).
The Normative Aging Study (Kawachi et al. 1996) explored the relationship
between anxiety and cardiac death and found that psychogenic mortality was not
associated with increased risk of myocardial infarction; rather, it was associated to
sudden cardiac death. However, significantly high levels of anxiety have been
found after acute myocardial infarction (Moser and De Jong 2006), which has
been associated with longer hospital stays in the cardiac care unit, as well as
increased medical service utilization and lower quality of life (Chiou et al. 1997;
Mayou et al. 2000; Lane et al. 2001). It has to be noted that these studies have
mostly focused on men, while anxiety disorders are more prevalent among women
(APA 2000). Current American Heart Foundation figures show that since the
mid-1980s, the number of cardiovascular disease deaths in females has exceeded
that of men (AHF 2014).
Ventricular Arrhythmias
In other clinical contexts, most notably in patients with heart failure, activation of
the sympathetic outflow to the heart can also lead to the development of ventricular
arrhythmias and sudden death. The risk of fatal CAD events which has been shown
to increase during acute stressful events, such as fright during natural disasters, can
be attributed to the influence of the preferential activation of the cardiac sympa-
thetic outflow which occurs with acute mental stress (Esler et al. 2004b).
During the classic “fight-or-flight” stress response, sympathetic nervous system
activation leads to catecholamine release, which increases heart rate and
256 M.E. Alvarenga and D. Byrne
a dispositional tendency to exhibit exaggerated heart rate and blood pressure responses
when encountering behavioural stimuli as engaging, challenging or aversive. (Rozanski
et al. 1999, p. 2207)
Conclusions
The perception of threat and the development of chronic anxiety expressed either as
generalized anxiety disorder, panic disorder, or posttraumatic stress disorder appear
on the basis of a great deal of evidence to pose a real and severe danger to life
through their impact on the cardiovascular system. Anxiety in one clinical form or
another has been found to be associated with coronary artery disease and sudden
cardiac death, but not myocardial infarction, indicating that anxiety’s impact on the
heart might be both formative (as evidenced by its association with coronary artery
disease) and more abrupt and deadly than the impact of other psychosocial factors,
such as depression. The evidence documenting these associations is now suffi-
ciently well established and well accepted that there can be no doubt of a role for
anxiety in understanding at least some aspects of CVD. The psychobiology of this
link is also now well established and understood, giving greater credence to a claim
of causality as opposed to a simpler association explaining anxiety as more a
reaction to the experience of a serious physical condition (CVD). Anxiety in
those with already manifest CVD should certainly warrant appropriate psycholog-
ical management. However, the evidence reviewed in this chapter also quite clearly
underscores the need to take CVD as a potential sequel to clinical anxiety in some
identified patients and to implement targeted and evidence-based psychological
interventions in this light.
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Posttraumatic Stress Disorder and Risk
of Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
Definition and Diagnosis of PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267
PTSD and Incidence of Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268
PTSD and Incidence of Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
PTSD as a Consequence of Acute Cardiovascular Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270
Potential Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
Neurobiology of PTSD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272
Stress Reactivity in PTSD and IHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274
Vascular and Immune Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 278
Abstract
PTSD is a disabling mental disorder with health consequences that reach far
beyond the neuropsychiatric domain. Growing evidence links PTSD to increased
risk of cardiovascular conditions including ischemic heart disease and
V. Vaccarino (*)
Department of Epidemiology, Rollins School of Public Health, Department of Medicine, School of
Medicine, Emory University, Atlanta, GA, USA
e-mail: [email protected]
J.D. Bremner
Emory University School of Medicine, Atlanta, GA, USA
Mental Health Research, Atlanta VAMC, Decatur, GA, USA
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine,
Atlanta, GA, USA
e-mail: [email protected]
thromboembolic stroke. Emerging data also suggest that PTSD may be a con-
sequence, in addition to a cause, of acute, life-threatening cardiovascular events.
Individuals with PTSD are more likely to engage in adverse lifestyle behaviors,
which may predispose to cardiovascular risk factors such as obesity, diabetes,
and hypertension. PTSD is also frequently comorbid with other psychiatric
conditions which may affect cardiovascular risk, such as depression and sub-
stance abuse. However, additional plausible mechanisms exist that go beyond
these associated conditions and risk factors. An emerging model of cardiovas-
cular risk in PTSD is that neurobiology plays a role. Specifically, mechanisms
such as repeated and heightened physiological activation in association with
intrusive memories in PTSD could lead to cumulative long-term damaging
effects on the cardiovascular system. This could be mediated through vascular,
immune, or other mechanisms. This chapter will review the existing evidence
linking PTSD to major cardiovascular disorders, discuss potential underlying
pathophysiology, and provide suggestions for future research.
Keywords
Posttraumatic stress disorder • Cardiovascular disease • Stress • Myocardial
ischemia • Stroke • Acute coronary syndromes
Introduction
While these associated conditions and risk factors are likely to play a significant
role in the observed link between PTSD and CVD, other plausible mechanisms
exist, mostly related to the peculiar neurobiological features of this psychiatric
disorder. There are also emerging data to suggest that PTSD may be a consequence,
in addition to a cause, of acute coronary syndromes or acute stroke events, due to
the intense stress associated with these life-threatening episodes (Edmondson
et al. 2012, 2013).
In the past several decades, a wealth of studies have documented many physical
health problems in PTSD, especially cardiac symptoms (Wentworth et al. 2012).
However, until recently most of these studies have used a cross-sectional design,
which has limited the ability to infer a temporal relationship between PTSD and
cardiac conditions such as IHD (Qureshi et al. 2009; Vaccarino and Bremner 2013).
Studies that have used self-report assessments of cardiac symptoms are especially
problematic. There could be recall bias, and in fact PTSD patients tend to report
more symptoms and medical problems in general, not just IHD, compared with
persons without PTSD (Qureshi et al. 2009). There could be reverse causation,
since PTSD can be a consequence, in addition to a cause, of a heart attack
(Edmondson et al. 2012). Selection bias is also a potential problem, since many
studies have relied on clinical samples of self-referred patients who may have a
higher prevalence of medical problems compared with PTSD cases from the
general population.
In the past 10 years, a number of longitudinal studies have been published
linking PTSD symptoms or a PTSD diagnosis to IHD incidence (Boscarino 2006,
2008; Dirkzwager et al. 2007; Kang et al. 2006; Kubzansky et al. 2007, 2009;
Scherrer et al. 2010). All these studies have shown significant associations,
although many have lacked validated measures of IHD outcomes and have relied,
in several instances, on death certificate codes or administrative records. More
recent investigations that used objective measures of coronary atherosclerosis or
myocardial ischemia, however, have confirmed these observations (Ahmadi
et al. 2011; Turner et al. 2013; Vaccarino et al. 2013). These recent studies have
found substantial evidence of increased coronary artery disease or myocardial
perfusion abnormalities in individuals with PTSD compared to those without
PTSD. Ahmadi et al. studied veterans who underwent clinically indicated computed
tomography for evaluation of coronary artery calcification, a marker of coronary
atherosclerosis, and found that PTSD patients had twice the odds of coronary artery
calcification than those without PTSD (Ahmadi et al. 2011). In another veteran
sample from the Veteran Health Administration outpatient clinics, Turner
et al. found about twice the prevalence of myocardial ischemia assessed by exercise
electrocardiography (ECG) in patients with PTSD than those without PTSD (Turner
et al. 2013). These studies provide important new evidence for a link between
PTSD and IHD, but a remaining concern is possible selection bias because they
were based on clinical samples from medical encounters. Compared with persons
without PTSD, those with PTSD may differ in their likelihood to seek care, or to be
referred for, medical evaluation, or treatments for CVD, since they tend to report
more symptoms and health problems in general (Qureshi et al. 2009). Thus, PTSD
patients selected from hospitals or clinics may have an increased likelihood to be
Posttraumatic Stress Disorder and Risk of Cardiovascular Disease 269
diagnosed with IHD than it would be found in individuals with PTSD from the
community or patients without PTSD.
A recent twin study of PTSD and IHD was able to address this concern since it
was based on a registry of twins (Vaccarino et al. 2013). The study followed a
sample of 562 military veteran twins from the Vietnam Era who did not report a
previous history of IHD at baseline, when PTSD was measured with the Diagnostic
Interview Schedule (Robins et al. 1981) and when the mean age of the twins was
43 years. After an average follow-up of 13 years, IHD was measured. Assessment
included the occurrence of clinical events (myocardial infarction, other hospitali-
zations for IHD, and coronary revascularization) by self-report, in conjunction with
objective measures of IHD using myocardial perfusion imaging with N-13 ammo-
nia positron emission tomography (PET). Twins with PTSD were greater than
twofold more likely to report hospitalizations or revascularization procedures for
IHD over the follow-up compared with twins without PTSD (23 % vs. 9 %). The
association was robust to adjustment for lifestyle factors, IHD risk factors, and even
depression (adjusted odds ratio, 2.2, 95 % CI, 1.2–4.1). PET measures of coronary
perfusion and myocardial blood flow supported the self-reported results. A quanti-
tative measure of perfusion defects, the stress total severity score (STSS), was
significantly higher (+95 %, p = 0.001) in twins with PTSD than those without,
denoting almost twice as many myocardial perfusion abnormalities. PET-measured
coronary flow reserve was also lower in twins with PTSD compared to those
without PTSD ( 0.21, p = 0.02), denoting worse coronary microvascular function.
In addition, there was a graded association with increasing PTSD symptom quar-
tiles for both IHD events and STSS. Associations were only mildly attenuated
within 117 twin pairs discordant for PTSD, even after adjusting for traditional IHD
risk factors, health behaviors, depression, and other psychiatric diagnoses. Figure 1
shows a representative twin pair discordant for PTSD. The co-twin design that
compares brothers within twin pairs controls for unmeasured genetic and familial
confounders that could be shared between PTSD and cardiovascular diseases and
lends further support to a possible causal relationship between PTSD and IHD
(McGue et al. 2010).
In addition to IHD, there is also evidence that severe stress increases the risk of
stroke even after many years from the original exposure (Thurston et al. 2014;
Wilson et al. 2012), but data related specific to PTSD are limited. In a study of
former World War II prisoners of war (POWs), those with PTSD had an almost
twofold, albeit not statistically significant, increased risk of stroke, 13 % (20 of 158)
vs. 8 % (24 of 317), relative risk = 1.7, and 95 % confidence interval 0.95–2.9
(Brass and Page 1996). The small number of stroke events and the similarity of
exposures between POWs with and without PTSD are limitations of this study. This
study did find a sevenfold difference in stroke between POW and non-POW
veterans. In a cross-sectional survey of female veterans who received care at the
270 V. Vaccarino and J.D. Bremner
Fig. 1 Positron emission tomography myocardial perfusion scan in a representative twin pair. (a)
Twin with PTSD. (b) Twin without PTSD. In the polar maps on the left, the extent of
hypoperfusion is shown as blackout. The severity of hypoperfusion was quantified by a stress
total severity score (STSS) that measured the total number of standard deviations below the mean
for the entire extent of the abnormality compared to a normal database
VA Puget Sound Health Care System, there was an association between PTSD and
self-reported history of stroke, although, again, the number of stroke events was
small. Of the female veterans with PTSD, 5 % (13 of 256) reported a history of
stroke as compared with 3 % (28 of 905) of those without PTSD (age-adjusted odds
ratio = 2.9, 95 % confidence interval 1.4–6.0) (Dobie et al. 2004). A study of
trauma and PTSD among 3,171 men and women from a German community sample
found that those with a history of trauma or PTSD had higher odds of self-reported
stroke, as well as of other cardiovascular diseases, compared with those without
trauma, after adjusting for demographic factors, CVD risk factors, and lifestyle
factors (Spitzer et al. 2009). Thus, although more data are needed, the overall
evidence points to a possible increase in stroke risk associated with PTSD.
Potential Mechanisms
The mechanisms behind the relationship between PTSD and CVD incidence or
recurrence are not entirely clear and are likely to be multifactorial. It is believed that
acute CVD events are triggered by a confluence of several factors including
biological, environmental, and emotional factors, like a “perfect storm” (Arbab-
Zadeh et al. 2012). Maladaptive behaviors are likely to be important contributors,
272 V. Vaccarino and J.D. Bremner
Neurobiology of PTSD
low-frequency HRV than their brothers without PTSD ( p < 0.001). Remitted
PTSD was not associated with HRV. Results were robust to adjustment for depres-
sion and other risk factors. These data suggest that PTSD, especially current PTSD,
is associated with autonomic inflexibility indices previously shown to be prognostic
and that this effect might reverse with remission of PTSD (Shah et al. 2013).
One of the biological hallmarks of PTSD is enhanced sensitivity of the norad-
renergic system resulting in heightened SNS activity, particularly during trauma
reminders (Bremner and Charney 2010; Yehuda 2002; Zoladz and Diamond 2013).
For example, combat veterans with PTSD, compared with controls, exhibit an
increase in catecholamines, heart rate, and other physiological parameters in
response to reminders of trauma such as sound of gunfire, combat slides, or scripts
of their traumatic experiences (Blanchard et al. 1982; Pitman et al. 1987). They also
show altered brain function (especially decreased frontal lobe function) compared
to non-PTSD subjects in response to traumatic reminders (Bremner and Charney
2010). Most of these responses are not observed when using neutral stressors such
as mental arithmetic (Blanchard et al. 1982).
In addition to dysfunction of the autonomic nervous system, PTSD is character-
ized by dysregulation of the HPA axis. Overall, individuals with PTSD show
enhanced negative feedback sensitivity of the glucocorticoid receptors, as
evidenced by increased corticotrophin-releasing factor and decreased peripheral
cortisol concentrations at rest, suggesting that the HPA system may be
downregulated (Bremner and Charney 2010; Yehuda 2002; Zoladz and Diamond
2013). However, there is enhanced cortisol release with reminders of the trauma in
PTSD compared with controls. For example, women with abuse-related PTSD
listening to traumatic scripts had a fourfold salivary cortisol response than
women with abuse without PTSD (Elzinga et al. 2003). PTSD patients also show
increased cortisol response to the type of cognitive mental stress challenge used in
studies of patients with CVD (Bremner et al. 2003). Patients with PTSD, however,
have lower serial cortisol levels throughout the day and a blunted effect of dexa-
methasone on declarative memory function.
A commonly endorsed pathway for the increased CVD risk in PTSD is neuroen-
docrine, hemodynamic, and immune hyperreactivity during psychological stress,
which has been related to cardiovascular risk factors such as hypertension and to
CVD events (Chida and Steptoe 2010; Treiber et al. 2003). PTSD patients subjected
to a stress challenge in the laboratory involving personalized trauma scripts show
higher increases in blood pressure, heart rate, and other indicators of activated SNS
compared with controls (Bremner et al. 1999). Patients with depression and CVD
and a history of childhood abuse (many of whom had comorbid PTSD) showed an
increase in myocardial ischemia in response to mental stress relative to patients
with CVD without depression or abuse (Bremner et al. 2009). This suggests that
early abuse may play a role in sensitizing patients to stress-induced myocardial
Posttraumatic Stress Disorder and Risk of Cardiovascular Disease 275
Clinical Implications
PTSD is a common condition in the general population and in patients with CVD. It
is associated with considerable disability and impaired quality of life and is now
emerging as an important risk factor and prognostic factor for CVD. Nonetheless,
PTSD symptoms are often overlooked in general clinical practice. Clinicians who
care for patients in primary care settings or in cardiology clinics should be aware
that PTSD may have adverse effects on the cardiovascular system including
increased risk of adverse cardiovascular events and mortality.
In the United States alone, about one million patients are discharged each year
with a diagnosis of acute coronary syndrome (Go et al. 2014); of these, over
100,000 patients could develop clinically significant PTSD symptoms. In addition,
Posttraumatic Stress Disorder and Risk of Cardiovascular Disease 277
about 800,000 people experience a new or recurrent stroke each year, which may
translate into approximately 180,000 patients with PTSD secondary to stroke. To
these numbers, one should add PTSD cases that preexisted the onset of CVD. It
follows that PTSD could contribute substantially to repeat hospitalization, mortal-
ity, and an increase in healthcare costs associated with acute cardiovascular disease.
Effective pharmacological and psychotherapy approaches for the treatment of
PTSD and ameliorating symptomatic distress are available (Bandelow et al. 2012;
Sullivan and Neria 2009), but whether such treatments also reduce CVD risk is
currently unknown. Similarly untested is whether reducing symptoms of PTSD
would improve adherence and other health behaviors in PTSD patients. The
advantages and disadvantages of routinely screening for PTSD symptoms in car-
diac patients are also unknown. Several primary care centers within the Veterans
Health Administration in the United States routinely screen for PTSD using ques-
tionnaires such as the four-item Primary Care PTSD Screen (PC-PTSD). Although
this approach may be useful to detect undiagnosed PTSD in high-risk populations,
its utility for CVD prevention or treatment is unknown, and there are currently no
guidelines for screening in the nonveteran population at large.
In order to optimize clinical outcomes of patients with comorbid PTSD and
CVD, the cardiologist or primary care physician should seek psychiatric consulta-
tion as needed, which may also be helpful if associated problems are present, such
as depression and substance abuse. In addition, some medications for the treatment
of PTSD, especially the older tricyclic medications, may adversely affect cardio-
vascular function, and thus drug treatment, if needed, should be carefully evaluated
within the overall management of the patient.
Conclusion
It will also be of interest to identify risk factors for susceptibility to both PTSD
and CVD, such as whether there are specific exposures, or genetic backgrounds,
that might increase individual predisposition to both disorders. Furthermore, it will
be important to clarify predisposing factors that might make patients more vulner-
able to develop PTSD after an acute cardiovascular event. Finally, research should
be directed toward the identification of effective treatments that may help reduce
cardiovascular risk and improve prognosis among persons with PTSD. As the
scientific community will continue to discover the most important mechanisms
underlying the link between PTSD and CVD, clues can be derived about the most
promising targets for reducing CVD risk in PTSD. New trials of pharmacologic and
behavioral treatments for PTSD should examine the effects of PTSD symptom
reduction on these potential mechanisms and on CVD outcomes.
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Natural Disasters and the Risk
of Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 284
Epidemiology of Cardiovascular Effects Related to Natural Disaster . . . . . . . . . . . . . . . . . . . . . . . . 285
Earthquakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
Other Natural Disasters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Tsunami . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Hurricanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Terrorist Attacks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288
Individual Vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289
Takotsubo Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
The Association of Posttraumatic Stress Disorder and Cardiovascular Disease . . . . . . . . . . . . . . 292
Epidemiology of PTSD and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292
Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
Implications for Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Pragmatic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
Pharmacological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
Psychosocial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Abstract
Cardiovascular events are a major cause of morbidity and mortality worldwide.
Such events can be triggered by both acute and chronic mental stress caused by a
number of known stressors, one of these being natural disasters. Triggering of
J. Zarifeh
Consultation-Liaison Service, Christchurch Public Hospital, Christchurch, New Zealand
e-mail: [email protected]; [email protected]
R. Mulder (*)
Department of Psychological Medicine, University of Otago, Christchurch, New Zealand
e-mail: [email protected]
Keywords
Acute myocardial infarction (AMI) • Coronary artery disease (CAD) • Cardio-
pulmonary arrest (CPA) • Coronary heart disease (CHD) • Cardiovascular
disease (CVD) • Pulmonary embolism (PE) • Posttraumatic stress disorder
(PTSD) • Sympathetic nervous system (SNS)
Introduction
myocardial infarction (MI), unstable angina, or sudden cardiac death (Steptoe and
Brydon 2009).
Acute physical and psychological stress, induced by catastrophic events such as
natural disasters, can contribute to CVD morbidity and mortality (Watanabe
et al. 2008). The apparent growing number of natural disasters, their ramifications,
and increasing urbanization imply that health services must be prepared and
resourced to manage large numbers of patients with (acute and) chronic cardiovas-
cular disease symptoms in disaster situations (Miller and Arquilla 2008).
Earthquakes
caused “in a complex way by the consequences of the humanitarian catastrophe: the
trauma, the breakdown of lifelines (water, food, electricity, traffic, the emergency
system), evacuation, temperature changes and aspiration pneumonia” (Wilbert-
Lampen and Steinbeck 2012).
Whatever the mechanisms, it seems clear that the ramifications of a catastrophe
such as a large earthquake is a challenge to any healthcare system which is forced to
deal with increased cardiovascular disease, not only for the initial days, but for
months and possibly years afterward.
On the other hand, the data has not always been consistent when investigating
the impact of earthquakes on CVD. Brown (1999) reported that the 1989 magnitude
7.0 Loma Prieta earthquake in San Francisco, California, was not associated with an
increase in AMI. Similarly, no increase in acute myocardial infarction onset due to
physical and psychological stress was noted following the 5.6 magnitude earth-
quake in Newcastle, Australia, in 1989 (Dobson et al. 1991). These inconsistent
findings may be due to “the size and region of the earthquakes, the time of day that
the earthquakes occurred, the length of the study observation period, the number of
injuries/deaths, and the rates of recognition of cases” (Tsai et al. 2004).
A number of conditions may cause decompensation of preexistent chronic
cardiovascular disease or contribute to the onset of new CVD. Older age, poor
nutrition, infection, injury, and physical and mental stress were conditions
discussed as exacerbating risk of CVD by Sofia et al. (2012). Kako et al. (2014)
reviewed all research regarding disaster health following the Great East Japan
earthquake in 2011. They also highlighted the vulnerability of older people and
discussed the environmental stress and the psychological and physical stress of
dislocation and demobilization. A limitation of the observational, population-based
studies is that the circumstances surrounding each cardiac event are not well
defined, and analyses usually take place weeks, months, or even years after the
trauma. Information about how the individuals who were affected specifically
experienced the trauma is seldom collected, making it difficult to prove a causal
link or to rule out alternative explanations of associations between disasters and
increased cardiovascular risk.
Tsunami
Prior to 2011 no study had investigated the impact of tsunamis on the incidence of
cardiovascular disease. Nakamura et al. (2012) reported that following the March
2011 tsunami which affected the northeastern coast of Japan, the number of
patients with acute decompensated heart failure in the tsunami area was around
twice the number compared to the pre-disaster period. They concluded that large
and sudden changes in daily life and the trauma associated with a devastating
tsunami have a significant impact on the incidences of acute decompensated heart
failure.
288 J. Zarifeh and R. Mulder
Hurricanes
Terrorist Attacks
While not strictly fulfilling the definition of a natural disaster, terrorist attacks have
many similar features; they occur with little or no warning and are associated with
much physical and psychological distress. Chi et al. (2003) investigated the rela-
tionship between the terrorist attacks of September 11, 2001 in the USA and cardiac
morbidity and mortality. They reported no acute increases in hospitalizations for
cardiac events after the September 11 attacks in the NYC hospitals they studied.
The authors speculated that cardiac events that occurred inside the World Trade
Center may have been masked by deaths, from crush or burn injuries, or that
exposure to an emotional or a psychological stressor may have to be direct to
trigger an adverse response. In contrast Goldberg et al. (2005) and Steinberg
et al. (2004) reported increased rates of AMI and ventricular arrhythmias, respec-
tively, in patients living in NYC. Their reports however were limited by small
sample sizes and failure to correct for seasonal variation in ventricular arrhythmias.
Jordan et al. (2011) reported that 9/11-related PTSD was associated with elevated
heart disease risk several years after the disaster.
Mechanisms
Individual Vulnerability
In humans there are substantial differences in the perception of stress and in the
subsequent physiological processes with inconsistent consequences across individ-
uals. Although stressors are often associated with illness, the majority of individuals
confronted with a traumatic event will remain disease-free. Therefore, there has
been considerable interest in identifying individual differences in vulnerability to
the potential pathogenic effects of stress with emphasis on genetic and psycholog-
ical factors (Cohen et al. 2007). One consistent difference reported is a stronger
association of emotional distress with AMI in women. This relationship extends to
traumatic events like earthquakes (Culic 2007) and suggests that the
290 J. Zarifeh and R. Mulder
Fig. 1 Hypothesized links between acute emotional triggers and clinical cardiac events, mediated
through physiological responses and their pathophysiological consequences (Adapted from
Bhattacharyya and Steptoe 2007)
Takotsubo Cardiomyopathy
Allostasis Adaptation
Allostatic load
Hypothalamus-pituitary-adrenal axis Sympathetic nervous system
Cardiovascular disease
The advantage of the emotions is that they lead us astray, and the advantage of science is
that it is not emotional.
(Oscar Wilde, The Picture of Dorian Gray, 1981)
There is overwhelming evidence both for the deleterious effects of stress on the
heart and for the fact that vulnerability and resilience factors play a role in
amplifying or dampening the effects of stress (Dimsdale 2008). Posttraumatic stress
disorder (PTSD) is the most studied and probably the most frequent and debilitating
disorder that occurs after traumatic events and disasters (Galea et al. 2005). PTSD
has been defined as an anxiety disorder initiated by exposure to a traumatic event,
characterized by intrusive thoughts about the event, attempts to avoid reminders of
the event (cognitive and behavioral), and heightened physiological arousal. Studies
report that regardless of the study population, the type of stressor exposure, or the
cardiovascular measures used, there is an association between PTSD and the onset
of CVD.
There have been nearly 100 disease studies conducted and published in the after-
math of a natural disaster, many noting an association between CVD and PTSD
(Kubzansky and Koenen 2009; Coughlin 2011; Boscarino et al. 2004). Substantial
rates of PTSD (ranging from approximately 5 % to 60 %) have been reported, with
rates differing according to length of exposure to trauma, and whether people have
been directly affected or less directly exposed.
Edmondson and Cohen (2013) summarized the findings of five prospective
cohort studies (with a total of 401,712 participants) – estimating the association
between PTSD with incident CVD and/or mortality. These studies adjusted for
multiple demographic, clinical, and psychosocial factors including depression.
They followed up participants from 1 to 30 years. The effect sizes reported range
from a hazard ratio for incident CVD and/or cardiac mortality of 1.46–3.28.
Another prospective study by Jordan et al. (2011) using 39,324 World Trade Center
Health Registry participants reported that men and women with PTSD at study
enrolment had significantly elevated risk of heart disease and that this risk had a
dose-response relationship with PTSD symptoms.
As well as exposure to an event, there are also a number of risk factors for PTSD
which increase the rate of PTSD across multiple studies. More vulnerable are
women, persons with preexisting or concurrent psychiatric comorbidity or previous
Natural Disasters and the Risk of Cardiovascular Disease 293
ABNORMAL
HPA METABOLIC ↑ ARGININE
SYMPATHETIC
DYSFUNCTION SYNDROME VASOPRESSIN
ACTIVATION
HYPER- CARDIAC
COAGULABILITY REACTIVITY IMMUNE
DYSFUNCTION
↑ platelet reactivity Hypertension
↑ inflammatory
↑Resting heart rate
cytokines
↓Heart rate variability
ENDOTHELIAL DAMAGE
↑ sTF
↑ VWF
↑ Coronary artery calcium
↓ Brachial reactivity ATHEROSCLEROSIS
CARDIOVASCULAR DISEASE
Fig. 3 Potential paths to cardiovascular disease in PTSD. PTSD indicates posttraumatic stress
disorder, HPA hypothalamic-pituitary-adrenal, CRH corticotropin-releasing hormone, sTF, vWF
von Willebrand factor (Adapted from Wentworth et al. 2013)
exposure to traumatic events, people of lower SES, those from an ethnic minority,
and those of older age (Galea et al. 2005; Bartels and VanRooyen 2012). Given the
consistent findings of these studies on PTSD and CVD, attention has turned to
understanding the pathologic mechanisms that connect these two disorders.
Mechanisms
There is no single causal pathway explaining the association between PTSD and
CVD, and it is likely to involve multiple pathways including behavioral risk factors
(Boscarino 2011).
Edmondson and Cohen (2013) classified potential mechanisms relating CVD
and PTSD into three categories. The first was biological risk factors, namely,
dysregulation of the hypothalamic-pituitary- adrenal (HPA) axis, autonomic ner-
vous system dysfunction, and increased inflammation. The authors commented on
how PTSD arises in response to overwhelming external stress, but simultaneously
generates ongoing internal distress. The second mechanism was behavioral risk
factors including medication nonadherence, substance abuse, decreased physical
294 J. Zarifeh and R. Mulder
Pragmatic
The response to natural disasters is generally that during the early phases attention
is focused on the care and prevention of primary illnesses, such as traumatic
injuries. However secondary illnesses comprise a sizeable disease burden
(Miller and Arquilla 2008). Negative effects on the cardiovascular system, if left
untreated, may be long lasting and possibly irreversible, resulting in permanent
elevation of CVD risk.
The identification of individuals at higher risk of becoming ill (Kurita
et al. 2001) is the essential first step in prevention programs aimed at reducing
the adverse effects of major disaster on health. Given the known risks associated
with the development of CVD following a natural disaster, there are some general
principles of prevention (Kurita et al. 2001). These include minimizing coronary
risk factors, regular physical examination of those patients with structural heart
disease (cardiomyopathy, congenital heart disease), avoidance of temperature fluc-
tuations and heavy physical activity, and monitoring of and adherence to prescribed
medications.
Ford et al. (2006) have promoted a behavioral risk factor surveillance system
(BRFSS) measure as a way of providing useful baseline information about the
number of people with cardiovascular and other chronic diseases and the treatment
that they receive. This may be useful to help assess the needs of already vulnerable
people after disasters and assist in planning relief efforts.
To better triage for disaster-associated cardiovascular events, Kario
et al. (2011) developed a web-based disaster cardiovascular prevention (DCAP)
network and have begun to implement it with survivors of the 2011 Japan disaster.
The DCAP system uses a risk score to identify survivors at higher risk of
Natural Disasters and the Risk of Cardiovascular Disease 295
Pharmacological
Psychosocial
fewer ischemic episodes during ECG monitoring, and fewer cardiovascular events
during follow-up (Blumenthal et al. 1997).
Transcendental meditation has also been widely studied in the scientific litera-
ture with results supporting its usefulness for treating a variety of cardiovascular
diseases and risk factors (Schneider et al. 2006). Data pooled from two randomized
trials with overall mean follow-up of 7–6 3.5 years show reduced all-cause and
cardiovascular mortality with transcendental meditation compared with combined
control groups (Walton et al. 2004).
Diverse and effective intervention programs have been tested in heart
patients that provide formal psychotherapy, psychotropic medications, time
management training, progressive relaxation training, meditation, and regular
exercise. The majority of these intervention programs improve patient morale
and functioning and decrease suffering. Therefore it would seem appropriate to
study such treatment programs for individuals and populations demonstrating
signs and symptoms of psychosocial stress following a natural disaster. It may
be time to develop and implement guidelines for both short- and long-term care
before, during, and in the immediate aftermath of natural disasters (Mokdad
et al. 2005).
Conclusion
professionals in preparing for the medical care of people with both acute and
chronic diseases after a disaster.
The field of behavioral cardiology would benefit from the development of
practical interventions since the etiologic links between psychosocial risk factors,
behavioral risk factors, and CVD are now consistently reported. Cardiologists will
regularly encounter patients with psychological distress and unhealthy behaviors in
their clinical practice. Therefore the development of interventions that may reduce
the behavioral and biological sequelae of natural disasters and the testing of their
efficacy in randomized clinical trials would provide important data to help people
following these very traumatic events.
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Psychoses and Cardiovascular Disease: The
Heart and Mind of the Matter
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304
Etiology and Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
Treatment and Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 310
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312
Abstract
Cardiovascular disease and its risk factors are markedly overrepresented in
people suffering with psychotic disorders such as schizophrenia. Adverse
sequelae of this association include heightened mortality, worsened quality of
life, and course of mental illness. Of further concern are that cardiovascular
disease is underreported and neglected in this population as well as low rate of
metabolic screening. The relationship of cardiovascular disease to psychosis is a
complex one, with core symptoms of psychosis, poor diet, smoking, sedentary
lifestyle, and socioeconomic factors predisposing to cardiovascular risk. These
factors act in combination with iatrogenically induced risk factors attributed to
antipsychotic medication, in particular weight gain. There are also syndromes
that predispose to both psychosis and cardiovascular disease, including
velocardiofacial syndrome, homocystinuria, and Cushing’s syndrome and pos-
sibly pro-inflammatory mechanisms. Psychotic symptoms are also
independently associated with coronary artery bypass and valve surgery. Stress
plays a role in the negative impact on both psychosis and cardiovascular disease
via the hypothalamic-pituitary-adrenal axis.
Regular metabolic monitoring and intervention for identified cardiovascular
risk factors in psychosis are mandatory. The latter includes education about diet,
exercise, and cardiac risk factors, as well as minimization of weight gain and
sedation associated with antipsychotic medication, with switching to more
weight-neutral and tolerable medication options. Metformin appears to have a
role in ameliorating antipsychotic-related weight gain. While there is a limited
evidence base about psychological and psychotherapeutic interventions for pri-
mary or secondary prevention of cardiac disease in people with psychoses,
behavioral and lifestyle interventions have emerged as showing benefit.
Varenicline, a medication not without its propsychotic risks, may also comple-
ment these lifestyle interventions via facilitation of smoking cessation.
Keywords
Schizophrenia • Psychotic disorder • Cardiovascular • Metabolic monitoring •
Intervention • Mortality • Lifestyle
Introduction
Cardiovascular disease and its risk factors are markedly overrepresented in people
suffering with psychoses. This includes first-episode patients with psychosis
(De Hert et al. 2008; Galletly et al. 2010). Comorbid cardiovascular disease in
schizophrenia impacts adversely on quality of life, as well as the course and severity
of the mental illness itself (Fagiolini and Goracci 2009). Mortality associated with
cardiovascular disease in psychosis is two to four times that of the general population
(Castillo et al. 2013), notwithstanding that there is an inherent 20 % lifespan
reduction in schizophrenia compared with the general population (Hennekens
et al. 2005). Alarmingly, in a large population-based survey of Australian adults
with psychosis: three-quarters were overweight or obese, about half were hyperten-
sive, two-thirds were current smokers, half had abnormal lipid profiles, a third had
elevated fasting glucose, greater than half met criteria for metabolic syndrome, and
the overall level of physical activity level was very low (Galletly et al. 2010).
Moreover, a retrospective cohort analysis of patients in primary care found that
people suffering with schizophrenia had earlier onset of cardiac risk factors and
disease than those with affective psychoses and those without disabilities
(McDermott et al. 2005). Concomitantly, cardiovascular disease in people with
psychoses can be underreported (De Hert et al. 2011; Smith et al. 2013) or even,
more disconcertingly, neglected (McNamee et al. 2013). Also, screening for the
metabolic syndrome is low in this population (De Hert et al. 2011). About one in six
patients with schizophrenia in a large survey across Europe reported experiencing
discrimination when accessing general medical care (Harangozo et al. 2013). Of
further concern, people suffering psychosis may not consider themselves to be at risk
Psychoses and Cardiovascular Disease: The Heart and Mind of the Matter 305
of cardiovascular disease and consequently do not attend for physical health mon-
itoring (Campion et al. 2005).
The term “psychosis” broadly and nonspecifically covers a clinically significant
distortion or abnormal inference of reality across a spectrum of diagnostic syn-
dromes. On utilization of modern classification systems such as the Diagnostic
and Statistical Manual of Mental Disorders, Fifth Edition (APA 2013) and the
International Classification of Diseases, Tenth Edition (WHO 1994), these syn-
dromes include schizophrenia and related disorders, major depression and bipolar
disorder with psychotic features, substance induction and intoxication or withdrawal
states, delirium, and neuropsychiatric disorders such as dementia. Transient psy-
chotic experiences may also occur as part of a continuum in the general population
(van Os 2009) and in those with personality vulnerabilities in the setting of signif-
icant stressors. This chapter will focus on “psychosis” in the context of schizophre-
nia and related disorders (Table 1).
death with antipsychotic medication (Ray et al. 2009), with ziprasidone, olanzapine,
haloperidol, thioridazine, and pimozide being most associated with QT prolongation
(BMJ 2010). Prolongation of the QT interval, which is associated with increased risk
of potentially fatal arrhythmias, such as torsade de pointes (polymorphic ventricular
arrhythmia), can occur in people presenting with acute psychosis, whether they are
prescribed antipsychotic medication or not. The mechanisms of prolonged QT
interval in this acute setting, apart from that associated with prescribed antipsychotic
medication, include hypokalemia (Hatta et al. 2000) and increased prevalence of
underlying cardiovascular disease and associated risk factors in people with schizo-
phrenia (Haddad and Anderson 2002; Lahti et al. 2012). Although the evidence
about the mortality associated with QT prolongation is conflicting, greater prolon-
gation and underlying cardiovascular or hepatic disease increase the risk of arrhyth-
mia (Mackin 2008).
Greater than half of people with severe mental illness, including psychosis, have
metabolic syndrome (John et al. 2009). While 40 % of people in this population have
impaired fasting glucose, the risk of diabetes in people with psychosis is up to six
times that of the general population, with the young at greatest risk (Lambert 2011).
Certain ethnic groups have greater predisposition to develop diabetes, including
people from Asia, the Middle East, and the Indian subcontinent and African and
Latin Americans (Lambert 2011). People in whom certain antipsychotic medications
have been prescribed are at up to five times at risk of hyperlipidemia in comparison
with the general population, with low levels of HDL and high triglyceride levels in
greater than half of those with psychosis (John et al. 2009).
Metabolic syndrome not only increases cardiovascular risk, but also that of stroke
and diabetes in people with psychosis. This is true for people with psychosis as well
as the general population. Metabolic syndrome refers to the presence of at least three
of the following cardiovascular risk factors: large waistline circumference (at least
102 cm in men and 89 cm in women), high triglyceride level (at least 150 mg/dL or
1.7 mmol/L), low-density lipoprotein (LDL) level (less than 100 mg/dL or
2.6 mmol/L in patients with high risk for cardiovascular disease, including
established disease and diabetes, and less than 160 mg/dL or 4.9 mmol/L in patients
at low risk for cardiovascular disease), high-density lipoprotein (HDL) level (less
than 40 mg/dL or 1.04 mmol/L in men and 50 mg/dL or 1.3 mmol/L in women),
hypertension (at least 130/85 mmHg), and high fasting glucose level (at least
5.6 mmol/L or >100 mg/dL) (Grundy et al. 2005).
While weight gain and metabolic dysfunction/syndrome is often secondary to
certain prescribed antipsychotic medication for the treatment of psychosis, insulin
resistance and hyperglycemia are also present in people suffering with psychotic
disorders who are medication naive. The antipsychotic medications that are partic-
ularly prone to these metabolic sequelae are olanzapine, clozapine, and quetiapine
(Ojalaa et al. 2008).
Smoking, a major risk factor for cardiovascular disease in its own right, is also
overrepresented in psychoses and the most common form of substance abuse in
Psychoses and Cardiovascular Disease: The Heart and Mind of the Matter 307
Clinical Implications
Assessment
Unfortunately, the screening for cardiovascular risk factors in people with psychosis
(Roberts et al. 2007), and the treatment of identified cardiovascular risk factors in
people suffering with schizophrenia and related disorders, is far from optimal
(Johnsen et al. 2011). Given the excess mortality in people suffering with psychosis,
regular metabolic monitoring and intervention for identified cardiovascular risk
factors is essential (Grundy et al. 2005; Organ et al. 2010).
Integrated, coordinated (e.g. recovery-focused care with a key coordinating
clinician), and holistic patient-centered care (Viron et al. 2012) approaches should
be the rule rather than the exception. Such care packages should entail primary care,
mental health, and allied health clinicians communicating and working collabora-
tively. This, in turn, is more likely to be an optimal framework for healthcare in this
vulnerable population, rather than a range of clinicians working in isolation from one
another. But, there has not been comprehensive evaluation of the effectiveness of
patient-centered care in people with psychosis, with, or at risk for cardiovascular
disease.
Monitoring for cardiovascular disease and its risk factors in psychosis is best
served in tandem with education about diet, exercise, and cardiac risk factors. These
should occur on at least a six-month basis. The monitoring includes fasting blood
glucose, body mass index, serum lipids (cholesterol, LDL, HDL, triglycerides), urea,
and electrolyte and liver function tests (Grundy et al. 2005).
Disconcertingly, antipsychotic medications are associated with significant weight
gain in at least half of people suffering with psychosis (Baptista 1999), including
first-episode patients. This is particularly true for olanzapine and clozapine (Ohlsen
2011). The risks of weight gain with antipsychotics are mediated by significantly
increased insulin levels and resistance and escalated glucose, cholesterol, triglycer-
ide, and C-peptide levels (Lancet 2011). This is in addition to the adverse impact of
these medications on histamine, dopamine, and 5HT2C blockade (Ohlsen 2011).
While these effects are not significantly different across olanzapine, risperidone,
sulpiride, and clozapine combined (Lancet 2011), olanzapine, clozapine, and
quetiapine are associated with a heightened risk of hyperlipidemia and metabolic
disturbance. The latter is lower with risperidone, aripiprazole, and ziprasidone
(Muench and Hamer 2010). Consequently, monitoring for and minimizing weight
gain and sedation associated with antipsychotic medication is essential in this
population and expressly for those on olanzapine, clozapine, and quetiapine.
Clozapine, a dibenzodiazepine antipsychotic medication, is efficacious in people
suffering with “treatment-resistant” schizophrenia, who have not had benefit with
therapeutic trials of other antipsychotic medication despite adequate dosage and
310 P. Bosanac and D. Castle
barriers to physical activity in people with schizophrenia are mediated by positive and
negative psychotic symptomatology, weight gain, and other medication side effects, the
specific factors in clinical practice that promote active engagement in increased physical
activity in people with psychosis require further study (McNamee et al. 2013).
In terms of an emerging evidence base, a novel healthy lifestyle intervention,
centered on primarily mitigating smoking and cardiovascular risk factors in people
with serious mental illnesses, including psychosis, was initially evaluated as a pilot
study. The pilot study found that goal setting and support for patients to modify their
unhealthy lifestyle led to improvements in cardiovascular risk, smoking (with nicotine
replacement therapy), weight, and physical activity. The latter was in the context of the
vast majority of patients completing all sessions (Baker et al. 2009). Following on from
this pilot study, the authors published a protocol for a larger-scale randomized control
study, in which participants are to be randomized to either a multimodal intervention or
telephone-based intervention for smoking after an initial face-to-face intervention
(Baker et al. 2011). Varenicline, a partial nicotine receptor agonist, which is prescribed
to reduce nicotine cravings and withdrawal, has also been utilized by this research
group in a small open-label pilot study as an adjunct to a healthy lifestyle intervention in
smokers with a psychotic disorder (Castle et al. 2012). The combination of varenicline
and the lifestyle intervention was associated with smoking cessation of 36 % and 42 %
at 3 months and 6 months, respectively. However, varenicline does carry psychotogenic
risks in both people with and without (Bancila et al. 2009) a history of psychosis (Gupta
et al. 2012) and needs to be used with due care and careful mental state monitoring.
Also, with all such interventions, long-term sustainability is difficult.
A joint primary health and mental health initiative, involving combined clinical
sessions and a shared protocol, demonstrated that the recording of cardiovascular
disease risk factors in people with psychosis (hypertension, glucose, lipid status,
waist circumference, smoking) significantly improved across these healthcare set-
tings (Vinas et al. 2013).
There also appears to be a role of metformin in mitigating metabolic sequelae
associated with antipsychotics (Curtis et al. 2012) and controlling glycosolated hemo-
globin (HbA1c) in people with psychoses suffering with diabetes or who are prescribed
antipsychotic medications (Gierisch et al. 2013). Metformin’s actions in this regard
include the inhibition of gluconeogenesis in the liver, improving insulin sensitivity, and
the peripheral uptake of glucose (Taylor 2012). But this intervention, along with
potential benefits of augmenting clozapine with aripiprazole or switching from another
antipsychotic (olanzapine, quetiapine, or risperidone) to aripiprazole in tandem with a
manual-based diet and exercise intervention) or adding topiramate, was
counterbalanced by limited information about any potential harm (Gierisch et al. 2013).
Conclusions
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
Historical Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
Models of Occupational Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
Occupational Stress and CVD Risk Marker Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Cigarette Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Blood Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
Fibrinogen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Occupational Stress and Incidence of Clinical CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Case-Control Studies (Theoretically Based) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
Case-Control Studies (Atheoretical) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Prospective Studies (Theoretically Based) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
Prospective Studies (Atheoretical) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
This chapter presents a revised version of a paper originally published in Stress and Health (2008),
24, 231–238, (Wiley Interscience) by the present authors (Byrne and Espnes). The revision has
been made with the permission of the publisher.
D. Byrne (*)
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
ANU Medical School, Research School of Psychology, Australian National University, Acton,
Canberra, ACT, Australia
e-mail: [email protected]
G.A. Espnes
Center for Health Promotion Research, Department of Social Work and Health Science,
Norwegian University of Science and Technology (NTNU), Trondheim, Norway
Australian National University, Canberra, ACT, Norway
e-mail: [email protected]; [email protected]
Abstract
This chapter reviews the evidence relating occupational stress (OS) to risk and
incidence of cardiovascular disease (CVD), from the simple notion of occupa-
tional level and type as a risk marker to the more complex and theoretically more
sophisticated models of occupational stress as a determinant of cardiovascular
risk and disease. It does so by mapping measures of occupational stress against
the three related CVD end-points of coronary risk profiles, clinical hypertension,
and diagnosed events or episodes of clinical cardiovascular disease. Taken
broadly, the evidence is consistently supportive of postulated links. While the
evidence from studies following established theoretical models of OS appears to
be both stronger and more easily interpretable, evidence from atheoretical
studies employing proxy measures of OS – work hours, shift work, or perceived
discrimination in the workplace, for example – has also produced evidence
which is strongly supportive of the OS/CVD link. The persuasiveness of the
evidence, overall, now points to the importance of OS intervention studies in the
workplace undertaken according to rigorous clinical trial methodologies as the
next major focus of research.
Keywords
Occupational stress • Job strain • CVD risk • Work environment • Employment
Introduction
Historical Evidence
Systematic research linking OS to CVD has been reported since the middle of the
last century. Both Russek (1965) and French and Caplan (1970) noted significant
variations in rates of CVD in relation to both occupational level and demand. Later
work extended this to a distinction in risk between public and private sector workers
(Kornitzer et al. 1981). Bolm-Audorff and Siegrist (1983) reported higher CVD risk
among those in blue-collar than white-collar occupations, suggesting the stress
attached to dull and monotonous work might account for this finding. Links
between more directly measured characteristics of the occupational environment
and CVD risk were first reported by Liljefors and Rahe (1970), where job demand
(assessed as the number of hours worked weekly) was related to the incidence of
clinical events of CVD. But simple associations such as this were not always found.
An examination of data from the Framingham study reported associations between
workload and CVD but only in older people (Haynes et al. 1978), where advancing
age might have an impact on workload tolerance. Much of this evidence has, of
course, been reviewed elsewhere (Byrne 2000) and need not be revisited here. What
is clear, however, is that a good deal of the early empirical work on OS and CVD
was largely intuitively driven and not strongly guided either by general theories of
stress or more specific theoretical models of OS. The remainder of this chapter then
focuses largely on recent theoretically driven evidence accessed through systematic
interrogation of standard publication databases, and in the light of the significant
volume of evidence, studies from the last 15 years were favored, except where
publications were considered to be seminal to the field (since good reviews of
earlier evidence already exist), as were studies with large samples, robust designs,
and theory-driven measures.
320 D. Byrne and G.A. Espnes
The structural nature of the workplace itself and the organizational challenges and
constraints it places upon individuals working in it (Carlsson et al. 2014) have been
seen as an important starting point in identifying the origins of OS. Most
approaches to the theoretical understanding of OS, however, go beyond structural
considerations alone and clearly integrate the worker/organization interaction into
the explanatory equation. A review of the current literature reveals many models of
OS; most however reflect more or less subtle variations on related themes, and on
examination, the theoretical approaches to OS really reduce to three dominant or
overarching models.
The Person-Environment Fit Model – proposing a dynamic interaction between
characteristics of the occupational environment and the individual resources each
person is able to mobilize in order to cope (French et al. 1982), with any significant
mismatch resulting in OS. And this, of course, reflects the now classical theoretical
view of stress proposed initially by Lazarus (1966).
The Demand/Control Model – which views OS arising from a tension between
the demands an occupational environment imposes on an individual and the level of
perceived control which the person has over that environment (Karasek and
Theorell 1990), with OS resulting maximally from situations of high demand and
low control. The demand/control model often refers to job strain as the descriptor of
OS; however, they are, to all intents and purposes, synonymous with one another.
And in an important refinement of the demand/control model, Johnson and Hall
(1988) proposed that it should consider the buffering effects of social support in the
workplace as a significant mediator of OS.
The Effort/Reward Imbalance Model – where OS is claimed to relate to the
balance between the degree of effort put into the job and the level of reward
resulting from that effort (Siegrist and Marmot 2004), with high effort and low
reward associated with sustained OS.
These models – and in particular, the latter two – clearly overlap both themat-
ically (Theorell 2003; Siegrist and Marmot 2004) and in terms of their respective
capacities to predict CVD risk in occupational populations (Bosma et al. 1998).
Nonetheless, they all represent conceptually strong approaches to explaining risk
and incidence of CVD, and most recently in particular, both the demand/control
model and the effort/reward imbalance model have been backed by a wealth of
empirical evidence. Comprehensive and systematic and critical reviews (e.g.,
Hausser et al. 2010) would suggest, however, that the weight of that evidence
comes out to favor the demand/control model in explaining the role of the occupa-
tional environment as it addresses risk or incidence of CVD.
This notwithstanding, the impact of the occupational environment on CVD risk
or incidence has been inferred from a wide range of studies employing an equally
wide range of research methodologies. And not all studies – and perhaps the
majority – have been driven by theoretical considerations. Moreover, the nature
and reliability of CVD end-points (levels of risk markers, indicators of preclinical
CVD, incidence of CVD events, and the like) have varied equally widely. This
Occupational Stress and Cardiovascular Disease 321
One of the central issues surrounding the link between OS and CVD has to do with
its directness – does OS directly compromise cardiovascular function and precip-
itate clinical events or is the link indirectly manifest through intervening factors?
CVD risk is predicted by an array of recognized risk factors, prominent among
which are elevated blood fats (principally cholesterol), cigarette smoking, and
hypertension. CVD risk profiles have been related even to such ambiguous indices
of OS as occupational class (Wamala et al. 2000) and in a manner not easily
explained by such theoretical models as the demand/control framework. Therefore,
while there is some argument that the OS/risk factor link may be tenuous (Siegrist
and Rodel 2006), it cannot be ruled out. Relationships between OS and recognized
CVD risk factors must therefore be considered.
Cigarette Smoking
Cigarette smoking poses an established and potent risk for CVD (Leone 2007).
Regardless of environmental setting, the experience of stress increases cigarette
consumption among established smokers (Byrne and Mazanov 2008). Associations
between OS and CVD risk may therefore be mediated through cigarette smoking.
The presence of work-related stress (including high concentration demand and
work dissatisfaction) predicted smoking status in middle-aged women (Jonsson
et al. 2003), and OS has been associated with a broad range of smoking measures in
both men and women (Ng and Jeffery 2003). Associations between OS and levels of
cigarette consumption particularly have emerged (Metcalfe et al. 2003) in a manner
consistent with the general evidence on stress and smoking (Byrne and Mazanov
2008). Smoking appears more prevalent among blue-collar than white-collar
workers (Rose et al. 2006), with this finding related to the claimed negative effects
of OS. And employed adults who perceive low procedural justice (poor involve-
ment in decision making) in the workplace are more likely to be heavy smokers
than those without such perceptions (Kouvonen et al. 2007), with this finding
unaffected either by adjustments for job strain or effort/reward imbalance.
Both the demand/control and effort/reward imbalance models have also been
more systematically applied to analyses of OS and smoking. High job demand has
been related to heavy smoking in middle-aged rural workers, though curiously, low
job control appeared to be related to lower cigarette consumption (Tsutsumi
et al. 2003). Job demand has been associated with cigarette smoking irrespective
of job strain (Albertsen et al. 2006). But job strain (high demand and low control)
322 D. Byrne and G.A. Espnes
too has been linked to smoking (John et al. 2006). And in fact both high job strain
and high effort/reward imbalance have been independently associated with
smoking intensity (Kouvonen et al. 2005), with lower levels of effort in the
workplace also predicting ex-smoking status. Sufficient empirical evidence there-
fore now links OS and smoking, that it must be seen as one credible pathway
through which OS influences CVD risk.
Blood Pressure
Hypertension
A combination of high effort and low reward in the workplace has been clearly
associated with a diagnosis of clinical hypertension in middle managers (Peter and
Siegrist 1997) and shift workers (Peter et al. 1999). Job strain too has been related
to the prevalence of clinical hypertension, but curiously one study reported this
only in men (Tsutsumi et al. 2001) and another only in women (Alfredsson
et al. 2002).
However, beyond the strict confines of theoretical models of OS, the prevalence
of clinical hypertension has also been associated, and in some cases conspicuously,
with the general experience of occupational stress (Djindjic et al. 2012). At a finer
level of detail, hypertension has been statistically associated with a range of proxy
measures of OS, including organizational job constraints (Radi et al. 2005), exces-
sive work hours (Yang et al. 2006), job insecurity, and low occupational prestige,
but only in men – low work status predicted hypertension in women (Levenstein
et al. 2001), covert (but not overt) coping with unfair treatment at work, but only in
men (Theorell et al. 2000), perceived job barriers and job intensity (Greiner
et al. 2004), BP reactivity to acute stressors in the workplace (Ming et al. 2004),
and race-related workplace stress (Din-Dzietham et al. 2004).
This last issue is of particular psychosocial concern since it identifies a signif-
icant aspect of social inequality – still apparently endemic in many workplaces –
which constitutes, over and above the serious personal distress it clearly causes, an
identified risk for hypertension (Dolezsar et al. 2014).
The evidence implicating OS in the genesis of clinical hypertension is therefore
persuasive though much of it goes beyond the framework of established theoretical
324 D. Byrne and G.A. Espnes
models. The capacity for OS to influence CVD risk through the intermediary effects
of hypertension must therefore be seriously contemplated.
Blood Lipids
Levels of blood lipids, and particularly levels of LDL fractions of cholesterol, have
long been associated with elevated CVD risk (Campbell et al. 2007). Recent studies
have established reliable links between OS and this component of CVD risk. An
early alert to this link (Siegrist et al. 1988) examined chronic OS in middle-aged
men, measured as an interaction between objective (job instability and shift work)
and subjective (perceived job insecurity and increased workload) factors; after
controlling for such confounds as age, weight, and cigarette smoking, OS was
significantly associated with elevated LDL cholesterol.
More recently however, OS conceptualized specifically within the demand/
control model has been linked with elevated blood lipids. Curiously though,
elevated cholesterol was related only to low decision latitude (control) and not to
job strain. The composite index of job strain has been related to elevated lipids
(Tsutsumi et al. 1998), but only in working females.
Turning to the effort/reward imbalance model, the most impressive link between
OS and blood lipids probably comes from the WOLF (work, lipids, and fibrinogen)
study (Peter et al. 1998). Examination of baseline data from employed males and
females aged between 30 and 55 years showed that in men, effort/reward imbalance
was significantly related both to high total cholesterol and to a total cholesterol:
HDL ratio indicating CVD risk. In women, high effort was related both to increased
LDL levels and to a cholesterol: LDL ratio indicating CVD risk. Westerlund
et al. (2004) extended analyses of the WOLF study data to include indices of
organizational (employment) stability, reporting elevated cholesterol among
employees of companies where instability was evident either as change and growth,
economic threat, or because of small size.
The evidence associating OS with potentially harmful levels of blood lipids
therefore is well established. Given the recognized link between blood lipids and
coronary atherosclerosis, it is interesting to note that in one study at least (Hintsanen
et al. 2005), an association between job strain and the extent of early and
nonsymptomatic atherosclerosis was evident in both young men and women.
Metabolic Syndrome
An interesting and recent extension of this work focuses on OS and the metabolic
syndrome (Melamed et al. 2006). Diagnosis of metabolic syndrome, which has
been reliably linked with CVD risk (Salsberry et al. 2007) is defined by obesity
(waist circumference) along with any two of elevated triglycerides, low HDL
levels, hypertension, and elevated plasma glucose (Hildrum et al. 2007). Job strain
is strongly associated with rates of metabolic syndrome, and this relationship
Occupational Stress and Cardiovascular Disease 325
Fibrinogen
While the evidence here is by no means uncontested, plasma fibrinogen has been
implicated as a predictor of CVD (Woodward et al. 2007), and it has been suggested
that this too may mediate a link between OS and CVD risk (Theorell 2002). A number
of well-conducted studies have indeed reported associations between plasma fibrinogen
and low job control generally (Clays et al. 2005), low job control in female workers
only (Tsutsumi et al. 1999), job strain in males but not females (Kittel et al. 2002), and
both occupational burnout in women and occupation-related depression in men (Toker
et al. 2005). Unsupportive evidence however (Alfredsson et al. 2002) indicates that
some caution needs to be exercised in regard to OS and fibrinogen until further
corroborative evidence is available.
Both the demand/control (Theorell and Karasek 1996) and effort/reward imbalance
(Siegrist 2005; van Vegchel et al. 2005) models of OS have figured prominently in
studies of OS and clinical CVD, and the evidence linking both to clinical CVD is
impressive. Largely atheoretical constructs have also driven many studies in this
area, and while the evidence is somewhat more difficult to interpret unequivocally,
it is also persuasive. And both case-control and prospective studies are available in
support of the view that OS directly relates to CVD morbidity and mortality.
An early study utilizing job strain as the index of OS in the workplace found it to be
related to a significant elevation in clinical CVD incidence among middle-aged
326 D. Byrne and G.A. Espnes
men, independent of other CVD risk factors (Alfredsson and Theorell 1983); a
strenuous occupation also elevated CVD risk. Evidence of a synergistic interaction
between demands and decision latitude further strengthened associations between
job strain and clinical CVD risk (Hallqvist et al. 1998). A more recent study of job
strain strongly associated it with heart disease in a large sample of men, again
independent of other CVD risk factors; however, heart disease as a clinical
end-point here was largely self-reported (Sacker et al. 2001). The relationship,
however, was also evident in a sample of men who had survived a clinically
diagnosed CVD event (Malinauskiene et al. 2005). Overcommitment to work, the
intrinsic part of effort/reward imbalance, was strongly related to the likelihood of
clinical CVD in women occupying male-dominated jobs (Peter et al. 2006). And
interestingly, recent work suggests that a combination of the demand/control and
effort/reward imbalance models even further strengthens the capacity of OS to
predict clinical events of CVD (Peter et al. 2002).
Chronic high workload arising from the structural characteristics of the occupa-
tional situation has long been associated with the prevalence of clinical CVD
(Siegrist et al. 1982). So too has both shift work and monotonous work (Alfredsson
et al. 1982), but not hectic work unless it was also associated with low decision
latitude in the workplace. The causal significance of shift work for CVD risk has,
however, been queried (Frost et al. 2009). Self-reported OS, again focusing on the
workplace structure, significantly predicted risk of clinical CVD in a large sample
of patients having experienced their first clinical event (Panagiotakos et al. 2003).
And general but essentially work-related life events were reported to act as “trig-
gers” to the onset of a clinical episode of CVD in middle-aged men and women
(Moller et al. 2005). Moreover, the experience of unfairness in the workplace has
been linked with an elevated risk of clinical incidents of CVD (De Vogli
et al. 2007).
While prospective studies are clearly more difficult to conduct than retrospective or
case-control studies, and they therefore appear less frequently in the literature, they
are crucial to exploring hypothesized links between OS and clinical CVD since they
give greater insights into possible causality than other research designs (Kivimaki
et al. 2006a). In that light, Lee et al. (2002) found no evidence to causally associate
job strain with the emerging incidence of clinical CVD in a large sample of women
followed over 4 years. By contrast, a more than 25-year follow-up of a large and
initially healthy sample of both men and women found OS, evident as both job
strain and effort/reward imbalance, to significantly predict risk of CVD mortality
(Kivimaki et al. 2002). High demand and low decision latitude also predicted the
Occupational Stress and Cardiovascular Disease 327
incidence of clinical CVD, again in a large sample of both men and women free
from CVD at outset and followed over 11 years (Kuper and Marmot 2003). And in a
large general population cohort (N = 6070) of Swedish men followed over several
decades, OS (again conceptualized and measured as job strain) clearly predicted
CVD risk – but not risk of stroke (Toren et al. 2014). In women, job strain has been
linked to progression of coronary atherosclerosis over a 3-year period (Wang
et al. 2007), and while atherosclerosis does not constitute a clinical event of
CVD, it is a clear precursor of that outcome.
Conclusions
This has been a selective review, and it has focused largely (though not exclusively)
on published research material from the past 15 years. Moreover, the review is
essentially descriptive – formal comparative procedures such as meta-analyses
have not been used. Nonetheless, a large volume of empirical evidence from
well-conducted studies with robust research designs can be brought to bear on the
issue of OS and CVD. Studies relating OS and CVD risk factors are particularly
supportive of a link, albeit an indirect one, between OS and ultimate clinical CVD –
and evidence focusing on BP and hypertension is strong in this regard. Evidence
from both case-control and prospective studies also persuasively supports a link
between OS and clinical events of CVD, though prospective studies are under-
standably fewer in number since they are more logistically difficult to undertake.
Both the demand/control (job strain) and effort/reward imbalance models appear to
offer powerful conceptual frameworks linking OS with CVD, and incorporating a
combination of the two into research designs achieves useful synergies in
predicting CVD. However, even atheoretical approaches provide convincing evi-
dence of a link between OS and CVD. Therefore, while additional prospective
evidence based on one (or both) of the existing theoretical models would be useful,
the collective evidence now available must be viewed as sufficiently consistent and
robust to support the very clear conclusion that OS is causally linked, either
indirectly or directly, with CVD.
This being so, the next generation of research may well need to focus on
interventions to reduce OS in the workplace (Nieuwenhuijsen et al. 2010), either
through strategies targeted at individual workplace behaviors or on efforts to
328 D. Byrne and G.A. Espnes
modify the workplace itself to reduce those structural and organizational factors
predisposing to OS. There is already emerging evidence that targeted interventions
to reduce OS in the workplace have utility to achieve stress reduction (Werneburg
et al. 2011) though nothing yet which bears on the extension of this finding to
reductions in CVD risk. Speculation suggests that the overall result may be modest
(Kivimaki et al. 2012). But to effectively demonstrate the role of OS reduction in
reducing risk of CVD, future intervention-based research must of necessity involve
longitudinal studies of large samples, diverse in regard to occupational status, age,
and gender. That research must also apply theoretically driven strategies of psy-
chological intervention based on the best available overall evidence demonstrating
the therapeutic effectiveness of those strategies. And almost inevitably this work
will need to address the legal and political realm of industrial relations. However,
the provision of a fully safe workplace – now mandated in a growing number of
countries – needs to encompass freedom from OS, and if this achieves an effective
lowering of CVD risk in the working population, it is a freedom well worth seeking.
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Disorders of Sleep and Cardiovascular
Disease
Matthew T. Naughton
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Normal Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
The Glymphatic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Melatonin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337
Flip-Flop Switch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
Two-Process Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
Polysomnography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
Actigraphy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Disorders of Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Sleep Deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 340
Insomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Circadian Rhythm Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Hypersomnia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
Mood and Sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Parasomnias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Restless Legs Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 344
Sleep-Related Breathing Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345
Treatment of Snoring and Obstructive Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Cardiovascular Complications of Snoring and Obstructive Sleep Apnea . . . . . . . . . . . . . . . . . . . . . 350
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Systemic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
Cardiac Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
Ischemic Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
Congestive Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Central Sleep Apnea Related to Established Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Abstract
Despite decades of effort, one of the greatest mysteries in biology is to under-
stand sleep. Sleep is more than simply rest. Depriving someone of sleep has
powerful adverse effects on their mental, metabolic, and cardiovascular health.
The timing of sleep also plays an important role in terms of the onset of
cardiovascular events. Finally, the effects of sleep on ventilation and the down-
stream effects of sleep apnea in the pathogenesis of all cardiovascular conditions
have come of age in the evidence-based medicine field.
Keywords
Sleep • Apnea • Mood • Cardiovascular disease
Introduction
Disorders of sleep, mood, and associated cardiovascular disorders are common and
the interaction is quite complex. It is estimated that a disturbance of sleep is an
extremely common symptom in relation to most cardiovascular illnesses and
psychological and psychiatric conditions. This chapter will outline normal sleep,
insomnia, hypersomnia, and obstructive sleep apnea (OSA). Thereafter, the chapter
will focus on common cardiovascular conditions which interact with OSA, namely,
systemic hypertension, atrial fibrillation, ischemic heart disease, and heart failure.
Finally, the interaction between heart failure and central sleep apnea (also known as
Cheyne–Stokes respiration) will also be discussed.
Normal Sleep
Table 1 Blood pressure, heart rate, and heart rate variability (mean (SD)) in healthy patients
while awake, and stage 2, slow-wave, and rapid eye movement sleep (From Trinder et al. (2001))
Wake Stage 2 Slow-wave sleep REM
SBP 108(13) 104(12) 109(13) 94(13)
DBP 56(8) 55(13) 57(7) 48(7)
Heart rate 64(13) 57(10) 58(10) 60(10)
High frequency 72(56) 186(161) 184(177) 126(112)
Low frequency 141(105) 122(86) 80(61) 209(177)
hormone and cortisol), and protein synthesis become activated. Memory is also
highly reliant upon sleep (Stickgold 2005).
Considerable variation exists in the “normal” amount of sleep required. It has
been estimated that prior to the widespread availability of electricity in the 1890s
(and when physical labor was commonplace), 9–10 h sleep per night was the norm.
Currently, 7–8 h appears to be considered “the norm” due to greater “electrical” and
Internet connectivity. Combined with a more sedentary lifestyle, sleep quality and
quantity have suffered.
Melatonin
and then to the pineal gland which releases melatonin (Armstrong et al. 1986).
Darkness results in the release of melatonin, whereas light suppresses melatonin
release. This chain reaction with melatonin also controls three groups of neurons
(thalamus–VLPO, hypothalamus, and pons) and their neurotransmitter release
(Saper et al. 2005).
Flip-Flop Switch
Two-Process Model
Polysomnography
Sleep can be objectively measured by EEG, EMG, and EOG analysis from which
REM and non-REM can be identified. REM sleep was identified and defined by
Disorders of Sleep and Cardiovascular Disease 339
additional sleep
pressure Increased SWS
process S
Increased TST
process C
7 23 7 23 7 23 10
time of day
Fig. 1 Two-process model (Borbely 1982) to illustrate the natural circadian aspect of sleepiness
(process C) with an additional accumulative sleep debt (process S) over three 24 h cycles. Note the
accumulation of sleep debt and the impact upon increasing total sleep time (TST) and slow-wave
sleep (SWS)
Sleep architecture
W
S1,2
SWS
REM
Sleep (8 hrs)
Child Adult
Stage 1+2 (%) 10 70
Slow wave sleep (%) 30 15
Rapid Eye Movement (%) 60 15
Fig. 2 Diagram of a typical sleep architecture. Note the cyclic nature of stages 1 and 2, slow-
wave, and REM sleep, each cycle lasting about 1.5 h and four to five cycles per night. Note also the
increased amount of REM in childhood compared with adults
Aserinsky and Kleitman in 1953 (Aserinsky and Kleitman 1953). Non-REM sleep
can be further broken down to stage 1, stage 2, and stage 3 (slow-wave) sleep. REM
sleep can be subdivided into phasic and tonic REM.
Under normal circumstances, there are four to five REM–non-REM cycles per
night, usually 1.5 h each cycle. This cyclic REM–non-REM pattern is often
described as the sleep architecture (Fig. 2). The amount of sleep per time of
recording is the sleep efficiency.
340 M.T. Naughton
Actigraphy
The timing of sleep within the 24 h cycle is called the circadian rhythm. In many
developed countries, sleep is taken in one “dose” overnight, whereas in others it is
taken in two parts: overnight and early afternoon (i.e., siesta). Indeed the latter
siesta pattern is associated with a chronic low-grade overnight sleep deprivation, a
common lifestyle pattern in developed world.
Measurement of circadian rhythm can be estimated from a sleep diary, usually
over 7–14 days. Alternatively, measurement can be made objectively when a
lightweight wrist actigraph is worn for 7–14 days. Actigraphy provides a reliable
estimate of movement and light, from which circadian rhythm can be estimated
(Fig. 3). For experimental situations, core temperature and serial plasma or salivary
melatonin levels can also be used.
Disorders of Sleep
Introduction
Lack of sleep is extremely common. Reduced duration of sleep can result from choice
(i.e., volitional), societal pressures (e.g., work or family commitments), or during times
of illness (hospitalization in noisy environments). Fragmented or poor quality sleep can
occur due to medical (e.g., arthritis, asthma, apnea), psychological (e.g., anxiety), or
psychiatric disorders. Pharmaceutical drugs (antidepressants, beta blockers, narcotics,
glucocorticoids), devices (pacemakers, dialysis), and interventions (e.g., ventilatory
support in an intensive care unit) can result in marked derangement in sleep quality.
Overall classification of sleep disorders can be summarized as follows:
1. Insomnia
2. Sleep-related breathing disorders
3. Hypersomnia
4. Circadian rhythm disorders
5. Parasomnias
6. Sleep-related movement disorders
7. Isolated sleep symptoms
8. Others
Sleep Deprivation
Fig. 3 Example of an actigraphy report. Note the movement (black line) and the light sensor
(white, green, and light-blue lines) across seven consecutive 24 h periods. Sky-blue boxes
represent periods of estimated sleep
while clinically the rats developed sepsis, cardiomegaly, fluid retention, and a
catabolic state (increased appetite with weight loss). These pivotal studies lay the
basis of human sleep deprivation studies thereafter.
In humans, a reduction in sleep quality or quantity can result in behavioral
change (change in appetite (Spiegel et al. 2004)), neurocognitive impairment
(e.g., memory loss (Stickgold 2005), personality change, judgment, physical agility
342 M.T. Naughton
0 hrs/night 4 hrs/night
16
12
Psychometric 6 hrs/night
Vigilance
8
Task
Lapses
8 hrs/night
0
0 2 4 6 8 10 12 14
Days Sleep Deprivation
Fig. 4 Graph indicating the effects of varying degrees of sleep deprivation upon performance.
Note four groups of otherwise healthy young adults who had 0, 4, 6, and 8 h sleep over 14 days
upon performance as measured by lapses in the psychometric vigilance test. Note the 0 h sleep
group was unable to complete more that 48 h of testing before withdrawing from the study (Graph
is redrawn from data of Van Dongen et al. (2003))
(Dinges et al. 1997; Van Dongen et al. 2003) (Fig. 4)), hormonal change (insulin
resistance and hyperglycemia) (Spiegel et al. 1999) which may lead to adverse
health effects, prolonged reaction times (Van Dongen et al. 2003) and resultant
accidents (work and/or motor vehicle (Taffinder et al. 1998; Landrigan et al. 2004;
Lockley et al. 2004)), infections (Majde and Krueger 2005), impaired response to
immunizations (Spiegel et al. 2002), obesity (Gangwisch et al. 2005), and diabetes
mellitus (Spiegel et al. 1999). Sleep deprivation is also a powerful trigger of
seizures. Epidemiological evidence from large cohorts in Japan (Tamakoshi and
Ohno 2004) and the USA (Ayas et al. 2003) followed for 20 years indicates sleep
deprivation may also contribute to cardiovascular disease and premature death.
Importantly, sleep deprivation appears to more important cause of motor vehicle
accidents than does OSA (Pack et al. 2006).
Insomnia
Insomnia is defined as >30 min inability to sleep when desiring to sleep plus
impairment of cognition while awake (e.g., drowsiness). Short-term insomnia is
common, experienced by most people at some stage of their lives. Chronic insom-
nia (>6 months) is less common and should be considered seriously. Insomnia has
also been classified as difficulty initiating sleep or difficulty maintaining sleep.
Insomnia can result from poor sleep hygiene. Sleep hygiene is a term used to
describe lifestyle choices which impact upon sleep. Good sleep hygiene includes
choosing to sleep in a cool dark quite room; avoiding strenuous exercise within 2 h
Disorders of Sleep and Cardiovascular Disease 343
Timing of sleep, i.e., disorders of circadian rhythm, has health important implica-
tions. Shift work, defined regular work outside the normal 8 am to 6 pm time slot,
can be further subdivided into those with regular and irregular rotations. About
30 % of the working population are shift workers and in general sleep ~2 h less than
the non-shift working population. Occupational areas which commonly employ
shift workers include the healthcare arena, transport industry, and the computer
industry. Given the huge numbers of aircraft, relatively inexpensive airfares, and
the global structure of many businesses, a huge population of “white-collar” trans-
meridian travelers are emerging as another important class of shift workers. Ado-
lescents commonly have a delayed sleep phase syndrome, such that they retire to be
late and “sleep in” to late morning. Advanced sleep phase syndrome is character-
ized by early to bed early to rise: often seen in elderly. Both advanced and delayed
patterns improve with light therapy and melatonin.
Several cardiovascular disorders (stroke, fatal arrhythmias, myocardial infarc-
tion) have a strong circadian pattern (Muller et al. 1989). Shift work as also been
observed to contribute as a cardiovascular risk factor (Boggild and Knutsson 1999).
Although precise mechanisms are not clear, it well regarded that shift workers are
more likely to smoke, be overweight and of lower socioeconomic status, and have
less access to healthcare.
Hypersomnia
REM occurs episodically throughout the day and night. There is a theory that low
orexin (aka hypocretin) in the hypothalamic region is associated with the develop-
ment of narcolepsy. Some believe narcolepsy to be post-viral or autoimmune. There
is an association with a specific human leukocyte antigen subtype (HLA
DQB1*0602). Narcolepsy is confirmed with a clear history of cataplexy and a
positive MSLT (<10 min) sometimes with sleep onset REM. Idiopathic
hypersomnia, aka atypical narcolepsy, occurs in the absence of cataplexy.
Strategies to overcome drowsiness due to the lack of quality, quantity, or timing
(i.e., circadian) of sleep include social drugs (caffeine, alcohol, nicotine) and
prescribed medication such as stimulants (e.g., dexamphetamines and modafinil),
chronotropics (e.g., melatonin), or sedatives. Three classes of sedatives are com-
monly used: benzodiazepines (e.g., temazepam), cyclopyrrolones (e.g., zolpidem),
and imidazopyridines (e.g., zopiclone). Novel ideas such as blue light therapy times
to a specific phase in the circadian rhythm may also assist as does physical activity.
Parasomnias
move, which has a partial relief of symptoms (Earley 2003). There is a strong
circadian aspect, which can be used to measure severity: severe = onset before
dinner, modest = after dinner, and mild = in bed. In addition, frequency of nights
per week affected by RLS can guide severity. The etiology of RLS is unclear
although some evidence suggests low neurotransmitter dopamine and/or low
ferritin. In others, there is either antidepressant use (especially SSRIs) or a strong
family history. Often periodic limb movements occur in such patients during
non-REM sleep. Treatment of RLS usually involves iron therapy and dopamine
agonists.
Sleep-related breathing disorders can be classified as relating to (a) the upper airway
pathophysiology (e.g., benign snoring and obstructive apnea); (b) hypoventilation
due to chest wall (e.g., kyphoscoliosis), neuromuscular disease (e.g., motor neuron
disease), pulmonary disease (e.g., COPD), drugs (e.g., sedatives), or morbid obesity
(obesity hypoventilation syndrome); and (c) hyperventilation disorders (e.g., heart
failure and Cheyne–Stokes respiration).
Physiologically, sleep has a huge impact upon respiration. The first is that
muscle tone drops with sleep onset: this includes skeletal muscles mainly of posture
but also the upper airway. There are 13 pairs of muscles from the tip of the nose to
the larynx (Earley 2003; Dempsey et al. 2010), which when relaxed increase
inspiratory resistance and also result in a reduction in the diameter of the orophar-
ynx. In contrast to the nose and trachea, the oropharynx has no bony or cartilaginous
rigid support, allowing it to narrow during sleep.
The second event unique to sleep is that the lung volumes fall, by about 20 %. As
~50 % of the body’s oxygen stores are kept within the lungs, a reduction in lung
volume (oxygen store) will cause an amplification of hypoxemia for any given
apnea length.
The third event is that the factors that control ventilation change from wakeful-
ness to sleep (especially non-REM sleep). While awake, our cerebral cortex and
brain stem “waking neural drive” operate in addition to a chemical drive (mainly
arterial CO2 sensed at the carotid body). With the transition from wake to sleep,
cerebral cortex and waking neural drive are lost and arterial CO2 is the main driver
of ventilation. With each level of sleep “depth” (stage 1–2 to 3–4), the ventilation
sensitivity to CO2 becomes more blunted. The importance of this is that during
normal sleep, the prevailing CO2 level rises about 2 mmHg, to allow minute
volume of ventilation to drop ~20 % and thereby allow the normal subject to sleep.
Sleep apnea can occur when there is a disturbance to either of these three
physiological mechanisms.
At the most basic level, excessive narrowing of the oropharynx, while
maintaining ventilation at ~80 %, will result in a reverberating noise. This is
most prominent when there are gravitational factors interplaying (i.e., in the supine
position) during slow-wave sleep (when arousability from sleep is impaired) –
346 M.T. Naughton
Fig. 5 Three
polysomnograms, each of
5 min duration. (a)
Represents snoring and please
note the increase in
intrathoracic pressure swings.
(b) Represents obstructive
sleep apnea with large
negative intrathoracic
pressures. (c) Represents
central sleep apnea with a
Cheyne–Stokes pattern of
respiration. Legend: EEG
electroencephalogram; EOG
electrooculogram; EMG
electromyogram of
submentalis or anterior
tibialis, thermistor marker of
oronasal flow; Pnasal nasal
pressure; Pintrathoracic
intrathoracic pressure
measured by esophageal
manometer; chest and
abdominal movt chest and
abdominal movement sensed
by inductance
plethysmography; SpO2 pulse
oximetry; PtcCO2
transcutaneous CO2; body
position left, right, front, back
348 M.T. Naughton
Surfactant –
the upper airway musculature,
and the surfactant properties Weight
Snoring
of the upper airway
– +
+
Size of airway
+
UAW muscle tone
Open
↓
Mechanisms Events consequences Features
transmural pressures across vascular structures, the heart and aortic arch barore-
ceptors, which can lead to reduced cardiac output and resetting of baroreceptors.
In addition, it is thought the reverberation effects of snoring can cause fracture
of coronary atheromatous plaques. Large intrathoracic pressures can also alter
pulmonary vascular pressures to cause transient right to left shunts via open
patent foramenovale (i.e., episodic profound falls in SpO2) (Shanoudy
et al. 1998). Finally large intrathoracic pressures can induce an exaggerated
vagal response (hypoxia without airflow). Third, arousals at the end of the
apnea/hypopnea, which fragment sleep and reduced amounts of “quality REM
and slow-wave sleep,” cause further augmentation of sympathetic activity and
vasoconstriction.
Disorders of Sleep and Cardiovascular Disease 349
Background
Systemic Hypertension
Treatment of OSA with CPAP has been shown to lead to a reduction in mean
systemic blood pressure measured over 24 h, although these falls are small
(~2–3 mmHg), with the greatest benefit seen in those with more severe OSA
(Bazzano et al. 2007). A greater fall is seen in subjects with drug-resistant hyper-
tension (Martinez-Garcia et al. 2013). There is also evidence that treatment with
mandibular advancement splints leads to an improvement in hypertension
(Gotsopoulos et al. 2004), suggesting the benefit of OSA treatment with respect
to blood pressure is independent of the treatment modality.
Despite this, pharmacological antihypertensive therapy (e.g., valsartan) is more
effective (~9 mmHg fall in mean 24 h blood pressure) than CPAP (~2 mmHg fall)
over 8 weeks according to one randomized controlled study of 23 patients with
hypertension and obstructive sleep apnea (Pepin et al. 2010).
An important consideration is the breath by breath variability in systemic blood
pressure when measured continuously (Davies et al. 1994). Large swings in blood
pressure (i.e., large standard deviation) are thought to be more detrimental in terms
of stroke risk than is the mean blood pressure (Rothwell et al. 2010). Obstructive
sleep apnea is characterized by huge swings in systemic blood pressure in addition
to an increased mean blood pressure. The treatment of sleep apnea with CPAP will
reduce the swing in blood pressure considerably; however the mean may fall only
2–3 mmHg (when measured by ambulatory blood pressure monitoring). In contrast,
antihypertensive drugs may drop the mean blood pressure, but will have very little
impact upon OSA, and thereby the large swings in blood pressure due to the
ongoing OSA may persist. A combination of CPAP and antihypertensive drugs is
sometimes required (see Fig. 8).
Four important messages need consideration regarding OSA and hypertension.
First, clinicians should assess for OSA symptoms and consider a sleep study in
patients with resistant hypertension (Levy and McNicholas 2013). Second, OSA
treatment in hypertensive OSA patients may improve blood pressure control but
without large reductions, while snoring and quality of life should improve. Third,
CPAP is not a substitute for pharmacological treatments. Finally, obesity is a
unifying factor and accordingly assistance with weight loss is a good objective
for clinicians.
Cardiac Arrhythmias
200
Blood 100
Pressure
(mmHg)
Fig. 8 Illustration of swings in systemic blood pressure with untreated OSA, CPAP-treated OSA,
drug-treated hypertension, and both drug- and CPAP-treated hypertension. Note that OSA causes
wide BP swings which are attenuated by CPAP, although mean may fall only 2–3 mmHg. Also
note that antihypertensive medications may drop the mean BP but unless OSA is treated the wide
swings in blood pressure will remain
Some data suggest all arrhythmias improve with CPAP treatment (Ryan
et al. 2005), whereas other data are not as supportive (Craig et al. 2009). One
study suggested the 12-month recurrence of atrial fibrillation post-cardioversion
was significantly lower if coexistent OSA was treated with CPAP compared with
untreated OSA (Kanagala et al. 2003).
Although the risk of fatal arrhythmias from OSA is unknown, an increased risk is
suggested from data showing that subjects with OSA who die of sudden death are
more likely to do so at night compared to those without OSA (Gami et al. 2005).
Although randomized controlled trials of OSA treatment upon cardiac arrhyth-
mia frequency and severity are lacking, it does appear prudent to question for OSA
symptoms in patients with difficult to control arrhythmias, such as tachy–brady
syndrome or atrial fibrillation, especially when they occur during sleep.
The prevalence of OSA is high in patients with ischemic heart disease (IHD),
estimated to be between 30 % and 58 % (Peker et al. 2002). In the general
community, cross-sectional epidemiological evidence supports a link between
OSA and IHD. OSA is associated with a greater risk for acute myocardial infarction
than with smoking or hypertension (Hung et al. 1990). Furthermore, the presence of
OSA in patients with established IHD is associated with greater 7-year mortality
Disorders of Sleep and Cardiovascular Disease 353
compared with those without OSA (Peker et al. 2002). Whether underlying OSA is
contributory to the well-described circadian distribution of myocardial infarction
(peak incidence ~8 am) (Muller et al. 1989) remains to be determined. Randomized
controlled trials of OSA treatment upon the development or outcomes of IHD are
presently lacking.
Both diastolic and systolic heart failures (HFs) are common in OSA populations
(Kee and Naughton 2009). In addition to OSA’s proposed effect upon CVD, large
swings in negative intrathoracic and positive intravascular pressures which result
from OSA are thought to contribute to the development of cardiomyopathy (Demp-
sey et al. 2010). Epidemiological data indicates an ~threefold greater prevalence of
diastolic and systolic HF in community dwellers with severe OSA (AHI >30)
compared with no OSA (Chami et al. 2008). Furthermore, the risk of developing
incident HF due to untreated OSA is estimated to be 1.6 times greater, based upon
4,422 community dwellers (controlled age, gender, race, diabetes, and hyperten-
sion) followed for a mean of 8.7 years (Gottlieb et al. 2010).
OSA and central sleep apnea are also commonly seen within HF populations.
One study has demonstrated that 55–85 % of HF patients have sleep apnea (either
obstructive or central) when patients were tested several times over a 12-month
period (Pinna et al. 2010). In general, central sleep apnea is seen in more advanced
severe spectrum of HF and can be explained by additional pathophysiology to that
seen in pure OSA. This high prevalence of either apnea type does not appear to have
been affected by the introduction of beta blockers or spironolactone (Yumino
et al. 2009).
Evidence suggests that coexistent OSA worsens heart failure and is improved by
CPAP therapy. Two randomized controlled studies show that the treatment of
patients with OSA (AHI >15/h) and systolic HF with fixed pressure CPAP over
1–3 months is associated with improvements in systolic function, quality of life,
exercise capacity, and autonomic control (Mansfield et al. 2004). Nevertheless, the
data is not universally positive. Neither study was large enough to assess mortality;
however an observational study suggests an improvement in survival with long-
term CPAP treatment, compared to untreated OSA (Wang et al. 2007).
Stroke
Patients with untreated OSA have an elevated risk of developing stroke, and the
data are more consistently positive than for cardiac disease (Loke et al. 2012),
including in the elderly (Munoz et al. 2006). Mechanisms include large swings in
systemic blood pressure, local vibrational damage to the carotid artery bifurcation
(Lee et al. 2008), increased coagulopathy, surreptitious development of atrial
fibrillation during sleep with thrombus formation, and paradoxical emboli through
354 M.T. Naughton
Mortality
Patients with heart failure of all causes commonly exhibit hyperventilation, which
drives the PaCO2 level low. During non-REM sleep, when the drive to breathe is
exquisitely controlled by the CO2 level, oscillatory breathing patters occur. Typi-
cally these are ~1 min cycles of crescendo then decrescendo ventilation followed by
a central apnea (i.e., no respiratory effort). Initially thought to be deleterious
because of associated hypoxemia and fragmented sleep which may occur, it has
now been thought to be simply a marker of severe heart failure.
Given many such patients can live for many years with CSA and that certain
physiological benefits are associated with CSA, it has been thought by some that
Disorders of Sleep and Cardiovascular Disease 355
CSA in the setting of heart failure may be compensatory (Naughton 2012). The
physiological benefits of CSA include (a) transient rest in a high work of breathing
environment, (b) maintaining an alkalotic pH to avert patients from deleterious
acidosis in times of HF instability, (c) transient increase in end-expiratory lung
volume and thereby oxygen stores, and (d) low cyclic intrathoracic pressure swings
that assist forward cardiac output.
These theoretical benefits of CSA in heart failure should not preclude optimiza-
tion of heart function. It has been shown that CSA in heart failure resolves with
improved cardiac function following medical therapy, valve replacement, pace-
maker insertion, LVAD, and cardiac transplantation.
In the event ongoing CSA occurs despite optimization of therapies directed
toward the failing heart; continuous positive airway pressure may be beneficial as
it is for OSAH and acute cardiogenic pulmonary edema. These CPAP mechanisms
of action, beyond pneumatically maintaining a patent oropharynx during sleep,
include increasing lung volume and oxygenation and reducing cardiac wall tension
and chamber size and thereby reducing bother the work of breathing and of the
heart.
Conclusions
Sleep has emerged as an intriguing physiological state that has huge influences
upon how one feels, performs, and reacts to external factors. Importantly, sleep also
places the cardiovascular system under stress, as does an exercise test. The most
powerful components of sleep, namely, sleep deprivation and obstructive sleep
apnea, place enormous strain upon the cardiovascular system.
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Psychogenic Hypertension
Murray Esler
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
Experimental Models of Stress-Induced Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Epidemiological and Clinical Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
Epidemiological Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
A Psychodynamic and Biological Formulation of Stress-Induced Hypertension . . . . . . . . . . . . . 365
Aversive Stressors for Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 366
Stress Biological Markers (Stress “Finger Prints”) in Essential Hypertension . . . . . . . . . . . . . . . 366
Increased Brain Norepinephrine Turnover in Essential Hypertension . . . . . . . . . . . . . . . . . . . . 367
Sympathetic Nervous System Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
Plasma Cortisol Concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Epinephrine as a Sympathetic Nerve Cotransmitter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
Pathophysiological Mechanisms of the Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
The Sympathetic Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
Does this Sympathetic Activation Cause the Blood Pressure Elevation? . . . . . . . . . . . . . . . . . 370
Neurogenic Hypertension: A Final Common Pathway for “Lifestyle Hypertension?” . . . . . . . 371
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
The Renal Sympathetic Nerves Provide a Universal Common Pathway
of Hypertension Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
Abstract
In searching for biological evidence that essential hypertension is caused by
chronic mental stress, a disputed proposition, parallels are noted with panic
disorder, which provides an explicit clinical model of recurring stress responses:
(i) There is clinical comorbidity; panic disorder prevalence is increased threefold
M. Esler (*)
Human Neurotransmitters Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC,
Australia
e-mail: [email protected]
Keywords
Hypertension • Brain norepinephrine turnover • Epinephrine • Plasma cortisol •
Stress biomarkers • Sympathetic nerve cotransmitter • Sympathetic nervous
system • Neurogenic hypertension • Phenylethanolamine-N-methyltransferase
(PNMT) • Stress-induced hypertension
Introduction
The idea that essential hypertension may arise through psychosomatic mechanisms is an
old one, invoked before the standard methods of indirect blood pressure measurement
were used clinically. Concerning his male patients with hypertension (systolic pressure
having been measured with a finger plethysmograph), Geisbock wrote: “one finds an
unusual frequency of those who as directors of big enterprises had a great deal of
responsibility and demanding jobs, and who, after a long period of mental overwork,
became nervous” (Geisbock et al. 1976). Although providing proof that essential hyper-
tension is a psychosomatic disorder has been difficult, the supporting evidence which has
accumulated slowly over the succeeding century is now very persuasive (Folkow 2004).
This support comes from three evidence streams, from experimental models of
stress-induced hypertension, from epidemiological and clinical studies testing for a
nexus between mental stress and hypertension, and from pathophysiological studies
documenting the presence of stress-related biology in essential hypertension
patients.
Psychogenic Hypertension 363
Because of the logistic and ethical difficulties which exist in exploring the relation
of chronic mental stress to the development of human hypertension, animal models
have been developed. An acceptable animal model of presumed psychogenic
hypertension should meet the following criteria:
(i) The blood pressure elevation should be permanent, persisting after removal of
the stimulus.
(ii) Cardiovascular complications of hypertension, such as strokes, atherosclero-
sis, left ventricular hypertrophy, and myocardial infarction, should develop.
(iii) The model should be plausible and have points in common with human
circumstances and behavior.
While the studies with experimental stress in animals are interesting and important,
in demonstrating that psychological stressors can cause permanent hypertension,
and in identifying the crucial role of neural mechanisms in the development of the
hypertension, it is another matter to demonstrate that essential hypertension is due
to chronic mental stress.
Clinical Studies
Epidemiological Studies
Epidemiological and clinical studies provide increasingly strong support for the
notion that behavioral and psychological factors, in particular suppressed hostility,
are of importance in the pathogenesis of human hypertension (Harburg et al. 1973;
Esler et al. 1977; Perini et al. 1986; Henry and Grim 1990). Importantly, the
increased prevalence of hypertension in Afro-Americans has been linked to high
levels of psychosocial stress, associated with an underlying genetic propensity to
sodium retention by the kidneys, perhaps attributable to the survival benefit this
might have provided at times of severe dietary sodium shortage on slave ship
voyages (Harburg et al. 1973; Henry and Grim 1990).
Long-term follow-up studies of human populations, such as the celebrated study
of cloistered nuns in Umbria (Timio et al. 1988), who live in a secluded and
unchanging environment, and in whom blood pressure does not show the expected
rise with age, have been influential. Also important are studies linking hypertension
development to chronic mental stress in the workplace (Steptoe and Willemsen
2004; Chandola et al. 2006). Additional key observations have been made on
human populations who demonstrate blood pressure elevation soon after migration
(Poulter et al. 1990), this rise in pressure being attributed primarily to mental stress,
although changes in physical activity and diet are also operative. Pertinent also is
the observation that panic disorder and essential hypertension are commonly
comorbid conditions (Davies et al. 1999). Patients with panic disorder have recur-
ring and often severe stress responses accompanied by sympathetic nervous system
activation and acute blood pressure elevation (Alvarenga et al. 2006). The inference
here is that the recurring stress responses in panic disorder can initiate the devel-
opment of persistently elevated pressure.
In short, although the concept that in some patients essential hypertension may
be psychogenic in origin is not definitively proven, there is a wealth of supporting
experimental and clinical evidence. As discussed below, long-term neural effects
of stress on renal function are most likely the principal blood pressure elevating
mechanism (Light and Obrist 1980; Koepke et al. 1988; DiBona 2005).
Psychogenic Hypertension 365
Fig. 1 What might be the mechanism by which chronic mental stress leads to essential hyper-
tension? The figure presents a general scheme for the path to stress-induced illnesses, including
high blood pressure. An ongoing aversive stimulus, which can be modified, extinguished or
perpetuated, in particular circumstances can lead to illness. As indicated in this formulation, the
existence of strong social supports in a person’s life or their possession of good coping strategies
can dampen the stressor impact, minimizing its transfiguration into pathophysiology or psycho-
pathology. For hypertension there are two well-documented aversive patterns of work environ-
ment demonstrated to be causal for high blood pressure (Karasek et al. 1981; Siegrist 1996;
Steptoe and Willemsen 2004; Chandola et al. 2006). The first is the “high job strain” workplace,
characterized by lack of control over the pace of work and its targets and deadlines. The second is
the “effort-reward imbalanced” workplace, typified by demanding work which causes little
personal gratification. Additionally, inescapable time pressure constitutes a unique stressor of
the present day (Klein 2007), this being intensified by the immediacy demands of the electronic
age. The mediating pathophysiology involves ongoing activation of the sympathetic nervous
system, specifically of the renal sympathetic outflow, interacting adversely with excess dietary
intake of sodium (Koepke et al. 1988; DiBona 2005; DiBona and Esler 2010)
What might be the mechanism by which chronic mental stress leads to essential
hypertension? Figure 1 presents a scheme for the path to stress-induced high blood
pressure. Ongoing aversive stimuli, described below, which can be modified,
extinguished or perpetuated in particular circumstances can potentially lead to
hypertension. As indicated in this formulation, the existence of strong social
supports in a person’s life or their possession of good coping strategies can dampen
the stressor impact, minimizing its transfiguration into pathophysiology or psycho-
pathology. Also impacting on this is the presence or absence of genetic and lifestyle
366 M. Esler
The hypothalamus and amygdala receive projections from brain stem noradrenergic
neurons. These projections have been shown in experimental animals to be impor-
tant in stimulating sympathetic nervous system outflow. Using internal jugular
venous sampling, we have developed methods to measure brain norepinephrine
turnover (synthesis rate) differentially in subcortical and cortical brain areas, to test
whether this mechanism applies in human hypertension (Ferrier et al. 1992). By
measuring the overflow of norepinephrine and its lipophilic metabolites into the
internal jugular veins, the turnover of norepinephrine in suprabulbar subcortical
brain regions can be measured. The internal jugular vein which predominantly
drains subcortical brain regions (usually the left vein) is identified using a cerebral
venous sinus scan (Ferrier et al. 1992). This sampling excludes the brain stem,
which drains primarily into the spinal veins.
We have documented that norepinephrine turnover in the brain is increased in
patients with essential hypertension but in subcortical areas only. The findings
suggest an importance of increased firing in noradrenergic A1 and A5 brain stem
neurons which project rostrally to the hypothalamus and amygdala, and underlying
mental stress in hypertension pathogenesis, mediated by sympathetic nervous
activation. Our results find a parallel in the primary importance of the medial
amygdala in the blood pressure elevation of the BPH/2J genetically hypertensive
mouse (Jackson et al. 2014), and in the linking of activation of the amygdala,
demonstrated with MRI, to the magnitude of stress-induced blood pressure eleva-
tion in humans (Gianaros et al. 2008).
documented the presence of PNMT in four of five patients with essential hypertension
but in none of six healthy people (Esler et al. 2008a, b).
Illustrative parallels can be drawn between hypertension, and panic disorder,
which provides an explicit clinical model of recurring stress responses (Davies
et al. 1999; Esler et al. 2008a, b). The findings reinforce the biological case for
essential hypertension being caused by chronic mental stress, in that there were
many instances of parallel neural biological disturbance:
400
300
200
100
0
Normal Essential Resistant
Hypertension Hypertension
Fig. 2 Sympathetic activity in the kidneys, assessed using isotope dilution measurements of renal
norepinephrine spillover to plasma, in healthy volunteers and patients with arterial hypertension,
in whom renal sympathetic activation was evident in many. In untreated patients with mild-
moderately severe essential hypertension (middle column), renal norepinephrine spillover was
increased overall and elevated in approximately 50 %. In drug-resistant hypertension, with patients
administered on average five antihypertensive drug classes, renal norepinephrine spillover was
higher again, attributable to their hypertension, and also perhaps its treatment; vasodilators,
dihydropyridine calcium channel blockers, and diuretics stimulate the sympathetic nervous sys-
tem. From unpublished results of the author, Markus Schlaich, Gavin Lambert, and Dagmara
Hering
There is strong evidence, both historical and contemporary, that the answer to this
question is “yes.” In earlier times, prior to the availability of antihypertensive drugs,
extensive surgical sympathectomy was effectively used as a treatment of severe
hypertension (Smithwick et al. 1956). Of the antihypertensive drugs subsequently
developed in the mid-twentieth century, most were antiadrenergic.
Activation of the sympathetic nervous outflow to the kidneys (Fig. 2) is pivotal
in hypertension pathogenesis (Dibona and Esler 2010). Once it was thought that the
sympathetic nervous system exerts minute by minute circulatory control only and
was not of importance in causing hypertension. The regulatory effects of the renal
sympathetic nerves on renal tubular reabsorption of sodium, renin release, renal
blood flow and glomerular filtration rate are, however, now seen to provide
hypertension-producing mechanisms. The renal sympathetic nerves are stimulated
in patients with hypertension at all phases of the disease, in mild, developing
hypertension through to severe grades, of drug-resistant hypertension (Fig. 2).
Psychogenic Hypertension 371
Hypertension commonly arises from societal ills, from the obesity epidemic, from
sedentary lifestyle, and as emphasized here from chronic mental stress both in the
workplace (Steptoe and Willemsen 2004; Chandola et al. 2006) and in the life of
nations (Poulter et al. 1990). There is compelling evidence that each elevates blood
pressure primarily through neural mechanisms and, in particular, through activation
of the renal sympathetic outflow (Esler et al. 1988, 2010; Rumantir et al. 1999;
DiBona and Esler 2010).
No doubt it would be best to catch this pathophysiological fault of chronic
renal sympathetic activation at its roots, through applying non-pharmacological
treatment measures. The application of relaxation and stress reduction therapies
has a helpful antihypertensive effect, but less than anticipated, given the impor-
tance of stress in pathogenesis, and surprisingly this effect is outstripped by
weight loss from calorie restriction and by aerobic exercise training (Table 2).
For minimal elevations of blood pressure, these non-pharmacological preventive
and treatment modalities may be powerful enough. In more severe hypertension,
although chronic mental stress may be an important causal factor, rather than
changing the world, my colleagues and I have used a new device-based antihy-
pertensive treatment, inhibiting what is the common final pathway, the renal
sympathetic nerves, by ablating them using an intravascular radiofrequency
catheter. In patients with resistant hypertension, although the final place of this
technique in treating hypertension remains uncertain (Esler 2014a, b), the strategy
has produced encouraging results (Krum et al. 2009; Symplicity Investigators
2010).
Conclusion
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Stress Cardiomyopathy
Ilan S. Wittstein
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377
Patient Demographics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Clinical Symptoms and Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378
Diagnosis and Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 380
Other Helpful Diagnostic Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Treatment of SCM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385
Prognosis and Recurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Pathophysiology of SCM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
Factors that May Increase Susceptibility to Stress Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . 391
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397
Keywords
Stress cardiomyopathy • Takotsubo cardiomyopathy • Apical ballooning •
Catecholamines • Sympathetic nervous system
Introduction
Considerable evidence has emerged during the past few decades to support a strong
association between acute psychological stress and cardiovascular morbidity and
mortality. Well-designed case-crossover studies have demonstrated that acute emo-
tional stressors such as anger and sadness more than double the risk of myocardial
Nomenclature
During the past 20 years, SCM has been referred to by a variety of names in the
medical literature. In the early 1990s, Japanese authors introduced the syndrome as
takotsubo cardiomyopathy, which at the time they believed was a syndrome of
acute myocardial dysfunction due to multivessel coronary artery spasm (Dote
et al. 1991). The name takotsubo referred to an octopus-trapping pot with a wide
base and narrow neck whose appearance resembled the unusual left ventricular
shape of patients with this condition. Reports of takotsubo cardiomyopathy
appeared almost exclusively in Japanese medical literature throughout the 1990s.
When Japanese authors finally published a large series of these patients in an
American medical journal in 2001, they introduced the condition as transient left
ventricular apical ballooning syndrome (Tsuchihashi et al. 2001), a descriptive
term that they likely felt would be more acceptable to a Western audience. The
Stress Cardiomyopathy 377
syndrome remained relatively obscure in the medical literature until 2005 when two
separate series from the United States were published in the same week (Sharkey
et al. 2005; Wittstein et al. 2005). The names stress cardiomyopathy and broken
heart syndrome were formally introduced (Wittstein et al. 2005) and were quickly
popularized by the media, helping to bring worldwide attention to this previously
underappreciated medical condition. In 2006, SCM was formally classified as an
acquired primary cardiomyopathy in an American Heart Association scientific
statement (Maron et al. 2006). Over the past 10 years, the medical literature
regarding SCM has increased dramatically, and all four names have continued to
be used interchangeably. The syndrome will be referred to as stress cardiomyopa-
thy throughout this chapter, but the reader should be aware that at the present time a
clear consensus regarding the optimal name for the syndrome has still not been
established.
Incidence
While SCM was once felt to be a rare medical condition, it is clear from the rapidly
expanding medical literature that the syndrome is far more prevalent than what was
originally believed. A large number of retrospective series have demonstrated that
approximately 1–2 % of patients admitted to the hospital with suspected acute
coronary syndromes (ACS) are ultimately diagnosed with SCM (Akashi et al. 2005;
Bellandi et al. 2012; Bybee et al. 2004; Eshtehardi et al. 2009; Haghi et al. 2006;
Parodi et al. 2007; Previtali et al. 2009; Showkathali et al. 2014; Wedekind
et al. 2006). In women presenting with suspected ACS, the incidence of SCM is
even higher with rates ranging from 5 % to 7.5 % (Elian et al. 2006; Parodi
et al. 2007; Previtali et al. 2009; Sy et al. 2013; Wedekind et al. 2006). Deshmukh
and colleagues used the Nationwide Inpatient Sample database (a 20 % sample of
US community hospitals) to estimate the prevalence of SCM in the United States in
2008. Using the ICD-9 discharge diagnosis code 429.83, they identified 6,837 cases
of SCM, a cohort that accounted for approximately 0.02 % of all hospitalizations in
the United States that year (Deshmukh et al. 2012). All of these studies likely
underestimate the true incidence of SCM since they include only those patients
presenting with suspected ACS who undergo coronary angiography, and they
exclude the majority of cases that occur on inpatient wards and in medical, surgical,
and neurologic intensive care units where the syndrome is prevalent but often under
recognized. This is supported by the study from Park and colleagues that showed
that 28 % of patients admitted to a medical intensive care unit with a noncardiac
illness had echocardiographic evidence of left ventricular apical ballooning (Park
et al. 2005). More widespread recognition of this syndrome by physicians in diverse
subspecialties and larger prospective studies will be necessary before the true
incidence of SCM can be fully appreciated.
378 I.S. Wittstein
Patient Demographics
Patients with SCM can present with symptoms that are indistinguishable from an
acute myocardial infarction. The most common symptoms are chest pain and
shortness of breath (Table 1), but other symptoms can include diaphoresis, nausea,
weakness, and even syncope. The majority of patients are hemodynamically stable
Table 1 Clinical characteristics of stress cardiomyopathy from large case series
VT/
Number Trigger Mean age Female HTN HLD DM TOB CP SOB CHF Shock VF Inpatient
Reference patients identified (%) (Yrs) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) death (%)
Tsuchihashi et al. (2001) 88 73 67 86 48 24 12 NR 67 7 37 20 9 1
Elesber et al. (2007) 100 56 66 95 52 33 5 38 77 8 44 7 2 2
Stress Cardiomyopathy
at the time of presentation, but up to a third can have serious complications that
include decompensated heart failure, cardiogenic shock, and malignant ventricular
arrhythmias. Some centers have reported the incidence of heart failure in SCM to be
as high as 45 % (Table 1), and risk factors for the development of acute heart failure
include age >70 years, the presence of a physical stressor, and an ejection fraction
(EF) <40 % (Madhavan et al. 2011). Cardiogenic shock necessitating vasopressor
support or intra-aortic balloon counterpulsation (IABP) occurs in up to 20 % of
cases, while life-threatening arrhythmias have been reported in fewer than 10 % of
patients in most series (Table 1). Other complications of SCM include left ventric-
ular outflow tract obstruction (De Backer et al. 2014), acute mitral regurgitation
(Izumo et al. 2011), apical thrombus formation and cardio-embolic stroke
(de Gregorio et al. 2008), pericarditis, and rarely cardiac rupture (Kumar
et al. 2011).
Several reports have suggested that SCM may have a temporal pattern of
occurrence. In contrast to acute myocardial infarction that peaks during winter
months, a number of groups have demonstrated that the incidence of SCM is
highest during the summer (Aryal et al. 2014; Citro et al. 2009; Deshmukh
et al. 2012; Song et al. 2013). Some reports also suggest that SCM occurs most
commonly during morning hours (Citro et al. 2009; Song et al. 2013), though
Sharkey and colleagues found the incidence to be highest between noon and
4 PM (Sharkey et al. 2012). More studies will be necessary to better understand
whether these observations are the result of a circadian pattern of sympathetic
nervous system activity in patients with SCM or simply reflect the time of day
when these individuals are most often subjected to surgeries, procedures, and other
daily stressors.
Despite the fact that SCM was first described almost 25 years ago, uniformly
accepted diagnostic criteria are still lacking. The first and most widely cited criteria
were proposed by Mayo Clinic investigators in 2004 and then modified in 2008
(Prasad et al. 2008). Since that time, other groups that have suggested diagnostic
criteria include the Japanese Takotsubo Cardiomyopathy Study Group (Kawai
et al. 2007), the Takotsubo Italian Network (Parodi et al. 2014), the Gothenburg
group (Redfors et al. 2014b), and the Johns Hopkins group (Wittstein 2012). All of
these proposed criteria have subtle differences and limitations that have recently
been reviewed (Redfors et al. 2014b). The Johns Hopkins diagnostic criteria are
comprised of both mandatory and nonmandatory criteria and are shown in Table 2.
The following six criteria can be used to reliably make the diagnosis of SCM and
distinguish it from acute myocardial infarction:
Presence of an acute trigger: While not required to make the diagnosis of SCM, an
acute emotional or physical stressor can be identified in the majority of patients
presenting with this syndrome. It is precisely this observation that inspired the
Stress Cardiomyopathy 381
name stress cardiomyopathy (Wittstein et al. 2005), and it is one of the many
reasons why enhanced sympathetic stimulation is believed to be central to the
syndrome’s pathogenesis. Early reports highlighted primarily the emotional
triggers of SCM, but increased recognition of the syndrome has made it clear
that SCM can also be precipitated by a wide variety of physical stressors
(Sharkey et al. 2010). The most frequently seen emotional trigger at Johns
Hopkins is grief due to the loss of a loved one, while commonly observed
physical triggers include neurologic disorders (e.g., stroke, seizure, subarach-
noid hemorrhage), respiratory problems (e.g., pneumonia, asthma exacerbation),
and surgical procedures (Table 3). While identification of an acute stressor is
common and should raise suspicion for SCM, not all patients present with an
obvious precipitant. About 5 % of patients admitted with SCM at Johns Hopkins
have no identifiable trigger, and this number is considerably higher in other
reported series (Table 1). In a systematic review of 1,109 patients with SCM,
74 % presented with an acute emotional or physical trigger while 26 % had no
identifiable precipitant (Pelliccia et al. 2015).
Characteristic electrocardiographic features: Patients with SCM can have a wide
variety of electrocardiographic (ECG) findings. At the time of the acute presen-
tation, the ECG may be normal, may have nonspecific ST-segment and T-wave
abnormalities, or may even demonstrate frank ST-segment elevation (Fig. 1). It
is important to emphasize that no ECG findings have been identified that are
absolutely diagnostic of SCM or that can reliably distinguish the syndrome from
acute myocardial infarction, and therefore patients presenting with ST-segment
elevation are typically referred for urgent coronary angiography. Some investi-
gators have found that compared to acute infarction, patients with SCM typically
have a smaller magnitude of ST elevation in precordial leads (Sharkey
et al. 2008) and are less likely to have reciprocal inferior ST-segment depression
382 I.S. Wittstein
(Ogura et al. 2003). Patients with SCM can also present with Q waves in
precordial leads. In contrast to acute myocardial infarction, these Q waves are
typically transient and are thought to be secondary to myocardial edema and not
tissue necrosis. Within 24–48 h of the initial presentation, many patients with
SCM develop distinctive ECG findings that include deep symmetric T-wave
inversion and QT interval prolongation that frequently involve both precordial
and limb leads (Fig. 1) (Wittstein et al. 2005). While the QT interval prolonga-
tion typically improves within a few days, the T-wave inversions may take days,
weeks, or even months to normalize (Mitsuma et al. 2007).
Characteristic cardiac biomarker profile: The majority of patients with SCM have
an elevation in cardiac enzymes at the time of presentation. The levels of these
enzymes are typically low and disproportionate to the extensive amount of left
ventricular dysfunction typically seen in these patients, suggesting a minimal
amount of myocardial necrosis in SCM. In contrast, brain natriuretic peptide
(BNP) levels in patients with SCM are usually markedly elevated at the time of
Stress Cardiomyopathy 383
Fig. 1 Electrocardiographic findings of three patients with stress cardiomyopathy at the time of
admission and at follow-up (within 48 h of admission). The ECG of patient 1 shows mild
nonspecific T-wave changes at the time of admission, while patient 2 has more diffuse ST–T-
wave abnormalities on admission. Patient 3 has marked ST-segment elevation diffusely with
anteroseptal Q waves at the time of initial presentation. Despite the very different appearing
electrocardiograms initially, all three patients develop characteristic ECG findings within 48 h of
admission that include deep diffuse T-wave inversion and a markedly prolonged QT interval. Note
also that the anterior Q waves seen at the time of admission in patient 3 are already resolving on the
follow-up electrocardiogram
admission (Wittstein et al. 2005) and tend to be much higher than the levels seen
in patients with acute myocardial infarction (Doyen et al. 2014). While the
diagnosis of SCM cannot be definitively made from cardiac biomarkers alone,
several authors have shown that an elevated BNP/troponin ratio at the time of
presentation can help distinguish SCM from acute infarction with reasonable
sensitivity and specificity (Doyen et al. 2014; Frohlich et al. 2012).
384 I.S. Wittstein
Fig. 2 Left ventriculography of a patient with stress cardiomyopathy during diastole (left) and
systole (right). Note the typical pattern of apical ballooning which is characterized by akinesis of
the apical and mid-ventricular walls with normal contractility of the basal segments
Absence of acute plaque rupture and coronary thrombosis: Most patients with SCM
have normal coronary arteries at the time of angiography (Gianni et al. 2006;
Pilgrim and Wyss 2008), but nonobstructive coronary atherosclerosis has been
frequently reported in these patients (Hoyt et al. 2010; Winchester et al. 2008).
Because patients with SCM present with chest pain, dynamic ECG changes,
elevated cardiac enzymes, and focal left ventricular wall motion abnormalities,
coronary angiography is recommended in most cases to rule out acute plaque
rupture and coronary thrombosis, findings that would be diagnostic of an acute
coronary syndrome and that would exclude the diagnosis of SCM. Interestingly,
despite the absence of obstructive epicardial disease, patients with SCM often
have abnormal coronary flow, suggesting that acute microcirculatory impair-
ment may be central to the pathogenesis of this syndrome.
Ventricular “ballooning”: Perhaps the most defining clinical feature of SCM is the
unusual appearance of the left ventricle that is seen with ventriculography or
echocardiography at the time of presentation. Unlike patients presenting with
acute infarction, patients with SCM have left ventricular contractile abnormal-
ities that extend beyond a single vascular territory. The majority of patients have
akinesis or dense hypokinesis of the apical and mid-ventricular segments with
sparing of the base of the ventricle, a contractile pattern that has been referred to
as “left ventricular apical ballooning” (Fig. 2). Variants of the syndrome have
been described, however, in which the mid- and basal portions of the heart are
dysfunctional and the base is spared (Hurst et al. 2006; Reuss et al. 2007). These
“mid-ventricular” and “basal” ballooning patterns account for approximately
20 % of SCM cases and are more commonly seen in men and in younger patients
Stress Cardiomyopathy 385
(Nishida et al. 2014; Song et al. 2011). While SCM is characterized primarily by
left ventricular contractile dysfunction, approximately one third of patients will
have concurrent right ventricular dysfunction (A. A. Elesber et al. 2006).
Patients with biventricular involvement are more likely to have heart failure
and hemodynamic instability during the acute presentation.
Recovery of left ventricular function: SCM is characterized by complete and rapid
recovery of ventricular systolic function. While the rate of recovery is variable,
most patients demonstrate significant improvement in systolic function within a
week of the initial presentation, with complete recovery occurring by the end of
the third week. Cases of very slow left ventricular recovery taking up to a full
year have been reported (Sharkey et al. 2010), but these cases are atypical. In
general, if left ventricular contractile function has not completely normalized
within 12 weeks of the initial presentation, alternative diagnoses should be
considered.
Several imaging modalities have been used to help make the diagnosis of SCM and
to distinguish the syndrome from acute infarction. Cardiac magnetic resonance
imaging (MRI) provides analysis of regional wall motion abnormalities in both
ventricles and can effectively identify the various ballooning patterns. Several
studies have shown that the cardiac MRI of patients with SCM is characterized
by myocardial edema and the absence of late gadolinium enhancement (LGE).
These findings are indicative of myocardial viability and the absence of necrosis
and help to distinguish SCM from other acute processes such as myocardial
infarction and acute myocarditis (Eitel et al. 2011; Haghi et al. 2007; Sharkey
et al. 2005; Wittstein et al. 2005).
Positron emission tomography (PET) has also been used to study myocardial
metabolic activity in patients with SCM. Studies using F-18 fluorodeoxyglucose
(FDG) PET have demonstrated marked metabolic impairment in regions of ven-
tricular akinesis despite normal or only mildly impaired myocardial perfusion
(Feola et al. 2006; Yoshida et al. 2007). The mechanism of this unique metabolic
derangement is unknown but may result either from sympathetically mediated
microcirculatory dysfunction or direct catecholamine-mediated impairment of
myocyte glucose utilization.
Treatment of SCM
Most of the literature to date suggests that SCM has a favorable short- and long-
term prognosis and relatively low risk of recurrence. In-hospital mortality from
reported series has ranged from <1 % to as high as 9 % (Table 1), and the vast
majority of deaths that occur in the hospital are from noncardiac causes. In a large
meta-analysis of 2120 patients with SCM from 11 different countries, the
in-hospital mortality rate was 4.5 % and was threefold higher in men than in
women (Singh et al. 2014). Brinjikji and colleagues looked at 24,701 patients
diagnosed with SCM in the National Inpatient Sample 2008–2009 and found a
similar inpatient death rate of 4.2 % (Brinjikji et al. 2012). The vast majority of
the patients who died had an underlying critical illness, and this is consistent with
a previous observation that acute mortality in patients with SCM is associated
with more severe systemic illness as determined by a higher Acute Physiology
and Chronic Health (APACHE) II score (Joe et al. 2012). With respect to long-
term prognosis, Redfors reported a 30-day mortality rate of 4.1 %, while Cacciotti
found a death rate of 2.6 % at 2 years (Cacciotti et al. 2012; Redfors et al. 2015).
In a large single-center retrospective experience from the Mayo Clinic, the 4-year
mortality was 17 % which was similar to that observed in an age- and gender-
matched population (Elesber et al. 2007). Sharkey and colleagues reported a 15 %
5-year mortality rate in a large series of patients with SCM. These patients had
reduced survival compared to an age- and sex-matched population, but most of
the deaths occurred within the first year and were due to noncardiac causes
(Sharkey et al. 2010). Song reported an even higher mortality of 23 % at a median
follow-up of 42 months, but once again only two of these patients died from
cardiac causes (Song et al. 2010). When compared to patients with acute myo-
cardial infarction, patients with SCM in one series were far more likely to develop
malignancies at a median follow-up of 2.8 years. While the overall mortality did
not differ significantly between the two groups, cardiac causes of death were
relatively rare in patients with SCM (Burgdorf et al. 2008a). It is reasonable to
conclude from these reports that cardiovascular mortality is quite low in patients
with SCM, but overall prognosis is dependent on the presence and severity of
underlying systemic disease.
The majority of patients with SCM will not experience a second episode,
though recurrences have certainly been reported. In the series from Song et al.,
there were no recurrences during a median follow-up of 42 months (Song
et al. 2010). This is in contrast to the Mayo Clinic series that reported a 4-year
recurrence rate of 11.4 % (Elesber et al. 2007) and to the series from Sharkey and
colleagues that reported a 5-year recurrence of 5 % (Sharkey et al. 2010). In a
meta-analysis of 1664 patients with SCM, the annual rate of recurrence was 1.5 %
with a cumulative incidence of recurrence of ~5 % at 6 years (Singh et al. 2014). It
is interesting to note that recurrent episodes of SCM can occur many years apart
and that each event may be characterized by a different ventricular ballooning
pattern (Gach et al. 2012).
388 I.S. Wittstein
Pathophysiology of SCM
Fig. 3 A proposed paradigm illustrating the link between acute stress and the syndrome of stress
cardiomyopathy. Increased sympathetic stimulation may mediate myocardial stunning through a
variety of mechanisms that include coronary vasospasm, microvascular dysfunction, and myocyte
calcium overload. Risk factors that may increase individual susceptibility to sympathetic stimu-
lation are also shown (Modified from Prog Cardiovasc Dis 49(5), Bhattacharyya MR, Steptoe
A. Emotional triggers of acute coronary syndromes: strength of evidence, biological processes,
and clinical implications. Page 354, Fig. 1, copyright # 2007, with permission from Elsevier
(Bhattacharyya and Steptoe 2007))
must occur in a long wraparound left anterior descending (LAD) coronary artery
to explain the apical ballooning pattern. Eccentric atherosclerotic plaque in the
midportion of the LAD has been reported in a small number of patients with
SCM, but intravascular ultrasound has failed to identify plaque in most studies
(Delgado et al. 2011; Haghi et al. 2010). It has also been clearly shown by
several investigators that apical ballooning can occur even in the absence of a
wraparound LAD and that this coronary anatomy is no more prevalent in SCM
than in a control population (Hoyt et al. 2010). Further, ischemia in a wrap-
around LAD would not explain the non-apical variants that also characterize this
syndrome. These data all support the conclusion that catecholamine-mediated
plaque rupture with aborted myocardial infarction is not the primary pathophys-
iologic mechanism responsible for SCM.
390 I.S. Wittstein
Epicardial spasm: It has been proposed that SCM results from transient myocardial
ischemia due to sympathetically mediated coronary artery spasm. While epicar-
dial spasm has been reported in a small number of patients with SCM (Fiol
et al. 2012), the vast majority of patients do not have spasm at the time of
angiography. In the series from Tsuchihashi (Tsuchihashi et al. 2001) and Sato
(Sato et al. 2008), coronary spasm could only be provoked with acetylcholine in
21 % and 23 % of the patients, respectively, and some investigators have been
completely unable to provoke spasm with agents such as ergonovine (Martinez-
Selles et al. 2010). Further, it is difficult to explain the unusual contractile
patterns observed in this syndrome from coronary spasm alone since none of
the ballooning variants correspond with an epicardial vascular distribution.
These data would suggest that while abnormal coronary vasomotion may
occur in some patients with SCM, sympathetically mediated epicardial spasm
is unlikely the primary pathophysiologic mechanism underlying the syndrome.
Microvascular dysfunction: There is considerable evidence that catecholamine-
mediated microvascular dysfunction may be central to the pathogenesis of
SCM. Decreased coronary flow reserve (CFR) has been demonstrated noninva-
sively during the acute presentation with positron emission tomography/com-
puted tomography (PET/CT) (Ghadri et al. 2014) and with echocardiography
following the infusion of adenosine (Meimoun et al. 2008) and dipyridamole
(Rigo et al. 2009). Invasive techniques demonstrating microcirculatory dysfunc-
tion in patients with SCM have included the use of Doppler flow wires showing
decreased CFR (Kume et al. 2005) and intracoronary pressure/temperature guide
wires that have demonstrated an increase in the index of microcirculatory
resistance (IMR) (Daniels and Fearon 2011). Patients with SCM who undergo
angiography also have elevated thrombolysis in myocardial infarction (TIMI)
frame counts (Bybee et al. 2004) and abnormal TIMI myocardial perfusion
grades (A. Elesber et al. 2006), both well-validated indexes of coronary blood
flow. In most of these patients, TIMI frame counts are increased in multiple
vessels, and perfusion abnormalities involve multiple coronary territories,
suggesting a diffuse microcirculatory abnormality. Catecholamine-mediated
endothelial dysfunction is further supported by an endomyocardial biopsy
study from Uchida and colleagues who found that patients with SCM have
elevated catecholamine levels and histologic evidence of microvascular endo-
thelial cell apoptosis (Uchida et al. 2010). Further evidence suggests that sym-
pathetically mediated endothelial dysfunction in SCM is a systemic process that
involves more than just the coronary microcirculation. At the time of presenta-
tion, patients with SCM have marked impairment in brachial artery flow-
mediated dilation compared to patients with myocardial infarction and to healthy
controls, and this abnormality gradually improves over several weeks (Vasilieva
et al. 2011).
Direct myocyte effects: The transient left ventricular dysfunction that characterizes
SCM could alternatively result from the direct effects of catecholamines on
cardiac myocytes. Catecholamines can decrease myocyte viability through
cyclic adenosine monophosphate-mediated calcium overload (Mann
Stress Cardiomyopathy 391
et al. 1992), and there is evidence that patients with SCM may have abnormal
cardiomyocyte calcium regulation at the time of presentation. Looking at
myocytes from left ventricular endomyocardial biopsy samples, Nef and col-
leagues demonstrated significant downregulation of sarcoplasmic Ca2+ ATPase
(SERCA2a) gene expression, increased ventricular expression of sarcolipin, and
dephosphorylation of phospholamban (PLN) (Nef et al. 2009). They hypothe-
sized that the increased PLN/SERCA2a ratio could potentially result in myo-
cardial contractile dysfunction through decreased calcium affinity, and repeat
biopsies performed after left ventricular function had recovered demonstrated
normalization of these intracellular proteins. An abnormality of calcium han-
dling has also been demonstrated in a rat model of SCM where acute beta-
adrenergic stimulation resulted in left ventricular dysfunction and myocyte
injury due to calcium leakage from hyperphosphorylation of the ryanodine
receptor 2 (RyR2) (Ellison et al. 2007). More recently, Paur and colleagues
used a rat model to demonstrate that high circulating levels of epinephrine had a
negative inotropic effect on the cardiac myocyte by causing a switch from Gs to
Gi protein signaling via the β2-adrenergic receptor (Paur et al. 2012). This effect
was most pronounced at the apex of the ventricle where β2-adrenergic receptor
density was highest, and blocking Gi protein signaling resulted in increased
mortality. The authors proposed, therefore, that reduced left ventricular apical
contractility due to a switch from Gs to Gi protein signaling was cardioprotective
during periods of hyperadrenergic stimulation. While this hypothesis is intrigu-
ing, it does not readily explain the mechanism underlying the non-apical variants
of SCM or why some patients with recurrent episodes present with variable
ballooning patterns.
Despite the fact that psychological and physical stressors are ubiquitous and a
normal part of everyday human life, only a relatively small number of individuals
develop the clinical syndrome of SCM. This suggests that there are risk factors that
make certain individuals particularly susceptible to this condition, likely by either
augmenting the sympathetic stress response or by increasing cardiomyocyte and
microcirculatory susceptibility to the effects of catecholamines (Fig. 3). It is likely
that many such risk factors exist, but only those most supported by clinical
observations and research will be discussed here.
Psychological disorders: Many investigators have reported a high incidence of
mood disorders and anxiety in patients with SCM (Table 4). In a retrospective case-
control study, Summers demonstrated that 68 % of patients with SCM had either
anxiety or depression, and the prevalence of these disorders was higher than in
patients with myocardial infarction or in healthy controls (Summers et al. 2010).
El-Sayed looked retrospectively at over 24,000 patients with SCM and similarly
found that psychological disorders occurred more frequently in patients with SCM
392 I.S. Wittstein
Table 4 (continued)
Prevalence of
# SCM psychological
Study Study type patients disorders Observations
Dias Retrospective 78 21 % depression; SSRI use associated with
et al. (2014) 30 % anxiety; 19 % increased hospital death and
taking SSRI decreased long-term
survival
Pelliccia Systematic 1109 9 % mood disorders, Psychological disorders
et al. (2015) review 13 % anxiety common in SCM
ACS acute coronary syndrome, MI myocardial infarction, NR not reported, SCM stress cardiomy-
opathy, SSRI selective serotonin reuptake inhibitor, STEMI ST-segment elevation myocardial
infarction
Conclusion
In just a few short years, SCM has evolved from an obscure and relatively unheard
of condition to a widely accepted clinical syndrome. Better recognition of the
unique clinical features of SCM has made it possible to readily distinguish the
396 I.S. Wittstein
Fig. 4 A proposed model to explain how stress cardiomyopathy can be precipitated by triggers of
variable intensity. The amount of stress needed to precipitate the clinical syndrome is dependent
on individual risk factors that likely influence catecholamine production and/or myocyte and
microvascular sensitivity to sympathetic stimulation (see text). SCM stress cardiomyopathy
(Reproduced with kind permission from Springer: Cell Mol Neurobiol, Stress Cardiomyopathy:
A Syndrome of Catecholamine Mediated Myocardial Stunning, 2012, page 855, Wittstein, IS,
Fig. 3 (Wittstein 2012))
syndrome from acute myocardial infarction, and it is now clear that a broad
spectrum of emotional and physiologic stressors can indeed acutely precipitate
cardiac contractile dysfunction and heart failure. The preponderance of evidence
suggests that SCM results from sympathetically mediated microcirculatory dysfunc-
tion, though the precise mechanism of catecholamine-mediated myocardial stunning
remains incompletely understood. A number of risk factors have been identified that
appear to increase individual susceptibility to SCM, possibly by either enhancing
catecholamine production or by increasing myocyte and microcirculatory sensitivity
to catecholamines. In particular, there is increasing evidence that mood disorders,
anxiety, and chronic psychological stress may increase the risk of acute stress-related
myocardial dysfunction, but it is unknown whether treatment of these psychological
conditions will result in improved cardiovascular outcomes. Behavioral and psycho-
logical interventions have never been studied in patients with SCM, and commonly
used antidepressants could potentially have deleterious effects by increasing local
myocardial catecholamine levels. It seems clear that future research examining the
psychological constructs of SCM will be vital to not only better understand the
Stress Cardiomyopathy 397
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Congenital Heart Diseases
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408
Normal Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Anatomy of the Normal Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
Congenital Heart Diseases (CHDs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Definition of CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Incidence of CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Classification of CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412
Cyanotic Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Tetralogy of Fallot (ToF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423
Pulmonary Atresia (PA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 424
Transposition of the Great Arteries (TGA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427
Truncus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Total Anomalous Pulmonary Venous Return (TAPVR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 430
Ebstein Anomaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
Hypoplastic Left Heart Syndrome (HLHS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 432
Interruption of the Aortic Arch (IAA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434
Abstract
– Introduction: Congenital heart defect (CHD) may be defined as an anatomic
malformation of the heart or great vessels which occurs during intrauterine
development. CHDs are serious and chronic illnesses. Congenital heart defects
M. Chessa (*)
Pediatric and Adult Congenital Heart Centre, IRCCS-Policlinico San Donato-University Hospital,
San Donato Milanese (Milan), Lombardy, Italy
e-mail: [email protected]
F.A. Taha
Faculty of Medicine, Tanta University, Tanta, Egypt
e-mail: [email protected]; [email protected]
Keywords
Congenital heart diseases (CHDs) • Atrial and ventricular septal defects • Patent
ductus arteriosus (PDA) • Stenotic cardiac lesions • Coarctation and interruption
of the aorta • Tetralogy of Fallot (ToF)/pulmonary atresia (PA) • Transposition of
the great arteries (TGA) • Truncus arteriosus • Anomalous pulmonary venous
return (APVR) • Ebstein anomaly
Introduction
Normal Heart
Definition
The human heart is a vital organ that functions as a pump, providing a continuous
circulation of blood through the body, by way of the cardiac cycles (Taber and Venes
2009).
Development
The heart is the first functional organ to develop in the embryo. The human
embryonic heart begins beating at around 21 days or at 5 weeks after conception
(DuBose et al. 2010) (Figs. 1 and 2).
Trachea Esophagus
Thoracic Duct
Right Phrenic Nerve
Left Phrenic Nerve
Superior Vena Cava
Aorta
Right Bronchus Pulmonary
Trunk
Right Atrium
Mitral Valve
Pulmonary Valve
Aortic Valve
Tricuspid Valve
Left Ventricle
Pulmonary Artery
Septum Secundum
ASD (Ostium Secundum)
Septum Primum Mitral Valve
Right Ventricle
contractions and to the movements of adjacent structures as the diaphragm and lungs.
It also serves as protection from infection and knocks (Levine and Miller 2002).
Blood Supply
As well as the blood being pumped within the heart, the heart has its own blood
supply that surrounds it. This is the coronary circulation (Taber and Venes 2009).
Conduction System
Signals arising in the SA node stimulate the atria to contract and travel to the AV
node. After a delay, the stimulus is conducted through the bundle of His to the
Purkinje fibers and the endocardium at the apex of the heart, then finally to
the ventricular epicardium (Anatomy and Function of the Heart’s Electrical
System 2013).
• The heart acts as a double pump. The function of the right heart is to collect
deoxygenated blood, in the right atrium, from the body (via the superior and
inferior venae cavae) and pump it, via the right ventricle, into the lungs (pulmo-
nary circulation) where carbon dioxide can be exchanged for oxygen. This
happens through the passive process of diffusion. From there, blood flows back
through the pulmonary vein to the left atrium (Anderson 2012).
• The left heart collects oxygenated blood from the lungs into the left atrium. From
the left atrium the blood flows to the left ventricle which pumps it out to the rest of
the body (via the aorta). The (relatively) deoxygenated blood finally returns to the
heart through the superior and inferior venae cavae (Anderson 2012).
Definition of CHD
Incidence of CHD
CHDs are among the most pervasive and serious chronic illnesses found in children.
It is estimated that 8 of every 1,000 babies are born with a congenital heart defect
(Behrman et al. 1992).
Classification of CHD
Congenital heart defects may be classified into acyanotic and cyanotic depending
upon whether the patients clinically exhibit cyanosis. The acyanotic defects may
further be subdivided into obstructive lesions and left-to-right shunt lesions. The
cyanotic defects, by definition, have right-to-left shunt (Syamasundar 2012).
Acyanotic Conditions
• Natural history and prognosis: Complete anatomic closure of the foramen ovale
occurs in 70–75 % of adults. It assumes clinical importance in certain congenital
heart defects and in older patients with paradoxical emboli and stroke (Schneider
et al. 1996).
Pulmonary Artery
prolapse of one or more aortic valve leaflets into the defect during systole leads to
aortic regurgitation (AR) (Brickner et al. 2000; Graham and Gutgesell 1995).
• Associated anomalies: It may occur in isolation or, less commonly, as a part of a
complex cardiac malformation (Brickner et al. 2000).
• Pathophysiology: The physiologic consequences of a VSD are determined by the
size of the defect and the relative resistance in the systemic and pulmonary
vascular beds. Left-to-right shunting predominates (Fig. 6). Over time, the pul-
monary vascular resistance usually increases, and the magnitude of left-to-right
shunting declines. The pulmonary vascular resistance equals or exceeds the
systemic resistance, and right-to left shunting begins (Brickner et al. 2000).
• Management: Catheterization and angiography confirm the presence and location
of the defect, as well as the magnitude of shunting and the pulmonary vascular
resistance. Surgical closure of the defect is recommended, if the magnitude of
pulmonary vascular obstructive disease is not prohibitive (Brickner et al. 2000;
Boehrer et al. 1992).
• Natural history and prognosis:
– It depends on the size of the defect and the pulmonary vascular resistance.
Adults with small defects and normal pulmonary arterial pressure are generally
asymptomatic, and pulmonary vascular disease is unlikely to develop (Kidd
et al. 1993). Such patients do not require surgical closure, but they are at risk
for infective endocarditis and should receive antibiotic prophylaxis (Brickner
et al. 2000; Kidd et al. 1993).
– Patients with large defects who survive to adulthood usually have left ventric-
ular failure or pulmonary hypertension with associated right ventricular failure
(Perloff 1998).
– Complete heart block secondary to injury to the conduction system during
repair of a VSD may require a postoperative pacemaker. Now, awareness of
Congenital Heart Diseases 417
the location of the conductive system in relationship to the defect makes this a
rare complication (Perloff 1998; Kidd et al. 1993).
• Etiology:
– In valvular AS, the most common pathological finding in patients who are
younger than 65 years of age is a bicuspid aortic valve.
– In subvalvular aortic stenosis there is either an isolated fibrous ring (membra-
nous subaortic stenosis) or a septal hypertrophy (idiopathic hypertrophic
cardiomyopathy).
– In supravalvar aortic stenosis, there is either Williams syndrome, in which a
defect in the elastin gene is present, or familial supravalvar aortic stenosis, which
probably carries a mutated elastin gene (Brickner et al. 2000; Friedman 1995).
• Incidence: Aortic stenosis represents about 6 % of CHD. Bicuspid aortic valve is
found in 2–3 % of the population. It is four times as common in men as in women.
Twenty percent of patients with bicuspid aortic valve have an associated cardio-
vascular abnormality, such as patent ductus arteriosus or aortic coarctation
(Brickner et al. 2000; Friedman 1995).
• Pathophysiology:
– In patients with bicuspid aortic valve, the bicuspid valve has a single fused
commissure. Although the deformed valve is not stenotic at birth, it is
subjected to thickening and calcification of the leaflets, with resultant immo-
bility. In many patients, there is a coexisting abnormality of the medial layer of
the aorta above the valve, which predisposes to dilatation of the aortic root.
Left ventricular hypertrophy results from gradually worsening aortic stenosis
(Brickner et al. 2000).
– In patients with fibromuscular membrane with a small central orifice located in
the left ventricle, a jet of blood passes through the orifice and strikes the aortic
valve. The energy of the jet results in alterations in the aortic valve and aortic
insufficiency (Friedman 1995).
Congenital Heart Diseases 419
– Supravalvular PS: Treatment with catheter balloon dilation, sometimes with place-
ment of endovascular metal stents, is widely used, although with variable results
depend on the etiology and severity of the stenosis (Johnson and Moller 2014).
– The neonate with critical stenosis and an extremely hypoplastic pulmonary annu-
lus requires outflow tract widening by use of a patch (Johnson and Moller 2014).
• Natural history and prognosis:
– Adults with valvular pulmonary stenosis are often asymptomatic (Brickner
et al. 2000).
– When the stenosis is severe, dyspnea on exertion or fatigability may occur.
Eventually, right ventricular failure may develop, with resultant peripheral
edema and abdominal swelling. Finally, if the foramen ovale is patent,
shunting of blood from the right to the left atrium may occur, causing cyanosis
and clubbing (Brickner et al. 2000).
Cyanotic Conditions
• Definition: ToF involves four anatomical abnormalities of the heart which are
(Syamasundar 2012) malaligned VSD, (Behrman et al. 1992) anterior shift of the
aorta over the VSD (overriding aorta), (Taber and Venes 2009) obstruction of the
right ventricular outflow tract, and (Green 2004) right ventricular hypertrophy
(Fig. 10). Approximately 25 % have a right-sided aortic arch, and about 4 % have
a coronary artery anomaly (Lillehei et al. 1986).
• Incidence: It constitutes 4–9 % of CHD and is the most common cyanotic CHD
(Lillehei et al. 1986).
• Pathophysiology: The major right ventricular outflow obstruction in ToF is
infundibular stenosis. The degree of cyanosis depends on the degree obstruction.
This is quite variable, from a slight obstruction, to severe obstruction with
pulmonary atresia. With mild pulmonary stenosis, also known as “pink tetralogy
of Fallot,” ToF behaves as a VSD with pulmonary overflow. As infundibular
stenosis increases, progressive cyanosis due to less pulmonary blood flow
develops. ToF with pulmonary atresia, also known as pulmonary atresia with
VSD, is a ToF severe variant in which there is complete obstruction (atresia) of
the right ventricular outflow tract (Marelli and Gurvitz 2011).
• Management: Total surgical correction can now be performed in young infants
from 3 to 6 months of age or earlier (Koenig et al. 2004). Surgical treatment of the
defect includes patch closure of the VSD and relief of pulmonary outflow
obstruction with patch augmentation of the outflow at the expense of creation
of free pulmonary regurgitation (PR) (Romfh et al. 2012).
Overriding Aorta
Pulmonary Valvular
Stenosis
Malaligned Perimembranous
Infundibular Stenosis Ventricular Septal Defect
Aorta
Atretic Pulmonary Valve
Subaortic Ventricular
Septal Defect
Hypoplastic Right Ventricle
Underdeveloped
Tricusoid Valve
• Management:
– PA/IVS early palliation involves starting on PGE1 infusion to keep widely
open the ductus arteriosus until Blalock-Taussig (BT) shunt surgery (Fig. 13),
which helps to augment pulmonary flow for PA, and the eventual surgical goal
may usually be “Fontan”-type operation (Fig. 14), more often a
cavopulmonary shunt achieving a right heart bypass. In selected cases with
particular anatomic features, bypass of obstruction can be done using an
RV-to-pulmonary artery conduit (Yun 2011; Nadas and Fyler 2006).
– Management of PA/VSD depends on the pulmonary blood supply. About half
of those will be suitable for corrective surgery with VSD closure and connect
the right ventricle to the pulmonary arteries using the conduit placement (Yun
2011; Nadas and Fyler 2006; Gewitz and Woolf 2006).
426 M. Chessa and F.A. Taha
Bidirectional Glenn
Systemic
Ventricle
Fontan Extracardiac
Tunnel
Fenestration
Inferior vena Cava
• Definition: The great arteries are placed across the ventricular septum with
atrioventricular concordance and ventriculoarterial discordance (the aorta arising
from the right ventricle and the PA from the left ventricle) (Hoffman and
Christianson 1978).
• Incidence: TGA accounts for 4–5 % of all CHDs (Hoffman and Christianson
1978), and is one of the most common cyanotic heart diseases in the early
presentation (Martins and Castela 2008).
• Pathophysiology: This is incompatible with life unless a communication exists
between systemic and pulmonary circulation, as the two circulations are in
parallel and independent. During the newborn period, the PDA and PFO maintain
this communication. As the PDA starts to close and the PFO by itself is inade-
quate in size, the patient develops intense cyanosis. Its severity and onset depend
on the degree of mixing between the two circulations. Eventually progress into
obstructive pulmonary vascular disease can occur (Reddy 2002).
• Associated anomalies: In 50 % of the cases, the TGA is an isolated finding. This
condition is designated as “simple” or “complete” TGA or TGA/IVS (Fig. 15). By
contrast, complex transposition includes all the cases with coexisting malformations,
such as VSD (Fig. 16), PS (Fig. 17), left ventricular outflow tract obstruction, aortic
arch anomalies, and anomalous venous systemic return (Yun 2011).
• Management:
– Babies with TGA should be started on PGE1 infusion to maintain ductal
patency which increases the pulmonary flow. If the foramen ovale is restricted,
PGE1 alone could not achieve clinical improvement, and emergency balloon
atrial septostomy (Rashkind balloon septostomy) is the only way to rescue
these infants (Yun 2011; Martins and Castela 2008).
– In surgical repair, the circulations are placed in series either by switching the
inflow sources (atrial switch operation) or by switching the outflows (arterial
switch operation) (ASO) and placement of the RV-PA conduit (Rastelli opera-
tion) (Rastelli et al. 1969). After an atrial switch operation, the RV remains the
systemic ventricle while after an ASO the LV becomes the systemic ventricle.
Patients born before the early 1980s most likely underwent an atrial switch
operation Mustard (1964) or Senning (1959) or a Rastelli et al. (1969) operation.
Patients born after the late 1980s were most likely repaired using the ASO.
428 M. Chessa and F.A. Taha
Pulmoary Artery
Left Ventricle
Fig. 17 Transposition of the great arteries with ventricular septal defect and pulmonaru artery
stenosis
Truncus Arteriosus
• Definition: In truncus arteriosus both the ascending aorta and main pulmonary
artery or branch pulmonary arteries arise from a common trunk, positioned over a
ventricular septal defect that supplies systemic, coronary, and pulmonary circu-
lations (Fig. 18) (Rodefeld and Hanley 2002).
• Incidence: It accounts for about 1–4 % of the congenital heart defects (Rodefeld
and Hanley 2002).
• Associated anomalies are common, such as DiGeorge syndrome (Rodefeld and
Hanley 2002).
430 M. Chessa and F.A. Taha
Aorta
Pulmonary Arteries
Truncus Arteriosus
Pulmonary Trunk
Truncal Valve
Right Ventricle
Left Ventricle
Ventricular Septal Defect
Fig. 18 Truncus
• Definition: All four pulmonary venous directly connect to the right atrium instead
of the left atrium. There are four main types according to the connection (Yun
2011): (1) supracardiac type (50 %) to the innominate vein; (2) infradiaphragmatic
type (20 %) to the hepatic or portal vein; (3) cardiac type (20 %) to the coronary
sinus; and (4) mixed type (10 %) combination of any of type (Fig. 19) (Yun 2011;
Seale et al. 2010).
• Incidence: TAPVR represents around 1 % of CHD (Seale et al. 2010).
• Pathophysiology: The timing and mode of presentation depend on the type and
degree of obstruction. Infracardiac type is the most commonly obstructed and
may have serious manifestations. Fifteen common pulmonary venous channels
are delivered to the right atrium, and there the mixing of the pulmonary and
systemic circulations occurs. Systemic desaturation occurs as the result of mixing
Congenital Heart Diseases 431
Pulmonary veins
Right Ventricle
Infracardiac Type of
TAPVD
Ebstein Anomaly
• Definition: The left side of the heart is unable to support systemic circulation. It
includes aortic valve atresia and some forms of mitral atresia (Yun 2011). Absent
forward flow through the left ventricular outlet is characteristic. Left ventricle is
markedly underdeveloped and often rudiment. Aortic arch is also hypoplastic,
and ascending aorta is very small, acting simply as a passage into the coronary
arteries (Yun 2011).
Congenital Heart Diseases 433
• Incidence: It is rare, accounting for 2–3 % of all CHD (Barron et al. 2009).
• Pathophysiology: Pulmonary venous return can only reach systemic circu-
lation by traversing the patent foramen ovale to reach the right atrium. This
implies mixing of pulmonary venous and systemic venous flow, creating a
mild cyanotic condition (Yun 2011; Barron et al. 2009). All systemic
circulation is absolutely dependent to the ductus arteriosus. After birth,
systemic vascular resistance is higher than pulmonary, with the ductal
closure after birth; nonfunctioning left ventricle cannot take charge of the
cardiac output. This leads to circulatory deterioration and shock (Nadas and
Fyler 2006).
• Management: PGE1 infusion is necessary to survive. In previous years HLHS
showed high mortality because of the poor interventional outcome. However, in
recent years, radical palliative surgery (Norwood and its variants) has become
more widespread, and the outcome has improved (Yun 2011).
• Natural history and prognosis: Early death with almost no prospect of prolonged
natural survival usually occurs (Yun 2011).
Conclusion
People with congenital heart disease often would need treatment over their life and
therefore require specialist review during childhood and adulthood. This is because
people with complex heart problems can develop further problems with their heart
rhythm or valves over time. Psychological assessment and support must be part of
the routinely follow-up of these patients.
434 M. Chessa and F.A. Taha
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Psychosocial Aspects of Adults with
Congenital Heart Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440
Psychological Characterization of Adults with Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . 442
The Role of Psychologists in the Care for Adults with Congenital Heart Disease . . . . . . . . . . . 445
Provision of Clinical Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 445
Multidisciplinary Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Professional Education: Increasing Psychosocial Awareness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
Abstract
During the last few decades, the survival rate of adults with congenital heart
disease (ConHD) has increased considerably. The psychological characteriza-
tion of adults with ConHD is very different from patients with acquired cardiac
pathologies. Recent guidelines of cardiology associations indicate the necessity
for specialized psychosocial support. The majority of the studies in the literature
indicate the absence of a relationship between diagnosis, physical functionality,
and the presence of residual symptoms and a worse psychological functioning in
these patients. The variables which seem to be related to psychological well-
being in these patients are the following; negative thoughts, solitude, social
support, fear of negative evaluation, imposition of limits, perceived health
status, somatic symptoms, perception of an economical difficulty, and restric-
tions linked to the surgical scar in females. Interestingly, studies, which utilized
psychiatric interviews or similar methodologies, outlined that it was common for
patients, who were diagnosed with a mood or anxiety disorder, not to have
received any appropriate treatment and often they were assumed to be well
psychologically. When it comes to the life experiences of adults with ConHD, it
has been outlined how these patients feel different from their healthy peers. It
has been seen that often there is a struggle to feel normal and also to be perceived
by others as being normal. This could lead to denial of the conditions and also
efforts to exceed their physical boundaries imposed by their condition. Three
main domains in which clinical health psychologists can contribute in the
handling of adults with ConHD were identified: provision of clinical services,
multidisciplinary research, and professional education.
Keywords
Congenital heart disease • Psychology • Clinical psychology • Psychosocial •
Life experiences • Anxiety • Depression
Introduction
When it comes to studies assessing the psychological aspects of these patients, there
is either a comparison with other healthy groups or an attempt to correlate psycho-
logical functioning with other variables, including the ones pertaining to the
medical condition.
The majority of the studies in the literature indicate the absence of a relationship
between diagnosis, physical functionality, and the presence of residual symptoms
and a worse psychological functioning (Cox et al. 2002; Kovacs et al. 2008;
Rietveld et al. 2002; Utens et al. 1994, 1998; van Rijen et al. 2003, 2005; Callus
et al. 2014). There are only a few studies which suggest a weak link between
physical functionality and psychological functioning (Popelova et al. 2001; van
Rijen et al. 2004).
There are two literature reviews regarding the psychological aspects of these
patients (Callus et al. 2013a; Kovacs et al. 2005). In the review by Kovacs and
colleagues (2005), it is indicated that these patients often have to deal with
psychosocial difficulties which can influence their emotional functioning, the
perception of themselves and their relationships. There patients often have to pay
particular attention to their lifestyle as there could be limits to their physical
capacity and the possibility of proceeding with pregnancy when it comes to the
females with ConHD.
In another more recent review (Callus et al. 2013a), the comparison between the
population of these patients and healthy ones and which variables (both related to
the cardiac condition and others) are linked to the psychological functioning of
these patients is explored.
In some studies, in which a comparison was made between adults with ConHD
and the healthy and other populations (Cox et al. 2002; Utens et al. 1994, 1998; van
Rijen et al. 2003, 2005), no significant differences were found and in some cases a
better psychological functioning was found in these patients. In a more recent study,
the only difference found between these patients and the general population was on
the subscale of somatic symptoms, which were linked to anxiety and depression
symptoms (Eslami et al. 2013).
Some authors have indicated that the possible reasons for these results are linked
to the fact that these patients could have a higher “sense of coherence” (Moons and
Norekval 2006). Sense of coherence represents the generalized world view of an
individual and expresses the extent to which he/she perceives: (1) stimuli as
structured and predictable (i.e., comprehensibility), (2) the availability of resources
to meet the demands posed by these stimuli (i.e., manageability), and (3) that these
demands are challenges in which it is worth to make an investment (i.e., meaning-
fulness). This theory aims to try to give a description of the processes through which
people remain healthy even though they are exposed to ubiquitous stressors. It is
hypothesized that sense of coherence exerts its positive influence on health through
adaptive health behaviors and coping behavior (Antonovsky 1987).
Psychosocial Aspects of Adults with Congenital Heart Disease 443
Other factors which could be influencing these results could be denial and “high-
achievement motivation” which could lead to these patients indicating that they are
feeling better than they really are in self-report questionnaires (Utens et al. 1994;
van Rijen et al. 2003).
Interestingly, in a study in which psychiatric interviews were utilized (Kovacs
et al. 2008), it was outlined how an elevated percentage (39 %) of patients who were
diagnosed with a mood or anxiety disorder had not received any type of psycholog-
ical treatment. This was confirmed in two other studies in which similar assessment
methodologies were utilized (Bromberg et al. 2003; Horner et al. 2000), where a
significant portion of the patients, who were thought being well psychologically, were
diagnosed with mood or anxiety disorders (9/29 and 8/22, respectively).
When it comes to the exploration of which variables impact on the psychological
functioning of adults with ConHD, the pertinent literature indicates the absence of a
relationship between diagnosis, physical functionality, and the presence of residual
symptoms and psychopathology (Utens et al. 1998; van Rijen et al. 2005); hostility,
neurosis, and a low self-esteem (Utens et al. 1994; van Rijen et al. 2003); anxiety
and depression (Cox et al. 2002; Kovacs et al. 2008; Eslami et al. 2013; Bromberg
et al. 2003; Horner et al. 2000); and psychological well-being (Callus et al. 2014).
Only a few studies suggest a weak link between physical functionality and psycho-
logical functioning (Popelova et al. 2001; van Rijen et al. 2004).
A study which does not confirm this trend is the one by Brandhagen
(Brandhagen et al. 1991), in which it is specified that adults with congenital heart
disease have lower scores when compared to the healthy population. Interestingly,
another study on adult patients with ConHD who had to implant an ICD showed
high levels of anxiety, and this was also connected to a lower sexual functioning
both in males and females (Cook et al. 2013). It was also reported that patients with
a high level of trait anxiety were more vulnerable to overperceive symptoms which
are connected to the heart (Karsdorp et al. 2009).
In other studies there was an exploration of the variables which are connected to
psychological well-being (intended as less anxiety and depression, minor symp-
toms of psychopathology, and more psychological well-being, on the basis of the
different instruments utilized in the various studies) (Kovacs et al. 2008; Rietveld
et al. 2002; Callus et al. 2013a, 2014; van Rijen et al. 2004; Eslami et al. 2013), and
these resulted as being the following:
As specified previously, being born with a congenital cardiac condition has very
different implications when compared to patients who acquire an illness at a much
later stage in their life. Complex congenital heart conditions can be assimilated to
chronic conditions because of the long-term nature of the condition, the uncertainty
of its course and prognosis, the signs and symptoms of the condition, and also the
restriction on their everyday lives (Moons et al. 2002).
It is important to take into consideration qualitative studies exploring the life
experiences of these patients, so as to improve the medical care provided to them
and in order to improve medical adherence.
In the literature it is indicated that adolescents with ConHD struggle with
physical limitations and face social exclusion (McMurray et al. 2001; Tong
et al. 1998). The severity of the condition influenced the type of the limitations
the patients felt. As many as one-fourth of adults with ConHD report their parents as
being overprotective during their childhoods and adolescence (Brandhagen
et al. 1991; McMurray et al. 2001; Arnett 2000). The tendency for these patients
to live longer with their parents could be linked to them being overprotective, and it
could be that this also creates difficulty for the patients to become more autonomous
(Gersony et al. 1993; Kokkonen and Paavilainen 1992).
When it comes to the life experiences of adults with ConHD, it must be
considered that this population is a highly heterogeneous one and this entails very
different life experiences; however, some common patterns of experience and
perspective seem to have been found in this broad diversity (Verstappen
et al. 2006). In fact, in the qualitative studies which have been carried out on this
population, it has been outlined how these patients feel different from their healthy
peers (Verstappen et al. 2006; Berghammer et al. 2006; Claessens et al. 2005; Gantt
1992, 2002; Callus et al. 2013b). It has been seen for often there is a struggle to feel
normal and also to be perceived by others as being normal. This could lead to denial
of the conditions and also efforts to exceed their physical boundaries imposed by
their condition (Berghammer et al. 2006).
Particular issues which could be present in the female population are concerns
regarding fertility, contraception, pregnancy, and their surgical scar. It seems that
scarring and cyanosis could bear a more negative influence in females and that for
men the difficulties related to their body image are more present during adoles-
cence, probably due to the involvement in sports activities (Claessens et al. 2005;
Gantt 1992; Callus et al. 2013b).
Since many of the patients have to spend a lot of time in hospital, these
experiences are often referred to in the qualitative studies. In one particular study,
it was observed how different expectations about the management of the patients’
conditions from the patients, their families, and the nurses were associated with
interpersonal conflict, distrust, anxiety, and dissatisfaction with the healthcare
provided (Kools et al. 2002), outlining the importance of a transparent communi-
cation in these settings.
In a very interesting article (Verstappen et al. 2006), quotations from patients are
reported from the Adult Congenital Heart Association in an attempt to address the
patients’ perspectives in order to outline the implications for care.
Psychosocial Aspects of Adults with Congenital Heart Disease 445
There was often an ambiguity regarding their condition and their prognosis, also
because of language-based misperception in understanding if the condition is
completely cured or not. Many patients reported difficulties when having to go to
the “regular” medical system, where the sanitary personnel is not specialized in
ConHD. They also reported that the people who are close to them sometimes had
difficulties to understand the entity of their restrictions. Other patients have
described that information about their condition was withheld from them and
they got to know about their real condition at the onset of new problems, causing
psychological distress and trust issues.
Interestingly, having this condition does not only have negative consequences,
but it can also be linked to having some benefits. Some patients report receiving
special attention, gaining an increased resilience and maturity, and also gaining a
clearer sense about the meaning of life. There can be an increased appreciation of
life, more clarity of purpose, and better decision-making when one has to deal with
an ongoing awareness of one’s mortality due to specific health conditions (Mathieu
2005).
Three main domains in which clinical health psychologists can contribute in the
handling of adults with ConHD were identified. Kovacs and colleagues (Kovacs
et al. 2006) identified: provision of clinical services, multidisciplinary research, and
professional education.
they are going through is common. Finally, when it comes to screening, the
following four A’s have been suggested to detect and manage psychosocial issues:
Patients going through different phases of the illness could benefit from psycho-
logical support, in particular:
Multidisciplinary Research
Conclusion
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The Interaction Between Psychological
Health and Valvular Heart Disease:
Pathogenesis, Clinical Course,
and Treatment
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454
Valvular Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
Prevalence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Treatment and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456
Prevalence of Depression and Anxiety in Patients with Valvular Heart Disease . . . . . . . . . . . . . 458
The Etiology of Psychological Conditions in Patients with Valvular Heart Disease . . . . . . . . . 460
The Role of Psychological Disturbance in the Etiology of Valvular Heart Disease . . . . . . . . . 460
The Impact of Psychological Illness on Valvular Heart Disease and Its Treatment . . . . . . . . . . 461
Testing and Costs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462
Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463
Surgical Valve Repair or Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464
The Impact of Valvular Heart Disease Treatment on Psychological Illness and Quality
of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465
Surgical Valve Repair or Replacement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Transcatheter Aortic Valve Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466
Percutaneous Mitral Valve Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468
Abstract
Valvular heart disease is an increasing health concern in most developed coun-
tries due to aging populations resulting in increased prevalence. While there is
significant focus on ensuring timely medical care and developing less-invasive
procedures to treat the functional valve lesions, there is often little attention
given to the psychological impact of valvular heart disease.
Indeed while the impact of ischemic heart disease on psychological health and
even the potential causative association between psychological illness and ischemic
heart disease have been widely acknowledged, such a link is often not recognized in
valvular heart disease. However among this unique population who are often older
and frailer, assessment of psychological health may be even more important.
Keywords
Valvular heart disease • Aortic stenosis • Mitral regurgitation • Transcatheter
aortic valve implantation • Percutaneous mitral valve repair • Surgical valve
replacement
Introduction
Valvular heart disease encompasses numerous conditions that are united by dysfunc-
tion of one or more of the four cardiac valves: tricuspid, pulmonary, mitral, or aortic.
In the majority of conditions, this is manifested as either obstruction to normal blood
flow across the valve or regurgitation of blood in a retrograde direction. The clinical
sequelae of a specific valve lesion are highly variable, from complete lack of
symptoms to resultant heart failure and potentially death. The etiology of valvular
dysfunction varies depending on the type of valve lesion, with the prevalence varying
based on geographical location and age of the individual.
The aging population of most developed nations has resulted in an increased
prevalence of valvular heart disease and resulted in a new health epidemic. In
addition, treatment options are continually expanding, with the development of
minimally invasive surgical and percutaneous valve repair and replacement tech-
niques, leading to treatment of a cohort previously deemed inoperable due to age,
frailty, or other comorbidities.
Like most chronic illnesses, patients with valvular heart disease experience a
higher prevalence of psychological conditions including depression, anxiety, and
personality disturbance. The significant impact these conditions have on patients’
perceptions of their disease, treatment, and prognosis is often under-recognized.
This chapter will explore the interaction between psychological factors and
valvular heart disease from etiology to treatment and to prognosis. We will also
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 455
explore the psychological impact of new valvular heart disease treatment modali-
ties compared to traditional approaches of care. The psychological aspects of
valvular heart disease overlap with those of other chronic cardiac conditions such
as ischemic heart disease, heart failure, and cardiac transplantation. Where relevant
the interaction and comparison with these conditions will be emphasized.
Definition
The human heart contains four cardiac valves, composed of either two or three
connective tissue leaflets. The valves separate the four cardiac chambers; the tricus-
pid valve is positioned between the right atrium and right ventricle, the pulmonary
valve between the right ventricle and pulmonary artery, the mitral valve between the
left atrium and left ventricle, and the aortic valve between the left ventricle and aorta
(Fig. 1). In health, the valves facilitate unidirectional, antegrade flow of blood
through the heart when a forward pressure differential forms and close to prevent
regurgitation of blood when a negative forward pressure differential forms.
Valvular heart disease collectively refers to conditions that result in either
obstruction to antegrade flow or regurgitation of blood through one or more of
the cardiac valves. Valvular heart disease, therefore, encompasses a diverse number
of conditions covering more than 25 International Classification of Disease
(ICD-10) categories (World Health Organization 2010).
Fig. 1 Normal transthoracic echocardiographic images. (a) Apical four-chamber image demon-
strating the mitral valve separating the left atrium and left ventricle and the tricuspid valve
separating the right atrium and right ventricle. (b) Parasternal long-axis image demonstrating
the mitral valve separating the left atrium and left ventricle and the aortic valve separating the left
ventricle and aorta
456 R. Gooley et al.
Prevalence
Etiology
The etiology of each valve condition differs; however common causes of regurgi-
tation include rheumatic valve disease, ischemic heart disease, connective tissue
conditions, congenitally abnormal valves, and endocarditis, while causes of valve
stenosis include age-related calcific degeneration, rheumatic valve disease, and
congenitally abnormal valve architecture. A more detailed list of potential etiolo-
gies for common valve lesions is presented in Table 1.
Even within a single country, there is variability in the rates of valvular heart
disease and also the predominant etiology. While rheumatic heart disease is now an
uncommon cause of valvular dysfunction in most western countries, within Australia
there remains a significantly higher incidence among the indigenous Aboriginal
population. Within Australia’s Northern Territory, 93 % of patients with rheumatic
heart disease are indigenous with prevalence among indigenous women of 3.2 % and
indigenous men of 1.7 % compared to 0.2 % and 0.1 % for their respective
nonindigenous contemporaries (Australian Institute of Health and Welfare 2011).
The majority of people with mild or moderate valve dysfunction remain in a latent
phase without any subjective or objective symptoms. This asymptomatic period has
a variable duration but generally lasts decades before disease severity progresses
and symptoms are identified. Often no specific treatment is required in this phase of
valvular heart disease.
Guidelines recommend that patients identified with valvular heart disease be
monitored for development of symptoms and with transthoracic echocardiogra-
phy to allow early identification of negative compensatory cardiac changes such
as chamber dilatation (Nishimura et al. 2014). This watchful waiting approach
may lead to a prolonged latent period with no symptom burden but significant
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 457
Fig. 2 The natural history of aortic stenosis includes a long latent period prior to the development
of symptoms. After symptom development there is a rapid decline in survival
anticipation driven by awareness of the underlying condition and the need for
regular surveillance investigations. Some people will never move beyond this
latent period due either to lack of disease progression or because other medical
illnesses intervene first. Such anticipation may, however, be associated with
psychological impact such as development of anxiety or depression in susceptible
patients.
While the asymptomatic disease phase may last for a number of years or even
decades, progression to severe dysfunction generally heralds the development of
heart failure symptoms and associated morbidity and mortality (Fig. 2). Mild symp-
toms such as dyspnea or fatigue may be countered by commencement of medication,
particularly diuretic therapy. The onset of symptoms together with identification of
severe valvular dysfunction on echocardiography, however, warrants consideration
of definitive treatment. This has traditionally centered on open-heart surgery with
repair or replacement of the affected valve. Given the older demographic, up to 30 %
of patients with symptomatic severe valvular heart disease have previously been
denied or refused surgery (Iung et al. 2005). This has lead to the development of
newer, less-invasive catheter-based treatments that have proven, in appropriate
patients, to be as efficacious as open surgery. The advent of these catheter-based
therapies has opened treatment to a group of patients previously denied operative
management due to real or perceived risks by the patient or physician.
It is generally acknowledged that patients with valvular heart disease, like other
chronic illnesses, have a high rate of psychological conditions such as depression
and anxiety. The actual prevalence of depression and anxiety, however, has not
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 459
been widely studied. The rate of depression in patients with cardiovascular disease,
a condition that shares some symptoms and treatment modalities with valvular heart
disease, approaches 15 % (Colquhoun et al. 2013), while rates of 20–30 % (Rums-
feld et al. 2003; Rutledge et al. 2006; Sullivan et al. 2004) have been reported
among patients with chronic heart failure, a condition that is a common sequelae of
valvular heart disease. Among the limited published data, the reported rate of
depression in patients with valvular heart disease has reached 80 % (Carney
et al. 1990).
The significant variability in reported prevalence of psychological disturbance
in valvular heart disease is likely multifactorial. Existing studies are generally
small and potentially underpowered to give a true prevalence rate in the general
valvular heart disease population. Populations studied can also vary significantly,
from relatively asymptomatic patients in the community to hospitalized patients
with end-stage heart failure. Perhaps one of the greatest limitations to determining
true prevalence of psychological disturbance among people with valvular heart
disease is the lack of consistent definitions of depression, anxiety, and personality
disorder together with variable tools employed for disease detection. While the
Diagnostic and Statistical Manual of Mental Disorders is used to formally
diagnose these conditions in clinical practice, most research studies rely on
simpler and potentially less accurate means of detection. Some studies rely on
self-diagnosis and reporting of symptoms; others use various standardized ques-
tionnaires or scoring symptoms, while only a few utilize formal psychological
assessment by a trained professional.
The significant degree of variability in detection was eloquently demonstrated in
a study examining a cohort of elderly women with mitral stenosis. When the cohort
was assessed using the Hospital Anxiety and Depression Scale (HADS), both
anxiety and depression were significantly higher than age-matched controls. How-
ever, administration of the Short Form (36) Health Survey in the same population
did not elicit any difference between the groups in mental health scores (Shuldham
et al. 2001). This suggests that while individual studies may be able to show an
increased rate of psychological disturbance between cohorts, results are often not
comparable between studies.
Despite high prevalence of psychological disturbance among people with val-
vular heart disease, the issue receives little to no attention in published guidelines
(Nishimura et al. 2014; Vahanian et al. 2012). While national guidelines rely
heavily on a sufficient evidence base prior to making formal recommendations,
the omission of the significant psychological/cardiac interplay fails to address this
important aspect of holistic care. The European Society of Cardiology guidelines,
in only one paragraph regarding assessment of comorbidities, lists frequently
encountered physical conditions but no psychological conditions. It briefly states
that “validated scores enable the assessment of cognitive and functional capacities
which have important prognostic implications in the elderly” (Vahanian
et al. 2012). The guidelines do not state which validated scores should be used,
and indeed it is unclear if they are instead focused more on the detection of
cognitive impairment in the elderly rather than psychological illness in the entire
460 R. Gooley et al.
cohort. Unfortunately, this lack of guidance regarding the need for screening for
psychological symptoms, the optimal screening tool, and the best treatment of
psychological disorders when present is likely to contribute further to lack of
detection, lack of understanding, and suboptimal care within both the research
and clinical environments.
While the association between psychological conditions and valvular heart disease
is generally accepted, a causal relationship is far more difficult to establish and
prove. Valvular heart disease is a chronic illness that is associated with significant
morbidity and mortality, and there is an extensive evidence pool that depressive and
anxiety disorders are more common in patients with chronic illnesses (Katon
et al. 2007). The health impact of a chronic illness often leads to reactive depressive
disorders with an increasing prevalence as the severity of the underlying medical
illness worsens (Cassem 1995). If the patient is unable to employ appropriate
adaptive responses, these reactive disorders can develop into major depressive or
anxiety disorders.
Further pathophysiological mechanisms to explain the development of psycho-
logical conditions in the setting of valvular heart disease have been postulated. Left-
sided annular and valvular calcification is associated with increased subclinical
cerebral infarcts identified on magnetic resonance imaging (Rodriguez et al. 2011).
It has been demonstrated that up to half of presenile major depression may be
associated with similar silent cerebral infarction (Fujikawa et al. 1993). While this
offers a potential mechanistic association between valvular heart disease and higher
rates of psychological disturbance, reactive psychological disturbance remains a
more feasible explanation in the majority of cases.
While it is generally accepted that the presence of a chronic illness can lead to
reactive psychological conditions, a number of hypotheses exist regarding a
pathobiological role for psychological conditions exacerbating or contributing to
the development of cardiac disease. The majority of these theories were developed
in populations with chronic ischemic heart disease but may also hold in association
with valvular heart disease.
Major depressive disorder has been shown to result in alteration of the
neurohormonal milieu including up-titration of a number of pro-inflammatory
cytokines including TNF-alpha, IL-10, IFN-gamma, BNP, and ADMA (Anisman
and Merali 2002; Zorrilla et al. 2001). This has led to the suggestion that
depression may be considered a low-grade chronic inflammatory condition.
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 461
Heart Failure
Progression in the severity of valvular heart disease can result in complications such
as heart failure, arrhythmia, and stroke, each of which has psychological implica-
tions for patients. Heart failure is the most common clinical sequelae of valvular
heart disease and occurs when the cardiac output is not sufficient to meet the
metabolic demands of the organs despite normal filling pressures. The symptoms
of heart failure include dyspnea, fatigue, lethargy, and peripheral edema. The
presence of heart failure is associated with increased rates of depression with
reported prevalence of 11–58 % (Koenig 1998; Havranek et al. 1999; Turvey
et al. 2002) and anxiety with reported prevalence ranging from 29 % to 45 %
(Friedmann et al. 2006; Jiang et al. 2004). Despite the high rate of comorbid
psychological disturbance in the heart failure population, there is evidence that
early intervention can ameliorate this. The presence of strong social supports and
family relationships may, however, counter the onset of depression (Friedmann
et al. 2006; Scherer et al. 2007).
There is evidence that as heart failure severity worsens, as measured by the
New York Heart Association class, the incidence of depression increases (Scherer
et al. 2007). The New York Heart Association classification grades heart failure
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 463
Table 2 The New York Heart Association (NYHA) classification of heart failure symptoms
NHYA
class Definition
I Documented cardiac disease without symptoms or physical limitation. Ordinary
physical activity does not cause fatigue, palpitation, dyspnea, or angina
II Documented cardiac disease resulting in slight limitation of physical activity.
Ordinary physical activity results in fatigue, dyspnea, palpitation, or angina. No
symptoms are present at rest
III Documented cardiac disease resulting in marked limitation of physical activity.
Less than ordinary activity causes fatigue, palpitation, dyspnea, or angina. No
symptoms are present at rest
IV Documented cardiac disease resulting in inability to perform physical activity
without symptoms. Symptoms may also be present at rest
severity based on the degree of functional limitation due to heart failure symptoms
(Table 2). However such results may be confounded by over-reporting of symptoms
in patients with depression. Although not consistently demonstrated, the majority of
evidence suggests that the presence of a depressive disorder adversely affects heart
failure prognosis, independent of other measures of disease severity (Faris
et al. 2002; Jiang et al. 2001; Murberg et al. 1999). One such study, a retrospective
analysis of 396 patients hospitalized with nonischemic heart failure, identified those
with a documented history of depression. When adjusted for conflicting variables, a
history of depression predicted mortality with a hazard ratio of 3.0 (CI 1.4–6.6,
p = 0.004) (Faris et al. 2002). A similar association has been demonstrated in
patients with stable heart failure symptoms not necessitating admission. A popula-
tion of 119 stable Norwegian outpatients attending a cardiology clinic were
enrolled. These patients were assessed for depressive symptoms using the Zung
Depression Scale (Zung 1965). Depressed mood was found to inversely predict
2-year survival with an almost doubling of the hazard ratio (HR = 1.9, p = 0.002)
(Murberg et al. 1999).
Pharmacological Treatment
Medical management remains the mainstay of treatment for patients with valvular
heart disease during most phases of care as opposed to surgical or percutaneous
intervention, which are generally only required in symptomatic severe dysfunction.
In the setting of valvular dysfunction, medication may be used to prevent the
development of, or mitigate the clinical effect of, valvular heart disease symptoms.
In patients who have undergone percutaneous or operative intervention, medication
is even more important in preventing complications such as prosthesis thrombosis
or systemic thromboembolism.
Comorbid depression has been shown to correlate with reduced medication
compliance in a number of chronic illness settings. A meta-analysis looking at
this issue analyzed 31 studies with chronic illnesses including heart failure,
464 R. Gooley et al.
While some patients with existing depressive illness may be unfairly denied
definitive treatment, the presence of depression adversely affects patients who do
undergo surgery. One study comparing patients with baseline depression to those
without prior to coronary artery bypass grafting found that it was independently
associated with increased mortality with an adjusted hazard ratio of 2.4
(Blumenthal et al. 2003).
While the presence of psychological illness may affect treatment offered or the
efficacy of treatment for valvular heart disease, the effect of valvular heart disease
interventions on patients’ psychological health must also be considered. Treatment
of advanced valvular heart disease often involves invasive surgical or complex
percutaneous interventions. Even among patients without pre-existing psycholog-
ical illness, such major events may result in new onset depression or anxiety. In
patients with existing depression or anxiety, the effect of invasive treatment on the
underlying psychological illness is variable. The advent of percutaneous valve
interventions has led to treatment of an older, frailer, and generally more physically
unwell cohort whose psychological response to valvular treatment may differ from
patients undergoing traditional operative valve replacement and from reported
community cohorts with valvular heart disease.
Pharmacological Treatment
Fig. 3 Transcatheter aortic valves are delivered in a constrained form to the native aortic valve.
The valve frame is then expanded by balloon, self-expansion, or mechanical expansion, exposing
the new tissue leaflets within the frame and displacing the native leaflets into the sinuses of
Valsalva
across the native valve and expanded. This displaces the native valve leaflets
between the valve frame and the sinuses of Valsalva while new tissue leaflets
sutured to the valve frame begin to function (Fig. 3). This percutaneous approach
negates the need for a midline sternotomy, reduces risk, and hence hastens
recovery.
TAVI, while less invasive than open surgery, has modest yet significant compli-
cation rates that may directly or indirectly impact on patients’ psychological well-
being. The TAVI procedure often involves a balloon valvuloplasty followed by
passage of a delivery catheter across the aortic arch to the native aortic valve.
Manipulating the native aortic valve and maneuvering the delivery catheter through
an often-diseased aorta may result in embolization of atherosclerotic and/or calcific
debris. This has been demonstrated in clinical trials where the rate of clinically
detected stroke has been reported to be between 2 % and 5 %. The rate of magnetic
resonance (MR) detected cerebral lesions, however, is much higher at 60–100 %
(Ghanem et al. 2010, 2013; Kahlert et al. 2010). The majority of MR-detected lesions
are randomly distributed throughout the subcortex. While this has led to the assertion
that the majority of new cerebral lesions do not result in clinical sequelae, it is highly
likely that the means of symptom detection used in published trials as well as in
clinical practice are flawed and inadequate. Commonly used assessments vary but
may include patient reports of symptoms, non-neurologist physical assessments, or
global assessment tools such as the Modified Rankin or NIH Stroke Scale. Subtle
neurocognitive and behavioral changes are likely to be missed in such global
cognitive assessments (Barber et al. 2008). Nonspecialist review in such situations
is likely to focus on the presence of new gross sensory or motor deficits rather than
mild psychological disturbance, which may also be a clinical consequence of stroke.
While the rate of new onset psychological disturbance due to procedural com-
plications may be under-recognized, the majority of studies have shown that
patients undergoing TAVI have an improvement in quality of life, including mental
health scores (Ussia et al. 2009; Kala et al. 2013). In some studies the improvement
in self-reported quality of mental health was greater than that in physical quality of
468 R. Gooley et al.
Similar to the advent of TAVI, the need for percutaneous mitral valve repair has
been identified as a preferable treatment modality among a cohort of patients who
are highly symptomatic due to severe mitral regurgitation yet are at high or extreme
operative risk. The MitraClip (Abbott Vascular, IL, USA) device functions by
clipping the leading edge of the anterior and posterior mitral leaflets together to
form a double-orifice valve (Fig. 4). Approximating the two leaflets in this manner
reduces the degree of mitral regurgitation in a similar mechanism to the surgical
Alfieri (or edge-to-edge) repair.
The MitraClip device is inserted via the femoral vein with a transseptal puncture
performed to gain access to the left atrium. The MitraClip entered clinical practice
after TAVI and as such the body of evidence regarding its effect on psychological
health is limited. In one large reported cohort of 127 patients, however, it was
demonstrated that the SF36 quality of life scores improved significantly post
procedure. This improvement was seen in both the physical and mental component
SF36 summary scores (Lim et al. 2013). To date no published studies have looked
at the rate of subclinical stroke by routine cerebral imaging.
Fig. 4 Three-dimensional
echocardiographic image of
the mitral valve following
deployment of a MitraClip.
The MitraClip (red arrow)
approximates the edge of the
two mitral valve leaflets
leaving a double-orifice
mitral valve (blue arrows)
The Interaction Between Psychological Health and Valvular Heart Disease:. . . 469
With the increasing burden of valvular heart disease on the health service and on
patients’ quality of life, most clinicians, not only cardiologists but also other
medical professions including psychologists, psychiatrists, and allied health pro-
viders, will encounter affected patients. The role of psychological conditions that
patients experience during all stages of valvular heart disease is probably grossly
under-recognized. Prompt diagnosis and treatment of depression, anxiety, and/or
personality disorders may result in reduction of somatic symptom burden,
increased efficacy of treatment, and improved rapid recovery following interven-
tion. With the advent of new technologies opening treatment to a new, potentially
more high-risk cohort, the importance of multidisciplinary care is imperative and
now well recognized. Within most jurisdictions the “Heart Team” has been
adopted for the care of patients in whom TAVI has been considered and, however,
is often limited in its composition to include only cardiologists, cardiothoracic
surgeons, anesthetists, and primary care physicians. While limited in the diversity
of healthcare providers, such Heart Teams are in line with current societal
guidelines with the current 2014 American Heart Association/American College
of Cardiology guidelines stating the importance of the Heart Team, in particular to
decisions regarding TAVI, but mention only the need to include professionals
with expertise in valvular heart disease, cardiac imaging, interventional cardiol-
ogy, cardiac anesthesia, and cardiac surgery (Nishimura et al. 2014). Given the
importance of psychological health and early detection of depression or anxiety,
thought should be given to expanding this team to include psychologists and/or
psychiatrists while ensuring that the “Heart Team” is involved in most patients
with valvular heart disease, not just those undergoing transcatheter procedures
(Fig. 5). The current European Society of Cardiology guidelines fail to mention
the importance of a more diverse Heart Team, stating only that the Heart Team
should include cardiologists and cardiac surgeons and other specialists if neces-
sary (Vahanian et al. 2012). It could be argued that recognizing when other
specialists “are necessary” is unlikely to occur if appropriate specialists are not
routinely involved to detect the patient need.
Conclusion
There is no doubt that valvular heart disease is a health epidemic predominantly due
to the aging population of most western societies. At the same time, treatment
options are growing, leading to a larger population of treated patients. Psycholog-
ical disturbance occurs in a valvular heart disease cohort at a higher rate than
age-matched controls and can occur at all phases of the disease process. Depression
and anxiety remain under-reported, underdiagnosed, and undertreated. Failure to
diagnose and treat conditions such as depression, anxiety, and personality disorders
may lead to increased morbidity, inappropriate denial of access to treatment,
470 R. Gooley et al.
Cardiothoracic
Surgeon
Psychologist Cardiac
and or Anaesthetist
Psychiatrist
Treating
Imaging
Cardiologist/
Cardiologist
Physician
Heart
Team
Fig. 5 The Heart Team concept was formally introduced with the advent of TAVI though used
prior to this in many institutions. The inclusion of a trained psychologist or psychiatrist is,
however, not currently mandated in European or United States guidelines
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The Psychosocial Impact of Syncope
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Vasovagal Syncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476
Psychosocial and Quality-of-Life Impact of VVS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477
Postural Orthostatic Tachycardia Syndrome (POTS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479
Psychogenic Pseudosyncope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483
Abstract
Syncope is a transient and abrupt loss of consciousness and postural tone due to a
transient reduction in cerebral blood flow, typically due to a fall in blood
pressure. There are many causes of syncope, and some people may suffer from
recurrent and unexplained episodes. Recurrent t syncope can be challenging to
diagnose and treat with the potential for severe psychosocial morbidity.
Keywords
Neurocardiogenic syncope. See vasovagal syncope (VVS) • Noradrenaline
transporter (NET) dysfunction • Postural orthostatic tachycardia syndrome
(POTS) • Psychogenic pseudosyncope (PPS) • Syncope • Causes • Prevalence •
Transient loss of consciousness (TLOC) • Vasovagal syncope (VVS)
G. Vaddadi (*)
Department of Cardiology, The Alfred Hospital, Melbourne, VIC, Australia
e-mail: [email protected]; [email protected]
M.E. Alvarenga
MonashHEART, Monash Cardiovascular Research Centre, Monash Health and Department of
Medicine (SCS at Monash), Monash University, Melbourne, VIC, Australia
e-mail: [email protected]
Introduction
Syncope is a transient and abrupt loss of consciousness and postural tone that is
generally followed by rapid recovery without the need for major intervention
(Vaddadi et al. 2007). It is due to a transient reduction in cerebral blood flow and
is perhaps the most common cause of syncope in the general population. Syncope
has a lifetime cumulative incidence of 35 % (Ganzeboom et al. 2006) and accounts
for 1–2 % of all emergency department visits (Mathias et al. 2001). The morbidity
from syncope can be profound and often underappreciated in the health-care sector,
with 70 % of people with recurrent syncope suffering from impairments to their
activities of daily living, 6 % have fractures, 64 % restrict driving, and 39 % may
change employment (Vaddadi et al. 2007). Some studies also suggest that recurrent
syncope can have the same impact on psychosocial quality of life as other major
chronic illnesses.
The common causes of syncope include but are not limited to:
Thus, it can be appreciated that causes of syncope are varied and range in risk of
morbidity and mortality. Psychiatric illnesses have been touted as a possible cause
of syncope. The still limited research in this area proposes that psychiatric diseases
account for 1–7 % of all causes of syncope and that in psychiatric patients with
medically undetermined syncope, the figures can be as high as 26 % (Gomes-
Andrghetto et al. 1999). For the purpose of this chapter, we will focus on vasovagal
syncope and postural tachycardia syndrome (POTS) which commonly cause recur-
rent syncope and result in significant psychosocial morbidity.
Vasovagal Syncope
spells to be correlated with quality of life (QoL) in patients who had experienced
more than or equal to six episodes.
In 2006 van Dijk published a much larger study of the QoL of patients with
transient loss of consciousness in a population of patients that is more reflective of
what is seen in routine clinical practice (van Dijk et al. 2006). It is the most
comprehensive evaluation of QoL to date and provides valuable and detailed
insight into the heavy burden VVS and other causes of transient loss of conscious-
ness (TLOC) can have on our patients. The two studies referred to earlier were in a
population of patients with more severe syncope. A disease-specific scale assessing
QoL was employed, consisting of 11 yes/no questions, assessing the degree to
which syncope interferes with a patient’s daily life and three 8-point Likert-scale
questions that assess a patient’s fear and worry about syncope. A syncope dysfunc-
tion score (SDS) was calculated, which is a mean of the composite of the impair-
ment score and the fear-worry score.
In this study transient loss of consciousness (TLOC) (syncope being a very
common cause) had a serious effect on the QoL of patients. Patients had signifi-
cantly lower scores on all scales compared to the reference population, with
moderate to large effect sizes. Disease-specific QoL was seriously affected, with
an average impairment in 33 % of applicable areas. The QoL of patients presenting
with TLOC is comparable to that of patients with chronic arthritis or recurrent
moderate depressive disorder.
Gender, higher level of comorbidity, and the presence of presyncopal episodes
(feeling like one may faint but not actually losing consciousness) were associated
with poorer physical functioning. Presyncopal episodes predict worse mental func-
tioning and disease-specific QoL. Patients with a longer period of complaints show
better mental functioning and disease-specific QoL than those with a recent onset of
symptoms in this study. This suggests that patients with new-onset syncope should
be more aggressively supported and counseled in the hope of having a positive
impact on QoL. The presence of more than one episode of syncope in the year
before presentation is associated with worse disease-specific QoL. QoL scores, as
would be expected, correlate well with presyncope and syncope frequency.
Patients with recurrent syncope, even though they should be quite “normal”
between episodes, experience significant physical limitations comparable to that of
chronic illnesses. This is probably due to a range of factors such as fear of a
recurrence, perceived risk of injury, and legal restrictions, for instance, on driving,
that may limit the patient in performing daily physical activities and embarrassment
should syncope occur in a public setting. Patients with syncope and their family
members often worry that syncope may occur when the patient is alone and help
may not be accessible. It is not uncommon for doctors to be dismissive of VVS
because it is not lethal. The psychosocial burden of disease may be under-
recognized or dismissed which is usually to the detriment of the patients’ long-
term health.
Psychological triggers such as anxiety and emotional stress are well-recognized
precipitants for VVS. Anxiety and depression may be caused by syncope and can
The Psychosocial Impact of Syncope 479
also act as a trigger for syncope. It is therefore essential to engage in this space
effectively, utilizing standard treatment techniques.
POTS is a diverse and challenging condition that has only become more widely
recognized over the last 20 years (Vaddadi et al. 2007; Raj 2006). It is characterized
by a marked and sustained increase in heart rate when going from lying to standing
(>30 beats per minute increase over supine heart rate). In addition to the marked
tachycardia, presyncope, and syncope, patients with POTS often complain of light-
headedness, fatigue, and difficulty in concentrating. It affects women substantially
more commonly than men and typically presents in those aged 15–50 years. The
mechanism driving presyncope and syncope in this patient group is not understood
because blood pressure is usually normal or high during the episodes which should
in theory result in “normal” cerebral perfusion. Some studies suggest abnormalities
in the sympathetic nervous system (Lambert and Lambert 2014; Lambert
et al. 2008) and with cerebral blood flow (Ocon et al. 2009; Del Pozzi
et al. 2014a, b; Stewart et al. 2015), but no study has conclusively identified the
mechanism which remains speculative at best. Some researchers have endeavored
to “subtype” POTS. This has been controversial and challenging, but the most
reasonable two subtypes from a clinical perspective are “neuropathic” POTS which
is characterized by reduced adrenergic vasoconstriction and may have an overlap
with various connective tissue disorders that reduce the ability of the peripheral
vessels to constrict, promoting venous pooling when standing, and the
“hyperadrenergic” POTS characterized by enhanced arterial vasoconstriction
(Ross et al. 2014).
POTS patients often struggle with chronic fatigue, difficulty concentrating that is
often worse during orthostatic stress (Ross et al. 2013) (upright posture), brain fog,
and anxiety, and there is generally a significant impact on activities of daily living,
educational prospects, and employment. Again, the mechanisms driving this are
unknown. Cognitive impairment is commonly reported as one of the top complaints
of young patients with POTS and is often referred to as “brain fog” by patients
(Ross et al. 2013). Brain fog is an imprecise term and is thought to be similar in
meaning to mental fatigue. It is characterized by being forgetful and cloudy with
difficulties in focusing, thinking, and attention. Although brain fog is often worse
when standing, lying down does not consistently ameliorate the symptom suffi-
ciently to normalize performance on tasks a patient with POTS wishes to achieve.
Over 80 % of patients believe that their brain fog is brought on by prolonged or
intense concentration, while almost 70 % of patients feel this can trigger brain fog
even when lying down (Ross et al. 2013). The top triggers for brain fog are fatigue
and sleep deprivation. Sleep disorders appear to be common in patients with POTS,
affecting at least 30 % of subjects. Common diagnoses include insomnia, sleep
apnea, and restless leg syndrome. Sleep disturbance itself is well recognized to
480 G. Vaddadi and M.E. Alvarenga
et al. 2002, 2003; Thieben et al. 2007) but not all previously reported data (Raj
et al. 2009). Individuals with disorders of postural syncope may be more likely to
focus attention on the negative consequences of fainting, a preoccupation which
subsequently contributes to reduction in perceived health-related quality of life
(McGrady et al. 2001). Hypervigilance to somatic sensations has been associated
with greater limitations on day-to-day activities and increased perception of dis-
ability (Benrud-Larson et al. 2003).
Reduction in cognitive performance is significantly associated with the magni-
tude of the change in heart rate during head-up tilt, and patients with POTS display
significantly elevated anxiety sensitivity in relation to cardiac symptoms; it is
possible that, in the context of increased vigilance to somatic sensations, attention
is diverted and impaired cognitive performance follows (Anderson et al. 2014);
indeed, fear of arousal may amplify the physiological signs associated with syncope
and lead to an increase in the fear associated with syncope (Rapee et al. 1992).
Treatment of POTS involves the implementation of a disease management plan
encompassing education, pharmacotherapy, and exercise. Remaining hydrated;
avoidance of excessive heat; wearing compression tights in order to reduce venous
pooling; administration of fluid retaining agents, low-dose propranolol, midodrine,
and acetylcholinesterase inhibitors; and exercise are all important elements of the
POTS treatment arsenal (Vaddadi et al. 2007; Ross et al. 2014; Anderson
et al. 2014; Fu and Levine 2015; Mallien et al. 2014; Figueroa et al. 2014).
Psychological interventions aimed at facilitating stress reduction such as relaxation
techniques and cognitive behavior therapy, with an emphasis on identifying and
restructuring unhelpful beliefs, primarily those catastrophizing consequences of
physical symptoms from standing, may aid in recovery and facilitate uptake and
adherence of other treatment modalities (Anderson et al. 2014). Indeed, helping
patients with syncope to identify and restructure unhelpful beliefs, address mal-
adaptive somatic attention, and reduce avoidance of certain situations has been
shown to be helpful (Gracie et al. 2004).
Psychogenic Pseudosyncope
assessments for epilepsy (Raj et al. 2014). In our clinical experience, PPS is most
commonly seen in adolescent females although it can affect all age groups and is
not gender exclusive. It is likely that most cases of PPS represent conversion
disorder (Raj et al. 2014).
Traditionally, it has been a clinical challenge to recognize functional neurolog-
ical symptom disorders such as conversion disorder. In assessing syncope the
measurement of psychological constructs is narrow and with a focus on simply
identifying the presence or absence of distress (Gracie et al. 2004). Measures such
as the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory
(STAI) provide a measure of the depth of depression and anxiety those affected
with the syncope presentation might be experiencing, but they do not provide an
understanding of the reasons why someone might be depressed or anxious and how
this impacts on their syncope presentation. Therefore, a psychiatric interview of the
patient is recommended to ascertain whether the presentation of syncope is part of a
psychosomatic manifestation, such as conversion disorder. Although the precise
cause of a conversion disorder is unknown, it seems that the part of the brain that
controls muscles and senses may be involved, and it may be the brain’s way of
reacting immediately to something that seems like a threat in what might be an
extreme manifestation of the “fight/flight response” (Coversion Disorder). Indeed,
conversion disorders typically follow a traumatic event or occur in the context of
psychological conflict (Raj et al. 2014).
Raj et al. (2014) published a leading text on the diagnosis and management of
PPS and reported a high prevalence of comorbidity between syncope and psycho-
pathology. Research into the quality of distress in patients experiencing nonorganic
syncope proposed that anxiety and characteristics associated with anxiety (avoid-
ance, concern about people and situations, high personal standards, and overall
sensitivity to self and environment) appeared to be more prominent than depression
in this patient cohort (Shafffer et al. 2001). Anxiety disorders such as somatoform
disorders distinguish themselves by a high level of interoceptive acuity on the part
of the patient. Indeed, it has been suggested that interpretive cognitive bias for
ambiguous interoceptive stimuli may be a risk factor for the development of these
sorts of anxiety presentations (Richards et al. 2001). Therefore, there is further
scope in the research literature to more carefully assess constructs of anxiety
sensitivity and the experience of syncope. Such analysis would be particularly
significant in better understanding the nature of PPS and guiding more effective
treatment interventions.
Treatment guidelines for PPS proposed by Raj et al. (2014) outline the impor-
tance of psychoeducation and the inclusion of psychotherapy as the treatment of
choice in these patients. Cognitive behavioral therapy (CBT), which addresses the
patient’s thoughts, feelings, and associated behaviors, is particularly identified as an
effective form of intervention (LaFrance et al. 2013). It is in the context of CBT that
patients can also learn stress management and relaxation techniques as well as
address avoidance behaviors, insomnia, as well as fear of anticipation to faint. The
use of pharmacotherapy in PPS has been inconsistent in its success, although Linzer
et al. (1992) stated that clonazepam and fluoxetine reduced the symptoms of
The Psychosocial Impact of Syncope 483
syncope in most patients (Linzer et al. 1992). In perhaps the same way as with
somatoform disorders, pharmacotherapy might be best seen as an adjunct to
psychotherapy in bringing about successful outcomes in PPS patients. An analysis
of the literature points to additional studies required in exploring PPS phenomena.
Conclusions
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Psychological Responses to Acute Coronary
Syndrome
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Seeking Treatment for an ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Understanding ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Coping with an ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492
Adjustment to an ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Grief and Loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Adjusting to Treatments and Lifestyle Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494
Self-Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
Adjustment Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 495
ACS and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496
Suicide Risk Following ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
ACS and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497
Stress and ACS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 499
Post-trauma Responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 500
ACS and Anger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
ACS and Interpersonal Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 501
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 503
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 504
A. Turner (*)
IMPACT SRC, School of Medicine, Deakin University, Geelong, VIC, Australia
School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia
Department of Psychiatry, University of Melbourne, Parkville, VIC, Australia
e-mail: [email protected]
A. O’Neil
Melbourne School of Population and Global Health, The University of Melbourne, Parkville
VIC, USA
School of Public Health and Preventive Medicine, Monash University, Clayton, VIC, USA
IMPACT Strategic Research Centre, Deakin University, Geelong, VIC, USA
e-mail: [email protected]
Abstract
Psychological reactions to a cardiac event differ among patients, impacting upon
individual presentation and recovery. Cognitive response to symptoms and
resulting coping mechanisms will impact on how quickly a patient will seek
help, comprehend, and adjust to their condition and engage in interpersonal
relationships. Negative cognitive responses can result in, or be a product of,
common mental health issues often seen following acute coronary syndrome
including adjustment disorder, depression, anxiety, stress, trauma, anger, or
hostility. The increasing recognition of the link between these negative emotions
and cardiac disease has increased the focus on whether treatment can mitigate
negative outcomes. Findings highlight the importance of elucidating beliefs and
understanding around illness and targeting interventions appropriately to modify
any maladaptive beliefs. This includes implementing routine screening pro-
cesses that identify patients at risk of persistent mental health problems.
Keywords
Acute coronary syndrome • Acute myocardial infarction • Illness perceptions •
Coping • Adjustment • Depression • Anxiety • Anger • Post-traumatic stress •
Interpersonal relationships
Introduction
period can be marked by emotional shock, particularly at the speed of the event
(Astin et al. 2009), feeling overwhelmed and powerless, and finding the situation
chaotic and dealing with a loss of independence (Kerr and Fothergill-Bourbonnais
2002). Initially, many have difficulty making sense of their condition, lack knowl-
edge and understanding, and perceive their condition as acute and curable (Astin
et al. 2009). For many, developing an understanding of the condition may lead to
positive transitions, including adoption of recommended treatments and lifestyle
changes, and shifts in values, responsibilities, and identity (Groleau et al. 2010;
Gulanick et al. 1998).
Concurrently, patients often experience ongoing physical symptoms, particu-
larly in the ensuing 3–4 months, including persistent chest pain, dyspnea or
shortness of breath, palpitations, dizziness, and swelling in the lower extremities
(Barnason et al. 2012). Other less anticipated symptoms include fatigue, exhaustion
or tiredness, sleep disturbance, gastrointestinal distress, and appetite problems, all
of which impact day-to-day functioning. For example, people with fatigue follow-
ing ACS have more limited physical activity and impaired physical functioning, as
well as greater interference of usual routines and activities (Barnason et al. 2012).
Unsurprisingly, fatigue is also associated with reduced quality of life (Brink
et al. 2012).
ACS survivors with persistent depression symptoms have reported that living
with physical limitations contribute to low mood (Grace et al. 2005). Other factors
exacerbating depressive symptoms include uncertainty around the future, knowl-
edge of their cardiac condition, rehospitalization, and living with the prescribed
treatments for coronary heart disease (adverse effects of medication, quitting
smoking, and dietary changes) (Grace et al. 2005). Participants in the UPBEAT-
UK study also identified a range of interpersonal, health, and control losses that
they believed linked CHD and depression (see Fig. 1) (Simmonds et al. 2013).
While some patients experience persistent depression post-ACS, for most, symp-
toms will either be sufficiently mild to result in little or no impact on an individual’s
day-to-day life or will be transitory, resolving spontaneously over the first 4 months
(Barnason et al. 2012). In addition to depression, people recovering from ACS also
report feelings of anxiety, uncertainty, apprehensiveness, ambiguity, and insecu-
rity; apprehension and fearfulness, particularly of a recurrence or deterioration in
health; or of boredom and inertia. Dependency and feelings of overprotection,
discouragement, tearfulness, and powerlessness are common, as are anger and
frustration (Barnason et al. 2012). Normal day-to-day activities may be attached
to new fears and uncertainties, for example, avoiding sexual activity for fear of
having another AMI or uncertainty about safe levels of physical activity. As with
depression, for a small proportion of people, symptoms of anxiety- or adjustment-
related emotional distress may be more severe or pervasive, or the trauma of the
event may trigger a more severe post-traumatic stress response. An acute cardiac
event can also impact on an individual’s social network which can influence the
survivor’s recovery and quality of life. This chapter will review each of these
important issues.
490 A. Turner and A. O’Neil
Fig. 1 A model of participants’ perceptions of links between coronary heart disease and depres-
sion (Originally published by BioMed Central in Simmonds et al. (2013))
“Decision delay” refers to the delay between the time of onset of cardiac symptoms
until the decision is made to seek professional care. A range of factors have been
associated with decision delay time. Female gender and increased age are associ-
ated with increased delay time (Khraim and Carey 2009). Gender differences may
be due to the perception of heart disease as being a “male” problem (Higginson
2008), the onset of heart disease at an older age in women than men, and also their
difference in symptom presentation which may affect symptom recognition and
interpretation. Women are less likely to experience chest pain at all during AMI,
while symptoms that are more intense, continual, and have a fast onset are associ-
ated with shorter delay (Khraim and Carey 2009). Preexisting mental health
conditions and traits have been associated with increased delay, including depres-
sion (Bunde and Martin 2006), PTSD (Newman et al. 2011), neuroticism
(Rosenfeld 2004), and alexithymia (Preti et al. 2013). Physical health conditions
Psychological Responses to Acute Coronary Syndrome 491
may affect decision-making, with some studies finding past AMI associated with
reduced delay (potentially due to knowledge and experience), while a history of
angina and diabetes was associated with longer delay (Khraim and Carey 2009).
Other factors associated with delay include context (onset while at home or
alone), cognitive factors (symptom expectations, perceived control over symptoms,
knowledge, and perceived threat), affective factors (fear of consequences or trou-
bling others, denial, embarrassment), and behavioral factors (contacting emergency
services vs. primary healthcare provider vs. others; choosing to wait it out or trying
to relax) (Khraim and Carey 2009). Feelings of anxiety and vulnerability have been
reported acting as both triggers and barriers to seeking treatment (Johansson
et al. 2007). People may delay seeking treatment as they believe they could never
have an AMI (Harralson 2007), or symptoms are minimized, denied, or
misattributed to other conditions (Hwang and Jeong 2012), and/or they prefer to
self medicate (Higginson 2008). Treatment-seeking decisions may further be
influenced by healthcare factors, including access to, or knowledge about, emer-
gency services and treatment and past experience with services (Kaur et al. 2006).
Other sociocultural factors such as the family situation, social support, cultural
beliefs, and practices may also impact on decision-making.
Psychosocial support and guidance from the environment are often fundamental
to the patient’s management of the situation (Johansson et al. 2007). Often, relatives
will act as the decision-maker to seek care, even providing transportation to hospital
to expedite admission (Henriksson et al. 2007). One study found that if the patient’s
partner understands the severity of the situation, has knowledge, and was rational
and consulted with others as needed, prehospital time is reduced. Conversely, delay
can occur when a partner restrained their own emotions and sought agreement from
the partner as a result of established roles and experiences (Johansson et al. 2008).
Understanding ACS
During recovery from ACS, survivors will seek to understand what happened and
why, to make sense of the event and their condition, the cause, and the personal
significance of the illness and to answer the question “Why me?” (Baldacchino 2010).
Cognitive representations of an illness constructed by the patient, including beliefs
about symptom constellation (identity), cause of the condition (cause), condition
duration (timeline), lifetime consequences of the condition (consequences), and the
extent to which it can be cured or controlled (control/cure), are collectively known as
illness perceptions (Cameron and Leventhal 2003). Additionally, the extent to which
the patient’s illness makes sense (illness coherence) has been found to be important,
particularly if self-management ideas differ from those of their healthcare provider
(Gardner et al. 2003). Illness perceptions can be transient depending on the stage of
illness, diagnosis, and information given and are thus amendable to intervention
(Broadbent et al. 2009).
A meta-analysis by Foxwell and colleagues (2013) found that illness perceptions
in people with CHD were associated with physical, social, and emotional aspects of
492 A. Turner and A. O’Neil
quality of life (QOL) and depression and anxiety. Physical and emotional QOL
were positively associated with identity, consequences, coherence, perceived per-
sonal and treatment control, chronicity, and a belief that stress caused the illness.
Social QOL was associated with perceived consequences, coherence, and a cyclical
timeline. Elevated depression and anxiety were associated with lower illness
coherence, lower perceived personal control, and increased perception of chronic-
ity; the former also contributed to perceived negative illness consequences and a
belief that stress or personality caused the cardiac condition. Anxious patients
attributed more symptoms to their condition. Another study of AMI survivors
found that higher perceived risk of future AMI was associated with illness percep-
tions including worse consequences of the AMI and lower beliefs in the benefits of
treatment, as well as higher levels of anxiety (Broadbent et al. 2006). Perceived risk
was not associated with demographics (age or sex), history of previous AMI, or risk
factors (family history of CHD, diabetes, current smokers).
Coping refers to the use of an array of dispositions and cognitive, emotional, and
behavioral strategies that people draw on to maintain well-being and avoid harm in
the face of significant internal and external demands and stressors such as those
precipitated by physical illness. ACS survivors will draw on a range of coping
strategies throughout their recovery period. Coping strategies and behaviors are
flexible and situational, influenced by duration, severity, and nature of the crisis,
trauma, or loss (Lazarus and Folkman 1984). Early taxonomies of coping included
problem-solving coping (active efforts to address the stressor) and emotion-
focused coping (focusing on managing the resulting emotions due to the assump-
tion that the problem faced cannot be modified) (Lazarus and Folkman 1984).
Additional coping styles have since been proposed; however, many still fit broadly
into the problem-focused or emotion-focused styles. Denial, a form of avoidance
coping (fitting into the emotion focused style), is often mentioned with regard to
people with a new diagnosis of a chronic illness. Interestingly, denial has been
associated with positive emotional outcomes in the short term following a cardiac
event, possibly due to protecting the person from taking on too much new infor-
mation at once (Bennett and Boothby 2007). In the longer term, avoidant- and
emotion-focused coping have been associated with poorer physical and emotional
outcomes (Chiavarino et al. 2012; De Fazio et al. 2012). Patients who feel
powerless as a result of the illness, and those who have expectations that healthcare
providers are responsible for their care, tend to display poorer coping strategies.
These patients are less likely to make significant lifestyle modifications following
ACS (Bonsaksen et al. 2012).
ACS patients most commonly use adaptive, problem-solving style coping
strategies, such as optimistic coping, active coping, active problem solving,
Psychological Responses to Acute Coronary Syndrome 493
positive reappraisal, and seeking social support (Bennett and Boothby 2007), and
these coping strategies are associated with positive outcomes. For example, social
support has been found to be associated with lower levels of anxiety, while people
with more coping strategies were more likely to attend cardiac rehabilitation
(French et al. 2006). Women have been shown to more often use supportive
coping and more coping strategies overall, while men more heavily rely on their
spouses and use more informational and instrumental support (Bennett and
Boothby 2007).
Spirituality (existential and religious coping) may play a role in coping
(Baldacchino et al. 2012). Walton reported that AMI survivors in a predominantly
Christian region of the United States described going through five spiritual phases
during recovery: facing mortality, relinquishing fear and turmoil, identifying and
enacting lifestyle changes, seeking God’s purpose, and finding meaning in every-
day life (Walton 2002). Positive associations have been shown between religious
coping and spirituality and outcomes in people with chronic illness, such as more
effective coping and greater health-related QOL (Mueller et al. 2001). Cardiac
patients specifically have identified religion as a source of strength and comfort
following the event (Kamm-Steigelman et al. 2006). However, another US study
found that measures of religiosity and religious coping were not associated with
quality of life or self-esteem, while discontent coping (a sense of anger or distance
from God) was associated with lower levels of physical self-efficacy at the end of
cardiac rehabilitation (Miller et al. 2007). Park et al. found that positive and
negative forms of religious coping were associated with increased depression
symptoms in hospital and at 1 month follow-up and argued that active
coping strategies be promoted in the recovery period (Park and Dornelas 2012).
Illness perceptions, specifically helplessness and illness acceptance, can mediate
the relationship between intrinsic religiousness and subjective health in chronic
cardiac patients (Karademas 2010). A recent meta-analysis of the effects
of spiritual interventions within cardiac rehabilitation programs reported encour-
aging findings; however, more studies are required (Nadarajah et al. 2013).
A qualitative study found a sense of control is central to coping for ACS patients
(Salminen-Tuomaala et al. 2012). Other factors promoting coping include personal
coping resources, sense of coherence, acceptance of the situation, spiritual convic-
tion and prayer, a safe care environment and rapid alleviation of symptoms, keeping
up to date via information and counseling and test results, support from and sharing
with fellow patients, encouraging the patient room atmosphere, and emotional
support from family. Factors that interfere with coping include experiencing
acute, serious illness and difficult symptoms, different fears, denial of the situation,
sense of losing control over the situation, depression and powerlessness, strange
hospital environment and culture, constant waiting and state of readiness, lack of
emotional support from healthcare staff, lack of open communication between the
patient and family, hiding the seriousness of the situation from family, and diffi-
culties speaking about the illness with the family.
494 A. Turner and A. O’Neil
Adjustment to an ACS
Self-Efficacy
Adjustment Disorder
While adjustment following AMI is straightforward for some, for others, the
process incites significant symptoms of emotional distress that impinge day-to-
day life. The diagnostic term “adjustment disorder”, first appearing in the Diag-
nostic and Statistical Manual III (DSM-III), is used when the “emotional or
behavioral symptoms” in response to an identifiable stressor, such as ACS,
“cause distress that is out of proportion to the severity or intensity of the stressor
and/or significant impairment in social, occupational, or other important areas of
functioning.” Symptoms start within 3 months of the stressor and resolve within
6 months following its termination. Adjustment disorder diagnosis is applied only
in the absence of fulfillment of criteria for another disorder (e.g., depression or
anxiety), and symptoms are not due to normal bereavement (American Psychiatric
Association 2013).
496 A. Turner and A. O’Neil
Risk factors for persistent depression identified from these studies include a first
language other than English, comorbid diabetes, cardiac history, prior depression,
and Type D personality (Martens et al. 2008; Murphy et al. 2008). The Type D
personality construct was developed by Denollet (Denollet and Brutsaert 1998),
triggered by observations of cardiac patients, and refers to a “distressed” personal-
ity type characterized by a high level of negative affectivity and high level of social
inhibition. Doyle found that selected theoretical depression vulnerabilities (stress-
ful life events; reduced reinforcing events; cognitive distortions; and Type D
personality) predicted depression trajectories (Doyle et al. 2011).
The differential effects of more depression subtypes on key clinical outcomes of
ACS patients have also been documented. Of note is the predictive role of cognitive
subtypes such as anhedonia (Leroy et al. 2010), helplessness and hopelessness
(Pedersen et al. 2007), and pessimism (Tindle et al. 2009). Somatic subtypes of
depression have been shown to predict CV prognosis and mortality (Rumsfeld and
Ho 2005). It is plausible that routine depression screening at the granular level
following ACS may facilitate long-term functioning and recovery (Clarke 2003).
Studies examining the prognostic role of latent classes of depression and anxiety
symptoms in ACS patients are currently underway (Oldroyd et al. 2013).
While often a symptom of depression, suicidal ideation can occur in the absence of
clinical depression. Physical illness is a risk factor for suicidal ideation and attempts
in higher- and lower-income countries; a positive relationship has been observed
between suicide risk and number of physical illnesses (Scott et al. 2010). Several
studies have confirmed an association between coronary heart disease and AMI and
suicidal ideation (Kim et al. 2006; Kishi et al. 2001; Larsen et al. 2010). A
population-based, case-control study conducted in Denmark found that AMI was
associated with an increased risk of suicide for up to 5 years post-AMI (Larsen
et al. 2010). Risk was more pronounced in the first month following discharge for
AMI. Perhaps most notably, suicide risk was 64 times greater for those with a
recorded history of psychiatric illness (compared with those without). The risk tended
to decrease with age, with no gender difference found despite males being at greater
risk of completed suicide in the general population. Clinicians should be aware of the
increase risk of suicide and suicidal ideation at any time post-AMI, particularly in the
early post-discharge period and in those with a psychiatric history.
and physical symptoms such as racing heart, hot and cold flushes, tightening chest,
agitation, dry mouth, nausea, numbness, and tingling in hands or feet. A reaction
that is designed to help deal with danger, anxiety can be adaptive when a situation
calls for a “flight or fight” response or when activating active coping strategies such
as gathering further information to address concerns or following health recom-
mendations. It can also be maladaptive when it persists or worsens to the point
where it impedes a person’s day-to-day functioning.
Anxiety following a significant health event such as ACS is extremely common,
precipitated by a range of factors such as pain; fear of recurrence, disability or
death, and uncertainty around prognosis; dealing with new and complex treatment
regimens including lifestyle changes; and wider life stressors such as financial
concerns and restrictions to usual work and social activities. Approximately half
of ACS patients experience significant anxiety symptoms in the early post-event
period (De Jong et al. 2004), and (as with depression) symptoms can persist into the
longer term for some. There are a range of clinical anxiety disorders that are
diagnosed when anxiety levels are pathological, with two particularly relevant
disorders to ACS being panic disorder and generalized anxiety.
Panic disorder is an anxiety condition that involves recurrent panic attacks.
Panic attacks are common in the general community, with around 35 % experienc-
ing one at some time in their life, although recurrent panic attacks are less common.
A challenge for a person living with panic disorder, their family, and clinician is the
overlap between ACS symptoms and panic attack, such as chest tightness or
discomfort, shortness of breath, sweating, palpitations, light-headedness, nausea,
and vomiting. Panic attacks also involve feelings of dread, danger or foreboding,
fear of going mad, losing control, and dying. Over one-third of patients who present
with noncardiac chest pain have panic disorder (Soh and Lee 2010). However,
panic disorder has also been found to be common in people with established CHD,
compared with the general population, with rates between 11–27 % (Soh and Lee
2010) and 2–3 %, respectively (Kessler et al. 2005).
Generalized anxiety disorder (GAD) is characterized by at least 6 months of
feeling very worried to the extent that it is difficult to stop, impacting on everyday
activities. In addition, people experiencing GAD may feel restless or on edge, easily
tired, difficulty concentrating, irritable, muscle pain, and sleep disturbance. A meta-
analysis of studies investigating GAD in cardiac populations revealed a prevalence
of 11–14 % in people with existing CHD, while lifetime prevalence was found to be
26 % (Tully and Cosh 2013). This compares with a yearly prevalence of 3 % and
lifetime prevalence of 5 % in the general population (Weisberg 2009). While some
have found GAD to be associated with increased mortality (Roest et al. 2012),
Parker and colleagues (2011) found that both a current and a lifetime diagnosis of
GAD was associated with a superior 5-year outcome, particularly in those with no
other anxiety disorder. This suggests that there may be an element of “constructive
worrying” precipitating help seeking and adherence to treatment recommendations
(Parker et al. 2011). In the general community, high rates of comorbidity have been
found for GAD and major depressive disorder (MDD), with the two conditions
sharing a number of symptoms and features (e.g., concentration and sleep
Psychological Responses to Acute Coronary Syndrome 499
Stress refers to both an external event, or “stressor,” and the physical and psycho-
logical reactions to the stressor, or the “stress response.” Stress has long been linked
with heart problems in the public view, with some ACS survivors perceiving stress
as being a more likely and greater cause of their heart problems than known risk
factors such as smoking and diet (Clark 2003). Stress following an ACS can be
multifactorial, consisting of different and interrelated elements. In addition to the
health event itself and directly related stressors (seeking understanding, dealing
with medical treatments and lifestyle changes), external stressors such as job stress,
adverse life events, and financial problems may also result, be exacerbated, or be
harder to deal with due to compromised resources.
The stress response varies between individuals but consists of cognitive symp-
toms (e.g., memory and concentration problems, poor judgment, worrying, anxious,
or racing thoughts), emotional symptoms (e.g., feeling down, depressed or
unhappy, feeling overwhelmed, agitated, irritable, or moody, and a sense of isola-
tion and loneliness), physical symptoms (e.g., rapid heartbeat or chest pain, nausea,
dizziness, diarrhea or constipation, aches and pains, loss of libido, frequent colds),
and behavioral symptoms (change in appetite and sleeping patterns, isolating self,
procrastination, substance use, nervous habits). In addition to triggering symptoms
of emotional distress, stress can also be a risk factor for the onset or exacerbation of
many mental health conditions.
Qualitative studies reveal personal experiences of stress post-ACS. A study of
female ACS survivors reported that while their life pre-AMI was stressful due to
multiple roles, they needed and wanted support in the post-discharge period and
were fearful about returning home. Patients and their relatives were uncertain about
their capacity (Sjostrom-Strand and Fridlund 2007). Upon investigating lifestyle
factors, Condon and McCarthy (2006) identified stress as a major concern for
participants who reported overwork, poverty, addictions, and managing multiple
roles (homemaker, breadwinner, parent, partner, etc.) as key sources. However,
despite believing that stress contributed to their AMI, patients were unsure about
everyday stress management (Condon and McCarthy 2006).
500 A. Turner and A. O’Neil
Post-trauma Responses
In some cases, the response to the stress and trauma of an ACS can trigger a psycho-
logical disorder. Acute stress disorder and post-traumatic stress disorder (PTSD) are
significant post-traumatic syndromes precipitated by traumatic events, for example, a
natural disaster, combat, or sexual assault. Symptoms include reexperiencing the event,
avoidance of reminders of the event, negative changes to mood and cognitions, and
physiological hyperarousal. The DSM-IV specified that the triggering events could also
include life-threatening illness such as ACS, stroke, and cancer; however, its successor,
the DSM-V, is less clear, stating medical triggers must involve sudden, catastrophic
events such as anaphylactic shock and waking during surgery. The primary difference
between acute stress disorder and PTSD is the timing of symptom presentation and
persistence, with acute stress disorder more immediate and PTSD a longer-term
disorder. To fulfill criteria of acute stress disorder, symptoms are required to be present
within 2 days and 4 weeks of the event, while PTSD is diagnosed at least 1 month post-
event. Acute stress disorder is often a precursor to PTSD.
A number of studies have demonstrated that a cardiovascular event, such as
AMI, can trigger a post-trauma disorder in some survivors. Prevalence of acute
stress disorder in ACS survivors has been reported as 4–18 % (Roberge et al. 2008),
while the prevalence of ACS-induced PTSD has been found to be 12 % (95 % CI
9–15 %) (Edmondson et al. 2012). Some studies have identified potential risk
factors for PTSD following ACS including acute stress disorder, as well as a history
of other psychiatric disorders and symptoms or traits (including a history of
psychiatric disorder before ACS, depression symptoms during hospitalization,
alexithymia, and neuroticism), responses during the event (including intense fear,
perceived life threat, helplessness, dissociation, and lack of control), chest pain
during the event, and demographic variables (younger age, female gender, ethnic
minority, and low socioeconomic status) (Edmondson et al. 2012). Wilkman and
colleagues (2008) found that PTSD symptoms persisted in a group of ACS patients
for at least 3 years post-event. This suggests a chronic and persistent course and
highlights the importance of early detection and intervention.
While some experience deleterious trauma reactions, others not only recover but
experience positive change, termed “post-traumatic growth.” A review of the
qualitative post-traumatic growth literature in those with life-threatening physical
illness suggests change occurs over four domains – reappraisal of life and priorities,
trauma equaling development of self, existential reevaluation, and a new awareness
of the body (Hefferon et al. 2009). In ACS patients, reappraisal of life and priorities
was demonstrated by a new appreciation of life and time and being alive, priori-
tizing friends, an increased importance of and improved relationship with family,
and prioritizing health. ACS patients also report increased empathy as a form of
self-development, as well as an existential reevaluation, with recognition of mor-
tality and the brevity of life. Finally, a new awareness of the body occurs for some
post-ACS, characterized by an increased awareness, importance and sense of
responsibility for their own health, and engagement in preventative health behav-
iors such as diet, exercise, reduced stress, and reduced substance use.
Psychological Responses to Acute Coronary Syndrome 501
ACS can have a significant impact on a patient’s friends and family, as well as their
relationships and interactions. Partners of AMI survivors are at increased risk of
depression and suicide with male partners at higher risk of depression than female
partners (Fosbol et al. 2013). Female partners report suffering a major loss, missing
their “former” partner sexually and emotionally, while also feeling their partner is
controlling them or limiting their life (Arenhall et al. 2011). A systematic review on
the impact of cardiac disease on the partner relationship revealed five themes:
overprotection, communication deficiency, sexual concerns, changes in domestic
roles, and adjustment to illness (Dalteg et al. 2011).
Reports of overprotective behavior by the patient were often around carrying out
“allowable” activities and lifestyle changes. Partners often worried about recurrent
AMI or angina attack when the patient was alone. While patients needed and valued
family support and often recognized the good intentions of their partner and
children, resistance and residual tension in the household could occur (Condon
and McCarthy 2006). Overprotectiveness led to feelings of resentment and
502 A. Turner and A. O’Neil
frustration in the patient as they felt controlled or “on probation” and compelled to
report back to their partner, resulting to conflict and arguments (Dalteg et al. 2011).
Overprotectiveness could also encourage dependency, which contrasted with the
patient’s desire to “get back to normal” as soon as possible and to regain and
maintain independence (Condon and McCarthy 2006).
Communication challenges were reported, particularly with regard to inhibition
of emotions (Dalteg et al. 2011). Patients did not want to provoke anxiety in their
partner or be perceived as whining. In turn, partners did not want to upset the
patient. Often couples did not discuss the disease or handle its implications
together and were sometimes uncertain how to talk about the experience and
potential of death with the other. Partners found it stressful dealing with the
patient’s emotional distress. However, if partners disengaged this could lead to
further anxiety in the patient. So and La Guardia found that greater inhibition of
feelings about an AMI leads to poorer psychological and relational functioning,
while closeness to their partner was associated with greater disclosure (So and La
Guardia 2011).
Another common concern for patients and partners centered on sexual relation-
ships. Frequency of sexual activity is known to decline following AMI, with sexual
dysfunction seen as a direct consequence of cardiac disease and medication
(Mosack and Steinke 2009). One study found that fewer than half of patients
interviewed had resumed sexual activity 12 weeks post-discharge. Resumption
was significantly more likely in those completing cardiac rehabilitation (Eyada
and Atwa 2007). Another longer-term study found sexual concerns and dysfunction
were present 6 months post-AMI (Mosack and Steinke 2009). For many, there is a
fear that resuming sexual activities will trigger another ACS event, while other
factors delaying return to sexual activity include continued health problems, med-
ication, sexual dysfunction, lack of information or partner concerns, health prob-
lems, or decline in sexual interest (Mosack and Steinke 2009). For some people,
there is a belief that no one would be interested in a relationship with them because
of their health problems (Mosack and Steinke 2009). Furthermore, most patients
were either unsatisfied or mostly dissatisfied with their sexual activity (Eyada and
Atwa 2007). Those who participate may experience overall dissatisfaction with
their sex life due to decreased frequency of activity or decreased sexual desire and
ability to satisfy their partner (Mosack and Steinke 2009). Another study found that
higher anxiety was associated with lower sexual satisfaction (Steinke and Wright
2006).
A shift in domestic roles and responsibilities during recovery (and potentially in
the longer term) can occur for AMI patients cohabitating with a partner (Dalteg
et al. 2011). An increase in partner workload occurring as a result of patient
incapacitation may cause frustration and anxiety, or guilt if the patient performed
physically stressful chores. The extra workload compromising other enjoyable
activities can be perceived as limiting a partner’s life.
Finally, in addition to their individual adjustment to the heart condition, the dyad
team also undergoes an adjustment process (Dalteg et al. 2011). Adaption and
Psychological Responses to Acute Coronary Syndrome 503
adjustment issues include incorporation of new diets, routines, and healthy lifestyle
practices into both the patient and partners life, resulting in feelings of stress for the
partner but also solidarity with the patient; a diminishing of joint activities, partic-
ularly those that were more physically demanding; and attempts to lead a normal
life and regaining balance while being hopeful for improvement in the future. While
the experience of an ACS can result in great distress for the couple, it can synergize
some couples through reconnection and new meaning. However, partner anxiety or
depression has been found to negatively impact on the adjustment of the patient;
some couples withdraw from each other or avoid discussing or making future plans,
goals, or hopes.
Clinical Implications
Conclusions
Psychological reactions to a cardiac event vary and impact upon individual presen-
tation and recovery. The processes of help seeking, understanding, and adjusting to
the event can be impacted by, and impact on, cognitive responses to symptoms,
coping mechanisms, and interpersonal relationships. Emotional distress is common
and may present as adjustment disorders, depression, anxiety, stress, trauma, anger,
or hostility. Conversely, many individuals report positive or post-traumatic growth
responses. The increasing recognition of the link between these emotional
responses and health outcomes has increased the focus on whether treatment can
mitigate negative outcomes.
504 A. Turner and A. O’Neil
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Anxiety, Depression, and Psychological
Adjustment After an Acute Cardiac Event
Contents
Prevalence of Anxiety and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512
Impacts of Anxiety and Depression on Health Behaviors, Morbidity, and Mortality . . . . . . . . 513
Identification of Depression in Cardiac Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Current Depression Screening Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516
Problems with Depression Screening in Cardiac Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 517
Indications for Risk Stratification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522
Implications for Clinical Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524
Abstract
Psychological adjustment following acute cardiac events such as acute myocar-
dial infarction (AMI) and coronary artery bypass graft surgery (CABGS) has
received increasing attention in the last three decades. While physical recovery
remains the highest priority, psychological recovery is now considered a primary
Keywords
Anxiety • Depression • Emotional adjustment • Distress • Screening
Many studies document high levels of both anxiety and depression in patients at the
time of or soon after an acute cardiac event (Andrew et al. 2000; Barefoot
et al. 2000; Berkman et al. 2003; Frasure-Smith and Lesperance 2003; Thombs
et al. 2006). A 2006 review of 24 studies involving over 14,000 patients reported
prevalence of depression in patients hospitalized after acute myocardial infarction
(AMI). Prevalence rates varied depending on the assessment method. Across the
eight studies that used a standardized diagnostic interview, the prevalence of major
depression varied from 16 % to 27 %, with a weighted prevalence of 19.8 %
(Thombs et al. 2006). The largest of the included studies – the Enhancing Recovery
in Coronary Heart Disease (ENRICHD) study, which involved over 9,000 patients –
reported a prevalence of 20 % (Berkman et al. 2003). Across the 17 studies that used
a validated questionnaire, the prevalence of “clinically significant depression”
varied from 10 % to 47 %, with variation depending on the instrument used (Thombs
et al. 2006). When depression was classified as Beck Depression Inventory (BDI)
scores 10, the prevalence rates were relatively high, ranging from 20 % to 37 %,
with a weighted prevalence of 31 %. In contrast, when depression was classified as
Hospital Anxiety and Depression Scale – Depression (HADS-D) scores 8, the
prevalence was considerably lower, ranging from 11 % to 17 %, with a weighted
prevalence of 15.5 % (Thombs et al. 2006). Given these variations, it is difficult to
categorically report prevalence rates for in-hospital depression post-cardiac event.
However, it is generally agreed that 15–20 % of patients meet diagnostic criteria for
major depression while in hospital after acute myocardial infarction (AMI) or
coronary artery bypass graft surgery (CABGS) (Colquhoun et al. 2013; Lichtman
Anxiety, Depression, and Psychological Adjustment After an Acute Cardiac. . . 513
et al. 2008), with many more showing elevated depressive symptoms (Barefoot
et al. 2000; Carney and Freedland 2003; Frasure-Smith and Lesperance 2003).
Relatively few studies have reported prevalence rates for in-hospital anxiety. In
studies of CABGS patients, both presurgical and postsurgical anxiety rates tend to
be reported. In some cases, anxiety is shown to remit after surgery. For example, in
a German study of 142 CABGS patients, with anxiety classified as Hospital Anxiety
and Depression Scale – Anxiety (HADS-A) scores 8, the presurgical rate was
34 % (Krannich et al. 2007). By 10 days postsurgery, the prevalence of anxiety had
reduced, albeit nonsignificantly, to 25 % (Krannich et al. 2007). Symptom remis-
sion was more likely in younger than in older patients (Krannich et al. 2007).
However, in other studies, anxiety rates increase after surgery. For example, in an
Australian study of 147 CABGS patients, with anxiety classified using the Depres-
sion, Anxiety and Stress Scale (DASS), the preoperative prevalence of mild to
severe anxiety was 27 %, whereas the postoperative prevalence was significantly
higher at 45 % (Andrew et al. 2000). The inclusion of patients with “mild”
symptoms (DASS anxiety scores 8–9) may have inflated these rates: excluding
these patients, the presurgical and postsurgical prevalence of moderate to severe
anxiety (DASS anxiety 10) was 20 % and 33 %, respectively (Andrew
et al. 2000). In addition, some patients awaiting surgery have either generalized
anxiety disorder (GAD) or panic disorder, as assessed by structured diagnostic
interview. A recent review indicated prevalence rates varying from 2 % to 10.2 %
for GAD and 10.8 % for panic disorder presurgery (Tully and Baker 2012). The
review confirmed that many more patients have subclinical anxiety symptoms both
pre- and postsurgery (Tully and Baker 2012).
These rates of in-hospital post-event anxiety and depression are considerably
higher than seen in the general community. For example, approximately 5 % of
Australian adults report a depressive illness and around 4 % anxiety-related prob-
lems (AIHW 2012). Similarly, the prevalence of major depression in American
adults is approximately 5 % (American Psychiatric Association 2013; Egede 2007).
In a study comparing AMI and CABGS patients with healthy adults, rates of
anxiety and depression were significantly higher in both patient groups (Moser
et al. 2010). It appears that rates of anxiety and depression among cardiac patients
are up to four times that seen in the general population.
Modifiable risk factors account for up to 90 % of the overall risk of acute myocar-
dial infarction (AMI) (Yusuf et al. 2004). In patients with established coronary
heart disease, modifiable risk factors affect the progression of the disease and the
likelihood of a future event, while lifestyle changes improve risk factor profiles and
prognosis (Euroaspire II Study Group 2001). In particular, smoking cessation
reduces cardiac patients’ mortality risk by 36 % after 5 years (Critchley and
Capewell 2003) and by 50 % after 10 years (Cavender et al. 1992). Increasing
514 B.M. Murphy et al.
physical activity also reduces the risk of further events and death (Iestra et al. 2005;
Moholdt et al. 2008), as does reducing dietary fat intake (Iestra et al. 2005; Mead
et al. 2006). Nonetheless, the prevalence of unhealthy lifestyles and modifiable risk
factors remains high in cardiac populations (Euroaspire II Study Group 2001;
Murphy et al. 2011).
Post-event anxiety and depression put cardiac patients at a distinct disadvantage
in terms of engagement in activities that promote health and well-being. Compared
with their nondepressed counterparts, depressed patients are more likely to smoke
(Gravely-Witte et al. 2009; Kronish et al. 2006; Murphy et al. 2012) and to relapse
after quitting (Perez et al. 2008). They consume higher levels of dietary fat (Murphy
et al. 2012; Ziegelstein et al. 2000) and engage in less physical activity (Allan
et al. 2007; Kronish et al. 2006; Murphy et al. 2012; Ziegelstein et al. 2000) than
those who are not depressed. Similarly, anxious patients have higher smoking rates
(Kuhl et al. 2009; Murphy et al. 2012; Perez et al. 2008) and dietary fat intake
(Murphy et al. 2012), although, once sociodemographic factors are taken into
account, their physical activity levels tend to be similar to those of non-anxious
patients (Kuhl et al. 2009; Murphy et al. 2012).
In addition to their poor health behaviors, depressed patients are less adherent to
recommended treatments (DiMatteo et al. 2000). First, they show poorer medica-
tion adherence than nondepressed patients, being more likely to forget to take their
medications and to skip doses and less likely to take medication as prescribed (Gehi
et al. 2005; Kronish et al. 2006). Second, they are disinclined to attend cardiac
rehabilitation programs (Frasure-Smith et al. 1993; Kronish et al. 2006; Whitmarsh
et al. 2003; Blumenthal et al. 1999; Lane et al. 2001) and, if they do attend, are more
likely to discontinue (Blumenthal et al. 1999; Kronish et al. 2006). Both medication
adherence (Ho et al. 2006) and attendance at cardiac rehabilitation (Beauchamp
et al. 2013; Denollet and Brutsaert 2001) have been shown to impact positively on
survival.
It is not surprising then that cardiac patients who are anxious or depressed after
an acute cardiac event have poorer morbidity and mortality outcomes than their
non-anxious and nondepressed counterparts (van Melle et al. 2004; Barth
et al. 2004). For example, anxious patients are at increased risk of hospital
readmission within 30 days of discharge after CABGS (Murphy et al. 2008b) and
of reinfarction following a first AMI (Strik et al. 2003). In terms of mortality
outcomes, presurgical anxiety has been shown to predict all-cause mortality,
independent of age and comorbid disease (Tully et al. 2008a). Post-event anxiety
has also been shown to predict cardiac mortality up to 3 years after a first event,
independent of other risk factors (Strik et al. 2003). A recent review included four
studies reporting associations between generalized anxiety disorder (GAD) and
cardiac morbidity and mortality among CHD patients (Tully et al. 2013). The
earliest study, involving 804 acute coronary syndrome (ACS) patients, reported a
2.29 increased risk of re-event or death at 2 years in patients shown to have GAD at
2 months post-event (Frasure-Smith and Lesperance 2008). The largest study,
involving over 1,000 CHD patients, demonstrated a 74 % increased risk of
re-event or death, with adjustment for confounders, among patients with GAD
Anxiety, Depression, and Psychological Adjustment After an Acute Cardiac. . . 515
(Martens et al. 2010). An Australian study of 158 CABGS patients showed that
GAD conferred a threefold increased risk of in-hospital re-events and death, after
adjustment for confounders (Tully et al. 2011). Contrary to other findings, a 2011
study of 436 ACS patients found that GAD was associated with a reduced risk of
death over 5 years post-event, suggesting that GAD may have a protective effect
(Parker et al. 2011). Likewise, a study of over 2,000 cardiac patients referred for
exercise testing found that elevated anxiety as assessed by the HADS-A was
associated with lower 5-year mortality (Herrmann et al. 2000). While it increases
risks via physiological mechanisms (Olafiranye et al. 2011), anxiety may simulta-
neously encourage help-seeking behaviors that reduce risk (Herrmann et al. 2000).
Consistent with this view, it has been suggested that some forms of anxiety,
particularly generalized anxiety about health, might actually improve cardiac
medication adherence (DiMatteo et al. 2000).
Depressed patients are similarly at risk of reinfarction after AMI (Frasure-Smith
et al. 1993; Strik et al. 2003) and of a recurrent cardiac event and hospital
readmission in the first 12 months after bypass (Connerney et al. 2001; Tully
et al. 2008b). Likewise, numerous studies conducted in the late 1990s and early
2000s demonstrated that post-event depression predicts mortality up to 10 years
later (Barefoot et al. 2000; Frasure-Smith et al. 1999; Welin et al. 2000). Two meta-
analyses published in 2004 confirmed the earlier findings, demonstrating that
depression more than doubles the risk of mortality after a cardiac event (Barth
et al. 2004; van Melle et al. 2004). One meta-analysis included 20 studies of
patients with a range of CHD diagnoses, with the length of follow-up varying
from 3 months to 10 years (Barth et al. 2004). The authors reported an unadjusted
odds ratio of 2.24 between depression and all-cause mortality (Barth et al. 2004).
The other meta-analysis was restricted to studies of post-AMI patients, involved
6,367 patients across 16 cohorts, and endpoints within 2 years (van Melle
et al. 2004). The authors reported odds ratios for all-cause and cardiac mortality
of 2.38 and 2.59, respectively (van Melle et al. 2004). Of note was the finding that
the association between depression and mortality was more pronounced in studies
undertaken prior to 1992, possibly due to improved treatments for CHD which may
simultaneously reduce the negative physiological impact of depression (Carney
et al. 2004; van Melle et al. 2004).
Indeed, the mechanisms whereby depression might adversely affect patients’
outcomes have been well documented and debated. In particular, depression and
CHD share several biological mechanisms. Depressed patients have higher levels of
biomarkers that promote atherosclerosis, reduced heart rate variability suggesting
increased sympathetic activity, increased C-reactive protein, an indicator of
increased inflammatory response, altered serotonergic pathways, and altered plate-
let aggregability (Carney et al. 1988; Lichtman et al. 2008; Sheps and Rozanski
2005; Soufer et al. 2002; Taylor 2010). It has also been postulated that CHD and
depression have common genetic patterns related to serotonin and inflammatory
responses (McCaffery et al. 2006). Together with their behavioral disadvantage,
depressed patients are also socioeconomically disadvantaged through their lower
income and education, manual occupations, and social isolation (Cheok
516 B.M. Murphy et al.
et al. 2003), all of which are associated with increased mortality risk (Brummet
et al. 2003; Case et al. 1992). Importantly though, it has been suggested that more
research is needed on possible mechanisms underlying the relationship between
depression and mortality (Carney et al. 2004).
So what of the role of cardiac disease severity in explaining the association
between post-event depression and mortality? Is it possible that depressed patients
are at increased risk of re-events and earlier death largely because of their advanced
atherosclerosis? Unfortunately, some studies have not adequately controlled for
disease severity in investigating the causal relationship between depression and
death. Only six of the studies included in the meta-analysis by Barth and colleagues
controlled for disease severity, using either ejection fraction (Carney et al. 2003;
Connerney et al. 2001; Welin et al. 2000), Killip class (Frasure-Smith et al. 1993,
1995), or a combined hazard score including ejection fraction and other indicators
of myocardial damage (Barefoot et al. 2000). A further two controlled for previous
AMI (Herrmann et al. 2000; Irvine et al. 1999). Six also controlled variously for
other potential confounders, including age (Barefoot et al. 2000; Carney et al. 2003;
Herrmann et al. 2000; Ladwig et al. 1994), smoking status (Carney et al. 2003;
Frasure-Smith et al. 1993, 1995; Welin et al. 2000), diabetes (Carney et al. 2003),
hypertension (Herrmann et al. 2000; Welin et al. 2000), and hypercholesterolemia
(Welin et al. 2000). In the meta-analysis, the adjusted odds ratio remained signif-
icant but dropped to 1.76 indicating that depression conferred a 75 % increased risk
of death rather than the doubling of risk seen prior to adjustment (Barth et al. 2004).
Nonetheless, depression remained predictive independent of disease severity. The
meta-analysis by van Melle and colleagues involved only bivariate analyses and
thus did not take into account the effects of possible confounders such as disease
severity, diabetes, smoking, and other elevated risk factors. Several authors have
noted the importance of adjusting for confounders, particularly disease severity
(Lane et al. 2005; Murphy et al. 2013). The postulated physiological and biochem-
ical mechanisms for the link between post-event depression and mortality suggest
that it is imperative that disease severity is accounted for in such studies.
Given their poorer prognosis, it is important to identify and support patients who are
anxious or depressed after their cardiac event. This section focuses on strategies for
identifying depressed cardiac patients in particular and discusses the inherent
difficulties in ensuring accurate identification. The treatment of anxious and
depressed patients is discussed in other chapters.
around the time of their cardiac event. Specifically, in 2008, the American Heart
Association recommended that all cardiac patients be screened for depression “in
various settings, including the hospital, physician’s office, clinic, and cardiac reha-
bilitation centre” (Lichtman et al. 2008). Australian guidelines, released in 2013,
similarly recommend routine depression assessments “at first presentation and again
at the next follow-up appointment,” with repeat assessments recommended on a
yearly basis (Colquhoun et al. 2013). The Australian guidelines specifically recom-
mend a screen 2–3 months after the cardiac event (Colquhoun et al. 2013).
Both guidelines recommend using the Patient Health Questionnaire (PHQ) for
screening, with endorsement of either or both of the PHQ-2 items warranting
administration of the full PHQ-9. The PHQ-9 has been shown to have good
sensitivity and specificity when used with cardiac patients (Gilbody et al. 2008).
It can be completed in less than 5 min and yields both a provisional depression
diagnosis and a severity score (Lichtman et al. 2008). The items correspond with
the nine features of depression used in determining a diagnosis of major depressive
disorder (MDD), as outlined in the Diagnostic and Statistical Manual of Mental
Disorders (DSM) (American Psychiatric Association 2013).
A positive screen requires specific action, depending on the severity of depres-
sion indicated. For patients with mild symptoms (PHQ < 10), a “wait and watch”
protocol applies, with rescreening during a subsequent medical appointment
recommended (Colquhoun et al. 2013; Lichtman et al. 2008). For patients with
high scores (PHQ 10), referral for more comprehensive clinical evaluation by a
professional qualified in the diagnosis and management of depression is advised
(Colquhoun et al. 2013; Lichtman et al. 2008).
Since the release of the depression screening guidelines, there has been some debate
as to the appropriateness of depression screening recommendations. Some authors
have noted that there is insufficient evidence that routine depression screening is
beneficial, with no clear evidence of positive patient outcomes (Ski and Thompson
2011; Thombs et al. 2009; Tully and Baker 2012). Indeed, shortly after the
American guidelines were released, a systematic review reported that no trials
had tested the impacts of depression screening on either depression or CHD out-
comes (Thombs et al. 2008). A systematic review of five trials of “screen and refer”
protocols undertaken in the primary care setting concluded that while screening
improves detection and increases treatment, it does not improve depression symp-
toms or patient outcomes (Gilbody et al. 2008). As noted by Thombs and col-
leagues, screening protocols “cannot be advocated until a thorough evaluation of
risk and benefit is completed” (Thombs et al. 2009). Clearly more research on the
impact of depression screening is required.
In addition, it has been noted that there would be significant costs if screening
and referral guidelines were strictly followed, both in terms of burden on the service
system and negative impacts on the patient. In particular, Thombs and Ziegelstein
518 B.M. Murphy et al.
patients, reinforcing the notion of a normal emotional reaction that passes with
time. When patients are reassessed within the first 2 months of their cardiac event,
persistence of depression is quite prevalent: typically, around 60 % (Davis and
Jensen 1988) to 70 % (Lauzon et al. 2003) of patients who are depressed in hospital
remain so at 2 months. However, when patients are reassessed at later timepoints,
depression persistence is less likely. For example, of 30 patients with in-hospital
major depression in Schleifer and colleagues’ study of 190 AMI patients, major
depression persisted in only 11 (36 %) by 3–4 months post-event (Schleifer
et al. 1989). This constitutes less than 6 % of the full baseline sample, a rate similar
to that seen in the general population. In a Norwegian study of 288 AMI patients,
rates of both anxiety and depression at 3, 6, 12, and 18 months post-event were no
higher than seen in the general population (Hanssen et al. 2009). Indeed, in regard
to depressive symptoms, AMI patients showed significantly lower HADS-D scores
than the reference group at the 3- and 12-month assessments (Hanssen et al. 2009).
Some studies have used statistical modeling techniques to track the possible
trajectories of depression in patients after AMI and CABGS. These studies have
similarly shown considerable resolution of in-hospital depressive symptoms. For
example, in an Australian cohort of 184 CABGS patients, all 26 (14 %) patients
who were above threshold for depression in hospital followed a trajectory of
symptom resolution, mostly in the first 2–3 months, and were under threshold by
the 6-month mark (Murphy et al. 2008a). Similarly, in a cohort of 160 AMI and
CABGS patients, all 27 (17 %) who were above threshold in hospital showed
resolution by 6 months (Murphy et al. 2014). In a Netherlands study of 475 AMI
patients, where five depression trajectories were identified, a lower but still sub-
stantial 26 % of patients who were depressed in hospital showed remission of
symptoms over the 12 months after their event (Kaptein et al. 2006). These findings
suggest that, for many patients, in-hospital depressive symptoms resolve during
convalescence. Several authors have agreed that early depressive symptoms remit
spontaneously for many cardiac patients (Hare et al. 2013; Tully and Baker 2012).
At the same time, other patients who are not depressed in hospital go on to
become depressed in the months that follow. For example, in a cohort of
555 CABGS patients, 36 (6.5 %) developed depression in 6 months after discharge,
representing 9 % of initially nondepressed patients (Blumenthal et al. 2003). Sim-
ilarly, in a cohort of 123 CABGS patients who were nondepressed at baseline,
22 (10 %) had developed depression by 6 months (Peterson et al. 2002). Likewise,
in the cohort of 184 CABGS patients, 26 (14 %) who were not depressed in hospital
had become depressed by the 6-month mark, representing 16 % of the initially
nondepressed patients (Murphy et al. 2008a). These findings suggest that between
10 % and 16 % of initially nondepressed CABGS patients go on to develop
depression by 6 months after surgery.
It is useful to overlay a trauma framework when considering trajectories of
depressive symptoms after an acute cardiac event. While much of the early trauma
research focused on responses to external events such as war, terrorism, accident,
assault, and natural disasters, more recent studies have considered acute health
crises as “traumatic” events (Tedstone and Tarrier 2003). Traumatic events are
Anxiety, Depression, and Psychological Adjustment After an Acute Cardiac. . . 521
defined as events that are out of the ordinary, leave people with a perceived lack of
control or sense of powerlessness, and create long-lasting problems leading to a
sense of hopelessness (Cavalcanti-Ribeiro et al. 2012). Some of the common
psychological problems associated with traumatic events are intrusive thoughts
and memories, flashbacks, hypervigilance, mental and behavioral avoidance, sad-
ness, and sleep problems (Joseph 2011). Depending upon the nature of the stressor,
its intensity, severity, and duration of suffering or threat, psychological responses
such as anxiety, fear, guilt, anger, and irritability may be present for a long time
after the threat has receded (Tedeschi and Calhoun 2004). Thoughts and feelings
are affected, especially if the event was sudden (such as an AMI), with initial
reactions of shock, psychological numbness, disbelief, anger, fear, and worry.
Anxiety is one of the most commonly reported responses and tends to be associated
with a perception of significant threat to life or health (Tedeschi and Calhoun 1995).
Depressive symptoms – including sadness, low energy, and decreased interest in
life – are also common and tend to be associated with the perception of significant
loss (Hodgkinson and Stewart 1991). It is not necessarily the type of event but
rather an individual’s perception of it and response to it in the aftermath that renders
it as stressful or traumatic.
According to trauma theory, there are four typical responses to a traumatic event
such as an acute cardiac event or, indeed, other life-threatening illnesses or unex-
pected diagnosis of disease. First, there are those – such as the patients described
earlier – “who recover.” Second, there are those with “chronic” symptoms, whose
early depression symptoms persist beyond the period of physical recovery. Third,
there are those with “delayed” symptoms, as outlined above, which do not appear
until further into the convalescence period. And finally, there are “resilient” patients
who do not experience depressive symptoms after their acute event. These four
typical responses to trauma are depicted in Fig. 1.
There is some evidence in the cardiac literature that only patients whose
symptoms are present beyond initial convalescence after the acute event – those
with either chronic or delayed symptoms – are at increased mortality risk
(Blumenthal et al. 2003; Murphy et al. 2008a, b; Tully and Baker 2012). In the
US study of CABGS patients, those whose in-hospital depression resolved in the
first 6 months had a 5-year mortality risk of 10 %, identical to that of nondepressed
patients, whereas those whose in-hospital depression persisted had almost twice
that mortality risk (Blumenthal et al. 2003). Patients with “new” depression had an
intermediate mortality risk of 14 % (Blumenthal et al. 2003). In a 3-year follow-up
of 124 CABGS patients, the rates of re-events and death were significantly higher in
those with “new” depression at 6 months: the 3-year re-event/mortality rate was
14 % in those who developed “new” depression compared to 3 % in those who
remained nondepressed over the 6-month post-event period (Peterson et al. 2002).
In a 12-year follow-up of 180 Australian AMI and CABGS patients, there was a
high 64 % mortality among those whose in-hospital depression persisted or wors-
ened and a low 14 % mortality rate among those whose in-hospital symptoms
resolved (Murphy et al. 2013). Indeed, the death rate among those with remitted
depression was lower than that among patients who were nondepressed in hospital
522 B.M. Murphy et al.
0
In hospital 6 months
Resilient Recovered
Delayed Chronic
and remained so during convalescence (Murphy et al. 2013). These findings suggest
that in-hospital depressive symptoms do not necessitate a poor prognosis and
further point to the probability of misclassification of “at-risk” patients if identifi-
cation is based purely on an in-hospital assessment.
(Cheok et al. 2003; Gallagher et al. 2003; Mallik et al. 2005; Strik et al. 2004)
consistently show higher rates of depression than males and older patients, respec-
tively. Social isolation, lack of social support, and living alone also increase the risk
of post-event depression (Burker et al. 1995; Cheok et al. 2003; Frasure-Smith
et al. 2000). Unemployment also confers increased risk (Cheok et al. 2003;
Gallagher et al. 2003), as does poor physical health and lower physical functioning
(Cheok et al. 2003; Mallik et al. 2005), the presence of comorbidities (Mallik
et al. 2005; Watkins et al. 2003), and other associated conditions such as diabetes
(Frasure-Smith et al. 1999, 2000). While relatively few studies have identified
predictors of post-event anxiety, female gender (Duits et al. 1998; Moser
et al. 2010) and low education (Moser et al. 2010) have been identified as significant
risk factors. There is some evidence that AMI patients experience more anxiety and
depression than CABGS patients in early convalescence (Westin et al. 1997),
although there is no evidence that this difference is sustained (Moser et al. 2010;
Westin et al. 1997).
Some studies have specifically focused on the identification of red flags for
persistent, worsening, or new depressive symptoms in the post-event period, as a
means of identifying patients at high risk of chronic or delayed depression (Murphy
et al. 2008a, 2014). Key red flags include having a history of depression or anxiety,
younger age (aged <55), living alone or other indicators of social isolation, poorer
self-rated health, financial difficulties, diabetes and other comorbid conditions,
smoking, and compounded loss (Murphy et al. 2008a, c, 2014). Key red flags for
increased depression risk are shown in Box 2. Several authors have similarly
emphasized the importance of the patients’ mental health history as a strong
indicator of depression risk post-event (Martens et al. 2008; Spijkerman
et al. 2005). Rather than relying on depression screen results in isolation, health
practitioners could be guided by the presence or absence of these red flags as to
whether a particular patient is at heightened risk of a poor depression trajectory.
Patients who screen positive and also present with specific red flags could be
stratified for more rigorous follow-up, rescreening, referral, and treatment. Simul-
taneously patients who initially screen negative but who present with red flags for
increased depression risk could be targeted for repeat screening.
What are the implications of these findings in terms of clinical practice? Given that
early distress resolves for many patients, patients who present with early symptoms
can be reassured that their distress, worry, and other changes in mood and behaviors
are likely to be transient and can be considered part of a “normal adjustment
response.” Normalizing common emotional reactions to a cardiac event may well
enhance psychological recovery and warrant empirical investigation. Already there
is some evidence that it is desired by patients. A study of 160 Australian cardiac
patients demonstrated that over 80 % want to be told about what to expect
emotionally after they leave hospital (Murphy et al. 2015). The symptoms com-
monly experienced by patients after the event – low or fluctuating mood, tearful-
ness, loss of pleasure in usual activities, sleep disturbance, reduced self-esteem,
changes in appetite and sex drive, concerns about role changes, and worries about
the future (Goble et al. 1989; Higgins et al. 2007) – are typical of a normal grief
response to an experience of loss or trauma (Goble et al. 1989). “Prevention and
management depend on the patient’s learning that a depressed mood is a normal
temporary response to the illness. . . and that recovery is the rule” (Goble
et al. 1989).
Nonetheless, identification of depressed patients is essential. Given that one in
five patients goes on to experience serious depression and is thereby at increased
morbidity and mortality risk, patients also need to be alerted that depression is
possible. If patients are alerted to this risk early on, before hospital discharge, they
may be better placed to identify depressive symptoms if and when they arise. Again
this hypothesis warrants empirical investigation.
Health professionals can be guided by both the trajectories of the symptoms,
based on repeat screens, and the presence of other risk indicators or red flags as to
whether a particular patient is likely to be experiencing a normal emotional reaction
or is, indeed, likely to be depressed. Stratification of high-risk patients toward more
rigorous follow-up, referral, and treatment may improve patient outcomes without
unduly burdening the health system and warrants further investigation.
The importance of repeat screening cannot be overemphasized. Health profes-
sionals across a range of healthcare settings need to be equipped to undertake
depression assessment. These include cardiologists, who see the patient on multiple
occasions from the time of the event, physicians and practice nurses working in
general practice, and nurses and other health professionals working both on the
hospital ward and in cardiac rehabilitation. Approaches might include routine
screening for all presenting patients or, in some settings, targeted screening of
high-risk patients.
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Quality of Life in Survivors of Myocardial
Infarction
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 534
Introducing the Concept of Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535
Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 537
Measuring HRQoL in MI Survivors: Methodological Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
Generic and Disease-Specific Instrument for HRQoL Measurement . . . . . . . . . . . . . . . . . . . . . . 538
HRQoL Scale Versus Single-Item Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538
Procedure of HRQoL Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539
What Do We Know About Quality of Life After MI? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
Level of HRQoL After MI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 540
Changes over Time in HRQoL After MI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Clinical and Sociodemographic Predictors of HRQoL After MI . . . . . . . . . . . . . . . . . . . . . . . . . . 541
Positive Psychosocial Predictors of HRQoL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 542
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546
Abstract
The concepts of quality of life and health-related quality of life (HRQoL) are
wildly used in literature but lack agreed formal definitions. It is however broadly
accepted that they are complex, multidimensional, and dynamic constructs,
which should be assessed on the basis of positive and negative indicators. The term
HRQoL is used to clarify the health-disease context of the analyzed QoL. Both
generic and disease-specific instruments are used for HRQoL measurement.
Results of the studies on the level and changes in HRQoL after MI are
inconsistent. Some studies show HRQoL as being minimally affected by MI,
while others indicate major reduction in at least some of its dimensions. More-
over, minor fluctuations to significant changes in HRQoL’s different dimensions
are reported. The dynamic of these changes varies depending on the period since
an MI and between different dimensions of HRQoL.
A number of clinical, sociodemographic, and psychosocial characteristics are
recognized as predictors of HRQoL in MI survivors. Among sociodemographic
characteristics, age, gender, and education are of a special interest with higher
education predicting better HRQoL, but age and gender’s role being unclear.
Among psychosocial resources, e.g., self-esteem and various social resources
were recognized as strong predictors of HRQoL, with higher levels of psycho-
social resources predicting better HRQoL.
More work still needs to be performed to fully understand the dynamics and
complexity of quality of life in the context of myocardial infarction and CVD in
general. But the results support a need for a comprehensive and patient-centered
medical practice.
Keywords
Quality of life • Health-related quality of life • Psychosocial resources • Self-
esteem • Social cohesion • Social support • General life satisfaction • Myocardial
infarction
Introduction
The concept of quality of life (QoL) was rarely mentioned in the literature until the
twentieth century (Fayers and Machin 2007). Though Shaw, an early commentator
on the subject, noted in 1900 that “happiness” could be “sacrificed” for quality of
life: “Life at its noblest leaves mere happiness far behind; and indeed cannot endure
it . . .Happiness is not the object of life: life has no object: it is an end in itself; and
courage consists in the readiness to sacrifice happiness for an intenser quality of
life” (as cited in Fayers and Machin 2007, p. 6). As Fayers and Machin (2007)
suggest, this note made by Shaw in 1900 indicates that by his time, “quality of life”
had become a familiar term that did not require further explanation. In fact, some
modern investigators argue that, at least in the Western world, most people are
generally familiar with the term “quality of life” and intuitively understand what it
comprises, and thus no formal definition is needed (Fayers and Machin 2007). Such
approach, even though satisfactory for a general deliberation, seems insufficient for
the goals of scientific research and clinical practice. Thus, numerous attempts
across many disciplines (not only medical, health and social sciences, or philosophy
but also economy, geography, literature, architecture, banking, or advertising) were
made to clarify the concept of quality of life (Bowling 2001).
In medical, health, and health-related social sciences, quality of life has been
defined as, e.g., the degree of human needs satisfaction (Hörnquist 1982), the sum
536 M.A. Lazarewicz et al.
of those aspects of life, and human function considered essential for living fully
(Mor 1987), “. . .the degree to which a person enjoys the important possibilities of
his or her life in the area of . . .being [“who one is” on the physical, psychological,
and spiritual components], . . .belonging [the fit between a person and his or her
physical, social, and community environments] . . .and becoming [whether one
achieves one’s personal goals, hopes, and aspirations]” (Raphael et al. 2001,
p. 181). Finally, according to WHO quality of life is “an individual’s perception
of their position in life in context of the culture and value system in which they live
and in relation to their goals, expectations, standard, and concerns” (1995, p. 1405).
QoL has been referred to or used interchangeably with such terms as “personal
well-being”, “health status” (Bergner 1987), or “life satisfaction” (Campbell 1981).
When operationalized, its measurements range from assessment of functional
ability, physical and social activity, or activities of daily living (historically
assessed by healthcare staff) through physical and psychological symptoms check-
lists, pain, sexual performance, and impact of illness to emotional, role, social, and
cognitive functioning and self-assessment of global life satisfaction (Fayers and
Machin 2007).
The above presentation of a variety of definitions, terms, and measurements
serves to highlight the lack of agreement within the literature regarding what
exactly quality of life is: what are its indicators and what is its true nature. It is
often addressed as a vague or amorphous concept (Fayers and Machin 2007).
Nevertheless, even in the absence of a formally agreed definition of QoL, some
common trends in its conceptualization and operationalization are observed. Ever
since the review of QoL concepts, formulation of the definition and suggestions for
ways of assessment of QoL has been published by the World Health Organization
Quality Of Life Assessment Group (WHO 1995, the definition was already cited
above), and there is a consensus between the medical, health, and social sciences’
researchers about some of the characteristics of this construct. It is nowadays
broadly accepted that QoL:
Preparing for HRQoL measurement both for clinical practice and for research, it is
important to begin with a clear definition of HRQoL and its operationalization. The
next step is a choice (or preparation) of a questionnaire that will satisfy specific
psychometric standards and perform best in providing the most appropriate
and required information. Methods of developing and testing new QoL instruments
and standards for adequate psychometric properties of the inventories are
broadly described in the literature and will not be discussed in this chapter (see,
e.g., Fayers and Machin 2007). When selecting the inventory most appropriate for
the particular aim, one may choose a generic instrument, a disease-specific
instrument.
Generic HRQoL instruments are intended for general use and are applicable for
healthy and sick people and for patients with various conditions. Thus, they are a
good choice when, e.g., MI survivors’ QoL is to be compared with healthy people’s
QoL. Generic instruments are usually multidimensional (e.g., they measure phys-
ical, social, and emotional functioning as well as enquire about overall QoL). The
examples of reliable and valid generic HRQoL instruments include the Nottingham
Health Profile (NHP) developed by Hunt et al. (1981), the Medical Outcomes Study
36-Item Short Form (SF-36) developed by Ware et al. (1993), EuroQoL (EQ-5D)
by Brooks and EuroQoL Group (1996), or WHOQOL-100 and WHOQOL-BREF
developed by WHOQOL Group (1998). All of the above have a number of cultural
and language adaptations allowing transcultural comparisons.
Disease-specific HRQoL instruments assess the influence of a particular disease
or condition on QOL. When compared to generic instruments, they are more
clinically sensitive, potentially more responsive in detecting change, and are better
discriminators of differences between subgroups within a disease category (Wiebe
et al. 2003). However, they will not allow comparisons with a control group of
healthy people or patients with another condition. Examples of instruments
designed to examine specifically the impact of angina or MI on QoL include: the
Seattle Angina Questionnaire (Spertus et al. 1995), the MacNew questionnaire
(Dixon et al. 2002), or the Myocardial Infarction Dimensional Assessment Scale
(Thompson et al. 2002). The abovementioned questionnaires were broadly
discussed by Thompson and Yu (2003).
Classical test theory has generally been fairly consistent in indicating that single
items are at a relative disadvantage to multi-item measures, as more items will
allow the random error of the measurement to be ruled out and therefore the results
Quality of Life in Survivors of Myocardial Infarction 539
to be more reliable and precise (Gardner et al. 1998). Single-item measures of QoL
are often thought to generate less reliable responses over time (Fayers and Machin
2007), to be less responsive to specific treatment effects (Bernhard et al. 2001), and,
generally, to provide less information about participants’ QoL than multi-item
questionnaires. The use of single-item measures also limits or at least complicates
some of the analyses, as not all of the parametric tests have nonparametric equiv-
alents. However, single-item instruments also have a number of advantages, being
the simplest approach to measure QoL (Boer et al. 2004), being easier to administer
(Fayers and Machin 2007), and being less burdensome to participants than multi-
item measures (Cunny and Perri 1991). This simplicity and ease of use may prevent
missing data and result in operational efficiency such as data entry and data
analyses (Boer et al. 2004). Generally, valid, reliable, and responsive single-item
questions are of great interest for use in clinical setting (especially when the
participants are severely ill, have concentration problems and poor eyesight, are
in pain, etc.) or when a broad set of variables are to be measured at the same time as
it is, for instance, in population-based health surveys. Single-item self-rated health
measures were used in a number of studies and were found to be very good
predictors of future health, morbidity, mortality, and health service attendance
(e.g., Idler and Benjamini 1997).
Several single-item general life satisfaction or global QoL measures were
previously used in clinical and population-based studies and were compared to
multi-item questionnaires. Basing on such comparisons, they were found to be
instruments with good validity and reliability, moderate estimates of
distribution-based responsiveness, and good anchor-based responsiveness
(e.g., Boer et al. 2004, where a visual analog scale for global quality of life
was used and compared to Medical Outcome Studies SF-20 and the Rotterdam
Symptom Checklist, or Kuppens et al. 2008, where results of single-item mea-
sures of global life satisfaction and Satisfaction With Life Scale were compared
for 37 countries).
(10 years) perspective, and it was not a significant predictor of cognitive HRQoL
(general life satisfaction) or emotional HRQoL (anxiety, depression, and positive
affect) (Lazarewicz et al. 2014, unpublished thesis). To sum up, the results differed
depending on the investigated indicators of HRQoL and time perspective included
in the analyses.
Results of the studies also show inconsistency as to whether and how HRQoL
changes over time after MI. Minor fluctuations (Eriksson et al. 2012) to significant
changes in its different dimensions were reported (Kristofferzon et al. 2005). Also,
reports of both deterioration and improvement in HRQoL over time can be found in
the literature. Simpson and Pilote (2003) concluded that physical HRQoL (physical
capacity, symptoms, functional status, and general health perceptions) declined the
most after MI. However, the majority of these HRQoL domains “improved to
normal levels with time” (p. 507) (the studies reviewed by Simpson and Pilote
followed the patients since an MI up to max. 5 years after it). Furthermore, a gain
over time was reported in such dimensions as role fulfillment, pursuit of normal and
social activities (Lacey and Walters 2003), physical functioning, vitality, or social
functioning (Kristofferzon et al. 2005).
These results were also confirmed in the authors’ studies based on the HUNT
data (Lazarewicz et al. 2014, unpublished thesis). In the already quoted study where
changes over a period of 20 years in male MI survivors and MI-free men HRQoL
were analyzed, the somatic HRQoL decreased over time in both samples, while
general life satisfaction increased over time. In the case of MI survivors,
this increase was especially significant over the period of the first 10 years of
the study and present but insignificant in the later period. This suggests that
the experience of an MI may have a delayed negative effect on general life
satisfaction, suppressing its increase after a longer (over 20 years) period since an
MI (while such increase in general life satisfaction was observed in MI-free
participants).
Summing up, the results of the reviewed and own studies suggest that the
changes in HRQoL after MI are dynamic and their direction (increase or deterio-
ration) depends on the time since an MI experience (Pettersen et al. 2008a; Simpson
and Pilote 2003) and the investigated dimension of HRQoL.
Apart from time since MI, previous studies report several clinical and
sociodemographic characteristics that influence HRQoL in MI survivors. Among
the clinical factors, the following are often found to predict lower future HRQoL of
MI survivors: previous (additional) MI (Pettersen et al. 2008a), higher left ventric-
ular ejection fraction (Pettersen et al. 2008b), high number of atherosclerosis risk
542 M.A. Lazarewicz et al.
The majority of the studies reviewed above concentrate on a search for factors
responsible for the deterioration of HRQoL. A search for factors that protect
HRQoL from deterioration and stimulate its increase has only started recently but
attract an increasing amount of attention. Rapidly growing interest in this area of
health research reflects a growing popularity of salutogenic approach (Antonovsky
1987) and of positive psychology in general (e.g., Seligman and Csikszentmihalyi
2000; Snyder and Lopez 2005). An interest in HRQoL itself was a first step toward
this more positive approach in health science. An interest in the HRQoL’ positive
determinants seems to be an important next step.
Investigation in the area of positive determinants of HRQoL and adaptation to
chronic disease has mainly concentrated on psychological and social characteris-
tics, often labeled as “psychosocial resources.” Psychosocial resources are defined
as “individual differences and social relationships that have beneficial effects on
Quality of Life in Survivors of Myocardial Infarction 543
mental and physical health outcomes” (Taylor and Broffman 2011, p. 1), on health
and quality of life.
Both psychological and social factors can impact the way in which people
approach life circumstances (e.g., a stressful situation such as a somatic disease),
what in turn can impact their well-being and HRQoL. Such approach stays in line
with, broadly discussed in the literature, Lazarus and Folkman’s (1984) cognitive
and transactional model of stress, in which personal and social coping resources are
conceptualized as elements of the theoretical model of stress. A number of positive
psychological resources, e.g., self-esteem (Rosenberg 1965), self-efficacy (Bandura
1997), dispositional optimism (Scheier and Carver 1985), and sense of coherence
(Antonovsky 1987), and a number of aspects of social resources experienced within
family, friends, or broader community groups, conceptualized as, e.g., social
cohesion, social support, or sense of community (Schwarzer and Leppin 1991),
were suggested and investigated in the literature. Including such factors in the
studies of MI survivors was indicated as being of a great importance (Wrzesniewski
and Wlodarczyk 2012) and an increased number of studies concentrated on selected
resources and HRQoL, also in the context of cardiac patients.
For example, higher self-esteem was associated with better physical and psycho-
social recovery after CABG (Artinian et al. 1993). It was also a significant predictor
of quality of life 1–2 years after such surgery (Dantas et al. 2002). In a study, that
focused on older adults (over 60 years old) with CVD, higher self-esteem was
significantly associated with subsequent maintenance or improvement of physical
and psychosocial function over a 12-months period, especially among women (it was
a stronger predictor of physical and psychosocial functioning than demographic and
clinical factors) (Forthofer et al. 2001). In a cross-sectional study investigating a
group of 96 female MI survivors, higher self-esteem significantly predicted higher
multidimensional QoL (four dimensions were specified: health and functioning,
socioeconomics, psychological and/or spiritual, and family life) (Wingate 1995).
Good social resources were also found to have a positive effect on various
aspects of HRQoL in cardiac patients (Bennett et al. 2001; Emery et al. 2004).
Lack of social support after a coronary event was found to be related to poorer
physical and mental outcome both in men (Conn et al. 1991) and in women (Lett
et al. 2005). However, the results are not fully consistent when gender and age
differences are considered (e.g., Emery et al. 2004). The absence of a spouse,
partner, or confidant was often associated with greater depression, and this relation
was found particularly strong for men (e.g., Frasure-Smith et al. 1999). In other
study (where other measures were used), lower social support was also associated
with more depressive symptoms and worse health status over the first year of acute
MI recovery, but it was particularly significant for women (Leifheit-Limson
et al. 2010).
The authors’ research on the already quoted HUNT population (n = 55,253)
(Lazarewicz et al. 2014, unpublished thesis) confirms a significant predictive role of
self-esteem (as an example of a psychological resource) and social cohesion (as an
example of social resource) for somatic, cognitive, and emotional dimensions of MI
survivors’ HRQoL both in cross-sectional and 10-year perspective.
544 M.A. Lazarewicz et al.
Clinical Implications
Conclusion
The concept of quality of life is wildly used in the literature but lacks agreed formal
definition. However, most of its recent operationalizations stay in line with the
WHO QoL Assessment Group’s definition of QoL, which states that it is “an
Quality of Life in Survivors of Myocardial Infarction 545
individual’s perception of their position in life in context of the culture and value
system in which they live and in relation to their goals, expectations, standards, and
concerns” (1995, p. 1405). It is complex and multidimensional dynamic construct,
which should be assessed on the basis of positive and negative subjective indicators.
The term health-related quality of life is often used to clarify the health-disease
context of the analyzed QoL.
Prior research has documented profound negative effects of poor HRQoL on
morbidity and mortality in general population and in cardiac patients, and numer-
ous studies indicate that in many groups of cardiac patients, HRQoL is significantly
diminished. However, it is unclear in the case of MI survivors. Some studies show
HRQoL as being only minimally affected by an experience of MI, while others
indicate major reduction in at least some of its dimensions both in short- and longer-
term perspective. Results of the studies also show inconsistencies as to whether and
how HRQoL changes over time after MI: minor fluctuations to significant changes
in its different dimensions were reported. The dynamic of these changes probably
varies depending on the period since an MI (after initial deterioration, there is an
improvement) and between different dimensions of HRQoL.
A number of clinical and sociodemographic characteristics are recognized as
predictors of HRQoL in MI survivors. Among sociodemographic characteristics,
age, gender, and education are of a special interest with higher education predicting
better HRQoL, but age and gender’s role being unclear. However, in most studies,
higher age and male gender predict better HRQoL, and a gradual improvement in
HRQoL (often observed after its initial deterioration after MI) seems to happen
more slowly in female than in male MI survivors.
A growing interest in the importance of psychosocial resources for HRQoL in
general population and in MI survivors is also observed. Among others, self-esteem
and various social resources were recognized as strong predictors of HRQoL (often
stronger than clinical and demographic factors), with higher levels of psychosocial
resources predicting better health and quality of life outcomes.
However, more work still needs to be performed to fully understand the dynam-
ics and complexity of quality of life in the context of myocardial infarction and
CVD in general. Due to a prior concentration mainly on pathology and prevention
of loss, especially little is known about the positive correlates and determinants of
health-related quality of life. Moreover, results of many studies should be
interpreted or generalized with caution, because they often had some methodolog-
ical limitations. They were mainly cross-sectional. Prospective studies often cov-
ered only a short period of time (usually a couple of month up to a year after an MI).
Moreover, most of the reviewed studies concentrate predominantly on middle age
male populations, with female and elderly MI patients often not being included or
being underrepresented. The studies recognizing a need for investigation of HRQoL
in female and elderly MI survivors often studied only women (or older patients),
making gender and age comparisons impossible. Only some studies had a control
group which allowed to check if recognized relations or differences were indeed
specific for MI survivors. Furthermore, in many of the reviewed studies, QoL or
HRQoL was not clearly defined, or a construct similar but not identical to HRQoL
546 M.A. Lazarewicz et al.
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Psychological Consultation for Patients
with Implantable Cardioverter
Defibrillator: Confounding Challenges
of Cardiac Disease, Technology,
and the Patient Experience
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 552
Medical Background and the Biopsychosocial Model for ICD Patients . . . . . . . . . . . . . . . . . . . . . . 553
Psychological Functioning and the ICD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 554
Demographic and Patient Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Special Populations and Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 557
Assessment Tools . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 562
Abstract
Sudden cardiac arrest is a common and often lethal event, claiming roughly
400,000 lives annually in the United States alone. Implantable cardioverter
defibrillators (ICDs) represent a significant technological advance in the medical
arena and are the best available intervention for sudden cardiac arrest and
subsequent prevention of sudden cardiac death. Over the last two decades,
research has increasingly focused on understanding how living with an ICD
presents unique and serious psychological challenges for many patients benefit-
ing from this lifesaving technology. Employing a biopsychosocial model in
caring for these patients’ psychological health helps address relevant factors
that can contribute to their psychologically distressed presentation, including
cardiac disease burden, ICD treatment delivery (i.e., shock), psychiatric (s)
disorder or symptoms, health behaviors, and disruption of day-to-day life or
social functioning. This chapter highlights known, common psychological risks
for ICD patients, which include depression, anxiety, and compromised quality of
life. It further explores some key considerations or groups that are associated
with risk for psychological distress, such as pediatric ICD patients, devices
under recall, and end-of-life issues. Several relevant assessment measures are
provided to assist providers in identifying which psychological risks are realities
for each particular patient. In total, this information is designed to lend knowl-
edge and confidence to consulting mental health providers, leaving them well
equipped to deliver state-of-the-art assessment of ICD patients – a medically
complex, and often psychologically distressed, group of individuals.
Keywords
Anxiety • Depression • Device acceptance • Device technology • Implantable
cardioverter defibrillator • Post-traumatic stress disorder • Quality of life • Shock
anxiety
Introduction
Sudden cardiac arrest remains the most significant life threat for adults in the developed
world with as many as 400,000 Americans experiencing a cardiac arrest each year
(Go et al. 2014). The implantable cardioverter defibrillator (ICD) has evolved since its
approval by the US Food and Drug Administration (FDA) in 1988 (precursory
implantable defibrillators were first approved in 1985) to be the best available inter-
vention for preventing sudden cardiac death. Large trials have shown greater benefit
from the ICD in regard to mortality when compared to medications (Bardy et al. 2005;
Moss et al. 2002). Subsequent to increased sophistication and effectiveness of ICDs,
more patients are surviving potentially lethal arrhythmias and living longer. In the
wake of optimized patient survival, psychological hazards that accompany living with
an ICD readily emerged. In other words, although ICDs provide protection in terms of
quantity of life (i.e., years of survival), they also confer risk of psychological distress
and compromised quality of life for patients if patient centric approaches are not
engaged. Further, the presence of the underlying cardiac disease substrate confounds
clear attributions and targets of psychological treatment. Both the disease and treatment
can be challenging to manage for patients. Modern health psychology can provide
strategies for ICD patients as they simultaneously cope with the potential for life-
threatening arrhythmias, cardiac disease management, and psychological challenges.
The purpose of the current chapter is to review the significant medical and psychosocial
factors to be considered in the psychological consultation with patients with ICDs.
Psychological Consultation for Patients with Implantable Cardioverter. . . 553
Depression and Anxiety. Patients with cardiac illness, or other chronic health
conditions, experience a significant level of distress above and beyond the level
that is seen in their relatively healthy counterparts. The prevalence of these issues
has been shown to be upward of 15–20 % in cardiac illness (see Rozanski
et al. 2005). By comparison, psychological distress in ICD patients is much higher.
There is a general consensus across studies that psychological distress is present in
25–33 % of patients with ICDs. A recent, systematic review specifically of anxiety
and depression in ICD patients demonstrated that approximately 20 % of ICD
patients are subject to clinically significant distress in point prevalence studies
(Magyar-Russell et al. 2011). More specifically, between 11 % and 28 % had either
an anxiety or depressive disorder when structured interviews were used. Estimates
ranged more broadly for anxiety (i.e., 8–63 %) and depression (5–41 %) when
questionnaires were the mode of assessment. Regardless of the specific study cited,
the consulting psychologist can have a relatively high index of suspicion diagnos-
tically for anxiety and depression in ICD patients.
Longitudinal assessment of psychological functioning has also been studied but
definitive conclusions are difficult to draw. For example, when attempting to
characterize the trajectories of distress in ICD patients over the first 1.5 years
after implantation, type D personality (tendency toward high negative affect and
social inhibition) and anxiety sensitivity predicted upward trends in distress (van
den Broek et al. 2014). The persistence of anxiety has been demonstrated (Pedersen
et al. 2011a), but some evidence also shows reductions in anxiety in ICD patients
over time (Lang et al. 2014; Pedersen et al. 2009a). For depression, symptoms may
decrease over time in ICD patients (Pedersen et al. 2009a); however, there appears
to be a great deal of individual variance, with some patients who maintain psycho-
logical distress within the first months or years after implantation (e.g., Pedersen
et al. 2011a, b; Suzuki et al. 2010). A number of factors have been shown to
influence anxiety, depression, or a mixture thereof, including type D personality,
disease severity, comorbidity burden, and ICD shock (Hoogwegt et al. 2013; Jacq
et al. 2009; Pedersen et al. 2009a; Schulz et al. 2013).
Post-traumatic Stress Disorder. PTSD has garnered increasing attention
among the anxiety disorders (Sears et al. 2011). Initial research indicated that
PTSD was prevalent and influential on survival (Ladwig et al. 2008). Significant
Psychological Consultation for Patients with Implantable Cardioverter. . . 555
levels of PTSD symptoms at the time of implantation have been found to be just
over 20 %, and these rates were somewhat reduced at 6- (12 %) and 12-month
(13 %) follow-up intervals (Kapa et al. 2010). There are likely two factors that
have caused focus on PTSD. First, for those receiving ICDs as secondary
prevention, the index event that precipitated implantation (e.g., sudden cardiac
arrest) is often traumatic for patients. Second, the experience of ICD shock
itself can be traumatic and trigger related symptoms of anxiety, hypervigilance,
avoidance of feared activities, and other hallmark symptoms that can be con-
ceptualized within the framework of PTSD. The confound between disease
process and diagnosis, rather than shock itself, may be the more prevalent
contributor to PTSD symptoms, as shock has at times failed to be linked to
PTSD symptoms (Habibovic et al. 2012; Ladwig et al. 2008). Recently, shock
anxiety (specific fears of ICD shocks) was associated with PTSD symptoms,
which lends credence to the possibility that an acute stress reaction to shock, not
simply experiencing shock, could be a key ingredient in development of PTSD
(Morken et al. 2014).
Longitudinal research examining predictors of PTSD at 18-month
postimplantation in a Dutch sample of ICD patients found that type D personality
and general baseline anxiety were significant predictors, whereas shock was not a
significant predictor (Habibovic et al. 2012). Prospective research has attempted to
describe two sets of predictors of PTSD, one relevant to predicting PTSD at the
time of implantation and another relevant to predicting PTSD at follow-up (von
Känel et al. 2011). Female sex, depression, and dissociation around the time of
trauma predicted PTSD symptoms at the time of implantation, whereas greater
PTSD symptoms at implantation, alexithymia, and experiencing five or more
shocks predicted PTSD at follow-up. The authors also reported that PTSD symp-
toms increased in prevalence from the time of implantation to follow-up, suggesting
that chronicity may be a germane issue when considering PTSD in ICD patients.
Type D Personality. Type D personality research has increased in popularity
over recent years as research teams have set out to understand the ICD patient
experience. Some estimates have placed the prevalence of type D personality
around 21–23 % in ICD patients (e.g., Pedersen et al. 2008, 2010). Being a
personality factor, the focus has not been on how ICDs change one’s personality,
but rather how one’s personality affects the ICD patient experience. Patients with
type D personality have shown a range of poorer outcomes, including more anxiety
and depression (Habivovic et al. 2012; Pedersen et al. 2011a, 2013a). It may
represent a more macro level of distress overall, or susceptibility to distress from
the potential stressors living with an ICD can present and subsequently experience
increased psychological morbidity. However, some recent reports have revealed
difficulty with the primary measure of type D personality (see Suls 2014). None-
theless, the existing research base employing type D constructs in ICD patient
research is significant and highlights the consideration of psychological factors in
patient care.
Quality of Life. Significant large-scale randomized studies have indicated that
the quality of life of ICD patients is at least equal to, if not better than, the quality of
556 A. Whited et al.
life in patients treated with anti-arrhythmic drug therapy (e.g., Irvine et al. 2002;
Schron et al. 2002; Sears et al. 2009a). The importance of this conclusion cannot be
overstated because patients often have to make the decision about receiving an ICD
in short order. ICDs have a known survival advantage so patients are asked to
consider the quality of life impact likely as the second most significant consider-
ation. These data indicate that the ICD becomes an increasingly more desirable
choice as long as the downsides of treatment with an ICD could be mitigated. The
experience of ICD shock is often faulted, and initial research consistently focused
on that theme. A cluster of studies has shown a linear relationship between
frequency of ICD shocks and psychological distress (e.g., Passman et al. 2007;
van den Broek et al. 2008), whereas another group of studies has failed to show an
association between shock and psychological distress (e.g., Piotrowicz et al. 2007;
Crössmann et al. 2007). Overall, the evidence suggests that for patients who meet
the threshold of five or more shocks, this is the cut point where detriments in quality
of life tend to be most reliably shown (e.g., de Ornelas Maia et al. 2013; Irvine
et al. 2002; Passman et al. 2007).
A number of intuitive factors have been shown to be negatively related to quality
of life in ICD patients, such as anxiety and depression (e.g., Dickerson et al. 2010;
Wong et al. 2014; Hallas et al. 2010), whereas optimism and positive health
expectations may be protective for quality of life (Sears et al. 2004). The reason
for implantation of an ICD has also been consistently identified in the clinical
context as a potentially important factor in the quality of life outcome. Debate
persisted for some time regarding whether primary prevention patients’ quality of
life was impacted differently than that of patients receiving ICDs for secondary
prevention. However, a review of the evidence concluded that patients receiving
ICDs for either indication were not significantly different in regard to quality of life
outcomes (Pedersen et al. 2009b).
Type of device has been related to quality of life outcomes as well. A meta-
analysis delineated quality of life outcomes in patients with ICDs versus CRT-D
devices. CRT-D devices provide continual treatment for patients with heart failure
via biventricular pacing in addition to acute provision of shock as needed, the
former being a unique feature of CRT-D devices that is not offered by ICDs. The
meta-analysis showed that patients with CRT-D devices, particularly with moderate
to severe heart failure, had significantly better reports of quality of life than ICD
patients (Chen et al. 2012). However, as a study published around the time of that
review indicates, there may be subtleties when understanding differences in quality
of life based on device type. Ford and colleagues showed that patients with CRT-D
devices reported poorer physical and disease-specific quality of life compared to
ICD patients; but CRT-D therapy was associated with improved mental quality of
life over time, a finding not shared in the subset of ICD-only patients in that study
(Ford et al. 2014). Therefore, a range of factors impact quality of life for ICD
patients, so it is important to consider both medical and psychological contributors
when understanding the degree of functional impairment ICD patients are
experiencing. Understanding how a patient’s quality of life is impacted by living
with a device is a paramount task when embracing the biopsychosocial model
Psychological Consultation for Patients with Implantable Cardioverter. . . 557
Stratifying risk based on sex and age has been addressed by a wide range of studies.
Although the evidence is mixed to a degree (see Bostwick and Sola 2007), many
studies demonstrate that ICD patients who are female and/or are younger at the time
of implantation could be more likely to experience distress and disrupted quality of
life when compared to male and/or older counterparts. The link between female sex
and greater risk may be attributable to negative impacts, body image (e.g., scars),
social role shifts, greater awareness of bodily sensations, or greater levels of pain
and functional limitation in the context of caregiving duties (e.g., Brouwers
et al. 2011). However, the investigation of gender is often difficult as most studies
include a vast majority of male patients, and needed analyses may be underpowered
to detect valid sex differences. Young age (less than 50 years of age) also places
ICD patients at potential risk for poorer adjustment (Sears et al. 2001; Dubin
et al. 1996). Several reasons for the age difference have been offered and include
body image concerns, disruption of quality of life (e.g., via numerous medical
visits), avoidance of physical activities, and higher rates of emotional distress.
Relative to analysis of sex and age differences, little research addresses racial
differences in ICD recipients. In one sample, African Americans had poorer
psychological response profiles to ICDs when compared to whites (Wilson
et al. 2013). Specifically, African Americans reported lower acceptance of their
devices and higher shock-related anxiety. They also demonstrated less knowledge
of their devices in comparison to whites. Although differences among races,
ethnicities, or cultures have not gained traction in similar magnitude of that gained
by sex and age research with ICD patients, this is an important next direction for the
field as it attempts to understand the ICD patient experience in increasing levels of
detail to optimize patient adjustment and understanding.
Pediatric Patients. The challenges of coping with cardiac disease and an ICD are
particularly salient in the pediatric context (Sears et al. 2001, 2009). Children with
ICDs have consistently demonstrated increased and specific psychological chal-
lenges in ICD patient research. Although the strength of conclusions remains
limited by the relatively small samples of ICD patients available in single centers,
researchers have delineated concerns spanning both affective and behavioral prob-
lems. In a study of children with ICDs or pacemakers, increased risk was demon-
strated for anxiety in ICD patients (27 % vs. 11 % respectively), but not for
depressive symptoms (Webster et al. 2014). The type of device was not a significant
predictor of distress after controlling for possible confounds, and parental distress
558 A. Whited et al.
was not different between groups. Another study showed that 22 % of their
pediatric ICD patient sample experienced problematic anxiety (Stefanelli
et al. 2002), which, when combined with the previous study, estimates that the
likelihood of psychological distress in children with ICDs is to be between 22 %
and 27 %.
Researchers have sought to examine whether the distress is meaningfully dif-
ferent than in children with other chronic diseases. Pediatric patients with ICDs do
appear to be uniquely impacted by living with a device in some ways. Although
rates of depression and anxiety in children with ICDs were not shown to be
significantly different than in children with chronic illness (DeMaso et al. 2004),
lower physical functioning, psychosocial functioning, and quality of life have been
demonstrated in pediatric ICD patients when compared to healthy or chronically ill
reference groups (DeMaso et al. 2004; Sears et al. 2011b). Within the same studies,
parental reports echoed these findings, showing that parents of children with ICDs
also perceived that their children were negatively impacted in those domains. In
fact, parent reports of negative impacts were higher than the children’s reports in
some instances (Sears et al. 2011b). In the largest study on quality of life with
pediatric ICD patients, Sears et al. (2011b) further demonstrated that the occurrence
of ICD shock and medical severity were not predictive of patient distress. Addi-
tionally, sex differences emerged in that study, with girls reporting lower physical,
psychosocial, and cardiac quality of life than boys. A separate, and smaller, study
did not find sex differences in children’s adjustment to living with an ICD, but ICD
shock was linked to depressive symptoms (Koopman et al. 2012). That study also
provided some evidence of increased anxiety, depression, and sleep problems in
children with ICDs relative to normative samples. Although some findings may be
mixed, clarification and specificity will be better accomplished as research in this
population accumulates over time. Nonetheless, the pattern of increased risk for
negative psychosocial impact in pediatric ICD patients is clear.
Despite the limited nature of research with pediatric ICD samples, specific
pediatric ICD patient concerns have begun to emerge. Perhaps the most significant
finding from any of these studies is that approximately 84.7 % of these young ICD
patients reported strong avoidance behaviors in an attempt to manage anxiety
(Sears et al. 2011b). In addition, Koopman et al. (2012) highlighted some specific
worries that provide some additional insights into pediatric ICD patients. For
example, the majority of pediatric ICD patients endorsed the following: “I am
afraid of being alone if the ICD fires and I need help,” and “I’m nervous that if I
exercise, my heart might start beating faster and make the ICD fire.” This statement
highlights the role of fear generalization beyond simply ICD shock and extends to
behaviors that would be associated with even normative exertions or normal
elevation of heart rate. These types of survey responses could provide specific
targets of information and strategies in designing a pediatric treatment study.
Devices Under Recall and Leads Under Advisory. Although such events are rare,
ICDs have at times been subject to “field actions” or “recalls” due to evidence of
malfunctions or increased risk of adverse events, some of which could cause death.
Naturally, some researchers have set out to examine how this affects the patient
Psychological Consultation for Patients with Implantable Cardioverter. . . 559
Table 1 Assessment tools for measuring quality of life and psychological distress
No.
Source or Concept of
Measure reference measured Subscales items
Device- Aquarel Stofmeel Device Cognition, chest 20
specific questionnaire et al. 2001 acceptance discomfort,
measures (pacemaker only) dyspnea,
arrhythmias
Florida Burns Device Return to function, 18
patient et al. 2005 acceptance device-related
acceptance distress, body
scale image concerns
Florida shock Kuhl Device-specific Consequence of 10
anxiety scale et al. 2006 anxiety shock, trigger of
shock
ICD patient Frizelle Device-related Device-specific 20
concerns et al. 2006 concerns concerns,
questionnaire perceived
limitations
Unnamed Luderitz Device N/A 8
et al. 1993 acceptance
Generic Cardiac Eifert Disease-specific Fear, avoidance, 18
measures anxiety et al. 2000 anxiety heart-focused
questionnaire attention
Hospital See Depression and Anxiety, 14
anxiety and Bjelland anxiety in depression
depression et al. 2002 nonpsychiatric
scale medical settings
Beck Beck Depression N/A 21
depression et al. 1996
inventory II
Beck anxiety Beck Anxiety N/A 21
inventory et al. 1988
State-trait Spielberger Anxiety State anxiety, trait 40
anxiety et al. 1983 anxiety
inventory
Patient health Spitzer Depression N/A 9
questionnaire et al. 1999
(PHQ-9)
Impact of Weiss and Post-traumatic Avoidance, 22
event scale – Marmer stress hyperarousal,
revised 1997 intrusion
PTSD Weathers Post-traumatic N/A 17
checklist et al. 1994 stress
end of life (Pedersen et al. 2013b). There is evidence that patients feel that
education around deactivation is desirable (Pedersen et al. 2013b) and that patients
may favor deactivation when they understand the overall function of their ICD
(Dodson et al. 2013). Ultimately, the risk is high for acutely and severely
compromised quality of life during the end-of-life phase if patients are not ade-
quately informed about both their devices and device management during the end
of life.
Assessment Tools
Conclusions
ICDs save lives and have been one of the most rapidly innovating technologies in
recent history. The patient experience with the ICD readily intertwines the process
of cardiac disease with the implantation of a technology. Psychological aspects are
inherently central to understanding and producing the best possible health out-
comes. Approximately one in five ICD patients experiences significant psycholog-
ical distress (Magyar-Russell et al. 2011), but very few receive treatment (see
Hoogwegt et al. 2012; Magyar-Russell et al. 2011). Therefore, both medical and
mental health providers have an obligation to be aware of the psychological hazards
likely to be faced by ICD patients so that the need for treatment can be recognized
and referral for effective services can be facilitated. Chapter “▶ Adding Psycho-
logical Intervention to High-Tech Care for Patients with Implantable Cardioverter
Defibrillators” in this edition outlines available treatments for these patients’ needs.
562 A. Whited et al.
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Psychological Effects of Invasive Cardiac
Surgery and Cardiac Transplantation
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Post-CABG/Valve Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 568
Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 570
Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 571
Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 573
Neurocognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 574
Outcomes After Heart Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
Health-Related Quality of Life . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 576
Mania/Psychosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
Anxiety and Posttraumatic Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
Outcomes After Placement of a Ventricular Assist Device . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 578
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580
Abstract
Psychiatric symptoms are common after cardiac surgery, particularly adjustment
disorders, major depressive disorder, posttraumatic stress disorder, delirium, and
cognitive disorders. Depression has been reported in up to 37 % of patients after
Keywords
Depression • Delirium • Posttraumatic stress disorder • Sexual dysfunction •
Cognition • Coronary artery bypass surgery • Heart valve surgery • Heart
transplantation • Left ventricular assist device
Introduction
Coronary artery disease is the leading cause of death and disability in the developed
world, as a result of myocardial infarction, congestive heart failure, and sudden cardiac
death. Significant additional morbidity and mortality result from valvular heart disease,
congenital and familial heart diseases, and various acquired cardiomyopathies. Coro-
nary artery bypass surgery and valve repair and replacement procedures are common,
may be lifesaving, and may enhance quality of life, even in patients for whom no
benefit with respect to survival is expected; for example, coronary artery bypass for
obstructive lesions outside the left anterior descending artery or left main coronary
artery reduces the frequency of angina and improves functional status without chang-
ing survival. For selected patients, heart transplantation provides an escape route from
end-stage heart disease when other therapeutic options are exhausted. However, with
the number of heart transplant procedures performed annually limited by lack of organ
donors, heart transplantation is not an option for most patients dying of heart failure.
Implanted mechanical cardiac support therapies such as left ventricular assist devices,
originally deployed as “bridge to transplant,” now also serve as “destination therapy.”
All of these surgical procedures have associated risks of psychiatric and psychological
morbidity, especially mood disorders, anxiety and stress-related symptoms, delirium,
and neurocognitive impairment (Go et al. 2014; Murray and Lopez 1997).
Post-CABG/Valve Surgery
Depression
There is some evidence to suggest that patients suffering from depression before
surgery may experience a reduction in symptoms afterward, related to improved
physical functioning (Nemati and Astaneh 2011; Rothenhausler 2010). In a 2003
review of the literature, anxiety and depression seemed to improve from preoper-
ative to postoperative assessments. However, levels of anxiety and depression
remained higher among patients with preoperative anxiety and depressive syn-
dromes than in those patients without identified psychopathology before surgery
(Pignay-Demaria et al. 2003).
Depression Treatment
Serotonin reuptake inhibitors (SSRIs), specifically sertraline and citalopram,
have been shown to be safe and at least modestly effective for treatment of
depression in patients with coronary artery disease, and these agents are favored
as first-line pharmacotherapy for depression in patients with coronary heart
disease (CHD) or congestive heart failure (CHF) (Glassman et al. 2002;
Lesperance et al. 2007). Electrocardiographic QTc prolongation is associated
with increasing citalopram dose (Castro et al. 2013) and may increase the risk
of torsade de pointes, leading to a United States Food and Drug Administration
warning against the use of citalopram in doses above 40 mg daily. The clinical
significance of this finding remains controversial (Pae et al. 2014; Zivin
et al. 2013). In a recent randomized controlled trial of 361 patients, antidepressant
therapy with escitalopram 10 mg resulted in improvement in depressive symp-
toms and overall quality of life as well as reduction in postoperative pain 6 months
after CABG. There was no adverse effect on all-cause morbidity and mortality.
No adverse events beyond typical side effects expected for SSRIs were identified
(Chocran et al. 2013). Despite known effects of SSRIs on platelet serotonin
storage and possible interactions with warfarin, a study of 246 patients taking
SSRIs at the time of CABG found no effect of SSRI use on the rate of abnormal
bleeding events (Xiong et al. 2010).
570 M.G. Ackerman and P.A. Shapiro
association does not provide grounds for causal inferences. Female patients are also
more likely to manifest impairments in HRQOL both before and after cardiac
surgery than age-matched male counterparts (Martin 2006).
While CABG has been shown to be effective in improving most domains of
HRQOL, sexual dysfunction continues to be problematic for many patients post-
operatively. Lindau et al. (2012) investigated sexual function in the year following
acute myocardial infarction and found that 48 % of men and 59 % of women
reported decreased frequency of sexual activity, and 11 % of men and 13 % of
women did not return to sexual activity (Lindau et al. 2012). In a study of
100 patients who underwent CABG, only 57 % of patients reported satisfaction
with their sexual function prior to surgery and 62 % 8 years after CABG
(Lukkarinen and Lukkarinen 2007). There is some evidence to suggest that patients
who undergo off-pump procedures are less likely to report sexual dysfunction than
patients undergoing traditional CABG (Mohamed et al. 2009).
Anxiety Disorders
Anxiety after cardiac surgery is common, and the differential diagnosis of anxiety
symptoms is broad, including primary anxiety disorders, delirium presenting with
restlessness or fear, and anxiety secondary to a general medical condition. For the
clinician evaluating “anxiety” after cardiac surgery, it is essential to first consider
the possibility of delirium or postoperative anxiety as a manifestation of a general
medical condition, such as hypoxia, substance withdrawal, infection, or metabolic
derangement. Anxiety can also be iatrogenic, i.e., secondary to various medica-
tions, particularly steroids or beta-2 agonists, or withdrawal from anesthetics.
Withdrawal from sedatives can become a particular problem when trying to wean
patients from the ventilator. Sedative tapering and discontinuation can result in
either withdrawal symptoms or emergence delirium, either of which can result in
difficulty weaning. Withdrawal from alcohol or illicit substances can also present as
anxiety and should be considered especially in the setting of hemodynamic insta-
bility, tremulousness, or cognitive changes. More broadly, anxiety is a common
presentation of postoperative delirium (for review, see Shapiro et al. 2008).
Some studies have actually found improvements in anxiety following cardiac
surgery. A 2003 review found that new onset of anxiety symptoms in the setting of
planned surgery tended to improve after surgery, but patients with elevated preop-
erative anxiety levels continued to have elevated rates of anxiety as compared to
patients without identified psychopathology prior to surgery (Pignay-Demaria
et al. 2003).
less than 6 months after resolution of the stressor and its consequences; symptoms
do not meet criteria for another disorder. Adjustment disorder with anxiety can have
preoperative onset (i.e., the anticipation of surgery may be anxiety provoking) or
occur after surgery (i.e., problems during recovery may precipitate anxiety). Man-
ifest postoperative anxiety can also represent an underlying anxiety disorder, most
often a pre-existing disorder such as generalized anxiety disorder, panic disorder, or
a simple phobia. It is uncommon for these disorders to have first onset in this
setting. However, posttraumatic stress disorder does have an increased incidence
after cardiac surgery.
Delirium
Management of Delirium
Behavioral Interventions
Ultimately, treatment of delirium requires identification and treatment of the
underlying medical condition responsible for the delirious state, for example,
correction of hypoxia, resolution of metabolic disturbances, treatment of infection,
and pain management. Reduced use of deliriogenic medications, such as opiates,
anticholinergic agents, barbiturates, and benzodiazepines (while avoiding induction
574 M.G. Ackerman and P.A. Shapiro
Neurocognitive Impairment
largely mild cognitive impairment, 6 months after surgery. Patients with cognitive
impairments also manifested impairments in general health-related quality of life
(Rothenhausler 2010; Rothenhausler et al. 2005). In the immediate postoperative
period, valve replacement surgery seems associated with a slightly higher risk of
postoperative memory impairment and a longer time to neurocognitive recovery
than CABG alone (Ebert et al. 2001).
Psychiatric disorders are common after orthotopic heart transplantation. The most
frequent psychiatric disorders after transplantation include major depression,
adjustment disorder, and transplantation-related PTSD. Mood and anxiety disorders
are most common in the first year after surgery, with declining incidence over the
next several years. Notably, the risk of these disorders during the first-year
posttransplant is significantly higher than patients’ lifetime rates of the disorders
before transplant (Dew and DiMartin 2005). Risk factors for the development of a
psychiatric disorder after transplant include pre-transplant psychiatric history,
lower social supports, younger age, more impaired physical functioning, and longer
hospitalization (Dew et al. 2001a Dew and DiMartini 2005; Eshelman et al. 2009).
Psychopathology is correlated with worse posttransplant outcomes, including graft
rejection, nonadherence, recurrent hospitalization, infection, and death (Shapiro
et al. 1995; Eshelman et al. 2009).
576 M.G. Ackerman and P.A. Shapiro
Depression
Depression is common after heart transplantation with peak incidence in the first
year after surgery (Dew et al. 2001a Dew and DiMartini 2005; Favaro et al. 2011;
Sirri et al. 2010). In a review of the literature, Dew et al. reported that up to 63 % of
posttransplant patients reported symptoms of depressive illness (primarily MDD
and dysthymia) (Dew and DiMartini 2005). Risk factors for depression after heart
transplant include female gender, younger age, personal and family history of
psychiatric illness, lower socioeconomic status (Dew and DiMartini 2005;
Eshelman et al. 2009), worsening of physical illness (Fusar-Poli et al. 2005;
Havik et al. 2007), and being unemployed or on disability (Fusar-Poli
et al. 2005). Longer hospitalization and a greater number of “false alarm” calls to
present for transplantation have also been associated with increased risk for depres-
sion (Pudlo et al. 2009). Furthermore, a lack of social supports (Favaro et al. 2011),
avoidant coping styles, low perceived control, low levels of optimism, and poor
self-esteem are psychological risk factors for posttransplant psychiatric pathology
(Dew and DiMartini 2005; Eshelman et al. 2009). Not surprisingly, patients who
experience medical complications and sleep disruption posttransplant are more
likely to develop psychiatric complications. Notably, transplant patients tend to
experience relatively severe episodes of depression, and a minority report receiving
treatment (Dew et al. 2001b; Dew and DiMartini 2005). Controlled trials of
antidepressants in heart transplant recipients are lacking; case series and case
reports describe effective treatment with ECT and with nortriptyline (Fusar-Poli
et al. 2005), but in contemporary clinical practice, serotonin reuptake inhibitors are
more likely to be utilized as “first-line” therapy (Fusar-Poli et al. 2005). The
differential diagnosis of depression in recent transplant patients should include
the possibility of opportunistic infections, including cytomegalovirus.
Depression after transplantation has a negative impact on survival (Sirri
et al. 2010; Favaro et al. 2011; Havik et al. 2007). In a prospective cross-sectional
study of patients who were at a minimum 5 years posttransplant, depression was
associated with an almost threefold increase in mortality (Havik et al. 2007). In a
longitudinal study conducted over 8 years, Favaro et al. found that MDD was an
independent risk factor for posttransplant malignancy (44 % vs. 25 %, P < 0.05).
Mania/Psychosis
Delirium
Many patients struggle with anxiety following heart transplant. In a review of the
literature, Dew et al. found that up to 26 % of patients experience one or more
anxiety disorders (e.g., adjustment disorder with anxiety, generalized anxiety
disorder, panic disorder, or posttraumatic stress disorder related to the transplant
experience). Anxiety disorders are most common in the first year after transplant
(Dew and DiMartini 2005), and in a small cohort study, Pudlo et al. found that in the
first 8 weeks after transplant, half of patients studied manifested anxiety symptoms.
Older patients were more likely to experience anxiety symptoms; patients with
longer hospitalizations or more false alarms were more likely to have severe
anxiety (Pudlo et al. 2009).
PTSD
Transplantation-related posttraumatic stress disorder (PTSD-T) is characterized by
hypervigilance, avoidance, nightmares, flashbacks, and insomnia and is related to
an aspect of the transplant process. Triggers may include learning of the need for
transplant, events during the waiting period, the surgery itself, and events during the
postoperative recovery period. The reported rates of patients meeting criteria for
PTSD-T range from 10 % to 17 % (Favaro et al. 2011; Dew et al. 2001a; Stukas
et al. 1999). Similar to other mood and anxiety disorders, PTSD-T most commonly
occurs within the first year after transplant (Dew et al. 2001a). Patients with PTSD-
T were more likely to be female and to have a prior psychiatric history, lower sense
of mastery (Stukas et al. 1999), or lower perceived social support (Favaro
et al. 2011; Stukas et al. 1999). Most cases of PTSD-T have a chronic course
(>3 months), and patients frequently do not receive treatment for their symptoms
(88 %) (Dew et al. 2001a). Transplantation-related PTSD symptoms have been
associated with poor adherence (82 % vs. 48 %, P < 0.04, OR = 4.9, 95 %
CI = 1.0–23.8). Poor adherence was associated with increased mortality (adjusted
OR for nonadherence=3.5, 95 % CI 1.2–9.7, P < 0.02) (Favaro et al. 2011).
eligible for heart transplantation. LVAD treatment was also associated with better
quality of life. While potentially lifesaving, life with a VAD carries significant
medical and psychiatric morbidity. VAD patients are at elevated risk for throm-
boembolism, infection, bleeding, and cerebrovascular events and often require
extended and recurrent hospitalization (Petrucci et al. 1999). VADs demand
active device management by patients and/or their caregivers. However, VADs
can also significantly improve quality of life in advanced heart failure patients. In
a study of patients with VAD as bridge to transplant versus medical management,
VAD patients were more likely to report improved physical functioning in the first
year after transplant. However, VAD patients had significantly worse cognitive
functioning secondary to a higher rate of neurologic events. Social functioning
improved in both groups, though VAD patients were less likely to return to work
and described more social isolation (Dew et al. 2001b). VAD patients are at risk
for psychiatric morbidity, most commonly delirium, anxiety, depression second-
ary to the medical condition, and adjustment disorder (Shapiro et al. 1996; Baba
et al. 2006; Eshelman et al. 2009). Psychiatric morbidity negatively impacts
cardiac outcomes and is associated with impaired cardiac rehabilitation (Shapiro
et al. 1996), graft rejection, nonadherence, hospitalizations, infection, and death
(Eshelman et al. 2009).
An early study found that patients with preoperative cognitive impairment were at risk to
experience a postoperative organic mental syndrome following VAD placement (Shapiro
et al. 1996). In the REMATCH trial of destination LVAD versus medical management
(Lazar et al. 2004), 44 % of patients in the LVAD arm developed a neurological complication
(TIA, toxic metabolic, or stroke). Furthermore, patients in the LVAD arm had a stroke rate of
0.19 per year as compared to a rate of 0.052 per year in the medical management arm over
the course of the 2-year follow-up. The mean interval between LVAD implantation and
stroke was 221.8 days (70.4 days). A revised survival analysis indicated that LVAD therapy
has significant benefit when compared to medical management when assessing combined
stroke or death risk (Lazar et al. 2004).
Adjustment disorder has been reported in as many as 50 % of patients receiving
VADs (Baba et al. 2006; Eshelman et al. 2009). In terms of adjustment issues,
patients frequently worry about their risk of death and exhibit hypervigilance to
sensations related to the device (Petrucci et al. 1999). In Petrucci et al.’s study,
behavioral techniques including orientation aids, desensitization, relaxation tech-
niques, hypnosis, music and art teleconferencing with families, computer access,
and group and community interaction were found to be helpful, though these
interventions were not studied in a controlled design.
Depression is also a significant problem among VAD patients. In a sample of
30 consecutive VAD patients, Shapiro and colleagues found that 20 % experienced
a major depressive episode, with new onset depression occurring in 16 % (Shapiro
et al. 1996). Baba et al. (2006) found depression symptoms in 14 % and major
depression in 7 % among their cohort of 14 VAD patients. Depression was treated
with intensive observation, supportive psychotherapy, and/or serotonin reuptake
inhibitor antidepressants (Shapiro et al. 1996; Baba et al. 2006).
580 M.G. Ackerman and P.A. Shapiro
Conclusion
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ajp.2013.12030408
Cognitive Impairment After Cardiac
Surgery: Confounding Factors
and Recommendations for Improved
Practice
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 586
Cognitive Impairment Following Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Surgical Factors Implicated in POCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 587
Differences Between CABG and Valve Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 589
Summary of Cardiac Surgical Factors Associated with POCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Nonsurgical Factors Implicated in POCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590
Effect of Emotional State on Cognitive Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 591
Preoperative Cognitive Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Neuropsychological Testing Following Cardiac Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 592
Neuropsychological Tests for Measuring POCD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 593
Computerized Cognitive Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 594
Statistical Approaches for Defining Postoperative Cognitive Change . . . . . . . . . . . . . . . . . . . . . 594
Cognitive Impairment Following CABG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Cognitive Impairment Following Conventional and Robotically
Assisted Valve Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 596
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620
Abstract
Impaired cognition following cardiac surgery is a common complication. Esti-
mates of the incidence of postoperative cognitive decline/dysfunction (POCD)
vary from 20 % to 70 % of patients in the week after cardiac surgery to 10–40 %
Keywords
Cardiopulmonary bypass (CPB) machine • Cognitive impairment • Post-cardiac
surgery (see postoperative cognitive decline/dysfunction (POCD)) • Median
sternotomy • Neuropsychological testing • POCD • Postoperative cognitive
decline/dysfunction (POCD) • Anesthesia • CABG vs. valve surgery • Cardiac
surgical factors • Cardiopulmonary bypass machine • Clinical implications •
Emotional state effects • On cognitive performance • Median sternotomy •
Neuropsychological testing • Preoperative cognitive performance • Statistical
approaches for
Introduction
intensive care units, delays discharge from hospital, and reduces compliance with
postoperative cardiac rehabilitation programs, with some patients requiring
readmission (Lewis et al. 2004). As POCD is also associated with a decreased
quality of life and early withdrawal from the workforce, it represents a considerable
burden to society (Van Harten et al. 2012).
The intention of this chapter is to provide an overview of the substantial obstacles
surrounding the determination of cognitive change following cardiac surgery and to
discuss risk factors associated with cognitive change during cardiac surgery. Subse-
quently, the assessment of cognitive change and the methods used to define this
change will be discussed. The chapter will conclude with an overview of the current
estimates of cognitive impairment following coronary artery bypass graft (CABG)
surgery, conventional valve surgery, and robotically assisted valve surgery.
Much of the literature dealing with POCD has been concerned with the extent to
which surgical factors influence cognitive outcome. The surgical factors implicated
in POCD following CABG and valve surgery include the use of the cardiopulmo-
nary bypass (CPB) machine, the role of anesthesia, and the use of a median
sternotomy to access the surgical field.
be performed with or without the CPB. In off-pump CABG surgery, the heart is
chemically slowed to 40 beats per minute and is mechanically stabilized, so that the
operation can be performed on the beating heart without the need for a CPB machine
(Rankin et al. 2003). However, despite the strong a priori reasons for expecting CPB
machines to contribute to postoperative cognitive impairment, the data from com-
parative studies of CABG with or without CPB are equivocal. While some studies
found that off-pump CABG produced better cognitive outcomes immediately fol-
lowing surgery and just prior to discharge (Motallebzadeh et al. 2007; Ngaage 2003;
Zamvar et al. 2002), these results were not supported by other studies that found no
difference in cognitive performance between groups immediately after surgery or up
to 6 months following surgery (Ernest et al. 2006; Farhoudi et al. 2010; Jensen
et al. 2006; Lund et al. 2005). Conversely, another study reported no change
immediately following surgery but reported better function at 6 months in the
off-pump CABG surgery group (Stroobant et al. 2002). Further to this, other studies
that assessed cognitive function 12 months following surgery reported no significant
differences between patients who underwent CABG with or without CPB (Rankin
et al. 2003; Van Dijk et al. 2002). This variation in outcomes is likely to be due to
methodological differences in study design, such as a lack of consistency between
studies in (i) the cognitive tests used, (ii) the time points used for reassessments, (iii)
the criteria used to define POCD, and (iv) the statistical methods used to correct for
bias in the data (Farhoudi et al. 2010). There is a lack of consensus regarding which
tests to include, which cognitive domains to examine, what postoperative intervals to
use when testing patients, and even what constitutes a significant degree of cognitive
impairment (Arrowsmith et al. 2000; Lewis et al. 2004).
While it is possible that CPB machines do contribute to cognitive impairment,
on-pump CABG is associated with a similar incidence of POCD to that found after
other forms of major surgery which do not use a CPB machine (Moller et al. 1998).
The conflicting results from the comparison between off-pump and on-pump CABG,
and the results showing that similar rates of POCD occur from noncardiac surgery,
raise the possibility that factors other than CPB, such as general anesthesia, may be
responsible for the POCD seen following on-pump CABG surgery (Browne
et al. 2003).
Anesthesia
Anesthetic agents allow surgery to occur by immobilizing the body, inducing
amnesia, and providing an absence of awareness. While the exact mechanisms by
which this occurs are unknown, it is evident that anesthetic agents act on the central
nervous system and influence mental functioning on recovery from anesthesia
(Bruce and Bach 1976; Istaphanous et al. 2010). Evidence suggests that anesthetic
agents affect the blood-brain barrier, which exists to provide physical and metabolic
protection from neurotoxic substances circulating in the blood (Correale and Villa
2009). There is also evidence that neuroinflammation occurs in response to circu-
lating cytokines that are released in response to the surgical trauma (Minagar
et al. 2002; Wilson et al. 2002). Neuroinflammation can cause cognitive impairment,
and when coupled with the disruption of the blood-brain barrier caused by anesthetic
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . . 589
agents, the combined effects may promote POCD (Ben-Nathan et al. 2000; Wu
et al. 2012).
Research into the impact of anesthesia on cognitive function began with cardiac
surgery about 25 years ago and now includes other major forms of surgery, especially
orthopedic and abdominal surgery (Silbert et al. 2011). While recovery from anesthe-
sia does affect cognition postoperatively (Farag et al. 2006; Steinmetz et al. 2010), the
duration of this effect has been difficult to assess due to variable outcomes (Sutton
2007). Estimates of the duration of POCD resulting from anesthesia range between 1 h
and 1 week after surgery (Papaioannou et al. 2005; Rasmussen et al. 2003).
Median Sternotomy
A median sternotomy provides excellent exposure of the surgical field, yet it can
cause significant pain and distress to the patient in the weeks after surgery (Stahle
et al. 1997). There is clear evidence that pain can disrupt attention and memory and
reduce mental flexibility (Dick and Rashiq 2007; Karp et al. 2006). Further, since
performance on most neuropsychological tests is suboptimal if the subject is dis-
tracted or is lacking in motivation (e.g., due to pain and discomfort), there is a high
probability that some of the “cognitive impairment” reported after cardiac surgery is
due to an inability to fully concentrate on the cognitive tests. Furthermore, a number
of cognitive tests (e.g., Rey Osterrieth Complex Figure Test, Grooved Pegboard)
involve drawing or fine movement control, which may be impaired if the patient is in
physical discomfort. Thus, if performance on these tests is worse than it was prior to
surgery, it may be due to physical restriction rather than to cognitive impairment.
It is possible that pain and physical restriction following cardiac surgery has
contributed to overestimates of the extent of cognitive impairment that exists
immediately after surgery. In addition, the majority of patients receive analgesics
postoperatively (generally opiates), which may also have adverse effects on cogni-
tive performance (Wang et al. 2007). It is possible, therefore, that much of the
“recovery” in cognitive performance seen in the weeks and months after surgery is
due to a reduction in pain and physical restriction and to the withdrawal of
analgesics.
The obvious difference between these two forms of surgery include the more
invasive nature of valve surgery, requiring incision of the chambers inside the
heart, rather than having vessels bypassed on the surface of the heart, as occurs in
CABG surgery. Studies that have assessed POCD following valve surgery have
concluded that valve patients exhibit higher levels of POCD than CABG patients,
which is thought to be due to the introduction of air and tissue debris into the heart
during the open-chamber procedure (Braekken et al. 1998; Ebert et al. 2001; Hong
et al. 2008; Nussmeier 1996).
There are several surgical factors common to both CABG and conventional valve
surgery that may contribute to POCD. Both procedures involve the trauma of a
median sternotomy. The physical trauma of having the chest wall incised and opened
is severe, and compounding this is the invasiveness of the actual cardiac procedure
and the acute postoperative pain. The development of robotically assisted valve
repair surgery eliminates the need for a median sternotomy, and studies have found it
to improve the rate of physical recovery following surgery. To date, only a study by
the present authors has assessed POCD following this type of surgery (Bruce
et al. 2014), and the results are discussed later in the chapter.
In summary, the main cardiac surgical factors that have been implicated in POCD
are the CPB machine, accessing the surgical field via median sternotomy, the use of
general anesthesia, and whether the surgery is intracardiac or extracardiac. Due to
the numerous surgical factors that can influence cognitive function after surgery, it is
essential that studies which aim to ascertain the unique contribution of cardiac
surgery use a comparator group that have undergone another form of major surgery.
While the need for a surgical control group might seem to be self-evident, the vast
majority of studies of POCD following cardiac surgery have not included such a
group (Bruce et al. 2008; Selnes et al. 2006; Silbert et al. 2011). Thus, it is unclear
what proportion of the POCD reported by these studies was due to factors associated
with surgical procedures in general, rather than to cardiac surgery in particular
(Bruce et al. 2008, 2013a, b; Selnes 2013).
Nonsurgical factors that have been implicated in POCD include age (Bishop
et al. 2010; Cargin et al. 2006; Li et al. 2001; McDaniel and Einstein 2011; Resnick
et al. 2003) and education level (e.g., dos Santos et al. 2011; Meng and D’Arcy 2012;
Sachdev and Valenzuela 2009; Satz et al. 2011). These two factors have
been extensively reviewed elsewhere and will not be discussed here. Other factors
include the pre- and postsurgical emotional state of patients and their pre-existing
disease state.
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . . 591
The requirement to undergo cardiac surgery is a major life-altering event for most
patients, and understandably it affects their emotional state. While much of the
research into emotional disturbances has focused on depression, a number of studies
have found increased levels of anxiety before and after CABG surgery. Depression
and anxiety are associated with deficits in working memory, processing speed, verbal
and visual memory, and various aspects of executive function (Andersson
et al. 2010). Both appear to be associated with a significant risk of readmission
following CABG, and preoperative levels of depression and anxiety are associated
with an increased incidence of cardiac morbidity following CABG surgery (Bankier
et al. 2004; McKenzie et al. 2010; Pignay-Demaria et al. 2003; Tully et al. 2008).
Given that both depression and anxiety affect cognitive function, their impact on
cognitive performance before and after cardiac surgery needs to be considered when
investigating POCD (Tsushima et al. 2005). Andrew and colleagues (2001) found
that preoperative depression, anxiety, and stress were not related to preoperative
neuropsychological performance, but they additionally found that high levels of
preoperative depression and anxiety predicted deficits on attention and verbal
memory tasks following CABG. Stroobant and Vingerhoets (2008) also showed
that while preoperative depression was not associated with preoperative neuropsy-
chological performance, it was associated with postoperative impairments in
visuomotor tasks. Conversely, in 2009, Tully and colleagues found that levels of
postoperative depression and anxiety had minimal effects on cognitive function after
CABG. Freiheit and colleagues (2012) found that preoperatively, the average cog-
nitive domain scores in attention/executive function, learning/memory, verbal flu-
ency, and global cognition were lower in patients with depressive symptoms, and
this difference persisted for up to 30 months postoperatively.
Most studies that have assessed emotional state following cardiac surgery have
only included measures of depression and anxiety; they have not investigated the
impact of pre- or postoperative levels of stress. As a major traumatic event, cardiac
surgery will induce significant amounts of stress. Stress increases cortisol levels,
which can impair cognitive performance (Peavy et al. 2009; Sandi and Pinelo-Nava
2007). Initial research (Andrew et al. 2001) found that while preoperative mood state
is a critical predictor of postoperative mood state, stress was not associated with a
reduction in cognitive performance in these patients. However, more recent studies
have shown that CABG patients are significantly more stressed, anxious, and
depressed than valve and nonsurgical control groups prior to surgery, and this stress
influences the degree of cognitive impairment that is present after surgery (Bruce
et al. 2013a, b, 2014).
Many CABG patients are required to wait for surgery for months, with some
patients even being prepared and placed on the gurney waiting for surgery, only to be
informed that the surgical procedure has been canceled due to the need to operate on
another patient with a condition requiring more urgent attention. For example, the
OECD reported that in 2010, 25 % of patients in Canada, 22 % in Sweden, 21 % in
Norway and the United Kingdom, 18 % in Australia, and 7 % in France,
592 K.M. Bruce et al.
Switzerland, and the USA waited for 4 or more months before their surgery (Siciliani
2013). The uncertainty and false starts associated with the elective surgery process
are likely to contribute to the heightened levels of stress, anxiety, and depression
detected in CABG patients prior to surgery. The possibilities of permanent deterio-
ration and myocardial infarction are another source of psychological distress for
CABG patients (Koivula et al. 2002; Lamarche et al. 1998). While waiting for
surgery, CABG patients suffer from impaired functional status, chest pain, shortness
of breath, and fear of death. The situation also has a negative impact on the patient’s
family and their social interactions (Koivula et al. 2002). Most cardiac patients who
reported elevated levels of depression, anxiety, or stress postoperatively also had
these symptoms preoperatively, and these states were associated with slower phys-
ical recovery, more persistent symptoms, and longer time before resuming former
activities (Gallo et al. 2005).
The preceding findings indicate that many cardiac surgery patients experience
depression, anxiety, and stress prior to and after surgery and that these emotional
states do affect cognitive performance. In view of this, we suggest that an emotional
state measure ought to be routinely included in every preoperative and postoperative
neuropsychological assessment.
The estimated levels of POCD may be inflated by a failure to assess the preoperative
cognitive performance (Bruce et al. 2013a, 2014; Selnes et al. 2012; Sweet
et al. 2008). CABG patients with atherosclerosis or coronary artery disease/cardio-
vascular disease have a high risk of developing hypertension, diabetes mellitus,
hyperlipidemia, peripheral arterial disease, and cerebrovascular changes, all of
which negatively affect cognitive function (Maekawa et al. 2011; McKhann
et al. 2005; Selnes and Zeger 2007). The restriction of blood flow through the
heart will decrease cerebral perfusion, potentially causing cerebral ischemic damage
and cognitive dysfunction (Hoth et al. 2008).
naming test, visual naming test, verbal fluency test (e.g., COWAT), and verbal
learning test (e.g., RAVLT). Since all of these tests measure some aspect of language
proficiency, it appears that language is a domain that is frequently affected by cardiac
surgery. Other tests that often detect POCD are the Trail Making Test, digit symbol,
and the Grooved Pegboard. These tests are sensitive to impairments in several
domains, but their area of commonality is concentration, making it likely that this
domain is affected. The data summarized in Appendix A indicate that language,
concentration, and motor control are commonly affected during the recovery period
following cardiac surgery. Memory, attention, and executive function may also be
impaired, but it is difficult to conclude whether these impairments are as common,
due to the lower proportion of studies that have investigated these domains and a
lack of consistency in the choice of tests used to assess these domains.
The growing availability of personal computers from the 1980s has led to an
increase in the use of computers for cognitive testing (Butcher et al. 2000; Schlegel
and Gilliland 2007). Existing pen and paper tests were translated into a computer-
ized format, and new cognitive tests were developed, taking advantage of the
automated timing of stimulus presentation and data collection (Wild et al. 2008).
Computerized cognitive tests are now widely employed because, if developed
correctly, they can overcome many of the limitations associated with conventional
tests. Computer-based tests are generally quick and easy to use, results can be
analyzed automatically, and they may be able to overcome cultural and language
barriers (Collie et al. 2003; Silbert et al. 2004). Some computerized tests can be
conducted at the bedside by nurses or other hospital personnel because they do not
need to be administered or scored by neuropsychologists. This facility makes it
possible to screen patients, both before and after surgery, in order to track a
patient’s recovery from POCD. Computerized tests that have been used to assess
POCD following cardiac surgery include CogState (Silbert et al. 2004), MicroCog
(Raymond et al. 2007), the CANTAB (Kidher et al. 2014), and the SCIT (Bruce
et al. 2013a, 2014).
The statistical approach used to define postoperative cognitive change can have a
substantial effect on the estimated incidence of POCD. Some approaches depend on
the availability of presurgical test results, whereas others compare performance
against population norms or the performance of a control group. Definitions of
impairment have included:
1. One standard deviation decline from the preoperative test score on each test
(Vingerhoets et al. 1997; Ebert et al. 2001; Rosengart et al. 2006).
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . . 595
2. One standard deviation from the preoperative group mean on a specified number
of measures (i.e., usually 20 % or 2 tests) (Silbert et al. 2001; Zamvar
et al. 2002; Hogue et al. 2003; Ho et al. 2004).
3. Twenty percent decline from preoperative test results on 20 % or more tests (Van
Dijk et al. 2002; Ho et al. 2004; Keizer et al. 2005).
4. One standard deviation below published normative means for each test
(Rosengart et al. 2006).
5. Z-score: the mean difference between patient and control group is calculated, and
the z-score is determined by subtracting from it the mean learning effect in the
control group and then dividing by the standard deviation measured in the control
group. Z-scores can be calculated for each test or each cognitive domain being
assessed. Decline is defined by a cut-off value (e.g., Z 1.96) that can differ
between studies (Rasmussen et al. 2004; Selnes et al. 2005).
6. Composite score: a combined score containing results from all or only some of
the tests in the battery (Motallebzadeh et al. 2007).
7. Reliable Change Index (RCI): specifies the degree of change from pre- to
postoperative test results that is required to achieve a decline in performance
that is statistically reliable after the practice effects have been removed
(Kneebone et al. 1998; Keith et al. 2002; Keizer et al. 2005; Raymond
et al. 2006; Rosengart et al. 2006). The RCI method tends to produce more
conservative estimates of POCD because it eliminates the distorting effects of
patient familiarity with the testing procedure.
8. Standardized regression-based technique, a modified z-score procedure that takes
into account the change from baseline, and the influence of any demographic
variables chosen (Raymond et al. 2006).
This lack of concordance regarding how to define POCD has itself contributed to
the large variance in estimates of the incidence of cognitive impairment following
cardiac surgery. Of the methods detailed above, the RCI and the standardized
regression-based techniques are the most rigorous (Rosengart et al. 2006), as they
account for the measurement error and practice effects that are a feature of repeated-
measure tests (Jacobson and Truax 1991).
Studies are beginning to show that the 20 % or 2SD definition can lead to over-
estimates of cognitive decline after CABG surgery (Raymond et al. 2006; Selnes and
Zeger 2007; Selnes et al. 2006; Stroobant et al. 2010). Several studies have reported
that the prevalence of POCD differs according to the definition of impairment used.
For example, Keizer et al. (2005) assessed cognitive decline following CABG
surgery at 3 months using three different definitions of decline: a one standard
deviation decrease in test performance on 20 % of the tests, a 20 % decrease in
test performance on 20 % of tests, and the RCI. The incidence of decline was 10.5 %
using the standard deviation method, 31 % using the 20 % method, and 7.7 % using
596 K.M. Bruce et al.
the RCI. The same group reanalyzed results from a previous study that had reported
that 28 % of patients showed POCD 3 months after surgery (using the 20 %
definition of decline) and found that this proportion decreased to 9.9 % using the
RCI method (Van Dijk et al. 2000). These analyses indicate that the RCI method is a
more conservative measure. Together, these results suggest that the RCI has greater
external validity than other measures for determining the incidence of POCD
following cardiac surgery. The present authors recommend that the RCI method be
regarded as the method of first choice in future studies of POCD.
In a study by the present authors (Bruce et al. 2013a), the RCI was used in
combination with a more tightly controlled study design. It was found that the
majority of CABG patients recovered to baseline cognitive performance or better
within 8 weeks of surgery. Furthermore, when the RCI was used to assess cognitive
performance on an individual patient basis, only a small proportion of patients
exhibited cognitive impairment. These impaired patients strongly influenced the
overall results at a group level (Bruce et al. 2013a).
Robotically assisted valve surgery offers the opportunity to investigate whether the
pain and physical restriction caused by the median sternotomy during conventional
valve surgery contribute to overestimates of cognitive impairment in the weeks
immediately after surgery.
In the only study that has assessed cognitive performance following robotically
assisted surgery, the present authors found that the patients performed worse than
conventional valve patients in the first testing session after surgery (Bruce
et al. 2014). While this result was unexpected, it should be noted that the average
interval between surgery and cognitive testing was 6.6 days for robotically assisted
patients and 10 days for conventional valve patients. The reason for this difference is
that the robotically assisted patients experienced less pain and discomfort and were
discharged more quickly from hospital. This difference in re-testing time provided
the conventional valve group with more time to recover from the effects of anesthe-
sia and on-pump surgery. In both groups, any cognitive change that was present in
the week after surgery had resolved within 8 weeks (Bruce et al. 2014).
Clinical Implications
The data reviewed in the present chapter indicate that the domains of language,
concentration, and motor control are commonly affected during the first week after
cardiac surgery and that memory and executive function can also be affected. There
is considerable variability between patients in the degree of POCD, and some of this
variability seems to be associated with emotional state. Importantly, most cardiac
patients improve to their presurgical levels of cognition (or better) within 8 weeks of
surgery. Awareness of these patterns may help clinicians to prepare their patients for
the surgical outcomes and to allay patient fears of the risk of permanent impairments.
The current data indicate that a proportion of CABG patients exhibit cognitive
impairment prior to undergoing surgery; typically, this impairment does not improve
after surgery (Bruce et al. 2013a). While the cause of this permanent impairment is
not yet known, it seems likely to be due to hypoxic brain injury resulting from
cerebrovascular or cardiovascular disease. It is suggested that earlier interventions
are needed in order to avoid permanent brain damage. This would require at-risk
patients to be screened for the presence of cognitive impairment and for priority to be
given to CABG patients who have cognitive impairment and are on surgical waiting
lists.
Conclusion
There is a need to identify the risk factors and surgical techniques that influence
POCD, yet it is difficult to reach definitive conclusions from the present data, due to
the heterogeneity in experimental design and methods of data analysis. As these
factors can greatly affect the estimated magnitude of cognitive impairment following
cardiac surgery, it is imperative to develop a consistent research methodology in
order to obtain more reliable results. We suggest that future studies should include
both nonsurgical and surgical control groups. Nonsurgical control groups help to
address changes that occur in cognitive performance as the result of repeated testing,
often due to a learning effect. They also control for any impairments that are a
function of normal, healthy aging. Surgical control groups address factors related to
the surgical procedure that can influence cognitive performance, such as stress and
anxiety, duration of anesthesia, and surgical trauma. The present authors also
recommend that the cognitive function and emotional state of patients be assessed
prior to and after surgery. The DASS is a useful tool for assessing the levels of
depression, anxiety, and stress. Computer-based tests are convenient ways to screen
for global changes in cognition, and they can be complemented (if needed) by
pencil-and-paper tests of specific cognitive domains.
Appendix A
See Table 1.
598
Table 1 An illustrative sample of studies reviewing the neuropsychological tests used, the methods used to define cognitive impairment and the cognitive
impairment found in their studies
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
O’Brien On-pump 10 days 24–40 days Othera Digit span, CPT, CVLT, No Tl: CVLT#, Tl: #
et al. (1992) CABG visual reproduction and CPT#, T2: $
valve logical memory subtests T2: CVLT#
of WMS, PERT
Vingerhoets On-pump 7–8 days 6 months 1 RCFT, RAVLT, TMT Yes Tl: line Tl: 45 %
et al. (1997) CABG A and B, Purdue bisection#, T2: 12 %
valve Pegboard, digits test and RAVLT#, TAPS
TAPS test, Stroop color- test"; COWAT",
word test, dot TMT A", token
cancellation test, line test"
bisection test, COWAT, T2: CFT",
token test TMT A",
COWAT", Stroop
Test"
Andrew On-pump 7 days Nil 7 CVLT, Purdue Yes MIDCAB: no Tl: decline on
et al. (1998) CABG Pegboard, COWAT, tests declined four or more
MIDCAB, TMT A and B, digit over 30 % SGC: measures:
9 SGC, symbol, Boston naming Purdue Pegboard 14.3 %#
27 MGC test, NART, DASS 55.6 %; MGC: MIDCAB;
Purdue Pegboard 11.1 %# SGC;
44.4 %#., TMT B 44.4 %# MGC
40.7 %#., digit
symbol 40.7 %#
K.M. Bruce et al.
Braekken On-pump 3–5 days 2 months 1 COWAT, CVLT, No Tl: valve only: Tl: valve 67 %
et al. (1998) CABG Grooved Pegboard, Grooved T2: valve 23 %;
valve TMT A and B, WMS, Pegboard#, letter CABG 14 %
serial digit learning, cancellation test#,
letter cancellation test, digit symbol#,
digit symbol, T2: valve:
computerized reaction CVLT", state-
time test, State-trait trait anxiety
anxiety inventory inventory"
CABG: CVLT",
WMS", digit
symbol"
Kneebone On-pump 7 days Nil 1,7 CVLT, Purdue Yes Tl: RCI method: Tl: RCI 36 %,
et al. (1998) CABG Pegboard, COWAT, Purdue SD 0 %
TMT A and B, digit Pegboard#, TMT
symbol, Boston naming B#, digit
test symbol#, Boston
naming test#,
Selnes et al. (1999) On-pump 1 month 1 year 5 RAVLT, RCFT, symbol No No individual test Study looking at
CABG digit, Boston naming stats given association
test, digit span, written between cognitive
alphabet task, Grooved decrease and
Pegboard, Stroop, medical and
NART, MMSE intraoperative
variables. No
overall stats given
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
on performance
Andrew On-pump 6.5 days Nil 5,7 CVLT, Purdue Yes Digit symbol Tl: 70 %#. on one
et al. (2000) CABG Pegboard, COPWAT, 28.8 %#., TMT or more test,
valve TMT A and B, digit B 24 %#. 42 %# on two or
combined symbol, Boston naming more tests
test, NART
(continued)
599
Table 1 (continued)
600
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Diegeler On-pump 7 days Nil 4 Syndrom Kurztest No Tl: Syndrom Tl: 90 %#.on-
et al. (2000) CABG (cognition) Kurztest; 90 %#. pump CABG;
off-pump on-pump CABG; 0 %#. Off-pump
CABG 0 %# off-pump CABG
CABG
Andrew On-pump 7 days 6m 7,2 CVLT, Purdue Yes Tl: digit symbol#. Tl: CABG 50 %,
et al. (2001) CABG Pegboard, COWAT, (valve and valve 50 %
valve TMT A and B, digit CABG), TMT B#
symbol, Boston naming (valve and
test CABG), CVLT#
(valve only)
T2: TMT A# T2: CABG 27 %,
(valve and valve 40 %
CABG), TMT B#
(valve and
CABG), digit
symbol# (valve
only)
Baker et al. (2001) On-pump 7 days 6 months 7 CVLT, Purdue Yes Tests most No difference
CABG Pegboard, TMT susceptible to between groups at
off-pump A and B, digit symbol deficits: on-pump Tl or T2
CABG CABG-Purdue
Pegboard,
TMT B, digit
symbol. OPCAB-
CVLT, digit
symbol (not
identified as
K.M. Bruce et al.
significant deficit)
Basile et al. (2001) On-pump 6 months Nil 2 MMSE, Randt memory No Tl: MMSE"; Tl: 37.5 %#,
CABG test, judgment of Randt paired 62.5 %"
similarities and words
differences, (acquisition and
interpretation of recall)#
proverbs, nonsense
stories, token test,
naming of pictures and
definitions
Di Carlo On-pump 6 months Nil 1 MMSE, Randt memory No T2: MMSE#, Tl: 29 %
et al. (2001) CABG test, token test, Randt memory
valve confrontation and test#, token test#,
definitional naming, confrontation
similarities and naming#
differences
Ebert et al. (2001) On-pump 2 days 7 days 2 MMSE, COWAT, No Tl: CABG and Tl: CABG 57 %,
CABG picture naming, valve: # on all valve 71 %
valve 12 arithmetic tasks, tests except T2: CABG 19 %,
verbal memory, clock naming but valve valve 36 %
reading tasks had significantly
greater decline
than CABG on
COWART, verbal
memory, and
arithmetic tasks.
T2: CABG:
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
verbal fluency#,
clock reading#,
arithmetic#.
Valve: verbal
fluency#,
arithmetic#,
verbal learning#
(continued)
601
Table 1 (continued)
602
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Grigore On-pump Nil 6 week 1 Randt memory test, digit No T2:Means and SD T2: 39.3 %#
et al. (2001) CABG span, digit symbol, given only, no
modified visual significant
reproduction test, changes identified
TMT B in individual tests
Kilo et al. (2001) On-pump 7 days 4 months 1 MMSE, TMT A No No significant Tl:$
CABG changes on tests T2:$
off-pump
CABG
Millar et al. (2001) On-pump 6 days 6 months 1 Stroop test, beck No Pre-existing Tl: 14 %b
CABG depression inventory cognitive T2: 2 %b
impairment and independent of
depression depression and
significant factors existing
in decline impairment
Newman On-pump 7 days 6 weeks, 2 Randt memory test, digit No T2: TMT B# Tl: lwk: 53 %
et al. (2001) CABG 6 months, span, Benton revised T2: 6 weeks,
5 year visual retention, digit 36 %; 6 months,
symbol substitution, 24 %; 5 years,
TMT B 42.5 %
Selnes et al. (2001) On-pump 1 year 5 year 6 RAVLT, RCFT, symbol No Tl (ly): "RAVLT, No percentage
CABG digit, Boston naming "RCFT, "Stroop, impairment given
test, digit span, written "Grooved
alphabet task, Grooved Pegboard, "symbol
Pegboard, Stroop test, digit. T2 (5 years):
MMSE #RCFT, "Stroop,
#symbol digit and#,
written alphabet
K.M. Bruce et al.
Silbert et al. (2001) On-pump 18 h 5 days 2 WMS, TMT A&B, digit Yes No individual test Tl: 30 %
CABG span, COWAT scores given T2: 10 %
Abildstrom On-pump 5–7 days 3 months 5 ISPOCD test battery: No No individual test Tl: 26.7 %#
et al. (2002) CABG visual verbal learning stats given. Study T2: 20 %#
test, Concept shifting looked at
test, Stroop test, letter- comparing
digit coding test patients with and
without POCD to
cerebral blood
flow. No
significant
difference in
cerebral blood
flow between
groups with
POCD and
without POCD
Ahlgren On-pump 4–6 weeks Nil 2 TMT A, RCT, RAVLT, No Decline most Tl: CABG 48 %#,
et al. (2003) CABG, computerized driving frequently seen in PCI 10 %#
PCI test: K-test (focused TMT A&B,
attention), simple RAVLT, K-test,
reaction time, complex simple reaction
reaction time, time, and reaction
simultaneous capacity, time on two
reaction time on two choice visual
choice visual stimuli stimuli, but no
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
numerical stats
given to state that
they were
significantly
declined
(continued)
603
604
Table 1 (continued)
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Rasmussen On-pump 7 days 3 months 5 ISPOCD test battery: No No individual test Tl: 46.7 %#
et al. (2002) CABG visual verbal learning scores given T2: 6.7 %#
test, Concept Shifting
Test, Stroop Test, Letter-
Digit Coding Test
Van Dijk On-pump 3m 12 months 5 RAVLT, Grooved Yes No individual test Tl: on-pump
et al. (2002) CABG Pegboard, TMT A a scores given 29.2 % Off-pump
Off-pump ndB, Sternberg memory 21.1 %
CABG comparison, Line T2: on-pump
Orientation Test, Stroop 33.6 % Off-pump
Test, CPT, self-ordering 30.8 %
tasks, visuospatial
working memory test,
digit symbol
Zamvar On-pump 7 days 10 weeks 2 RAVLT, TMT A&B, Yes Tl: on-pump, Tl: on-pump
et al. (2002) CABG digit symbol, digit span, Grooved 66 %, off-pump
off-pump Grooved Pegboard, Pegboard#, digit 27 %
CABG COWART symbol#, T2: on-pump
T2: on-pump, 40 %, off-pump
TMT B#, 10 %
Grooved
Pegboard#, digit
symbol#,
K.M. Bruce et al.
Zimpfer On-pump 7 days 4 months 1 TMT A, MMSE No No individual test Tl: $
et al. (2002) CABG scores given T2: $
valve
Browne On-pump 2 days 5 days, 6 Adult Memory No No individual test Tl: 5 days, #
et al. (2003) CABG 3 months Information Processing scores given T2: 3 months, "
Battery (increased beyond
Battery, TMT B, baseline)
RAVLT, COWAT
Grimm et al. (2003) Valve 7 days 4 months 1 MMSE, TMT A No Replace No change in
vs. repair: 7 days valve repair group
and 4 months, at 7 days or 4 m.
#TMT A. MMSE #decline in
$ at either time replace group at
point 7 days and 4 m
Hogue et al. (2003) On-pump 4–6 weeks Nil 2 TMT A&B, digit Yes TMT A&B#, Tl: $
CABG symbol, digit span, Benton Visual
Grooved Pegboard, Form
WMS, Benton Visual Discrimination#,
Form Discrimination, Grooved
RAVLT Pegboard#
Lee et al. (2003) On-pump 2 weeks 1 year 3 Vocabulary of WAIS, Yes On-pump: no Tl: on-pump
CABG RAVLT, Benton Visual significant 15.4 %#.
off-pump Retention Test, TMT difference on any vs. off-pump
CABG A&B, Grooved test at 2 weeks or 16.1 %#
Pegboard, finger- 1 year. Off-pump: T2: on-pump
tapping test, digit significant " on 14.8 %#
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
(continued)
606
Table 1 (continued)
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Lund et al. (2003) On-pump 3 months Nil 3 Grooved Pegboard, digit No No individual test Tl: on-pump
CABG symbol, TMT A&B, scores given 35 %#, off-pump
off-pump digit span, Stroop Test, 29 %#, no
CABG RAVLT, similarities and significant
vocabulary from WAIS, difference
COWAT, between groups
visuoconstructive
abilities from WAIS
Rankin et al. (2003) On-pump 10 week Nil 5,6 Boston naming test, Yes CFT" (both on- No significant
CABG COWAT, Rey and and off-pump) decline in off- or
off-pump Taylor Complex on-pump CABG
CABG Figure Tests, Judgment
of Line Orientation,
digit span, TMT A&B,
Stroop Test, CVLT,
Grooved Pegboard, Ruff
Figurai Fluency, MMSE
Selnes et al. (2003) On-pump 3 months 12 months 5 RAVLT, RCFT, Boston No CABG " in verbal Tl: $
CABG naming test, MMSE, memory and T2: $
TMT A, written global summary
alphabet, Grooved measure. Overall
Pegboard, TMT B " in CABG group
on RAVLT, BNT,
pegboard
compared to
nonsurgical
controls
K.M. Bruce et al.
Stygallet al (2003) On-pump 6 days 8 weeks, 6 RAVLT, nonverbal No 5 years: RAVLT + Most tests decline
CABG 5 years recognition memory TMT A", all other at 6 days, improve
task, TMT A&B, block tests decline at 8 weeks, then
design, finger-tapping decline at 5 years
test, letter cancellation
test, symbol digit
replacement test, choice
reaction time, displaced
reaction time test
Ho et al. (2004) On-pump 6 months Nil 2,3,6 Blessed Orientation- No Behavioral Tl: >0.5SD =
CABG Memory-Concentration Dyscontrol 4.7 %,
Test, Behavioral Scale#, Blessed >1SD = 8.2 %
Dyscontrol Scale, TMT A Orientation- >20 % = 36.6 %
Memory-
Concentration
Test#,
Kanbaket al. (2004) On-pump 3 days 6 days 1 MMSE, visual aural 3 days: VADST#, No overall
CABG digit span MMSE $ 6 days: percentage
VADST return to change given.
baseline level, Two clinical
MMSE $ groups are
ofluorane
vs. propofol, no
difference
between groups
Silbert et al. (2004) On-pump 6 days Nil 7 CERAD, Symbol Digit Yes Conventional Tl: conventional
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
accuracy
(continued)
608
Table 1 (continued)
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Askar et al. (2005) On-pump 7 days 3 months 3 COGNISTAT No No individual test Tl: group
CABG: (10 subtests assessing scores given 1 48.2 %#; group
orientation, attention, 2 58.8 %#
comprehension, T2: group
repetition, naming, 1 37.5 %#, group
constructions, memory, 2 29.4 %#
calculations,
similarities, judgment
Carrascal On-pump 7 days Nil 1 PASAT (Paced Auditory No Tl: 45.5 %7# Tl: 45.5 %#
et al. (2005) CABG Serial Addition Test) PASAT
Kadoi et al. (2005) On-pump 7 days 6 months 2 MMSE, RAVLT, TMT Yes TMT A#, TMT Tl: 68 %#
CABG A&B, digit span, B# (7 days), T2: 28 %#
Grooved Pegboard RAVLT#
Keizer et al. (2005) On-pump 3m 12 months 2,3,7 RAVLT, Sternberg letter No Data on T1:>SD =
CABG test, TMT A&B, statistically 10.5 %, >20 % =
off-pump Grooved Pegboard, different changes 31 %, RCI =
CABG Stroop Test, Symbol in performance on 7.7 % T2:RCI =
Digit Modalities Test, individual tests 12.3 %
self-ordering tasks was not provided
Kneebone On-pump 6 months Nil 6,8 CVLT, Purdue Yes TMT#, digit Tl: 43.5 %# on
et al. (2005) CABG Pegboard, COWAT, symbol# 1 test, 18.8 %# on
TMT, Boston naming 2 tests, 7.1 %#
test, digits symbol, on3 tests
NART, DASS
K.M. Bruce et al.
Knipp et al. (2005) Valve 4–7 days 4 months No TMT A&B, digit span, No Discharge:#TMT Tl: discharge: #on
definition Corsi block-tapping test, A&B, digit span, 5 of 13 tests/
given Horn’s performance test, Corsi block- subtests
Zimmerman’s divided tapping test. T2: 4 months $
attention test, verbal 4 months: "digit from baseline
learning test, von Zircon span, Horn’s
test (mood), general performance,
depression scale depression and
mood scales
McKhann On-pump 3 months 12 months 5 RAVLT, RCFT, Boston No T2: (3 months and Tl and T2:
et al. (2005) CABG naming test, digit span, 12 months) no on-pump CABG
off-pump symbol digit, written significant $; Off-pump
CABG alphabet, Grooved cognitive decline CABG $
Pegboard, Stroop Test, in any cardiac
MMSE surgical group
Rothenhausler On-pump 6–7 days 1 year 2 Syndrom Kurztest No No significant Tl: 38.2 %#
et al. (2005) CABG (SKT), German version correlation (17.6 % minimal,
combined of the ten-item between cognitive 11.8 % mild,
Montgomery-Asberg dysfunction and 2.9 % severe)
Depression Rating MADRS or T2: 20 %#
Scale, PTSS-10 (stress PTSS-10 scales (13.3 % minimal,
scale) (i.e., depression or 6.7 % moderate)
stress levels)
Selnes et al. (2005) On-pump 12 months 36 months 5 RAVLT, RCFT, Boston No Boston naming Tl: $
CABG naming test, MMSE, test#, RAVLT#, T2: $
TMT A&B, written Grooved
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
Table 1 (continued)
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Stroobant On-pump 6 days 6 months 3 RAVLT, TMT B, No Tl: block taps Tl: 60 %#.
et al. (2005) CABG Grooved Pegboard, test#, line (59.4 % on-pump
off-pump block taps test, line bisection test# CABG, 61.2 %
CABG bisection test, COW AT, T2: (on-pump) off- pump CABG)
Judgment of Line line bisection T2: 24.2 % #
Orientation test# (on- and (31.8 % on-pump
off-pump) TMT CABG, 9.1 %
B#, block taps off-pump CABG)
test#
Boodhwani On-pump 6–7 days Nil 2 Verbal list learning Yes 61 %# in Tl: 59 %#
et al. (2006) CABG procedure, digit span, 1 domain, 30 %#,
Grooved Pegboard, in 2 domains,
symbol digit, TMT 9 %# in
A&B, RAVLT, WMS 3 domains. No
Memory Scale individual test
data given
Dupuis et al. (2006) On-pump 5–12 months Nil 1 Boston naming test, No No individual test No overall
CABG COWAT, digit symbol, scores given percentage
Logical Memory Scale, change given
Visual Reproduction
Scale, facial recognition
test
K.M. Bruce et al.
Emest et al. (2006) On-pump 2 months 6 months 4 RAVLT, Grooved Yes Tl: no difference Tl: $
CABG Pegboard, TMT A&B, between tests and
off-pump digit span, digit symbol, groups in tests
CABG letter cancellation test, T2: "COWAT T2:$between on-
COWAT, Boston score in off-pump and off-pump
naming test, WMS-R vs. on-pump at group or baseline
Visual Reproduction, 6 months
Judgment of Line
Orientation, Stroop
color-word test
Hammon On-pump 3–5 days 6 weeks, 3 Not defined: stated in Yes No individual test Tl: MC 59.5 %#;
et al. (2006) CABG 6 months text “Patients underwent scores given SC 59.5 %#;
off-pump an 11-part OPCAB;
CABG neuropsychological 70.2 %#,
examination, which was T2: MC 51 %#;
administered by a SC 31.8 %#;
psychologist. The OPCAB 39.2 %#,
elements of the test and T3: MC 57.1 %#;
its results in large SC 29.7 %#;
numbers of patients in OPCAB 31.7 %#
this institution and
others have previously
been published” referred
to Murkin et al. (1995)-
statement of consensus
Jensen et al. (2006) On-pump 3 months Nil 2,3 MMSE, visual verbal Yes No individual test Tl: 1. OPCAB
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
(continued)
Table 1 (continued)
612
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Lewis et al. (2006) On-pump 1 week Nil 2 WLT, TMT A&B, digit No T1:CERAD#, Tl: two tests =
CABG symbol, COWAT, TMT A&B#, 13.3 %#; seven
Grooved Pegboard COWAT#, tests = 49.4 %#;
Grooved adjusted for
Pegboard# controls =
8–17.5 %#
Raymond On-pump 2 weeks Nil 2, 3, 7, 8 MicroCog: assessment No Tl: SRB: Tl: >1SD =
et al. (2006) CABG of cognitive function information 3.6 %#, 65.5 %"
processing >20 % = 5.5 %#,
speed#, general 9.1 %t
cognitive RCI =
functioning# all 16.4 %#,<7 %"
methods: SRB = 32.7 %#,
attention/mental <7 %"
control#
Rosengart On-pump 3 weeks 4 months 1, 4, 7 Digit span, Grooved No T1:RCI, visual Tl:$
et al. (2006) CABG Pegboard, digit symbol, naming of the T2:$
TMT A&B, Stroop Test, multilingual
COWAT, visual naming aphasia exam#
of the Multilingual
Aphasia Exam, Hopkins
verbal learning test
Szalma et al. (2006) On-pump 6 weeks Nil 1 Word fluency test, digit No No significant Tl: $
CABG symbol, digit span, changes found on
block design subtest of any tests in
WAIS, TMT placebo group
(Hungarian), RAVLT
(Hungarian), Pieron test,
K.M. Bruce et al.
Simple Reaction Time,
Choice Reaction Time,
serial reaction time,
Spielberger State-Trait
Anxiety Inventory, Beck
Depression Inventory
Cook et al. (2007) On-pump 7 days 4–6 weeks 3 RAVLT, nonverbal Yes No individual test Tl: 88 %#
CABG, memory test, symbol scores given T2: 30 %#
valve digit, letter cancellation,
combined TMT A&B, Grooved
Pegboard, finger-
tapping test
Hammon On-pump 3–7 days 3–6 weeks, 3 WAIS, RAVLT, TMT No Data on T2 (6 months
et al. (2007) CABG 6 months A&B, Grooved statistically only given):
Pegboard, finger- different changes on-pump:
tapping test, digit in performance on 26.0–44.4 %#,
symbol, letter individual tests off-pump:
cancellation task, visual was not provided 11.5–38.4 %#
reaction time test
Hernandez On-pump Day of 6 months 3 Digit span, VIGIL, No 4 days: TMT A, Tl:$between
et al. (2007) CABG discharge Grooved Pegboard, and state anxiety# groups T2:$
off-pump RCF, COWAT, Hopkins in OPCAB between groups
CABG verbal learning test, compared to
WRAT-3, Brixton CABG. 6 months:
Spatial Anticipation $ in all tests
Test, Beck Depression
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
Inventory, Spielberger
State-Trait Anxiety
Inventory
(continued)
613
Table 1 (continued)
614
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Ille et al. (2007) Combined 7 days Nil 1 Test zur Fruherkennung No Only one test used Tl: 43.2 %#,
der Demenz mit 38.6 %"
Depressionsabgrenzung
(TFDD)
Motallebzadeh On-pump 7 days 6 weeks, 6 MCG complex figure Yes Data on Tl: on-pump#
et al. (2007) CABG 6 months test, Grooved Pegboard, statistically vs. off-pump
off-pump RAVLT, letter different changes T2: $
CABG cancellation test, in performance on T3: $
Symbol Digit Modalities individual tests
Test, verbal fluency test was not provided
Nathan et al. (2007) On-pump 1 week 5 years 6 Buschke Selective No Significant Tl: 45 %#
CABG Reminding, digit span, changes only T2: 44 %#
TMT A&B, Grooved identified between
Pegboard, Symbol Digit groups
Modalities Test
Puskas et al. (2007) On-pump 6 weeks Nil 6 Randt memory test, digit No No individual test Tl: diabetic
CABG span, digit symbol, scores given patients, 38 %#.
TMT B, modified visual With hyper,
reproduction test from 41 %#. Without
WMS hyper.
Nondiabetic:
40 %#. With
hyper, 29 %#
without hyper
Rubens et al. (2007) On-pump 5 days 3 months 6 TMT A&B, RAVLT, Yes Significant Tl: 39 %#
CABG digit span, COWAT changes only T2: 15.9 %#
identified between
groups
K.M. Bruce et al.
Selnes et al. (2007) On-pump 3 months 12 months, 5 RAVLT, RCF, block No 36 months: T2 (36 months
CABG 36 months design, Boston naming attention domain only stats
off-pump test, Grooved Pegboard, MMSE, "to above given):$ relative
CABG TMT A, written baseline levels to baseline across
alphabet, MMSE, all tests
TMT B
Tagarakis On-pump 1 month 1 year 1 MMSE, Wechsler No Tl: all test No overall
et al. (2007) CABG Memory Scale Revised, significant# percentage
Brief Psychiatric Rating change given
Scale, Delirium Rating
Scale
Van Dijk On-pump 5 years Nil 3,7 RAVLT, Grooved Yes Tl: individual test T2: 20 %
et al (2007) CABG Pegboard, TMT A&B, stats do not method, 50.4 %#
off-pump Sternberg memory indicate if off-pump CABG,
CABG comparison, Line significant change 50.4 %#.
Orientation Test, Stroop occurred within On-pump CABG.
Test, CPT, self-ordering groups RCI method:
tasks, visuospatial 33.3 %# off-pump
working memory test, CABG, 35.0 %#
Symbol Digit Modalities on-pump CABG
Test
Yin et al. (2007) On-pump 7–10 days Nil 2 MMSE, digit span, digit Yes Tl: Off-pump Tl (decline on
CABG symbol, TMT A, Stroop CABG: self- 2 or more tests):
off-pump Test, self-rating rating off-pump CABG
CABG depression scale, depression#., – 32.5 %#,
Spielberger State-Trait MMSE #, Stroop on-pump CABG
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
Table 1 (continued)
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Mathew On-pump 6 weeks Nil 2 Randt memory test No No individual test Tl: MH 37.5 %#,
et al. (2007) CABG (short story), digit span, scores given PH 42.5 %#
modified visual
reproduction test, digit
symbol, TMT B
Ropacki On-pump 1 week Nil 2 Digit span, digit symbol Yes Tl: 47.6 %# on Tl: 66.7 %#
et al. (2007) CABG coding, letter-number psychomotor
sequencing, vocabulary, speed (TMT A
FAS test, category and digit symbol),
fluency, Hopkins verbal 45.2 %#. On
learning test (HVLT), working memory
mental control subtest of and executive
WMS, Randt memory function (FAS
test (short story), RCFT, test, digit span,
TMT A&B TMT B, letter-
number
sequencing),
57.1 %#. Verbal
memory (short
story of Randt
memory test,
HVLT), 16.7 %#
visual memory
(RCFT)
K.M. Bruce et al.
Cicekcioglu Off-pump 6 days 2 months 1 Raven’s standard Yes Tl: RSPM$, No overall
et al. (2008) CABG progressive matrices LOT#., RAVLT", percentage
valve (RSPM), RAVLT, Stroop" decline stated
Stroop Test, Line T2: RSPM$,
Orientation Test (LOT) LOT$, RAVLT",
Stroop"
Hong et al. (2008) Valve 7 days Nil 1 MMSE, TMT A, No Tl: MMSE $, Tl: 23 %#
Grooved Pegboard TMT A#,
Grooved
Pegboard#
Sweet et al. (2008) On-pump 3 weeks 4 months, 5,7 Digit span; GP; digit Yes No clear pattern Tl: $
CABG 12 months symbol; TMT A; Stroop of change found T2: $
PCI color-word test; T3: $
COWAT; visual naming
of the multilingual
aphasia examination
(MAE); TMT B;
HVLT-R
Slater et al. (2009) On-pump 1 week 3 months 2 MMSE; TMT A; TMT Yes No individual test Tl: 60 %#
CABG B; HVLT; GP; Stroop scores given T2: 29 %#
color and word test;
saccadic/antisaccadic
eye movement; hospital
anxiety and depression
scale (HADS)
Kozora et al. (2010) On-pump 12 months Nil 2 Logical memory and No No individual test Tl: 12 % in-pump
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
Overall
Core Decline in prevalence of
Surgery Time Definition Psychological battery individual NP cognitive
Study type Time point 1 point 2 of decline assessment measures usedb tests impairment (%)
Anastasiadis On-pump 1 week 3 months 3 Judgment of Line Yes No significant Tl: 53 %#
et al. (2011) CABG Orientation Test; Stroop changes reported T2: 41 %#
color-word test; Symbol (reported as %
Digit Modalities Test; change instead)
digit span – forward;
digit span –backward;
Fuld Object Memory
Evaluation; Positive and
Negative Affect
Schedule; Spielberger
State-Trait Anxiety
Inventory; Geriatric
Depression Scale
Maekawa On-pump 1 week Nil 3 Hasegawa dementia No No individual test Tl: off-pump
et al. (2011) CABG scale; digit span; digit scores given CABG 18 %#;
off-pump symbol; Kana Pick-out on-pump CABG
CABG Test 23 %#; CABG/
valve Valve 11 %#;
combined valve 48 %#
K.M. Bruce et al.
Hudetz et al. (2011) On-pump 1 week Nil 5 Memory and work list No No individual test Tl: 50 %#
CABG memory from scores given
valve Repeatable Battery for
combined the Assessment of
Neuropsychological
status, brief visual
memory test revised,
backward digit span,
semantic memory,
phonemic memory,
geriatric depression scale
Djaiani et al. (2012) On-pump 12 months Nil 5 RAVLT; Rey visual No Significant Tl: 17.4 %#
CABG design learning test; decline on; Rey
TMT A&B; GP; forward visual design
digit span; backward learning test#;
digit span; spatial span GP#; verbal
forward; spatial span fluency test#
backward; choice and
simple reaction time
tests; verbal fluency test
Meybohm On-pump 5–7 days Nil 1,5 Core battery of ten tests Yes Summary Tl: SD method,
et al. (2013) CABG including the following statistics given for 52 %# and 23 %";
valve four main domains: SD method and z-score $
combined memory, motor skills, no individual test T2: SD method,
attention, and executive differences were 21 %# and 36 %";
function (no test names shown using z-score $
Cognitive Impairment After Cardiac Surgery: Confounding Factors and. . .
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George D. Bishop
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Type A Behavior Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 632
Hostility and Anger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633
Type D Personality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 634
Interpersonally Sensitive Disposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 635
Mechanisms Linking Personality to CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 636
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 640
Abstract
This chapter provides an overview of major attempts to relate personality in the
form of stable traits to the development and progression of coronary heart
disease (CHD). Among the first attempts to relate personality to CHD was the
Type A behavior pattern, a complex of emotion and action tendencies including
aggressive competitiveness, free-floating hostility, and time urgency. Although
evidence supported the relationship of the Type A pattern to CHD, questions
arose concerning the aspects of the Type A pattern that were the active ingre-
dients. Analysis of components of the Type A pattern suggested hostility as the
primary active ingredient. This has led to a large number of studies of the
relationship of hostility and anger to CHD, mostly with positive results. In
addition to this work, there is also a body of literature suggesting that a
combination of negative affectivity and social inhibition, a pattern known as
the Type D (distressed) personality, is associated with heightened CHD risk.
Although some studies have supported this idea, a number of studies have
obtained negative findings, and there are concerns about the way in which the
Type D personality is conceptualized and measured. Recently, an integrative
review has suggested that the personality trait of interpersonal sensitivity, a
concern with negative social evaluation, is associated with CHD. This review
concludes by considering possible mechanisms by which personality traits are
associated with CHD.
Keywords
CHD risk • Coronary-prone personality • Type A personality • Type D person-
ality • Hostility • Anger • Interpersonally sensitive disposition
Introduction
Among the first major attempts to relate personality to CHD derives from work by
two cardiologists Friedman and Rosenman (1959, 1974) who observed that individ-
uals at risk for CHD tended to be individuals who were highly competitive,
aggressive, and hostile and had a sense of time urgency. This clinical observation
became enshrined as the Type A behavior pattern. Different methods have been used
to measure Type A with the most common instruments being the structured inter-
view (SI; Chesney et al. 1980) and the Jenkins Activity Survey (Jenkins et al. 1971).
The two measures appear to actually measure slightly different things, and of the
two, the SI has the strongest relationship with CHD (Matthews 1988). Since chapter
“▶ Anger, Hostility, and Cardiovascular Disease in the Context of Interpersonal
Relationships” covers the Type A pattern in detail, this chapter will only mention
Type A briefly as part of the historical development of research on personality
and CHD.
Early evidence for the relationship of Type A to CHD came from the Western
Collaborative Group Study (WCGS; Rosenman et al. 1975) and the Framingham
Heart Study (Haynes et al. 1980), both prospective studies that showed a significant
relationship between the Type A pattern and CHD over periods of 8–9 years. By the
late 1970s, there was enough evidence that a review panel of the National Heart,
Lung, and Blood Institute (Cooper et al. 1981) issued a report declaring the Type A
Personality and Cardiovascular Disease: Overview 633
pattern to be a significant risk factor for CHD. This conclusion has been reinforced
over the years by meta-analyses that have shown a strong relationship between
Type A and CHD in a variety of both cross-sectional and prospective studies (Booth
Kewley and Friedman 1987; Matthews 1988).
Despite the generally positive results for the Type A pattern, a number of
questions remained including the composition of the pattern and which of its
ingredients were the most responsible for its relationship to CHD. Type A started
out as a clinical observation and contains several components including high
achievement striving, hostility, aggressiveness, and a sense of time urgency,
among others. These components are seen as forming an overall syndrome that
together elevate the person’s risk of developing CHD. However, it is not clear
whether all of these components are equally important or whether there are some
components that are more toxic than others. Initial evidence on this question came
from studies of the relationship of the components of Type A to CHD. For example,
Dembroski et al. (1985) found evidence for the primacy of hostility and anger as
key elements of the Type A pattern. Findings such as these have led to a focus on
hostility and anger as important predictors of CHD.
The hypothesis that hostility and anger play a role in heart disease goes back at least
to the nineteenth century (Smith et al. 2004). Empirical work on this topic,
however, began in earnest after analyses of the key components of the Type A
pattern. For example, Barefoot and his colleagues (Barefoot et al. 1983) in a 25-year
follow-up of 255 physicians found a nearly fivefold difference in CHD incidence
between those high and low in hostility as measured by the Cook and Medley
(1954) Hostility (Ho) Scale. Numerous other studies have since been done with
findings consistently showing an increased rate of CHD among those high in
hostility (Smith et al. 2004).
Although hostility and anger are conceptually separate, in practice, it is often
difficult to distinguish between them. Hostility is generally conceptualized in
cognitive terms as being “a negative attitude towards others consisting of enmity,
denigration, and ill will” (Smith 1994, p. 26). Among the measures of hostility that
have been related to CHD are the Cook and Medley (1954) Ho Scale and the
Interpersonal Hostility Assessment Technique (IHAT; Haney et al. 1996). Anger,
by contrast, is generally defined as an affect. Specifically, anger is defined as being
an unpleasant emotion that varies in intensity from mild irritation to rage. From a
personality point of view, trait anger is the enduring tendency to experience
frequent episodes of anger. Among the measures used to assess anger in relation
to CHD is the State-Trait Anger Expression Inventory (STAXI; Spielberger
et al. 1983).
Studies of the association of hostility and anger to CHD have generally
supported this relationship. Although there have been studies with negative find-
ings, a meta-analysis of studies examining the relationship of hostility to CHD
634 G.D. Bishop
found a significant relationship that seemed to vary by the measure of hostility used
(Miller et al. 1996). Since that review, a number of further studies have also found
supporting evidence. For example, the Multiple Risk Factor Intervention Trial
(MRFIT) found that hostility above the sample median, as measured by the
IHAT, was associated with a 60 % increase in risk of cardiovascular death over a
16-year follow-up period as compared with individuals low on the IHAT (Matthews
et al. 2004). Further, a study of 1,000 men over a 30-year period found that high
scores on a three-item measure of trait anger were associated with a three- to sixfold
increase in cardiovascular disease, CHD, and myocardial infarction, after control-
ling for traditional medical, demographic, and behavioral risk factors (Chang
et al. 2002). For further discussion of the relationship between hostility, anger,
and CHD, please see chapter “▶ Gender Differences in Psychological Risk Factors
for Development of Heart Disease”.
Type D Personality
More recently Denollet and colleagues (Denollet and Pederson 2011; Denollet
et al. 2010) have proposed that a general propensity for psychological distress is
a significant risk factor for CHD. Known as the Type D (distressed) personality, this
psychological configuration includes high negative affectivity (NA) combined with
high levels of social inhibition (SI). Assessment of the Type D personality is done
through the Type D Scale (DS14; Denollet 2005) which contains subscales for both
NA and SI. A person is considered to have a Type D personality when scoring high
on both scales. In most studies such individuals are then compared with individuals
scoring low on one or both scales.
Initial evidence for the association of Type D with CHD came from a prospec-
tive study of 303 coronary artery disease (CAD) patients who were assessed for
Type D at baseline and then followed for 6–10 years. At follow-up, 14 % of the
participants had died with those assessed as Type D being 3.8 times as likely to die
as those who were non-Type D (Denollet et al. 1996). Further studies replicated this
result, and a meta-analysis of studies of Type D by Denollet and his colleagues in
various populations showed that individuals assessed as Type D showed a relative
risk of poor prognosis of roughly three times that of non-Type D individuals
(Denollet et al. 2010). Evidence was also obtained that Type D was predictive of
prognosis in patients with heart failure although not all studies showed this effect
(Denollet and Pederson 2011).
Denollet and Pederson (2011) estimate that the prevalence of Type D among
CHD patients ranges from 20 % to 40 % with the prevalence in the general
population ranging between 13 % and 27 %. In addition to poor prognosis in
CHD patients, Type D has also been related to increased risk of emotional distress
among cardiovascular patients including depression, anxiety, mental distress, vital
exhaustion, and negative affect (Denollet and Pederson 2011). It is further argued
that Type D is a distinct construct from depression with Type D being an enduring
trait, whereas depression is episodic. In one study of 1,205 myocardial infarction
Personality and Cardiovascular Disease: Overview 635
(MI) patients, it was noted that 17 % met the criteria for depression, and 19 % were
assessed to have a Type D personality. However, only one in four of the patients
showing distress had both depression and Type D (Denollet et al. 2009).
Not all studies of Type D have produced positive results, however. For example,
a recent study by Meyer and colleagues (2014) did a 5-year follow-up of
465 patients who had undergone percutaneous coronary intervention (PCI). No
evidence was found for an association between Type D personality and major
adverse cardiovascular events (MACE). Negative results have also been obtained
with cardiac patients by Grande et al. (2011). In their study 1,040 cardiac patients
were followed for an average of 6 years. At follow-up there were no differences in
mortality rates between patients classified as Type D and non-Type D. Also Coyne
and colleagues (2011) found no prognostic value for Type D in a sample of
958 heart failure patients.
One key methodological issue concerns the way in which Type D is defined in
most studies. By comparing patients high on both NA and SI with all other patients,
a great deal of information is lost, and no account is taken of the independent effects
of each of these variables in their association with CHD. Further, the power of
statistical tests is reduced, and it is quite possible that the outcome of the study then
depends on “lucky cuts” (Smith 2011). It is of interest to note that four of the studies
obtaining negative results analyzed NA and SI as continuous variables (Coyne
et al. 2011; Grande et al. 2011; Meyer et al. 2014; Pelle et al. 2010). This strongly
argues that future studies of Type D should avoid dichotomization of NA and SI and
analyze these as continuous variables.
Currently available evidence indicates that Type D, while it is a theoretically
based and rigorously defined construct, may or may not be predictive of prognosis
in CHD. Most of the positive evidence for the validity of Type D comes from one
research group, and of late several studies have reported negative findings. As such
it is too early to draw firm conclusions about the role of Type D in CHD.
Recently, Marin and Miller (2013) have proposed the interpersonally sensitive
(IS) disposition as a potential risk factor for ill health including CHD. IS is defined
as “a stable trait characterized by ongoing concerns about negative social evalua-
tion” (Marin and Miller 2013, p. 942). As yet there is no psychometric instrument
specifically designed to measure IS, but Marin and Miller argue that evidence for IS
can be found in studies examining such concepts as rejection sensitivity, social
anxiety and avoidance, social and psychological inhibition, shyness, submissive-
ness, introversion, and Type D. All of these constructs overlap with the general
definition of IS although none of them entirely embody the concept. Marin and
Miller argue that research done on the relationship of these constructs to health can
be used as evidence for the role of IS in health outcomes and that IS provides a
common rubric for interpreting these results. IS is further conceptualized as being
broken down into a cognitive/affective component that represents vigilance for and
636 G.D. Bishop
Smith et al. (2004) as being the psychophysiological reactivity model, the psycho-
social vulnerability model, the transactional model, the health behavior model, and
the constitutional vulnerability model. Each of these will now be discussed in turn.
Psychophysiological reactivity model. Originally formulated by Williams and
his colleagues (Williams et al. 1985) to explain the relationship of hostility to CHD,
this model hypothesizes that personality confers risk through exaggerated physio-
logical reactivity on the part of certain individuals. Specifically, as generalized to the
personality characteristics reviewed here, it is hypothesized that individuals high in
anger or hostility or having a Type D personality or being high in IS show large
increases in blood pressure and heart rate as well as neuroendocrine responses to
various stressors. These exaggerated physiological responses are then hypothesized
to promote the development of atherosclerosis. Since its proposal this hypothesis has
gained strong research support. For example, Suarez and Williams (1989) randomly
assigned young men with high or low hostility, as measured by the Cook and Medley
(1954) Ho Scale, to either doing a set of anagrams while harassed by a rude research
technician or doing those same anagrams without harassment. Measurements of
blood pressure during this procedure revealed that those high on the Ho Scale
showed significantly larger increases in blood pressure when harassed than when
not harassed, whereas those low on the Ho Scale did not show this pattern. Similar
results have been obtained for Type D. In an experiment relating NA and SI to
cardiovascular reactivity, Habra et al. (2003) found that higher levels of SI were
related to blood pressure reactivity while doing a mental arithmetic task while being
harassed, whereas higher levels of NA were related to dampened heart rate change.
Additional evidence for the reactivity model has been obtained by Smith and
colleagues in studies of interactions of married couples (Smith et al. 2004). In
several studies it has been noted that husbands high in hostility show exaggerated
cardiovascular reactivity during stressful marital interactions as compared with
husbands low in hostility. Further, a similar pattern has been found for wives of
high hostile husbands. Evidence linking cardiovascular reactivity to the develop-
ment of atherosclerosis has been obtained by Kamarck et al. (1997) who found that
blood pressure reactivity was related to the development of atherosclerosis over a
4-year period as determined by ultrasound measurements of carotid artery wall
thickness in a sample of Finnish men.
More recently, the psychophysiological reactivity model has been extended to
include both baseline and stress-related increases in triglycerides and both total and
low-density cholesterol. For example, Siegman et al. (2002) found that a measure of
outwardly directed anger was significantly related a negative lipid profile (high
levels of total serum cholesterol, low-density lipoproteins, and triglycerides) among
health women who were physically unfit. Interestingly, this finding was not found
among physically fit women which suggests that physical fitness has a protective
effect in this situation. Also Finney et al. (2002) found high triglyceride reactivity to
a stressful speech task among men who either always expressed or always inhibited
their expression of anger.
Another possible set of mechanisms relates to the role of inflammatory processes
in the development of CHD. Along these lines Suarez et al. (2002) report that
638 G.D. Bishop
Conclusion
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Type A Behavior and Cardiovascular
Disease
Contents
The Early History of the Type A Behavior Pattern and Its Relation to Coronary
Heart Disease (CHD) Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 646
Assessment of the TABP: Measures and Their Relative Usefulness . . . . . . . . . . . . . . . . . . . . . . . . . . . 647
The TABP in the 1980s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 649
The TABP from the 1990s to the Change of the Millennium: What Happened to the
Construct? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 651
Research on the TABP in the Twenty-First Century . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 655
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 659
A Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 660
Abstract
The type A behavior pattern (TABP) showed immense success in predicting
coronary heart disease (CHD) incidence for three decades, from the 1960s onward,
and was considered a strong and independent risk factor for CHD development.
The TABP, or behavior classifications closely related to this pattern, are still used
both in practice and in research settings, for this purpose. But due to a number of
negative findings and critical commentaries on the relation between type A behav-
ior pattern and CHD from the middle of the 1980s and few positive findings in the
same period of time, researchers and practitioners have questioned whether the
TABP’s predictability of future CHD development was really quite so well
established. This chapter describes the early history of TABP and also scrutinizes
the related concept of type A personality, which became the concept to describe
what was the underlying personality of TABP. It sums up the research history for
the TABP construct by starting with a number of reviews and meta-analyses on the
concept from the late 1980s and until now. The chapter is based on a close
examination of the research on TABP involving extensive literature searches
conducted in 2003, 2010, and 2013 using PubMed, MEDLINE and PsycINFO,
and the search term “type behavior and CVD.” While the volume of evidence has
declined over time, recent work suggests a continuing utility for the construct.
Keywords
Type A behaviour • Coronary prone behaviour • Cardiovascular risk • Myocardial
infarction • Epidemiology
The Early History of the Type A Behavior Pattern and Its Relation
to Coronary Heart Disease (CHD) Development
One day in the early 1950s, an upholsterer repairing chairs in the waiting room of two
successful cardiologists in San Francisco, Dr. Ray Rosenman and Dr. Meyer Fried-
man, mentioned to the doctors, after again having redone the chairs of their waiting
room, that they had to have a rather special patient group since only the front edge on
the chairs was worn down. That made the two insightful cardiologists curious about
the behaviors of their patients and instigated both a discussion to conceptualize the
nature of the behaviors and, eventually, a program of research to determine whether
the speculation – for that is what it initially was – held any validity. And from small
beginnings, it was the motivation for the iconic Western Collaborative Group Study
(WCGS), a large study to reveal if there was a common behavioral pattern among
persons in danger of suffering a clinical event of coronary heart diseases (CHD). The
study concluded, on the basis of incontestable evidence, that there were indeed
similarities in the behavior of those at risk of CHD and the behavioral pattern that
emerged was named type A behavior pattern (TABP). The WCGS was the first study
to investigate behavior patterns as risk for heart attacks. Three thousand five hundred
twenty-four men aged 39–59 and employed in the San Francisco Bay or Los Angeles
areas were enrolled in 1960 and 1961. In addition to determinations of behavior
pattern, the initial examination included the person’s medical and family history and
a row of medical, biochemical, and biomedical tests. The WCGS concluded that type
A behavior pattern was a very significant risk factor for the development of CHD.
The TABP became well known and drew enormous attention through the 1950s
and 1960s and was for a long time recognized as the “coronary-prone behavior”
pattern (Friedman and Rosenman 1974). The overall hypothesis that a distinct
Type A Behavior and Cardiovascular Disease 647
The utility of any psychosocial construct in predicting illness events is only as good
as the availability of sound psychometric instruments to measure it. The TABP has
been assessed in many ways over the years, some being demonstrably better than
others – instruments derived from, or part of, existing personality measures have
been used, along with a plethora of short, ad hoc, and usually not well-validated self-
report inventories of behaviors, feelings, and attitudes. Perhaps the most widely used
instrument in the former of these regard was the Cook-Medley Hostility Scale
(Barefoot et al. 1989). But the consensus opinion now is that four assessment
instruments for type A behavior have acquired sufficient use, consistent success,
and well-respected psychometric properties that they can be considered the main-
stays of assessment in the type A story.
The structured interview (SI) for type A behavior was developed by Rosenman
and his colleagues for use in the iconic Western Collaborative Group Study (WCGS)
(Rosenman et al. 1966). The SI combined direct questions to respondents to elicit
648 G.A. Espnes and D. Byrne
TABP sometime into the future, it is now clear that it should take strong account of the
emotional side of the construct as well as the strictly behavioral.
In 1987 Booth-Kewley and Friedman published three articles based on a review and
a meta-analysis carried out on literature addressing the TABP (Friedman and Booth
Kewley 1987a, b; Booth Kewley and Friedman 1987). Two of these articles are
among the most cited articles in the area (Friedman and Booth Kewley 1987a; Booth
Kewley and Friedman 1987). This is mainly because of a general impression at the
time that the TABP was a flawed concept in explaining CHD development. The
feeling that type A was an obsolete concept was based on results from a number of
(largely) cross-sectional studies, carried out in the second half of the 1970s and first
half of the 1980s. Several investigators have since claimed that the reason for the
largely negative results relating the TABP to CHD was caused by flawed method-
ology in both design and measurement (Booth-Kewley and Friedman 1987) and also
by confusing the behavioral concept with a personality type – recognized as the type
A personality (Byrne 1996; Rosenman 1997, Lecture given at 14th world congress
of pychosomatic medicine, 31st Aug–5th Sept 1997, personal communication). A
change of journal editorial policies was also seen as an important factor (Booth-
Kewley and Friedman 1987). Others have suggested that a concept which, to a large
extent, conveniently explained CHD development at one stage of the CHD epidemic
but reflecting characteristics of the society largely tied to this phase of time may not
be transferable to new times and new lifestyles. There has also been a dramatic
change of CHD incidence since the WCGS was undertaken, which could have
changed the whole population of people in risk of having CHD (Espnes 1996;
Booth-Kewley and Friedman 1987).
The most important conclusion concerning the TABP in the Friedman and Booth-
Kewley evaluation of the literature was that the type A behavior pattern is sometimes
referred to as type A personality (Booth-Kewley and Friedman 1987): “Type A
behaviour is modestly but reliably related to CHD (and other occlusive diseases),”
but “Rather, the true picture seems to be one of a person with one or more negative
emotions: perhaps someone who is depressed, aggressively competitive, easily
frustrated, anxious, angry or some combination” (Friedman and Booth-Kewley
1987a, p. 551).
The role of negative emotions and its connection to CHD have been tested in a
number of studies, but the results are very contradictory (e.g., Espnes and Opdahl
1999; Todaro et al. 2003), and it is impossible presently to draw clear conclusions.
One of the reasons for that has been the lack of a “solid” operational definition of
which feelings or other psychological constructs should be included in “negative
emotions.”
In 1988 Karen Matthews wrote a commentary paper to the Friedman and Booth-
Kewley studies, which she called an “Update on and Alternative to the Booth-Kewley
650 G.A. Espnes and D. Byrne
and Friedman (1987) Quantitative Review” (Matthews 1988). She underlines that [in a
meta-analysis] “the reviewer must make a series of decisions about which studies
should be included, and how to weight the available studies, which affect the resulting
estimates.” She also points out that even if cross-sectional and prospective data
initially are analyzed separately in the Booth-Kewley and Friedman article (1987),
they are both included in the estimates of the overall influence of type A behavior on
CHD risk. She reminds the reader on the two independent epidemiological studies
(Cohen and Reed 1985; Johnston et al. 1987) which have found significant relation-
ships between TABP and CHD development in prospective studies but not in cross-
sectional ones.
In a later paper in Psychological Bulletin, Friedman and Booth-Kewley (1988)
addressed the critical comments made by Matthews (1988) and others. They underlined
correctly enough in their response and as the most important argument in favor of their
meta-analyses that “the construct of coronary prone behaviour and its incarnation as the
Type A behaviour pattern have been defined in so many ways and assessed so
unsystematically that some authors throw up their hands and conclude that the whole
matter is not worthy of attention” (Friedman and Booth-Kewley 1988, p. 381).
What Friedman and Booth-Kewley were stressing here is obviously an important
point. The line of research following up the Western Collaborative Group Study has
been very diverse. However, there is simply no other way to comparatively analyze the
predictive strength of the TABP for CHD for the present population than to follow the
line of research that has used the SI (see earlier section on instruments) to obtain data.
Krantz et al.’s (1988) review also (inter alia) examined the current status of the
TABP at that time. They began with a short overview of the landmark prospective
studies which had given the TABP the status of the “coronary-prone behavior,”
including the WCGS, the Framingham study, the Belgian-French Collaborative
Heart Study (see, e.g., Kornitzer et al. 1981), and the Recurrent Coronary Pre-
vention Project (Friedman et al. 1982). Results from the last of these showed that
the TABP could be altered by behavior intervention treatment, to then prevent
recurrent incidences of CHD. Krantz et al. (1988) also offered four possible
explanations for the paucity of findings relating the TAPB and CHD development
in the previous years. Firstly, they suggested that global TABP is not a risk factor
among CHD patients or with individuals with high levels of standard risk factors.
Secondly, they suggest that the positive findings in the Recurrent Coronary
Prevention Project but not in later similar studies might have been caused by the
nonspecific stress-reducing effects of the intervention or effects of social support.
They pointed to the fact that there had been a number of studies supporting the
view that more global stress-reducing interventions promote better clinical out-
comes. Thirdly, they underlined that most of the studies in the late 1970s and early
and mid-1980s were designed as treatment trials to evaluate the efficacy of either
drugs or behavior modification techniques to reduce CHD risk and participation in
such projects may alter aspects of TABP or modify its pathogenic qualities. And
finally, they noted that TABP may be so common among CHD patients that it
could therefore be an insensitive predictor of subsequent clinical outcomes
(Krantz et al. 1988).
Type A Behavior and Cardiovascular Disease 651
Systematic database searches to the end of the 1980s reveal a number of articles
on type A and CHD, but these appear to be papers simply summing up the past era of
the TABP, sometimes employing instruments not validated against the benchmarks
of the SI or JAS (Leon et al. 1988). These papers rarely deal with the major criticisms
of the predictive validity of the TABP for CHD development. There appear, in fact,
to be two parallel lines of publications at that time, those publishing on type A
behavior pattern as if it had not conceptually moved from its origins in the 1960s and
those heavily attacking type A for the lack of predictive value.
One example of the former approach is Harbin’s (1989) paper. He reviewed
reports linking type A behavior to physiological reactivity indicating both general
arousal and cardiovascular activation, pointing out that the conclusions of the
researchers investigating this possible link have been equivocal, with some asserting
that type A persons are more reactive whereas others finding no evidence for such a
conclusion. In Harbin’s (1989) report, a meta-analysis was employed to provide a
quantitative evaluation of the relationship between type A behavior and physiolog-
ical reactivity. Results indicated that (1) type As respond to cognitive and psycho-
motor stimulus situations with greater heart rate and systolic blood pressure
responses, (2) this relationship is not evident in females, (3) the relationship is
more evident for some cognitive tasks than for others, and (4) the strength of the
relationship depends upon the instrument used to assess type A behavior.
The TABP from the 1990s to the Change of the Millennium: What
Happened to the Construct?
A simple count of articles emerging from database searches using the central
keywords of TABP and CHD (spelled out in full) is one indication of the drop in
interest for the TABP pattern after the critical and somewhat negative reviews to the
end of the 1980s. One cannot, of course, be absolutely sure simply from this count
that this is what has happened. It could be that researchers simply lost interest in
investigations on the TABP and CHD, but nothing else points in that direction. The
pattern is therefore quite clear – the interest of TABP seems to vanish through the
1990s (Table 1).
As was obvious from the above searches, some researchers had still strong belief
in the TABP in the beginning of the 1990s (e.g., Craig and Weiss 1990; Zapotoczky
and Wenzel 1990; Strube 1991; Monat and Lazarus 1991; Snyder and Forsyth 1991;
Spielberger et al. 1991; Cooper and Payne 1991; Byrne and Caddy 1992;
Goldeberger and Breznitz 1993; Siegman et al. 1994; Carey and McDevitt 1994;
Friedman et al. 1996; Low 1991).
The overview of work from 1990 to the millennium change can fittingly start with
a paper by one of the fathers of the concept, Ray Rosenman (1990). In his paper
Rosenman gives a brief history of the type A behavior pattern (TABP) and discusses
measurement issues including the construct validation of the TABP concept. Studies
examining the relationship between TABP and coronary heart disease are discussed,
652 G.A. Espnes and D. Byrne
Table 1 Showing the development of publications containing the central keywords; type A
behavior pattern and coronary heart disease from 1990 to 2000
19
Year 90 91 92 93 94 95 96 97 98 99 Total
D-base
PubMed 25 19 8 10 8 4 8 5 4 3 94
MEDLINE 5 3 2 1 2 - 1 1 1 1 17
PsychINFO 10 20 7 7 7 4 5 5 6 3 74
Total 40 42 17 18 17 8 14 11 11 7 217
Book chapters 3 12 2 2 3 2 4 2 3 1 35
and factors that may be responsible for inconsistencies in the literature are empha-
sized. Interventions for TABP are mentioned; with an acknowledgment that
researcher’s varying conceptualizations of TABP make it difficult to develop effec-
tive interventions. Physiological and cardiovascular reactivity, and the roles of
hostility and competitiveness in TABP, are also described. Rosenman here especially
emphasizes the role of hostility as a predictor and as an important part of the type A
construct. This paper is one of the first argument against the conclusions drawn in
findings reported in the reviews and meta-analyses in the late 1980s. He makes it
clear that the inclusion of papers based on methodological flaws is at the root cause
of much of the negative views surrounding the TABP. Rosenman gives in this article
the most recent and comprehensive definition of the TAB: The TABP is, he states:
And it is clear here that in this new definition (Rosenman 1990), while the focus
remains on behaviors, there is now a place for emotions as well.
But as opposed to studies of TABP from the 1980s, a new focus has emerged –
there has been a developing interest in finding which of the components included in
the TABP might be uniquely cardiotoxic and may not be of the same level of
importance for the development of CHD (e.g., Williams et al. 1980).
In 1991 a new meta-analysis was published investigating Booth-Kewley and
Friedman’s (1987) and Matthews’ (1988) meta-analyses (Miller et al. 1991) and
the trend toward null findings in research attempting to link the TABP and CHD.
These authors also point to the fact that even over this period, there had been studies
where earlier findings of predictive validity had been replicated. Based on earlier
publications (Matthews 1988; Pearson 1994; Pickering 1985), Miller et al. (1991)
Type A Behavior and Cardiovascular Disease 653
offer a possible – and interesting – explanation for the null findings, which they
name disease-based spectrum bias (DBS). DBS is present in studies where subjects
are directed into or excluded from a study sample according to their disease status.
An example is the case when healthy individuals are excluded from and diseased
individuals are directed into referred samples (see Miller et al. 1988). The findings of
Kittel (1986) in her Belgian Heart Disease Prevention Project might be a good
example of DBS. Her study involved a successful intervention designed to prevent
CHD by reducing traditional risk factors. Kittel reported a strong relationship
between CHD and TABP in the control group, but no such relationship in the
treatment group. After having carried out a careful reanalysis of the literature, Miller
et al. (1991) emphasize that the finding that DBS occurs in studies of high-risk
populations really is an indication that the magnitude of the relation between TABP
and CHD is larger than has been suggested in recent research and points especially to
the findings of Booth-Kewley and Friedman (1987).
The suggestion that the global measure of TABP might not be the most profitable
strategy to use in the prediction of CHD incidence was also underlined strongly by
Edwards and Baglioni (1991) and Raeikkonen (1992). Raeikkonen (1992) goes on
to state that the many differing operational definitions of type A have resulted both in
conceptual confusion and in confusion with regard to the nature of the type A risk,
and she emphasizes that TABP should now be treated as a multidimensional
construct, since some aspects play a more important role than others in mediating
the association between this behavior pattern and CHD. Edwards and Baglioni
(1991) compared the global and component measures of TABP and concluded that
component TABP analyses show a great number of advantages over global TABP
measures. They also suggest that effort should be made to construct good component
measurements and note that in their study, the behavioral entities that showed the
clearest relationship with the development of CHD were those components reflecting
speed and time pressure.
In 1993, 4 years after Harbin’s (1989) meta-analysis of the research on the
relationship between type A and physiological reactivity, a new meta-analysis of the
data was published (Lyness 1993). Based on information from a total of 99 studies
which were included for analysis, Lyness concludes that type A persons showed
greater stress reactivity than did the type Bs, even if the effect is small. She also
argues that there is reason to believe that the difference in reactivity between the As
and the Bs may actually be larger than found in this meta-analysis, making reference to
the fact that recent studies (Chesney et al. 1988; Ganster et al. 1991; Williams and
Barefoot 1988) have gone into finer detail concerning pathogenic components of the
type A behavior patterns, such as hostility, anger suppression, or speech characteris-
tics, and their relationship to cardiovascular reactivity (Lyness 1993).
A great number of the relevant studies published at the beginning of the 1990s
were obviously in line with suggestions made in both Booth-Kewley and Friedman’s
(1987) and Matthews’ (1988) meta-analyses (e.g., Edwards and Baglioni 1991;
Grennglass and Julkunen 1991; Raeikkonen 1992). These studies include both
TABP (or type A personality) and other related personality or emotionality variables
and their impact on CHD development. But in a greater number of studies on the
654 G.A. Espnes and D. Byrne
psychosocial correlates of CHD, the TABP was often no longer included in inves-
tigations of the psychosocial explanations for CHD. What arose from this line of
investigations was the view that the main psychosocial factors impacting onto CHD
development were those already suggested in Booth-Kewley and Friedmans’s
(1987) meta-analysis, that is, anger and aggression, hostility, irritability, suspicion,
frustration, and guilt (see, e.g., Kopper 1993; Weekes and Waterhouse 1991; Eriksen
1994; Hill et al. 1991). But here as well, definitions and conceptualizations of the
TABP were often not especially precise.
Publications at that time quite often addressed both psychosocial risk factors for
CHD development and the personality characteristics in persons who had suffered
CHD, often mixed together. These studies did not take sufficient care that risk factors
for a first clinical event of CHD and a recurrent attack very well might be two quite,
if not, totally different things (e.g., Espnes 1996).
In 1995 a new paper on the reactivity of TABP persons appeared (Myrtek 1995).
This article presents a meta-analysis of the relationship between TABP or hostility
and personality factors, based on English and German articles published between
1983 and 1992. The author argues that the population effect sizes for other cardio-
vascular and peripheral parameters are very small, some supporting and others
contradicting the hypothesis of hyperreactivity in type A persons. The author
found no evidence for a significant effect on the catecholamine response associated
with individual characteristics of the TABP (Myrtek 1995).
Based on the information from this research, Byrne (1996) felt that the time was
right to carefully go through the newest research on TABP and to analyze what this
meant for the understanding and use of the TABP construct as coronary-prone
behavior. His attempt to solve the dispute on TABP was to fit the new information
into a model of how the TABP could explain both benign and pathological outcomes
with CHD. There had been a number of studies over some years attempting to reveal
the toxic components of TABP, commencing at the beginning of the 1980s (see, e.g.,
Williams et al. 1980; Shekelle et al. 1983; Barefoot et al. 1983). Byrne himself had
been a part of these attempts through his own research (see Byrne and Rosenman
1990). In this light, he suggested a model of the psychopathological paths which the
TAPB follows to “produce” CHD risk (p. 234). In his view, the competitiveness
aspect of TABP must be viewed as a “global motivational predisposition to behav-
ior,” while the rest of the TABP characteristics constitute the A behavior pattern
(recognized as goal oriented, achievement oriented, control oriented, time urgent,
job involved, and acquisitive). He argued that it is the ways in which the individual
characterized by the TABP solves the behavioral demands, whether that pattern of
behavior leads to expression or frustration of type A attributes, and decides whether
the likelihood of CHD risk is elevated or not. If the psychosocial situation allows
expression of the TABP, what follows will be emotional equilibrium and satisfaction,
and the CHD risk will not rise above the age standard risk. However, if the
psychosocial context causes frustration of type A behaviors in individuals charac-
terized by the TABP, what follows will be emotional distress and dissatisfaction and
a potentially elevated level of coronary risk.
Type A Behavior and Cardiovascular Disease 655
There is no doubt, as already suggested, that the publication rate of journal articles
researching the TABP has fallen dramatically over the last three decades. In this final
part of the chapter, this trend will be illustrated graphically, and published research
reports investigating the TABP as a contributor to CHD development will be
discussed. Published papers that simply mention the TABP, even though appearing
in literature searches, will not be included.
In 2000 Elianne Riska published a paper titled “The rise and fall of Type A man”
in Social Science and Medicine. She claims that the fall of type A man started when
researchers moved to viewing the type A concept more as a personality type than a
straightforward description of overt patterns of behaviors. Of course, this became
evident as far back as the 1970s and 1980s, in Riska’s assessment of the area. The
conceptual importance of this paper lies with the inevitable questions it poses on
the evolution and the decline of a once strong and widely accepted construct.
656 G.A. Espnes and D. Byrne
Table 2 Showing the development of publications containing the central keywords; type A
behavior pattern and coronary heart disease from 2000 to 2013
20
Year 00 01 02 03 04 05 06 07 08 09 10 11 12 13 Total
D-base
PubMed 8 4 3 8 7 4 9 8 6 3 - 1 2 -
MEDLINE 2 - - 1 1 - 2 1 1 - - - - -
PsychINFO 5 - 2 1 2 - 4 1 1 1 - 1 - -
Total 15 4 5 10 11 4 14 11 8 4 - 2 2 -
Book chapters - - 1 - - - - 2 - - - - - -
One of the articles found in MedLine in 2006 was a book review on Risk as Masculinity and Mens
Health, 2004. Two PhD dissertations 2004 and 2005 was also reported in MedLine
What happened? Had the TABP become out of date? Had scientific trials shown it to
be seriously flawed, either conceptually or in definition? Or had those contributing to
the scientific evidence underlying the acquisition of CVD risk research simply
forgotten about it (Table 2)?
Riska’s (2000) paper sums up the whole area of TABP research and tries to come
to terms with what happened over the course of time to a concept leading to a
description of a pattern of behavior, most often seen in white middle-class men,
where the possession of this behavior pattern endowed a conspicuous health risk.
One clear conclusion emerged from her conceptual analysis; the problem appeared
to arise when the TABP ceased to be a simple and pragmatic way to identify future
cardiac patients in the medical setting and evolved into a more complex psycholog-
ical or personality “type.” While originally only the surface of the type man was
mapped by means of behavioral typing, now the exploration of the interior of the
type A man had begun. Where the physicians saw behaviors, the psychologists were
looking for inner reasons and tried to redesign the TABP in line with their conceptual
predispositions. In a review of Riska’s book, Goldstein (2006) concluded that Riska
had shown that TABP and related concepts “medicalized” man’s suffering in ways
that denied the important role of social position.
The paper is interesting for many reasons; it gives an account of an alternative
way to evaluate what had happened with the construct of the TABP, but it is also
consistent with the critical comments often leveled at the two originators of the
TABP, Rosenman and Friedman. These critics seldom surfaced as long as the TABP
was a popular psychological construct. But Friedman and Rosenman were them-
selves quite often critical to the approach that psychologists took to the whole
concept, and Rosenman more than once expressed the view that “I know nothing
about personality and personality traits, I only know that this behaviour pattern as we
have described shows with great certainty who is going to suffer a cardiac attack”
(Rosenman 1997, Lecture given at 14th world congress of pychosomatic medicine,
31st Aug–5th Sept 1997, personal communication). Friedman was of the same
opinion and in a paper written in 1984 criticizing psychologists and the way they
treated the TABP (Friedman and Ulmer 1984). Another veteran of the type A
Type A Behavior and Cardiovascular Disease 657
conceptual debate, Virginia Price, was equally critical. She wrote: “In fact, the failure
to develop a conceptual model of Type A grounded in contemporary psychology
seems to be responsible for the rather slow accumulation of generalizable and
replicable findings in Type A research” (Price 1982, p. xiii).
Some of this understanding is also present in a later article (Myrtek 2001), in
which the author fails to use the descriptor “TAPB” when referring to the concept in
the title but rather refers to it as type A personality. It is quite clear from a
conceptual perspective that it is the type A personality he wants to explore and
not the TABP – because it employs only the keywords TAP (type A personality) and
coronary heart disease, to reveal 559 published studies. The article reports a meta-
analysis of prospective studies on CHD, type A [personality], and hostility covering
the period 1966–1998. By doing so, he appears to fall into the same trap as others
have; he mixes different concepts in undertaking the analyses without perhaps
realizing that semantic or superficial relationships between the concepts used (the
TABP, type A personality, and simply type A), with their varying meanings and
definitions, do not allow the research outcomes to be directly comparable to one
another.
The Fukoua Heart Study Group (2001) and Yoshimasu et al. (2002) report a
retrospective study of type A behavior patterns and job-related psychological factors
to the risk of myocardial infarction in 290 persons who have experienced a nonfatal
clinical event. Here yet another scale was in use, the Tokai Activity Survey (Maeda
1991), and while they report no association between type A and coronary athero-
sclerosis, the use of a nonstandard scale to measure the TABP does not allow for
direct comparison with studies of a similar intent.
In an attempt to establish a national consensus of psychosocial risk factors for
CHD, the Medical Journal of Australia a decade ago published a national position
statement on “stress” and coronary heart disease (Bunker et al. 2003). In this
statement it was noted that while there was a good deal of positive evidence from
early studies linking the TABP with CVD risk, many later studies concluded that
there was no evidence for an effect of the TABP on risk of CVD (Bunker et al. 2003).
Gallacher et al. (2003) reported on an investigation into whether the TABP acts as
a trigger for clinical events of CHD. The study included 2394 men and the TABP
was assessed by three different self-report instruments, the Jenkins Activity Survey,
the Bortner scale, and the Framingham scale. Interestingly, the most important
finding from the study was that while there was no difference in type A scores
between those who suffered a clinical event and those who do not, the TABP was
strongly associated with the timing of the event.
Discussed the relation between behaviors believed to be related to the develop-
ment of CHD and behaviors making up the TABP complex. They concluded that
both hostility and time urgency, both well-known behavioral characteristics of the
TABP, had been closely related to CHD development in published studies.
Oashi (2003) reviewed techniques reported in the published literature to be able to
alter the TABP as a risk factor for CHD. On the basis that the modification of the
TABP has resulted, in a number of reported investigations, to lower risk of CHD, he
concluded that the TABP remained an important risk for CHD development.
658 G.A. Espnes and D. Byrne
In 2009, again only a single relevant article for this discussion was found. It is on
the psychological vulnerability of persons from a university sample who display the
type A behavior pattern. The results indicate that type A individuals may experience
psychosocial vulnerability, particularly stress, which may put them at risk of the
experience of negative health outcomes.
For 2010 no research activity from international databases were reported, and for
the following 2 years, there was just one article on TABP and its relation to CHD
(Liu et al. 2012) but also a further article on the TABP and its relationship to type D
personality (Zhao et al. 2011) which also have attracted attention as a CHD-prone
characteristic in the research in the area. These together with a book chapter by
Robert Allan in Heart and Mind: The practices of Cardiac Psychology in 2011 are
the last publications on TABP and conclude this overview of TABP-related publi-
cations in the present era.
Conclusions
It is quite obvious from the evidence presented above that many of the studies of
type A behavior published in the last 20 years suffer from (1) poor and imprecise
operationalization of the theoretical concepts; (2) the use of number of different but
poorly validated scales and instruments which have been widely used to assess
TAPB or related concepts too often confused with the TABP; (3) investigations
focusing on groups and samples in which the links between the TAPB and CHD
have not been found for almost 40 years, namely, persons with existing CHD, or
those at high risk of a recurrent attack; (4) poor, inaccurate, or vague definitions of
the TAPB or its related constructs (e.g., type A personality), so mitigating against
the possibility of comparing studies across the field or of reexamining them; and
(5) a focus of the research in recent years on Eastern cultures that research which,
incidentally, suffers from many of the methodological and conceptual problems
outlined above. On these grounds, while there is clearly a need to critically
consider the concept of the TABP and the evidence linking it with CHD, caution
is needed lest we abandon the construct too quickly and throw out the baby with
the bathwater.
Large cohort prospective studies of the TABP and CVD have not been aban-
doned; the TABP is clearly an area of continuing interest in Japan and other Eastern
populations.
On balance, the emerging evidence indicates to us that completely discarding the
TABP would at this point be premature. A better integration of demographic and
cultural factors into predictive equations and the commitment to undertake the
“definitive” epidemiological study with sufficient statistical power, where the
TABP was the major focus of interest (a new WCGS, perhaps), would effectively
address the controversy once and for all. And so a final “burial” of the construct is
not yet indicated – the promise is still there.
660 G.A. Espnes and D. Byrne
A Dedication
It is with both affection and humility that we dedicate this chapter to Dr Ray H
Rosenman, the co-originator of the Type A construct, who passed away on 20 May
2013. Ray was a good friend and a generous mentor to many of us then working in
the field of Psychocardiology. His profound and original clinical insight in recog-
nizing in his patients what subsequently became known as Type A Behaviour, and
his outstanding scientific skill in turning this astute clinical observation into an
operational definition capable of objective measurement, gave rise to one of the
undisputed research landmarks in the area. He will be remembered by so many with
respect, admiration and appreciation.
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Anger, Hostility, and Cardiovascular
Disease in the Context of Interpersonal
Relationships
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Phenomenology of Anger and Related Constructs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 666
Operational Definitions and Anger Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 668
Diagnosis of Dysfunctional Anger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Anger, Hostility, and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 669
Anger in Interpersonal Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Anger Suppression and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
Treatment Options for Anger in CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Cognitive Behavioral Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Cognitive Behavioral Affective Therapy (CBAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 676
Interpersonal Therapy and Other Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
Usefulness in the Management of Coronary Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
Abstract
Anger and hostility are described with special attention to their cognitive-
motivational properties. Varying operational definitions related to anger self-
report and behavioral observation are presented. The idea that anger can be
maladaptive is now widely accepted as in DSM and alternative classifications of
dysfunctional anger. The idea that maladaptive anger raises risks for hypertension
and coronary heart disease is reviewed with reference to empirical findings on
mediators such as atherosclerosis, cardiovascular reactivity, immune system
E. Fernandez (*)
Department of Psychology, University of Texas, San Antonio, TX, USA
e-mail: [email protected]
T.W. Smith
Department of Psychology, University of Utah, Salt Lake City, UT, USA
e-mail: [email protected]
changes, and unhealthy lifestyles. Given that anger is a relational emotion, it is not
surprising that it befalls many interpersonal relations including close/intimate
relationships. Dimensions of affiliation and control in relationships are presented
as a framework for understanding how anger and hostility can develop and persist
in these contexts. The further connection between such anger and cardiovascular
function is illustrated. Fortunately, maladaptive anger is treatable, as explained
with meta-analytic evidence on cognitive behavioral therapy (CBT). Also avail-
able are recent enhancements like CBAT that involve sequencing multiple cog-
nitive, behavioral, and affective strategies appropriate to the process of anger from
onset, through progression, to offset. Finally, traditional interpersonal therapies
and newer therapeutic formulations such as acceptance and commitment therapy
may address major themes in interpersonal conflict underlying the onset and
maintenance of cardiovascular disease. Yet, many of these potential applications
still await research and implementation in the field of psychocardiology.
Keywords
Anger • Hostility • Cardiovascular disease • Reactivity • Hypertension • Inter-
personal relationships • Affiliation • Dominance-submission • Cognitive behav-
ioral affective therapy • CBAT
Introduction
The many definitions of anger differ in points of emphasis. At a basic level, anger can
be defined as, “an unpleasant emotion ranging in intensity from irritation or annoyance
to fury or rage” (Smith 1994, p. 25). Some definitions emphasize that anger is a moral
emotion in the sense that it implies a perceived discrepancy with a standard of conduct
(e.g., Hutcherson and Gross 2011). Others see it as an approach emotion that occurs
when progress toward desired goals is impeded (e.g., Carver and Harmon-Jones 2009),
though indirect and even detached expression of anger should not go unrecognized
especially in the present population of interest. Finally, a number of scholars point
out that anger is a relational emotion that occurs in a socially constructed context
(Laughlin and Warner 2005); this is highly consistent with the interpersonal perspec-
tive of anger in cardiovascular disease (Smith and Cundiff 2011).
Anger, Hostility, and Cardiovascular Disease in the Context of Interpersonal. . . 667
schema of strong disapproval toward others (Brodsky 2011). In short, anger takes
three main forms depending on such parameters as frequency, duration, and
intensity. To say that someone is in an angry state is quite different from saying
that she/he is in an irritable/irascible mood, which in turn differs from character-
izing someone as having a hostile temperament (Fernandez 2013).
The study of anger and related traits as influences on the development and course of
coronary heart disease (CHD) and other forms of cardiovascular disease (CVD)
such as essential hypertension and stroke has a long history in medicine (Smith
et al. 2004). In more recent decades, this topic was an outgrowth of research on the
Type A coronary-prone behavior pattern (Miller et al. 1996; Byrne 2000), in which
research sought to identify the “toxic core” of the multifaceted Type A pattern.
Quantitative reviews of prospective studies indicate that high levels of anger,
hostility, and aggressiveness increase the risk of the initial development of CHD,
as well as increase the risk of recurrent cardiac events and earlier mortality among
patients with existing disease (Miller et al. 1996; Chida and Steptoe 2009).
Given the decades-long natural history of CHD (see chapter 1, this volume),
these associations raise an important question as to which phases of the disease are
potentially influenced by anger and hostility. The current evidence suggests a role
in multiple disease stages. For example, among persons without any clinical signs
of clinical CVD, anger and hostility are associated with early, asymptomatic
indicators of atherosclerosis, including endothelial dysfunction and arterial stiffness
(Gottdiener et al. 2003; Williams et al. 2006), atherosclerosis in the carotid arteries
(Everson-Rose et al. 2006), and coronary artery calcification (Smith et al. 2007).
670 E. Fernandez and T.W. Smith
Episodes of anger can also precipitate or “trigger” acute cardiac events, such as
myocardial infarction (Mostofsky et al. 2013, 2014). Among patients with
advanced coronary atherosclerosis, experimentally evoked anger (e.g., recall and
discussion of anger-arousing events) can evoke myocardial ischemia (Strike and
Steptoe 2005). Thus, anger and hostility most likely predict the development of
CHD morbidity and mortality because they promote the initial development and
progression of the underlying atherosclerosis but also because these traits can
contribute to the precipitation of ischemia and acute coronary crises among persons
with advanced disease.
These associations likely reflect multiple biobehavioral mechanisms. For exam-
ple, anger and hostility are associated with unhealthy lifestyles, including tobacco
use, alcohol abuse, physical inactivity, and poor diet (Bunde and Suls 2006). In
some studies, these poor health behaviors mediate the association between anger /
hostility and CHD outcomes (e.g., Boyle et al. 2008). However, in many other
instances, anger and hostility predict CHD morbidity and mortality even when
health behaviors are statistically controlled, suggesting a role for mechanisms
beyond poor health habits.
The physiological effects of psychological stressors (e.g., Esler et al. 2008;
Wright and Stewart 2012) also may play an important role. Frequent and pro-
nounced increases in heart rate, blood pressure, and neuroendocrine events (e.g.,
catecholamines, cortisol) in response to stressful circumstances and the delayed
recovery of these physiological responses can contribute to atherosclerosis and the
triggering of acute CHD events (Chida and Steptoe 2009; Steptoe and Kivimaki
2013). Chronically angry and hostile persons, compared to more even-tempered
and agreeable individuals, show heightened physiological responses to a variety of
stressors but especially those involving interpersonal conflict or mistreatment
(Smith et al. 2004). Anger and hostility also interfere with the otherwise beneficial
effects of social support in dampening these physiological stress responses (Holt-
Lunstad et al. 2008; Smith et al. 2004). That is, unlike more trusting and agreeable
persons, chronically angry and hostile individuals do not display attenuated phys-
iological responses to acute stressors when they receive social support. Trait anger
and hostility are also associated with chronic systemic inflammation (Smith et al. in
press; Suarez 2012), and this sustained immune system response is closely tied to
the development and progression of atherosclerosis (Steptoe and Kivimaki 2013).
Thus, increased frequency, degree, and duration of physiological stress responses
may contribute to the association of anger and hostility with CVD in general and
with CHD in particular.
Physiological stress responses typically recover during sleep, falling below
daytime levels. Thus, adequate restorative sleep is associated with lower risk of
CVD, whereas poor or inadequate sleep is associated with greater risk (e.g., King
et al. 2008). Chronic anger and hostility are associated with poor sleep (Brissette
and Cohen 2002), which may be an additional mechanism contributing to the
association with CVD.
Anger, Hostility, and Cardiovascular Disease in the Context of Interpersonal. . . 671
DOMINANCE
Ambitious-Dominant
(PA)
Arrogant- C Gregarious-
Calculating O Extraverted
(BC) N (NO)
T
R
O
HOSTILITY L FRIENDLINESS
Cold-Quarrelsome AFFILIATION Warm-Agreeable
(DE) (LM)
Unassuming-
Aloof-Introverted Ingenuous
(FG) (JK)
Lazy-Submissive
(HI)
SUBMISSIVENESS
Fig. 1 The interpersonal circumplex. Social behavior is described as various blends of the two
basic dimensions of affiliation and control. Anger, hostility, and aggressiveness are all associated
strongly with low affiliation, but different aspects of this domain range from hostile dominance to
hostile submissiveness
INDIVIDUAL
COVERT EXPERIENCE
BELIEFS
LIFE TASKS OVERT BEHAVIOR
APPRAISALS EMOTION
AFFECT
COVERT EXPERIENCE
CONSTRICTED APPRAISAL
COMPLEMENTARY ATTRIBUTION
RESPONSES
AFFECT
ACTION TENDENCIES
Fig. 2 The transactional cycle. Individuals’ covert experiences (e.g., goals, affect, beliefs) guide
their overt behavior, in ways that tend to constrict the range of possible covert and overt reactions
by their interaction partners
explanation for other’s actions) lead him/her to behave outwardly with low warmth
and high hostility. These behavioral expressions limit the subjective impact of the
angry actor’s behavior on their interaction partners, increasing the likelihood that
angry, hostile, and aggressive behavior will be reciprocated, further maintaining
and perhaps exacerbating the angry actor’s emotional, cognitive, and behavioral
tendencies.
This perspective suggests an expanded view of the role of physiological reac-
tivity in the association of anger and hostility with CVD. As illustrated in Fig. 3,
compared to the blood pressure response of the friendly person depicted in the
lower panels, the hostile-dominant individual depicted in the upper panels responds
with larger and more prolonged increases in blood pressure in response to the same
674 E. Fernandez and T.W. Smith
HOSTILE-DOMINANT INDIVIDUAL
Laboratory Daily Experiences
Blood
Pressure
Stress
Magnitude
Blood
Pressure
Stress
Magnitude
Fig. 3 Conceptual depiction of effects of individual differences in stress reactivity and exposure on
overall levels of blood pressure observed during controlled laboratory conditions and during daily life
for a hostile-dominant person (upper portion) and a friendly individual (lower portion). When
experiencing the same stressor, the hostile-dominant individual displays greater blood pressure increase
than the friendly person. In everyday life, the hostile-dominant person also encounters more frequent,
severe, and prolonged stressors as a result of the impact on others of their own interpersonal behavior
degree of blood pressure reactivity in the daily life of the hostile-dominant indi-
vidual is due to not only greater reactivity to equivalent stressors but also to their
exposure to more frequent, severe, and prolonged interpersonal stressors, relative to
the friendly individual. That greater stress exposure, in turn, reflects the tendency of
the hostile-dominant individual to create more frequent and severe interpersonal
difficulties, through the impact of their actions and emotional expression on others.
This pattern is also exacerbated by the hostile-dominant individual’s tendency to
mentally rehearse past interpersonal difficulties and grievances (i.e., rumination),
their tendency to undermine potential sources of social support, and their tendency
to fail to benefit physiologically from social support when they get it.
The proverbial explosion or outburst is not the only way in which anger poses a
threat to cardiovascular health. Rather, anger can be suppressed or else manifested
in relatively attenuated and indirect ways (Fernandez 2008) consistent with the
hostile-submissive personality style (Smith et al. 2010). Interpersonal relations
within work and social contexts may place a premium on inhibition of angry
behavior. However, this often comes at a cost of well-being, especially a cost to
cardiovascular health (Mauss and Gross 2004).
Research points to a fairly reliable relationship between anger suppression and
blood pressure. For example, Hosseini et al. (2011) compared hypertensive patients
with a group of healthy normals matched on age, gender, and educational level.
Anger-in but not anger-out (as measured by the STAXI) was significantly higher in
the case group than the control group. Sharma (2003) found that in comparison to
normotensive individuals, hypertensive patients reported more stress from life
events, more suppression of anger, and more trait anger and trait anxiety. Con-
versely, hypertensives showed lower outward expression and control of angry
feelings as measured on the STAXI.
Going beyond self-reports of trait anger, Quartana and Burns (2010) used a
laboratory context to assess cardiovascular reactivity to experimentally induced
anger. It was reported that when participants underwent an experimental manipu-
lation to suppress anger, there was a delayed increase in systolic blood pressure.
Special attention has been directed at the cardiovascular effects of anger sup-
pression in women, in the light of gender differences in expression but not expe-
rience of anger (Fernandez and Malley-Morrison 2013). Based on a Canadian
sample of female managers, Greenglass (1996) suggested that cynical distrust and
internalized anger might be precursors of hypertension. Thomas (1997) reported
that when women suppressed anger in the home environment, it was accompanied
by increases in systolic blood pressure and diastolic blood pressure. Using electron
beam computed tomographic scans to determine coronary artery calcification, Low
et al. (2011) observed that in postmenopausal women, anger-in was part of a
psychosocial risk index predicting a significant increase in coronary artery calcifi-
cation and a trend toward atherosclerosis over a 3-year period. In a review of the
676 E. Fernandez and T.W. Smith
literature on psychosocial risks of CVD, Low et al. (2010) concluded that for
women, there is ample evidence that anger suppression and the stress of family
and interpersonal relationships are among the main psychosocial factors associated
with increased CHD.
For a critical review of the research on the cardiovascular effects of emotion
suppression, see Mauss and Gross (2004). As the authors point out, there is a
complexity in emotion suppression that may require further elaboration of the
findings in this area.
ANGER PREVENTION
Rehearsal
Response Prevention
Stimulus
Control
ANGER INTERVENTION
Thought-Stopping
Reappraisal
Distraction
Relaxation
ANGER POSTVENTION
Disclosure
Art Therapy
One reminder at this point is that like CBT for anger, CBAT is delivered very much
in the format of a skills training program. Rather than engaging in psychotherapeu-
tic dialogue, participants actually learn skills for implementation in everyday
naturalistic settings when anger is likely to occur. In other words, anger is treated
primarily as an intrapsychic problem. However, this chapter stresses that the anger
of CVD patients often arises within a relational context that is often beset with
perceived wrongdoings and conflict. The importance of addressing such interper-
sonal conflict is acknowledged in psychodynamic therapy. The tried and tested
tools of marital and family therapy are particularly relevant in this context. Also
productive may be strategies that have evolved within the conflict resolution
literature. In more recent times, acceptance and commitment therapy (ACT) has
rekindled interest in forgiveness, mindfulness, and other perspectives (e.g., Day
et al. 2008) that have roots in many theological and philosophical traditions.
Some rehabilitation programs for CVD have had elements of counseling and
therapy. A meta-analytic review found that stress management and related psycho-
social interventions for CHD patients reduce recurrent cardiac events and mortality
(Linden et al. 2007). Group-based therapy to reduce Type A behavior has been
found to reduce recurrent coronary events among CHD patients (Friedman
et al. 1986), and this approach also reduces anger and hostility (Mendes de Leon
et al. 1991). Although relaxation training and reduced stress is a cornerstone of
many of the CBT approaches to the treatment of anger described above, few studies
have examined the effects of anger treatment in CHD patients. In one exception, a
course of eight 90-min group CBT sessions reduced self-reports and behavioral
ratings of anger and hostility and also reduced resting blood pressure (Gidron
et al. 1999). The intervention also reduced rehospitalizations and related medical
costs (Davidson et al. 2007). This specific approach utilized cognitive restructuring
techniques to reduce hostile cognition, relaxation to address angry arousal, and
related CBT approaches to modify aggressive behavior. This preliminary evidence
suggests that cognitive, behavioral, and affective approaches to modifying anger
and hostility in CHD patients may have clinical benefits, and this is encouraging
news for further research in this field.
Conclusions
Anger and the closely related traits of hostility and aggressiveness are associated
with an increased risk of CVD generally and CHD in particular. These associations
have been demonstrated along the full course of the disease process, from the early
indications of asymptomatic atherosclerosis to the later emergence and course of
Anger, Hostility, and Cardiovascular Disease in the Context of Interpersonal. . . 679
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Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 686
Literature Search Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
The Epidemiological Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 688
Psychological and Psychosocial Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 689
Type A Behavior Pattern . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Negative and Troublesome Feelings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Hostility, Anger, Aggression, and Irritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 692
This chapter presents a revised version of a paper originally published in Stress and Health (2008),
24, 188–195, (Wiley Interscience) by two of the present authors (Espnes and Byrne). The revision
has been made with the permission of the publisher.
G.A. Espnes (*)
Center for Health Promotion Research, Department of Social Work and Health Science,
Norwegian University of Science and Technology (NTNU), Trondheim, Norway
Australian National University, Canberra, ACT, Australia
e-mail: [email protected]; [email protected]
C. Nguyen
Center for Health Promotion Research, Department of Social Work and Health Science,
Norwegian University of Science and Technology (NTNU), Trondheim, Norway
e-mail: [email protected]
D. Byrne
ANU Medical School, College of Medicine Biology and Environment, Australian National
University, Acton, Canberra, ACT, Australia
ANU Medical School, Research School of Psychology, Australian National University, Acton,
Canberra, ACT, Australia
e-mail: [email protected]
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
Type D Personality and Negative Emotions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 693
Pessimism and Optimism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694
Implications of the New Knowledge of Sex (and Gender) Differences for
the Understanding of Development of CHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 695
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 696
Abstract
While coronary heart disease (CHD) for decades was understood as mainly a
male disease group, it has through the last years become increasingly evident
that it is now an important disease causing premature death also in the female
populations throughout the Westernized world. Present paper scrutinizes via
literature searches and discussions of relevant data the sex and gender differ-
ences in psychological risk factors for CHD with an emphasis on female risk. It
is concluded that the risk factor picture in females is, due to limited research, still
far from clear, even if there are indications of sex differences in both the risk
factors picture and the trajectories of the disease development.
Keywords
Female • Women • Gender • Coronary heart disease (CHD) • Myocardial
infarction (MI) • Ischemic heart disease (IHD)
Introduction
opposite has happened in women, where in some societies, the female incidence in
fact has shown a remarkable upsurge in both severe and less severe coronary events
(e.g., Sclavo 2001; Burell and Granlund 2002).
Today it has become quite clear that there are important gender differences in
both physiological and biochemical risk factors for CHD and in symptoms of
CHD manifestation (Chiamvimonvat and Sternberg 1998; Miller 2002; Kyker
and Limacher 2002; Franklin 2002). It is now a consistent view that a better
understanding of the sex differences in risk factors will potentially lead to a slowing
of the CHD epidemic in women (Polk and Naqvi 2005; Witt and Roger 2003).
This chapter is an update of a journal article presented in Stress and Health in
2008 (Espnes and Byrne 2008). The literature searches have been following the
same patterns both times.
The objective of the present paper is to (1) examine the epidemiological
evidence from Western countries to establish consistency; (2) examine the primary
psychological coronary risks, impacting on women relative to men generally, and
risks from stress in particular (and to go at least part way to understanding the
narrowing margin in cardiovascular risk between women and men); (3) examine the
most important implications of these data for possible interventions to lower
cardiovascular risk in women and men; and (4) analyze and critique what seems
to be the existing assumption that identical approaches to women and men with
regard to managing cardiovascular risk represent best practice in both prevention
and treatment.
The literature searches for this review have been done at two different occasions but
following the exact same pattern (see Fig. 1). They were carried out on the Internet
using relevant library databases (PsycInfo, Medline, and PubMed). The first
searches were done by entering the primary search term related to psychological
risk factors. To narrow the searches, the second search term was entered, and,
finally, to be sure that we had narrowed down to absolute possible hits, the tertiary
terms were entered (see Fig. 1).
For the period before 2008, we ended up with 95 papers, 68 of which have been
included in the review because they add valuable information to the focus of
the paper; for the period post 2008, the numbers were, respectively, 48 and 20.
The searches were carried out in 2003/2004, 2007, and again in 2015.
While a total of around 510,000 men in the USA died from CVD during 1980, less
than 440,000 did in 2000. The trend among women, however, is almost opposite;
while about 470,000 died from CVD in 1970, about 505,000 died from CVD in
2000 (American Heart Association 2003, p. 4). Looking at CHD alone, representing
about 50 % of all CVD mortality, around 1,000,000 people every year experience
an initial or recurrent coronary event in the USA alone, and around 450,000 die
from CHD (both sexes included).
Somewhat curiously, however, our reanalysis of the data used by the Amer-
ican Heart Association to form the statistics for the period of 1987–1997 (WHO
data set) indicated that the trend for women relative to men was considerably
better than what the AHA publication (American Heart Association 2003, p. 4)
suggested. There are also studies from specific locations in Northern America
which actually show a drop in CHD mortality for both men and women in some
ares (Rosamond et al. 1998) and a drop, at least, in female incidence of CHD in
other areas (Hu et al. 2000). Lang et al. (1999) concluded that conflicting data
may stem from disparate reporting conventions and different definitions of or
criteria for CHD prevalence and incidence. It is, however, now clear that the
total incidence of CHD for women after menopause now equals that of men
(Chiamvimonvat and Sternberg 1998) and that death rates increase exponen-
tially with age, beginning at the age of 20 or 30, with no change in slope of
CHD rates between the ages of 45 and 55 years. CHD is therefore an adult
phenomenon in women and not just a postmenopausal one (Barrett-Connor and
Stuenkel 1999). The seriousness of the problem of CHD in women is clearly
addressed in the World Health Organization Newsletter, Heart Beat (Nishtar
2003) where it is referred to as “the escalating burden of cardiovascular diseases
among women.”
CVD is still the leading cause of mortality in both women and men worldwide; it
was responsible for 17.5 million deaths in 2012 (WHO 2014b) and is now consid-
ered one of the most important health threats in the United Nations (UN) and the
World Health Organization’s (WHO) fight against noncommunicable diseases
(NCDs) (WHO 2014a; UN 2012). Data from the (WHO 2014c) showed that, in
2012, the CVD mortality rates in the USA were 169.5 and 107.8 per 100,000 for
males and females consecutively. According to their recent report, the annual CVD
mortality is estimated to increase further toward 2030 (WHO 2014b).
Gender Differences in Psychological Risk Factors for Development of Heart. . . 689
When searching the literature for sex or gender differences of psychological risk
factors for developing CHD, we found that we can, in a broad overview, name three
main groups of psychological factors that have been researched for their connection
to CHD development. The groups can be named (I) emotional, (II) behavioral, and
(III) environmental. Together these three groups contain eight different subgroups
of risk factors. These are, first, the emotional (1) stress, (2) type A behavior pattern,
(3) different troublesome emotions (including the dichotomy of pessimism and
optimism), and (4) social support will, even if this factor can be defined to be both
behavioral and environmental, be included here. This group of factors will be of
special interest to this paper. The second group, behavioral factors, contains
(5) smoking, (6) physical inactivity/sedantivity, and (7) obesity/diet. These factors
are not the primary subjects to this paper and research from these areas will not be
included. There is also a purely environmental set of factors which we have called
(8) social class or socioeconomic status. This last group will be offered some more
attention since social class or occupational class has been shown to have impact on
stress development (e.g., Wamala et al. 2001) and will therefore be treated in
connection to stress. Of course, some of these factors are individually related,
precursors for, or facilitating or mediating each other, but they also appear as
independently investigated.
Stress
The term or concept stress is often defined as the physical and psychological result
of internal or external pressures. Stress is the one biopsychological factor that has
been linked to the largest number of diseases and, particularly, been connected to
development of CHD. Links between hypertension and stress have for many years
constituted the archetypal example of how physiological (or clinical) and psycho-
logical phenomena may be causally related. Stressors, whether mental or environ-
mental, are readily identified and reproduced, and one of the most active areas in
psychosomatic research has been the investigation of cardiovascular reactivity to
mental stress. Stress has been found to be a precursor for the development of other
risk factors, particularly hypertension and lipid levels. In the recent past, it has been
questioned as to whether stress is caused by the same kind of strain, whether stress
and strain are the same, and finally whether stress has the same consequences for
both sexes (Weidner et al. 1997, 2001; Taylor et al. 2000).
The Stockholm Female Coronary Risk Study demonstrated that women who had
suffered an episode of CHD showed lower heart rate responses to mental stress than
did their male counterparts (Weidner et al. 2001). Summing up another Swedish
study, the authors claim that stress is the main risk factor for development of CHD
in women and that women have more problems with stress stemming from home
and from within the family than do men (Balog et al. 2003). These results are
supported by results from the Family Heart Study (USA) showing that females
690 G.A. Espnes et al.
seem to feel less job strain from working outside the house than do either home-
makers or men (Weidner et al. 1997; Ferris et al. 2005) and also from studies on
burnout (Kinnunen et al. 2006).
As previously mentioned, the cause of stress can stem from a variety of strain
situations. To come from a disadvantaged social class or socioeconomic status and
to belong to a low occupational class are such situations that have been found to be
associated with CHD development. It has earlier been suggested that this stressor
(social class disadvantage) may have the same effect on CHD development in
males and females (Brezninka and Kittel 1995; Wamala et al. 2001), but there are
present indications of differences (e.g., Mobley et al. 2004). Lawlor et al. (2005),
examining socioeconomic position through the life span and its association to
CHD development in women, suggesting that neither cigarette smoking nor other
adult risk factors can fully explain the elevated CHD risk in females coming from
adverse socioeconomic positions. It is important, as underlined in one of the
studies (Wamala et al. 2001), that it is the cumulative effect of socioeconomic
disadvantage that is of interest. This is backed up by several independent studies
(Gliksman et al. 1995; Galobardes et al. 2006). However, there are also results that
indicate that the adult socioeconomic status is a more important predictor of
morbidity from coronary disease than measures of social status earlier in life
(Marmont et al. 2002), and in the NHANES III study, an overrepresentation of
CHD development was found among lone mothers (Young et al. 2005) compared
to partnered mothers.
To conclude, it seems that psychological stress might be caused by different
strain situations in the two sexes and give quite different CHD pathological out-
comes as well.
The main findings of CHD development linked to psychological factors remain
mainly the same from 2008 to 2015 without new relevant findings. A review from
2011 (articles = 67) further confirms that stress associated with relationships or
family responsibilities is linked with increased CHD risk among women, while
work-related stress is less consistently associated with CHD among women com-
pared to men (Low et al. 2010). In another systematic review of 26 studies, the
focus was on psychological job stress, which was found to be a significant cause to
CHD development in men but not in women (Backé et al. 2012). An empirical study
explored the potential association in job characteristics, biopsychosocial, lifestyle,
and coronary heart disease (CHD). Even though men were significantly worse on all
objective measures of CHD risk, there were no significant differences between men
and women in the relationships between variables (Ferris et al. 2012). Among
middle-aged patients with acute myocardial infarction, higher levels of perceived
stress were detected in women compared to men. This was mainly explained by
differences in comorbidities, physical and mental health status, intrafamily conflict,
caregiving demands, and financial hardship (Xu et al. 2015). This is supporting
studies we have shown earlier, which suggest that women and men experience
strain from different situations (Ferris et al. 2005; Balog et al. 2003; Weidner
et al. 1997).
Gender Differences in Psychological Risk Factors for Development of Heart. . . 691
This particular behavior pattern was first discovered, defined, and reported as the
coronary-prone behavior pattern in the 1950s by Meyer Friedman and Ray
Rosenman (1959) and has been more precisely defined later (Rosenman 1990;
Byrne 1996). Since it has so many emotional characteristics, there has always
been a tradition to treat this behavior pattern among other psychosocial risk factors.
Even if the type A behavior pattern’s (TABP) ability to predict CHD has been
heavily questioned, several of the characteristics that constitute the pattern, a strong
need to compete, hostility, and frustration, have through the last decade still been
reported to be strongly related to CHD development (Byrne 1996; Espnes and
Smedslund 2001). Differences in expression of the TABP between males and
females have been revealed. Females tend to display much less of the behaviors
most strongly connected to CHD development, and findings support the notion of
differences in the gender-related subcomponent routes for achieving type A status.
This may have implications for the higher incidence of CHD in males compared to
females scoring high on TABP (see, e.g., Wright et al. 1994; Matthews et al. 1998;
Espnes and Opdahl 1999).
Given that hostility has been suggested, and indeed shown, to have impact on CHD
development in male populations (e.g., Fowkes et al. 1992), it appears that surpris-
ingly few studies have investigated possible sex differences in hostility, irritability,
aggression, and anger connected to CHD development. In a meta-analysis of
relevant studies, it was concluded that no differences could be found between the
two sexes on how hostility influences CHD (Miller et al. 1996). Development of
coronary stenosis has however been shown to relate to hostility (Low et al. 1998),
and there has been a reported difference in hostility as a reaction to psychological
challenge as measured on cardiac reactivity (Guyll and Contrada 1998; Sloan
et al. 2001) and on irritability scores in relation to CHD in men and women
(Siegman et al. 2000). There is also some evidence that level of hostility (assessed
by the structured interview) reliably predicts resting blood pressure (BP) in both
males and females but not in the same way for each; hostility relates to higher
resting BP in men but lower resting BP in women (Davidson et al. 1996). Hostility
has also been found to be an independent risk factor for recurrent CHD in post-
menopausal women (Chaput et al. 2002).
Investigations of stress in marital situations have shown that high trait-anger
wives, who are also high on stress, display larger increases in blood pressure and
heart rate than those wives who are not high on trait anger (Glazer et al. 2002).
692 G.A. Espnes et al.
Depression
There have been reports of a relationship between depression and CHD for almost
seven decades (Malzberg 1937). This relationship has been shown in numerous
studies, especially in the 1970s through the 1990s (e.g., Booth-Kewley and
Friedman 1987), but there are few reports on depression and CHD in female
populations or on sex differences. However, in a study among elderly in New
Haven, USA, the researchers reported that even if the influence of depression
should not be an independent risk factor for CHD development, depression
increased the CHD risk among relatively healthy older women (Mendes de Leon
et al. 1998). We now suspect that depression has impact on the disease develop-
ment in a number of ways and, possibly, also in different ways in the two sexes.
For example, there have been findings of greater impact from depression on
development of hypertension in women than in men (Raikkonen et al. 2001).
Based on a large-scale study in Greece involving 848 men and women hospitalized
for their first CHD incidence, and 1,078 controls, the researchers concluded that
they found evidence for a greater association between depression and CHD risk in
women than in men (Chrysohoou et al. 2003). There are also findings that suggest
that sex differences, both in the ways that depression is a risk factor and has impact
on CHD (Polk and Naqvi 2005) and that the amount of effect depression has on
CHD development, are gender dependent (Espnes and Opdahl 1999; Espnes
2002).
The existence of characteristic differences between men and women with
depression has been supported by a number of studies after 2008 as well. Doering
et al. (2011) sought to distinguish men and women with depressive symptoms and
CHD. Women were found more likely to be single, unemployed, poorly educated,
Gender Differences in Psychological Risk Factors for Development of Heart. . . 693
and anxious and to perceive lower control over health than men. These findings
were similar to previous findings, where socioeconomic and psychosocial factors
were demonstrated to have a higher impact on women with CAD compared to men
(Möller-Leimk€uhler 2008). The female patients also showed higher levels of
depression than the male patients. A meta-analysis, exploring gender differences
in the prevalence of major depression in CAD patients, further confirms that the
prevalence of major depression was significantly greater in women than men
(Shanmugasegaram et al. 2012).
Anxiety
Anxiety, often defined as generalized, persuasive fear, is often seen together with
depression both when analyzing prognosis after having had a CHD event and also
when analyzing risk factors for CHD. Brezinka and Kittel suggested as long ago as
1995, after a large review of the area (with results primarily from the Framingham
Study on housewives), that anxiety is one of the “chronic troubling emotions” that
is a risk factor for CHD development in females. There are however no studies, to
our knowledge, showing sex differences in anxiety which might explain how
anxiety differentially affects CHD development in women. But given that anxiety
(Stern et al. 1977; Schleifer et al. 1989; Forrester et al. 1992; Lesperance and
Frasure-Smith 2000) is more common in women than men, and especially elder
women, an overrepresentation of anxiety could easily have a more severe impact
among women than among men (Rudisch and Nemeroff 2003).
The number of studies after 2008 that has explored the independent association
between anxiety and CHD is scarce. Findings from the Croatian Adult Health
Cohort Study (CroHort) showed a significant association between women with
psychological distress and the prevalence of hypertension, myocardial infarction,
angina pectoris, and self-reported heart failure. In men, a significant association was
only shown for psychological distress and self-reported heart failure (Rukavina
et al. 2012), indicating that psychological distress has a more negative association
in women compared to men. There have been reports that the somatic symptoms of
anxiety are more strongly associated with an increased risk of CHD in women than
in men (Nabi et al. 2010).
Although pessimism has been identified as a risk factor for poor psychological and
physical health (Peterson et al. 1988), no studies have to our knowledge explored
whether a sense of optimism may protect health and certainly nothing which might
indicate a sex difference. (For definitions, see Peterson et al. 1988; Jenkins 1996). It
is, though, on the basis of experimental research, now suggested that optimism/
pessimism have quite different effects of the different treatments in males and
females after experiencing a CHD (Burell and Granlund 2002), but there is no
research as far as we have been able to find that give argument for a gender
difference in pessimism/optimism orientation impact on the development of CHD.
After 2008, only a limited number of studies have looked at optimism. One study
examined sense of coherence (SOC) as a predictor of Quality of Life (QoL), 1 year
after myocardial infarction (MI) in men and women. The male participants dem-
onstrated stronger SOC and a better QoL in all dimensions (physical, emotional,
social, and global score) compared to the female participants (Wrześniewski and
Włodarczyk 2012).
Social Support
We certainly know that women with low social participation have an increased risk
of CHD development (Sundquist et al. 2004), as was earlier shown for men, but we
have found no evidence so far for a difference between the two sexes when it comes
to an effect from social support on CHD risk. To the contrary Rueda (2006) claims
that the impact on CHD risk from poor social support is the same for both sexes.
Loneliness is often considered as a lack of social support and is more often seen
in connection with health deterioration in the last years. A prospective study,
examining associations between loneliness and risk of incident CHD, showed that
in women, high levels of loneliness were associated with increased risk of incident
CHD. Interestingly, no such significant association was found among men
(Thurston and Kubzansky 2009), suggesting that loneliness has a more negative
effect in women. These findings are supported to those by Piwonsky et al. (2012)
who found an association between low social support and CHD risk and depressive
symptoms in both genders, especially evident in women. Collectively these studies
highlight the special attention that needs to be paid on women who are experiencing
low levels of social support.
We will now turn to a short discussion and a conclusion of the research findings
of sex differences on psychological risk factors for CHD and which implications the
new knowledge may give.
Gender Differences in Psychological Risk Factors for Development of Heart. . . 695
As we have seen, even if the total epidemiological evidence does not fully support
the view of the American Heart Association (AHA) (2003) regarding a postulated
upsurge of CHD among females, it more than indicates that the rates of cardiovas-
cular disease among women are now far closer to those of men than they were three
or more decades ago, and in some societies they may be higher than for males.
The lack of adequate knowledge, as revealed in previous part of this paper,
calls for action, both in promotional and preventive strategies, in treatment and
in rehabilitation. There is now sufficient research to conclude that the knowl-
edge and interventions, aimed at preventing the male population from suffering
from CHD or to assist with the treatment those who have suffered, are
only partly relevant to deal with prevention and treatment in female
populations. In the American Heart Association’s Guidelines for Cardiovascu-
lar Disease Prevention for Women – Expert Panel/Writing Group (Mosca
et al. 2004), the expert panel produced a list of clinical recommendations
based on the best evidence available. The best there is to say about this list
is that it really underlines the lack of knowledge and that fact has to be taken
very seriously.
This review, however, has established that there is some knowledge to use as a
basis for future research and practice. The specific knowledge profile that can be
singled out based on the present review is that:
Conclusion
What all this points to is the need for a substantial growth in research on the
interactions between psychosocial and biomedical factors in the development of
CHD in women, and it is important as shown in this chapter that both protective
factors and risk factors, as well as symptomatology, diagnostic criteria, procedures
of treatment, and rehabilitation, are covered in that research. CHD is clearly an
emerging problem for women (WHO 2014; UN 2012), and, in the absence of a
thorough knowledge of gender differences in all aspects of CHD development, the
creation of sound, evidence-based strategies for both prevention and treatment will
be significantly impaired.
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Stress and Social Support in Cardiovascular
Disease
Kristina Orth-Gomér
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
The Concept of Social Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 702
The Biological Effect of Social Networks and Social Supports on Heart Disease . . . . . . . . . . . 703
Population-Based Studies of Social Networks and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
Psychometric Studies of Social Supports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
Functional Measures of Social Supports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 704
Fifty-Year-Old Men in Göteborg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705
Stockholm Women: Their Social Supports and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . 706
New Psychosocial Intervention Trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 707
Psycho-cardiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
A Clinical Case of Sudden Cardiac Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 710
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 711
Abstract
The concept and the impact of inadequate social networks and poor social
support on health have been intuitively known since long. But it was not until
the 1970s that the significance of social relations was demonstrated, for the first
time in the Alameda county study in California.
Within a few years, several population-based prospective studies came to the
same conclusion: Poor social networks and support increased total and cardio-
vascular mortality. This was true even in the North Karelia, Eastern Finland, but
only in men. In North Karelian women, and also in other groups of women, the
function of the social relationships appeared to be more important than the
K. Orth-Gomér (*)
Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
e-mail: [email protected]
structure. North Karelia is a part of rural Finland, situated directly at the border
between Russia and Finland.
In Stockholm, women patients with coronary disease and social isolation
modified the role of depression so that only when they exist together, the factors
worsen prognosis and accelerate progression of coronary artery disease, as
measured by quantitative coronary angiography (QCA). Similarly using QCA
methodology, we could show that exhaustion, more clearly than depression,
worsened prognosis in women. The stress burden originating from the family
was more important than the stress burden of the job, although almost all of the
Stockholm women were employed outside home. Therefore, we designed a
cognitive behavioral intervention to reduce women’s stress. In a randomized
controlled trial, this proved to both prolong women’s lives and attenuate their
negative emotions.
Altogether around 800 women patients have been followed for up to 20 years.
They have been examined with a variety of psychosocial measures. Of psycho-
social measures, vital exhaustion was best fitting to the pattern of coronary artery
atherosclerosis progression and also seemed to yield the best fit to the multivar-
iate model of disease progression. Their precise psychobiological mechanisms
remain unclear. However, multivariate evaluations suggest that standard coro-
nary risk factors partly “explain” and metabolic, hemodynamic, immunologic,
and autonomic imbalances contribute to the final and complete remaining
psychobiological pathogenic pathways.
Keywords
Cardiovascular disease • Stress • Social network • Social support • Depression
Introduction
This chapter will review the epidemiological evidence of social support in cardio-
vascular disease (CVD) with a focus on methods to measure and quantify this
support. In addition, clinical and pathogenic issues around coronary heart disease
will be examined, and preventive psychosocial interventions aimed at strengthening
social support in CVD will be outlined.
“A lonely man is a strong man” is an old saying in Scandinavia: “A strong man makes
his own decisions without being in any way influenced by external cues. He is
independent, and therefore his decisions are clear and sound.” This may be true in
the cold and dark regions of Northern Sweden. This may be true for the inhabitants of
Kiruna in Northern Sweden and for people living in Rovaniemi in Northern Finland
or Tromso in North Norway. These places are all situated around the North Peak of
Scandinavia above the 65th northern latitude and above the Northern Polar Circle.
Stress and Social Support in Cardiovascular Disease 703
However, not even in these regions, where populations are scarce, where the sun
and the daylight vanish from November to February, where the children are happy
when the first snow comes so that they can ski to school and see the road in the
reflection of the white snow, not even where the distances are so long that you will
easily travel a hundred kilometers to visit a friend or look after an old relative, not
even in these regions are lonely men strong men. Life is hard; winters are dark,
long, and cold; and people do not talk more to each other than is absolutely
necessary. But still, people know that social ties are vital, that one cannot survive
without them, and that they need to be cherished and cultivated. Social supports are
as vital to the people in the depopulated North, as they are to the much more densely
inhabited regions around Copenhagen, Denmark, or Malmö, Sweden (Janlert
et al. 1992).
Social supports can be divided, on one hand, into the purely quantitative
assessment of social networks and the qualitative and functional assessment of
support on the other hand. Both aspects of social support constitute the basic human
need for social contact and for closeness (Ruberman et al. 1984).
The concept of social supports is almost as old as the Old World. Aristotle
argued around 350 years BCE that “friendship was a basic human need, along with
food, shelter and clothing. A totally loveless life – a life without friends of any sort –
is a life deprived of much needed good.” Much later, in 1599, Paracelsus, a
physician, alchemist, and natural scientist, prescribed “love as the best possible
cure for several diseases” (Rose 1992).
The first modern scientific evidence of a link between social support and health
was provided by Emil D€urkheim (1858–1917) in his extensive sociological studies
on the origins of suicide and self-destructive behavior. He found that marriage and
religion were the best protectors against such deviant self-destructive behavior.
Kropotkin, a Russian ethologist and psychobiologist, gave support to this notion by
stating in 1908 that “mutual help and support is a factor of great significance for the
maintenance of life and health in animals and in humans” (Stamler 1980).
The effect of social support on the heart has been intuitively known for centuries.
However, modern cardiology demands empirical evidence. In both the research and
clinical settings, the effects of social support on the heart have required verification.
The following population- and patient-based longitudinal studies describe this.
Jim House et al. (1988) in a summarizing review compared health effects of social
networks in cigarette smokers. They looked at longitudinal, representative popula-
tion-based cohorts in the USA from Alameda County (Berkmann and Syme 1979),
704 K. Orth-Gomér
Tecumseh (Michigan; House et al. 1982), Evans County (South Georgia; Blazer
1982), East Boston, Iowa, and New Haven (House et al. 1988). They also described
the findings from European studies, including North Karelia in Finland (Kaplan
et al. 1988), Gothenburg in Sweden (Orth-Gomer et al. 1993), and the SC ULF
study (Orth-Gomer et al. 1987), based on a representative sample of all Swedish
men and women, aged 15–75. All study groups were followed for several years,
looking at the same medical end points. All these longitudinal studies generally
agreed on the same broad conclusion, namely, that while the magnitude of the
health risks was about the same, social networks consistently promoted health, that
is, more frequent social contacts were prospectively associated with better physical
and mental health. The conclusions were clear and unambiguous (Orth-Gomer
1987). However, it was difficult to understand what the counts of friends, neighbors,
work mates, etc. really meant. It was hard to know which impacted psychological
function or which were the personality characteristics of individuals who were
sensitive to the variations in social ties. As a result, the literature was further
explored and a set of psychometric investigations were carried out, aimed at finding
or developing active and more easily interpreted examination methods for the role
of social support. The Interview Schedule for Social Interaction (ISSI; Henderson
et al. 1980) was found. This survey instrument was designed as an interview
instrument to assess the availability and perceived adequacy for any individual of
a number of facets of social relationships. The instrument is sufficiently valid and
reliable and also sensitive to predictable variations between sociodemographic
groups, so its use can be justified in clinical and epidemiological studies, both in
psychiatry and general medicine.
The ISSI had the functional approach that we were looking for, but it was very
cumbersome to use. In a pilot study, we developed a paper and pencil test, paying
particular attention to psychometric properties, including split-half reliability, face
validity, and internal consistency (Orth-Gomer and Unden 1987; Undén 1991).
The resulting scale had 13 items, 6 describing “attachment” and 7 describing
“social integration.” The instrument has now been implemented in several
population-based cohorts, such as in young men in North Sweden, Gampöjka; in
50-year-old men in Göteborg (Janlert et al. 1992); and in women with clinically
manifest CVD in Stockholm (Orth-Gomér et al. 1998, 2000; Horsten et al. 2000).
profiles in different age and gender groups in the most Northern part of Sweden. We
used the self-report measures that were agreed upon in the multicenter MONICA
studies, thus disentangling size and density of social networks from the quality and
function of social support. In most cohorts, we found the former scale, social
integration, to be predictive of health outcomes in the expected direction.
That is, the more numerous and more frequent social contacts were associated
with better health outcomes. One group in the North stood out on another dimen-
sion, namely, that of attachment, meaning the quality and function of close emo-
tional ties, relationships which are found within the family or with very close
friends. The items were concerned with whether there is someone to “hold you
for comfort,” and whether there is “someone to share happiness with, someone that
would be happy just because you are....”
The young men in Northern Sweden were nicknamed “Gampöjka.” They were
the only ones left when everybody else in the village had moved to the cities in the
South (such as Stockholm). These young men actually confirmed that they had few
or no relationships providing them with a sense of “attachment.” In addition they
were mostly unemployed and without family, many of them living with a widowed
mother. There was literally none to hold them for comfort as all the young women
from the north had gone south (Janlert et al. 1992).
as had previously been found in men (Orth-Gomer et al. 1998). However, when
examining the causes of distress, important gender differences were identified.
Women who had poor marital relationships, we called it marital stress, had three
times the risk of getting a recurrent coronary attack, as compared to women patients
without marital stress with the best prognosis found in women who had a good job
and a happy marriage (Orth-Gomér et al. 2000). In a subgroup analysis, this latter
group was found to be even more “health prone.” In coronary angiographic
examination with subsequent quantitative evaluation (QCA), which was repeated
after a 3-year follow-up period, coronary artery disease did not progress as
expected. In contrast, in this particular group of women patients, their CAD actually
regressed as if they had been on systematic statin therapy. However, none of them
was taking any statins at all. These were not used until much later in Swedish
patients.
Psycho-cardiology
The turn of the new century, between 2000 and 2004, became a marker for a new
line of scientific concepts (Wang et al. 2005). Our original work on the “ESC
clinical guidelines for CVD prevention in clinical practice” focused on psychoso-
cial risk factors. These clinical guidelines were published for the first time in
December 2003, together with consecutive publications in other journals (De
Backer et al. 2003), and provided a new perspective of understanding from the
patient’s perspective after an acute coronary event. Behavioral and psychosomatic
medicine then became recognized specialities, which were taken seriously and
acknowledged by the research community.
A year later, another important event occurred, the publication of the
INTERHEART study. Largely the same psychosocial risk factors were cited as in
the guidelines (see below). In addition, for the first time, coronary risk that could be
attributed to psychosocial factors was estimated to be around 30 %. As the
INTERHEART study included some 16,000 CVD patients and an equal number
of controls, representing over 50 countries, the results were robust and significant.
In addition, other risk factors detrimental to cardiac health were identified. These
included: Low SES, emotional stress from work and family, lack of social support,
and social isolation, along with the accompanying negative emotions (depression,
exhaustion, hopelessness, anger, and hostility), were definite, scientifically based
coronary risk factors (Yusuf et al. 2004).
Traditionally, an important part of cardiac rehabilitation is physical exercise.
More recently “rehabilitation has been found to be as much about reducing anxiety
and depression as it is about lifestyle change.” Of the ten core components of an
ideal rehabilitation program, psychosocial management ought to be considered the
most important.
The other nine core components can be addressed with lifestyle change.
However, although patients are carefully instructed, with great detail about
what they should do in order to prevent heart disease, little is said about how it
is done. Therefore, failure of cardiac rehabilitation could be attributed to this
aspect of lack of psycho-education. It is well known that the modern, life-saving
acute heart disease care constitutes a heavy burden on the healthcare system. The
acute phase is characterized by high impact and resourceful intensive care. An
acute patient with severe central chest pain, especially if it is a male patient, will
be treated using the best and newest technology and personnel skills. Often, even
before the patient has reached the hospital, his acute EKG will be transmitted
from the ambulance and interpreted by the cardiologist or related specialist who is
on call in the clinic. Yet an important question remains: Why are patients not
following this excellent expert advice? The pattern is clear: Cardiologists of today
have realized that patients have both body and mind and that both need to be cared
for. But they may not be able to fully meet the needs of the important “mental
half” of the body-mind complex. Help ought to be obtained from psycho-
cardiology.
Stress and Social Support in Cardiovascular Disease 709
transportation, giving their opinion, which is almost always right, directly to the
clinic. This is how the angiographic laboratory can be prepared while the patient is
arriving to the emergency unit. Specially trained nurses will assist the cardiologist
throughout the procedures. They are instructed, well trained, often constituting of
underestimated, poorly paid, highly competent professionals.
Conclusion
The introduction of intensive coronary care units (CCUs) have reduced the acute
mortality risks of myocardial infarction in hospitalized patients to about half. At the
same time, new surgery and catheterization techniques have been implemented.
Much experience was gathered, which lead to the development of stents, a devise
which is inserted into the coronary artery narrowing to keep it open and maintain
blood flow. Third –and probably most important for survival – the introduction of
efficient pharmacotherapy for prevention of death after an acute heart attack is
perhaps the most effective measure.
Today virtually all post-AMI patients are taking preventative drugs every day,
for the rest of their lives. First, the beta blockers were introduced on the market.
They were shown to help against angina pain, reduce blood pressure and relieve
symptoms of heart failure, and even postpone mortality (reference needed).
Furthermore, coenzyme A reductase inhibitors – statins – were introduced in
order to lower LDL cholesterol. But they were also found to have a substantial
beneficial effect on all cause and heart disease-related mortality, which could not be
explained by effects on LDL only (reference needed). In subsequent studies, statins
were found to have antithrombotic effects which were more important than could be
shown with any other drug (reference needed). In the recent SWITCHD study, it
appears as if the statins might reinforce the effects of the cognitive stress reduction
program (Orth-Gomer’ et al. 2009).
What are the possible explanations for this finding? This finding could be based
on patients’ greater motivation and discipline when taking our cognitive stress-
reducing program. But it could also be due to patients becoming more trustful and
having more faith and being psychologically more receptive when taking the
statins. This effect then would interact with the cognitive stress reduction program
by strengthening its efficiency.
In women patients who had received both statins and CBT, mortality was less
than 1 %, whereas in the other three groups, women who were taking only one –or
none – of the two therapy options, mortality rates over 7 years were between 15 %
and 20 %. Thus an interactive effect was noted between statins, the most potent of
the pharmacological preventive therapies and CBT and the most potent of the
psychosocial treatment modalities.
Altogether around 800 women patients have been followed for 20 years with the
same psychosocial measures using QCA, we showed that low social support,
depression, and exhaustion accelerate the atherosclerotic process in the coronary
arteries, worsen prognosis, and seem to yield the best fit to the multivariate model
Stress and Social Support in Cardiovascular Disease 711
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Mental Health and Cardiovascular Disease
Risk in Refugees
Harry Minas
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714
Mental Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
Mental Disorders in Refugees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 716
CVD Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 717
Mental Disorders and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 718
Health Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 722
Abstract
In 2013 there were 51.2 million persons worldwide who had been forcibly
displaced as a result of persecution, conflict, generalized violence, or human
rights violations. 16.7 million persons, half of whom were children, were
refugees. More than 80 % were living in refugee camps and other generally
temporary although often long-lasting arrangements, in developing countries.
From this massive population, only 98,000 were resettled in refugee-receiving
countries. The prevalence of mental disorders, particularly post-traumatic stress
disorder, depression, and anxiety, is greater in refugees than in non-refugees,
although prevalence estimates vary greatly. As well as having poorer mental
health, refugees are also more likely than non-refugee immigrants or host
populations to experience poorer physical health, higher all-cause mortality,
and higher cardiovascular mortality. Although the severe and persistent stress
that is a central element of refugee experience is probably an independent risk
factor for cardiovascular disease, it seems likely that the higher cardiovascular
H. Minas (*)
Global and Cultural Mental Health Unit, Melbourne Refugee Studies Program, School of
Population and Global Health, The University of Melbourne, Parkville, VIC, Australia
e-mail: [email protected]
Keywords
Cardiovascular disease (CVD) and mental disorders • Cognitive behavioral
therapy (CBT) • Heart rate variability (HRV) • Mental disorders • Post-traumatic
stress disorder (PTSD) • Refugees • CVD risk factors; see Cardiovascular
Disease (CVD) • UNHCR
Introduction
In 2013, the latest year for which comprehensive global data are available (United
Nations High Commissioner for Refugees 2014), there were 51.2 million persons
who had been forcibly displaced as a result of persecution, conflict, generalized
violence, or human rights violations. 10.7 million persons were newly displaced in
2013, of whom 8.2 million were internally displaced within their own country. The
other 2.5 million were new refugees, the largest number in a single year since 1994.
16.7 million persons were refugees, of whom 50 % were aged less than 18 years.
There were 33.3 million internally displaced persons and 1.2 million asylum seekers.
More than half of all refugees worldwide came from three countries: Afghani-
stan (2.6 million), Syria (2.5 million), and Somalia (1.1. million), followed by
Sudan, Democratic Republic of Congo, Myanmar, Iraq, Colombia, Vietnam, and
Eritrea. The five top refugee-hosting countries were Pakistan (1.6 million), Iran
(857,000), Lebanon (856,000), Jordan (642,000), and Turkey (610,000). Eighty-six
percent of the world’s refugees (compared to 70 % a decade previously) were being
hosted in developing countries, and more than 5.4 million refugees were in coun-
tries with a GDP per capita of less than US$ 5000.
1.1 million persons submitted applications for asylum or refugee status in 2013.
Only 98,000 refugees were resettled in countries, with the United States receiving
the largest number (66,000). More than 400,000 returned to their country of origin,
with most returning to Syria (141,000), Democratic Republic of Congo (68,000),
and Iraq (61,000). This was the lowest level of refugee returns in 25 years (United
Nations High Commissioner for Refugees 2014).
While these stark figures from UNHCR give an indication of the scale of the
global problem of forced displacement, they cannot convey the depth of suffering
experienced by asylum seekers and refugees who have fled their homes and
countries as a result of threats to personal safety, livelihood, freedom, dignity,
and an acceptable future for themselves and their children. Many have experienced
violence and injury and sexual assault. A significant number have been subjected to
persistent human rights abuses and state-sponsored torture. Most have witnessed
destruction, violence, killings, assaults, and disappearances. Loss of home,
Mental Health and Cardiovascular Disease Risk in Refugees 715
Mental Disorders
The World Health Organization’s World Mental Health Survey has generated
estimates of lifetime prevalence and age-of-onset distributions of anxiety, mood
disorders, and substance use disorders from a combined 85,052 participants in
17 countries in Africa, Asia, the Americas, Europe, and the Middle East (Kessler
et al. 2007). Median lifetime prevalence estimates are anxiety disorders 4.8–31.0 %,
mood disorders 3.3–21.4 %, substance use disorders 1.3–15.0 %, and any disorder
12.0–47.4 %. Median age of onset is very early for some anxiety disorders
(7–14 years) and impulse control disorders (7–15 years). The age-of-onset distri-
bution is later for mood disorders (29–43 years), other anxiety disorders
(24–50 years), and substance use disorders (18–29 years).
The authors suggest three possible biases that may have resulted in the under-
estimation of prevalence. The first is that people with mental illness are less likely
than others to participate in surveys, because of sample frame exclusions (e.g.,
excluding homeless people), differential mortality, or greater reluctance to partic-
ipate. It is suggested that the wide variation in estimates across countries may be
due to variation in the magnitude of such underestimation across countries. A
second possible bias is that lifetime prevalence is sometimes underreported because
of respondent reluctance to admit mental illness, which is also likely to vary across
countries. The third is possible interviewer error, with under-detection resulting
from rushing through interviews due to being paid by the hour. Although it is
possible that the estimates may be too high because thresholds for the presence of
mental disorder may have been too low, clinical reappraisal studies in some of the
countries with the highest prevalence estimates found no evidence of such bias.
716 H. Minas
even basic health and social services let alone skilled mental health services.
Emerging mental disorders are likely to be undetected and untreated, with negative
consequences for the mentally ill refugee and her/his family.
The major modifiable risk factors for CVD are well known and will be discussed
here only insofar as they may be relevant to refugees. There are consistent findings
of greater exposure to CVD risks and higher rates of CVD among refugees than in
host populations.
Chronic stresshas been identified as a significant risk factor for CVD. Among the
circumstances that give rise to chronic stress among refugees are exposure to
violence and more specifically sexual violence and torture. Refugee women are
particularly vulnerable to sexual violence in situations of conflict and displacement.
A systematic review yielding 19 eligible studies reported an estimate of prevalence
of sexual violence of 21.4 %. The authors considered this an underestimate because
of the substantial barriers to disclosure (Vu et al. 2014). In a review of 161 articles
reporting results from a combined total of 81,866 refugees and other conflict-
affected persons from 40 countries, Steel et al. (2009) reported the prevalence of
PTSD ranging from 0 % to 99 % and the prevalence of depressions ranging from
3 % to 85.5 %. This remarkable variation in estimates was attributed to methodo-
logical factors, such as nonrandom sampling, small sample sizes, and self-report
questionnaires, and to variations in substantive population risk factors. Among the
substantive risks reported, torture emerged as the strongest factor associated with
PTSD, followed by the level of exposure to traumatic events, time since conflict,
and assessed level of political terror (Steel et al. 2009).
While gender-based violence is known to be a common and disturbing refugee
experience, an attempt to carry out a systematic review of studies of strategies for
prevention and treatment of gender-based violence or to address the physical and
mental health consequences of gender-based violence, among refugees, yielded no
eligible studies. The authors found not a single article evaluating prevention,
treatment, or management of gender-based violence and its health consequences
in displaced populations that met the systematic review inclusion criteria. Although
there were many expert recommendations and guidelines from international orga-
nizations that presented specific strategies to prevent and/or treat the health conse-
quences of gender-based violence, none was supported by primary research on
displaced populations (Asgary et al. 2013).
There are few rigorous studies of the prevalence of torture among refugees.
Experience of torture varies greatly among different country-of-origin groups and
among different cohorts from the same country. A study of Iraqi refugees in the
USA found that 56 % had been subjected to torture and that torture is associated
with the presence of both mental and physical symptoms on the post-arrival health
screen (Willard et al. 2014).
718 H. Minas
There is clear evidence of PTSD being associated with increased risk of CVD
and with increased CVD morbidity and mortality. While there are many method-
ological challenges in studying PTSDand CVD in refugees, some methodologically
rigorous work that has been done with US military veterans can be instructive in
relation to refugees, since PTSD is a very common diagnosis in both groups.
A substantial follow-up project of 15,288 US Army veterans (Boscarino 2006a)
examined the link between PTSD and survival time and cause of death 30 years
after military service. The large sample size, the excellent sampling frame enabled
by military records, and the high participation rate by veterans in the study enable
some firm conclusions to be drawn. Thirty years postwar, mortality hazard ratios
were all-cause (HR = 2.2) and cardiovascular (HR = 1.7), cancer (HR = 1.9), and
external (including motor vehicle accidents, accidental poisonings, suicides, homi-
cides, and injuries of undetermined intent) (HR = 2.3) causes of death (Boscarino
2006b).
Factors that may increase vulnerability to obesity and cardiovascular disease
among refugees include both dietary changes and limited physical activity (Drum-
mond et al. 2011; Sundquist et al. 2010). Sub-Saharan refugees in Australia have
been found to be at risk of obesity and diabetes (Renzaho et al. 2011), and Bosnian
refugee women in Sweden have been found to have CVD risk profile lipids and
obesity (Sundquist et al. 1999).
The available evidence, although still limited, suggests that risk factors for CVD
may be substantially higher among refugees than among immigrants and host
populations, resulting in higher rates of cardiovascular morbidity and mortality.
particularly as a result of the stigma and discrimination and the daily humiliations
experienced by people with mental disorders, long-term poverty even in rich
countries, lack of access to safe housing and decent work, and the mental distress
that is a central experience of mental disorders.
It has also been suggested that mental disorders such as depression may be
directly related to increased arterial stiffness and abnormal endothelial function
even when compared with blood pressure-matched controls and that a possible
mechanism linking PTSD to arterial stiffness and cardiovascular disease is inflam-
mation, which has been shown to promote both conditions, with evidence
suggesting that PTSD may induce chronic low-level inflammation (Tomlinson
and Cockcroft 2011).
There is continuing disagreement concerning the question of whether effective
treatment of depression results in decreased risk of CVD and improved CVD
outcomes (Fernandez-San-Martin et al. 2014; Gierisch et al. 2014). In particular,
it has been suggested that effective treatment of depression may reduce CVD risks
(Halaris 2013) by, for example, increasing HRV, thereby reducing mortality after
acute myocardial infarction (Carney et al. 2005; Martens et al. 2008). A study of
treatment of depression with cognitive behavioral therapy (CBT) demonstrated
reduced heart rate and increased short-term HRV, suggesting that such treatment
may reduce the risk of cardiac events and mortality in depressed patients with
coronary heart disease (Carney et al. 2000).
Health Services
Immigrants, asylum seekers, and refugees face many obstacles in getting access to
effective culturally appropriate primary care (Bellamy et al. 2015), mental health
(Minas et al. 2013; Colucci et al. 2015), and general health services (Hollifield
et al. 2002), even in countries with high levels of health resources and highly
developed health systems. These problems are multiplied many times for the great
majority of refugees who are living in refugee camps and other less than adequate
settings in developing countries. Asylum seekers and refugees are also often not
reached by and do not benefit from national and local health promotion campaigns,
most commonly because of communication difficulties and also because the cam-
paigns are designed for the dominant cultural group. Even when refugees do get
access to health services, despite the high rates of mental disorders and CVD (Yun
et al. 2012) and complex health service needs (Renzaho et al. 2011, 2014), refugees
often receive suboptimal treatment (Tomlinson and Cockcroft 2011).
Because of this many authors have suggested that routine screening for depres-
sion among people with CVD would result in better detection, more appropriate
assessment, and better CVD outcomes (Callaghan et al. 2009; Callaghan and
Khizar 2010; Yun et al. 2012), and this has been supported by the American
Heart Association. Despite the many calls for screening, several authors have
expressed doubt about the value of routine screening for depression among people
with CVD. Thombs et al. (2013) have concluded that, while there is evidence that
Mental Health and Cardiovascular Disease Risk in Refugees 721
Conclusions
Refugees are more likely than non-refugees to develop cardiovascular disease and
have increased prevalence of anxiety and mood disorders and greatly increased
prevalence of PTSD. It would appear that central elements of the refugee experi-
ence – anxiety and chronic stress – may constitute a direct risk for CVD and
cardiovascular morbidity and premature mortality. It is probable, however, that
the main pathway between refugee experience and CVD is through mental disor-
ders. The American Heart Association has recognized depression as an independent
risk factor for coronary artery disease, although the quality of evidence underlying
this decision has been questioned.
In addition, there is accumulating evidence that both refugee status and the
presence of mental disorder are associated with reduced likelihood of early detec-
tion of CVD and appropriate treatment, resulting in avoidable cardiovascular
morbidity and mortality. It is not yet possible to draw confident conclusions
about the value of alertness by clinicians and health services to the increased risk
for CVD or of routine screening for CVD among refugees and when mental
disorder is present. However, until equitable and effective mental health and
general health services are available for refugees, particularly refugees with mental
disorder, it would seem prudent to encourage such alertness and screening and to
further evaluate whether this produces improved detection and reduced CVD
morbidity and mortality.
Finally, refugee research presents many methodological and practical chal-
lenges. The quantity and the quality of refugee research, and the level of support
for such research, are not consistent with the scale of the global refugee issue, the
possibility that the number of refugees globally may continue to increase, and the
population health and economic burden of unrecognized and ineffectively treated
mental disorders and cardiovascular disease in refugees. This issue of health system
inadequacy is particularly important in the context that the great majority of
refugees live in countries with underdeveloped health systems and that many
722 H. Minas
refugee-receiving countries with the health system capacity to do better than is now
the case are developing increasingly restrictive and sometimes punitive asylum
seeker and refugee policies.
Asylum seeker and refugee research, and more effective health system responses
to the needs of refugees, must become clearer priorities and more prominent
components of global health and global mental health programs and of global
disaster risk reduction programs.
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Social Disadvantage
and Cardiovascular Disease Risk
Contents
Social Disadvantage, CVD Morbidity, and Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
Socioeconomic Position: Disadvantaged Individuals and Disadvantaged Places . . . . . . . . . 729
Measurement of Health Inequalities: Relative and Absolute Measures . . . . . . . . . . . . . . . . . . . 729
Socioeconomic Gradients in CVD Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730
How To Understand the Relationship Between Social Disadvantage and CVD Risk . . . . . . . . 730
Social Disadvantage and Social Position . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730
How Can Social Disadvantage Influence Risk Factors for CVD? . . . . . . . . . . . . . . . . . . . . . . . . . 731
Social Disadvantage, Psychosocial Factors, and Health-Related Behavior . . . . . . . . . . . . . . . . . . . 734
Social Disadvantage, Psychosocial Exposure, and CVD Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
Social Disadvantage and Health Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
Social Disadvantage and Clinical Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
Traditional Clinical CVD Risk Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
High-Risk Strategy and Population Strategy (Strategies of CVD Prevention) . . . . . . . . . . . . 737
Population-Wide Reductions in Dietary Salt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
Abstract
In western societies there is a persistent social patterning of cardiovascular
disease (CVD) risk. Social disadvantaged (SD) people are at greater risk of
CVD than people in more advantageous positions. Both individual and contex-
tual risk factors are of importance. Several models have been put forward to
understand the relationship between social disadvantage and CVD risk. The
concept psychosocial reflects psychological processes that are linked to the
social environment and directs attention to both behavioral and endogenous
biological responses to human interactions. The physical and social environment
shapes health behaviors as health behaviors are observed socially patterned.
Today, one must expect that clinicians are aware of the fact that SD increases
CVD risk and thus manage to think beyond traditional individual-based CVD
risk assessment.
Keywords
Disadvantage • Cardiovascular diseases • Risk factors • Socioeconomic status
Introduction
There has been considerable debate in health inequality research surrounding what
measures should be utilized to present health differences between social groups.
There is consensus on the importance of choice of measure, but less consensus on
which measure – absolute or relative – should be reported and interpreted
(Houweling et al. 2007). The controversy applies in particular in cross-country
730 S. Krokstad et al.
There is substantial evidence for an association between SEP and CVD morbidity
(Kaplan and Keil 1993) and mortality (Mackenbach et al. 2000). Similarly, there
are numerous studies demonstrating associations between SEP and risk factors for
CVD like: body mass index, cholesterol, systolic blood pressure, smoking,
and diabetes (Ernstsen et al. 2012; Strand and Tverdal 2006). In general, many
behavioral and modifiable risk factors for CVD have a clear SEP gradient (Pampel
et al. 2010). While there is considerable disagreement in terms of the importance of
behavior for SEP inequalities in morbidity and mortality (Strand and Tverdal 2004),
there is a clear potential for improved population health by the elimination or
reduction of CVD risk factors. Trends in SEP inequalities for many classical
CVD risk factors are equivocal and are also dependent on country (Stringhini
et al. 2011) as well as methodological issues (Lynch et al. 2006; Singh-Manoux
et al. 2008).
Ecological factors
Exposure
Environmental to physical
resources and pathogenes
constraints
Level of social
disadvantage Health
(social releated CVD
position)in behavior
the life-course
Psychological
influences
(affect, CNS and
cognition) biological
response
Fig. 1 A model to understand the relationship between social disadvantage and CVD risk
(Krieger 2001; Adler and Ostrove 1999)
The terms inequity and inequality are closely related in origin and in some of
their secondary definitions, but there are distinct differences between them.
Inequality refers primarily to the condition of being unequal, and it tends to relate
to things that can be expressed in numbers. Inequity, in its main sense, is a close
synonym of injustice and unfairness, so it usually relates to more qualitative matters
(Whitehead 1992). As this chapter is about social disadvantage, differences in CVD
risk by SD are largely interpreted in terms of inequity.
The majority of diseases accumulate to a larger extent in groups with a low SEP.
However, some risk conditions and diseases show less distinct or opposite patterns
(Clegg et al. 2009). This may have implications for the hypotheses that evolve in
terms of disease causation. The larger the inequalities in health by social position,
the more likely it is that diseases can be caused by socioeconomic disadvantages.
Adler and Ostrove suggested a model to explain how SEP can influence risk factor
levels and health integrated in Fig. 1 (Adler and Ostrove 1999). SEP is important to
health not only for those in poverty but at all levels of SEP below the top level. On
average, the more disadvantaged individuals are, the worse their health. The
threshold model, i.e., the idea that only the most SD or poor people suffer or have
worse health than all the other, was challenged forcefully by the Whitehall study
(Marmot et al. 1978). In virtually all socioepidemiological studies, a gradient
pattern emerges. However, reversed causation might cause some health inequal-
ities, most likely for diseases with early onset with profound effects on life
trajectories (e.g., schizophrenia). But here is overwhelming evidence that increas-
ing SD contributes to health differences.
732 S. Krokstad et al.
One pathway from low SEP or SD to increased risk factor levels is through
exposure to different environments and adaptations to these environments. One
aspect of environments is differential exposure to physical pathogens, like tobacco
smoke polluted air. More important are probably the social and interpersonal
factors in the environments, particularly exposure to threats and stress in both the
work and the private environment. With increasing SD, decreasing levels of control
and decreasing degree of emotional and instrumental support will be experienced,
and exposure to conflict and threats increase.
The social and physical environments people experience, different levels of
demands and supports, shape patterns of psychological responses. Individuals that
experience SD are more likely to develop a sense of helplessness, low self-esteem,
hostility, and distrust than others.
The physical and social environment also shapes health behaviors. Health
behaviors are clearly socially patterned, and this might be caused by fewer oppor-
tunities for exercise and less access to nutritious foods. The combination of
individual characteristics, formed by the social background and the environmental
factors, will affect the likelihood of enacting health-related behaviors such as
tobacco use, alcohol use, exercise, and dietary practice.
Ecosocial Theory
These suggested causal pathways are of course oversimplified. The pathways by
which SD can influence CVD risk factors are likely to be influenced by feedback
loops and interaction effects. Mechanisms on all levels, from societal to subcellular
level, may be involved (Fig. 1). Ecosocial and other multilevel epidemiologic
frameworks seek to integrate social and biological factors and a dynamic, historical,
and ecological perspective to develop new insights into why SD influences health
(Krieger 2001).
Neo-material Theory
In research, only selected aspects or pathways may be explored in observational
studies. The neo-material interpretation argues that SD affects health through
differential accumulation of exposures and experiences originating in the material
world. It is a combination of negative exposures and lack of resources held by
socially deprived individuals, along with systematic underinvestment across a wide
range of human, physical, health, and social infrastructure where socially deprived
people live (Lynch et al. 2000).
Psychosocial Explanation
But if the neo-material alone explained the relationship between SD and CVD
risk, giving every family enough money to have enough food and a house, deal with
air pollution, and provide a physically safe environment should solve the problem.
But this is obviously insufficient. The psychosocial effects of relative deprivation
involving control over life, insecurity, anxiety, social isolation, socially
Social Disadvantage and Cardiovascular Disease Risk 733
Health-Related Behavior
An individualistic paradigm has influenced thinking and practice regarding
management of health lifestyles in several disciplines, but this approach neglects
the structural dimensions and has limited applicability to understand the
challenge. A tendency to focus on individual behavioral patterns that affect
CVD is observed, thereby neglecting the collective (structural) characteristics.
However, all theories of social life suggest that something (structure) exists
beyond the individual to give rise to habits and patterns of behavior. People are
linked together through social relationships, such as family ties, work, religion,
and politics. Their shared norms, values, ideals, and social perspectives constitute
intersubjective communities where behavior varies systematically (Cockerham
2005).
Life-Course Perspective
It may be hard to understand how relatively small socioeconomic differences in
modern societies affect risk factor levels and health as observed in the socioeco-
nomic gradients (Marmot et al. 1978). However, the life-course perspective refers
to how risk factors and health status at any given age, for a given birth cohort or an
individual, reflect not only contemporary conditions but are embodiments of prior
living circumstances, in utero onward (Corna 2013). In such a perspective, when the
accumulation of the effects of SD over time is taken into account, understanding of
the health effects may be easier.
While social factors include general factors at the societal and structural level that
affect individuals, psychological factors include individual-level processes that
influence mental state and emotions. The concept psychosocial reflects psycholog-
ical processes that are linked to the social environment and directs attention to both
behavioral and endogenous biological responses to human interactions (Stansfeld
and Marmot 2002). The health-damaging potential of psychological stress is gen-
erated by the imbalance between exposure to adverse conditions (daily hassles,
acute or chronic stress) and psychosocial resources (social support, personality
factors, coping strategies, resilience) (Hjemdahl et al. 2012). Beside the physiolog-
ical responses on psychological stress, individuals may use certain behaviors (e.g.,
smoking, drinking, overeating) to cope with stress and reduce unpleasant arousal.
In the INTERHEART study, a standardized case–control study of acute myo-
cardial infarction (including 29,972 participants from Asia, Europe, the Middle
East, Africa, Australia, North America, and South America), psychosocial stress
was assessed by questions about stress at work and at home, financial stress, major
life events in the past year, and feelings of depression. The psychosocial factors
increased the odds of first myocardial infarction by approximately threefold and
accounted for 33 % of the population-attributable risk for the development of
myocardial infarction (Yusuf et al. 2004). A large body of research supports that
emotional factors such as anxiety, depression, psychosocial work characteristics,
and low social support are independently involved in the etiology and prognosis of
coronary heart disease (Kuper et al. 2002; Van der Kooy et al. 2007). Several
studies also support that workplace-related stress, defined by high demands and low
control and/or by effort-reward imbalance, elicits sustained stress reactions with
negative long-term consequences for cardiovascular health (Siegrist and Marmot
2004).
Empirical evidence indicates that socioeconomic position is adversely associ-
ated with psychosocial factors linked to CVD risk (Gallo and Matthews 2003;
Skodova et al. 2008). In the literature, the leading candidate psychosocial pathways
connecting social disparities and CVD risk are through stress and emotions (Gallo
and Matthews 2003). A number of studies have also shown a dose–response
relation between social position and depression (Andersen et al. 2009; Lorant
et al. 2003; Melchior et al. 2013).
If psychosocial factors represent a causal pathway between social disparities and
health, studies should evaluate and support mediation, but several studies find that
psychosocial factors such as anxiety and depression do not mediate the association
between social position and CVD risk (Kittleson et al. 2006; Thurston et al. 2006).
In a recent progress report on psychosocial mediators of SEP-health associa-
tions, Matthews et al. (2010) conclude that the evidence is insufficient to draw
strong conclusion about the hypothesized pathway and that the limited existing
Social Disadvantage and Cardiovascular Disease Risk 735
literature has produced mixed findings (Matthews et al. 2010). Opposite to the
mediator (causal) pathway, psychosocial factors may moderate the association
between social position and CVD which means that the effects of any psychosocial
variable are dependent (increase or decrease) upon social position. A recent pro-
spective study of 6,070 men free from previous history of CHD and stroke at
baseline found that the effect from job strain on risk of coronary heart disease is
higher in blue-collar workers compared to white-collar workers (Torén et al. 2014).
The results are in line with another recent prospective study of 66,500 participants
free of CVD and cancer at baseline, which suggested that the harmful effect of
psychological distress (measured by the 12-item General Health Questionnaire) on
mortality from coronary heart disease and stroke is significantly higher in lower
occupational grades (Lazzarino et al. 2013).
The vast majority of observational studies on social disparities conclude that even if
health-related behaviors do not explain all social difference, it makes an important
contribution to the social gradient in cardiovascular morbidity and mortality
(Beauchamp et al. 2010), especially smoking (Jha et al. 2006; Mackenbach 2011)
and physical inactivity (Ernstsen et al. 2010). Different measures of social dispar-
ities (education, income, occupation, gender, poverty) represent different theoret-
ical bases. For example, in studies that define social position as occupational
position, health-related behavior often contributes less to inequalities in CVD
than studies using education or prestige-based measures. The main explanation
for this is that behavior to a great extent reflects “exposure” through culture and
norms that are established in relatively early in life (Marmot and Bartely 2002).
Recent results from several different data sets from the USA and the UK suggest
that income, health insurance, and family background explain about 30 % of the
educational gradient in health behaviors, while knowledge and cognitive ability
account for an additional 30 %. Social networks account for 10 % of the gradient,
while self-esteem, sense of control, stress, depression, and anxiety do not appear to
mediate the association between education and health behavior (Cutler and Lleras-
Muney 2010).
A growing body of literature investigates associations between neighborhood
social environments and coronary heart disease. It is hypothesized that neighbor-
hood social interactions affect a wide set of affective, cognitive, and relational
experiences which in turn influence the cognitive-emotional antecedents of behav-
ior which is the end shape health behavior (Chaix 2009). In a recent study on CVD
risk factors, the authors found that Black Americans in the US Virgin Islands had
better cardiovascular health profiles and healthier lifestyles than their counterparts
residing in 50 US states, despite having lower education, and that CVD differences
were largely unchanged after accounting for health behaviors or social position
(Lee et al. 2013). The authors suggest that there may be contextual factors, both
social and physical, that influence these differences in health behaviors and CVD
736 S. Krokstad et al.
outcomes among Black people living in different continents. Health behavior also
differs between ethnic groups. In a systematic review of racial/ethnic disparities in
CVD risk factors, the authors found that Mexican Americans had a significantly
lower prevalence of smoking than Whites and Blacks and that American Indians/
Alaskan Natives (AIANs) had significantly higher prevalence of smoking com-
pared to Whites. Mexican Americans had the highest prevalence of no leisure-time
physical activity, followed by AIANs and Blacks (Kurian and Cardarelli 2007).
Despite the fact that health behaviors are strongly associated with CVD mortality,
their contribution to socioeconomic differences in mortality differs by their social
patterning. This was recently illustrated in a prospective study where the contribu-
tion of health behaviors in explaining the social gradient in mortality by SEP was
assessed in the British Whitehall II study and the French GAZEL study. The
association between socioeconomic factors and mortality and that between health
behaviors and mortality were similar in both cohorts, but behaviors attenuated the
association of social position with mortality by 75 % in the Whitehall II study and
only 19 % in the GAZEL study (Stringhini et al. 2011). The authors propose three
explanations for their findings. Firstly, they suggest that smoking, eating, and
drinking habits are more linked to cultural norms in Southern European regions
compared to the Northern European regions. Secondly, the social distribution of
unhealthy behavior may represent the epidemiologic transition from behaviors of
“affluence” to behaviors of “the poor,” especially smoking, and that this transition
is at different stages in the two countries. Thirdly, country-specific factors such as
welfare policies, bans on smoking, and taxes are likely to influence behavior.
Based on a recent review of broad literatures in sociology, economics, and
public health, Pampel et al. (2010) classified explanations of higher smoking,
lower exercise, poorer diet, and excess weight among low-SEP persons into nine
broad groups (including deprivation, inequality, and stress) that specify related but
conceptually distinct mechanisms. The authors (Pampel et al. 2010) found no clear
support for any one explanation and concluded that the literature on social dispar-
ities in health and health behaviors should do more to design studies that better test
for the importance of the varied mechanisms involved.
industrialized countries and involves all relevant CVD risk factors (Al-Qaoud
et al. 2011; Franks et al. 2011; Jenkins and Ofstedal 2014; Schumann et al. 2011;
Subramanyam et al. 2013; Tamayo et al. 2012).
The prevailing practice in most countries is the high-risk strategy, i.e., identifying
high-risk individuals, assessing the risk by clinical examinations and laboratory
tests, and initiating treatment accordingly. The treatment is often lifestyle interven-
tion in combination with drug treatment, like antihypertensive drugs and statins.
Such treatment should be continued for years, probably for rest of the life.
However, not only the CVD risk profile but also the healthcare is often
unfavorable to the low-SEP groups. “The inverse care law,” stated by Hart in
1971 (Hart 1971), still seems to operate (Grintsova et al. 2014), resulting in
increased gap between SEP groups (Eggen et al. 2014). Rose addressed this
issue already in 1985, arguing for a population strategy in preventive health
work (Rose 2001), and this debate is still ongoing. In 2006 Manuel and coauthors
revisited Rose (Manuel et al. 2006), arguing that “population health strategies that
target the majority of the population (people at low coronary heart disease risk)
have little effect on population outcomes because the population risk is low in this
group” and concluding that “medicine has developed analytical tools, such as the
Framingham risk algorithms which use multiple factors to better characterize
baseline risk of health outcomes. The result is a much improved effectiveness
and efficiency of drug treatment for improving coronary heart disease.” This is a
controversial area, and Manuel et al. were criticized for having greatly
underestimated the effect of population strategies by including patient with
established CVD, inflating the numbers in the “high-risk” group, assuming that
effectiveness in routine clinical practice equaled efficacy in RCTs (randomized
controlled trials) and ignoring undertreatment and poor long-term adherence.
Secondly, they systematically underestimated the contribution of population
strategies (Capewell and Graham 2010). According to Capewell and Graham,
there is increasing evidence that inequalities in risk factors can widen when
effects are mediated through individual-level changes in knowledge, motivation,
and behavior. High-risk intervention, which requires mobilization of an individ-
ual’s resources, whether material or psychological, generally favors those with
more resources, thus leading to increased social inequalities. Disadvantage
can occur at every stage of the process, from the person’s beliefs about health
and disease, and actual health behavior, to presentation, screening, risk assess-
ment, negotiation, participation, program persistence, and treatment adherence
(Capewell and Graham 2010). Consequently, it is referred to substantial socio-
economic gradients in statins use, both in the UK and in Denmark. Likewise,
inequalities in antihypertensive therapy have been reported. Long-term adherence
(compliance) with primary prevention medications barely reaches 50 %, and is
738 S. Krokstad et al.
Clinical Implications
Today, one should expect that clinicians are aware of the association between SD
and CVD risk and thus manage to think beyond traditional individual-based CVD
risk assessment that include blood pressure, heart rate, lipids, BMI, waist/hip
circumferences, glucose, creatinine, MA, and CRP in addition to information
about food habits, smoking, alcohol use, physical activity, and family history.
The SEP of the patient must be taken into account. In the health services, it is
important to be aware of the inverse care law and the tendency to provide the best
services for those who need it least and thus have a reduced cost-effectiveness.
Finally, it is important to be aware of the health services’ limitations in terms of
reducing CVD in the population because it only uses individual-based high-risk
strategies. Healthcare workers should contribute to the understanding of the poten-
tial of population-based prevention strategies in society, to both reduce social
inequalities in CVD risk and reduce CVD risk in total population.
Conclusion
In western societies there is a persistent social patterning of CVD risk (Diez Roux
2005). Social disadvantaged people are at greater risk of CVD than people in more
advantageous positions. Social disadvantage may be defined as being subjected to
racial or ethnic prejudice or cultural bias because of identity as members of a group.
However, it is not only the most vulnerable groups that have poorer health than
others. Different social positions possess different degrees of social disadvantage.
Relevant literature shows that there is a gradient in CVD risk throughout the
population, depending on people’s SP (Marmot 2004). The health services have
serious limitations in terms of reducing CVD and SEP inequities in CVD in the
population. In addition to individual-based high-risk preventive strategies applied
in clinics, population-based prevention strategies are necessary (Rose 2001).
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Part IV
Psychology and Cardiovascular Biology:
The Linking Mechanisms
Role of the Sympathetic Nervous System
in Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 748
Mechanisms of Sympathetic Nervous Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
Central Determinants and Reflex Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 749
Obesity and Increased Body Fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
Obstructive Sleep Apnea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
Stress and Hypothalamic-Pituitary-Adrenal Axis Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Consequences of Sympathetic Nervous Activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
Cardiac Structure and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
Renal Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
Hyperglycemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752
Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
Abstract
The sympathetic nervous system is pivotal in both circulatory and metabolic
control. While acute activation of the sympathetic nervous system is important
during regular daily activities in order to maintain homeostasis or in times of
stress in order to initiate a fight or flight response, chronic activation of the
sympathetic nervous system is associated with disease development and
end-organ dysfunction. Of particular importance is the role of the sympathetic
nervous system in the initiation and maintenance of hypertension and the
development of left ventricular hypertrophy, diastolic dysfunction, and insulin
resistance. Given the undoubted role of the sympathetic nervous system in
generating cardio-metabolic illness, inhibition of the sympathetic nervous
system seems a logical choice in order to alleviate disease burden associated
with these conditions. Lifestyle changes involving diet, exercise, and
cognitive-based therapies as well as pharmacological and device-based inter-
ventions directly targeting the sympathetic nervous system are likely to be of
benefit.
Keywords
Autonomic nervous system • Stress • Metabolic syndrome • Depression • Hyper-
tension • Noradrenaline • Insulin resistance • Obesity
Introduction
Insulin
The repetitive bouts of hypoxia that occur during sleep in patients with obstructive
sleep apnea are associated with a pronounced increase in muscle sympathetic nerve
activity (Somers et al. 1995), most likely as a result of stimulation of peripheral
chemoreceptors (Narkiewicz et al. 1999b) coupled with an impairment of the
arterial baroreflex (Parati et al. 1997). Treatment of OSA with continuous positive
airway pressure reduces sympathetic activity (Hedner et al. 1995; Narkiewicz
et al. 1999a) and is associated with an improvement in insulin sensitivity, blood
pressure, and plasma lipids in patients with OSA and the metabolic syndrome
(Dorkova et al. 2008; Harsch et al. 2004).
Mental stress is associated with increased sympathetic nervous activity and activa-
tion of both the adrenomedullary and adrenocortical systems. In fact, laboratory
mental stress is associated with a specific activation of the cardiac sympathetic
outflow (Esler et al. 1989). Glucocorticoid levels are elevated in response to stress
and have been associated with the development of hyperinsulinemia, insulin resis-
tance, glucose intolerance, increased blood lipids and visceral fat (Bjorntorp 1995),
and hypertension (Esler et al. 2008). Longitudinal data from the Whitehall II study
shows that both the HPA axis and the sympathetic nervous system are activated in
subjects with the metabolic syndrome, with psychosocial factors being associated
with the increased normetanephrine levels observed in these subjects (Brunner
et al. 2002). Moreover, work-related stress has been demonstrated to be related to
metabolic syndrome development (Brunner et al. 2007).
Role of the Sympathetic Nervous System in Cardiovascular Disease 751
Depression
Approximately one third of patients with major depressive disorder have substan-
tially elevated sympathetic nervous activity (Barton et al. 2007). Depression has
also been associated with activation of the HPA axis (Gold and Chrousos 2002) and
increased inflammatory cytokine production (Alesci et al. 2005). Data from the
longitudinal Health, Aging, and Body Composition Study demonstrated that the
presence of depressive symptoms on entry to the study was associated with a
subsequent increase in abdominal obesity (Vogelzangs et al. 2008). Recent inves-
tigations have shown an association between depression and the metabolic syn-
drome (McCaffery et al. 2003; Skilton et al. 2007), with the number of components
of the metabolic syndrome being increased in proportion to the degree of depres-
sion. Previous reports have also demonstrated an association between depression
and insulin resistance, one of the hallmarks of metabolic syndrome development
(Timonen et al. 2007). The use of serotonin specific reuptake inhibitors is associ-
ated with a reduction in sympathetic activity in some patients with depression
(Barton et al. 2007) and improves glucose control in men with abdominal obesity
(Ljung et al. 2001).
Hypertension
associated with a lower risk of cognitive decline, with the degree of improvement
being proportional to the duration of therapy and the degree of blood pressure
control (Peila et al. 2006).
Renal Damage
Hyperglycemia
glucose production (Shimazu and Ogasawara 1975; Takahashi et al. 1997) by the
liver. Previous studies in dogs indicated that the hepatic sympathetic nerves inhibit
liver glucose uptake and that hepatic sympathetic denervation is associated with an
increase in net hepatic glucose uptake in response to hyperglycemia (Dicostanzo
et al. 2006). Impaired glucose tolerance and insulin resistance are often found in
patients with liver cirrhosis (Petrides and DeFronzo 1989; Proietto et al. 1980).
Following liver transplantation, these metabolic impairments are improved (Merli
et al. 1999).
Insulin Resistance
Conclusion
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Sympathetic Nerve Activity, Stress,
and Cardiovascular Risk
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 760
Assessing Human Sympathetic Nervous Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 761
The Sympathetic Nervous System and Stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 762
Sudden Cardiac Events Associated with Increased Sympathetic Activity . . . . . . . . . . . . . . . . . . . . . 762
Deep Brain Stimulation, Sympathetic Outflow, and Cardiovascular Function . . . . . . . . . . . . . . . . 763
Takotsubo Stress Cardiomyopathy or Broken Heart Syndrome: When an Emotion
Changes the Shape of Your Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 764
Sympathetic Outflow in Stress-Induced Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 765
Why the Female Predisposition? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 766
The Midbrain Periaqueductal Gray (PAG), Estrogen, and Emotional Stress . . . . . . . . . . . . . . . . . . 766
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Abstract
Recent discoveries supporting a functional and structural link between the brain
and the heart emphasize the importance of understanding the cross talk for cardio-
and cerebrovascular health. Stress has been shown to play a crucial role in the
generation of cardiovascular diseases and has a major impact on neurodegener-
ative diseases and mental disorders presumably through activation of the sympa-
thetic branch of the autonomic nervous system. It is well established that
overactivity of the sympathetic nervous system plays a central role in the devel-
opment of cardiovascular disease and constitutes an important risk factor for
cardiovascular morbidity and mortality. Further, increasing evidence suggests the
Keywords
Sympathetic nervous system • Mental stress • Cardiovascular disease • Women
Introduction
With the aid of modern techniques to assess SNS activity, we now have better
understanding of how the SNS maintains normal cardiovascular function on a
beat-to-beat basis. In contrast to somatic motor nerves, sympathetic nerves are
shown to be tonically active (Adrian et al. 1932), so all innervated blood vessels
remain under some degree of continuous constriction. By rapidly regulating the level
of activity, the degree of vasoconstriction in the blood vessels of many key organs
around the body is altered. As the SNS plays such an important role in peripheral
vascular resistance and shows a close relation to baroreceptor function, its involve-
ment in the development of cardiovascular diseases has been vastly studied.
The different components in sympathetic nervous control of the cardiovascular
system have provided a basis for various techniques for assessing sympathetic cardio-
vascular control in humans. These techniques are complimentary rather than compet-
ing methodologies and provide different aspects of sympathetic nervous function.
Microneurography: This electrophysiological technique, developed in Uppsala,
Sweden, in the early 1960s, by Hagbarth and Vallbo (Vallbo et al. 1979), provides
direct measure of sympathetic nerve firing from efferent postganglionic unmyelinated
“C” nerve fibers in limb nerves of awake, unanesthetized humans. Postganglionic
sympathetic nerves are composed of hundreds to thousands of unmyelinated fibers
whose individual contributions to the recorded signal are exceedingly small. However,
accumulation of these thinnest of all human nerve fibers makes it possible to lodge the
tip of an electrode in their vicinity and record their ongoing activity. Virtually any
human mixed nerve is accessible to the recording electrode, but studies have been
confined mainly to the peroneal, tibial, or median nerves. Though visceral sympathetic
and parasympathetic activity is still inaccessible, two sympathetic subdivisions are
accessible, which are those to the skin vascular bed (SSNA) made up of a mixture of
sudomotor and vasomotor impulses and to the muscle vascular bed (MSNA) which is
dominated by vasoconstrictor impulses. The marked differences in temporal patterns
of sympathetic activity in human skin and muscle nerves have challenged the concept
of a “common sympathetic tonus,” as the findings indicate that there are different
populations of sympathetic neurons subjected to their own homogenous supraspinal
drive which may be different from that of other populations.
The noradrenaline spillover measurements: The methodology, which was intro-
duced by Murray Esler and colleagues in Melbourne, Australia, in 1979, is based on the
use of a radiotracer (radiolabeled noradrenaline (NA)) employed to measure the rates of
turnover of tissue NA and organ-specific spillover of NA to plasma. The method has
aided insight into the sympathetic neuronal outflow to internal organs, the inaccessibility
of which has been a limitation in cardiovascular research (Esler et al. 1979, 1988, 1990).
Power spectral analysis of circulatory rhythms: With this method, which is based
on mathematical partitioning, individual, superimposed rhythms producing cyclical
variations in heart rate or arterial pressure can be separated and quantified (Pagani et
al. 1986). The variability in heart rate, which is largely attributable to the influence of
the autonomic nervous system, can be divided into high (0.3 Hz) and low (0.1 Hz)
frequency components, proposed to reflect the vagal parasympathetic and cardiac
762 Y.B. Sverrisdóttir
It is well established that acute coronary syndromes and sudden cardiac death can be
triggered by acute psychological distress, such as intense emotions, anger, and
mental stress (Samuels 2007). The SNS is known to be active in sudden cardiovas-
cular death. Though not fully understood by which mechanism increased SNS
activity to different organs can lead to such events, the parallel increase in SNS
activity and morning peaks in acute MI, transient ischemia, and stroke indicates that
increased SNS activity may be a trigger for sudden cardiovascular events.
The interaction between central and autonomic nervous system responses may
have implications for further investigations of the brain-heart associations and
mechanisms by which acute and chronic psychological distress increase the risk of
myocardial infarction, cardiac arrhythmias, and sudden cardiac death.
Sympathetic Nerve Activity, Stress, and Cardiovascular Risk 763
The main central nervous system components associated with autonomic regulation
constitute the Central Autonomic Network (CAN). This is a functional network of
cortical and subcortical central nervous system structures that receive information
from humoral, visceral, and environmental sources and integrates these inputs to
generate preganglionic autonomic, neuroendocrine, and behavioral outputs essential
for survival (Benarroch 1993).
The primary brain areas involved in the autonomic modulation of the brain-heart
association are the insula, medial prefrontal cortex, and cerebellum. Other areas
involved in stress-induced autonomic modulation are the (anterior) cingulate cortex,
parietal cortex, somatomotor cortex/precentral gyrus, and temporal cortex.
One of the main structures of the central autonomic network is the subcortical
periaqueductal gray (PAG), a complex midbrain region involved in regulating bodily
as well as behavioral functions and which is routinely used to treat chronic neuro-
pathic pain. Electrical stimulation of this area has been shown to have cardiovascular
effects in humans (Pereira et al. 2010; Green et al. 2005). The PAG contains four
longitudinal columns, referred to as the dorsomedial (dmPAG), dorsolateral
(dlPAG), lateral (lPAG), and ventrolateral (vlPAG) subdivisions, which collectively
have a pivotal role in integrating behavioral and physiological responses to external
stressors as well as other functions. Activation of the vlPAG column produces a
reduction in cardiovascular activity, while activation of the dlPAG column, believed
to be an important component of the central mechanisms that generate the defensive
response to acute psychological stressors, is associated with an increased cardiovas-
cular activation (Dampney et al. 2013). The dorsolateral, lateral, and ventrolateral
columns of the PAG have distinct reciprocal connections with autonomic centers of
the lower brainstem and hypothalamus that differentially regulate activity in neurons
of the peripheral autonomic pathways (Bandler et al. 2000).
In the early twentieth century, development of techniques aimed to electrically
stimulate specific areas of the brain provided a vital tool to illuminate the role of the
brain in regulating autonomic function. With more widespread use of deep brain
stimulation (DBS) for otherwise treatment-resistant disorders, reports of autonomic
side effects became an area of attention and interest, providing a unique insight into
central autonomic regulation and pathophysiology. In rats stimulation of the dlPAG
was shown to evoke flight behavior and autonomic changes characteristic of panic
(Yardley and Hilton 1986); in humans, DBS at midbrain sites for treating neuro-
pathic pain reported the procedure often evoked intolerable side effects, which
resembled the symptoms of panic (Kumar et al. 1997; Nashold et al. 1969; Rich-
ardson and Akil 1977). In a recent study by Sverrisdóttir and colleagues (2014),
stimulation of the dorsolateral PAG in patients with neuropathic pain was shown to
result in a distinctive sympathetic nerve firing pattern previously reported in condi-
tions associated with anxiety and mental stress (Wilkinson et al. 1998; Donadio
et al. 2002). An active coping response (“fight and flight”) occurs when an individual
encounters a threatening stimulus that may be harmful or cause pain. This defense
764 Y.B. Sverrisdóttir
pattern is represented in the dmPAG and dlPAG and is classically associated with
endogenous non-opioid analgesia, increased arterial blood pressure, and heart rate,
although recent evidence in humans suggests that it may in fact be opioid-mediated
(Pereira et al 2013, Wang et al.). In the absence of an external threat, Sverrisdóttir
and co-workers showed that by directly stimulating the midbrain region where the
defense pattern is orchestrated, the nerve firing pattern and cardiovascular response
resemble that of anxiety, mental stress, and fight and flight response.
While emotional stress and emotion have long been associated with ventricular
arrhythmias and sudden cardiac death, in the past decade, cases and conditions have
been identified in which severe mental distress has resulted in physical changes to
the heart muscle, resulting in a spectrum of stress-related neurogenic cardiomyop-
athy syndromes, which includes the takotsubo or broken heart syndrome.
The English artist Walter Langley’s emotional painting from 1894, which title
arises from Tennyson’s poem In Memoriam, is about loss and heart break. The
painting portrays a young woman being comforted by an older woman as she holds
her head in her hands and cries. The turmoil of human emotions displayed is in direct
contrast to the flat calm sea in the background; it is the calm after the storm which
took the life of the young woman’s beloved and broke her heart.
The idea of the heart as the vulnerable locus of emotion is as old as time. Irish
mythology has Deirdre of the Sorrows and her lover Naoise; Greek mythology has
the tragedy of Apollo and Daphne, Wagner’s opera of Tristan and Isolde, and
Shakespeare’s Romeo and Juliet. Tales of death from a broken heart feature through-
out history and are as genuine today as they were yesterday.
activity is recorded in the acute phase, it would not capture the early acute catechol-
amine release as the reflex would already have “kicked in.”
The underlying cause for the evident female predisposition of SIC is unknown, but
may be related to gender differences in vulnerability to emotional stress (Orth-
Gomér et al. 2000) and myocardial sensitivity to catecholamine toxicity (Kneale
et al. 2000). That SIC seems to predominantly occur in postmenopausal women
indicates that their declining levels of estrogen in the absence of testosterone may
also explain their greater vulnerability to SIC (Zhou et al. 2010). In postmenopausal
women, estradiol and estrogen levels are closer to those of healthy adult men than
those of premenopausal women. Estradiol reduces the response to vasoconstrictors
in both male and female arteries. Increasing estrogen levels by means of transdermal
estrogen replacement therapy has been shown to decrease SNS activity in postmen-
opausal women (Vongpatanasin et al. 2001).
Equally, the lower incidence of SIC in healthy males suggests that androgens may
play a protective regulatory role in the pathophysiology of SIC.
A big man with a broken heart. In a recent clinical observation of a takotsubo
stress-induced cardiomyopathy in a morbidly obese man (Zhou et al. 2010), free
testosterone level was found to be lower and estrogen level higher than for an adult
male, probably due to aromatization of androgens to estrogens; hence the protective
role of androgens may be lost in obese men.
Depression and panic disorders are more common in women than in men and occur
at times of extreme hormonal change, such as the premenstrual period, following
pregnancy, and during the menopause (Lovick 2014). In mammals, 17β-estradiol
(E2) has powerful effects on numerous central neural networks, reduces the response
of vasoconstrictors in both male and female arteries, and can modulate pain, anxiety,
depression, and cognitive function (García-Villalón et al. 1996).
There exists a reciprocal relationship between the hypothalamic-pituitary-adrenal
(HPA) stress axis and the hypothalamic-pituitary-gonadal (HPG) hormonal axes.
Both testosterone and estrogen can modulate the response of the stress axis, whereas
activation of the stress axis inhibits estrogen and testosterone secretion (Toufexis
et al. 2014).
The dorsolateral part of the periaqueductal gray, where the fight and flight
reaction resides, is shown to be dense with estrogen receptors. Whether the decline
in estrogen levels associated with the menopause affects the function and density of
estrogen receptors in the dlPAG is not known. However, one may speculate that
without the protective shield of estrogen, a change in estrogen receptor function and
Sympathetic Nerve Activity, Stress, and Cardiovascular Risk 767
density might affect women’s response to emotional stress, rendering them more
vulnerable and defenseless in the event of a sympathetic storm.
Conclusion
This chapter has taken a closer look at the link the autonomic nervous system
provides between the brain and the heart, serving as a “telephone line” between
the two and forming a basis for the connection. Evidence of a linking between
emotional stresses and cardiovascular risk has been explored and more specifically,
stress-induced cardiomyopathy and a plausible explanation for the female predispo-
sition of the condition have been discussed.
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Immunology, Inflammation, Mental
Disorders, and Cardiovascular Risk
Bernhard T. Baune
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 770
Clinical Relationship Between Mental Disorders and Cardiovascular Risk Factors
and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 771
Subtypes of Depression Related to Cardiovascular Disease and Risk Factors . . . . . . . . . . . . . . . 772
Mechanisms of Immune Dysfunction, Mental Disorders, and Cardiovascular Risk
and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
Immune System Dysregulation in Depression and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773
Correlation Between Severity of Depression and Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
HPA Axis Dysregulation in Depression and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
Endothelial Dysfunction in Depression and CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
Stress, Diabetes, and Obesity as Risk Factors for Inflammation in Comorbid
Depression and Vascular Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 781
Abstract
The clinical relationship between mental disorders and cardiovascular disease
and risk factors is highly important with serious consequences for morbidity and
mortality. A key biological mechanism in this complex and bidirectional rela-
tionship is related to immune dysregulation and inflammation in particular. This
review critically evaluates the existing literature on the bidirectional nature of
this relationship, the contributing clinical factors, and the role of inflammation in
prevalent risk factors for both mental disorders and cardiovascular disease
including obesity, endothelial dysfunction, and diabetes mellitus type 2. This
chapter outlines the lines of biological mechanisms in the bidirectional relation-
ship between mental disorders and cardiovascular disease by exemplifying this
Keywords
Inflammation • Obesity • Mental disorders • Depression • Cardiovascular disor-
ders • Diabetes mellitus type 2
Introduction
The association between cardiovascular diseases (CVDs) and mental disorders has
long been recognized. Early reports go back to the first half of the twentieth century
when Benjamin Malzberg noticed in 1937 that institutionalized psychiatric patients
had a higher mortality rate than the general population. In his seminal report, he
described that the age-adjusted mortality rate among patients with involutional
melancholia was almost eight times higher than that of the population with “dis-
eases of the heart” accounting for almost 40 % of these deaths (Malzberg 1937).
In the following decades, the comorbidity of depression and CVDs has been
rigorously investigated in many cross-sectional and longitudinal studies. Current
literature suggests that the relationship between CVD and depression is bidirec-
tional. Numerous clinical and epidemiological studies investigating the association
between depression and cardiovascular disease have suggested that depression
increases the risk of subsequent CVD by 1.5-fold on average (Grippo and Johnson
2002; Thombs et al. 2006; Lippi et al. 2009; Nicholson et al. 2006) and that patients
with coronary artery disease and depression have a two- to threefold increased risk
of future nonfatal and fatal cardiac events compared to those cardiac patients
without depression (Goldston and Baillie 2008; Kooy et al. 2007; Rudisch and
Nemeroff 2003; Frasure-Smith and Lesperance 2010). Moreover, depression has
been found to be an independent predictor of a poorer outcome after an ischemic
event (Barth et al. 2004; Nicholson et al. 2006; Meijer et al. 2011). The behavioral
and biological mechanisms by which cardiovascular disease and mental disorders
and depression specifically are linked are manyfold. A more recently developed
theory places immune response and inflammation specifically at the center of this
discussion. Inflammation has classically shown to be related to cardiovascular
diseases, to depression, and to numerous comorbidities such as obesity and diabetes
mellitus that increase the risk for depression and cardiovascular disease indepen-
dently. The complexity of the role of immune dysregulation and inflammation
specifically in cardiovascular disease and mental disorders with a focus on depres-
sion and common risk factors such as diabetes, obesity, stress, and endothelial
dysfunction will form the main focus of this chapter.
Immunology, Inflammation, Mental Disorders, and Cardiovascular Risk 771
↓ BDNF B
Caspase activation B
↑ ROS
C
Clinical/
Depression-like symptoms/Sickness behaviour Behavioural
changes
Fig. 1 Shared pathophysiology between mental disorders and cardiovascular risk and
disease. HPA hypothalamic-pituitary-adrenal axis, GC glucocorticoids, GR glucocorticoid recep-
tor, IDO indoleamine 2,3 diaoxygenase, Trp tryptophan, KYN kynurenine, QUIN quinolinic acid,
NMDA N-methyl-D-aspartate, 5-HT serotonin, NA noradrenaline, DA dopamine, O&NS oxidative
and nitrosative stress, ROS reactive oxygen species, BDNF brain-derived neurotrophic factor,
TrkB tyrosine kinase-B, BH4 tetrahydrobiopterin. A, B and C: Connectors
Grippo and colleagues observed anhedonia, fatigue, elevated heart rate, reduced
heart rate variability, and elevated sympathetic cardiac tone in rats exposed to CMS
relative to controls (Grippo et al. 2003). Rats in the CMS group also showed
significantly higher plasma corticosterone, circulating TNF-α, IL-1β, plasma
renin activity, and aldosterone relative to controls (Grippo et al. 2005a). Addition-
ally, cytokine levels were correlated with the degree on anhedonia in rats exposed
to CMS (Grippo et al. 2005a).
Endothelial dysfunction is a recognized risk factor for CVD that is also often
observed in patients with depression (Shimokawa 1999; Rybakowski et al. 2006;
Bonetti et al. 2002; Cooper et al. 2011). In one study, Rajagopalan et al. (2001)
demonstrated abnormal endothelial function in patients with MD on antidepressants
without typical CAD risk factors relative to matched controls, while Sherwood
et al. (2005) found abnormal endothelial function in depressives as measured by
flow-mediation dilation relative to those without depression. However, these stud-
ies were limited in that they did not measure the severity of the depressive
symptoms or differentiate between depressive subtypes to examine any associations
between level of endothelial function and depressive severity and diagnosis.
Only one study has examined endothelial functioning and depressive symptom
severity. Rybakowski et al. (2006) assessed arterial endothelial function among
patients in the major depressive episode (MDE) of unipolar or bipolar disorders
(BD) without medications for 7 or more days and CVD risk factors. The results
indicated that patients with a mood disorder had impaired endothelial function.
However, there were no significant correlations between endothelial function and
duration of the mood disorder, age of illness onset, and duration of the current
depressive episode. There also were no significant correlations between endothelial
function and intensity of depression. Arterial endothelial dysfunction was also
observed in patients in the remitted stage. The researchers suggested that arterial
endothelial dysfunction may constitute a biological trait marker among those with
these mood disorders and is a factor which increases their risk for cardiovascular
diseases (Rybakowski et al. 2006).
A number of other risk factors such as stress, diabetes, and obesity exert immuno-
logical changes, often associated with inflammation that is a key mechanism of the
biological relationship between mental disorders and cardiovascular risk and dis-
ease. The following paragraphs investigate these vascular risk factors for their
ability to induce inflammation, thereby increasing vascular risk in addition to
their risk to increase the likelihood of a mental disorder such as depression.
Immunology, Inflammation, Mental Disorders, and Cardiovascular Risk 777
Katon et al. 2009; Koopmans et al. 2009; Le et al. 2006; Lin et al. 2010, 2010; Maraldi
et al. 2007; Molife 2010; Musselman et al. 2003; Thaneerat et al. 2010; Winkley
2008). It is tempting to speculate that patients with comorbid depression may have a
greater elevation in pro-inflammatory mediators than non-depressed patients with
T2DM, thereby increasing vulnerability to complications; however, recent literature
does not support this conclusion (Carnethon et al. 2007; Golden et al. 2008).
Alternatively, several other factors have been identified that may act as mediators
of this relationship. These include poorer adherence to treatment and self-care activ-
ities (Yang et al. 2009), poorer metabolic control (Thaneerat et al. 2010), and exposure
to the potential metabolic side effects of antidepressant medications. The use of
antidepressant pharmacotherapy is frequently considered as a mediator of the rela-
tionship between depression and T2DM. Several studies have found that certain
antidepressant medications are associated with long-term weight gain and suggested
that this may represent a key biological factor; however, a recent meta-analysis found
that the effects of antidepressants on glucose control remain ambiguous (van der Feltz-
Cornelis et al. 2010). This may be due to significant heterogeneity in the pharmaco-
logical mechanisms of various antidepressant drugs (McIntyre et al. 2010b). Similarly,
the effects of antidepressants on other aspects of metabolic disturbance such as weight
gain and dyslipidemia appear to be closely related to the specific antidepressant
evaluated in each study (McIntyre et al. 2010b; Serretti and Mandelli 2010). Although
this body of literature does demonstrate an association of some antidepressant med-
ications with the later onset of T2DM, this alone does not explain the observed
association between the two conditions (Pyykkonen et al. 2011).
Diabetes
Depression Inflammation
Obesity
Other Mediators
Fig. 2 The interrelationship between depression, diabetes and inflammation. BDNF brain derived
neurotrophic factor
Conclusions
Mental disorders and cardiovascular disease have long been described as comorbid
conditions in a complex bidirectional relationship. A key biological mechanism that
leads to support of a shared pathophysiology between mental disorders and CVDs
includes alterations of the immune in general and of inflammation in particular.
Inflammation has also been shown to be mechanistically linked to risk factors of
both mental disorders and cardiovascular disease such as endothelial dysfunction,
obesity, and diabetes mellitus type 2 which are regarded as independent risk factors
for mental disorders such as depression and CVDs. The literature suggests that a
biological model of the relationship between depression and CVDs should consider
clinical-biological subtypes of depression and CVDs in favor of a generalized and
possibly oversimplified global relationship between depressive symptoms and CVD
risk factors and disease regardless of diagnostic subtypes. The presented approach
enables a diagnostic classification of such subtypes based on inflammation, and
novel treatments targeting the immune system and inflammation in particular might
be clinically beneficial in treating and preventing the common comorbidity between
mental disorders and CVDs.
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Genetics and Epigenetics in Cardiac
Psychology
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 790
Evidence of Dysfunctional Sympathetic Nerve Activity and Noradrenaline Reuptake . . . . . . 791
The NET Gene and Its Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791
Statistical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793
Epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794
NET . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795
BDNF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796
DISC1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 797
TH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
GR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
5-HTT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 798
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 799
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 800
Abstract
Precisely how regulated patterns of gene expression under the control of diverse
signaling pathways underlie the homeostatic control of neuroanatomical aspects
of cardiac function remains unclear. The autonomic nervous system is
R. Bayles (*)
Laboratory for Vascular Translational Science, Inserm UMR-S1148, Paris, France
e-mail: [email protected]
A. El-Osta
Epigenetics in Human Health and Disease Laboratory, Epigenomics Profiling Facility, The Alfred
Medical Research and Education Precinct, Baker IDI Heart and Diabetes Institute, Melbourne,
VIC, Australia
Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
Central Clinical School, Department of Medicine, Monash University, Melbourne, VIC, Australia
e-mail: [email protected]
Keywords
Sympathetic nervous system • Noradrenaline transporter • Epigenetics • Chro-
matin modification
Introduction
Statistical Analysis
A common limitation, and one which besets most previous NET SNP association
studies, is the number of SNPs analyzed. In a recent study which attempted to
replicate candidate gene associations in MDD in the large-scale genome-wide
association data from the GAIN study (Boomsma et al. 2008), the SLC6a2 gene
was one of only four genes out of 57 to be supported as a statistically significant
candidate gene (Bosker et al. 2011). The SNP coverage in this analysis was enriched
by using HapMap data to address SNPs that were not present on the arrays used.
Individual SNPs could not reach statistical significance for association with MDD
when correcting for multiple comparisons. However, a significantly higher number
of SNPs in the SLC6a2 gene were associated with MDD than could be expected by
chance, taking into account linkage disequilibrium (Bosker et al. 2011). No common
794 R. Bayles and A. El-Osta
Epigenetics
The inherited biological component of complex diseases may involve much more
than simple sequence variation (Mill and Petronis 2007), when it comes to tran-
scriptional regulation. Epigenetic analyses may provide alternative mechanisms by
which heritable gene expression can be explained. Epigenetics is the study of
heritable changes in gene expression without a change in the sequence of DNA.
Investigation of how the genomic expression profile can be modified by the
environment in a long-term, intergenerational manner is an exciting prospect in
the study of complex diseases.
Two main mechanisms are involved in alterations in gene expression, a change
in DNA sequence or a change in local chromatin (Turner and Morris 2010).
Chromatin is the complex of DNA, noncoding RNAs (ncRNAs), histones, and
other proteins in the cell nucleus. The sum of the DNA methylation state, histone
modifications, and chromatin structure together determine the efficiency with
which a gene can be transcribed. There are four main mechanisms involved in
heritable epigenetic regulation: DNA methylation, ncRNAs, chromatin remodeling,
and histone modifications. All of these regulatory mechanisms, unlike DNA muta-
tion, are reversible and dynamic processes (Henikoff and Matzke 1997); however it
is important to note that even a transient environmental stimulus can have long-
lasting intergenerational effects on chromatin state (Anway et al. 2005). In the
transcriptionally inactive state, chromatin is tightly compacted (heterochromatin),
restricting access of transcriptional machinery to genes. In the transcriptionally
active state, chromatin opens up and allows transcriptional machinery to freely
transcribe genes (euchromatin) (Tsankova et al. 2007).
There has been a lot of talk of gene-environment (GxE) interactions recently, in
psychiatry in particular. Essentially it is epigenetics and dynamic chromatin regu-
lation that are at the interface of GxE interactions. Perhaps the greatest difficulty in
studying epigenetic regulation in psychocardiology lies in the inability to access the
Genetics and Epigenetics in Cardiac Psychology 795
NET
As discussed previously, functional variation of the NET gene sequence is rare, and
evidence of NET dysfunction in the clinic is variable in terms of the specific
location in the body and age of onset. Epigenetics may provide a mechanism by
which long-term changes in NET gene expression can be controlled. Promoter
hypermethylation was originally hypothesized to be a potential mechanism of
transcriptional silencing of the SLC6a2 gene in diseases with evidence of NET
dysfunction (Esler et al. 2006, 2008). Analyses of the SLC6a2 gene promoter in
both human blood and mouse neurons did not associate DNA methylation with
NET expression however (Bayles et al. 2013). Expression of NET was in fact
correlated with histone modifications and binding of the transcriptional regulatory
complex methyl-CpG binding protein 2 (MECP2) (Harikrishnan et al. 2010; Bayles
et al. 2010, 2012) (see Fig. 1). In particular, depolarization of neurons in vitro was
shown to induce an increase in NET expression (Harikrishnan et al. 2010; Habecker
et al. 2006). This may be of particular relevance to diseases with evidence of NET
dysfunction, since many of these diseases are also characterized by altered nerve
firing patterns (Lambert et al. 2006, 2007a, 2008a, b, 2010). The potential clinical
relevance of understanding the transcriptional mechanisms of the SLC6a2 gene is
high. Functional expression of NET in response to histone deacetylase (HDAC)
inhibition is currently being exploited in the treatment of cancer, with preclinical
evidence of enhanced drug delivery to tumors via increased NET expression (More
et al. 2011; Jia et al. 2011). Characterizing the interplay between genetic variation,
transcription factors, and chromatin regulation at the SLC6a2 locus in the context of
disease is an important area of future research.
796 R. Bayles and A. El-Osta
Healthy?
POTS HDACi
Other diseases? Neuronal depolarisation
DNA
Histones MeCP2
co-regulator
Acetylation of H3K9/14 complex
Methylation of H3K4
SUPPRESSED
Methylation of H3K9/27
Fig. 1 Chromatin-based regulation of the SLC6a2 promoter. Representation of the SLC6a2 gene
promoter associated with histone proteins in active and suppressed state. Activation of SLC6a2
transcription in response to treatment with a histone deacetylase inhibitor (HDACi) or depolari-
zation has been shown to involve the release of the transcription factor MECP2 and the modifi-
cation of lysine residues of histone H3
BDNF
agreement with this finding, reduced BDNF levels have been associated with
increased BDNF gene promoter methylation in the postmortem brains of suicide
completers (Keller et al. 2010).
The integrity of the BDNF gene appears to be clinically relevant at both the
genetic and epigenetic level. Multiple studies have associated reduced levels of
BDNF with altered DNA methylation, and many believe that BDNF gene methyl-
ation may be useful as a biomarker of depression (Song et al. 2014). The BDNF
Val66Met polymorphism is a common coding variant in the BDNF gene, which has
also been associated with many psychophysiological traits, including trait anxiety
and sympathovagal balance (Montag et al. 2010; Yang et al. 2010). BDNF has been
shown to be expressed in the nodose ganglion and released in the nucleus tractus
solitarius through vagal afferents, directly enhancing autonomic regulation of
cardiovascular function and especially the baroreflex response (Clark et al. 2011).
The functional expression levels of BDNF in the nucleus tractus solitarius may be
important, especially in relation to the changes in heart rate variability and cardiac
baroreflex associated with anxiety (Sevoz-Couche et al. 2013). Centrally derived
BDNF has been shown to be cardioprotective, preventing cardiac remodeling
following myocardial infarction in mice (Okada et al. 2012). How this may relate
to the poorer cardiovascular outcomes associated with depression post MI remains
to be investigated.
DISC1
may directly lead to the disruption of DISC1 in the brain, for example, leading to
predicted/associated chronic psychological phenotypes (Pirola et al. 2010). While
much work would be required to validate such a hypothesis, this is an example of
how it is hoped that an understanding of epigenetic regulation of transcription may
begin to explain associations determined at the epidemiological level.
TH
GR
The glucocorticoid receptor (GR) has long been studied in relation to its role in the
hypothalamic-pituitary-adrenal stress axis. Glucocorticoid involvement in the reg-
ulation of sympathetic nerves has also long been established, including modulation
of TH expression (Stachowiak et al. 1988; Brown and Fisher 1986). The gene
encoding the GR was one of the first examples of a gene being epigenetically
modified in response to stress, with those modifications and associated behavioral
alterations being inherited by subsequent generations (Weaver et al. 2004). These
findings in rats were ultimately translated to humans, where in postmortem brain
samples, altered GR gene methylation and expression was correlated with child-
hood abuse (McGowan et al. 2009). Other studies attempting to correlate MDD or
PTSD with altered GR gene methylation in a peripheral tissue source have also met
with some success (Carvalho et al. 2014; Labonte et al. 2014). The lasting influence
of stress on glucocorticoid signaling could potentially play an important and
sustained role in the regulation of the autonomic nervous system.
5-HTT
The serotonin (5-HT) transporter (5-HTT) remains the primary target of first-line
treatments in affective disorders, and both the genetic and epigenetic regulation of
the 5-HTT gene SLC6a4 are important. There are a number of common variations
in the sequence of the 5-HTT gene promoter, including long and short forms, with
and/or without other single nucleotide polymorphisms. There is little agreement
Genetics and Epigenetics in Cardiac Psychology 799
however on the significance of the many associations between the serotonin trans-
porter gene-linked polymorphic region (5HTTLPR) and stress or affective disor-
ders however (Karg et al. 2011). Serotonergic neurotransmission is highly complex,
and dissecting the precise functional role of 5HTTLPR variants in humans is
difficult. Analysis of serotonin turnover specifically in the brain revealed higher
turnover in patients with MDD compared to healthy controls, and higher serotonin
turnover was also associated with the short allele of the 5HTTLPR (Barton
et al. 2008). Further studies are required to resolve the relevant mechanisms
involved at the brain region specific, neuronal, and synaptic level.
Recent studies have been successful in identifying differences in 5-HTT mRNA
expression in peripheral blood samples of healthy and diseased populations. In
separate analyses of patients with depression or bipolar disorder, differences in
5-HTT mRNA expression have been associated with differences in SLC6a4 pro-
moter methylation (Sugawara et al. 2011; Wankerl et al. 2014). Importantly, the
study of twins discordant for bipolar disorder provided strong evidence for differ-
ences in SLC6a2 methylation being related to the environmental factors rather than
genetic background (Sugawara et al. 2011). It is hoped that findings of such changes
at the level of chromatin regulation in peripheral tissues will correlate with systemic
differences in serotonergic neurotransmission, providing biomarkers for affective
disorders. Little is known about the importance of 5-HTT genotype and expression
in relation to cardiovascular homeostasis; however, serotonergic signaling has been
shown to be an important mediator of anxiety-induced changes in heart rate
variability and the sensitivity of the cardiac baroreflex response (Sevoz-Couche
et al. 2013).
Conclusions
Mapping a new route to understand the regulatory pathways that underlie the
neurocardiovascular axis is a challenge because of the complexity of transcription
factors and proteins that alter chromatin structure and gene function. While the
SLC6a2 gene is implicated in disease with evidence of NET dysfunction specified
by histone tail modification, deconvoluting how the epigenome regulates patterns
of gene expression remains complicated. With more than 100 histone modifications
implicated in transcription, repair, replication, and genome stability, the challenge
is now to understand their specific combinatorial functions. Whereas determining
specific biological function given the expansive size of the human genome remains
a formidable task, genome-wide mapping approaches provide new opportunities to
unravel the importance of regulatory networks. In one attempt to characterize
functional elements in the human genome, the National Human Genome Research
Institute (NHGRI) launched a public research consortium named ENCODE (Ency-
clopedia of DNA Elements) to identify functional elements in the human genome
sequence (Anonymous 2004). Since its launch in September 2003, the ENCODE
consortium has discovered many new transcription-factor binding site motifs (Yip
et al. 2012; Neph et al. 2012), integrating chromatin patterns (Thurman et al. 2012;
800 R. Bayles and A. El-Osta
Wang et al. 2012a), as well as the importance of intergenic regions and gene
definitions (Djebali et al. 2012; Harrow et al. 2012). In short time, these and
many other studies have shown that patterns of gene expression are mapped by
histone modifications, transcription factor binding, and DNA methylation, includ-
ing noncoding RNA characterization (Banfai et al. 2012; Wang et al. 2012b). While
big studies such as these have contributed some unexpected findings in genome
biology, they have also stimulated new areas of research (Rafehi et al. 2014). Open
data from large-scale epigenome sequencing projects remain a critical resource, and
early access allows researchers to interconnect clinical and preclinical observations
with informative genomics to unravel the complexity of the epigenetic-
psychocardiovascular axis.
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Gene-Environment Interactions, Stress,
and Depression
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 808
Heritability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 809
Gene-Environment Interactions and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 810
The Hypothalamic-Pituitary-Adrenal Axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811
The Neurotrophic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 819
The Monoamine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 820
Clinical Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 823
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 825
Abstract
Depression is one of the most prevalent disorders worldwide, with high comor-
bidity with cardiovascular disease (CVD). Despite significant heritability,
robust genetic associations are yet to be identified in depression. Multiple
factors are accountable for this, including that genetic studies have not widely
considered environmental factors, despite their established association with
depression. One such factor is stress, a robust risk factor for depression; many
genetic studies have failed to include nurture in their research into depression.
The first gene-environment interaction (GxE) study in depression was
published in 2003, reporting a significant interaction between a functional
polymorphism in the serotonin transporter gene (5-HTTLPR) and recent
S. Cohen-Woods (*)
Matthew Flinders Fellow, School of Psychology, Flinders University, Adelaide, SA, Australia
e-mail: [email protected]
K.N. Harkess
School of Psychology, University of Adelaide, Adelaide, SA, Australia
e-mail: [email protected]
Keywords
Gene-environment interaction • Depression • Stress • Childhood maltreatment •
Psychiatric genetics • Serotonin transporter • HPA axis • Brain-derived
neurotrophic factor (BDNF)
Introduction
Heritability
Environment
been reported in individuals that have experienced stressful events and/or suffered
depression (Danese et al. 2008). This is particularly exacerbated in individuals
experiencing a current depressive episode with a history of stressors in childhood
(Danese et al. 2008). Such findings emphasize the influential role of early-life
environment and potential impact across the life-span.
While significant, environmental effects do not impact all individuals in the same
way. Stress-diathesis and vulnerability-stress models suggest some individuals are
more susceptible to negative effects of stress than others: psychiatric symptoms
develop as a result of personal vulnerability (e.g., genetics) and environmental
stressors (e.g., childhood abuse) (Myin-Germeys et al. 2003). Gene-environment
interactions fall within this, hypothesizing a causal mechanism where an individ-
ual’s genetic profile mediates the effects of (or their sensitivity to) environmental
exposures, impacting on the development of behavior or illness such as depression
(Rutter et al. 2006). Gene-environment correlations differ to interactions, describ-
ing the probability of an environmental exposure and not the effects or sensitivity to
exposure (see Fig. 1).
Variability in behavioral responses to stress dependent on genotype have been
reported in both primates and humans (Bennett et al. 2002; Caspi et al. 2002). In
2002, Caspi and colleagues conducted a seminal GxE study demonstrating a genetic
variant in the monoamine oxidase gene (MAOA) that moderates the effect of
childhood maltreatment and subsequent development of antisocial behaviors
Fig. 1 Basic methods used to understand genetic and environmental etiology of depression.
(a–c) Do not use interaction terms, testing for an association between the hypothesized predictor
and depression; (d) applies an interaction term (this is typically gene [coded 0,1,2]* environment
[coded categorical or continuous]) – multiplicative and additive (using risk differences) interac-
tions can be analyzed
Gene-Environment Interactions, Stress, and Depression 811
(Caspi et al. 2002). This was followed up by a study investigating genetic risk in the
serotonin transporter gene (5-HTT or SLC6A4) interacting with recent life stress to
moderate risk of developing depression (Caspi et al. 2003). This emerging field has
gained pace dramatically in the last 10 years, eliciting much scientific discourse;
these studies have been cited over 3,400 and 5,800 times, respectively. As interest
in gene-environment models of depression grows, more genetic polymorphisms and
systems have been investigated. While monoaminergic genes interacting with
stressful life events were a natural starting point for gene-environment investiga-
tions in depression, these will be discussed later in the chapter due to the many
lessons this literature now presents. Instead, two other commonly implicated
systems will be the first to be addressed: the HPA axis and neurotrophic system.
First
author Outcome Effect/primary study
(year) Sample size Population (instrument) Stress measure Gene SNP findings (p-value)
Liu (2013) 528 (256 Chinese Depression Life stress (The Holmes CRHR1 rs1876828 Significant interaction
MDD) (HAMD-21, and Rahe stress scale) rs242939 increasing risk of
CGI) rs242941 persistent MDD between
negative life events and
the G-allele (rs242939)
(p=.023), and/or GGT-
haplotype (p=.037)
Cicchetti 439 children African- Depressive/ Childhood maltreatment CRHR1 rs7209436 Depression: No
(2011) (51 early abuse, American, internalising (DHS records assessed rs110402 significant interaction
187 maltreated Latino, and symptoms (CDI, with Maltreatment rs242924 between childhood
not early Caucasian; TRF), salivary Classification System maltreatment and the
abuse) 7–13 years cortisol and Maternal TAT-haplotype
Maltreatment (p =.276) on depressive/
Classification Interview) internalising symptoms
Significant G-G-E
interaction of risk
between childhood
maltreatment, TAT-
haplotype, 5-HTTLPR
genotype on depressive/
internalising symptoms
(p=.04)
Cortisol phenotypes:
Significant interaction
between early abuse and
high depression/
internalising symptoms
on cortisol slope
S. Cohen-Woods and K.N. Harkess
(p =.008), with a flatter
slope. Significant
interaction of risk
between abuse and two
copies of TAT-
haplotype on cortisol
levels (p=.003), marked
by an attenuated slope of
change
Kranzler 3,080 1,211 Major Adverse childhood CRHR1 rs7209436 Depression: Significant
(2011) European- depressive experience (SSADDA) rs110402 interaction increasing
Americans & episode rs242924 risk of depression
1,869 (SSADDA) between adverse
African- childhood experiences
Americans and the TAT-haplotype
(p=.005) in African-
American women; no
significant interaction in
European-American
Gene-Environment Interactions, Stress, and Depression
women or men, or
African-American men
Depressive Episode:
Significant interaction
increasing risk of MDE
between adverse
childhood experiences
and the TAT-haplotype
(p=0.035) in African-
American women; no
significant interaction in
the other groups
(continued)
813
Table 1 (continued)
814
First
author Outcome Effect/primary study
(year) Sample size Population (instrument) Stress measure Gene SNP findings (p-value)
Grabe 1,683 Caucasian Depression Childhood maltreatment CRHR1 28 SNPs Significant interaction
(2010) (German) (BDI-2) (CTQ) (3 haplotype- increasing risk of
block depression between
analyses, and physical neglect and 23
TAT- of the 28 SNPs
haplotype) (polymorphism),
reaching gene-wide
significance. The largest
effect stemmed from
rs17689882 (p=0.0013)
Significant interaction
increasing risk of
depression between
physical neglect and
TAT-haplotype (p
=.0156; 1.4 increase in
BDI score per
haplotype). Other
haplotypes also
presented evidence for
interaction with physical
neglect, yielding a
protective or risk effect
dependent on the
haplotype measured,
with most significant p-
value of 0.0061 relating
to 1.6 point increase on
S. Cohen-Woods and K.N. Harkess
the BDI scale (ACC risk
haplotype comprising
rs171440, rs8072451,
rs81189). Please refer to
original paper for details
on other haplotypes
Polanczyk Discovery English Depression Childhood maltreatment CRHR1 rs7209436* Significant protective
(2009) 1116 women (Diagnostic (CTQ) rs110402* interaction between
(>90 % Interview rs242924* childhood maltreatment
Caucasian) Schedule for rs4792887 and TAT-haplotype(*)
DSM-IV) on development of past-
year (p=.04), and
recurrent MDD (p=.03)
Replication New Depression Compilation of 5 CRHR1 rs7209436 No significant
1037 Zealanders (Diagnostic measures rs110402 interaction
(>90 %+ Interview Prospective: 1) rs242924
Caucasian) Schedule/DSM- behavioural
IV) observations of mother-
Gene-Environment Interactions, Stress, and Depression
child interactions 2)
parental reports of
discipline, 3) changes in
role of primary
caregiver;
Retrospective: 4)
physical abuse 5) sexual
abuse
Bradley 560 African- Depression Childhood maltreatment CRHR1 15 SNPs Significant interaction
(2008) Americans (BDI and SCID- (CTQ) (including protective of depression
I) TAT between childhood
haplotype) abuse and the TCA-
haplotype comprising of
(continued)
815
816
Table 1 (continued)
First
author Outcome Effect/primary study
(year) Sample size Population (instrument) Stress measure Gene SNP findings (p-value)
rs7209436, rs4792887,
and rs110402 (p<.001),
and/or TAT=haplotype
(p<.005)
Bet (2009) 901 (244 with Caucasian Depression Childhood Adversity GR/ 22/23EK Significant interaction
childhood Dutch, 65+ (CES-D) (No formal scale - asked NR3C1 N363S increasing risk of
adversity) years if person had 9beta depressive symptoms
experienced personal BclI between childhood
life events during youth) adversity and 22/23EK
allele (p=.02) and 9beta
allele (p=.04)
Significant protective
interaction on recurrent
depressive symptoms
between childhood
adversity and one BClI
allele (p=.01)
Trend for interaction
between childhood
adversity and the 22/
23EK allele with
reduced cortisol levels,
and elevated cortisol
binding globulin (CBG)
S. Cohen-Woods and K.N. Harkess
(p=.10), as opposed to
without childhood
adversity (p=.21)
Trend for protective
interaction between
childhood adversity and
carrying one BclI allele
with lower CBG levels
(p=.07). This is also
observed in those
without childhood
adversity (p=.03),
indicating that genetic
basis is important alone
Literature investigating FKBP5, BDNF, and 5HTT have not been detailed in this table as they have been previously tabulated due to thorough review articles
and/or meta-analyses (Zannas and Binder 2014; Hosang et al. 2014; Karg et al. 2011)
MDDmajor depressive disorder, MDEmajor depressive episode, G-G-E gene by gene by environment interaction, CES-DCenter for Epidemiological Studies
Depression scale, CASIcomprehensive addiction severity index for adolescents, HAMD-21Hamilton depression rating scale 21-item, CGIclinical global
impression scale, CDIchildren’s depression inventory, TRFteacher’s report form, DHSdepartment of human services, SSADDAsemi-structured assessment
Gene-Environment Interactions, Stress, and Depression
for drug dependence and alcoholism, BDIbeck depression inventory, BDI-2beck depression inventory 2nd edition, CTQchildhood trauma questionnaire,
DSM-IVdiagnostic and statistical manual of mental disorders, 4th edition, DEXdexamethasone, CRHcorticotropin-releasing hormone, SCID-Istructured
clinical interview for DSM disorders – research version. *single nucleotide polymorphisms constituting the TAT-haplotype
817
818 S. Cohen-Woods and K.N. Harkess
substantiated by a number of studies, although these findings have not been consistent
(see Hosang et al. 2014). Due to the inconsistent findings, a recent meta-analysis
combined these studies to determine if an interaction of BDNF’s rs6265 (Val66Met)
and life stress does mediate depression (Hosang et al. 2014). A higher number of
Met-alleles were associated with a greater susceptibility to depression in the event of
life stress, with the strongest interaction observed in response to daily stressors; Met
carriers experienced a greater risk of depressive outcome compared to Val/Val
individuals (Kalueff et al. 2006; Wichers et al. 2008). The effect of the Met-alleles
was strongest in the case of stressful life events in adulthood, rather than childhood
adversity (Hosang et al. 2014). For instance, a study examining both childhood
adversity and recent life stress in women found that only recent life stress interacted
with BDNF to predict onset of a depressive episode (Brown et al. 2014). In fact, it has
been suggested that this outcome may be independent in females, while the BDNF
rs6265 (Val66Met) interaction with childhood adversity remains significant in males
(van Oostrom et al. 2012). Such results demonstrate gender may moderate gene-
environment interaction pathways.
Another neurotrophic gene investigated is 8-sialyltransferase (ST8SIA). ST8SIA
is involved in neuronal plasticity through assisting the folding of related proteins;
restriction of this plasticity has been linked to other disorders such as schizophrenia,
autism, and bipolar disorder (McAuley et al. 2012). McAuley et al. (2012) suggest
that vulnerability to later environmental insults may then stem from a lack of
plasticity. A small study investigating stressful life events (SLEs) and short-term
antidepressant response supports that BDNF and ST8SIA polymorphisms affect the
carriers’ response to treatment (Mandelli et al. 2014). One hundred and fourteen
patients with mood disorders were evaluated retrospectively and prospectively for
4 weeks. Their individual short-term response to antidepressant treatment was not
associated with genetic variation when they had experienced an SLE at the onset of
their mood disorder (Mandelli et al. 2014). However, not being exposed to an SLE
at the onset of mood disorder predicted a slower response to antidepressants in
carriers of both a BDNF haplotype (rs11030101 A-allele and rs11030104 G-allele)
and a ST8SIA haplotype (rs11853992 A-allele and rs17522085 G-allele) (Mandelli
et al. 2014). These results were unexpected as neuroplastic factors were hypothe-
sized to act as pro-survival variants and thereby enhance antidepressant responses
(Mandelli et al. 2014). As SLEs are generally considered risk factors for mood
disorder onset, it is particularly interesting that their precedence predicted a swifter
antidepressant response. To explain seemingly contradictory results in this area,
more complex networks are starting to be investigated in the form of gene-gene-
environment interactions; however, these studies face significant challenges with
respect to power.
alleviate the symptoms of depression. Thus, it has been hypothesized that poly-
morphisms in the monoamine system are implicated in the etiology of depression
(Lerer et al. 2001). The serotonin system has been the most widely studied in
depression due to the target of modern antidepressants (selective serotonin reuptake
inhibitors). Serotonin is a protein that is critical for central nervous system function
and has been heavily implicated in mood regulation (Lesch et al. 1996).
The first psychological/psychiatric study to investigate serotonin at the molec-
ular genetic level was in 1996 and analyzed 5-HTTLPR and neuroticism (Lesch
et al. 1996). The serotonin transporter (5-HTTor SLC6A4) gene has an upstream
region called the serotonin-transporter-linked polymorphic region (5-HTTLPR),
which is responsible for the production of the 5HTT and reuptake of serotonin
(Cohen-Woods et al. 2013; Lesch et al. 1996). The repeats are reduced to two
alleles: long (L) and short (S); the S-allele results in reduced 5-HTTLPR expression
(Lesch et al. 1996). This initial study reported an association accounting for 7–9 %
of genetic variance contributing to anxiety-related personality traits; however, this
has not been robustly replicated, and this estimate of genetic variance is extremely
large. It is now accepted that where individual genetic risk factors are identified,
contribution will be much smaller (<1 %) (Wray et al. 2011).
The 5-HTTLPR has been widely investigated in depression; however, results
with straight genetic association analyses have been inconsistent (e.g., Collier
et al. 1996; Furlong et al. 1998; Hauser et al. 2003). Due to this gene’s strong
candidacy in depression and that findings in gene-depression association studies
had not been consistent, this was the first gene (and 5-HTTLPR, the first variant) to
be investigated in context with stressful life events (SLEs) and depression (Caspi
et al. 2003). This was the first GxE study in depression and as mentioned previously
has created a large amount of academic discourse. Caspi and colleagues reported a
significant GxE interaction, with the S-allele predicting vulnerability to depression
in individuals that experienced stressful life events in the 5 years preceding and also
in those that experienced childhood maltreatment (Caspi et al. 2003). Individuals
with the L-allele were at reduced risk, as were S-allele carriers that had not
experienced stressful events. This resulted in a proliferation of studies attempting
to replicate this finding: some successful, some not (see Karg et al. 2011). While it
might be unexpected that the 5-HTTLPR studies have not been described first in
this chapter, as the most widely studied gene, it has also taught researchers in the
field the most lessons in GxE analyses to date.
With many studies published (>55), lacking consistency in their conclusions,
two meta-analyses were published in close succession stating there is no evidence
for a significant interaction between 5-HTTLPR and stressful life events in
predicting depression (Munafo et al. 2008; Risch et al. 2009). This had a significant
impact on the field. A striking point is that these studies included a very small subset
of available studies investigating the 5HTTLPR and stressful events (not restricting
to SLEs), just 5 (Munafo et al. 2008) and 14 (Risch et al. 2009) out of 56 publica-
tions. This was for many reasons, including a lack of primary raw data being
available and analyses being restricted to SLEs and no other kind of stressors
(childhood maltreatment or medical conditions) (Karg et al. 2011). Karg and
822 S. Cohen-Woods and K.N. Harkess
colleagues addressed this issue by running meta-analyses that included all studies,
combining them at the level of significance tests with no requirement for equivalent
raw data (method by Hedges and Olkin 1985). They also investigated if the type of
stressor analyzed was important, separating SLEs, childhood maltreatment, and
specific medical conditions. Through meta-analysis of 54 studies, many more than
those included in the first two meta-analyses, a highly significant interaction was
reported between the 5HTTLPR (S-allele as risk) and stress in predicting risk for
depression, restricted to childhood maltreatment and specific medical conditions
with SLEs providing less robust evidence (Karg et al. 2011). This could be due to
less consistent reporting of SLEs relative to childhood maltreatment or clear
medical conditions and/or an indication that timing of stressors could be important
in the understanding of GxE interactions and mechanisms. One potential mecha-
nism by which GxE interactions may act is through epigenetic changes such as
DNA methylation. Epigenetic changes may occur in response to a stressful expo-
sure but only at critical time points in the life-span.
Other factors have also been suggested to have a significant impact in under-
standing the interaction between 5-HTTLPR and stress in depression, such as
persistent (recurrent) depression rather than single-episode depression being
a more robust outcome (Brown et al. 2013; Uher et al. 2011). Subjectivity of
the stress measures themselves also influences how replicable findings are in the
context of this gene, with less subjective measures eliciting greater evidence
for interaction, particularly longitudinal measures that do not rely on recall
(Uher and McGuffin 2010). Of course, different variants are likely to be sensitive
in different ways, for example, it has been suggested that the haplotype in
CRHR1 might possess a more robust interaction with retrospective measures
such as the Childhood Trauma Questionnaire, which was attributed to emotional
memories rather than the stressor being the interactive factor (Polanczyk
et al. 2009).
In addition to the serotonin transporter gene, other serotonergic and monoam-
inergic genes have also been examined in depression in adolescents and
adults exposed to a variety of stressors including composite measure of “family-
based environmental risk,” SLEs, and childhood maltreatment: HTR2A, HTR2C,
MAOA, TPH, DRD2, DRD4, DAT1, and AP-2b (e.g., Dunn et al. 2013; Eley
et al. 2004; Kim-Cohen et al. 2006). Some studies indicate timing of stressors is
important (i.e., DRD4 variation and sexual abuse; (Dunn et al. 2013) or gender (i.
e., MAOA variation and childhood maltreatment or SLEs; (Kim-Cohen et al. 2006;
Ma et al. 2013)); however, these genes have been less widely studied with
variable conclusions. It is currently difficult to assess how much the reported
interactions are robustly sensitive to factors such as timing of the stressors, type
of stressors measured, types of measures (objective, subjective, retrospective, or
prospective), outcomes measured (i.e., recurrent depression, single episode, or
current mood state), or gender, but as more studies are published, this will become
clearer.
Gene-Environment Interactions, Stress, and Depression 823
Clinical Significance
The scale and impact of depression on global health directly (World Health
Organization 2008) and indirectly through increased incidence of comorbid illness
including cardiovascular disease (Bondy 2007) mean that understanding the bio-
logical etiology of depression has the potential to have a huge clinical impact. It is
significant not only that CVD and depression are highly comorbid (Bondy 2007)
but that they share significant risk factors, such as stress (Rosengren et al. 2004;
Yusuf et al. 2004). GxE studies in depression have potential to inform future
investigations in CVD through candidate systems in association with stress and
also through methodological issues such as those described in this chapter. Further,
through understanding how gene-environment interactions can have their impact
(e.g., epigenetic changes such as DNA methylation), it will also inform studies
investigating the overlap between CVD and depression. In the long term, this will
help inform mechanisms by which significant stressors have the potential to impact
so negatively on some people but not all. Environmental “programming” effects of
early experience (such as low “maternal affection”) can be reversed through
pharmacological and environmental (cross-fostering) interventions (Weaver
et al. 2004). Histone deacetylase inhibitors (used to reverse methylation) are highly
toxic and not appealing in the clinical setting where onset of illness (or risk through
stress exposure) occurs early in life; however, less toxic compounds with antitumor
efficacy in the context of cancer are being identified and trialed (Vigushin and
Coombes 2004). It is therefore not implausible that less toxic agents may be
identified in the future in the context of other illness. Through the establishment
of robust GxE interactions, further pharmacological and/or sociological or psycho-
logical interventions could be identified, which have real potential to impact policy,
health, and the future of many individuals globally.
One such challenge that needs to be addressed is that biological and statistical
interactions are different, and this is not widely recognized in the literature
(Rothman and Greenland 2005). A vast majority of studies apply multiplicative
(statistical) interactions, with no consideration for additive (the more biologically
plausible) interaction terms; to clarify the role of GxE interactions in depression
risk, it will be important to pursue multiple different methods with greater trans-
parency of researchers in reporting their findings (Caspi and Moffitt 2006; Uher
2014). GxE studies have faced some other significant criticisms, such as robust
replications being needed that anticipate methodological issues such as those
described in this chapter, and also a problem with studies being underpowered to
detect effects (Duncan and Keller 2011). Unfortunately, in contrast to straight
genetic studies where just some basic demographic information and phenotype
categorical data are typically required, GxE studies require more in-depth assess-
ment. This impacts the sizes of samples available, which can be striking particu-
larly in the context of large genetic association studies. Another common criticism
is that the field is “susceptible to the publication bias” (Duncan and Keller 2011).
However, researchers are addressing this through meta-analyses where possible.
Two meta-analyses published (analyzing 5-HTTLPR and BDNF rs6265) have
demonstrated that publication bias is unlikely to have a significant impact on
their (positive) findings as multiple studies of a moderate size (700) would be
required to change significant findings (Hosang et al. 2014; Karg et al. 2011).
Challenges faced by meta-analyses include the use of multiple methods applied to
published data, with a lack of raw data being available. As mentioned earlier in the
chapter, there are statistical methods around this, but also there is openness in the
field to collaborate to address these concerns head on. Culverhouse and colleagues
have brought together as many researchers as possible to analyze the raw
5-HTTLPR and stress (adult- and childhood) data from each group using stan-
dardized analytic script to enable “pure” meta-analyses to be run (Culverhouse
et al. 2013). All published study authors were requested to participate, and many
individuals with unpublished data are also participating; inevitably, some authors
declined the invitation (Moffitt and Caspi 2014); however, secondary meta-
analyses including these studies will also be run. This demonstrates a willingness
to address issues where possible that have been raised by critics (Duncan and
Keller 2011).
A priority now must be ascertaining large samples with reliable phenotypic and
good quality temporal environmental measures, with careful consideration given to
environmental factors measured and hypotheses tested. Systematic genome-wide
GxE studies will not be possible without this due to restricted power with samples
currently available. This will require collaboration between researchers to obtain
sufficient numbers and strong consideration given to optimal approaches to achieve
this (i.e., starting from scratch or, perhaps more financially feasible, obtaining
genotype data for cohorts where strong environmental data is already available
but no genetic data). This is an exciting time for the psychiatric genetic and
epidemiological communities, with nature and nurture merging together to yield
interesting and promising research.
Gene-Environment Interactions, Stress, and Depression 825
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Diabetes, Depression, and
Cardiovascular Risk
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 832
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
Depression in Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 834
Depression in Type 2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 835
Bidirectional Relationship of Diabetes and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 836
Depression as a Risk Factor for Cardiovascular Diseases and Mortality . . . . . . . . . . . . . . . . . . . . . 836
Mechanisms Explaining the Link Between Depression and Cardiovascular Risk . . . . . . . . . . . . 837
Does Successful Treatment of Depression Improve CVD Outcomes? . . . . . . . . . . . . . . . . . . . . . . . . 839
Evidence Regarding Screening for Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 841
Future Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 842
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 843
Abstract
Diabetes and depression are major public issues that often co-occur. Both
diseases affect a growing number of people worldwide and are projected to
be among the five leading causes of disease burden in 2030. Approximately
10–30 % of the people with type 1 (5–10 % of all diabetes cases) or type
2 diabetes is affected by depression. There is ample evidence that the associ-
ation between type 2 diabetes and depression is bidirectional. Depression is
M. Adriaanse (*)
Department of Health Sciences and the EMGO+ Institute for Health and Care Research, VU
University Amsterdam, Amsterdam, The Netherlands
e-mail: [email protected]
F. Pouwer
Center of Research on Psychology in Somatic diseases (CoRPS) FSW, Tilburg University,
Tilburg, The Netherlands
e-mail: [email protected]
Keywords
Diabetes • Depression • Cardiovascular risk • Mechanisms • Treatment •
Screening
Introduction
Diabetes and depression are major public health issues. Worldwide, more than
382 million people are estimated to have diabetes (International Diabetes Federa-
tion 2013) and approximately 300 million people have major depression (Vos
et al. 2012). These figures are expected to increase, and both disorders are projected
to be among the five leading causes of disease burden by 2030 (Mathers and Loncar
2006). Diabetes and depression often co-occur and have attracted much research
attention in the last two decades. It has been estimated that people with diabetes are
twice as likely as the general population to suffer from depression (Roy and Lloyd
2012). Patients with depression and diabetes, compared with patients with diabetes
alone, generally have lower quality of life (Ali et al. 2010), less optimal self-care
and decreased adherence to medical treatment recommendations (Gonzalez
et al. 2008), poor glycemic (HbA1c) control (Lustman and Clouse 2005), lower
levels of physical activity (Koopmans et al. 2009), and less healthy eating behav-
iors. Moreover, comorbid depression among diabetes patients has a profound
negative impact on poor cardiovascular outcomes including mortality (van Dooren
et al. 2013). In addition, diabetes patients with depression use healthcare services
more often than their nondepressed counterparts, which is associated with a sub-
stantial increase in healthcare-related costs (Bosmans and Adriaanse 2012).
Diabetes, Depression, and Cardiovascular Risk 833
Diabetes
develop type 2 diabetes after the age of 40, although the age of onset for type
2 diabetes decreases. Treatment of type 2 diabetes consists of healthy lifestyle
advices, glucose lowering drugs, and/or insulin therapy.
Depression
Depressive disorders are among the most common psychiatric disorders, with the
overall prevalence of current depressive symptoms being 8.7 %; the lifetime
prevalence rate of a diagnosis by a health professional is 15.7 % (Strine
et al. 2008). Major depressive disorder (MDD), the most serious form of the
unipolar depressive disorders, is the most prevalent disease among adults that is
described in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-
TR, American Psychiatric Association 2000), with a lifetime prevalence of 16.6 %
(Kessler et al. 2005). The key symptoms of depression are anhedonia (loss of
interest or pleasure) and dysphoria (low mood). Other symptoms include fatigue;
change in appetite (with weight loss or weight gain as a result); sleep disturbances;
loss of self-esteem; inappropriate feelings of guilt, agitation, or psychomotor
retardation noticed by others; inability to concentrate; and suicidal ideation (Amer-
ican Psychiatric Association 2000). Less optimal self-care behaviors, such as
decreased medication adherence, poor nutrition, and lack of exercise, are common
in persons with depression and diabetes (Lin et al. 2004).
Barnard et al. conducted a systematic review including 14 studies and found that the
prevalence of clinical depression in controlled studies was 12 % for adult people
with type 1 diabetes compared with 3.2 % for control subjects. In studies with no
control group, the prevalence was 13.4 %. However, of these 14 studies, only
4 examined prevalence in control groups, and only three used a psychiatric,
diagnostic interview; the other studies relied on self-report measures of depression
(Barnard et al. 2006). In 2009, Gendelman et al. reported that depression was more
common in persons with type 1 diabetes compared to nondiabetic subjects, using
the Beck Depression Inventory II (BDI-II) cut score (17.5 vs. 5.7 %) or by using
either BDI-II cut score or antidepressant use (32.1 vs. 16.0 %; men 25.5 vs. 11.6;
women 37.9 vs. 20.5 %) (Gendelman et al. 2009). These conclusions were based on
458 patients with type 1 diabetes and 546 without diabetes within the coronary
artery calcification in type 1 diabetes study. More recently, using cross-sectional
data from outpatients with type 1 diabetes in the Netherlands, Pouwer
et al. observed that 33–36 % reported elevated depression scores when using the
WHO-5 questionnaire, 25–33 % when using the Centre for Epidemiological Studies
Depression Scale (CES-D), and 8–10 % when using the WHO Composite Interna-
tional Diagnostic Interview (CIDI). Johnson et al. (2013) reviewed the prevalence
of depression among young people (up to 25 years old) with type 1 diabetes.
Diabetes, Depression, and Cardiovascular Risk 835
Twenty-three articles were included; three out of the five studies that had used a
comparison group found no differences between young persons with type 1 diabetes
and controls (Johnson et al. 2013). However, three other studies showed higher
rates of depression compared to population norms. Based on these eight studies, the
authors concluded that current evidence is inconclusive about whether there is an
increased prevalence of depression among young adults with type 1 diabetes
(Johnson et al. 2013).
In sum, there is as yet no clear evidence to support that individuals with type
1 diabetes have increased rates of depression. This is mainly due to the restricted
number of studies, the quality of the studies (lack of a control group), the research
design (majority of studies is cross-sectional), and the measurement of depression
(not using a diagnostic interview) (Barnard et al. 2006; Johnson et al. 2013).
There is now abundant evidence from longitudinal studies that the association
between type 2 diabetes and depression is bidirectional with depression increasing
the risk of type 2 diabetes and type 2 diabetes increasing the risk of depression
(Mezuk et al. 2008; Golden et al. 2008). Depression is a stronger predictor of type
2 diabetes than vice versa. People with type 2 diabetes have a 15 % increased risk of
depression compared to people without diabetes, whereas depression is associated
with a 60 % increased risk of developing type 2 diabetes (Mezuk et al. 2008).
Golden et al. reported a modest association of baseline depressive symptoms with
incident type 2 diabetes that was partially explained by lifestyle factors, i.e., daily
caloric intake, smoking status, alcohol use, and physical activity. In the same study,
impaired fasting glucose and untreated type 2 diabetes were inversely associated
with incident depressive symptoms, whereas treated type 2 diabetes showed a
positive association with depressive symptoms (Golden et al. 2008). Further sup-
port for the bidirectional relationship between diabetes and depression has been
provided by several other recent studies (Pan et al. 2010; Renn et al. 2011; Chen
et al. 2013; (Nouwen et al. 2010; Rotella and Mannucci 2013).
30 % increase for myocardial infarction, and patients with type 2 diabetes alone
were at 82 % increased risk for myocardial infarction, compared with patients
without either condition (n = 214.749) (Scherrer et al. 2011). The results of the
ACCORD study (Action to control Cardiovascular Risk in Diabetes), examining a
total of 2053 type 2 diabetes participants, however, showed that depression was not
significantly related to the primary composite outcome (cardiovascular death,
nonfatal heart attack, or stroke) (HR 1.53 [95 % CI 0.85–2.73]) or to the microvas-
cular composite outcome (0.93 [0.53–1.62]), but all-cause mortality was signifi-
cantly increased both in those with PHQ-assessed probable major depression (2.24
[1.24–4.06]) and PHQ score of 10 (1.84 [1.17–2.89]). The effect of depression on
all-cause mortality was not related to previous cardiovascular events or to assign-
ment to intensive or standard glycemic control (Sullivan et al. 2012). Finally, in a
7-year follow-up study of 7835 Chinese type 2 diabetes patients, depression was
associated with a two- to threefold increase in the risk of incident cardiovascular
disease, especially stroke (Ting et al. 2013). Interestingly, Katon and colleagues
studied whether macrovascular or microvascular or coronary, cerebrovascular, or
peripheral vascular procedures were associated with depression within the path-
ways epidemiological study. The results of this prospective study show that base-
line severity of depressive symptoms, coronary procedures (i.e., coronary artery
bypass surgery, angioplasty, and coronary stent placement) during follow-up, and
baseline severity of diabetes symptoms were each independently associated with
risk of major depression at 5-year follow-up (Katon et al. 2009).
Depression and cardiovascular mortality. A recent meta-analysis was carried out
which examined the relationship between depression, cardiovascular, and all-cause
mortality of prospective studies in people with diabetes (van Dooren et al. 2013). A
total of 16 studies were included. Depression was associated with an increased
mortality risk of all-cause mortality (HR = 1.46, 95 % CI = 1.29–1.66). Although
based on only five studies, the results showed a 39 % increased risk for cardiovas-
cular mortality (HR = 1.39, 95 % CI = 1.11–1.73) associated with the presence of
depression in diabetes (van Dooren et al. 2013). Based on the evidence of these
prospective epidemiological studies, the conclusion can be drawn that depression is
likely to increase the risk of cardiovascular diseases and cardiovascular mortality in
diabetes. Adjustment for clinical characteristics and health behaviors seemed to
attenuate these relationships and thus vital in future studies. Future meta-analysis
should confirm the direction and magnitude of these relationships.
There are several potential behavioral and biological mechanisms by which depres-
sion may interact with diabetes to worsen the prognosis of cardiovascular risk.
Behavioral mechanisms. A meta-analysis showed that in diabetes patients,
depression was associated with reduced treatment nonadherence (z = 9.97, P <
0.0001) to a wide range of self-care activities (e.g., diet, exercise, medication use)
838 M. Adriaanse and F. Pouwer
in both patients with type 1 or type 2 diabetes (Gonzalez et al. 2008). The weighted
effect size was near the medium range (r = 0.21, 95 % CI 0.17–0.25).
As a consequence of impaired self-care activities, depression may lead to poor
glycemic control (Lustman et al. 2000) and diabetes complications (de Groot
et al. 2001).
The associations between depression, physical activity, and cardiac outcomes
are complex. Depression generally has a strong negative impact on physical activity
levels, and this may contribute to the increased cardiovascular risk. Physical
inactivity is a common risk for the development of both type 2 diabetes and
depression (Buijsse et al. 2011; Dugan et al. 2014; Mammen and Faulkner 2013).
In addition, results from a Cochrane review suggest that exercise is moderately
more effective than no therapy for reducing symptoms of depression (Cooney
et al. 2013). The pooled standardized mean difference (SMD), for the 35 trials,
was 0.62 (95 % CI 0.81 to 0.42), indicating a moderate clinical effect in favor
of exercise. The methodologically robust trials showed a smaller effect in favor of
exercise (Cooney et al. 2013). The SMD from the 8 trials (out of 35) that provided
long-term follow-up data found only a small effect in favor of exercise 0.33 (95 %
CI 0.63 to 0.03). Depressive symptoms were associated with physical inactivity
in primary care type 2 diabetes patients (Koopmans et al. 2009). In the Heart and
Soul Study, a prospective cohort study of 1017 outpatients with stable coronary
heart disease, it was concluded that the association between depressive symptoms
and new cardiovascular events was largely explained by behavioral factors, partic-
ularly physical inactivity (Whooley et al. 2008).
Dietary factors may also play a role in linking depression and cardiovascular
outcomes in persons with diabetes. For example, change in appetite with subsequent
weight gain or weight loss is one of the DSM-IV-TR (American Psychiatric Associ-
ation 2000) criteria for depression. A poor diet increases the risk of overweight and
obesity which are driving factors of the type 2 diabetes epidemic. The Look AHEAD
(Action for Health in Diabetes) trial showed that intensive lifestyle intervention can
produce sustained weight loss, mean change of 6.15 % of participants initial weight
across 4 years, and improvements in fitness, glycemic control, and CVD risk factors
(hemoglobin A(1c) levels, systolic blood pressure, and high-density lipoprotein
cholesterol levels) in individuals with type 2 diabetes (Look Ahead Research Group
and Wing 2010). Alternative behavioral mechanisms that could act as an intermediary
between diabetes, depression, and cardiovascular risk are smoking (Ye et al. 2013)
and poor sleep (Knutson et al. 2006; Barone and Menna-Barreto 2011).
Biological mechanisms. Depression increases activity of the hypothalamus–pi-
tuitary–adrenal (HPA) axis and the sympathetic nervous system (Knol et al. 2006;
Krishnan and Nestler 2008), resulting in increased release of cortisol and other
glucocorticoids. It is postulated that chronically high cortisol concentrations
(as reported in about 50 % of patients with depression) might result in obesity,
insulin resistance, and diabetes (Golden 2007). HPA dysregulation has also been
associated with CHD risk factors (e.g., abdominal obesity, hypercholesterolemia,
hypertension) and is implicated in the pathogenesis of diabetes and CHD (de Jonge
et al. 2010; Rosmond and Bjorntorp 2000).
Diabetes, Depression, and Cardiovascular Risk 839
coronary heart disease, or both and coexisting depression (Katon et al. 2010).
Patients in the intervention group had greater overall 12-month improvement across
glycated hemoglobin levels (difference, 0.58 %), LDL cholesterol levels (differ-
ence, 6.9 mg per deciliter [0.2 mmol per liter]), systolic blood pressure (difference,
5.1 mmHg), and SCL-20 depression scores (difference, 0.40 points) (P < 0.001). In
2013, Huang et al. conducted a meta-analysis to examine whether collaborative
care can improve depression and diabetes outcomes in patients with both diseases
(Huang et al. 2013). Eight trials containing 2.238 patients showed a significant
improvement in depression treatment response (RR = 1.33, 95 % CI = 1.05–1.68),
depression remission (adjusted RR = 1.53, 95 % CI = 1.11–2.12), higher rates of
adherence to antidepressant medication (RR = 1.79, 95 % CI = 1.19–2.69), and
oral hypoglycemic agent (RR = 2.18, 95 % CI = 1.61–2.96), but indicated a
nonsignificant reduction in HbA1c values (MD = 0.13, 95 % CI =
0.46–0.19). Unfortunately, none of the eight included collaborative care studies
in the meta-analysis (Huang et al. 2013), except the study of Katon et al. (2010) on
cardiovascular risk, cardiovascular disease, or mortality.
Screening for depression in people with diabetes does not meet all criteria for
screening. Criteria for appraising the viability, effectiveness, and appropriateness of
a screening program were first described by Wilson and Jungner for the World
Health Organization (WHO) in 1968, but are still applicable today (Wilson and
Jungner 1968). The criteria are based on ten original principles and relate to
knowledge of the disease (e.g., there must be a recognizable latent or early
symptomatic stage), knowledge of the test (e.g., suitable test or examination),
treatment for the disease (e.g., facilities for diagnosis and treatment available),
and cost considerations. Uncertainties remain about the time interval for screening,
optimal frequency, the instrument, effectiveness in specific (ethnic) groups, and the
overall cost-effectiveness. There is also uncertainty about the implementation of a
depression screening program, with extra burden for clinical practices owing to
increased numbers of newly detected patients. Furthermore, screening for depres-
sion will result in a substantial number of false-positives and unintended harmful
consequences and is resource-intensive (Thombs et al. 2012).
So far, there are no randomized controlled studies that evaluated the effects of
depression screening on cardiovascular outcomes in patients with diabetes. Given
the limited effects of screening on depressive symptoms, it is highly unlikely that
screening of depression will subsequently result in a reduction of cardiovascular
diseases and mortality. At present, there is no substantial evidence of the effective-
ness of screening for depression among diabetes patients and is therefore not
recommended.
Future Trials
In the future, efficacy trials should focus on the key questions, such as how to find
more optimal ways to prevent and treat depression in persons with diabetes. Ideally,
researchers should develop innovative interventions that can help to prevent depres-
sion, type 2 diabetes, and cardiovascular diseases or reduce mortality rates, in a
cost-effective way (Baumeister et al. 2012). Also, long-term prospective studies are
needed to disentangle the mechanisms that link depression with unfavorable car-
diovascular risks in diabetes patients. These studies should focus on type 1 or type
2 diabetes patients only; adjust outcomes for clinical characteristics, health behav-
iors, and complications; and examine whether the associations are attributable to
depressive symptoms scales rather than clinically diagnosed depression (diagnostic
interview).
Conclusion
Diabetes and depression are public health issues that often co-occur. Approximately
10–30 % of the people with type 1 or type 2 diabetes is affected by depression. The
odds of depression in people with type 2 diabetes were twice that of nondiabetic
controls. This is less clear for type 1 diabetes patients. There is ample evidence for a
Diabetes, Depression, and Cardiovascular Risk 843
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Insulin Resistance, Glucose Regulation,
Obesity, and Mood
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 850
Insulin Resistance and Glucose Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 851
Insulin Resistance and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 853
Insulin Affecting the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
Affective States: Affect, Mood, and Emotion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
The Relationships between Insulin Resistance, Obesity, Glucose
Regulation, and Mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
Abstract
The following chapter details current understanding of interactions between
insulin, or insulin resistance, obesity, and mood and affect as key mediators of
this association. The functions of insulin in the periphery and central nervous
system are reviewed, and insulin resistance is explained. Three different levels
of affective states are defined: pure affect, mood, and emotion, although it is
noted that more research currently focuses on mood and mood disorders.
Insulin crosses the blood-brain barrier using saturable transporters, whereupon
R. Keegan (*)
Research Institute for Sport and Exercise, Faculty of Health, University of Canberra, Canberra,
ACT, Australia
e-mail: [email protected]
N. Naumovski
School of Public Health and Nutrition, Faculty of Health, University of Canberra, Canberra, ACT,
Australia
e-mail: [email protected]
Keywords
Heart disease • Psychogenic heart disease • Aetiology of heart disease •
Psychocardiology • Mental illness • Cardiovascular disease • Insulin Resistance
- Mood
Introduction
The following chapter details the current empirical understanding of the role of
insulin resistance, glucose regulation, and mood in obesity and related disorders.
For many years, the scientific subjects of nutrition, psychology, pharmacology, and
physiology have often progressed quite independently. It is possible to work as a
scientist in some of these fields with relatively little knowledge of the others and to
do so quite comfortably. In recent years, however, and particularly in tackling
important and complex problems such as obesity, the need for interdisciplinary
research and theories has become increasingly clear. Research drawn from different
disciplines typically uses different methodological approaches, different language,
and interpretations and produces different types of theories or models. As such, if
we are to successfully generate solutions to problems that span disciplinary bound-
aries, we will need to use interdisciplinary strategies. Obesity, diabetes, and car-
diovascular disease are inarguably significant problems, spanning several
disciplinary boundaries. Thus the following chapter will explore the interplay
between insulin resistance, glucose regulation, and mood in relation to obesity
and related illnesses.
Insulin Resistance, Glucose Regulation, Obesity, and Mood 851
Insulin is one of the most potent anabolic agents involved in the synthesis and
storage of macronutrients (lipids, proteins, and carbohydrates) as well as being
involved in their breakdown and release into circulation (Chang et al. 2004). The
secretion of insulin from the pancreatic islets of Langerhans into the circulation is
characterized as pulsatile, due to the secretory bursts of millions of islet cells. This is
also well characterized; the β-cells are stimulated by glucose leading to the secretion
of insulin in two phases (biphasic). An initial rapid burst (within 1 min, peaking at
3–5 min and lasting around 10 min) is closely followed by a less dense but more
sustained and prolonged release of the insulin (Bratanova-Tochkova et al. 2002;
Wilcox 2005). Once plasma glucose concentration is increased, such as after the
consumption of a meal, glucose enters the pancreatic β-cells via the glucose trans-
porter located on the cell plasma membrane. The intracellular glucose is then
phosphorylated by glucokinase producing the glucose 6-phosphate and generating
adenosine triphosphate (ATP). The ATP itself is a signaling molecule for the insulin
secretion in the β-cells as the cell itself is equipped with the ATP-sensitive potassium
channels (KATP channels). The KATP channels close on increase in cytoplasmic ATP
and therefore depolarize the membrane and as a consequence open the voltage-
dependent calcium channels. This is followed by the influx of Ca2+ ions, and this
increase in the Ca2+ concentration rapidly increases the rate of insulin excretion via
exocytosis (Komatsu et al. 2013). Although glucose is the primary stimulus for
insulin secretion, other macronutrients (proteins and fats), hormones, and various
inputs from the neuronal stimuli can also modify this response of the β-cells.
Similarly to many other peptide hormones, insulin exhibits its action by binding
to specific receptors found throughout the body including fat, liver, and muscle cells
(and the central nervous system). The main action of insulin in the periphery is to
stimulate reduction in circulating glucose levels by triggering cells to increase the
uptake of glucose. Furthermore, insulin also signals the liver to increase and
promote glycogenesis, and it simultaneously inhibits the secretion of another
hormone, glucagon from pancreatic cells. Glucagon has the opposing effects of
insulin and, as such, works in the regulation of circulating glucose (Aronoff
et al. 2004; Samuel and Shulman 2012). Hepatic glucose production maintains
the basal blood glucose regulation during the fasting stage, and once circulating
glucose levels become depleted and fall below the normal range, termed hypogly-
cemia, secretion of glucagon is increased. This effectively leads to the hepatic
glucose stimulation and increase in gluconeogenesis with return of plasma glucose
to normal levels. This mechanism is not required during and immediately following
the meal, as glucagon secretion is suppressed, and when coupled with the insulin
effect on the liver, it results in near total suppression of hepatic glucose output
(Aronoff et al. 2004).
Insulin resistance (IR) occurs when cells in the body fail to respond to insulin
(Chiu et al. 2007). As such, insulin continues to be produced, but cells do not
respond to its presence, leading glucose in the blood to accumulate, termed
852 R. Keegan and N. Naumovski
It is well documented that IR and obesity appear to be closely related. While the
causal system behind this is arguably very complicated, there are clear links to be
made. Excess body weight can lead to increased free fatty acids and triglycerides in
the blood (Roden et al. 1996), which in turn appear to increase IR (Koyama
et al. 1997; Roden et al. 1996; Schinner et al. 2005). Likewise, once established,
insulin resistance results in hyperinsulinemia. Given that insulin stimulates the
storage of energy into fat cells – which tend to retain their sensitivity even as
hepatic and skeletal muscle cells become resistant – IR stimulates the formation of
new fatty tissue and accelerates weight gain (Isganaitis and Lustig 2005). Further-
more, both IR and obesity often have the same underlying cause: systematic
overeating. Chronic and repeated hyperglycemia and hyperinsulinemia as well as
elevated levels of blood lipids, all caused by a hypercaloric diet, would both
854 R. Keegan and N. Naumovski
contribute to increased IR and trigger the storage of energy in adipose tissue (Unger
and Scherer 2010). In relation to the effects of mood, high levels of cortisol within
the bloodstream (a key indicator of stress) can contribute to the development of
insulin resistance (Giovannini et al. 1982; Sluijs et al. 2010). Further still, resistance
to the appetite-suppressing hormone leptin, which is released to trigger feelings of
fullness and discourage further eating, also tends to accompany both obesity and IR
(Myers et al. 2008). Hence, while the two are closely related, it is not possible to say
which is the primary cause of this relationship, and as such, it can be postulated that
IR can display without obesity and vice versa obesity without IR.
which is commonly associated with IR and diabetes (Chiu et al. 2007; Dou
et al. 2005; Hoyer 2004; Valenciano et al. 2006). Insulin receptors are distributed
throughout the CNS, but are highly concentrated in the olfactory bulb, cerebral
cortex, hypothalamus, hippocampus, and cerebellum (Havrankova et al. 1978;
Unger et al. 1989). Further, the rate of insulin uptake in these various tissues can
be significantly different (Banks 2004), and it is proposed that IR can manifest to
different degrees in different CNS tissues – mirroring the variability that occurs in
resistance to thyroid hormones (Banks et al. 2012). The number of insulin receptors
also decreases with age, suggesting a key role for insulin and IR in the aging process
(Bosco et al. 2011; Chung et al. 2002). Such changes could also compound any
effects of IR, as receptors would be both fewer in number and less responsive to
insulin within the CNS.
One core mechanism through which insulin can be seen to regulate cognition,
affect, and behavior is the hypothalamic-pituitary-adrenal (HPA) axis. Insulin
signaling, as well as lipid sensing, in the hypothalamus triggers a negative feedback
system to inhibit glucose production and appetite (Caspi et al. 2003; Schwartz and
Porte 2005; Yue and Lam 2012). The HPA axis is a complex set of direct influences
and feedback interactions among three endocrine glands: the hypothalamus, the
pituitary gland, and the adrenal glands (small organs on top of the kidneys). The
HPA axis is a central component in the neuroendocrine system’s regulation of
reactions to stress, regulating many body processes, including: digestion, the
immune system, mood and emotions, and energy storage/expenditure.
Release of corticotropin-releasing hormone (CRH) from the hypothalamus is
influenced by stress, physical activity, illness, blood cortisol levels, and the sleep/
wake cycle (circadian rhythm). Typically, cortisol rises rapidly after wakening,
peaking after 30–45 min, before falling over the course of the day, and then rising
again in late afternoon. As nighttime approaches, cortisol levels fall in late evening,
reaching a minimum in the middle of the night. Increased production of cortisol
during times of stress increases the availability of glucose in order to facilitate the
“fight-or-flight” response. As well as directly increasing glucose availability, cor-
tisol also suppresses the metabolic processes of the immune system that would
consume glucose, further increasing its availability (Besedovsky et al. 2008). As
such, prolonged chronic stress can contribute to obesity, IR, and type 2 diabetes by
disrupting the hormonal balance of the HPA axis (Gohil et al. 2001; Rosmond and
Bjorntorp 2000; Tsigos and Chrousos 2002). A dysfunctional HPA axis causes high
serum cortisol levels, which results in raising glucose and insulin levels, which in
turn cause insulin-mediated effects on adipose tissue, ultimately promoting visceral
adiposity and IR (Tsigos and Chrousos 2002). HPA-axis dysfunction and/or chronic
psychological stress may explain the reported risk indication of abdominal obesity
to cardiovascular disease (CVD), NIDDM, and stroke (Brunner et al. 2002;
Rosmond and Bjorntorp 2000). With dense concentrations of insulin receptors in
the hypothalamus and olfactory bulb, and the above-described close relationships
between the HPA axis, insulin, and glucose, any chronic disorders of insulin
regulation would appear to be extremely problematic.
856 R. Keegan and N. Naumovski
As noted in the preceding text, there are a number of important structures in the
CNS that are affected by insulin and therefore a number of important functions that
may be influenced too. Any effects on the HPA axis are likely to influence affect,
moods, and feelings of stress, whereas any influences on cognition may affect our
ability to perform the cognitive appraisals that precede emotions. As an example of
a relatively direct effect, dopaminergic receptors in the ventral tegmental area
(VTA) of the brain contain insulin receptors (Figlewicz et al. 2003), and insulin
in this area regulates dopamine reuptake (Figlewicz et al. 1994). Mice with dam-
aged insulin receptors in the VTA increase food intake and adiposity (Konner
et al. 2011). In humans, these neural circuits play a key role in motivation and
decision-making (DeLong and Wichmann 2010) as well as regulating a variety of
motor control functions (Bjorklund and Dunnett 2007). The VTA is strongly
associated with the experiencing of “rewards” following behaviors such as eating
and sex, and stimulation of the area by drugs or electrodes is also reported to
generate pleasurable experiences (Arias-Carrion and Poppel 2007; Wise 1996).
However, in addition to simple “rewards,” dopamine in the VTA is also associated
with increased action tendencies and movement (Schultz 2002). Overall, dopamine
appears to be important in both “reward” experiences and “seeking” tendencies, and
so depending which specific circuits are more or less affected by insulin, appetite
and/or enjoyment of eating may be influenced in this way. The amount of feeding as
well as the nutritional constitution – glucose, carbohydrate, and lipids – will likely
produce different impacts on mood. For example, fasting may gradually decrease
CNS insulin, leading to a VTA-dopamine response that both motivates feeding and
overestimates the likely pleasure/reward that will be derived (Schultz 2002). Feed-
ing on foods that generate a lower-than-expected reward may decrease dopamine
levels, whereas foods that produce a greater-than-expected reward may temporarily
increase dopamine (the “prediction-error” hypothesis – cf. Schultz 2002). In fact,
fMRI imaging studies have shown differences between the need to eat and the
pleasure of eating within the VTA system (Tataranni and DelParigi 2003; Wang
et al. 2001). Further, chronic stress, along with the accompanying chronic increases
in neural glucocorticoids, appears to stimulate a preference for sweet and fatty
foods, in a process believed to occur in the VTA-dopamine system (Lindley
et al. 1999; Volkow et al. 2002; Wang et al. 2002). As such, any dysfunction or
degradation of this system, such as IR or chronic hypo/hyperglycemia, may gener-
ate long-term problems for both mood/affect and obesity.
Following this line of reasoning, recent research has shown a longitudinal
association between eating “palatable” food in order to cope (e.g., with stress or
unhappiness) and subsequent increases in BMI in adults (Boggiano et al. 2015a; see
also Boggiano et al. 2014; Burgess et al. 2014). In contrast, for adolescents
perceptions of reward correlated most strongly with BMI, not coping motives
(Boggiano et al. 2015b). These findings raise the possibility that eating highly
Insulin Resistance, Glucose Regulation, Obesity, and Mood 859
palatable foods to experience reward may subsequently catalyze such eating to cope
and the development of obesity. This possibility is supported by the link between
reward sensitivity and obesity in children (Faith et al. 2013; Graziano et al. 2010;
Rollins et al. 2014). Hence, the development of IR may accompany and compound
obesity by affecting the way humans both seek rewards and cope with negative
affect, stimulating the overconsumption of highly palatable foods (i.e., high fat,
high sugar, or high salt and calorie dense).
Obesity is known to impair the transit of insulin across the blood-brain barrier
(Kaiyala et al. 2000), and IR – in the form of reduced effects on feeding and glucose
regulation – is more pronounced in high-fat fed rodents (Clegg et al. 2011; Ono
et al. 2008). The mechanism of impairment is proposed to be through interrupted
insulin signaling in the hypothalamus (Belgardt and Bruning 2010; Clegg
et al. 2011). Effectively, the high lipid levels and inflammation cause damage to
the endoplasmic reticulum, and this leads to IR in both peripheral (Hotamisligil
2010) and CNS tissues (De Souza et al. 2005). Such increases in IR in both the
periphery/liver and in the brain have been observed in both rats and dogs and would
appear to constitute a vicious cycle of unhealthy eating triggering obesity, low
mood, and further unhealthy eating (Yue and Lam 2012). Given the above descrip-
tions of how insulin and IR may influence mood and affect, we should expect a clear
association between obesity and mood disturbances.
Accordingly, in a study of children aged 5–13 years, depressive symptomatology
at baseline was predictive of IR 6 years later, suggesting that low mood may be a
key precursor to IR, obesity, and related disorders (Shomaker et al. 2011). This
association was subsequently observed from early adolescence (mean age 12 years)
into adulthood (mean age 33) in women, but not men (Pulkki-Raback et al. 2009).
Associations have also been reported between depressive symptoms (and/or per-
ceived stress) and IR in adults (Arroyo et al. 2004; Eaton et al. 1996; Everson-Rose
et al. 2004; Golden et al. 2004; Kawakami et al. 1999; Suarez 2006). A relatively
recent meta-analysis concluded that depressive symptoms were associated with a
37 % increased risk of subsequently developing NIDDM, independent of confounds
such as body mass index (BMI) (Knol et al. 2006). Hence, chronic low mood and
diminished affect appear to be good predictors of subsequent IR. Depressive
symptomatology also accompanies diabetes and IR (Eckel et al. 2005; Okamura
et al. 2000; Ramasubbu 2002; Timonen et al. 2005), particularly when comorbid
cardiovascular disease is present (Engum et al. 2005; Gans 2006). It even seems
that the degree of metabolic control maintained by diabetes patients plays an
important role in determining whether depressive illness develops as a comorbidity
(Lustman and Clouse 2005). This connection suggests a breakdown of a common
system (or systems) that regulates glucose, insulin, and affective states with likely
important roles for dyslipidemia and cortisol (Grundy et al. 2005).
IR and major depressive illness share several pathologies, including disorders
of the HPA axis, the autonomic nervous system, platelets, and endothelial func-
tion (Gans 2006; Reagan 2007; Tamashiro et al. 2011). In fact, Gans (2006)
outlined a range of possible pathways through which these symptoms may be
860 R. Keegan and N. Naumovski
doubled in the presence of diabetes (Anderson et al. 2001; de Groot et al. 2001;
Labad et al. 2012). Depressed mood is also associated with abdominal obesity and
poor diet (Dong et al. 2004; Hamer et al. 2012; Luppino et al. 2010; Roberts
et al. 2003; Simon et al. 2006; Zhao et al. 2011). In animal models of mood
disorders, a consistent link is found between obesity and depressive symptoms,
again suggesting a common signaling pathway (Akubuiro et al. 2013; Chuang
et al. 2011; Dallman 2010; Diz-Chaves 2011; Kumar et al. 2013; Maniam and
Morris 2010; Spence and Courbasson 2012). As is the case throughout this field of
research, the relationship does not appear to be one of linear causation (Singh
2014). As such, obesity can contribute to low mood (e.g., low energy, low self-
esteem), but persistent low mood can contribute to obesity by prompting both
increased feeding behavior and biasing food selection towards high-fat and high-
sugar sources. Additionally, the IR, hyperglycemia, and chronic stress (i.e.,
HPA-axis activation) that often accompany obesity are likely to compound and
propagate these issues. Hence, not only are IR and mood clearly linked, but so are
obesity and mood, and there is clear evidence of the signaling pathways being
closely related albeit complex.
One core issue for consideration is the role of pro-inflammatory cytokines from
immune activity. Emerging evidence suggests an important link between increased
production of these small proteins and neurochemical/neurotropic changes to the
brain (Raison et al. 2006). When considered alongside their likely interactions with
stress hormones and the endothelial membrane, cytokines stemming from autoim-
mune dysfunction and/or chronic stress appear strong candidates for further
research (Craft et al. 1996; Reagan 2007). Likewise, chronic, or repeated episodes
of, hyperglycemia may further compound this threat to the cell membranes of both
the heart tissue (Rubin et al. 2012) and key neurological functions (Pais et al. 2007;
Sommerfield et al. 2004). In fact, the administration of inflammatory cytokines such
as IFN-α, IL-1, IL-2, IL-6, TNF-α, and C-reactive protein has been reliably shown
to induce changes in mood, cognition, and behavior, similar to those observed in
mood and anxiety disorders (Dantzer and Kelley 2007; Kent et al. 1992; Raison
et al. 2006). Further still, blocking the receptors for these proteins has been shown
to reduce sickness behavior and depressive symptoms in laboratory animals, even
when the symptoms develop as a result of psychological stress (Milligan et al. 1998;
Persoons et al. 2005; Tyring et al. 2006). Pro-inflammatory cytokines also have
well-described effects on the HPA axis that are consistent with the changes seen in
major depression and mood disorders (Raison et al. 2006). Specifically, increased
production of CRH and cortisol as well as decreasing tissue sensitivity to gluco-
corticoid hormones (Hasler et al. 2004; Pace et al. 2007; Silverman et al. 2004).
Pro-inflammatory cytokines also appear to mediate IR (Dandona et al. 2004;
Shoelson et al. 2007). Hence, we have a developing picture of a system linking
IR, obesity, and mood in complex and multifaceted ways, including the separate
actions of insulin in the CNS and periphery, HPA-axis dysfunction, autoimmune
responses, endothelial dysfunction, inflammatory responses, and chronic psycho-
social distress (Gans 2006).
862 R. Keegan and N. Naumovski
Clinical Implications
When facing such a complex and interactive system, we rarely deal in clear-cut
diagnoses and treatment indications. Instead, we must observe the totality of the
system, make measured and careful changes, and carefully monitor the effects.
Further still, there is no reassurance that such a system will return to homeostasis
if we remove a stimulus that has caused an unwanted change. We are faced with the
famous “butterfly effect” problem, popularized by Lorenz (1963). There are rela-
tively clear diagnostic tests and criteria for IR, metabolic syndrome, diabetes
mellitus, mood disorders, and obesity. It is not clear, however, whether practitioners
detecting one such disorder may wish to test for others in order to reach a more
complete diagnosis of the evolving system. There is evidence that treating individual
problems can also affect other aspects of the system, for example, antidepressant use
appears to remove or attenuate inflammatory responses (Musselman et al. 2003;
Yirmiya et al. 2001). Given the variability in how symptoms manifest and present, it
seems sensible to approach issues on a case-by-case basis. There is no clear evidence
to date that any specific aspect of the problem – obesity, IR, or mood disturbance – is
primary in driving the pathology. Individual patients should arguably be assessed,
evaluated, and treated in relation to their individual symptoms, while remaining
cognizant of the potential comorbidities and developmental trajectories/prognoses.
Conclusions
This chapter has presented a brief but comprehensive overview of current knowl-
edge in relation to IR, glucose regulation, obesity, and mood. Not only does this
topic span disciplinary boundaries, but we also see an emerging picture of a
complex regulatory system with no clean “directional causality.” This situation
challenges conventional approaches to science, which are often neatly segregated
by topic area and which frequently assume a simple causal chain. However, by
acknowledging both that our work must span disciplinary boundaries as well as
addressing a highly complex phenomenon, we give ourselves the best chance of
eventually understanding and even mastering an extremely important problem. The
methods, analysis, training, and recruitment technique we adopt will therefore
change accordingly. By developing specialists, researchers, and practitioners in
this unique topic area, we may begin to construct a common understanding, and this
approaches a clear consensus regarding best practice.
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Insulin Resistance, Glucose Regulation, Obesity, and Mood 871
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874
Cardiac Disturbances Provoked by Acute Psychophysical Stressors . . . . . . . . . . . . . . . . . . . . . . . . . 875
Causes of Sudden Cardiac Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875
Heart Rate Is Not an Adequate Biomarker for Ventricular Changes . . . . . . . . . . . . . . . . . . . . . . 876
Ventricular Arrhythmias in Stressed Animals with Predisposed Hearts . . . . . . . . . . . . . . . . . . 876
Ventricular Electrical Events in Stressed Animals with Intact Hearts . . . . . . . . . . . . . . . . . . . . 877
Animal Models of Stress Cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 878
Importance of Social Factor and Cardiac Disturbances Provoked
by Acute Social Stressors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 879
Acute and Chronic Effects of Social Defeat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 880
Effects of Social Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881
Chronic Social Stressors and Interaction Between Depression and Cardiac Disorders . . . . . . 881
Assessment of Depression-Like State in Experimental Animals . . . . . . . . . . . . . . . . . . . . . . . . . . 881
Mechanistic Links Between Depression-Like State and Cardiac Disorders . . . . . . . . . . . . . . 882
Behavioral Coping Style and Cardiac Vulnerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 883
Psychogenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
Epidemiological Evidence of Psychogenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
Early Animal Models of Psychogenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
Role of Genetic Makeup in Psychogenic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 884
E. Nalivaiko (*)
School of Biomedical Sciences Flinders Medical Centre, University of Newcastle, Callaghan,
NSW, Australia
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW,
Australia
e-mail: [email protected]
L. Carnevali • A. Sgoifo
Department of Neuroscience, University of Parma, Parma, Italy
A.J. Grippo
Department of Psychology, Northern Illinois University, De Kalb, IL, USA
Abstract
Close causative relationship between psychological stresses and cardiovascular
morbidity is now well documented. Research on humans has been attempting to
unravel the significance of this association by investigating psychological and
social characteristics in relation to cardiovascular health. However, this research
is limited by the difficulty to control and standardize for the individual social
history, the impossibility to apply psychosocial stress stimuli for mere experi-
mental purposes, as well as the long time span of cardiovascular pathogenesis in
humans. Animal studies controlling for social environment and adverse social
episodes allow for partially overcoming these limitations. The aim of this review
is to provide an up-to-date reference of the experimental evidence so far col-
lected on the link between psychosocial factors and cardiovascular dysfunction
in rodents, with special emphasis on modeling stress-induced sudden cardiac
death, cardiac arrhythmias, stress cardiomyopathy, and psychogenic hyperten-
sion and with focusing on acute and chronic psychological and social stresses,
aggressiveness, and negative mood states as causative factors.
Keywords
Stress • Arrhythmia • Social defeat • Depression • Hypertension
Introduction
The variety of psychosocial risk factors can be classified into three major catego-
ries, namely, the social environment, personality traits, and negative affect (von
Kanel 2012). Numerous studies, both clinical/epidemiological and experimental in
humans and animals, provide compelling evidence of a tight link between psycho-
social factors and cardiovascular morbidity (Costoli et al. 2004; Krantz and
McCeney 2002; Rozanski et al. 1999; Sgoifo et al. 2009; Verrier and Lown
1984). Factors such as anxiety and mood states, personality traits such as anger
and hostility, coping strategies, socioeconomic status, acute and chronic psycho-
logical or social stressors, as well as the absence of significant social support have
all been shown to modulate and interfere with cardiovascular health (Albus 2010;
De Vogli et al. 2007; Steptoe et al. 2010; Van der Kooy et al. 2007). These
psychosocial variables appear to be independent risk factors, as important as
traditional ones (smoking, cholesterol levels, waist fat, body mass index, and
poor physical activity), for the onset and progression of coronary artery disease,
hypertension, myocardial stunning, stroke, and cardiac arrhythmias (Hemingway
et al. 2001; Strike and Steptoe 2004; Wittstein et al. 2005).
Animal Models of Psychogenic Cardiovascular Disorders 875
Psychological distress can provoke sudden death in humans. There is now solid
clinical evidence that the principal cause of sudden death is ventricular arrhyth-
mia, which is often preceded by acute psychological disturbances (Lampert
et al. 2000; Reich et al. 1981; Rozanski et al. 1999). Other studies reinforce the
importance of the link between psychological stress and cardiac arrhythmias (see
Rozanski et al. (1999) for comprehensive review). Well-known examples are a
sixfold increase in the sudden cardiac death rate on the day of Los Angeles
(Northridge) earthquake in 1994 (Leor et al. 1996) and tripling of the incidence
of arrhythmias in patients with implanted cardioverting defibrillators following the
World Trade Center terrorist attack (Steinberg et al. 2004). An important question
in the field of stress-induced cardiac arrhythmias is why some individuals are more
susceptible to them than others. The causative role of myocardial electrical
instability in the genesis of these arrhythmias is now firmly established, mainly
due to extensive studies of patients with long QT syndrome. In these patients,
sudden alerting stimuli may trigger polymorphic ventricular tachycardia, with a
latency of just a few seconds (Wilde et al. 1999), indicating the neurogenic nature
of these arrhythmias.
876 E. Nalivaiko et al.
In rodents, a single episode of social defeat has a strong physiological and behav-
ioral impact. Social defeat is obtained by means of the resident-intruder test, which
consists in introducing the experimental animal in the territory of a conspecific
dominant male. Defeat is the outcome of repeated attacks by the resident rat, and
the declaration of subordination by the intruder is clearly detectable on the basis of
characteristic behavioral patterns (Koolhaas et al. 2013). In the short term (minutes
to hours), defeat produces tachycardia, vagal withdrawal, cardiac arrhythmias,
hypertension, hyperthermia, and elevated plasma levels of glucocorticoids and
catecholamines (Sgoifo et al. 1999). Interestingly, 8-OH-DPAT (a 5-HT1A recep-
tor agonist) attenuates defeat-induced tachycardia and arrhythmogenesis, due to
suppression of both cardiac sympathetic drive and vagal withdrawal (Nalivaiko
et al. 2009).
In the long term (days/weeks), social defeat dramatically affects animals’
behavior (McGrady 1984; Meerlo et al. 1996a; Ruis et al. 1999), memory (Von
Frijtag et al. 2000), and neuroendocrine and immune function (Buwalda et al. 1999;
Engler et al. 2004; Meerlo et al. 1996b; Stefanski and Engler 1998). In particular,
social defeat may result in severe perturbations of circadian rhythms of heart rate
(Meerlo et al. 1999), which consist mainly in a dampening of the rhythm amplitude
that may be due to an increase in the resting phase values and/or a decrease in the
active phase ones (Meerlo et al. 2002). These alterations could persist for up to
2 weeks after challenge termination (Meerlo et al. 1999; Tornatzky and Miczek
1993).
When social subordination becomes a chronic state, consequences can be irre-
versible. For instance, repeated defeat episodes associated with the threat
represented by the constant vicinity of the aggressor were shown to produce
permanent cardiac anatomical alterations (Costoli et al. 2004). Specifically, when
a male mouse was exposed for 2 weeks to a daily episode of aggression and was
permanently maintained under the threat of further attacks, a structural damage at
the level of the heart was observed, with substantial accumulation of fibrotic tissue
– a well-documented substrate for the development of cardiac arrhythmias (Costoli
et al. 2004). The outcome of this experiment supports the hypothesis that the
physiological responses to an intermittent homotypic stressor, although allowing
short-term adaptation and gradually fading in intensity across days, can bring about
an overload for the organism in the long term and contribute to permanent patho-
logical alterations (McEwen 1998). The precise mechanisms underlying these
alterations are currently unknown; they may include massive release of catechol-
amines in response to the persistent social threat condition.
When a similar chronic psychosocial stress protocol was applied to mice lacking
1A serotonin receptors (5-HT1A KO mice), a quarter of the animals died from
cardiac arrest (Carnevali et al. 2012a). Indeed, genetic lack of 5-HT1A receptors
appears to be detrimental for cardiovascular health, by increasing the risk of fatal
cardiac events in mice undergoing chronic stress. This evidence corroborates the
protective role of these receptors for cardiovascular stress homeostasis, as
Animal Models of Psychogenic Cardiovascular Disorders 881
Deleterious effect of another social challenge – social isolation – has been exten-
sively studied by Grippo and colleagues in prairie voles (Microtus ochrogaster)
(see for instance Grippo 2009; Grippo et al. 2011). The advantage of this animal
species is in their stable monogamous social relationships and engagement in the
surrounding social context (Carter et al. 2008; Young and Wang 2004) These
unique features of sociality make this animal model extremely interesting in
translational terms. Female and male prairie voles are sensitive to long-term
deprivation of social contact from a sexual partner or a family member, with
significant behavioral and physiological consequences including anxious and
depressive behavior, as well as autonomic, neuroendocrine, and cardiac dysfunc-
tions (Grippo et al. 2011, 2012; McNeal et al. 2014).
pro-depressive indices; the two most commonly used are the sucrose preference and
the immobility in the forced swimming test. The former is based on reduced
animals’ normal preference for sugar-sweetened water; this is believed to reflect
anhedonia, a classical symptom of depression. In the latter test, reduced swimming
activity is believed to reflect despair, another feature of depression in humans.
Cardiovascular measures thus are of substantial value here as they can be objec-
tively measured. One possible pathophysiological mechanistic link between depres-
sion and cardiac health appears to be an alteration of cardiac sympathovagal
balance, due to elevated cardiac sympathetic and/or reduced cardiac vagal tone
(Barton et al. 2007; Carney et al. 1988; Kemp et al. 2010; Pitzalis et al. 2001;
Rechlin et al. 1994). Perturbations of the autonomic nervous system may result in
ventricular tachyarrhythmias and sudden cardiac death, the latter being one of the
leading causes of cardiovascular mortality (Zipes and Wellens 1998).
Social stress is a critical environmental factor for the development of both clinical
depression (Kendler et al. 1999) and cardiovascular disease (Steptoe and Brydon
2009). Major social life events, such as job strain, the loss of a family member, and
social isolation, may sensitize individuals to subsequent stress and thereby increase
the risk of developing such disorders (Post 1992). To understand the associations
among social stress, depression, and cardiovascular dysfunction, various experi-
mental approaches have been used (Nestler and Hyman 2010). Among them, social
challenge based on a single episode of social defeat followed by a period of
isolation is an experimental paradigm that relies on robust theoretical prerequisites
to meet construct and etiological validity. As previously summarized, social defeat
and social isolation separately induce acute and long-lasting behavioral and phys-
iological changes that well resemble core aspects of mood disorders in humans.
Using this combined social defeat/social isolation paradigm in rats, Carnevali and
colleagues (2012b) recently found that this challenge induced behavioral signs of
depression, functional and structural changes of the hypothalamic-pituitary-adre-
nocortical axis, and increased anxiety levels. The cardiovascular consequences
consisted of transitory heart rate circadian rhythm alterations and moderate cardiac
hypertrophy.
Only a few studies assessed mechanistic links between chronic social stress and
cardiac malfunction. In one of them, Carnevali and colleagues (2013) demonstrated
that subjecting rats to repetitive social defeats over 3 weeks results not only in
behavioral (reduced sucrose preference) and biological (loss of body weight and
alterations in circadian rhythm amplitudes) pro-depression signs but also caused
pro-arrhythmic effect on cardiac electrophysiological variables. The high-density
epicardial mapping analysis revealed a significant decrease in transversal conduc-
tion velocity of the electrical wavefront, a shortening of the effective refractory
Animal Models of Psychogenic Cardiovascular Disorders 883
In humans it is now well established that certain patterns of behavior are associated
with elevated cardiovascular risk. Specifically, individuals with so-called “type A”
behavior (aggressive, hostile, impatient, competitive, achievement striving) are
more vulnerable to heart disease than type B counterparts (relative absence of
type A characteristics) (Betensky and Contrada 2010; Friedman and Rosenman
1959; Kop 1999; Rozanski et al. 1999; Smith 1992; Smith et al. 2004). Putative
pathophysiological mechanisms that mediate this link may include an impairment
of autonomic nervous system control over cardiac function. Abundant evidence
demonstrates that reduced autonomic modulation of the heart, as shown by HRV
measurements, predicts the development of heart disease in initially healthy sub-
jects (Liao et al. 1997; Tsuji et al. 1996), as well as poorer survival rate in patients
with myocardial infarction or heart failure (Bigger et al. 1992; La Rovere
et al. 1998, 2003). A deeper insight into the underlying mechanisms might be
gained by the use of animal models, since most described behavioral traits in
humans are identifiable in animals as well. In rats, the extent of the trait level of
aggressiveness could be assessed on the basis of the latency time to attack a male
intruder in a classical resident-intruder test (Koolhaas et al. 2013). In line with the
characterization of personality in many other animal species (Bell and Sih 2007;
Groothuis and Carere 2005; Reale et al. 2007; Sih et al. 2004), high levels of
aggression in rodents are considered an important indicator and component of a
more general proactive coping style, whereas low levels of aggression are believed
to be a reflection of a reactive coping style (Koolhaas 2008; Koolhaas et al. 1999).
These divergent behavioral coping styles have frequently been associated with
different patterns of both autonomic nervous and endocrine (re)activity (de Boer
et al. 2003; Koolhaas et al. 1999). However, the investigation of the cardiac
autonomic control of these distinct behavioral and physiological coping styles has
been conducted only sporadically and provided inconclusive evidence (Sgoifo
et al. 2005, 1996). In a recent rat study specifically addressing this issue, Catnevali
and colleagues (2013) found that high-aggressive rats had reduced resting heart rate
variability, mostly in terms of lower vagal modulation, compared to nonaggressive
animals. Most importantly, high-aggressive rats had higher incidence of ventricular
tachyarrhythmias during stress or during pharmacological beta-adrenergic stimula-
tion. These findings are consistent with the view that high levels of aggressive
behavior in rats are associated with signs of cardiac autonomic impairment and
increased arrhythmogenic susceptibility that may predict vulnerability to cardiac
morbidity and mortality.
884 E. Nalivaiko et al.
Psychogenic Hypertension
Wexler and Greenberg (1978) who also found that maintaining an unstable social
hierarchy, by frequently moving males from one communal cage to another, pro-
vokes dramatic hypertension (+80 mmHg), even in normotensive Sprague-Dawley
rats. Several years after, however, Harrap et al. (1984) put these findings under
serious doubt by demonstrating that a similar chronic stress paradigm had abso-
lutely no effect on AP, not only in normotensive SD and WKY but also in BHR rats.
In response, Henry conducted a very detailed and prolonged (6-month) study using
exactly the same stress protocol as Wexler and found that, indeed, AP remains
unaffected in WKY rats, is slightly elevated (~10 mmHg) during some measuring
monthly points in SD rats, and slowly raises in Long-Evans rats (Henry et al. 1993).
Authors explain this interstrain difference by the higher levels of aggression and
more frequent fights displayed by Long-Evans rats. It remained however entirely
unexplained why identical stress procedures applied to the same strain (Sprague-
Dawley) provoked rapid and dramatic hypertensive effects within 1 month in the
first study (Wexler and Greenberg 1978), but had only very mild and delayed action
in the later one (Henry et al. 1993).
It must be noted that in most of the above-cited studies, AP was assessed using
the tail-cuff method – a simple noninvasive technique based on the same principle
as indirect measurement of arterial pressure in humans. However, tail-cuff mea-
surement has some serious limitations. Firstly, the tail vascular bed is thermoreg-
ulatory in rats and mice, and at normal laboratory ambient temperatures of
20–25 C, tail blood flow varies very significantly, sometimes falling near zero
(Blessing 2005; Garcia et al. 2001). Thus, in order to maintain it at a constant and
measurable level, animals should be kept in a warm environment (33–38 C) before
and during the measurements. Secondly, animals should be restrained, and
restrainers used for this purpose – plastic cylinders – are not dissimilar to those
used for provoking restraint stress. Thirdly, it is not widely recognized that the tail
vascular bed is controlled separately from other vasculatures, and even mild
stressors can provoke dramatic selective vasoconstriction in the tail vascular bed
(Blessing 2005). Thus, it is questionable whether AP measures taken by means of
tail cuff represent true resting values. Indeed, several recent studies where AP was
assessed telemetrically during tail-cuff procedure support this doubts: Van Acker
et al. (2001) found that tail-cuff measurement provokes substantial increases in both
AP and heart rate. In another carefully designed study, it was convincingly dem-
onstrated that even after 3 weeks (nine sessions) of habituation, restraint and
heating still provoked dramatic pressor and tachycardic responses, as well as
elevation in plasma noradrenaline and angiotensin II concentrations (Grundt
et al. 2009). Finally, handling alone, as well as handling and restraint, provoke
substantial rises in AP and heart rate, and these responses do not habituate even
after ten sessions (McDougall et al. 2005).
Biotelemetry is a “gold standard” for assessing cardiovascular parameters in
conscious unrestrained animals. So far there are four published studies that used this
method in order to determine whether chronic stress has any sustained effects on AP
(Bobrovskaya et al. 2013; Gelsema et al. 1994; Lemaire and Mormede 1995; Muller
et al. 2001). Together, these studies involved four rat strains, including BHR and
Animal Models of Psychogenic Cardiovascular Disorders 887
SHR, and employed the same stress paradigms that caused hypertension in previous
studies using tail-cuff measurements. Marginal elevation of AP was found in only
one of them (Bobrovskaya et al. 2013); in three other instances, AP remained
consistently stable.
In summary, it appears that experimenters using tail-cuff measurements
succeeded in demonstrating that only some stressors evoke rise in AP in only
some rat strains, whereas most biotelemetric studies failed to demonstrate any
effect on the blood pressure of any stressor in any strain. It is thus most likely
that the major cause of such dramatic discrepancies is the intrusiveness of the tail-
cuff method, with associated restraint: values measured in this case may reflect the
animal’s reaction to the measurement procedure rather than the basal levels of AP
in the undisturbed state. This most probably happened at least in those cases where
these measurements were performed only once a week (Lawler et al. 1984; Wexler
and Greenberg 1978) or even once a month (Henry et al. 1993), without any
preliminary habituation. It could be that previously stressed animals responded
more vigorously to the tail-cuff procedure compared to unstressed controls. While
manufacturers recommend that prior to the tail-cuff measurements, the animals
should be habituated to measurement conditions, it is currently not clear how many
habituation sessions are sufficient.
Tail cuff is still widely used, and several more recent studies employed it to
document the hypertensive effects of chronic stress in normotensive rat
strains (Andrews et al. 2003; Blake et al. 1995); in one instance, this was confirmed
by direct measurements as well (Alkadhi et al. 2005). The dynamics of developing
hypertension in this later study (plateau at +40 mmHg in just 4 days) is in
sharp contrast with several other previous reports where pressor changes
required 2–3 weeks of stress exposure. Presented above considerations suggest
that positive pressor effects of prolonged stressors must be taken with some
caution.
It may be that factors other than the method of AP assessment contributed to
discrepancies in results from different studies as well as to inconsistencies between
animal models of psychogenic hypertension and the actual condition in humans. In
his seminal review, when discussing psycho-emotional causes of hypertension,
Folkow (1982) suggested that if pressor-inducing stress episodes are repeated
frequently enough, this may lead to sustained elevation of AP. In most works
reviewed here, stressful procedures were either performed daily or were lasting
permanently, and further increasing the frequency of stressful interventions does
not seem to be a promising idea. Another issue that could contribute to the
conflicting results in animal models of psychogenic hypertension is the type of
stressor that is employed. It is now accepted in the field of stress research that a
critical determinant for a stressor to induce adverse consequences is the ability of
the animal to exert control over these events (Maier 1984). Having actual or
perceived control over a stressful situation powerfully reduces its negative phys-
iological consequences. It is likely that animals exposed to chronic or repetitive
aversive stressors develop effective coping strategies to these putative adverse
events that somehow combat the deleterious effects of these stressors. It thus
888 E. Nalivaiko et al.
From the data summarized in this chapter, it is evident that animal models of acute
and chronic stress-induced cardiac disturbances are extremely useful. They allowed
researchers to reproduce human clinical conditions, provided insight into patho-
genesis, and also suggested new therapeutic strategies. In some instances, they
preceded and predicted clinical findings made in humans. It is likely that by
following this research direction with rodent models, it will be possible to obtain
not only clearer insights into the physiological/neural/behavioral substrates of
psychological and social stress-related psychosomatic disorders but also the bio-
logical evidence of the beneficial effects of social support and, more generally
speaking, of positive social relationships.
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Nonlinear Analyses of Data
in Cardiovascular Physiology
and Epidemiology
Robert A. M. Gregson
Contents
Operation at Various Dynamic Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 900
Relevance to 5-Hydroxytriptamine (5HT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 901
Misdiagnosis and Inverse Probabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902
Epidemiological Survey Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 904
Grounds for Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 909
Abstract
The nonlinear dynamics of heart action are such as to generate and to support
irregular nonrandom variations in the main output parameters of pulse and
Notes: I am indebted to Prof. Don Byrne for drawing my attention to a diversity of valuable
sources on anxiety and heart function, including his own work. The mathematical interpretations
are mostly my own.
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC7, May 2003, in the USA) introduced the notion of
prehypertension. If this condition is defined by a single threshold value for SAP (120–139 mmHg
is suggested), then logically, given the nonlinear variability of cardiac function, virtually all
persons over a cutoff age of around 50 years will be at some times prehypertensive, and for them
medical intervention is commended, including the reduced use of sodium in diet and at least to
advise on lifestyle. It has been noted (www.medscape.com) that most of the authors of the report
have extensive financial disclosures with numerous pharmaceutical companies. It must be
emphasized that the recommendations of JNC7 have been strongly criticized, based in part on
findings from the Second Australian National Blood Pressure Study (Wing et al. 2003). Some
medical specialists, not starting from a base of nonlinear cardiac dynamics, but considering high
plasma renin levels, have ridiculed the very existence of prehypertension.
R.A.M. Gregson (*)
Research School of Psychology, Australian National University, Canberra, ACT, Australia
e-mail: [email protected]
Keywords
Nonlinear dynamics • Coupled attractors • Cardiology • Bayesian inference •
Clinical misdiagnosis • Epidemiology
Any mammal’s heart is always subject to untimely stimuli along the pathways of the
autonomic nervous system from the brain and its nervous input tracts. (Winfree 1987, p. 46)
The human heart is one of the best known examples of a biophysical system that
in its dynamics is not linear, not stationary, operates at a multiplicity of scales
simultaneously, and exhibits fluctuating variability that is not noise but self-
stabilizing responses to the diversity of transient stimuli, both physical and psy-
chological, that constitute its environment.
Winfree’s extensive work on recurrent quasiperiodic dynamics, summarized in
his 1987 book on the three-dimensional dynamics of electrochemical waves and
cardiac arrhythmias, is interesting not only for its clinical relevance but for the
parallels and differences it establishes with other problems and modeling in
nonlinear dynamics using complex polynomials (Gregson 1995). The heart has
been treated as driven by coupled oscillators, and this sort of dynamical structure
does have properties of self-regulation and sensitivity to external pulsed inputs
(Murray 2002; Steeb 2002) that are biologically advantageous but sometimes
terminally vulnerable to acute trauma (Chang et al. 2000). The ubiquitousness of
forced coupled attractor dynamics in a diversity of scientific disciplines has recently
been reviewed because of its importance (Nadis 2003).
A critical feature in the modeling is the identification of singularities. If the
system is forced by external inputs onto the region of a singularity, then the
rhythms are lost and may be irrecoverable, thus leading to what is popularly
called a heart attack and death. The models used are different from those in
psychophysics because the circadian rhythms are a dominant feature, and the
regular or irregular fast local heartbeat periodicities (with at least two modes) are
carried on the slower circadian processes. This dominance of circadian rhythms
in pulse rate (RR) is so marked that attempts have been made to exploit its slow
variations as being psychiatrically diagnostic (Iverson et al. 2000; Krypotos
et al. 2011).
Nonlinear Analyses of Data in Cardiovascular Physiology and Epidemiology 899
This means that real time series of diastolic, systolic (SAP), and pulse rate (RR) in
parallel have a complicated nonlinear nonstationary structure that cannot be modeled
simply. Experimental evidence on mammalian heart action has shown that in some
cases it is chaotic (Bassingthwaighte and coworkers have also modeled cardiac
dynamics as fractal, on the basis of the frequency distribution of blood flows through
the capillaries of the heart musculature (Bassingthwaighte et al. 1989; Herbert 1995),
in the technical sense of the word, and not simply nonlinear (Ditto 1996).
As Winfree has shown, the phase-space portrait of the four-dimensional attractor
that resembles heart action is such that it is fundamentally wrong to describe it as
stability about a point attractor with random perturbations. Sufficient statistics to
characterize trajectories, at most scales from such a complicated attractor, cannot
be simply the mean and variance of outputs, though these are almost invariably used
in the reports of epidemiological and even within-subject analyses that are numer-
ous in the relevant literature. There are, almost inevitably, large individual differ-
ences in the dynamics of open-loop and closed-loop coupling between RR and SAP,
apart from the slower circadian rhythms upon which more rapid fluctuations are
superimposed (Malliani et al. 1991).
It is important to emphasize that the time scales of the dynamics involved may be
critical in determining the favorable or unfavorable implications of instabilities in
pulse phase and/or pressure amplitude. Ely (1995) refers to the Akron police force
study and the detectable adverse effects of shift work schedules, which disrupt
circadian rhythms at a slow time scale. At the same time, instabilities at the ECG
level, at high frequency, appear to be a good predictor of resistance to cardiac arrest.
There are also possible variations due to the health, culture, age, and sex of the
subject, and even in whose presence the SAP is measured; what is called,
unfacetiously, “white-coat hypertension” exists. The whole topic of blood pressure
averages and relatively fast variations within the individual over time and more slowly
across age and social groups (Stolarz et al. 2003; Wong and Wolf 2003) has acquired a
vast research literature, with continued disputes on what figures actually mean (Freitag
k Vasan 2003). A standard of 140/90 systolic/diastolic blood pressure had been
adopted in recommendations by the World Health Authority in the 1970s, as a marker
for clinical intervention, but this figure is not realistic for many healthy populations in
the Western world, apart from undiagnosed or untreated hypertensives. Porta
et al. (2002, p. 241) comment, “In elderly healthy men at rest, the RR interval and
SAP are highly correlated at the LF and HF.” “Elderly” here meant from a sample with
a mean of 57 10 years. These data were drawn from a large database constructed by
Borne et al. (1998) as a baseline for studying heart transplant recipients. “Links in both
causal directions are found and some closed-loop interactions in the HF region.” They
give an example (p. 248) from an elderly healthy man under control conditions, in
which the RR ranges over about 65 b/min to 84 b/min and the SAP ranges between
180 and 200 mmHg (This implies that an elderly healthy man with an average SAP of
about 160 mmHg would be over four standard deviations from and below the
reference data, with a consequent probability of having high blood pressure defined
relative to the SAP range of less than 1 in 5,000). The contrast is with a postoperative
heart transplant recipient, where pulse rate is higher but SAP is lower.
900 R.A.M. Gregson
where ti are the RR intervals, μ is their mean, and a = 0.1. The normalized entropy
of the si distribution is a basis for identifying persons with high cardiac risk; it is
relatively low compared with healthy subjects. If the circadian rhythm is taken as a
slow limit cycle, then with regular appropriately spaced multiple daily readings, the
4-state transition probability matrix based on the symbolic dynamics would be
expected to show the characteristic off-diagonal form, with x indicating a dominant
probability, that is, with anticlockwise or
2 3 2 3
x x
6x 7 6 x 7
6 7or6 7
4 x 5 4 x 5
x x
From a computational viewpoint, I find this sufficient set of only four levels surpris-
ing (Gregson and Leahan 2003), but it does not exclude partitioning to more than
four, to maximize the entropy of a basal condition against which the typical degraded
entropy of clinical cases may be compared, as indeed Ebeling et al. do.
The situation is such that not only is it misleading to draw any scientific or
clinical conclusions from a single RR or SAP reading, but analysis of the dynamics
Nonlinear Analyses of Data in Cardiovascular Physiology and Epidemiology 901
The repeated random resetting of the phase of the component rhythms is due to
inputs that are not part of the intrinsic cardiac dynamics, but are essentially transient
destabilizing. They are obviously part of the way that stress could act on the heart,
and pathways from the brain to the heart appear to be involved (Byrne and
Rosenman 1990). Stimuli creating acute anxiety usually input through the eyes or
ears and not directly to the heart. Seeing or hearing of an unexpected horrific
incident can it is widely believed induce cardiac arrest in some frail persons, who
are usually protected so far as possible from getting such news. This precaution may
be folklore; only chronic stress may be the critical factor. Winfree (1987, p. 101)
writes: “spasm in a coronary artery temporarily makes the muscle more susceptible
to arrhythmias, in part by eliciting neural traffic from the brain (Shepherd 1985;
Skinner 1985).” That is, the neural brain-heart link is two-way and may form closed
loops; positive feedback could induce tachycardia.
902 R.A.M. Gregson
Suppose we label a set of cardiac dynamical conditions as {C}, and a set of blood
pressure patterns as {B}. Most generally, we have then that
p Bx Cy (1)
is the probability of one (Bx) of the set {B} being a consequence of one (Cy) of the
set {C}; x and y are just labels. Expressions like (1) are called likelihoods or
conditional probabilities, and when they refer to real systems, then they are state
descriptions. If we are given only Bx and asked to infer Cy, then this is a judgment
about the probability
p Cy jBx (2)
p ð Bx j C z Þ (3)
where Cz is another condition alternative to and distinct in its causality from the Cy
we thought of first. It is also necessary, from research data and the history of
the case in hand, to have good estimates of (1) and (3). It is not sufficient to have
only (1).
Nonlinear Analyses of Data in Cardiovascular Physiology and Epidemiology 903
We are now in a position to get (2) that we want from Bayes’ theorem, provided
that we also have the base rates p(Cy),p(Cz), viz.,
p Bx Cy p Cy
P Cy jBx ¼ (4)
p Bx Cy p Cy þpðBx jCz ÞpðCz Þ
To illustrate, put in some numbers. Let Bx = 150 mrnHg SAP, let Cy = chronic
high blood pressure, and let Cz – transient anxiety (I could have written transient
depression here, with consequent low 5HT levels, which is expected in the elderly,
and relevant evidence is accumulating about mood
and SAP or cholesterol (Niaura
2002; Pollard and Schwartz 2003)). Then let p Cy ¼ :35, pðCz Þ ¼ 1 p Cy as we
are only considering two mutually exclusive and exhaustive alternatives, put
[1] = 0.7, [3] = 0.9, and solve for [2]; we get
:35 :7
p Cy jBx ¼ ¼ :295 (5)
½:35 :7 þ :65 :9
Clearly 0.295 is a minority diagnostic probability, as compared with (1) that was
0.7, a most likely diagnostic probability. It also now follows that the inverse
probability
The situation gets worse (but is still computationally tractable) if in fact the values
of (1) and (3) are not nice simple constants but distributions with variability across
heterogenous patients or if we have to sample variability within a patient in order to
get estimates and use whole time series of observations. Of course variability may
be as much a danger sign in itself as an average of a stable process; this can be seen
in intensive care conditions, and it is why pacemakers are installed in cardiac
patients, to inhibit and stabilize the natural variability that follows from phase
(i.e., pulse) resetting.
The importance of sequential information about baroreflex sensitivity has been
explored by Parati et al. (2001), using very short high-frequency observations,
based on the computer identification in the time domain of spontaneously occurring
sequences of four or more consecutive beats, characterized by either a progressive
rise in SAP and increase in RR or by a progressive decrease of SAP and shortening
of RR. Such subsequences are obviously of low probability in stochastic random
dynamics.
The interesting complication, that variability rather than average values may be
the most informative diagnostic measure, implies that we have to replace Bx|Cy a set
{Bx1, Bx2, Bx3, . . .}|Cy and do something analogous for Bx|Cx. This means that unless
you have reference tables from a relevant population of patients and conditions,
with the appropriate base rates p(Cy), p(Cz), contingent upon age and sex, then you
are making risky decisions and it is easy to get the reverse of what is the minimum-
risk case, or the precise nature of the risk may be misunderstood.
904 R.A.M. Gregson
A survey of the social distribution of a single stable variable, such as the height of
adults, is in sampling theory definable in terms of its sufficient statistics, and there is
some coherent associated account of the sources and extent of errors of measure-
ment. If, however, the process being studied is a dynamic time series within an
individual, then seeking to find the distribution of the variability of its parameters
over a population faces serious problems, because the sufficient statistics may not
exist in terms of the first two moments, and our understanding of sources of error
measurement is often, to say the least, opaque. The literature on SAP, RR, and pulse
pressure (the difference between SAP and diastolic pressure) as based on average
values over samples of patients can only be described as exasperatingly inconclu-
sive (The variability in the dynamic cross-coupling of the two blood pressure values
amplifies the variance of the pulse pressure and makes it uninterpretable within the
assumptions of linear stationarity, so that tests of significance, on which studies
rely, are incoherent), particularly on the question of what are the most valid
predictors of cardiac failure (Strandberg and Pitkala 2003). There is another
complication in that the social subgroups for whom the death risks are supposedly
highest are those for whom the epidemiological data are the most sparse, except in
the case of studying late-life diabetes, which has a complicated relation to
Nonlinear Analyses of Data in Cardiovascular Physiology and Epidemiology 905
and C0 has been introduced to symbolize normal cardiac activity. The likelihood
ratio Λ is then a measure of the odds that observing Bx is associated with hyper-
tension and not normal, in the absence of any other collateral evidence. Strictly the
conditional probabilities should be rewritten as
where β is a decision level. Here we will use the WHO 140 mmHg for SAP, because
there has been a change in clinical opinion that now focuses more on systolic than
on diastolic pressures (Strandberg and Pitkala 2003) in attempting to avoid cardio-
vascular risk. Let the total symptomatology of {C} be S; then (This now standard
backslash notation is to be read that S\T = “the set S excluding the subset T”)
Σ = S\Bx and ~ Σ means “none none of Σ.”
The blood pressure study of 1987 in Australia (NIOHS 1987) gives some
incomplete data that enables us tentatively to explore (8). Unfortunately we need
tables of age x sex x symptoms of hypertension x SAP, but the tabulation is split
between variables. Table 5.1.4 of that study, and recalculating using cumulative
percentages, suggests that of all men in the survey (N = 3,309), 17.7 % are over the
WHO 140 mmHg level on a single measurement at a medical examination.
(We have no data here on variability of SAP within a subject, nor any confidence
intervals on the raw percentages, and cohorts are confounded with time-slice
samples. Most modern studies cited here still have no outcome morbidity or
mortality sequelae tabulated.). The figure for 464 men in the 55–66 years of age
range is 36.4 %, which is
906 R.A.M. Gregson
it is not (8). It is not proper to conclude that one-third of older men walking around
should immediately fall dead in their tracks, though a follow up of the sample to
find when and why they each died would have been most helpful. One could do that
in the Scandinavian countries, because of the way that health records are kept there,
though not apparently in Australia.
Table 6.2.5 gives frequencies and percentages on hypertensive medication, and
in the 56–66 age group, 84, that is, 18 % or about one in five, are receiving some
medication. Ignoring the probability of overmedication, by the WHO criterion, at
least half are untreated and surviving at the time of the survey. They also thus have
time to die of something else, and about two-thirds of all men will do that. There are
no data for the over-66s, unlike the fuller data used by Porta et al. (2002) that was
cited in the first section of this chapter. We know that the proportion of men with
hypertension increases with age in some cultures (Wong and Wolf 2003), so the
best estimates of (8) for over-70s would be higher in Australia, but the Porta
et al. (2002) sample is still described (and hence untreated) as healthy.
The Wong and Wolf (2003) study is one of the few that separates cohort and
time-slice effects, by having 5- and 10-year follow-ups (of the study, not of the
same individuals, which preferably it would be; that way we get mortalities). So in
the Yugoslav cohort, the senescence rate was 0.87 mmHg/year, and the secular
trend over 10 years was 0.405 mmHg/year. The cohort (N = 119) that was in the
age range 65–69 in 1972 has a mean SAP of 148.94, with an s.d. of 21.71 (this is
rather disguised in the data tabulation by using s.e.s.). If the SAP is distributed
across subjects approximately normally, then 17 % will have SAPs of over
171 mmHg. Obviously more than half are over 140 mmHg.
We now come back to the questions of why about half of hypertensive men are
untreated by orthodox medicine, and why they are survivors. One answer is that
they don’t feel ill or they patronize alternative medicines, but another is that they
have a lifestyle that avoids stress, and so they minimize (mostly unknowingly) the
probability of pulse resetting onto singularities, but are still at the upper end of a
multimodal distribution of SAP readings. The shape of the frequency distribution of
Λ in (7) is not the same thing as the frequency distribution of SAP.
Patel (1990, p. 441) notes “lowering mild hypertension is important because it
has been shown that two-thirds of coronary heart disease and three-quarters of
stroke mortality occurs in patients with mild hypertension” (These mortalities don’t
correspond to (10) below; they are of the form p(B > β|D) and not p(D|B > β)).
The effects of such interventions as meditation on h.r.v. as inducing very
complex dynamics are related here (Sarkar and Barat 2008). Three-quarters of all
hypertensives are in the mild hypertension category, although the rate of compli-
cation in this group is low – approximately 1 % per year. Thus, even if we have
Nonlinear Analyses of Data in Cardiovascular Physiology and Epidemiology 907
effective antihypertension drugs, a large proportion has to be medicated for the rest
of their lives to prevent a small number of complications. Patel adds, “It is not
surprising that the Joint National Committee on Detection, Evaluation and Treat-
ment of High Blood Pressure (1984) has recommended that in all patients with mild
hypertension, nonphar-macological treatment should be tried first and
antihypertension medication added only when other treatment fails to produce
satisfactory control of blood pressure.”
We must stop to ask how does this 1 % that Patel cited relate to (7) and (8). It
doesn’t; it is yet another measure. In likelihood ratio terms it is
p ð Lj B > β Þ
ΛðL, DÞ ¼ ¼ 0:99 (10)
PðDjB > β
Conclusion
To summarize, there are now at least three distinct domains of discourse that
attempt to inform our understanding of cardiac dynamics, and it is often impossible
to translate from one to another or to reconcile their findings. We have (i) simple
measures, such as RR, that have been around since antiquity and extend into
epidemiological tabulations without causal insights, (ii) we have brain-heart rela-
tions mapping between anxiety and physiology, and (iii) we have the nonlinear
dynamics of complex systems. That one (iii) is the last to appear on the scientific
scene, because it requires methods of both mathematics and data analysis that were
not available before the 1980s.
The understanding of the complicated dynamics of the heart, and the relevance
of that nonlinear picture to clinical diagnosis and treatment, postdates by some
years the widespread use of indicators such as 140/90 popularized by the WHO.
Work in the manner of Winfree’s analyses and the tabulated epidemiological data
908 R.A.M. Gregson
on RR and SAP are almost mutually exclusive. They are two approaches that do not
interact, though logically they ought. If the critical variables in the dynamics are the
rate and magnitude of phase resettings, which correlate with the variance of the RR,
and these are not strongly correlated with the mean SAP and it is falsely assumed
that a single observation of SAP on one subject has an expectation of the mean
(which obviously does not if the SAP is distributed fractally multimodally), then the
apparent irrelevance of the mean SAP (though it is confounded with age) to
morbidity is explained. Errors in diagnosis are partly to be expected for cultural
reasons: Baron (1994, p. 350) notes that though many medical students are taught to
apply expected utility theory to decision making, few continue to use that approach
after finishing training.
Because of the intricate and subtle nonlinear dynamics of cardiac action, what is
at least needed are data on the variability (Vcv) of the coefficient of variation (s.d./
mean) over time within the time series of single individuals and between individ-
uals within cohorts of a limited age range. What is missing, on this argument, is
John W. Tukey (The life and work of Turkey is celebrated in an issue of The Annals
of Statistics in 200); “More lives have been lost looking at the raw periodogram than
by any other action involving time series.”
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Part V
Psychological Management of Patients with
Cardiovascular Disease
Psychosocial Interventions for Patients
After a Cardiac Event
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 916
The Impact on Depression of “Generic” Cardiac Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 917
Influence of Mood States on CR Uptake, Completion, and Lifestyle Modification . . . . . . . . . . 918
Psychological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
Brief Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 922
Alternative Modes of Psychological Service Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924
Psychosocial Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 928
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
Abstract
A large body of evidence links depression and coronary artery disease and
includes findings that patients who experience depression at the time of an
acute cardiac event die sooner than their nondepressed counterparts. Although
cardiac rehabilitation programs addressing medical, lifestyle, and psychosocial
issues have positive effects on behavioral change, significantly reduce the risk of
having future cardiac events, and reduce mortality, depressed mood and social
isolation can compromise the positive effects of these programs. Systematic
reviews have shown the effectiveness of psychological interventions for cardiac
patients; however, comparison of interventions is difficult due to variation in
target population, severity of depression, “dose” and mode of delivery of the
intervention delivered, variation in outcome measures used, varied follow-up
periods, and lack of detail on intervention content. Brief interventions have been
shown to be effective in reducing depression, as has Internet-delivered cogni-
tive-behavioral therapy for adults with high CVD risk. Interventions comprising
psychological and social support-enhancing components, when compared with
usual care, are also effective in reducing depressive symptoms in cardiac
patients. Although effect sizes reflect a small benefit of these psychosocial
interventions, it appears that they improve social support and possibly mental
health quality of life, but no firm conclusions can be drawn as to whether these
interventions impact on cardiac mortality and morbidity. Notwithstanding meth-
odological limitations and the modest effects achieved, psychological and psy-
chosocial interventions are worth implementing, post-cardiac event, as
unresolved depression is a major cause of death and disability in cardiac patients.
Keywords
Psychosocial intervention • Cardiac patients • Depression • Social isolation
Introduction
Over two decades of research has demonstrated the association between depression,
whether characterized as mild or as major depressive disorder (MDD,) and coro-
nary artery disease (CAD) (Whooley and Wong 2013). In addition to findings that
depression is an independent risk factor for the development of CAD in healthy
populations (Lett et al. 2004), the adverse effects of depression on patient outcomes
have been well documented. Depressed patients have higher levels of biomarkers
that promote atherosclerosis, reduced heart rate variability suggesting increased
sympathetic activity, and increased C-reactive protein, an indicator of increased
inflammatory response (Lichtman et al. 2008; Taylor 2010). Behaviorally,
depressed patients report lower medication compliance (Gehi et al. 2005;
Ziegelstein et al. 2000), higher rates of smoking (Kubzansky et al. 1998), more
intake of dietary fat (Murphy et al. 2013), lower physical activity (Murphy
et al. 2013), and higher rates of sedentary behavior (Brummett et al. 2003). Socio-
economic factors including social isolation, low income, low education, and man-
ual occupations are also associated with both depression and mortality (Brummett
et al. 2003; Case et al. 1992; Kaplan 1992).
There is growing evidence that cardiac patients who experience depression at the
time of an acute cardiac event die sooner than their non-distressed counterparts
(Barth et al. 2004; van Melle et al. 2004), with in-hospital depression shown to
Psychosocial Interventions for Patients After a Cardiac Event 917
predict 10-year mortality after both acute myocardial infarction (AMI) (Welin
et al. 2000) and coronary artery bypass surgery (CABGS) (Connerney
et al. 2010). It has been suggested that even mild depressive symptoms are
associated with poorer mortality outcomes (Bush et al. 2001; Murphy
et al. 2013). However, relatively few studies have investigated the prognostic
importance of “mild” in-hospital depression in cardiac patients.
Emerging evidence suggests that in-hospital depressive symptoms resolve for
many patients during early convalescence (Blumenthal et al. 2003; Murphy
et al. 2008a, b) and that these patients are not at ongoing risk for poor outcomes
(Blumenthal et al. 2003; Thombs and Ziegelstein 2010). This suggests that in-hospital
depression might not be the best indicator of later mortality risk. A meta-analysis of
34 studies of mortality in coronary heart disease (CHD) patients reported larger
effects when depression was assessed later rather than earlier, supporting this hypoth-
esis (Nicholson et al. 2006). As most change in depressive symptoms occurs in the
first 2 months after an acute event (Murphy et al. 2008a, b) and most outpatient
cardiac rehabilitation programs are offered around 4–6 weeks post-cardiac event, the
timing of this generic intervention fits well with the needs of those people with
unresolved depressive symptoms that may be amenable to change within the generic
cardiac rehabilitation programs or in adjunct psychosocial interventions.
showed no improvement in depression but did show reduced anxiety. The low level
of amelioration of depressed mood in the PAD patients was hypothesized to be the
result of a higher rate of chronic rather than reactive depression and impaired
functional capacity which impacted on these patients’ ability to achieve the psy-
chological benefits of improved and sustained physical exercise (Stauber
et al. 2013).
Among people eligible for CR, referral rates are generally low with fewer than one
in three people referred actually attending in Australia (National Heart Foundation
of Australia 2010) and around 40 % of heart attack patients and 28 % of angioplasty
patients attending in England, Northern Ireland, and Wales (British Heart Founda-
tion 2010). Those at highest risk of recurrent disease are least likely to participate in
CR and of those who do attend, not all complete the full CR program (Bunker
et al. 1999; Johnson et al. 2004; Redfern et al. 2007; Scott et al. 2003). A systematic
review of 32 studies identified 374 patient-reported factors associated with uptake
and completion of cardiovascular lifestyle behavior change programs (Murray
et al. 2012). Of the factors identified as inhibiting uptake of CR, depression and
stress were both independent predictors. Anxiety was not found to be predictive of
non-attendance with one study finding that anxiety may facilitate attendance (Grace
et al. 2002).
Even if people attend CR, sustained behavioral change and lifestyle modification
are not assured (Davies et al. 2010; Gupta et al. 2007; Murphy et al. 2006).
Psychosocial factors such as depressed mood (Ziegelstein et al. 2000) and social
isolation (Davies et al. 2010) exacerbate nonadherence to medication regimes and
lifestyle advice, as do cognitive barriers such as negative thoughts and beliefs
(Martins and McNeil 2009). Many of the same factors that deter people from
commencing CR also contribute to non-completion of the programs. While anxiety
may facilitate completion in the same way that it facilitates uptake, depressive
symptoms, being on antidepressant medication and greater neuroticism, all predict
greater attrition, as does social isolation and not being in the workforce which may
be an indicator of both social isolation and limited income (Murray et al. 2012).
Whooley (2006) and Whooley and Wong (2013) suggests that in cardiac patients
with mild to moderate depression, psychotherapy together with self-management is
the most appropriate first-line treatment. However, this treatment is dependent both
on its timely availability and the recognition of the depression or compromised
mood state.
As numerous studies have found, many people do not disclose their
compromised mood state (Jorm et al. 2004; Kessler et al. 2001), especially if they
perceive it to be serious. This emphasizes the importance of screening for depres-
sion in CR as recommended by the Heart Foundation of Australia (Colquhoun
et al. 2013), following the 2008 recommendations of the American Heart
Psychosocial Interventions for Patients After a Cardiac Event 919
Association (Lichtman et al. 2008). The Australian guidelines state that “routine
screening for depression is indicated at first presentation and again at the next
follow-up appointment. A follow-up screen should occur 2–3 months after the
event,” (44) in recognition of the higher risk of secondary events in those with
unresolved depression (Nicholson et al. 2006). Having identified depression in
cardiac patients post-event, treatment may comprise pharmacological or psycho-
therapeutic interventions administered singly or in combination over shorter or
longer periods. Psychotherapeutic interventions may be offered through a variety of
modes of delivery (face-to-face individual or group, telephone, Internet) and may
involve a variety of manualized or non-manualized therapeutic approaches offered
alone or in combination with self-management. The following sections review a
number of these psychotherapeutic interventions.
Psychological Interventions
Bearing in mind a fairly high risk of bias in the studies (unclear randomization
procedure, non-blinded outcome assessment), the review found that psychological
intervention resulted in small to moderate improvements in depression and anxiety.
There was no consistent evidence, however, of a positive effect on HRQoL or other
psychological outcomes, including perceived stress, type A behaviors, anger, and
perceived exhaustion. Targeted type A behavior was positively associated with
intervention effects for depression, while the inclusion of family in treatment,
provision of risk information, and inclusion of client-led discussion and emotional
support were negatively associated with depression outcomes. There was no strong
evidence that psychological intervention, compared to usual care, reduced total
deaths or risk of revascularization or nonfatal infarction in patients with CHD.
However, there were significantly fewer deaths attributed to cardiac causes among
treated patients. The authors suggest that (Whalley et al. 2011) the wide variation in
the types of intervention used to treat cardiac patients included in the review reflects
uncertainty in the theoretical and empirical literature linking emotion with cardiac
outcomes and that subtyping – what interventions work best for whom – is
premature.
Dickens et al. (2013) extended Whalley et al.’s (2011) review (with a 14 %
overlap of included studies) to explore which psychological treatments were most
effective for people with CHD. They reviewed 62 independent studies with out-
come data for 64 independent treatment comparisons (N = 17,397). As with other
reviews, there was a great deal of heterogeneity between studies: conditions
included both acute and stable CHD; treatment sessions varied between 1 and
156 sessions with a mean of 14.4; in 29 studies, intervention was by a single person
or unidisciplinary team and in 22 by a multidisciplinary team, and risk of bias
varied, for example, only 20 studies used researchers blinded to the intervention to
assess outcome. Again, bearing in mind the limitations of heterogeneity and risk of
bias, it was found through random-effect multivariate meta-regression that psycho-
logical interventions improved depression, although the effect was small (SMD =
0.18, p < 0.001). Problem solving (SMD = 0.34), general education (SMD = 0.19),
skills training (SMD = 0.25), cognitive-behavioral therapy (CBT; SMD = 0.23),
and relaxation (SMD = 0.15) had small effects on CHD patients irrespective of
their depression status. Among high-quality trials of depressed CHD patients, only
CBT showed significant albeit small effects (SMD = 0.31). When entered into
multivariable analysis, no individual treatment component, including increasing
social support, significantly improved depression.
Mavrides and Nemeroff’s (2013) review of depression treatment in cardiovas-
cular disease (CVD) included trials of tricyclic antidepressants (TCAs), TCAs and
bupropion (an atypical antidepressant and antismoking aid), and selective serotonin
reuptake inhibitors (SSRIs). Five trials involving psychotherapeutic techniques
and/or collaborative care were included. The review concluded that there was
considerable evidence from RCTs that antidepressants, especially SSRIs, are safe
in the treatment of major depression in patients with CVD and that acute coronary
syndrome (ACS) patients with persistent depression treated with problem-solving
therapy and pharmacotherapy show significantly reduced depression compared
Psychosocial Interventions for Patients After a Cardiac Event 921
with usual care patients in the Coronary Psychosocial Evaluation Studies (COPES)
Trial (Davidson et al. 2010). Post-CABG patients were also shown to benefit from
face-to-face CBT and supportive stress management as well as a telephone-
delivered collaborative care intervention. Similar effects of both pharmacological
interventions have been reported in heart failure patients (Woltz et al. 2012),
although this review provided much weaker evidence for the effects of CBT on
depression, with one study demonstrating sustained reduction in depression for
patients receiving a combination of CBT, exercise, and attention control, but no
reduction for patients receiving any of these in isolation.
It is clear from these systematic reviews of psychological interventions, with a
variety of cardiac patients, that comparison of interventions is difficult due to the
wide variation in target population; severity of depression being addressed; “dose”
of the intervention delivered, by whom and in what modality; primary and second-
ary outcome measures used and the measurement tools employed; and follow-up
periods. Of particular concern is lack of information on the actual components of
interventions, through reference to a treatment manual, for example.
With respect to specific interventions, a major issue is that many of the studies
report one-off interventions with little, if any, replication by other teams being
reported, making findings more difficult to interpret. For example, Chair
et al. (2012) conducted an RCT (N = 146) with CHD patients attending CR but
who had been assessed as having poor motivation, by low readiness to change
scores or having dropped out of CR previously. Patients (n = 73) in the control
group received usual care (23 sessions of supervised exercise, behavioral education,
and diet education), while those in the treatment group (n = 73) received usual care
plus four sessions of motivational interviewing each lasting 30–45 min. No details
of manualization are given, although motivational interviewing fidelity checking
was undertaken. There was no significant difference between the two groups on
clinical outcomes (e.g., body mass index (BMI), blood pressure, cholesterol),
although patients in the treatment group had greater improvement in health-related
quality of life (SF-36) scores in the “aspects of general health” (4.74, 95 % CI
0.04–9.44; p = 0.048) and “role limitation due to emotional problem” (8.80, 95 %
CI 1.16–16.43; p = 0.024) areas. While both groups improved in depression, there
was a greater increase in anxiety (HADS-A) in the treatment group than in the
control group (0.96, 95 % CI 0.09–1.83; p = 0.030). The authors note that this
unexpected result raises many questions: location of the study, belief systems of the
patients, and appropriateness of the motivational interviewing content. More evi-
dence, particularly from replication studies and preferably not excluding people
with comorbid mental health issues, as in this study, is needed to better understand
this phenomenon of increased anxiety.
Motivational interviewing was also assessed along with CBT in the Beating
Heart Problems RCT (Murphy et al. 2013). This program was designed to support
patients to develop behavioral and cognitive self-management skills. Patients (N =
275) consecutively admitted to two Melbourne hospitals after AMI (32 %) or for
CABG (40 %) or PCI (28 %) were randomized to treatment (T; n = 139) or control
(C; n = 136) groups. Treatment group patients were invited to participate in the
922 A.C. Jackson et al.
Brief Interventions
Minimal or brief interventions are those treatments involving less professional time
and/or resources than are typical of traditional therapy (Heather 1986). In other
areas of complex behavioral change, often with high levels of comorbidity, such as
in pathological gambling, such interventions are defined as ranging from 10 min to
four sessions (Petry et al. 2008). These interventions provide nonthreatening, cost-
effective, and time-efficient alternatives to traditional psychological interventions,
particularly to those with earlier onset and less severe behavioral and psychological
problems. Typically, these interventions involve minimal therapist contact, includ-
ing self-help workbooks with booster sessions, brief advice, face-to-face interven-
tions with up to four sessions, brief interventions delivered via telephone and online
Psychosocial Interventions for Patients After a Cardiac Event 923
based alternative settings include telehealth interventions that were either multi-
factorial individualized interventions, exercise-focused interventions, or recovery-
focused interventions following MI or CABG surgery; Internet-based risk factor
modification interventions; community- or home-based CR; rural, remote, and
culturally relevant interventions; multimodal interventions; and complementary
and alternative therapy interventions. Generalizing from these studies is difficult,
however, as they reflect a high level of heterogeneity in conditions addressed, time
spent with patients, person delivering the intervention, and whether they were
alternatives or adjuncts to “standard” CR. There are few reports of psychologically
focused interventions in these reviews, with interventions more likely to focus on
risk factor behavioral change and post-event adjustment. Of the few reporting a
psychological or psychosocial focus, one showed no benefits in psychosocial
adjustment following nurse-delivered telephone counseling (Gallagher
et al. 2003), while the other showed no difference in depression or perceived social
support in a peer-delivered telephone intervention for male CABG patients at 6- and
12-week follow-up. However, at 12-week post-discharge, the control group had
significantly greater utilization of health services (family physician visits, emer-
gency room visits) than the telephone intervention group ( p = 0.02, p = 0.04,
respectively) (Colella 2009). This impact on health service use is similar to that
reported by Oranta et al. (2012) in their Finnish interpersonal counseling study.
A further telehealth study (Cartwright et al. 2013) found no main effect on health-
related quality of life, depression, or anxiety in heart failure patients, while in
contrast, the “ProActive Heart” telephone coaching study found statistically sig-
nificant reductions in anxiety and a trend to reduction of depression in MI patients
(O’Neil et al. 2014). The reported effects on PHQ-9 measured depression were
higher, however, in the tele-HEART intervention with an older group (mean age =
79 years, with 22.5 % over 85) of heart failure patients (Gellis et al. 2012).
One positive arising from alternative modes of delivery of psychological inter-
ventions may be higher rates of take-up and retention of patients receiving
web-based interventions (70–95 %) compared with face-to-face interventions
(30 %) (Paul et al. 2013). Greater adherence and adoption of beneficial physical
activity as well as small but robust improvements in depression have also been
reported for the use of Internet-delivered CBT for adults with high CVD risk but
low to moderate depression (Glozier et al. 2013). The InterHerz trial (Messerli-
Burgy et al. 2012) will test whether such depression and stress can be ameliorated
by a web-based interactive intervention (Deprexis) that is responsive to patients as
they complete modules which are not manualized but broadly consistent with a
CBT perspective.
Psychosocial Interventions
interventions (Thompson and Ski 2013), for people with CHD and depression
(Berkman et al. 2003; McLaughlin et al. 2005). The results of these studies suggest
that psychosocial interventions are effective at reducing depressive symptoms.
This section reviews a number of RCTs to assess the effectiveness of psycho-
social interventions, compared to usual care, for people with CHD and depression.
Four studies are two-group, parallel designs which compared a psychosocial inter-
vention with usual care (Barth et al. 2005; Berkman et al. 2003; McLaughlin
et al. 2005; Salminen et al. 2005). One study is a 2 2 factorial design which
evaluated a psychosocial intervention compared with usual care and a selective
serotonin reuptake inhibitor antidepressant with placebo (Lesperance et al. 2007).
Sample sizes range from 59 to 856 (for patients with depression). Mean ages range
from 56 to 75 years, and percentage of male ranges from 48 % to 82 %. The studies
were undertaken in a range of hospital, academic, and community settings.
The studies enrolled participants with a variety of CHD diagnoses and levels of
depression. With regard to depression, one study enrolled patients with unipolar
affective disorder (major depression, dysthymia, or depressive adjustment disorder)
(Barth et al. 2005), and one study included participants with major depression
(Lesperance et al. 2007); these diagnoses were based on Diagnostic and Statistical
Manual of Mental Disorders (DSM) criteria. One study included participants with
mild or moderate depressive symptoms based on the HADS. The ENRICHD study
included participants with major depression, minor depression with a history of
major depression, or dysthymia (based on DSM criteria) or with low perceived
social support (LPSS); however, only participants with depression and LPSS
received psychological and social components (Berkman et al. 2003). Another
study (Salminen et al. 2005) included patients without depression but undertook
subgroup analysis on patients with moderate or severe depressive symptoms, based
on the Zung Self-Rating Depression Scale (ZSDS).
As with the psychological interventions reviewed earlier, the interventions
varied in their therapeutic elements, frequency, length, and mode of intervention.
Two interventions involved CBT (Barth et al. 2005; McLaughlin et al. 2005), two
studies incorporated counseling (McLaughlin et al. 2005; Salminen et al. 2005), and
one study utilized interpersonal psychotherapy (Lesperance et al. 2007). Social
isolation was addressed by four interventions (Berkman et al. 2003; Lesperance
et al. 2007; McLaughlin et al. 2005; Salminen et al. 2005) and one program aimed
to motivate patients to seek external services for enduring depressive illness (Barth
et al. 2005). The interventions were delivered by a variety of health professionals
(psychotherapist (Barth et al. 2005); clinical or counseling psychologists, clinical
psychiatrists, clinical social worker, or psychiatric nurse (Berkman et al. 2003);
experienced doctoral or master’s level therapist (Lesperance et al. 2007); doctoral-
level psychiatrist/clinical psychologist/intern (McLaughlin et al. 2005); and nurse
plus physiotherapist for exercise (Salminen et al. 2005)) in group and individual
settings and in-person and by telephone. All the included studies compared the
intervention with usual clinical management.
The five studies reported on a variety of outcomes. All studies reported on the
primary outcome of depressive symptoms and used a range of assessment tools
Psychosocial Interventions for Patients After a Cardiac Event 927
including the BDI (Barth et al. 2005; Blumenthal et al. 2003; Lesperance
et al. 2007), the HADS (Barth et al. 2005; McLaughlin et al. 2005), the Hamilton
Rating Scale for Depression (HAM-D) (Berkman et al. 2003; Lesperance
et al. 2007), and the ZSDS (Salminen et al. 2005). The studies reported a variety
of secondary outcomes including mortality (all-cause and cardiovascular) and
revascularization (Berkman et al. 2003), recurrent MI (Berkman et al. 2003;
Lesperance et al. 2007), anxiety (Barth et al. 2005; McLaughlin et al. 2005), social
support (Berkman et al. 2003; Lesperance et al. 2007), quality of life (Berkman
et al. 2003), and mental functioning (Mendes de Leon et al. 2006).
These studies suggest that psychosocial interventions, incorporating a focus on
affect and social support, compared with usual care, appear to be effective in
reducing depressive symptoms in patients with CHD and depression. The magni-
tude of the effect size reflects a small benefit of the intervention. In addition, it
appears that psychosocial interventions improve social support and possibly mental
health quality of life.
This small benefit seen in depressive symptoms is consistent with the systematic
reviews previously discussed which examined psychological (rather than psycho-
social) interventions in CHD patients (Dickens et al. 2013; Whalley et al. 2011).
The studies reported in this section focused on psychosocial interventions only in
patients with CHD and depression, and it should be noted that this population may
be more resistant to treatment than a population with a range of depressive
symptoms – including those without symptoms. As with the psychological inter-
ventions, these studies show that short-term interventions (3 months or less) may be
more effective than long-term interventions (more than 3 months). This result could
be due to a number of factors other than the intervention length. For example,
studies with short-term intervention also had short-term follow-up, and it is likely
that the effect of the intervention reduces over time.
The finding that psychosocial interventions improve social support and mental
health quality of life in addition to depressive symptom is not surprising given the
link between them (Rozanski et al. 2005). The outcomes of mortality, recurrent MI,
and revascularization were only assessed by one or two of the five studies noted
here, and no firm conclusions can be drawn as to whether psychosocial interven-
tions impact on these outcomes. Other systematic reviews have addressed these
outcomes, and there appears to be some evidence of a reduction in cardiac mortality
(Whalley et al. 2011), but none in total mortality or cardiac revascularizations or
nonfatal MI (Baumeister et al. 2011; Thombs et al. 2008; Whalley et al. 2011).
Although the evidence indicates that psychosocial interventions appear to reduce
depressive symptoms in people with CHD and depression, there are some caveats.
There are a number of components of any psychosocial intervention or indeed any
complex intervention, such as staff delivering it, mode of delivery, setting, timing,
frequency, and duration. Therefore, psychosocial interventions are not a standard-
ized package and cannot be replicated exactly, even in cases where there is
manualized treatment. Each psychosocial intervention is somewhat unique to the
interventionist and patient and likely to have a different effect on each individual
who receives it. However, despite the expected heterogeneity of the interventions,
928 A.C. Jackson et al.
the effect size for depressive symptoms was similar for each study suggesting that,
despite nonstandardized interventions being compared, they were of similar
effectiveness.
These studies are of patients who had CHD and depression. The severity of
depression varies in the studies (from major depression to mild depressive symp-
toms), but the effect size of the studies is statistically homogeneous. This suggests
that all patients with CHD and depression are able to benefit from the intervention
regardless of the severity of depression. It should be acknowledged, however, that
the ENRICHD trial (Berkman et al. 2003) contributed 63 % of all of the participants
included in the studies outlined here (856/1,358) and was responsible for 56 % and
70 % of the weight of the reported results for the depressive symptoms and social
support outcomes, respectively. Thus, the ENRICHD trial is driving or is solely
responsible for most of the results reported in this brief review of psychosocial
interventions.
A recent meta-analysis of the effect of psychosocial interventions on patients
with chronic heart failure found a significant overall improvement in quality of life
(Samartzis et al. 2013). However, psychosocial intervention was defined rather
loosely as a “structured nonpharmacologic intervention. . .focused on improving
psychologic and/or social aspects. . .” (p. 126). It did not necessarily include a social
component.
Conclusion
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Treatment of Anxiety Within the Practice
of Cardiology
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Definition and Measurement of Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Epidemiology of Anxiety Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
Anxiety in Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 938
Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 940
Janeway’s Treatment Algorithm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Pharmacotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 941
Psychoeducation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 942
Cognitive Behavior Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 943
Breathing Retraining and Relaxation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 945
Hypnotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 946
Values-Based Counseling and Perceived Locus of Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
Exercise Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 947
Conclusions and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 949
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 950
A. Sood (*)
Voice Psychologists and Allied Professionals, Melbourne, VIC, Australia
e-mail: [email protected]
M.E. Alvarenga
MonashHEART, Monash Cardiovascular Research Centre, Monash Health and Department of
Medicine (SCS at Monash), Monash University, Melbourne, VIC, Australia
e-mail: [email protected]
J.A. Blumenthal
Department of Psychiatry and Behavioral Medicine, Duke University School of Medicine,
Durham, NC, USA
e-mail: [email protected]
Abstract
This chapter will provide a definition of anxiety and describe methods for
assessing it within cardiac practice. Next the epidemiology of anxiety disorders
and prevalence of anxiety disorders in cardiovascular disease will be reviewed
followed by literature on anxiety and cardiovascular disease. Subsequently,
different treatment options including pharmacotherapy and different psycholog-
ical approaches will be evaluated. Other treatment measures discussed in this
chapter include breathing retraining, relaxation, and exercise therapy. The chap-
ter concludes with recommendations for treatment of anxiety in heart disease
along with future directions for research.
Keywords
Anxiety disorders • Breathing • Cognitive behavior therapy • Epidemiology •
Exercise therapy • Hypnotherapy • In cardiovascular disease • Perceived locus of
control • Pharmacotherapy • Psychoeducation • Relaxation therapy • Cardiovas-
cular disease • In anxiety disorders • Cognitive behavior therapy (CBT) •
Generalized anxiety disorder (GAD) • Noncardiac chest pain • Panic disorder •
Post-traumatic stress disorder (PTSD) • Selective serotonin reuptake inhibitors
(SSRIs) • Tricyclic antidepressants (TCAs)
Introduction
There is increasing recognition that the experience of worry and fear can lead to a
troubled mind as well as a troubled heart. During the experience of anxiety and
panic, the body’s natural emergency response to perceived threat appears to not
simply mimic the cardiac symptoms (i.e., palpitations, shortness of breath) but in
itself contributes to the development and maintenance of heart disease. Watkins
et al. (2013) found that people with comorbid anxiety disorders and heart disease
had twice the risk of dying from any cause and that the presence of anxiety and
depression in heart patients puts these patients at three times the risk of mortality.
Therefore, treatment of anxiety in cardiac patients is both an important and imper-
ative aspect of cardiac clinical practice.
the intensity, duration, and frequency of symptoms. The Diagnostic and Statistical
Manual of mental disorders, Fifth Edition (DSM 5), is the most commonly used
diagnostic instruments by allied health professionals to diagnose anxiety. In order
to warrant a diagnosis of anxiety or trauma–stress-related disorder, the DSM
5 criteria must be met. According to the DSM 5 (2013):
Anxiety disorders are the most commonly diagnosed forms of mental illness in the
Western world and in the USA are responsible for one-third of the total expendi-
tures of the federal government for mental illness. Approximately half of those
costs are due to the repeated use of health-care services since people with anxiety
disorders often solicit medical evaluation for symptoms that resemble physical
illnesses. Nationally representative surveys indicate that as many as 30 % of
patients will suffer from some kind of anxiety disorder during their lifetimes, a
figure that has increased significantly over the past two decades.
In the USA, one in four in the general population will meet criteria for an anxiety
disorder with a 1-year prevalence rate of 17.7 % (Kessler et al. 1994). Women are
more likely to have an anxiety disorder than men (30.5 % vs 19.2 % lifetime
prevalence), with lower socioeconomic status manifesting a higher prevalence
(Kessler et al. 1994). Although the actual prevalence of anxiety disorders among
cardiac patients is not known, Tully and Cosh (2013) reported an 11–14 % prev-
alence of generalized anxiety disorder (GAD) across 12 studies (N = 3485) and a
pooled lifetime prevalence of 26 %. Frasure-Smith and Lesperance(2008) noted
that 5.3 % of a sample of 804 patients with stable CHD had GAD and 41.4 % had
elevated anxiety symptoms measured by the Hospital Anxiety and Depression
Scale-Anxiety (HADS-A). Noncardiac chest pain is diagnosed in approximately
50 % of patients who present to the ED, with 30 % of these found to have panic
disorder with normal angiograms at follow-up (Fleet et al. 1998). Thus, the typical
cardiologist will likely encounter a patient suffering from anxiety symptoms
masquerading as cardiac disease.
precipitating factors for acute coronary syndromes. Several studies have demon-
strated a predisposition to CHD due to interaction between conventional risk factors
and psychological factors. Research has found that negative affective states con-
tribute to an increased propensity to CVD (Kubzansky and Kawachi 2000;
Kubzansky et al. 1997). Anxiety is not only considered as one of the most prevalent
psychiatric diagnoses but also among the most common complaint in patients with
CVD (Harter et al. 2003; Lavoie et al. 2004; Bayazi and Rastegari 2005). In
addition, anxiety is seen most among individuals with CHD. Research suggests
that 70–80 % of individuals suffering from an acute cardiac event tended to
experience anxiety (Kubzansky et al. 1998). Although anxiety related to living
with a debilitating condition is common among patients, chronic persistence is
found among 20–25 % patients (Kubzansky and Kawachi 2000). Fear of sudden
death, the lack of self-sufficiency, deficiency on sexuality, and the change of roles
on family relationships or fear of losing their status and the fear of having a new
infarction risk can all cause anxiety in patients. In addition, prevalence of anxiety is
a poor predictor of short- and long-term success of treatment and hinders psycho-
social adaptation and functionality by interfering in patient’s ability to self-care
(Kubzansky et al. 1998). Studies have demonstrated a link between CHD and
anxiety disorders and between anxiety disorders and hypertension (Davies
et al. 1999). In a study, Havik and Maeland (1990) found that patients suffering
from comorbid CHD and anxiety displayed a slow progression into the work force
and more often ceased employment than non-anxious patients with CHD. Anxiety
can also increase the risk of subsequent CHD events and CHD mortality (Denollet
and Brutsaert 1998).
Bankier et al. (2008) showed significant associations between generalized anxiety
and CHD. It has further been investigated that despite prevalence of cultural diver-
sity in how emotions can impact different individuals (Kirmayer 2001; Draguns and
Tanaka-Matsumi 2003), patients suffering from acute myocardial infarction (AMI)
displayed no difference in expression of anxiety (Moser and Jong 2005).
Elevated anxiety symptoms have been shown to be associated with a twofold
increased risk of mortality in CABG patients (Tully et al. 2008; Szekely et al. 2007)
and in outpatients with CHD (Rothenbacher et al. 2007; Strik et al. 2003). Furthermore,
Frasure-Smith and Lesperance (2008) reported that CHD patients with GAD assessed
2 months following hospital discharge showed a 2.3-fold increased risk of adverse
cardiac events, and Strik et al. (2003) reported a 2.8-fold increased risk of adverse events
in acute post-MI patients in which anxiety was measured 1 month following hospital
discharge. Similarly, a twofold increased risk of adverse events was observed in
76 stable CHD patients and in patients with elevated anxiety during annual clinic visits.
Considering that individuals with a diagnosis or incident of cardiac disease are
unexpectedly confronted with a risk of mortality followed by worrisome thoughts
about social, personal, and occupational lives, anxiety tends to be considered as
normative. Research has found associations between psychiatric diagnosis, par-
ticularly depression, anxiety, and psychological difficulty to adjust to the diag-
nosis and condition implications; however, it fails to provide potential
explanations of poor cardiovascular outcome in patients with depression and
940 A. Sood et al.
anxiety. Furthermore, several studies have shown links between anxiety disorders
and subsequent cardiovascular disease, sudden death, or increase risk of mortality
(Kawachi et al. 1994a; Watkins et al. 2013). The patients are often confronted
with numerous physical and mental stressors in coronary care units (Still 2002),
and anxiety predominantly poses a serious problem for patients in care units
where it can affect motivation and adherence to treatment and cause marked
distress (Maghsudlu 2001). Hence, treatment of anxiety in CVD is of paramount
importance. While treatment of depression in CVD has received significant
attention, surprisingly, treatment of anxiety in cardiac patients has been less
investigated. Thus, there is limited research on treatment options and implications
of treatment in anxious patients with CVD.
Assessment
Many epidemiological studies have highlighted that chronic anxiety might consti-
tute a risk for developing heart disease. Therefore, there is a need for specialist
medical associations like the Royal Australian College of Cardiologists, the British
Cardiovascular Society, and the American College of Cardiology, among others, to
adopt national standards regarding the screening of psychosocial risk factors, such
as anxiety. Psychological questionnaires have demonstrated high validity and
reliability in assessing anxiety and comorbid depression and/or distress. The Beck
Depression Inventory (BDI-II; Beck), the Patient Health Questionnaire-9 (PHQ),
and the Zung Self-Rating Anxiety Scale or Hamilton Anxiety Scale (HAM-A) are
psychometric tests which can accurately identify the presence of anxiety and
depression and which ought to be administered to all cardiac patients as part of
standard clinical practice. However, it might be that the time it takes to administer
psychological testing has discouraged the practice of screening by cardiologists. In
2003, the National Heart Foundation of Australia put forth a position paper
suggesting the use of an abbreviated version of the PHQ-9, the PHQ-2, as a way
of screening for the possibility of depression in cardiac patients (Colquhoun
et al. 2013). The position paper is yet to form part of clinical guidelines of the
Australian College of Cardiologists.
Murphy et al. (in print) have proposed a system which “red flags” cardiac
patients likely to suffer from depression and not just a normal reaction to a life-
threatening event, such as a heart attack. Such system is yet to be developed for
flagging patients at high risk of an anxiety disorder, such as panic disorder or post-
traumatic stress. Janeway (2008) developed a treatment algorithm for anxiety in
heart disease based on screening cardiac patients with the STOP-D, a screening tool
for psychological distress designed specifically for cardiac patients (Young
et al. 2007). This is a brief five-item self-report measure which is highly correlated
with other measures of depression, anxiety, anger, and poor social support. Janeway
(2008) points out that the advantage of this scale over others is its ease of
administration and scoring, as well as the fact that it is freely available online to
be used by cardiac nurses and cardiologists.
Treatment of Anxiety Within the Practice of Cardiology 941
The proposed treatment algorithm (Janeway 2008) uses the STOP-D scale as an
initial screening tool (Young et al. 2007). If anxiety symptoms score equal or more
than 4 points in the 8-point scale, a recommendation is made to monitor and
reassess after 2–4 weeks. If anxiety persists at the same high levels at reassessment,
cardiologists are asked to assess impact of mental state on treatment compliance
and ability to maintain a healthy lifestyle. At this point a referral to a mental health
professional is recommended. Patient ought to be reviewed again 2, 4, and 6 weeks
later. If there is improvement, continue to monitor patient over the next 1–2 months.
If the patient relapses or continues to worsen, a referral ought to be made to a mental
health professional. The author flags noncompliance with medication, alcohol
use/substance abuse, severe depression, mania, suicidality/homicidal ideation,
severe stress, and a history of sexual and physical abuse as factors which ought to
routinely form the basis of a referral to a mental health professional.
Treatment Options
Pharmacotherapy
Recognition of a biological basis for anxiety and depression lends support to treat-
ment approaches which focuses on altering and “correcting” brain biochemistry. In
particular, medical professionals find it reassuring to treat the body using a pharma-
cological paradigm. The right choice of medication for anxiety in cardiac disease is
an issue of high importance as it can significantly impact the clinical outcome of these
patients. A study indicated that deficiencies in the central neurotransmitter (serotonin)
may not only contribute to development of psychiatric conditions, but it may also be
implicated in the development and maintenance of hypertension and cardiovascular
risk (Vikenes et al. 1999). Considering the link between cardiovascular risk and
serotonin deficiencies, it is likely that targeting the same neurotransmitter may yield
positive treatment outcomes for both anxiety and CVD.
Lehnert et al. (1987) found that increased serotonin in cerebrospinal fluid con-
tributed to increased ventricular fibrillation and reduction in efferent sympathetic
activity from the heart. Furthermore, selective serotonin reuptake inhibitors (SSRIs)
tend to assist with heart rate variability, which is a marker of cardiovascular
reactivity and often reduced in anxiety disorders (Yeragani et al. 1990). The high
affinity of most SSRIs for the serotonin transporter contributing to reduced storage
of serotonin in platelets has further been recommended as a potential rationale for
cardioprotective action of SSRIs (Sauer et al. 2003). The SSRI paroxetine was found
to contribute to remission of depressive symptoms in most patients with ischemic
heart disease and was associated with less cardiovascular side effects (Roose
et al. 1998). Considering that the same neurotransmitter is believed to have an
association with depression and anxiety, the same medication may be ameliorating.
However, the study has not been replicated with patients with anxiety and CVD.
942 A. Sood et al.
Psychoeducation
As the old adage goes, understanding a problem is half its solution. Indeed, for
cardiac patients possessing knowledge and understanding of their condition can
assist with improved management and adherence to treatment.
Treatment of Anxiety Within the Practice of Cardiology 943
For many patients, a natural reaction to a heart attack can be similar to what is
observed in post-traumatic stress disorder. An individual is likely to be shocked by
a near-death experience and is likely to feel hesitant to do usual tasks. An individual
potentially may live the life-threatening event and avoid activities perceived as a
risk (Braunwald et al. 2004). Furthermore, recurring anxious thoughts tends to
impede ability to have a positive outlook of the future and is likely to negatively
impact sleep. In addition, sticking to exercise regimens becomes harder with
comorbid anxiety and CVD (Sardinha and Nardi 2012). Hence, normalization and
psychoeducation become of paramount importance. The goal of psychoeducation is
to provide patients with an explanatory model which includes anatomy, physiology,
symptoms, and their relationship between anxiety and CVD. Drawing pictures
which can help explain to the patient these relationships is also helpful.
It becomes integral for patients to have an understanding of biobehavioral pathways
linking anxiety and adverse health outcomes. Biologically, anxiety has an adverse
impact on the autonomic nervous system. Furthermore, with anxiety the lipid profile,
the immune system, and the coagulation cascade get compromised. The mental stress
associated with anxiety is known to have an association with excessive activation of
sympathetic nervous system (Medich et al. 1991; Veith et al. 1994) and catecholamine
release (Fehder 1999). This is found in both healthy individuals and people with poor
health as evidenced by increased plasma norepinephrine and decreased heart rate
(Yeung et al. 1991). Behaviorally, anxiety potentially reduces adherence to lifestyle.
The reasons for poor adherence have not yet been clearly determined. However,
patients with anxiety tend to have fewer coping mechanisms in response to stressful
situations and are likely to use unhealthy ways to alleviate anxiety (Stewart
et al. 2004). Feelings of not being in control, which is common in patients with
anxiety and CVD (Moser and Dracup 1995), can cause feelings of powerlessness
and poorer choices like unhealthy habits and lack adherence to cardiac rehabilitation.
Gaining insight into the strong association between biological and behavioral pathways
of anxiety and CVD is likely to promote sense of control and accountability in patients.
Other studies such as Recurrent Coronary Prevention Program (RCPP) were
carried out to reduce Type A behaviors in patients with MI. It was found that there
was 44 % reduction in Type A behavior (hostility, anger, depression) in patients
with MI who received psychological intervention in addition to cardiac education
compared to controls who received only cardiac education (Friedman et al. 1986).
The Enhancing Recovery in Coronary Heart Disease (ENRICHD) trial found that
behavioral treatment reduced depression and social isolation in patients with post
MI. Other clinical trials found that when patients with myocardial ischemia and
ventricular wall motion abnormalities were taught stress management and coping
skills, there was a reduction in CHD recurrences (Blumenthal et al. 1997).
Dealing with a debilitating physical condition can impact on mental health in the
form of stress. For some, it can feel much like recovering from a traumatic event.
The individual diagnosed with a heart condition has experienced a life-threatening
event that can cause them to respond with intense fear and helplessness. This fear
can provoke a flight or fight response, also known as acute stress response, in the
body. Rapid heartbeat, rapid breathing, and tense muscles are the most common
physiological reactions. When a person senses something perceived as potentially
threatening, a number of physiological changes take place in the body. The brain
sends warning signals through the central nervous system. It impacts the autonomic
nervous system (ANS) in our brain. The ANS control system can regulate heart rate,
digestion, and respiratory rate. The reaction to a threat begins in the amygdala
followed by activation of the pituitary gland. The adrenal glands also get activated
simultaneously in a process of co-transmission, releasing epinephrine into the
bloodstream. The release of chemical messengers increases blood pressure and
blood sugar levels. High blood pressure is a major risk and perpetuating factor for
heart disease. Hence, ways to respond to this physiological reaction warrant atten-
tion. One way is to invoke a relaxation response through various techniques, such as
meditation, yoga, progressive muscle relaxation (PMR), guided imagery, small
movements or posture change, and breathing instructions (sometimes aided by
biofeedback). Typically an individual learns to observe moments of low and high
tension in daily life, to practice during restful moments, and to manage periods of
high tension in a different way. Dixhoorn and Duivenvoorden (1999) defined
relaxation training as training an individual to allow and induce reduction in tension
internally, without the use of external means.
Relaxation therapy has been found to be effective as an adjunct to regular
medical care and standard cardiac rehabilitation. Linden et al. (1996) in a meta-
analysis found that psychosocial intervention, such as stress management, relaxa-
tion, and CBT, positively assisted in reducing blood pressure, distress, and choles-
terol levels in patients with coronary artery disease. Dixhoorn and White (2005)
concluded in their systematic review that relaxation therapy can enhance recovery
after cardiac ischemic event and intensive supervised relaxation is imperative for
cardiac rehabilitation. Studies found that training in relaxation skills augmented the
effects of psychoeducation (Amarosa-Tupler et al. 1989; Cowan et al. 2001; Nelson
et al. 1994). Skills such as classical relaxation method and PMR can be taught to
individuals through replicating symptoms of flight or fight response and/or anxiety
during sessions and practicing them so that they can be applied when stressors arise.
In PMR the aim is to reduce neuromuscular hypertension (McGuigan 1993).
Similarly, Linden (1993) indicated that in autogenic training, the goal is to restore
disturbed psychovegetative balance.
Winterfeid et al. (1993) found positive impact of autogenic relaxation training
on blood pressure in patients with coronary heart disease. A high level of blood
cholesterol level can contribute to atherosclerosis and an increased risk of heart
disease. Furthermore, LDL cholesterol is considered as a major cause of CHD. Pal
946 A. Sood et al.
et al. (2011) found that regular yoga interventions resulted in reduction in heart rate,
body fat, total cholesterol levels, and LDL levels. Yoga practices were found to be
beneficial for cardiac and hypertensive patients. Yoga practices also significantly
improved blood pressure among people with hypertension (Blumenthal et al. 1989)
and cardiovascular disease (Mahajan et al. 1999).
Anxiety in heart disease is sometimes manifested by the presence of panic
attacks. These discreet periods of physiological discomfort accompanied by a
sense of fear or loss of control are often difficult to recognize as their presentation
tends to overlap with the clinical features of coronary heart disease (CHD) and
cardiomyopathies (Tully et al. 2015) such as heart palpitations, shortness of breath,
and chest pain. Panic attacks have been shown to be alleviated by breathing
retraining (Lum 1983; Rapee 1985), mainly as hyperventilation appears to be a
key element of the panic attack experience. Used alone, this technique appears to
alleviate panic attacks but not necessarily extinguish the continued occurrence of
panic. Thus, it should be used in addition to other treatments such as exposure
therapy and cognitive restructure so to achieve long-term outcomes in anxious
patients with CVD. Hence, relaxation training can be considered as a beneficial
adjunct to existing treatment options. Research supports the utility of relaxation
practices as it can enhance recovery process. Research particularly in respect to
yoga practices was confined to Indian population, and future research could focus
on replicating the same in other populations.
Hypnotherapy
physical recovery of patients from surgery, and aid in the psychological and
emotional response of patients following surgery (Blankfield 2011). Indeed
research indicates that self-hypnosis has the potential to reduce anxiety following
coronary bypass surgery (Ashton et al. 1997). Hypnosis is also recommended as a
successful adjunct to cope with heart disease (Doran 1991) and reducing symptoms
of hypertension (Gay 2007). In a meta-analysis of surgical patients who had
undergone hypnosis, it was found that 89 % of patients who had undergone
hypnosis had better outcomes than 89 % of patients in control groups supporting
the notion that hypnosis is an effective adjunctive procedure for a wide variety of
surgical patients (Montogomery et al. 2002).
Exercise Therapy
who indicated that they exercise “regularly” were at reduced risk for being diag-
nosed with an anxiety disorder compared to their sedentary counterparts. Morgan
et al. (2013) reviewed the evidence for the benefits of exercise for anxiety disorders
and found that exercise tended to improve symptoms of anxiety.
The relationship between exercise and anxiety has been extensively examined
over the last 15 years. Petruzzello et al. (1991) conducted three separate meta-
analyses to quantitatively review the exercise–anxiety literature for state anxiety,
trait anxiety, and psychophysiological correlates of anxiety. They found that exer-
cise is indeed associated with reductions in anxiety, but only for aerobic forms of
exercise. These effects were generally independent of both subject (i.e., age and
health status) and descriptive characteristics. For state anxiety, exercise was asso-
ciated with reduced anxiety, but had effects similar to other known anxiety-
reducing treatments (e.g., relaxation). The trait anxiety meta-analysis revealed
that random assignment was important for achieving larger effects when compared
to the use of intact groups. Training programs also need to exceed 10 weeks before
significant changes in trait anxiety occur. This time line is important to emphasize
to patients who tend to show attrition after a couple of weeks of exercising due to
lack of results.
Stonerock et al. (2015) conducted a critical review of the literature looking at
12 randomized controlled studies which examined exercise training in adults with
either high levels of anxiety or an anxiety disorder. This group was chosen as it
offers insight into the most acutely exercise phobic group of patients, such as
patients with heart disease, who might perceive exercise as a threat to their well-
being. They found that exercise provided benefits greater than placebo. However,
most studies had significant methodological limitations, including small sample
sizes, concurrent therapies, and inadequate assessment of adherence and fitness
levels, which makes the findings inconclusive.
Williams et al. (2006) in a clinical review found evidence for positive health
impacts of exercise through cardiac rehabilitation programs in patients with
CHD, and hence it was recommended as a beneficial adjunct. Regular physical
exercise was found to have beneficial effects through decreased sympathetic
tone and increased parasympathetic tone (Adamu et al. 2006) and prevented
CHD (Hu et al. 1999). The World Health Organization recommended that
physical exercise must be sustained in the long term, be regular (at least
4–5 days per week), last for about 30 min, and be of mild to moderate intensity.
Although research has yet not determined clear consensus of optimal duration,
frequency, and type of exercises in prevention of coronary artery disease, the
World Health Organization recommends that in order for exercise to have a
positive impact, it needed to meet the aforementioned. Furthermore, patients
with MI, who engage in regular exercise, are less likely to develop complica-
tions as a result of vigorous exercise (Mittleman et al. 1993). In addition, good
evidence suggests that bouts of erratic exercise in middle age or those with a
diagnosis of coronary artery disease increased the risk of MI and sudden cardiac
death (Corrado et al. 2006).
Treatment of Anxiety Within the Practice of Cardiology 949
In conclusion, it can be established that patients with cardiac disease with comorbid
anxiety symptomatology are at increased risk of mortality, poor adherence to
treatment, and risk of slow recovery. High prevalence of anxiety in CVD warrants
that it clearly needs to be routinely assessed, possibly through psychological
questionnaires and tests.
Patients with CVD are also at risk of developing complications with antidepres-
sant treatment. When choosing medication in psychiatric morbidity with CVD,
clinicians must consider the type and severity of heart disease and the type and
severity of psychiatric condition and refer to clinical data evaluating efficacy and
safety of a particular medication. Hence, careful examination of risk-to-benefit ratio
must be conducted. It is important to note that although research indicates that
depression and anxiety in CVD are equally prevalent and can be equally fatal,
research in treatment of depression in CVD certainly outweighs research in treat-
ment of anxiety in CVD. Furthermore, the link between anxiety and CVD is well
established, and it becomes imperative to differentiate reaction to the experience of
a serious physical condition (CVD) from clinical anxiety. Therefore, anxiety in
CVD certainly warrants future research for better treatment options and recom-
mendations in respect to efficacy and safety of different psychological and phar-
macological treatments. Moreover, research has focused predominantly on the role
of anxiety in heart disease, and no differentiation has been made between different
types of anxiety disorders. Future research could also focus on identification and
treatment options of different anxiety disorders in heart disease.
Considering the mixed outcomes of the side effect profile and potential drug
interactions of SSRIs, larger and well-controlled trails are possibly needed to
further evaluate efficacy and safety of pharmacological treatment. Furthermore,
research has found significant positive outcomes with treatment with CBT, and it is
likely that CBT can be considered as having a good efficacy in patients with CVD
and depression and/or anxiety. However, research has focused more on treatment of
depression symptomatology than anxiety symptomatology in CVD. Although few
studies have shown cognitive restructuring to be beneficial, it is important to
replicate these studies to evaluate and confirm efficacy. The literature in respect
to nonpharmacological intervention treatment for anxiety in cardiac diagnosis is
sparse. In addition, it is proposed that fears and apprehensions that patients with
CVD experience are somewhat rationale in nature, and future research could
potentially also focus on efficacy of other treatment options, such as Acceptance
and Commitment Therapy (ACT) and rational emotive therapy. ACT focuses on
fostering acceptance of unhelpful thoughts and emotions and aims to enhance
committed action toward living a life toward chosen values. It is likely that ACT
therapeutic technique could potentially teach clients to better deal with anxiety-
related discomfort. In addition, although exercise is known to have a positive
impact on anxiety and it can be a great way to help patient regain their physical
confidence, there is lack of knowledge on how to best deal with anxiety-related
950 A. Sood et al.
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Psychological and Behavioral
Contributions to Rehabilitation
and Recovery in Heart Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 958
Chronic Disease Self-Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 960
Collaborative Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
The Whole Person Model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 962
Cardiac Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 964
Managing Depression and Anxiety in the Cardiac Patient . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
The Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 966
The Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 967
Implantable Cardioverter Defibrillator: A Special Case . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
Behavior and Behavior Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
The Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 968
The Solution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 969
Telephone and Web-Based Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 970
Improving Uptake of Rehabilitation Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 971
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 972
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 973
Abstract
From time immemorial, the mind and the body have been closely linked, and
research continues to show a high association of depression and anxiety with
heart disease. Depression is a risk factor for heart disease as well as risk for poor
recovery after a cardiac event. The Whole Person Model described here inte-
grates thinking about thoughts, emotions, bodily symptoms, and health behav-
iors, and can form the foundation of a powerful rehabilitation or disease
Keywords
5A’s approach • Cardiac rehabilitation and recovery • Behavior and behavior
change • CDSM. See Chronic disease self-management (CDSM) • Definition •
Depression and anxiety • Diet and smoking • Education • Exercise • Stress
management • Telephone- and web-based interventions • Type A behavior •
Weight loss programs • Collaborative care • Education programs • Effectiveness
of • Whole person model • Cognitive behavioral therapy (CBT) • ICD patients,
treatment of • Strategies • Telephone delivery of • Diet • Education • Exercise •
Implantable cardioverter defibrillators (ICD) • Interpersonal therapy • Motiva-
tional interviewing • Recovery and cardiac rehabilitation. See Cardiac rehabil-
itation and recovery • Smoking • Stress management
Introduction
From time immemorial the mind and the heart have been closely linked. People
often speak of the “broken heart” to be associated with grief, and much data
provides evidence supporting the increased mortality following bereavement
(Martikainen and Valkonen 1996). During the psychosomatic era of the 1930s
and since, many studies have investigated the links between personality (for
instance, type A, type D, hostility) and heart disease, and this volume chronicles
the history and current status of knowledge of the links between the “psyche” and
the heart, including the intricate biological connections provided by the autonomic
nervous system and the neuroendocrine system.
Medicine, however, has mostly been taking a different path. Ever since Des-
cartes gave permission to split the indivisible “psyche” from the divisible “soma”
(Descartes 1641/1972), science and medicine have pursued a relentless reduction-
istic process to understand the human person: firstly with anatomy and physiology
and later, with an increasingly narrower focus, molecular and genetic science.
Reductionistic science has brought enormous advances to clinical medicine and
the health of the population, and this is no less evident in the area of heart disease
than in other areas. Through new pharmaceuticals and amazing procedural inter-
ventions, the outcomes from coronary heart disease have vastly improved, and
hospital admissions significantly reduced, over the last 20 years (Mozaffarian
et al. 2015). The mortality, in absolute numbers and in proportion of overall deaths,
has significantly reduced in those 20 years (NHLBI 2012). With quick intervention,
heart muscle can be preserved following an ischemic episode.
However – and there is always an however – there are some areas in which
reductionistic science has failed to have much impact and that is in the prevention
of heart disease and in the rehabilitation and recovery following a cardiac event.
Psychological and Behavioral Contributions to Rehabilitation and Recovery in. . . 959
Heart disease and its common accompaniments of metabolic syndrome and diabe-
tes mellitus are predominantly lifestyle diseases, with the risk factors of diet,
exercise, obesity, and smoking being issues of behavior. Taken together – obesity,
diabetes, and the metabolic syndrome – Western societies are facing an epidemic
(Kereiakes and Willerson 2003). There has, perhaps, been a reduction in smoking,
with strong public health messages being effective in some sectors of society. On
the other hand, obesity is increasing enormously, with almost two-thirds of the
Australian population being overweight or obese (Thorburn 2005), and, in parallel
with that, rates of type II diabetes have been increasing worldwide (World Health
Organization 2006). Notwithstanding the contribution of genetic predisposition,
these are predominantly behavior-related disorders, and behavior change is
difficult.
The body and mind are inextricably linked. Over the past decade, there has been
an increasing awareness of the role that psychological and behavioral factors play in
the onset, course, and recovery of cardiac disease (Compare et al. 2015; Dyer and
Beck 2007; Srinivas and Reddy 2013). Three examples of “onset” factors include
the link between acute stress (e.g., earthquake) and sudden cardiac death (Leor
et al. 1996), stress and acute heat failure (Akashi et al. 2008), and the prospective
relationship between depression and cardiac events, with a two to four times
increased risk above that of the general population (Kuper et al. 2002). In regard
to “course,” evidence shows that depression is associated with poorer outcomes
even in people with established heart disease (Rutledge et al. 2006). This chapter
focuses on the recovery phase. Psychological and cardiac issues cannot be consid-
ered separately, and a multidisciplinary approach, adopting the use of psychological
and behavioral interventions, is required (Compare et al. 2015). As the Lancet
article proclaimed, “There is no health without mental health” (Prince et al. 2007).
In this chapter we use, as a framework, the “Whole Person Model,” built on the
principles of CBT (cognitive behavioral therapy), to explain how bodily health and
sickness are linked with emotions, thoughts, and behaviors. To make an impact on
the difficult problem of behavior change, we need a multipronged attack. We need
to take a holistic view of the problem.
The World Health Organization defines cardiac rehabilitation as “the sum of
activities required to ensure cardiac patients the best possible physical, mental and
social conditions, so that they may, by their own efforts, regain a normal place in the
community and lead an active productive life” (WHO 1964). The earliest cardiac
rehabilitation programs concentrated on physical training with the aim of improving
physical fitness so people could return to work. Over the last 30 years, programs have
evolved to use more holistic multidisciplinary approaches, focusing on patient
education, modification of risk factors, psychological impact of cardiac events, and
overall well-being of patients (Dusseldorp et al. 1999; Bennett 2012; Mampuya
2012). This transformation in cardiac rehabilitation has had a positive impact for
those attending, with resulting reduction in mortality, symptom relief, and enhanced
well-being. It is a cost-effective intervention that improves quality of life, reduces
hospital admissions, and improves survival (Hedback et al. 2001; Mampuya 2012;
Shepherd and While 2012). The scandal is that a minority of patients, following a
960 D.M. Clarke et al.
For all the reasons given above – the success of acute intervention and the growing
problem of chronic disease – much attention in health care is now being given to the
management of chronic disease and, in particular, the “self-management” of
chronic disease. This requires a different focus and a different set of skills to that
required in acute medicine. Chronic disease self-management (CDSM) requires full
and active engagement of the person with the disease and with health-care practi-
tioners. This in turn requires knowledge about the disease and its causes and
complications; knowledge and self-confidence in recognizing symptoms, managing
medication, and negotiating the health system when and as required; a general self-
efficacy and competence in goal setting and planning; and finally, the social and
emotional skills to cope with stress, disappointments, and challenges and to main-
tain good supportive relationships.
The sometimes quoted joke about how many psychologists are required to
change a light globe – one, but the light globe has got to want to change – is fairly
true when it comes to behavior change. Kate Lorig, one of the early pioneers in the
field of chronic disease self-management (CDSM), and her colleagues, following
on from the work of Corbin and Strauss (1988), emphasized three broad categories
of tasks involved in disease self-management: (1) medical management, such as
taking medications, monitoring illness, and adhering to diet; (2) adapting behaviors
and roles in life to fit to limitations caused by the disease; and (3) the management
of emotions such as depression, demoralization, anger, hopelessness, etc. (Lorig
and Holman 2003). To this we would add a fourth: managing and negotiating the
health system (see Fig. 1). Furthermore, life goes on, and while a person may have
Psychological and Behavioral Contributions to Rehabilitation and Recovery in. . . 961
Managing Emotions
Business as Usual
(controlling stress,
(shopping, working,
relaxation, reflection,
cooking, picking up
seeking support, saying
children)
no)
to manage their illness, there is also “business as usual” – meals to cook, shopping
to be done, and children to pick up. It takes a fair amount of organization and
discipline to accomplish all of this.
In order to achieve these goals, there is a whole set of skills that patients need to
learn. These have been studied in a number of programs across a range of chronic
diseases by Clark et al. (1991) and are summarized thus to include:
in improving health and health behavior and in reducing use of emergency depart-
ments (Lorig et al. 2001).
Despite evidence for the effectiveness of CDSM, there remain significant bar-
riers to their implementation (Kennedy et al. 2014), and Jordan and Osborne (2007)
describe the importance of enablers to overcome these barriers. These include doing
multifaceted health promotion, empowering patients, strengthening multidis-
ciplinary teams, structuring referral pathways and clinical networks, and making
access easier.
Collaborative Care
The Whole Person Model has been described by Baird and Clarke (2011, 2012) and
is represented in Fig. 2. Underpinning it is a framework of cognitive behavioral
therapy (CBT) that emphasizes, within a strong therapeutic relationship, assisting a
patient to explore the problem, whatever it is, in terms of emotions, thoughts, and
behaviors (Hawton et al. 1989). Strategies used are typical CBT strategies of
behavioral analysis, problem-solving, identifying and expressing emotions, cogni-
tive restructuring, and goal setting (Hawton et al. 1989). The Whole Person Model
assists patients to see how thoughts, feelings, behavior, and bodily states are all
related – each affecting the other, and it provides a framework for understanding
how psychological and behavioral interventions can be used in a rehabilitation
setting to maximize patient recovery, functioning, and well-being.
The Whole Person Model has been used in a chronic disease self-management
program in heart failure patients, which for the patient involves working through a
manual over a 4-week period, with the aid of a health coach or nurse. The manual
includes information about the disease process, diet, exercise, and medication, as
Psychological and Behavioral Contributions to Rehabilitation and Recovery in. . . 963
Case A: George was a 56 year old businessman who suffered an acute episode of chest pain,
with ST-elevation myocardial infarction (STEMI). He underwent a stenting procedure and
remained in hospital for 5 days, after which time he was discharged home. Cardiac
rehabilitation was mentioned to him as he left the hospital, although he did not take it
up. One month after the event he had returned to work, though by his own report he was not
performing well. He told the GP, and later the psychologist, that he seemed to be anxious –
though he could not see that he had any reason to be worried – and he was not sleeping well.
At work, he could not concentrate well, and would often leave early and go home. He had
been divorced two years previously and lived alone. At home he seemed to mope around,
and watch movies till late at night because he knew he would not sleep. When he took
himself to the GP he was feeling desperate. He knew things were going in the wrong
direction.
The above story is not uncommon. The heart beats continuously through our
lifetime and, if it stops, we die. Problems with the heart engender strong emotions,
particularly worry or worse, fear. At an unconscious level and sometimes at a
conscious level, it raises very basic existential anxieties about death and mortality.
This is particularly true of people who rely on implanted defibrillators (Frizelle
et al. 2004).
Using a Whole Person Model, we might assume that all people with heart
disease will, to some extent, be stressed. To a greater or lesser extent, they will
have anxieties, will be saddened, and may be angry. To a greater or lesser extent,
they will face these issues with courage or with avoidance. Their responses may be
964 D.M. Clarke et al.
Cardiac Rehabilitation
Cardiac rehabilitation is effective (Gellis and Kang-Yi 2012), and programs now
include the optimization of medical treatment, nutritional counseling, smoking
cessation, stress management, exercise, and psychosocial support (Mampuya
2012). They are run by multidisciplinary teams – often based around a physician
and cardiac nurses. But they can also usefully employ health coaches, exercise
physiologists, pharmacists, and behavioral medicine specialists (psychologists or
psychiatrists).
Education is the mainstay of CDSM programs. CDSM education programs
“aim to empower patients through providing information, and teaching skills and
techniques to improve self-care and doctor-patient interaction, with the ultimate
goal of improving quality of life” (Jordan and Osborne 2007). It is assumed,
perhaps, that with full information, people will have the requisite knowledge to
change and will change. But we know this is not true. In a recent report of an
evaluation of a health education program, the authors comment, “it was not enough
to effectively self manage. (Patients) were still not shifting the responsibility for
their health from the doctor or nurses to themselves. . . .and were not ready to
change their unhealthy lifestyles” (Tun 2014). Furthermore, psychoeducational
programs effect no change on depression and anxiety (Dusseldorp et al. 1999).
Information is crucially important, but it is not enough.
Psychological and Behavioral Contributions to Rehabilitation and Recovery in. . . 965
The Problem
Celano and Huffman 2011; Dyer and Beck 2007; Lichtman et al. 2014; Mampuya
2012). Depression and anxiety have also been found to be associated with poor uptake
of healthy lifestyle habits and cardiac risk-reducing behaviors (Abed et al. 2014).
Psychological symptoms following coronary events are associated with lower exer-
cise capacity, increased hospitalizations, fatigue, reduced QOL, and a lower sense of
well-being (Abed et al. 2014; Colquhoun et al. 2013; Ladapo et al. 2012).
The Treatment
On the other hand, in the MIND-IT study, mirtazapine was no more effective than
placebo (van den Brink et al. 2002).
The evidence that depression is a risk factor for coronary heart disease, cardiac
events, and outcomes in heart disease is strong (Colquhoun et al. 2013). Given that,
it would be nice to demonstrate that treatments that are effective in treating
depression also have an effect on the course of heart disease. Unfortunately, this
has not been robustly shown in a number of studies. The meta-analysis conducted
by Rutledge et al. (2013) concludes that psychiatric treatments (pharmacotherapy
or psychological interventions) did not reduce total mortality, although there was
moderate efficacy for reducing CHD events and improving depression.
The Problem
The Solution
Helping patients to become motivated and active in health behavior change has
proven to be a challenging task for health-care providers (Peitrabissa et al. 2015;
Shinitzky and Kub 2001). Therefore, interventions that include strategies to pro-
mote behavior change and reward changes are likely to be more effective than
standard educational programs (Bennett 2012). It is for this reason that cardiac
rehabilitation programs generally make explicit the goals of behavior change as
well as focusing on symptom control and emotional impact (Bennett 2012). This
requires both cognitive and behavioral interventions to modify unhelpful thoughts,
acknowledge distressing feelings and fears, and work toward changing behaviors
(Whalley et al. 2014; Beckie et al. 2011; Beswick et al. 2005; Charlson et al. 2014;
Pietrabissa et al. 2015; Stawnychy et al. 2014; Thompson et al. 2011).
A number of patient characteristics have been identified as being linked with
successful behavior change. Unsurprisingly, patients with positive affect, and
subsequent increased self-efficacy and confidence, are more likely to sustain
positive behavior change (Charlson et al. 2014), again underlining the impor-
tance of treating the whole person. Positive emotions and cognitions (i.e.,
optimism, perceived control, and contentment) may represent resilience in
individuals with CHD (Gallo et al. 2004) and are an essential requirement for
behavior change.
970 D.M. Clarke et al.
some positive effect. Telephone delivery of CBT has been successfully trialed in
the treatment of depression and anxiety disorders (Muller and Yardley 2011).
A recent tele-health program conducted by O’Neil et al. (2014) involved cardiac
patients receiving ten CBT sessions over a 6-month period primarily aimed at
reducing depression. The program involved a psychologist using techniques of
motivational interviewing, goal setting, behavioral activation, and cognitive
restructuring. It demonstrated effectiveness in reducing depression and anxiety
symptoms.
There have also recently been developed web-based treatments for cardiac
patients which have been shown to reduce depression and anxiety (Dew
et al. 2004; Kuhl et al. 2006; Messerli-Burgy et al. 2012). These techniques may
assist in overcoming barriers to people being involved in rehabilitation programs –
barriers such as distance, time, and travel – although adherence and attrition appear
to be common challenges for these types of interventions also (Habibovic
et al. 2014).
There has been little practical research done to date on mechanisms to improve
uptake of cardiac rehabilitation programs (Beswick et al. 2005). Clearly, the above
data tells us that there needs to be better information and stronger referral pathways.
It also seems, however, as if the process of rehabilitation needs to begin early –
when the patient is in hospital or in the cardiology clinic having their stent. Uptake
of a referral will be enhanced if patients have better and earlier information about
their condition and what they can do about it and have their questions and fears
(thoughts and feelings) listened to and addressed. And finally, patients need to be
assisted with the practical barriers. There seems to be a role here for an “in-reach”
nurse – a cardiac rehabilitation nurse visiting the clinic, spruiking the benefits of
cardiac rehabilitation.
Conclusion
The data presented in this chapter shows overwhelmingly that a holistic style of
cardiac rehabilitation has a lot to offer patients. Education about the disease,
treatment, diet, and exercise is important but needs a behavioral program to
facilitate real change. Cognitive and behavioral techniques can be used to facilitate
change in diet, exercise, and compliance to medications, while addressing the fears
associated with illness and barriers that exist in the way of patients making healthy
life choices. Cardiac rehabilitation and self-management programs have tended to
be either exercise based (Heran et al. 2011) or education based (Lorig and Holman
2003). They need to be holistic, paying due attention to the thoughts and feelings of
patients. It is these thoughts and feelings that are the barriers to full participation,
but paradoxically, it is the thoughts and feelings which will drive the motivation
and commitment for significant change. Combined with a strong psychoeducational
component, a CBT framework provides the structure and tools to do this, utilizing
any of the many techniques available: stress reduction, relaxation, problem-solving,
cognitive therapy, goal planning, pleasant events scheduling, graded exposure, etc.
Patients can learn to look after themselves, eat well, get exercise, and treasure
relationships such that they can live a full and satisfying life (Clarke 2007). The
Whole Person Model is a way to help patients understand how their thoughts and
feelings impact upon on their health and health choices.
The specific role of psychiatrists and psychologists in this field has been mapped
out in the model of consultation-liaison psychiatry (Wise and Rundell 2002),
which, as the name suggests, has a dual focus. We can work directly with patients,
but we also have a role in assisting the design and structure of the programs,
thinking about the referrals’ pathways and the barriers, and supporting the frontline
staff. Cardiac patients generally do not want to see a psychologist or a psychiatrist.
They have a heart problem after all. But we can support the frontline staff to
facilitate psychologically and behaviorally informed recovery-focused care.
Patients who are distressed should be referred to a psychologist or psychiatrist.
Although there is a dearth of good data supporting the efficacy of treatments for
anxiety and depression in cardiac patients specifically, there is plenty of general
Psychological and Behavioral Contributions to Rehabilitation and Recovery in. . . 973
Case B: George was a 56 year old businessman who suffered an acute episode of chest pain,
with ST-elevation myocardial infarction (STEMI). He underwent a stenting procedure, and
remained in hospital for 5 days. On day 4, he was visited by a cardiac nurse named Angela,
who went to talk to him about a referral to cardiac rehabilitation. She introduced herself and
then pulled up a chair and sat down. She started saying a little about what she knew about
George’s condition, and advised him that he would be referred for rehabilitation. She then
noticed that he was looking very distressed, with his eyes starting to moist up. What was
wrong, she thought. What had she said? So she asked him.
George told her how frightened he was. He had been increasingly miserable, perhaps
even depressed, since his divorce two years ago. His relationship with his children was
terrible, and he felt increasingly isolated and lonely. The quality of his work had deterio-
rated because he was finding it hard to give it the full concentration. He was sure that people
at work had noticed this. His life was falling apart. By this time the tears were flowing, and
Angela started to feel uncomfortable. She felt she probably needed some help here. She
continued, by acknowledging his awful predicament, and asking him a few more questions
to allow him to continue. He expressed the idea that perhaps the heart attack was a
punishment for him, and that he may not survive it.
After another fifteen minutes – though it seemed like an hour to Angela – she repeated
her recommendation, coming from the cardiology team, that he go to the rehabilitation
program. She acknowledged that it might be hard for him, but emphasised that it was
important. Because of his intense sadness, she asked George whether he would like a visit
from a psychologist who she knew could help him, and he agreed. In parting, she indicated
that she would come and see him again tomorrow, and would then see him on his first day at
the rehabilitation programme. She suggested she organise transport for the first day, which
he accepted.
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Adding Psychological Intervention to
High-Tech Care for Patients with
Implantable Cardioverter Defibrillators
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 982
ICD Patient Referral and Case Conceptualization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
Psychological Intervention Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 983
Cognitive-Behavioral Therapy Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 985
Traditional Cognitive-Behavioral Interventions (3–12 Sessions) . . . . . . . . . . . . . . . . . . . . . . . . . . . 987
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 991
Educational Resources for Clinicians, ICD Patients, and Their Families . . . . . . . . . . . . . . . . . . . . . . 992
Support Programs for Young ICD Patients and Their Families . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
Books . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 993
Abstract
Psychosocial challenges for ICD patients have been well established in research
and clinical practice. Anxiety secondary to disease management and/or fear of
ICD shock is among the most common concerns that lead to development and
maintenance of psychological distress in ICD patients. Researchers and clinicians
Keywords
ICD • Psychosocial treatment • Treatment • Intervention • Quality of life
Introduction
For patients with underlying cardiovascular disease, the confirmation of high risk for
sudden cardiac arrest, or survival thereof, can be profound, and their emotional
response may be further amplified by the need for an implantable cardioverter
defibrillator (ICD). ICD patients often describe initial feelings of confusion, disbe-
lief, fear, anger, frustration, and helplessness. For many, these initial emotions can be
intense but attenuate over time. However, in a subgroup of ICD patients, psycho-
logical symptoms persist or worsen and may lead to the development of clinically
significant anxiety (13–38 %), depression (10–41 %), and/or PTSD (21 %) (Sears
et al. 2009; Kapa et al. 2010). Patients and their families may also face additional
challenges related to cardiac disease management, medication adherence, fear of
ICD shock, body image concerns, fear of resuming intimacy, heightened feelings of
vulnerability, perceived loss/grief, inadequate social support, and end-of-life issues
(Sears and Conti 2002).
The need for routine assessment and treatment for these patients is clear, but
available and effective long-term management of psychological symptoms second-
ary to ICD implantation has been a challenge for healthcare providers. Over the past
two decades, a broad range of cognitive-behavioral, pharmacological, and
nontraditional (i.e., patient support groups, yoga, cardiac rehabilitation programs,
biofeedback) interventions have been developed for patients with ICDs and their
families (Dunbar et al. 2012). Technology-based treatments are also being increas-
ingly used to improve access to psychosocial care, particularly among underserved
patient populations (Bennett and Glasgow 2009). Nonetheless, practical consider-
ations for mental health providers remain about where, when, and which types of
interventions are most effective in ICD patients. The purpose of this chapter is to
highlight the evidence and breadth of empirically supported psychological treat-
ments for ICD patients and their families. Additional clinician resources and patient
education materials are provided at the end of the chapter.
Adding Psychological Intervention to High-Tech Care for Patients with. . . 983
The initial rationale and interest for psychological intervention for ICD patients were
strongly influenced by patients’ fear of ICD shock and the high rate of maladaptive
behavioral and psychosocial sequelae that emerge secondary to shock. Mowrer’s
two-factor theory of conditioned avoidance (Mowrer 1960) provides a theoretical
984 L. Rosman et al.
Fig. 1 Development of anxiety secondary to ICD shock. Note. HR heart rate. BP blood pressure
in ICD intervention research are generally small, which reduces researchers’ ability
to control for potential confounds or examine interaction effects. Small sample sizes
may also contribute to Type II errors (i.e., failing to statistically detect an effect when
one is actually present) and problems related to insufficient power in statistical
analyses to capture meaningful changes. Despite these challenges in regard to
research design and methods, the results from three decades of empirical research
are compelling and demonstrate an ability to reduce psychological distress and
improve quality of life in patients with ICD and their families (Dunbar
et al. 2012). For the purpose of this review, psychological interventions for ICD
patients and their families are broadly categorized as cognitive-behavioral, pharma-
cological, nontraditional, or technology-based treatments.
Table 1 Brief CBT interventions for common psychological symptoms in ICD patients
Behavioral or psychological
symptoms Suggested CBT intervention
Medication nonadherence Motivation interviewing, problem-solving techniques
Tobacco use or substance abuse Motivational interviewing
Provide referral for tobacco cessation or substance abuse
counseling, if indicated
Poor knowledge about ICD and Review established mortality benefit of ICD
ICD shock vs. medications alone from large clinical trials
Provide patient handout on How to Respond to ICD Shock
(see end of chapter)
Review shock plan verbally with patient and family
Concerns about sexual activity with Engage medical providers to confirm safety of sexual
an ICD activity with patient
Provide patient handout on Sexual Activity in ICD
Patients (see end of chapter). Review verbally with patient
Concerns about ICD device recall Provide patient handout on How to Respond to a Device
Recall (see end of chapter). Review verbally with patient
Review low probability of device malfunction and
extensive monitoring of device reliability
Family expresses questions or Acknowledge, normalize, and discuss the relatively
concerns about patient’s ICD increased stress in ICD partners and families
Provide patient handout on Coping with My Partners ICD
(see end of chapter). Review verbally with patient
Mild, intermittent depressive Behavioral activation. Provide referral for further
symptoms psychological treatment, if indicated
Weight management Introduce goal setting as a strategy to make small,
manageable changes in daily food consumption. Provide
referral to nutritionist (if available). Ask cardiologist to
prescribe a walking program or referral to cardiac
rehabilitation program, if indicated
Physical inactivity Review medical chart or consult with cardiologist about
activity restrictions
Introduce goal setting as a strategy to make small,
manageable increases in daily physical activity
Encourage use of personal activity trackers like Fitbit
Pharmacological Interventions
The clinical reality of a distressed patient on a cardiology consultation service with
relatively few specialty mental health providers in immediate availability often
prompts a call for psychopharmacological intervention. Research has demonstrated
that psychological distress is particularly pronounced in the 30 days following an
ICD shock event (Mark et al. 2008), and attending cardiologists often feel the need to
start psychiatric medications. However, psychopharmacological treatments for ICD
patients have not been the subject of any clinical trials to date. Small-scale trials
appear to be underway, but no published information on this patient population is yet
available.
Nonetheless, a great deal of research has focused on the cardiovascular side
effects of psychotropic medications. See Beach et al. (2013) for a detailed review
of cardiovascular risks associated with psychotropic medications. Overall, results
from these studies suggest that certain classes of medications should be avoided in
cardiac patients due to their risk for increased heart rate (sinus tachycardia) and/or
problems with cardiac conduction or rhythm disturbance (O’Brien and Oyebode
2003). Tricyclic antidepressants, typical and atypical antipsychotics, and
Adding Psychological Intervention to High-Tech Care for Patients with. . . 989
Nontraditional Interventions
Support groups. The rapid acceleration of the use of the ICD over the past decade has
produced new needs for the management of patients. Efficient methods of providing
patient education and support have been employed. Many of these methods are
reasonable to support the health literacy and adjustment of ICD patients and families.
The most common approach by medical treatment centers has been the initiation of
support groups. ICD support groups can take many forms ranging between provider-
led question and answer groups or didactic classes, to patient-led groups encourag-
ing emotional expression or peer-to-peer support. The efficacy or effectiveness of
ICD support groups has not been sufficiently studied (Sears and Conti 2002), but
they likely activate the known benefits of group interventions such as universality of
concerns, generation of hope, information sharing, and acquisition of coping skills
via vicarious learning. Despite the lack of clinical studies, support groups encourage
attention to the psychological adjustment of the novel concerns that many ICD
patients can face and likely provide at least some support to many patients.
Yoga and mindfulness. The availability and utility of complementary and alterna-
tive approaches, such as yoga and mindfulness, to address the emotional needs of ICD
patients represent a new avenue of potential benefit to aid ICD patient adjustment.
Initial results from research studies suggest that yoga interventions may be beneficial
for reducing psychological distress in ICD patients. Moreover, a trial of randomized
46 patients to an 8-week group-based yoga program vs. usual care (Toise et al. 2014)
demonstrated a significant reduction in shock anxiety that was maintained 6 months
after the intervention. The yoga group also showed benefit in yoga-specific metrics
such as greater self-compassion and mindfulness. Further, an intriguing finding
990 L. Rosman et al.
platforms are already available and provide patients with the opportunity to learn
about and track their cardiac functioning. This reality has great promise for increased
access and availability of information tempered by the validity and biases of the
provider of the information. Table 3 presents a list of websites developed by medical
device companies and patient groups that attempt to address the informational needs
of ICD patients.
The possibilities for mobile phone-based applications for ICD patients are
encouraging. The ubiquitous presence of mobile phones could provide the ICD
patient with personal medical information, coping support, or diagnostic discrimi-
nation. At present, ICD patients cannot access their own device data via the mobile
phone. However, smartphone applications such as AliveECG and Instant Heart Rate
can monitor heart rate and provide real-time EKG. For the right patient, this could be
a reassuring strategy to combat catastrophic cognitions related to perceived risk of
imminent danger, death, or ICD shock. However, clinical judgment should be
exercised as this type of strategy could be contraindicated for some patients. For
example, patients exhibiting symptoms of somatic hypervigilance may become
preoccupied with their cardiac function and spend an excessive amount of time
examining their heart rate, leading to increased behavioral dysfunction. Non-ICD-
specific sources of mobile mental health treatment are also available and offer
tremendous benefit to ICD patients. The popular “PTSD Coach,” created by the
US Veterans Administration Hospital, represents this kind of innovation. Collec-
tively, e-health is a frontier that will likely continue to attract ICD patients and may
have some clinical value. Continued research is needed to validate the most effica-
cious and beneficial aspects of these technologies.
Conclusion
This chapter reviewed the extant literature on psychosocial interventions for patients
living with ICDs. Overall, these data empirically demonstrate the value of psycho-
social treatments for ICD patients. Moreover, evidence from randomized clinical
trials supports the feasibility and efficacy of various treatment modalities to improve
patient’s emotional well-being and reduce ICD-specific distress. Innovative technol-
ogies may also help providers research previously underserved populations and
increase patient’s access to information about their device and ICD shock, participate
in online peer support groups, and engage in treatment via web-based psychological
interventions. Nonetheless, efforts to translate research findings into actionable
992 L. Rosman et al.
Cardiology Patient Pages. Cardiology patient pages are free and available online
from Circulation, a leading, peer-reviewed cardiology journal. They are specifically
written in patient-friendly language to address frequently reported questions and
concerns from ICD patients and their families. Go to http://circ.ahajournals.org/ for
more information or to print patient handouts listed in the chart below.
ICD Shock Plans. Websites that provide free printable ICD shock plans are listed
below. Professionally printed patient shock plan brochures can also be requested
from device manufacturers.
Boston scientific – my shock plan
http://www.bostonscientific.com/lifebeat-online/live/my-shock-plan.html
Device-advice.org
http://www.device-advice.org/shock-plan.htm
Camp Odayin
Supportive camp experiences and community building opportunities for young
people with heart disease and their families. Located in Stillwater, MN, this camp is
open to all patients and families coping with heart disease, including ICD patients.
They offer support programs throughout the year and have a scholarship program to
help with program costs. For more information, go to http://campodayin.org/.
University of Michigan Young ICD Connection Conference
Location: Ann Arbor City Club, Ann Arbor, MI
Contact: Donna Wilkin (734) 936-9218 email: [email protected]
Books
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Adding Psychological Intervention to High-Tech Care for Patients with. . . 995
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 998
Psychological Responses to Acute Cardiac Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
Anxiety after Acute Coronary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
Depression after Acute Coronary Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1000
Anxiety and Depression in Patients Undergoing Revascularization . . . . . . . . . . . . . . . . . . . . . . 1001
Denial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
Post-traumatic Stress Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1002
Delirium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Cognitive Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1003
Identification and Assessment of Psychological Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Recognition of Anxiety and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1004
Screening for Depression and Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1005
Screening for Other Conditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
Managing Psychological Responses of Patients in Hospital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
Modifying Negative Perceptions and Beliefs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1006
Providing Information to Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007
Discussing Patients’ Fears and Concerns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1008
Fostering Optimism and Enhancing Self-Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1009
Psychological Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1010
Collaborative Care Programs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
Pharmacological Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
Supporting Partners of Cardiac Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1011
The Multidisciplinary Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Discharge Planning and Follow-Up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Primary Care Professionals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1012
Cardiac Rehabilitation and Secondary Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1013
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1014
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1015
Abstract
Many patients experience significant psychological distress after admission to
hospital following acute coronary syndrome or to undergo percutaneous coro-
nary angioplasty, coronary artery bypass surgery, or other cardiac surgery.
Anxiety and depression are common emotional responses to these acute cardiac
events and may be preexisting conditions. Symptoms of cognitive impairment,
post-traumatic stress disorder, delirium, and major denial may also be present in
hospitalized cardiac patients. Although gaps in knowledge exist concerning the
impact and course of these disorders, there is now sufficient evidence showing
their detrimental effects upon patients’ recovery. The importance of early
detection and management of depression, in particular, is essential to help
prevent unwarranted psychological disability. Screening of patients is
recommended in hospital and at appropriate intervals during follow-up. Brief
screening tools are available which can be routinely administered. In addition,
doctors and other health professionals should be aware of the clinical features of
common psychological reactions of hospitalized patients to ensure prompt
recognition and assessment. The important role of doctors in the clinical man-
agement of patients with anxiety and depression symptoms is stressed. However,
referrals for the management of acutely distressed patients should be made to
health professionals who have specific training in the treatment of psychological
problems. Past studies have reported benefits from some depression treatments,
especially those based on cognitive behavioral therapy. However, further rigor-
ous research is required to develop, implement, and evaluate interventions for
the early alleviation of symptoms of depression and other psychological condi-
tions. Coordinated care of patients by a multidisciplinary team is essential.
Encouragement of patients to attend a group cardiac rehabilitation program is
highly recommended.
Keywords
Psychology • Psychiatry • Cardiac patient • Anxiety • Depression • Acute
coronary syndrome • Coronary artery bypass graft surgery • Cardiology • Hos-
pital • Cardiac rehabilitation
Introduction
et al. 1968, 1969; Goble et al. 1963; Goble 1983; Wynn 1967). Their insightful
clinical reports describing the symptoms, course, and treatment of anxiety and
depression, in particular, have been frequently cited in the literature over the past
50 years.
The present chapter focuses on psychological and psychiatric issues of cardiac
patients in hospital following ACS or to undergo coronary artery bypass graft surgery
(CABGS) or percutaneous coronary intervention (PCI). It provides a brief overview
of the typical symptoms, course, and impact of anxiety, depression, and denial. Other
psychological complications, including post-traumatic stress disorder, delirium, and
cognitive impairment, are also briefly described. Screening to enable early detection
of anxiety, depression, and other conditions is addressed. Issues concerning the
clinical management of cardiac patients in hospital are discussed, including the
importance of exploring and modifying negative beliefs, providing clear explanations
about the illness and the recovery process, and addressing patients’ fears and con-
cerns. Interventions for the management of depression, including pharmacological
treatment, are reviewed. The need for a multidisciplinary approach to patient care is
highlighted. The importance of careful discharge planning and follow-up is stressed,
including referral to cardiac rehabilitation. Finally, recommendations are made
concerning urgently needed research into the prevention and management of dis-
abling conditions, especially depression.
Earlier chapters of this handbook cover anxiety, depression, and other psycho-
logical conditions in greater depth, including their prevalence, long-term impact
upon mortality and morbidity, and possible mechanisms linking these conditions to
cardiac outcomes.
Admission to a coronary care unit (CCU) often leads to acute anxiety and fear,
especially the fear of dying. Other common fears of patients in the CCU include a
further cardiac event, invalidism, unemployment, loss of income, and family
distress. The CCU is a highly technological setting which is potentially frightening
to critically ill patients (Sanders and Cassem 1993). The presence of cardiac
monitoring devices and witnessing a cardiac arrest may exacerbate anxiety in
some patients.
Anxiety is usually the immediate emotional response to an AMI and ACS
(An et al. 2004), commonly peaking on admission to the CCU and again upon
transfer to the ward (Stern 1985). Although anxiety often decreases spontaneously
over time after hospital discharge, high levels of anxiety can persist for 1 year or
more (Lane et al. 2002). The prevalence of anxiety following AMI has been
reported to be between 24 % and 31 % (Frasure-Smith et al. 1995), with women
experiencing higher levels of anxiety than men (An et al. 2004).
1000 M.U. Worcester
Anxiety is the dominant feeling before coronary artery bypass graft surgery
(CABGS) (Duits et al. 1998) and has been reported to be present in 34 % of
patients, especially younger patients (Krannich et al. 2007). Among preoperative
concerns are fears relating to the impending surgery, postoperative pain, and having
a fatal heart attack prior to surgery. After surgery some patients react with a
decrease in anxiety (Krannich et al. 2007), whereas others exhibit increased feel-
ings of anxiety and depression (Duits et al. 1998).
The prevalence of depression postoperatively has been estimated to be between
19 % and 61 % (Pignay-Demaria et al. 2003). Connerney and colleagues found that
20 % of patients met the criteria for major depressive disorder after CABGS and
had higher rates of nonfatal cardiac events during the first 12 months after surgery
(Connerney et al. 2001). The incidence of clinical depression in one study of
women undergoing CABGS was 36 % before hospital discharge, with 9.3 %
meeting criteria for major depression (Doering et al. 2006).
High levels of preoperative depression ranging from 23 % to 47 % have been
reported (Pignay-Demaria et al. 2003; Krannich et al. 2007). Patients with a prior
history of depression are at greater risk of postoperative depression (McKhann
et al. 1997; Timberlake et al. 1997). Unfortunately the patient’s preoperative
depression status has not always been taken into account. Thus, the frequency of
new depression after CABGS is unknown (Selnes et al. 1999).
Depression is an important independent risk factor for adverse outcomes fol-
lowing CABGS, including further events (Connerney et al. 2001). Contrary to other
reports (O’Neil et al. 2010), depression was not found to predict resumption of work
in one recent study, although depressive symptoms did predict a slower return to
work (Worcester et al. 2014).
Relatively few studies have investigated in-hospital emotional responses to
percutaneous coronary intervention (PCI), largely because of patients’ short hospi-
tal stays. Patients’ concerns usually relate to the outcome of the procedure, includ-
ing a fear that surgery might be required. A high prevalence of anxiety and
depression has been found in patients prior to PCI, with relief of angina symptoms
1002 M.U. Worcester
and improved psychosocial functioning in most patients after PCI (White and
Frasure-Smith 1995). However, the procedure can be distressing to some patients,
and high expectations before PCI can set patients up for depression or anxiety
afterwards (Fitzgerald et al. 1989).
Denial
Denial is the most common defense mechanism used by cardiac patients to cope
with symptoms of anxiety and depression (Stenstrom et al. 2005). Deniers tend to
respond to an acute cardiac event by negating or minimizing its severity, symptoms,
and possible outcomes, including death or invalidism. Denial of fear is common,
with deniers often projecting their fears onto others or displacing their symptoms to
indigestion, influenza, or other organs. Denial can be expressed verbally, behav-
iorally, or both. For most deniers, denial has been a lifelong defense.
Denial may serve either a functional or dysfunctional role, with both excessive
and insufficient levels of denial leading to unacceptable outcomes (Dimsdale and
Hackett 1982). Early after AMI, arrhythmias and other complications can occur
which worsen the patient’s prognosis. Since strong denial lessens these responses,
chances of survival may improve for the first 48–72 hours (Levine et al. 1987).
Unfortunately, patients with a high level of denial typically disregard their cardiac
symptoms and delay seeking medical treatment (Stenstrom et al. 2005). Denial is
also associated with decreased retention of information (Fowers 1992),
nonadherence to advice (Levine et al. 1987; Stenstrom et al. 2005), and
nonattendance at cardiac rehabilitation (Stenstrom et al. 2005).
Denial is common in the immediate postoperative period among CABGS
patients who have a short history of angina and who undergo emergency surgery
with little time to adjust (Pignay-Demaria et al. 2003). Interestingly, high levels of
denial shortly after CABGS were associated in one study with less anxiety and
depression and better psychosocial adjustment postoperatively (Folks et al. 1988).
Acute cardiac events can cause significant distress and may trigger symptoms of
post-traumatic stress disorder (PTSD) (Alonzo 2000) within days of AMI or
CABGS (Kutz et al. 1994). Rates of PTSD after AMI have been reported to
range between 8 % and 24 % (Kutz et al. 1994).
Preexisting PTSD may be present in some patients following the accumulation
of previous traumatic events (Alonzo 2000). The diagnosis of PTSD requires the
patient’s response to a life-threatening event to include severe helplessness, fear, or
horror. Reexperiencing symptoms is a central feature of PTSD, provoking intense
negative emotions associated with the initial traumatic event (Alonzo 2000).
In cardiac patients, PTSD is associated with increased levels of anxiety, depres-
sion, hostility, and overall psychopathology. PTSD symptoms are strongly
In-Hospital Management of Psychological Responses to Acute Cardiac Events 1003
correlated with failure to return to work (Kutz et al. 1994), poor overall quality of
life (Shemesh et al. 2001), and nonadherence (Alonzo 2000). Patients who are
traumatized may avoid being reminded of their acute event by not taking their
medication or delaying seeking medical attention (Shemesh et al. 2001).
Delirium
Cognitive Impairment
There has been a robust debate in recent years concerning the desirability of routine
screening of patients for depression after an acute cardiac event (Whooley 2009;
Thombs et al. 2008). Although no clinical trials have assessed whether screening
improves depressive symptoms or cardiac outcomes in patients with cardiovascular
disease (Thombs et al. 2008), the current consensus of expert opinion is that
screening for depression is recommended because of the negative impact of depres-
sion upon outcomes, including quality of life and adherence (Lichtman et al. 2008).
Routine screening tests should identify patients who require further assessment,
treatment, or referral to a mental healthcare provider (Lichtman et al. 2008). The
use of the Patient Health Questionnaire-2 (PHQ-2) (Kroenke et al. 2003) has been
advocated as a first step in screening for depression. If there is an affirmative answer
to either or both questions, all 9 PHQ items should be asked (Kroenke et al. 2001).
Screening for depression is also recommended for patients about to undergo cardiac
surgery. In addition, a past history of depression should be explored.
Given the potentially negative impact of anxiety on mortality and quality of life
(Frasure-Smith et al. 1995; Moser and Dracup 1996; An et al. 2004), early screen-
ing for anxiety is also important so that it can be effectively managed. Possible
screening tools include the seven-item anxiety subscale of the Hospital Anxiety and
Depression Scale (HADS) (Zigmond and Snaith 1983), although the development
of briefer questionnaires to measure levels of anxiety has been recommended
(O’Brien et al. 2001).
For routine screening to be useful, effective management protocols need to be
devised (Thompson and Froelicher 2006) that clearly set out who should undertake
the screening, how results should be handled, and who should make decisions about
treatment. Importantly, the availability of well-trained professionals to provide
psychological and psychiatric care should be guaranteed (Luttik et al. 2011). A
recent study confirmed that systematic screening for depression by nurses was
feasible and not markedly resource intensive (Sowden et al. 2010).
Earlier chapters cover in greater detail the debates concerning the desirability of
routine screening and the choice of screening tools.
1006 M.U. Worcester
expectations have been associated with a slower return to work and poorer occu-
pational adjustment (Petrie et al. 1996; Maeland and Havik 1987). Further, patients
with more optimistic expectations that their illness was amenable to cure or control
have been found to be more likely than others to attend cardiac rehabilitation (Petrie
et al. 1996). Improving the accuracy of risk perceptions might help to reduce
unnecessary cardiac anxiety and invalidism in some patients while prompting
favorable behavior change in others (Broadbent et al. 2006).
Many PCI patients believe that their illness is not serious and that after their
procedure they are cured of coronary artery disease. As a result, such patients may
fail to adhere to medical and lifestyle advice. Such underestimation of the signif-
icance of the PCI procedure might be reinforced by short hospital stays (White and
Frasure-Smith 1995). The reality of the underlying disease and prognosis must be
discussed early with PCI patients in order to correct any misconceptions (Corones
et al. 2009).
Many patients demonstrate a limited awareness of major risk factors for cardio-
vascular disease. Further, they frequently attribute their illness to external factors,
commonly work or other stress (Maeland and Havik 1987; Thompson and Lewin
2000) and fail to recognize the causal role of lifestyle and physiological risk factors
(Murphy et al. 2005). Investigation of patients’ perceptions of causal factors is
essential in order to correct any erroneous beliefs, since faulty attributions about
causal factors can lead to nonadherence (Maeland and Havik 1987). Attitudes
toward return to work need to be carefully explored in case reluctance to resume
is based upon patients’ ill-founded fears about the role of work stress in causing
their heart disease.
A systematic review of interventions to change maladaptive illness beliefs in
cardiac patients found that some interventions were successful. Cognitive behav-
ioral interventions appeared to be the most consistently effective (Goulding
et al. 2010). For example, a brief hospital-based intervention using cognitive
behavioral therapy (CBT) was successful in changing illness perceptions after
AMI and in improving recovery (Petrie et al. 2002). A later replication study
found that the intervention was also effective in patients with ACS, those with
repeat MI (Broadbent et al. 2009a), and spouses (Broadbent et al. 2009b). Beliefs
should be explored and modified early in the recovery process to avoid protracted
disability at a later stage.
Patients require simple and clear explanations of the acute event, symptoms, and
projected treatment, including investigations or procedures. The typical recovery
process should be outlined and specific advice provided about resumption of
activities of daily living. The chronic nature of cardiovascular disease should be
emphasized. Modification of risk factors to reduce the risk of further events should
be discussed. Secondary prevention programs using behavioral techniques, includ-
ing the Women’s Initiative for Non-Smoking (WINS) trial, have been successfully
1008 M.U. Worcester
In addition to providing patients with clear explanations about their illness, careful
listening to their concerns can alleviate psychological distress (Pignay-Demaria
et al. 2003). Early discussion of the patient’s fears pays enormous dividends in
terms of the prevention of anxiety and unwarranted invalidism (Goble et al. 1963).
Fear of death or a further event is present in most patients in the CCU and ICU.
However, as previously noted, patients are generally reluctant to initiate discussion
of their fears or to ask for reassurance directly (Freedland et al. 1992). Thus, the
responsibility for enquiring about fears lies with the doctor or other health profes-
sional. Simply asking patients if they are frightened can help to uncover anxiety not
otherwise apparent. Initial denial is usual, but once rapport has been established,
admission of fear becomes more common. Depression can be detected from careful
history taking and observation. Simple questions to open the issue of emotional
distress but without using the word “depression” are recommended (Lesperance
and Frasure-Smith 2000).
It is obviously important not to foster iatrogenic anxiety by poor communication,
including making over-guarded statements or giving vague advice (Goble 1983;
Thompson and Lewin 2000). Medical advice, if not given with great care and
In-Hospital Management of Psychological Responses to Acute Cardiac Events 1009
recognition of what is already believed by the patient, may harm rather than help the
patient and considerably heighten anxiety (Goble et al. 1963). The daily medical
round can create anxiety in patients. If doctors discuss the patient’s condition at the
bedside, terminology and prognostic information will be heard but probably not
understood by the patient. It is preferable for the medical team to conduct such
discussions elsewhere. At the bedside, reassurance of progress is more appropriate.
It is also an opportunity to invite patients to ask questions about any matters which
are concerning them. It can be extremely helpful to reassure patients that “the worst
is over” after their first day in hospital. In addition to explanation and discussion,
normalization of emotional responses is important. Patients need reassurance that
an anxious or depressed mood is common after an acute cardiac event and is usually
transient (Goble et al. 1989; Thompson and Lewin 2000).
Cardiac rehabilitation should begin on day 1 of the patient’s admission. Because the
fear of weakness and disability is present in most patients, early ambulation is
essential to dispel these fears, followed by increasing mobilization to reassure
patients that they are improving and that physical activity is safe. Active mobiliza-
tion is especially helpful for patients with depressive symptoms (Pignay-Demaria
et al. 2003).
Forewarning patients about what to expect as they transition to the next stage of
recovery can help them to avoid unnecessary emotional distress. In particular,
educating patients about what to expect after discharge from hospital helps to
decrease depression and anxiety. It can be especially important to forewarn patients
that a depressed mood is common during convalescence and that such “homecom-
ing depression” should be regarded as a normal, transient response (Thompson and
Lewin 2000; Utriyaprasit et al. 2010). In one study, patients who received an
intervention of education and emotional support soon after their admission to the
CCU were found to be better prepared and more positive about their homecoming
and had significantly less anxiety and depression (Thompson and Meddis 1990a).
Similarly, education delivered prior to revascularization can have a positive effect
upon recovery, leading to less anxiety, greater self-confidence, more realistic
expectations, and increased compliance with medical advice (Veronovici
et al. 2014; White and Frasure-Smith 1995).
Observing other patients who have undergone the same procedure or experi-
enced a similar event can raise a patient’s expectations of mastering similar
situations. The vicarious experience of observing discharged patients leading active
lives can increase self-efficacy in hospitalized patients concerning their own ability
to engage in post-discharge activities. According to anecdotal evidence, patients
about to undergo surgery benefit from a visit by a patient who is recovering well
from recent CABGS. Similarly reassuring is a visit by inpatients to the cardiac
rehabilitation program, if sited within the hospital. Such visits reassure patients who
are about to undergo CABGS as well as those who are still in hospital recovering
1010 M.U. Worcester
from surgery. A trial of an intervention linking former patients who had recovered
from cardiac surgery with patients about to undergo cardiac surgery showed that the
intervention significantly reduced anxiety, improved self-efficacy expectations, and
accelerated recovery (Parent and Fortin 2000). In another study, patients randomly
assigned prior to surgery to a room with a postoperative roommate were less
anxious preoperatively, more ambulatory postoperatively, and discharged
1.4 days earlier than patients assigned to a room with a preoperative roommate
(Kulik and Mahler 1987).
Psychological Interventions
There are relatively few controlled studies of interventions which specifically aim
to reduce psychological distress in cardiac patients in hospital. Most are offered
after patients’ discharge from hospital or preoperatively to patients awaiting
CABGS. Because positive expectations have been associated with favorable out-
comes, a randomized controlled trial is currently in progress to determine whether a
brief psychoeducational intervention can optimize patients’ expectations prior to
CABGS (Laferton et al. 2013).
CBT, psychotherapy, and interpersonal psychotherapy have been recommended
as suitable approaches for managing depression in cardiac patients, either alone or
in combination with pharmacological therapies (Lichtman et al. 2008). However,
nearly all randomized controlled trials of depression treatments to date have been
conducted in patients without coronary heart disease (Lett et al. 2005). Some CBT
interventions, such as that implemented in the ENRICHD trial, have successfully
reduced depressive symptoms in cardiac patients (Berkman et al. 2003). However,
in that study the relative improvement in the intervention group compared with the
usual care group was less than expected due to substantial improvement in usual
care patients. A brief cognitive behavioral intervention delivered prior to CABGS
demonstrated small but significant differences in depression, but not anxiety, in
favor of patients receiving the HeartOp program (Furze et al. 2009). A recent
Australian trial of a group secondary prevention program based on CBT and
motivational interviewing, delivered 7–8 weeks after hospital discharge, led to
significantly greater improvement in depressive symptoms in depressed patients
(Turner et al. 2014).
A meta-analysis of psychological treatments for cardiac patients offered in
addition to usual care found a reduction of 27 % in mortality over 2 years in men,
but there were no mortality benefits for women. Studies included in this meta-
analysis in which patients were recruited at least 2 months after a cardiac event
showed much greater mortality benefits from psychological treatments than
patients receiving interventions which took place soon after the cardiac event
(Linden et al. 2007). Interventions for depression management which start later
might demonstrate greater effects, since they would have excluded patients whose
depression had already remitted spontaneously by the time of recruitment to the
study, or those who responded well to usual care (Schrader et al. 2004).
In-Hospital Management of Psychological Responses to Acute Cardiac Events 1011
Collaborative care programs have been recently introduced to improve the coordi-
nated management of depression in cardiac and other patients. Such programs
include systematic psychiatric assessment and the use of a nonphysician care
manager to monitor symptoms, treatment interventions, specialist-provided
stepped-care recommendations, and care coordination (Huffman et al. 2014;
Rollman et al. 2009). Collaborative care interventions for psychiatric disorders
are cost effective and are reported to be successful in improving outcomes
(Huffman et al. 2014). A recent trial of collaborative care for depressed cardiac
patients found significantly increased rates of appropriate care for the intervention
group, defined as either a discharge prescription of an antidepressant at a clinically
effective dose by the time of discharge from hospital or referral to a mental health
provider for psychotherapy (Huffman et al. 2011). A telephone-delivered collabo-
rative care program for CABGS patients also led to improved mood symptoms at
the 8-month follow-up (Rollman et al. 2009).
Pharmacological Treatment
The general practitioner and other primary care professionals are usually responsi-
ble for the long-term monitoring and management of patients’ mental health, with
referral to specialists, as required. It is critically important for hospital staff to liaise
In-Hospital Management of Psychological Responses to Acute Cardiac Events 1013
with these practitioners to ensure the coordinated care of patients after their
discharge from hospital (Goble and Worcester 1999), especially patients with
persistent depression (Rollman et al. 2009). Patients with high levels of denial
also need to be regularly monitored. Such patients commonly fail to adhere to
medical advice and ignore cardiac-related symptoms. They are likely to be among
those patients experiencing a further event who die before reaching hospital
(Carney and Jaffe 2002). Patients who successfully concealed their depressive
symptoms initially become more vulnerable once their defense of denial collapses.
Patients with PTSD also need ongoing monitoring. They typically avoid reminders
of traumatic events, including symptoms associated with their acute cardiac event
(Doerfler and Paraskos 2004).
Several guidelines recommend that ACS and CABGS patients should attend a
cardiac rehabilitation program soon after discharge from hospital (WHO Expert
Committee 1993; Wenger et al. 1995; Goble and Worcester 1999; Perk et al. 2012).
Numerous benefits of cardiac rehabilitation have been demonstrated (Wenger
et al. 1995). While other effective cardiac rehabilitation models have recently
been developed, a group program has important advantages. Exercise can help to
reduce depressive symptoms in patients (Lett et al. 2005), as can participation in a
group where patients recognize that others are experiencing similar emotions and
that their own responses are not unique. Patients also gain by observing a rapid
recovery in others (Goble et al. 1989; Thompson and Lewin 2000). Importantly,
cardiac rehabilitation programs provide significant social support during convales-
cence. Further, given the increasingly shortened hospital stays after ACS and
CABGS, outpatient cardiac rehabilitation programs offer an opportunity for
reinforcing education and providing more comprehensive and individualized
advice. Cardiac rehabilitation can also be an effective launching pad for secondary
prevention of CVD.
Further screening of patients for depression after hospital discharge has been
strongly recommended (Parashar et al. 2006). While spontaneous improvement
occurs in some patients, depression worsens in others or emerges only during
convalescence. Therefore resources for screening and treating depression might
be best directed at patients who are depressed during convalescence rather than in
hospital (Schrader et al. 2004). Rescreening patients for depression can be easily
incorporated into the routine of cardiac rehabilitation.
Referrals to cardiac rehabilitation need to be organized efficiently before
patients leave the hospital. A designated cardiac rehabilitation coordinator is
essential. Unfortunately, participation rates in many countries are disappointingly
low (Goble and Worcester 1999; Balady et al. 2011). However, a recent study found
that by adhering to best practice guidelines, some common barriers to attendance
were overcome, with a high attendance rate of 72 % being achieved (Higgins
et al. 2008). The policy in Australia of automatic referral to a cardiac rehabilitation
1014 M.U. Worcester
Conclusions
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Mindfulness- and Meditation-Based
Healthcare Approach Implications
for Prevention, Detection, and Treatment
in Cardiology
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
Yeshi Dhonden Does Rounds: By Richard Selzer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1024
The Relevant Evidence Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Phases in the Development of the Evidence Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1026
Levels of Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
General Introduction to Mindfulness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
What Is Mindfulness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1027
Mindfulness, Therapies, and Meditation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1029
Cultural Congruence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1031
Mindfulness for the Practitioner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1032
Mindfulness and Meditation for People at Risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
Smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1033
High Cholesterol and Otherwise Abnormal Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1034
Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035
Overweight or Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1035
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1036
Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1036
G. Meadows (*)
Department of Psychiatry, Monash University, Clayton, VIC, Australia
School of Global and Population Health, The University of Melbourne, Clayton, VIC, Australia
e-mail: [email protected]
F. Shawyer
Department of Psychiatry, Monash University, Clayton, VIC, Australia
e-mail: [email protected]
Abstract
The chapter opens with an account from an American physician of a meeting
with a Tibetan Buddhist practitioner for whom mindful awareness was central to
resolving a cardiological diagnostic question, and rather more than that.
After a note on the quality and level of evidence base in this area, a general
introduction to mindfulness and other meditative traditions follows, including
something of relevant history and cultural origins and the range of interventions
that may be considered related in contemporary healthcare.
The role of mindfulness- and meditation-based approaches will briefly be
considered as they may be relevant for the practicing clinician and as they have
been introduced into a number of medical educational settings.
This leads to considering the role of mindfulness-based interventions in
reducing risk factors (Yusuf et al. Lancet 364(9438):937–952, 2004), particu-
larly behavior and lifestyle factors but also psychiatric disorders, particularly
depression (Rosengren et al. Lancet 364(9438):953–962, 2004) as shown sub-
stantially to influence risk for cardiac conditions.
In the context of treatment of specific cardiac disorders, studies that involve
the application of mindfulness- or meditation-based approaches will be
considered.
As the chapter considers specific disorder contexts, there will in each case be
a drawing of the evidence together by the authors into some suggestions for how
mindfulness-based interventions may be relevant for clinical management.
Keywords
Mindfulness • Yoga • Meditation • Heart disease • Buddhist philosophy • Bible •
Risk factors • Hypertension • Overweight • Obese
Introduction
On the bulletin board in the front hall of the hospital where I work, there appeared
an announcement. “Yeshi Dhonden,” it read, “will make rounds at six o’clock on
the morning of June 10.” The particulars were then given, followed by a notation:
“Yeshi Dhonden is Personal Physician to the Dalai Lama.” I am not so leathery a
skeptic that I would knowingly ignore an emissary from the gods. Not only might
Mindfulness- and Meditation-Based Healthcare Approach Implications for. . . 1025
such sangfroid be inimical to one’s earthly well-being, it could take care of eternity
as well. Thus, on the morning of June 10, I join the clutch of whitecoats waiting in
the small conference room adjacent to the ward selected for the rounds. The air in
the room is heavy with ill-concealed dubiety and suspicion of bamboozlement. At
precisely six o’clock, he materializes, a short, golden, barelly man dressed in a
sleeveless robe of saffron and maroon. His scalp is shaven, and the only visible hair
is a scanty black line above each hooded eye. He bows in greeting while his young
interpreter makes the introduction. Yeshi Dhonden, we are told, will examine a
patient selected by a member of the staff. The diagnosis is as unknown to Yeshi
Dhonden as it is to us. The examination of the patient will take place in our
presence, after which we will reconvene in the conference room where Yeshi
Dhonden will discuss the case. We are further informed that for the past two
hours Yeshi Dhonden has purified himself by bathing, by fasting, and by
prayer. I, having breakfasted well, performed only the most desultory of ablutions,
and given no thought at all to my soul, glance furtively at my fellows. Suddenly, we
seem a soiled, uncouth lot.
The patient had been awakened early and told that she was to be examined by a
foreign doctor and had been asked to produce a fresh specimen of urine, so when we
enter her room, the woman shows no surprise. She has long ago taken on that
mixture of compliance and resignation that is the facies of chronic illness. This was
to be but another in an endless series of tests and examinations. Yeshi Dhonden
steps to the bedside while the rest stand apart, watching. For a long time he gazes at
the woman, favoring no part of her body with his eyes, but seeming to fix his glance
at a place just above her supine form. I, too, study her. No physical sign nor obvious
symptom gives a clue to the nature of her disease.
At last he takes her hand, raising it in both of his own. Now he bends over the bed
in kind of a crouching stance, his head drawn down into the collar of his robe. His
eyes are closed as he feels for her pulse. In a moment he has found the spot, and for
the next half hour, he remains thus, suspended above the patient like some exotic
bird with folded wings, holding the pulse of the woman beneath his fingers, cradling
her hand in his. All the power of the man seems to have been drawn down into this
one purpose. It is palpitation of the pulse raised to the state of ritual. From the foot
of the bed, where I stand, it is as though he and the patient have entered a special
place of isolation, of apartness, about which a vacancy hovers, and across which no
violation is possible. After a moment the woman rests back upon her pillow. From
time to time, she raises her head to look at the strange figure above her, then sinks
back once more. I cannot see their hands joined in a correspondence that is
exclusive, intimate, his fingertips receiving the voice of her sick body through the
rhythm and throb she offers at her wrist. All at once I am envious - not of him, not of
Yeshi Dhonden for his gift of beauty and holiness, but of her. I want to be held like
that, touched so, received. And I know that I, who have palpated a hundred
thousand pulses, have not felt a single one.
At last Yeshi Dhonden straightens, gently places the woman’s hand upon the
bed, and steps back. The interpreter produces a small wooden bowl and two sticks.
Yeshi Dhonden pours a portion of the urine specimen into the bowl, and proceeds to
1026 G. Meadows and F. Shawyer
whip the liquid with the two sticks. This he does for several minutes until a foam is
raised. Then, bowing above the bowl, he inhales the odor three times. He sets down
the bowl and turns to leave. All this while, he has not uttered a single word. As he
nears the door, the woman raises her head and calls out to him in a voice at once
urgent and serene. “Thank you, doctor,” she says, and touches with her other hand
the place he had held on her wrist, as though to recapture something that had visited
there. Yeshi Dhonden turns back for a moment to gaze at her, then steps into the
corridor. Rounds are at an end.
We are seated once more in the conference room. Yeshi Dhonden speaks now for
the first time, in soft Tibetan sounds that I have never heard before. He has barely
begun when the young interpreter begins to translate, the two voices continuing in
tandem - a bilingual fugue, the one chasing the other. It is like the chanting of monks.
He speaks of winds coursing through the body of the woman, currents that break
against barriers, eddying. These vortices are in her blood, he says. The last
spendings of an imperfect heart. Between the chambers of her heart, long, long
before she was born, a wind had come and blown open a deep gate that must never
be opened. Through it charge the full waters of her river, as the mountain stream
cascades in the springtime, battering, knocking loose the land, and flooding her
breath. Thus he speaks, and is silent.
“May we now have the diagnosis?” a professor asks.
The host of these rounds, the man who knows, answers.
“Congenital heart disease,” he says, “inter ventricular septal defect, with resul-
tant heart failure.”
A gateway in the heart, I think. That must not be opened. Through it charge the
full waters that flood of her breath. So! Here then is the doctor listening to the
sounds of the body to which the rest of us are deaf. He is more than doctor. He is
priest.
I know. . . I know. . . the doctor to the gods is pure knowledge, pure healing. The
doctor to man stumbles, must often wound; his patient must die, as must he.
Now and then it happens, as I make my own rounds, that I hear the sounds of his
voice, like an ancient Buddhist prayer, its meaning long since forgotten, only the
music remaining. Then a jubilation possesses me, and I feel myself touched by
something divine.
From the late 1990s forward, work more specifically coheres around the term
“mindfulness.” This is an alignment with a very strong growth in the general
volume of research in this area. The strongest strands of work in this area are
with group-based meditation techniques, by way of variants on mindfulness-based
stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT).
Levels of Evidence
In the case of conditions that are established risk factors and relating levels of
evidence to the GRADE classification (Owens et al. 2010), then for some clinical
questions, the evidence may be approaching “high” levels. However, in much of
this literature, especially as the concentration moves to smaller bodies of published
work, the evidence levels encountered will be more in alignment with GRADE
definitions of moderate, low, or very low, and not uncommonly there is insufficient
evidence to reach a conclusion.
Systematic reviews, where they exist so providing the potential to lift evidence
into higher categories, often will feature studies going back many years and
publication bias as an influence on findings cannot be excluded. It is only since
2005 that the International Committee of Medical Journal Editors (ICMJE) deter-
mined not to publish trials other than those formally registered, and much of the
literature is not in the ICMJE journals. It is only since 2008 that the revised
declaration of Helsinki (World Medical Association 2013) required trial registra-
tion. A systematic review published in 2008 of this area concluded that “Most
clinical trials on meditation practices are generally characterized by poor method-
ological quality with significant threats to validity in every major quality domain
assessed.” Some 10 % of surveyed studies were considered as of good quality
(Ospina et al. 2008). So until there are appreciable bodies of work with improved
quality and accumulated since the 2005 and 2008 safeguards were put in place,
practice will often need to be conducted in the context of a somewhat limited
empirical evidence base.
What Is Mindfulness
History
What is a man, that myndeful thou art of him?
Wycliffe’s Bible, Psalm viii. 6
The first generally recognized occurrence of the word mindful in the English
language is in 1382 in Wycliffe’s Bible, specifically in Psalms where the question is
asked of God why he is “myndeful” of man; much later (1970), the New English
Bible renders this as “what is man that thou should remember him?” Used in
1028 G. Meadows and F. Shawyer
English, then, for several centuries reflected a quality of recollection, also heedful-
ness and acting with care. Since the late nineteenth century, the term mindfulness
has been the most common translation of the term from the Pali Buddhist scriptures
“sati.” The earlier English usage, often regarded as obsolete, nevertheless probably
has some influence over how the term typically is understood and interpreted.
Mindfulness-Based Approaches
Not all mindfulness approaches involve formal meditation, and not all meditation
involves promotion of mindfulness. Meditation-based approaches that may be
introduced into healthcare and which are mindfulness-based include MBSR,
MBCT, Vipassana, and Zen meditation among others. MBCT and MBSR both
are described as mindfulness-based and this is very clear in their structure. Both of
them usually are presented as group-based experiences. They share a common
format of 8 weeks of approximately 2-hour group sessions, often with a full day
of meditation offered at some point. In both, the early focus is strongly toward the
development of meditation practices and, through that and other elements of
homework, the incorporation of mindful presence into daily life. Later on in the
usual 8-week course, with the expectation of being able to build on some acquired
capacity for mindful awareness, the focus shifts more toward the employment of
mindful approaches to specific coping strategies or developing new habitual ways
of responding intended as health promoting. MBCT and MBSR both make use of
poetry to evoke and facilitate the development of mindfulness. Here they draw on
materials from various cultural sources ranging from the Persian poet Rumi to the
American poet Mary Oliver.
The richness of such poetry can vividly illuminate the key qualities of mindful-
ness and help inspire the possibility of a radical shift in perspective from the future-
oriented and often predominant “doing” mode (such as when problem solving,
making plans, and achieving goals) to “being” (allowing things to be as they are in
the present moment).
In MBCT, for example, this quality of acceptance is considered to be critical for
preventing relapse in recurrent depression. Allowing difficult feelings to remain in
awareness, just as they are, is an important alternative to the automatic response of
1030 G. Meadows and F. Shawyer
aversion which can easily become the first link in the chain of habitual ruminative
patterns of thinking that can then lead to relapse of depression (Segal et al. 2013).
There is a risk, however, that “acceptance” can imply for some a sense of passivity
and resignation (Segal et al. 2013), while, for others, the prospect of allowing
difficult emotions may be frightening (Shapiro 2001). “The Guest House” poem
by Rumi (Barks and Moyne 1997) can dramatically transform these reactions,
inspiring a profoundly different and warm-hearted stance of welcoming difficult
feelings as transient but honorable guests in one’s metaphorical “house.” Another
poem, “The Summer Day” by Mary Oliver (1990), powerfully expresses to partic-
ipants the importance of taking care of themselves, also critical for preventing
depressive relapse. By reminding us of our mortality and that we can choose how
we live our “one wild and precious life” (p. 60), this poem opens up the possibility
of getting off the treadmill of rules that seem to constrain life to a series of tasks and
obligations that “should” be done. “Wild Geese,” also by Mary Oliver (1986),
conveys the sense of spaciousness that mindfulness can bring to experience, where
thoughts, feelings, and sensations can be held in awareness without being engulfed
by them, enabling an appreciation of the wider context (Segal et al. 2013).
Mindfulness-based approaches are available in a range of spiritual techniques
and also in lay settings. Interventions such as MBSR and MBCT are typically
conducted in secular environments and often with deliberate avoidance of overtly
spiritual symbolism. MBSR is quite readily available in many Western societies –
fees vary with healthcare systems. Mindfulness-based meditation courses also are
available in many spiritual traditions especially Buddhist ones. Naturally, these will
typically have overtly spiritual content and will include presentation of Buddhist
philosophical content as part of the course. This may be a source of attraction to
some but for others may make such opportunities inaccessible or inappropriate.
Cultural Congruence
To make the first directly clinical point in this chapter, in considering whether
someone may helpfully be referred for a mindfulness- or meditation-based inter-
vention, it will be important to explore with them what their history of connection
with meditation or mindfulness practices and the associated attitudes might be. It is
important to approach this without too much in the way of preconceptions, as the
reaction may occasionally be surprising.
Use your five senses. Learn to see, learn to hear, learn to feel, learn to smell, and know that
by practice alone you can become expert.
Listen to your patient, he is telling you the diagnosis
William Osler
Introduction
Smoking
Hypertension
Diabetes
In the context of diabetes, the rationale for the use of such techniques would seem to
be in areas of reduction of stress and perhaps assisting with lifestyle modifications.
Proposed effects on physiological parameters such as stress hormones including
cortisol would seem to provide a positive rational for expecting that there might be
clinically significant effects. As an intervention working in part through physical
exercise, yoga might reasonably be expected to have a role.
There is evidence that meditation-based approaches may be helpful for stress in
the context of diabetes, but to date, the picture is not so clear for diabetic control or
for impact on other associated physical problems (Alexander et al. 2012;
Berghmans et al. 2012; Krolikowski 2013; Schroevers et al. 2013; Schuster 2012;
van Son et al. 2014). Findings relating to stress hormones that might contribute to
diabetic control are somewhat inconsistent (Chiesa and Serrettiti 2009). A recent
systematic review concluded that there is presently not clear evidence that mind-
fulness training can improve diabetic control or investigated associated renal
dysfunction. Yoga has been studied as possibly having a role in diabetes self-
care; here, there are particular challenges in understanding whether effects are
specific or nonspecific and how much they relate to associated lifestyle changes
such as dietary modifications that are commonly advocated in yoga training and the
potentially beneficial effects of exercise itself. There are studies with positive
findings for improved diabetes control, but there is not as yet a body of high-
quality studies on which to base firm conclusions (Alexander et al. 2008).
Mindfulness- and meditation-based approaches may assist management of stress
in the context of diabetes – individual benefit from taking on such practices cannot
readily be estimated at this point, but it seems credible that for some patients, it may
prove helpful.
Overweight or Obesity
Depression
Alcohol
Introduction
Rationale
Evidence
relapse rates of depression (Chiesa and Serrettiti 2011). There seems no particular
reason why this funding among people with depression generally should not also
apply to people with cardiac problems. A small quasi-experimental study provides
support for this (O’Doherty et al. 2014).
Recently, a major meta-analysis of MBCT and MBSR studies in this area
(Abbott et al. 2014) found that MBSR or MBCT participation led to small-to-
moderate effects for stress and depression. Across studies in people having heart
disease and diabetes, there was also a moderate effect size observed for anxiety. By
way of example of a positive study, a brief MBSR intervention for people post
percutaneous coronary intervention showed greater improvement in psychosocial
and social quality of life than the self-help control condition though only for
patients below 60 years of age (Nyklicek et al. 2014).
Conclusion
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Psychopharmacology in the Treatment
of Patients with Cardiovascular Disease
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
Tricyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1044
Monoamine Oxidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1045
Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1046
Serotonin-Norepinephrine Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047
Other Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1048
Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Recommendations for Using Mood Stabilizers in Patients with Cardiac Disease . . . . . . . 1049
Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Conventional Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1049
Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1051
Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1053
Recommendations for Using Benzodiazepines in Patients with Cardiac Disease . . . . . . . . 1054
Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1054
Clinical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055
Abstract
Cardiac illness is frequently comorbid with psychiatric disorders, and patients
with heart disease are often prescribed psychotropic medications. Although
psychotropics are in general well tolerated and efficacious in patients with
cardiac disease, physicians need to be aware of key concerns related to side
effects and safety. Among the antidepressants, selective serotonin reuptake
inhibitors (SSRIs) have the most established track record for safety in cardiac
patients, although atypical antidepressants, such as mirtazapine and bupropion,
are also largely considered safe for use in these patients. Mood stabilizers, such
as lithium and carbamazepine, have been associated with arrhythmias. Typical
antipsychotics, such as haloperidol and chlorpromazine, increase the risk of QTc
prolongation; however, the degree of such prolongation varies significantly
among agents. Atypical antipsychotics, with the exception of ziprasidone, are
considered safer in this regard, but some are associated with metabolic side
effects that can increase the risk for coronary artery disease. The use of benzo-
diazepines is generally safe in patients with cardiac disease, and these agents
may mitigate symptoms of acute coronary syndrome (ACS) by reducing cate-
cholamine surges. Finally, stimulants, though relatively contraindicated in those
with various heart conditions, may be used cautiously to rapidly treat depression
and anergia in cardiac patients.
Keywords
Antidepressants • Selective serotonin reuptake inhibitors (SSRIs) • Mood stabi-
lizers • Antipsychotics • Stimulants • Benzodiazepines
Introduction
Cardiac illness is frequently comorbid with psychiatric disorders, and patients with
heart disease are often prescribed psychotropic medications. Although psychotro-
pics are in general well tolerated and efficacious in patients with cardiac disease,
physicians need to be aware of key concerns related to side effects and safety. This
chapter examines various classes of psychiatric medications and their effects on the
cardiovascular system.
Antidepressants
Tricyclic Antidepressants
as first-line agents for depression and anxiety; however, they remain in common use
for the treatment of insomnia and neuropathic pain.
TCAs cause a predictable increase in heart rate (of approximately nine beats per
minute) as a result of their anticholinergic effects; they can also induce orthostatic
hypotension due to blockade of alpha1 receptors on blood vessels (Dec and Stern
1990). Orthostasis is more common with tertiary amine TCAs (e.g., amitriptyline,
doxepin, clomipramine, imipramine) than with secondary amine TCAs (e.g., nor-
triptyline, desipramine, protriptyline).
TCAs also predispose to more serious but uncommon cardiac side effects. Since
these agents are structurally similar to class I antiarrhythmics, they are
pro-arrhythmic in roughly 10 % of the population in a dose-related fashion. In
addition, approximately 20 % of patients with preexisting conduction disturbances
have cardiac complications while taking TCAs (Roose et al. 1998). Moreover, the
TCAs can contribute to prolongation of the PR, QRS, and QT intervals on the
electrocardiogram (ECG), and TCAs have been associated with all manner of heart
block. Some have suggested that the effects on cardiac conduction are most severe
with desipramine, while other studies have found that amitriptyline and maprotiline
are most often associated with torsades de pointes (Vieweg and Wood 2004). Case
reports have also associated amoxapine with atrial flutter and atrial fibrillation.
After overdoses on TCAs, potentially lethal ventricular arrhythmias can arise.
Due to the increased risk of ventricular arrhythmias and myocardial infarction
(MI) following the use of TCAs, they are not recommended in patients with
coronary artery disease (CAD). In fact, a study that controlled for medical and
demographic factors found that depressed individuals receiving TCAs had more
than a twofold risk of MI (Cohen et al. 2000).
demand from rising heart rates and blood pressures. When a hypertensive crisis
arises in the setting of MAOI use, phentolamine is the recommended treatment. A
newer transdermal form of the MAOI, selegiline, carries a minimal risk of hyper-
tensive crisis when used at low doses, though higher dosages continue to require
adherence to a strict diet. Moclobemide, a reversible MAOI, is relatively safe (as it
does not tend to cause QTc prolongation or increase the risk of arrhythmias at
normal doses); moreover, it is not subject to the strict dietary requirements of other
MAOIs (Lofuto-Neto et al. 1999).
SSRIs have become the mainstay of treatment for depression and anxiety disorders
since their introduction in the late 1980s. Five SSRIs are in common use (fluoxe-
tine, paroxetine, sertraline, citalopram, and escitalopram), with a sixth
(fluvoxamine) prescribed less often (to treat obsessive-compulsive disorder).
SSRIs are generally considered to have a benign cardiovascular side effect
profile. SSRIs are associated with fewer anticholinergic side effects than TCAs;
they typically increase the heart rate by seven to eight beats per minute. Among the
SSRIs, paroxetine has the greatest anticholinergic load and is therefore most likely
to increase the heart rate. Orthostatic hypotension is an uncommon common side
effect of SSRI treatment.
SSRIs are generally considered as safe for use in those with CAD and in post-
MI patients; a small study of fluoxetine established the safety of SSRIs in this
setting (Strik et al. 2000), and the Canadian Cardiac Randomized Evaluation of
Antidepressant and Psychotherapy Efficacy (CREATE) trial found that
citalopram was safe and effective in treating depression in patients with CAD
(Lesperance et al. 2007). At least one study suggested that SSRI-treated
depressed patients had lower rates of MI than nondepressed controls (Cohen
et al. 2000). In the multicenter, double-blind, placebo-controlled SADHART
trial (Glassman et al. 2002), investigators found that sertraline significantly
improved depressive symptoms compared to placebo and was not associated
with changes in ejection fraction, cardiac conduction, or adverse cardiac events,
6 months following its initiation after MI. Importantly, study subjects were not
started on sertraline until 1 month after MI, and the safety of SSRIs in the
immediate (first month) post-MI period has not been established, though most
experts consider them safe for use in this context. Another study found that
sertraline was safe for use in patients with congestive heart failure (CHF),
though the use of sertraline did not improve depression or cardiac outcomes as
compared to placebo (Jiang et al. 2008). More recently, several studies have
linked SSRI treatment to lower rates of mortality and other adverse cardiac
events in both post-MI patients and healthy controls (Carney et al. 2004; Kimmel
et al. 2011; Tiihonen et al. 2006).
Psychopharmacology in the Treatment of Patients with Cardiovascular Disease 1047
Recently, concern has arisen regarding the possibility that SSRIs lead to prolon-
gation of the QTc interval and increase the risk of torsades de pointes. In fact, all
SSRIs except paroxetine have been associated (in case reports) with QTc prolonga-
tion at therapeutic doses and in overdose (Beach et al. 2013). In particular, citalopram
has been shown to have a modest QT-prolonging effect, which resulted in a Food and
Drug Administration (FDA) recommendation in August 2011 to limit the maximum
daily dose of citalopram to 40 mg per day (20 mg in patients with hepatic impairment
or those older than 60 years) because of the increased risk of QTc prolongation at
higher doses and to declare its use contraindicated in those with a congenital long QT
syndrome. Less stringent revisions were issued in March 2012; however, citalopram
remains not recommended for use at doses greater than 40 mg per day. No
QTc-related recommendations have been issued for other SSRIs, although
escitalopram appears to have a more modest, dose-dependent effect on prolongation
of the QTc interval (Castro et al. 2013). A meta-analysis (of 16 studies) of the impact
of SSRIs on the QTc interval found that SSRIs as a class prolonged the QTc by an
average of 6 ms, suggesting that these agents convey a very low risk when used
cautiously, even in patients with a history of cardiac disease (Beach et al. 2014).
Other Antidepressants
Mood Stabilizers
Lithium remains the “gold standard” treatment for bipolar disorder, and it is
sometimes used as augmentation in patients with unipolar depression. Lithium
has been reported to cause sinus bradycardia, sinus node dysfunction, atrioventric-
ular (AV) block, T-wave changes, and ventricular irritability (Freeman and Free-
man 2006). However, it has not been commonly associated with other effects on the
cardiovascular system; sick sinus syndrome is considered to be the only cardiac
contraindication to lithium use.
Valproic acid is an anticonvulsant that is frequently used in the treatment of
bipolar disorder, particularly for the treatment of manic episodes. Valproic acid has
been associated with thrombocytopenia, abnormal platelet function, and an
increased risk for bleeding following medical interventions or surgery. Otherwise,
no cardiac side effects have been linked with valproic acid use.
Carbamazepine and oxcarbazepine are other anticonvulsants used in the treat-
ment of bipolar disorder. Carbamazepine can slow cardiac conduction and should
be avoided in patients with high-grade AV block and sick sinus syndrome. Over-
dose of carbamazepine may cause high-grade AV block. Oxcarbazepine has not
been associated with adverse cardiac side effects.
Lamotrigine is an anticonvulsant that is commonly used to treat depressive
episodes in the setting of bipolar disorder. Cardiovascular effects of lamotrigine
have not been described, and it is considered safe for use in patients with cardiac
disease.
There have been no randomized trials of mood stabilizers in patients with cardiac
disease. Nonetheless, mood stabilizers are generally considered as being safe in this
population in the absence of a conduction delay. In cases of AV block and sick sinus
syndrome, lithium and carbamazepine should be avoided.
Antipsychotics
Conventional Antipsychotics
However, these medications can still be used for cardiac patients, most commonly
for the management of delirium.
Antipsychotic medications are the first-line treatment for the management of
agitation associated with delirium; haloperidol is the antipsychotic agent most
frequently used for this purpose (American Psychiatric Association 1999). Though
this medication can be administered orally or intramuscularly, its intravenous form
is preferred for several reasons: it is easy and painless to administer, it works
quickly (onset of action is ~15–30 min), and it is less likely to induce motor side
effects compared to its other formulations. From a cardiac perspective, its effects on
heart rate, blood pressure, or respiratory status are minimal; it has no active
metabolites and essentially no anticholinergic effects.
Though less commonly used, chlorpromazine, a low-potency typical antipsy-
chotic medication, also serves as a treatment for delirium, in large part because it
can be administered intravenously (allowing it to be fast-acting and sedating) in the
medically ill. Unlike haloperidol, chlorpromazine and other low-potency antipsy-
chotics (e.g., thioridazine) can have significant cardiovascular effects. Specifically,
their anticholinergic properties can cause tachycardia, and their alpha-1 blockade
can induce significant hypotension. As a result, these medications are commonly
avoided in cardiac patients, especially those with hemodynamic instability.
Additionally, all typical antipsychotic medications are linked with torsades de
pointes (TDP), a malignant polymorphic ventricular arrhythmia that can occur with
agents that lengthen the QTc interval (Beach et al. 2013; Wenzel-Seifert
et al. 2011). All typical antipsychotic medications can cause QTc prolongation,
and many have been associated with TDP. In general, there is a dose-response
relationship between antipsychotic dose and QTc prolongation (Reilly et al. 2000),
and lower-potency antipsychotics tend to cause more QTc prolongation than
higher-potency medications (Mehtonen et al. 1991). For example, thioridazine, a
low-potency antipsychotic medication, has consistently been shown to cause the
greatest degree of QTc prolongation of the antipsychotics (Beach et al. 2013;
Harrigan et al. 2004; Wenzel-Seifert et al. 2011). However, higher-potency medi-
cations, such as haloperidol, also cause QTc prolongation (Harrigan et al. 2004;
Ozeki et al. 2010). In general, haloperidol causes mild QTc prolongation (~5–7 ms
when given orally at 15 mg/day) (Harrigan et al. 2004). However, the risk of QTc
prolongation and TDP increases substantially when haloperidol is administered
intravenously. When administered intravenously, and especially at higher doses
(>35 mg daily), haloperidol has been associated with greater rates of QTc prolon-
gation and TDP (Ozeki et al. 2010; Sharma et al. 1998; Vieweg et al. 2009). More
than 70 cases of TDP have been reported in association with haloperidol (Wenzel-
Seifert et al. 2011), and rates of TDP from haloperidol in the treatment of delirious
patients have ranged from 0.36 % to 3.5 % (Sharma et al. 1998; Wilt et al. 1993).
Several other factors (e.g., structural cardiac disease, congenital long QT syndrome,
older age, female gender, electrolyte abnormalities (hypokalemia, hypomagnese-
mia), and endocrine and neurologic disorders) also contribute to QTc prolongation
and the risk of TDP (Vieweg 2002). Therefore, extra care should be taken when
using typical antipsychotics in these patients.
Psychopharmacology in the Treatment of Patients with Cardiovascular Disease 1051
Atypical Antipsychotics
Benzodiazepines
Benzodiazepines are commonly prescribed for anxiety disorders and for insomnia.
Though now largely intended for short-term use until other medications (such as
SSRIs) take effect, many patients are treated chronically with benzodiazepines. In
the hospital setting, benzodiazepines are also used to manage alcohol withdrawal.
One important caveat for the use of benzodiazepines is that they can exacerbate
confusion and paradoxically worsen agitation in patients with delirium or dementia;
therefore, other agents (e.g., antipsychotics) may be more appropriate for the
treatment of anxiety, fear, and distress in the delirious or demented cardiac patient.
Benzodiazepines are generally well tolerated, with low rates of hypotension,
virtually no anticholinergic effects, and very low rates of respiratory compromise
when standard doses are used. Benzodiazepines reduce catecholamine levels both
at baseline and during times of stress (Dixon et al. 1980; Melsom et al. 1976) and
decrease coronary vascular resistance (Nitenberg et al. 1983). Benzodiazepines
have also been linked to decreased left ventricular end diastolic pressure, decreased
platelet aggregation, and decreased rates of ventricular dysrhythmias (Huffman and
Stern 2003; Muenster et al. 1967; Van Loon 1968).
Benzodiazepines are frequently administered to patients with chest pain and are
thought to be safe for use and effective in both cardiac and noncardiac chest pain.
Wheatley found that the addition of benzodiazepines to standard cardiac medica-
tions in the post-MI period led to significantly lower rates of reinfarction in patients
not taking β-blockers (Wheatley 1984). It should be noted that the patients in these
studies, however, were not taking β-blockers.
Withdrawal from benzodiazepines leads to anxiety, tremor, diaphoresis, nausea,
insomnia, and irritability; vital signs—especially blood pressure and heart rate—are
1054 S.R. Beach et al.
Benzodiazepines are generally considered safe for use in patients with cardiac
disease and may fulfill a role as an important anxiolytic adjunctive medication in
patients presenting with cardiac chest pain. Benzodiazepines can worsen delirium
and increase the risk for falls and should therefore be used cautiously in elderly
patients and other populations at risk for such complications.
Stimulants
Conclusion
While many psychiatric medications are safe for use in patients with cardiac
disease, physicians need to be aware of and monitor for potential side effects that
may be specific to individual classes. The presence of heart disease should not
preclude necessary treatment of psychiatric comorbidity given the links between
cardiac disease and psychiatric illness, but may require thoughtfulness and careful
evaluation of risk/benefit on the part of the prescriber.
Psychopharmacology in the Treatment of Patients with Cardiovascular Disease 1055
Clinical Implications
Due to their efficacy and their established record of safety, SSRIs are the first-line
treatment for depression and anxiety in patients with cardiac disease. Bupropion is a
reasonable and safe augmentation strategy for depression. Mood stabilizers are
considered safe in cardiac populations in the absence of conduction delay. Antipsy-
chotics can be safely used in cardiac patients, with atypical agents considered first-
line treatment. Efforts should be made to minimize metabolic side effects in patients
with CAD or CHF. Antipsychotic agents also carry a risk of prolonged QTc intervals
and caution should be exercised in this regard. Benzodiazepines are typically safe for
use in cardiac patients and may alleviate anxiety associated with cardiac chest pain.
Stimulants can also be used safely in this population with some basic precautions.
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Impact of Cardiac Medications on Mood
Geoffrey A. Head
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1062
Beta-Adrenoceptor Antagonists and Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1063
Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1064
Beta-Adrenoceptor Antagonists and Other Adverse CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1065
Beta-Adrenoceptor Antagonists and CNS Indications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
Treatment of Aggression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1066
Treatment of Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1067
Treatment of Posttraumatic Stress Memories . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1068
Digoxin and Mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
Antiarrhythmic Agents and Mood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1069
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1070
Abstract
Cardiac medications including β-blockers, cardiac glycosides, and antiarrhyth-
mics have long been known to have CNS effects including alterations in mood,
emotion state anxiety, and depression. While the predominant effects come from
those with higher lipophilicity and when used at high doses, the evidence is
actually quite mixed. At cardiac therapeutic doses, lipophilic β-blockers like
propranolol have actually few CNS effects on mood. The effectiveness of
β-blockers is established for relieving performance anxiety, but the actions
involve more a peripheral relief of somatic symptoms rather than a central
effect. By contrast the reduction in consolidation of aversive and stressful
memory by propranolol appears to involve altering the functioning of the
amygdala and hippocampus directly. While evidence suggests that β-blockers
Keywords
Anti-arrhythmic effects • Arrhythmias • Beta-adrenoceptor antagonist • Adverse
CNS effects • Aggression treatment • Depression • Anxiety treatment • Mech-
anism • Post-traumatic stress disorder treatment • Cardiac arrhythmias • Cardiac
glycosides • Digoxin • Mood • Antiarrhythmic agents • Digoxin • Post-traumatic
stress disorder • Propranolol
Introduction
The concept that drugs prescribed to treat heart conditions may have central side
effects affecting mood has been around for a very long time (Celano et al. 2011).
The issue was highlighted by the very early suggestion of Waal who reported in a
letter to the British Medical Journal in 1967 that patients taking propranolol, the
prototype β-adrenoceptor antagonist developed by Sir James Black in the early
1960s, showed a high incidence of depression (Waal 1967). This observation was
treated with some skepticism that same year by Fitzgerald who stated that the
adverse reactions among the 60,000 patients receiving propranolol were low and
the incidence of depression was 0.1 % (Fitzgerald 1967). Fitzgerald was working
for ICI at the time who manufactured propranolol as sold as Inderil. Thus, the
debate began and over the last 47 years, there has been great interest in not only this
specific issue but also the wider area of whether and how cardiac drugs affect mood
and other CNS processes. Such side effects can undoubtedly affect the usage of
drugs like propranolol and the newer more selective β-blockers and is counterpro-
ductive to the appropriate use of these valuable agents if these side effects have not
been properly and scientifically validated. The confounding issue is that behavioral
and psychological symptoms including changes in mood are very common in
patients with cardiovascular disease (Pozuelo et al. 2009). Depression and anxiety
are associated with heart failure (Glassman et al. 1983), and its prevalence can
range from 15 % to 36 % (Konstam et al. 2005). Patients who have undergone
coronary artery bypass surgery or experienced a recent myocardial infarction are
well known to suffer more major depressive episodes and anxiety which is also
linked to subsequent events including death (Frasure-Smith et al. 1993; van Melle
et al. 2006). Thus, with anecdotal and case reports and even with small uncontrolled
studies, it is easy to see why particular medications that are cardiac specific might
Impact of Cardiac Medications on Mood 1063
infarction did not find that β-blockers reach significance as a predictor (Schleifer
et al. 1991). These findings were confirmed in a multicenter prospective trial of
nearly 400 post-myocardial infarction patients prescribed either beta-blockers or
other drugs and followed for 12 months (van Melle et al. 2006). A study from the
Harvard community health plan population who followed a large number of
patients starting a range of pharmaceutical treatments for at least 6 months found
that the rates of depression (major and minor) in those prescribed beta-blockers
after adjustment for age and sex were similar to those who were prescribed other
drugs (Gerstman et al. 1996). However, this study lacked any assessment of
baseline levels of depression. A Department of Veterans Affairs study of treating
hypertension in the elderly (older than 60) with hydrochlorothiazide found no
significant difference in the prevalence of depression for those additionally pre-
scribed β1 selective antagonist metoprolol compared to other antihypertensive
agents (Goldstein et al. 1990). A major multicenter double-blind randomized
controlled prospective trial of atenolol in the elderly did not find any deterioration
in measures of cognition, emotional state, physical function, or leisure activities
(Applegate et al. 1994). Also in a double-blind placebo-controlled study of the
nonselective β-blocker nadolol to treat chronic aggression, there was no difference
between control and treatment groups for symptoms of depression (Sorgi
et al. 1992). A large retrospective analysis of Odense University Pharmacoepide-
miological Database was used to determine the association between β-blocker and
antidepressant combined therapy whereby a depression-causing effect would result
in an excess of patients starting the drug first (Hallas 1996). This was not the case
for β-blockers. A major review of several clinical studies of a range of β-blocker
usage in nearly 6000 patients found that depression was rarely associated with
propranolol and only after long-term treatment at high doses (Stoudemire
et al. 1984). A review of the literature in 1996 cast further doubt on the depression
hypothesis and suggested that β-blockers may have been unjustly blamed and that
their use has been avoided for that reason (Ried et al. 1998). A more recent meta-
analysis of the association of β-blockers with CNS symptoms using 15 trials from
1966 to 2001 involving 35,000 subjects found no relationship with depression
(Ko et al. 2002). Chronic treatment with the newer third generation β1 selective
antagonist nebivolol in combination with other antihypertensive agents did not
result in listing of depression in the adverse side effects (Papademetriou 2009).
However, as pointed out in a commentary, there is little evidence to suggest that
depression is caused by β-blockers in any case (van Melle and de Jonge 2009).
Thus, while patients with cardiovascular disease are at greater risk of developing
major depressive illness, there is little convincing evidence that prescribing
β-blockers will add to that risk.
Mechanism
There is no question that some β-blockers penetrate the CNS effectively at dose
used to treat hypertension and other cardiac-related disorders (Middlemiss
Impact of Cardiac Medications on Mood 1065
et al. 1981). The level of CNS β-adrenoceptor antagonists is closely related to the
lipid solubility of the compound, but the issue is somewhat complicated by protein
binding in plasma and the uptake into lipophilic tissues (Taylor et al. 1981). A
single oral dose of 80 mg propranolol leads to concentrations in cerebrospinal fluid
likely to produce a high level of receptor blockade (Taylor et al. 1981). Interestingly
a 100 mg dose of atenolol leads to about five times higher cerebrospinal fluid
concentrations as it is not protein bound like propranolol which might be considered
sufficient for central β-adrenoceptor blockade (Taylor et al. 1981). However,
another study that same year measured brain concentration after 5–11 days of
treatment in patients and showed that propranolol had 250 times greater brain to
plasma rations that atenolol which would very much explain the low level of CNS
side effects with atenolol (Glaubiger and Lefkowitz 1977). Myers and colleagues
suggested the brain/plasma ratio in rabbit was ~15:1 and similar to that in post-
mortem human samples (Myers et al. 1975). In theory greater lipophilicity would be
expected to produce more CNS effects although the evidence supporting this is
practice is conflicting (Keller and Frishman 2003).
The mechanism by which these drugs could induce depression has been
suggested to involve an upregulation of β-adrenoceptors or compensatory postsyn-
aptic noradrenergic receptor hypersensitivity in the CNS (Charney et al. 1981;
Oppenheim 1983). Animal studies have confirmed that there is up regulation of
β-adrenoceptors in tissue with chronic treatment with propranolol (Glaubiger and
Lefkowitz 1977). Long-term treatment with antidepressants reduces β-adrenergic
sensitivity and increases responsiveness to serotonergic and α-adrenergic agonists
(Lerer et al. 1981), while treatment with β-adrenoceptor agonists decreases receptor
sensitivity (Neil-Dwyer et al. 1981). Further, chronic treatment agonists such as
salbutamol have been shown to be as effective as clomipramine in relieving
symptoms in depressed patients (Middlemiss et al. 1981).
While β-blockers have been incorrectly in most cases associated with depression,
there are other CNS effects worthy of note, including sedation, fatigue, reduced
cognition, anxiolysis, and reduction in aggressive behavior as well as being an
effective treatment for migraine. A placebo-controlled study in a small number of
volunteers using a range of acute doses of propranolol and a number of psycholog-
ical and psychomotor tests found that propranolol at doses between 40 and 320 mg
decreased alertness, prolonged reaction time, reduced response to digital copying
test, and increased detachment (Salem and McDevitt 1984). Thus, while the study is
well controlled and indicates CNS effect of propranolol, the effects were seen at
some doses, and there was not a clear dose-response relationship which is unusual.
A placebo-controlled comparison of a number of antihypertensive agents found that
propranolol was associated with drowsiness and impaired reaction time, symbol
copying, and memory (Frcka and Lader 1988). A later randomized double-blind
parallel study compared the effects on cognitive function of atenolol, captopril,
1066 G.A. Head
enalapril, and propranolol in hypertensive men and found that propranolol showed
worsening of or less improvement in distressing psychological symptoms compared
to the other drugs (Steiner et al. 1990). As this large trial included another less
lipophilic drug atenolol, these effects are not a class effect but are drug specific. An
analysis of 55 studies on the effect of β-blockers on cognitive function revealed that
perceptual motor cognitive was frequently affected by these drugs but there was no
trend for lipophilic drugs to be more indicated than lipophobic drugs (Dimsdale
et al. 1989). Further, this study found that while some positive effect on complex
task performance was observed, beta-antagonists are associated with increased
sedation (Dimsdale et al. 1989). Other trials have found that atenolol used as an
antihypertensive actually improved surveyed psychological well-being to a degree
similar to that observed following captopril (Fletcher et al. 1990). The meta-
analysis by Ko and colleagues that did not find any evidence for depressive effects
of β-blockers did reveal a greater risk of fatigue and sexual dysfunction although
the incidence was low (Ko et al. 2002).
Occasionally but very rarely are β-antagonists associated with psychosis (Love
and Handler 1995). In one case the symptoms associated with lower doses of
propranolol and other cases by changing to atenolol from propranolol (McGahan
et al. 1984; Parker 1985). An isolated case has also been reported for atenolol
(Viadero et al. 1983) and in an elderly patient given metoprolol (Fisher et al. 2002).
However, given the huge number of patients taking these agents, such reports are
extremely rare.
Treatment of Aggression
Treatment of Anxiety
There is a body of evidence that suggests that β-antagonists can be useful in the
treatment of anxiety, particularly related to performances and taken about an hour
before hand (Brantigan et al. 1982; Hartley et al. 1983; Liebowitz et al. 1985;
Schneier 2006). Propranolol has also been shown to improve test scores during
exams presumably by reducing the stress-induced impairment of cognitive func-
tioning (Faigel 1991). However, early placebo-controlled studies failed to find any
effect of propranolol on subjective anxiety ratings, while diazepam in the same test
was effective (Ashton et al. 1976). Also anxiety state before and after exercise was
not affected by propranolol or metoprolol at normal doses used to treat hypertension
(Head et al. 1996). Nevertheless, the prevailing view backed by numerous studies is
that the antianxiety effects of β-antagonists are not central effects but somatic due to
the reduction of the stress-induced tachycardia caused by peripheral β-blockade
(Granville-Grossman and Turner 1966; Kelly 1985; Hayes and Schulz 1987).
However, comparison between the non-lipophilic atenolol and propranolol in a
double-blind crossover study of a limited number of subjects showed clear effec-
tiveness of propranolol but not atenolol in formal psychological tests of mood,
motivation, and anxiety (Conant et al. 1989). The authors suggest that a direct CNS
action of propranolol is the likely explanation. Indeed in rats propranolol dose
dependently decreases anxiety in an open field test (Angrini et al. 1998) and also
during a startle in a bright light environment (Walker and Davis 2002).
β-Blockers have also been indicated in other situations as an adjunct to regular
therapy. Early studies suggested that propranolol is effective in suppressing panic
attacks and reducing avoidance behavior in patients (Ravaris et al. 1991). Pindolol
has been used in combination with selective serotonin uptake inhibitors to reduce
the time of onset of clinical efficacy in depressive and anxiety disorders. Also
pindolol has an augmenting effect on fluoxetine in treatment of resistant panic
disorder (Hirschmann et al. 2000). Studies in rats using an elevated T-maze test
indicate that pindolol combined with paroxetine (but not alone) had panicolytic
effects (Sela et al. 2010) which is supportive of the effectiveness of the
combination.
1068 G.A. Head
It has been well established that during trauma, the excessive levels of emotion and
distress that are experienced can augment memory processes that are readily
reactivated during a contextual stimulus. It is becoming increasingly recognized
that such traumas particularly early in life can dramatically increase the risk of
psychiatric disorders such as depression, panic attack, phobias, addiction, and
phobias (Carr et al. 2013; Lonergan et al. 2013). One can reduce the long-term
influence of emotional memory events associated with trauma by preventing
memory consolidation. In the seminal study published in Nature in 1994, the
effectiveness of propranolol compared to placebo in reducing the memories of a
set of emotionally disturbing pictures was demonstrated (Cahill et al. 1994). The
mechanism may involve reducing memory consolidation (Garakani et al. 2006) as
propranolol can reduce the consolidation and recall of negative emotional experi-
ences from pictures and words in normal subjects (for overview, see Lonergan
et al. 2013). The process affected may involve protein synthesis inhibition (Nader
et al. 2000) in specific nuclei within the amygdala and hippocampus which has been
demonstrated using functional magnetic resonance imaging of subjects (Schwabe
et al. 2009, 2012). Administration of propranolol within a few hours of the event
and continuing for several days has a long-term benefit (Pitman et al. 2002; Vaiva
et al. 2003). Oral administration of propranolol disrupted memory consolidation
and produced diminished fear (Kindt et al. 2009). Also it appears that such blockade
may prevent the rebuilding of the emotional memory. An important consideration is
the dose used and the sex of the patient as men are less sensitive to the effects of
propranolol and may need higher doses (Cahill and van Stegeren 2003; Lonergan
et al. 2013). Interestingly Soeter and Kindt noticed that the declarative memory of
the event was intact after propranolol which might result in the recovery of a fear
response. Importantly the effect of propranolol persisted for 1 month suggesting
that this does not occur suggesting that β-blockade may also disrupt memory
reconsolidation (Soeter and Kindt 2010). In addition to the effects of propranolol
on consolidation of fear, studies in animals have shown that the drug can reduce
expression and extinction conditioned fear in rats (Rodriguez-Romaguera
et al. 2009). This effect was not observed with sotalol even though both drugs
produced similar bradycardia. This suggests a clear centrally mediated mechanism.
It is not surprising then that lipophilic β-antagonists like propranolol are effec-
tive at treating posttraumatic stress disorder (Haspel 1995; Cukor et al. 2009; de
Kleine et al. 2013; Tawa and Murphy 2013). A recent review of the treatment of the
military for posttraumatic stress does support the use of propranolol as an effective
treatment (Tawa and Murphy 2013). However, there are some negative studies as
well which failed to find effects such as in the trauma associated with burns
although this was a retrospective study of limited quality (McGhee et al. 2009). A
placebo-controlled trial in posttraumatic stress disorder patients and controls
recalling an emotionally arousing story found that a very low dose of propranolol
was effective in reducing recall but there was no difference between groups (Reist
et al. 2001). Clearly there is good evidence of effectiveness of lipophilic β-blockers
Impact of Cardiac Medications on Mood 1069
Patients with arrhythmias have higher states of mood disorder than those without
arrhythmias (Dunbar et al. 1999). There are a variety of agents effective in treating
cardiac arrhythmias, some of which have been associated with delirium. Class I
agents that block sodium channels such as procainamide have not been tested for
psychological effects in randomized controlled prospective studies although there
are some case reports of delirium and mania (Keller and Frishman 2003). Class III
agents like amiodarone block sodium channels as well as influence calcium and
potassium currents. Its antiarrhythmic effects may be due to its perturbation of the
membrane lipids and may also have CNS effects as suggested by reports of
1070 G.A. Head
depression, delirium, and sexual dysfunction (Keller and Frishman 2003). Like
Class I agents there are few dedicated trials of these agents involving mood.
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Part VI
Lifestyle Management in Cardiovascular
Disease: Prevention and Secondary
Intervention
Changing Lifestyle Behaviors to Improve
the Prevention and Management
of Cardiovascular Disease
Contents
The Importance of Lifestyle Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1078
Principles of Lifestyle and Behavior Change . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1079
Health Behavior Change to Reduce CVD Risk: What Works? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
Smoking Cessation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1081
Nutrition and Dietary Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1082
Increasing Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Reducing Sedentariness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1083
Multiple Risk Factor Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
Considerations for Intervention Success . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
Settings for Program Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1084
Level of Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Features of Intervention and Program Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1085
Potential of New Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1086
Peer Support Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1087
Achieving Sustainability and Maintenance of Lifestyle Change . . . . . . . . . . . . . . . . . . . . . . . . . 1088
Conclusions and Practical Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1089
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1090
Abstract
Up to 80 % of the risk for cardiovascular disease (CVD) in the general popula-
tion is attributable to lifestyle factors. Hence, the modification of lifestyle
behaviors is important for reducing cardiovascular risk in the context of primary
and secondary CVD prevention. However, initiating and sustaining changes in
lifestyle behaviors remains challenging, particularly for patients who have
experienced a potentially life-threatening CVD event. This chapter reviews the
evidence base for changing lifestyle behaviors that contribute most to the
etiology, progression, and outcomes of CVD, that is, nutrition and dietary
behaviors, physical activity, and smoking. Furthermore, the evidence in relation
to the effectiveness of behavioral interventions and key factors to consider in the
implementation of effective behavior and lifestyle change programs in clinical
and non-clinical settings are discussed. Finally, the implications of these findings
for future research and practice in the field are considered.
Keywords
Cardiovascular disease • Lifestyle • Behavior interventions • Risk factors
Introduction
As already stated, health behaviors can be very difficult to change and to sustain in
the longer term. For example, following a heart event, many individuals will make
initial changes to their lifestyle, but maintenance is often poor, and relapse is
common within 6–12 months of the event (Mendis et al. 2005; Rosamond
et al. 2008). Key theories and models of health behavior, the change process, and
of health more broadly, can contribute to a better understanding of the development
of lifestyle behaviors the determinants of behavior change, and the change process
itself (Glanz et al. 2008; Lippke and Ziegelmann 2008). The following section
overviews key constructs from some of the most commonly used theoretical models
and frameworks.
1080 B. Oldenburg et al.
From the 1970s to the 1980s, on the intrapersonal factors that influence behavior
such as a person’s beliefs, knowledge, and skills. Such theories assume that lifestyle
behaviors and behavior change are largely determined by cognitive and psychoso-
cial factors at the individual level, with change being a result of rational, individ-
ualized decision-making. Examples of intrapersonal theories are the Health Belief
Model, Theory of Planned Behavior, and the Transtheoretical Model of Behavior
Change (Glanz et al. 2008). The Health Belief Model focuses on individual beliefs
concerning their perceived susceptibility to the severity of a health issue and the
perceived benefits and barriers that may result from taking action (Becker 1974;
Janz and Becker 1984). The Transtheoretical Model proposes key steps that are
involved in behavior change, including pre-contemplation, contemplation, prepa-
ration, action, and maintenance. The importance of identifying readiness to change
is a key construct in this model (Prochaska and Velicer 1997). Consequently,
proponents of this model argue that intervention strategies and programs be tailored
according to a group or an individual’s “stage of readiness.” Accordingly, different
intervention strategies are likely to be effective for one’s specific stage of change.
The Transtheoretical Model has been usefully applied to explain and predict
changes in behaviors such as smoking, diet, physical activity, as well as alcohol
and illicit drug use (Glanz et al. 2008). In contrast, interpersonal theories use the
premise that a person’s behavior is heavily influenced by one’s personal, family,
social relationships and context. Therefore, according to this level of theories, a
person’s social environment plays a very important role in determining his/her
health behaviors. Attention to these influences can also assist an individual in
changing health behaviors such as smoking, nutrition, and sedentariness.
The most popular interpersonal health behavior theory is Social Cognitive
Theory (Bandura 2001; Stokols et al. 2003; Yusuf et al. 2004), and over the past
30 years, this model has influenced the development of many other theories and
models. Social Cognitive Theory postulates one’s attitudes, cognitions, and beliefs,
environmental influences and behavior interact in a dynamic, reciprocal manner to
influence behavior and behavior change (Bandura 2001). Intervention strategies
based on this model are often derived from principles of learning that include
observational learning, positive and negative reinforcement, and strategies that
aim to improve self-control and self-efficacy. Socio-ecological models of health
explain behavior by considering multi-level and diverse influences in people’s
lives, including individual, interpersonal, organizational, and broader environmen-
tal level influences and how all of these can interact to determine and influence
lifestyle behaviors and the behavior change process. Indeed, there is now good
evidence that health interventions are likely to be more successful when they are
based on such a socio-ecological perspective (Brofenbrenner 1977; Glanz
et al. 2008).
Much of the early research concerning the determinants of health behaviors was
based on individual and intrapersonal theories of behavior. Hence, many of the
intervention strategies incorporated into the lifestyle change counseling and inter-
vention programs of the 1970s and 1980s focused on influencing individual factors
such as knowledge, attitudes, self-efficacy, and skills. However, as multi-level and
Changing Lifestyle Behaviors to Improve the Prevention and Management of. . . 1081
In the following section, we consider the evidence base concerning the effective-
ness of behavioral interventions and lifestyle change programs in relation to the
prevention and management of CVD and related chronic conditions. While a
substantial evidence base has established the effectiveness of lifestyle change
approaches as an important component of smoking cessation over more than
30 years (e.g., Barth et al. 2008; DiClemente et al. 1991), CVD prevention and
lifestyle change programs related to diet and physical activity are not nearly as well
established (Yach et al. 2005).
Smoking Cessation
linking ongoing tobacco use to poor health outcomes is very well established, and
programs can be delivered in a variety of modes and by a range of health pro-
fessionals. However, it is important to note that although such interventions can
significantly increase initial quit rates, absolute abstinence still remains very low,
regardless of the type of intervention used. Indeed, the evidence shows that the
majority of smokers will relapse several times before finally succeeding in quitting.
Hence, persistence is the key to long-term success with smoking interventions
(Rosengren et al. 2004).
Although various aspects of nutrition and diet such as low intake of fruit and
vegetables; high intake of (saturated) fat, sugar, and salt (World Health Organi-
zation 2002); and the consumption of a proinflammatory diet high in sugar,
highly processed foods, and trans fats (O’Neil et al. 2015) have been consistently
implicated as important risk factors for CVD, the effects of lifestyle-related
interventions targeting these have been modest. Nonadherence is also much
higher for nutritional advice when compared to other risk factor such as smoking
and medication taking. One possible reason is that instigating and maintaining
such changes can be complex in clinical populations, especially in combination
with other components of a complex treatment plan (Burke et al. 1997). Group-
based educational and lifestyle change programs have been somewhat successful
in reducing total calories, total and saturated fat, and cholesterol levels when
used in primary prevention (Burke et al. 1997). Individual counseling with a
dietician has also shown positive results, with significant reduction in dietary fat
and cholesterol consumption that was maintained after 7 years (Burke
et al. 1997). Furthermore, dietary advice from a health professional has been
linked to patients reaching their target LDL-cholesterol levels (Pearson
et al. 2000). Another key to success is social and family involvement, with
greater success attributed to their involvement, and community-based programs
(as distinct to those conducted in more clinical settings) tend to be more suc-
cessful, especially when they incorporate specific and practical dietary advice
(Hooper et al. 2012).
Despite a substantial focus on dietary interventions that reduce dietary fat intake,
the clinical outcomes of these studies remain mixed. In a recent systematic review,
nutritional interventions aimed at influencing dietary fat – that is, reducing and/or
modifying total fat intake – did demonstrate a significant reduction in the incidence
of combined cardiovascular events but no clear effect on total mortality, despite
reductions in weight, body mass index, total cholesterol, and LDL cholesterol
(Hooper et al. 2012). Further, these effects were only reported for trials where
participants were involved for more than 2 years, and overall, there was very little
evidence to support a direct link between dietary intervention that focuses on
modifying dietary fats and reductions in total mortality (Hooper et al. 2012).
Changing Lifestyle Behaviors to Improve the Prevention and Management of. . . 1083
Reducing Sedentariness
profiles, increased BMI, increased blood pressure, and other negative risk factors
associated with an increased risk of CVD (León-Latre et al. 2014). As the
deleterious effects of sedentary behavior are not necessarily negated by an overall
increase in physical activity, this presents a novel challenge and opportunity
within the context of disease prevention and control. Indeed, preliminary studies
have linked reductions in sedentary behavior to positive changes to triglyceride
levels, waist circumference, and inflammation (Ekblom-Bak et al. 2014; Ford and
Caspersen 2012). As a relatively new concept, sedentary behavior is a potential
modifiable risk factor for CVD that presents a promising avenue for future
research and interventions, particularly through the use of more environmental
interventions.
The majority of adults engage in two or more lifestyle behaviors that increase
their risk of CVD and related chronic conditions (King et al. 2015). More
specifically, prevalence rates of multiple risk behaviors in adult populations
worldwide have been reported as 68 % in England (Poortinga 2007) and 52 %
in the United States (USA) (Coups et al. 2004). Further, interventions targeting
multiple lifestyle behaviors can be more effective in terms of reducing disease
risk compared to those focusing on a single risk factor (King et al. 2015). Such
an approach also helps to address the complex interplay between lifestyle
behaviors and risk factors for CVD. Indeed, a recent meta-analysis of multifac-
torial interventions in patients showed a reduction of 18 % in fatal cardiovas-
cular events as well as a small but nonsignificant reduction in overall mortality
and hospital readmissions (de Waure et al. 2013). Multiple risk factor interven-
tions typically comprise multiple socio-behavioral strategies that variously tar-
get combinations of diet, exercise, weight loss, smoking cessation, and
medication adherence.
Level of Intervention
Rapid advances in interactive digital technologies have changed the way in which
communication and social interaction occurs worldwide, and these advances have
the potential to profoundly influence the design and delivery of lifestyle change
programs. Recent years have seen the rapid uptake and use of the Internet,
Facebook, Twitter, Wiki, and technology platforms using smartphones, tablets,
and other devices. For example, while Facebook had approximately 1 million
users at the end of its first year in existence in 2004, it now has well over 1 billion
monthly active users (eMarketer Inc 2013). Technology also provides the flexibility
of various modes of communication, including photos, videos, three-dimensional
images, visual simulations, and even virtual reality. Hence, use of the Internet and
mHealth interventions now offer opportunities to reach and engage with individuals
worldwide and beyond traditional “communities” (Smith et al. 2014).
Wantland et al. (2004) pooled studies of web-based interventions containing
nearly 12,000 participants, including cross-sectional, self-managed, and longitudi-
nal intervention studies ranging from 3 to 78 weeks. When compared to interven-
tions, utilizing more traditional means of delivery web-based interventions reported
reaching an equal proportion of men and women and having lower than usual rates
of attrition (21 %). However, although the average drop-out rate was relatively low,
measures of program exposure and intensity were also modest. For example,
participants showed significant variation in time spent per session and the number
of times the intervention site was visited. Despite wide variation in intensity, nearly
all of the studies showed an improvement in knowledge and/or behavioral out-
comes. Some examples of improved outcomes were increase in exercise duration,
18-month weight loss maintenance, and increased utilization of health care
(Wantland et al. 2004). In addition to improvements in knowledge and health
behaviors, interactive health communication applications have also been shown
to improve social support, self-efficacy, and clinical outcomes (Murray 2006).
The telephone provides another channel to promote participant access due to
freedom from spatial and temporal restrictions, and positive behavioral outcomes
observed in such programs have been linked to duration and intensity (number of
calls) of the intervention (Eakin et al. 2007). Other key factors that may impact on
the success of such programs may be targeting selected clinical samples and the use
of theory-based models including the transtheoretical model, social cognitive
theory, and motivational interviewing.
The use of new technologies, such as smartphones and apps, to deliver program
content and messages often demonstrate a high degree of fidelity, standardization,
and replicability, reducing the variability in content and delivery that is possible
Changing Lifestyle Behaviors to Improve the Prevention and Management of. . . 1087
when such programs are delivered by health professionals. For example, Mobile
Health (mHealth) platforms are now using smartphones and computer tablets to
deliver health behavior change programs to improve prevention and management of
lifestyle-related chronic conditions such as CVD, with high reach, fidelity, and a
good user experience (Oldenburg et al. 2015). Further, user engagement of Internet-
based behavioral interventions for chronic disease is improved by addressing health
concerns important to the individual and is further enhanced by incorporating
personally tailored advice and feedback (Kelders et al. 2011; Schubart et al. 2011).
The emergence of computer software and the development of “expert systems”
(originally developed in the 1990s) have also increased the sophistication of
tailoring of programs (Kong et al. 2012; Latimer et al. 2010) and led to
algorithm-driven approaches which combine the benefits of traditional mass
media campaigns with individually tailored interventions to reach a very large
number of individuals. By remembering preferences for content and mode of
delivery, an algorithm-driven approach combined with new technologies that
“crowd-source” feedback and “data” from thousands of participants in real time
allows the delivery of program content to be adapted to multiple circumstances,
contexts, and situations while remaining unique to individual users. Hence, while
traditionally delivered health education and health promotion programs can be
tailored for small numbers of individuals, new technologies can deliver highly
personalized, standardized, and tailored messages to whole populations (Oldenburg
et al. 2015) This is one of the reasons why the use of new technology for program
delivery may be particularly advantageous in developing countries (Peiris
et al. 2014).
The rapid evolution and uptake of smartphones and handheld computers will
inevitably lead to increased uptake and use of social media for health programs,
allowing individuals to interact with, shape, and even disseminate their own
intervention messages through their social networks. However, it is vital that pro-
grams delivered using such platforms are designed and delivered with an under-
standing of the user experience, predicting how individuals will respond to, shape
and share program content and the ramifications of this (Chou et al. 2013; Coley
et al. 2013). For example, positive and derisive viewer comments could shape other
users’ evaluations of the credibility of certain health messages delivered via new
technologies (Walther et al. 2010).
With some notable exceptions, the majority of published lifestyle change interven-
tion trials have still only achieved modest outcomes, even when evaluated under
controlled conditions. Further, the implementation and dissemination of such pro-
grams under more “real-world” settings is often poorly evaluated (Glanz
et al. 2008), diluting already modest effects. The Diabetes Initiative of the Robert
Wood Johnson Foundation in the United States evaluated the resources and sup-
ports for self-management of diabetes in various community settings. The program
identified six key supports for program success: individualized assessment and
tailored measurement; collaborative goal-setting; enhancement of key skills for
disease management, health behaviors, and problem solving; continuity of high-
quality, safe clinical care; ongoing follow-up and support; and a very important role
for supportive community resources (Fisher et al. 2011). The authors concluded that
the concept of “equifinality” is especially helpful for thinking about the way in
which such programs can work for individuals in community settings. In other
Changing Lifestyle Behaviors to Improve the Prevention and Management of. . . 1089
With a few notable exceptions, most published lifestyle intervention trials have
achieved only modest outcomes. Further, even when evaluated under controlled
conditions, their wider implementation and dissemination is seldom evaluated
(Glanz et al. 2008; Oldenburg and Glanz 2008). Moreover, intensive lifestyle
change interventions for people with minimal risk might not be particularly cost-
effective. Therefore, more population-based or upstream social and economic
interventions to reduce cardiovascular risk are likely to be more cost-effective.
Given the increasing pressures on limited resources for health care and prevention
in most countries, and the increasing burden of chronic diseases, it is important that
resources are prioritized for populations where the interventions will be most
effective and with the greatest reach.
If properly designed and implemented, lifestyle change interventions have
excellent potential to reduce CVD risk and to improve the quality of life and health
outcomes of those who already have CVD. Despite requiring more rigorous
research, early evidence points to the likely cost-effectiveness of some lifestyle
change interventions, even when compared to more traditional medical interven-
tions. The use of new technologies is an especially exciting recent development,
especially when combined with more traditional delivery approaches used by health
professionals, peer leaders, and others in health-care and community settings.
Given the very rapid increase of disease burden attributable to chronic
noncommunicable disease as a result of lifestyle behaviors in developing regions
of the world, these kinds of approaches urgently need further development and
adaptation to the growing health needs and challenges of the 80 % of the world’s
population living in these regions of the world (Beaglehole and Bonita 2008).
1090 B. Oldenburg et al.
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Physical Activity and Recovery from
Cardiovascular Disease: A Psychological
Perspective
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1096
Cardiac Rehabilitation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
Physical Activity and Post-MI Survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1097
Barriers to Physical Activity in Post-MI Survivors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1098
Depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
Socioeconomic Background and Neighborhood Socioeconomic Status (SES) . . . . . . . . . . 1100
Sense of Coherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1101
Anxiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Social Support . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1103
Risks of Exercise in Cardiovascular Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104
Methodological Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1104
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1105
Abstract
Lack of physical activity is a key risk factor for the development of coronary
heart disease, yet activity is decreasing in the modern world. Once cardiovas-
cular disease is present, physical activity is an essential ingredient of recovery
and rehabilitation. Heart patients who are regularly active have a much smaller
risk of dying compared with inactive patients. Several factors have been found to
be associated with the uptake and maintenance of physical inactivity in cardio-
vascular patients, including psychological, social, and socioeconomic factors.
This chapter will first describe the effects of physical activity on post-MI
survival and will subsequently examine issues which act as barriers to exercise
in this population.
Keywords
Physical activity • Myocardial infarction • Cardiac rehabilitation • Survival •
Depression • Anxiety • Socioeconomic status • Social support
Introduction
Physical fitness quantifies the ability of the lungs, heart, blood, and vascular system
to transport oxygen and the ability of the tissues and organs to extract and use
oxygen. Lack of physical activity is a key risk factor for many chronic illnesses, and
reams of evidence have accumulated over the years showing that a sedentary
lifestyle is a risk factor for CHD, yet physical activity is on the wane as Western
society becomes more urbanized, more automated, and less active. According to the
WHO’s European Health Report, 20 % of Europeans take little or no physical
exercise (WHO 2009). Physical inactivity has been estimated to cause approxi-
mately 600,000 deaths a year in Europe or 5–10 % of total mortality.
The twin burdens of inactivity and obesity are constantly on the increase leading to
higher risk of chronic illness. Healthcare professionals and government try to encour-
age and incentivize physical activity as a primary prevention strategy. Moderate to
high activity levels offer significant protection against developing CHD, as demon-
strated by numerous studies and meta-analyses; for example, a review of 26 studies
covering half a million people reported a 27 % reduced risk of CHD associated with
the highest category of activity (Sofi et al. 2008). Physical activity lowers CHD risk
via several pathways including lowering blood pressure, improving lipid profile,
decreasing obesity, and reducing levels of inflammatory markers.
What about secondary prevention? For patients who have already developed heart
disease and have suffered a myocardial infarction (MI), how does exercise fit into the
picture? In the past, the prevailing wisdom prescribed bed rest after MI and instilled
in heart patients a fear of exercise, with the suggestion that exercise could cause
overexertion and reinfarction. In recent years, the evidence has dispelled this myth,
and it is now widely understood – at least among healthcare professionals – that
physical activity is an essential ingredient of recovery and rehabilitation after MI. In
fact, the major component of most cardiac rehabilitation programs is exercise.
Physical Activity and Recovery from Cardiovascular Disease: A Psychological. . . 1097
Cardiac Rehabilitation
Beyond state-sponsored rehabilitation, what happens when patients are left to their
own devices? Do they continue to be active or fall back into old habits? With
improved cardiac care, patients now live longer after MI; therefore maintenance of
healthy lifestyle habits is essential, including maintaining an active lifestyle. Phys-
ical activity outside the framework of formal rehabilitation is also keenly associated
with improved prognosis in heart patients (Blumenthal et al. 2004; Al-Khalili
et al. 2007; Apullan et al. 2008). For example, a weekly session of exercise was
associated with lower all-cause mortality in CHD patients (Moholdt et al. 2008),
1098 V. Myers and Y. Gerber
while cardiac patients who engaged in exercise at least four times per week reduced
their risk of death and recurrent CHD by 30 % (Booth et al. 2014).
Results from a prospective cohort study: Since physical activity is an ongoing
lifestyle behavior with cumulative effects, prospective studies are useful for
assessing its relationship with health outcomes. The Israel Study of First Acute
Myocardial Infarction investigated the benefits of leisure-time physical activity
(LTPA) in an Israeli cohort of post-MI patients and the barriers to participation,
in an attempt to understand why so few heart patients are physically active (Gerber
et al. 2011). This longitudinal study followed patients aged 65 years from initial
hospitalization for first acute MI over 10–13 years, collecting data on socioeco-
nomic, clinical, psychological, and cardiovascular risk factors, including leisure-
time physical activity (LTPA), on five separate occasions. Participants self-reported
their activity levels including frequency, duration, and type of activity, including
walking, cycling, swimming, gardening, going to the gym, and team sports. These
responses were summarized into three groups: inactive, irregularly active, and
regularly active patients. Regular physical activity was defined as at least three
30-min sessions per week, according to published guidelines at the time (Pate
et al. 1995), although these guidelines have since been updated and increased to
30 min of moderate activity five times a week or 20 min of vigorous activity three
times a week. The study found a point prevalence rate of 40 % for regular LTPA
among MI survivors and a continuous rate of 18 % at 10 years post-MI.
Individuals who were regularly active had about half the risk of dying com-
pared with inactive patients, irrespective of pre-MI habits. Just three short ses-
sions of activity per week – which could be walking, cycling, gardening, or
organized sports – were associated with doubled odds of survival. And impor-
tantly, this survival benefit occurred in both individuals who were previously
active and in those who had been previously inactive. Although we may imagine
the effects of physical activity as being cumulative and therefore change in mid-or
later life to be pointless, these results show this not to be the case. Similar to
smoking cessation after MI, taking up exercise has a real effect on prognosis,
demonstrating that it is never too late to get active. This message should be made
clear to patients who have suffered a heart attack or who have developed CHD. If
the true influence of activity levels on survival was more widely understood,
people might be more inclined to take part.
Of course, motivation is not the only resource required for getting active.
Evidence has clearly shown that a sedentary lifestyle is a risk factor for developing
CHD. Previous research has further suggested that physical activity may be equally
vital in secondary prevention, for those who have already suffered an MI. However,
exercise participation is low in this population. Furthermore, typically only 50 % or
less of individuals who start an exercise program will continue. Several factors have
been identified which act as barriers to exercise participation in CHD patients.
Physical Activity and Recovery from Cardiovascular Disease: A Psychological. . . 1099
Research in CHD patients has focused on links between physical activity and
mental health, for example, depression, or has examined psychological constructs
which predict initiation and maintenance of physical activity, including perceived
control and sense of coherence (Allan et al. 2007; Petter et al. 2009). A recent
cohort study of all patients hospitalized with first MI within a year in central
Denmark reported a significant increase in death and reinfarction associated with
decreasing mental health status (measured via the SF-12 (Short-Form Health
Survey)) (Nielsen et al. 2013). Patients with the poorest mental health had almost
50 % higher risk of new cardiovascular events or death.
Depression
Depression is generally more prevalent in CHD patients and up to three times more
common in MI patients compared to the general population (Thombs et al. 2006).
Literature consistently puts the incidence of depressive symptoms in post-MI
populations at around 30 %, as assessed by the Beck Depression Inventory (BDI)
(Frasure-Smith et al. 1999; Lane et al. 2002a; Strik et al. 2004; Thombs et al. 2006;
Leung et al. 2007), while the presence of major depression, diagnosed by clinical
interview, has been reported in 15–20 % during hospitalization (Schleifer
et al. 1989; Lichtman et al. 2008). Depressive symptoms may persist several
months after MI (Schleifer et al. 1989; Strik et al. 2004).
cardiac rehabilitation – and lifestyle factors including diet, exercise and smoking
have a clear influence on prognosis. Research has shown that depressed patients are
less likely to engage in these behaviors. For example, depressed acute coronary
syndrome patients (BDI >10) were less adherent to aspirin than nondepressed
patients, and improvements in depression were associated with improvements in
adherence (Rieckmann et al. 2006).
Post-MI patients with depressive symptoms are less likely to be physically active
than nondepressed patients. Depression is also linked to increased risk of mortality
post-MI as well as increased hospital admissions during follow-up and lack of
exercise factors into the equation. A prospective cohort study of MI survivors found
that depressed patients were less likely to be physically active (OR, 0.80, CI,
0.69–0.94) than nondepressed patients, alongside reduced likelihood of stopping
smoking (OR, 0.75, CI, 0.60–0.94) and participating in cardiac rehabilitation (OR,
0.74, CI, 0.59–0.92) (Myers et al. 2011a). Moreover, depressed patients had a 50 %
higher risk of hospitalization for unspecified chest pain compared to nondepressed,
which was attenuated to 16 % on adjustment for sociodemographic and clinical
factors, and a 30 % (crude) increased risk of hospitalization for cardiac events,
reduced to 13 % when fully adjusted for covariates. Since depression is common
following MI, with reported prevalence of around 30 %, including 15–20 % who are
diagnosed with major depression, this is a sizeable problem (Strik et al. 2004).
60%
Lowest SES Highest SES
50%
40%
30%
20%
10%
0%
3-6 months 1-2 years 5 years 10-13 years
Fig. 1 Point prevalence of LTPA according to neighborhood SES tertiles in a post-MI cohort
odds ratios (95 % CI) for decreased LTPA level in the lower and middle vs. upper
neighborhood SES tertiles were 2.49 (2.05–3.02) and 1.60 (1.33–1.92) after age and
sex adjustment and 1.55 (1.26–1.90) and 1.23 (1.02–1.49).
Neighborhood wealth or deprivation affects the amount of physical activity
people do for a number of reasons which generally fall into physical and social
elements. Physical characteristics such as access to facilities, lighting, and accom-
modation for pedestrians may present physical barriers to exercise, while social
norms of the neighborhood or perceptions of safety or lack thereof may present
psychological barriers.
Recommendations for physical activity should be supported by appropriate
infrastructure and the provision of free or low-cost sports facilities in areas of
deprivation. Exercise-based rehabilitation should be available to all MI survivors,
with special efforts made to encourage participation in patients from deprived
neighborhoods.
Sense of Coherence
60
Point prevlance of LTPA (%)
50
40
30
20
10
0
Per-MI 3-6 months 1-2 years 5 years 10-13 years
Timepoint during follow-up
lifestyle changes – individuals with low SOC may perceive their condition as
overwhelming and beyond their capability to overcome, heeding implementation
of preventive behaviors such as exercise.
An individual’s SOC is based on the presence or absence of generalized resis-
tance resources (Antonovsky 1979). In the case of physical activity, these may
include material and financial resources necessary to engage in sports such as gym
membership or equipment; social support, for example, encouragement from a
partner; flexibility; knowledge; and physical health status.
SOC, a summary measure of personal, social, psychological, and economic
resources, may be used to facilitate identification of high-risk MI survivors. It is
easy to determine with a simple questionnaire and can help to identify patients who
are less likely to incorporate physical activity in their daily life, who may require
additional support in implementing preventive health behaviors, which can dramat-
ically improve post-MI prognosis.
Anxiety
Anxiety is another factor which may affect uptake of exercise in CHD patients and
is fairly prevalent following acute coronary events, particularly in younger patients
(Lavie et al. 2009). In a group of MI patients assessed for anxiety during hospital-
ization and 4 months later, anxiety was associated with poorer adherence to
exercise, in addition to lower likelihood of smoking cessation (Kuhl et al. 2009).
On the other hand, participation in cardiac rehabilitation has the potential to reduce
anxiety, as reported by a cardiac rehabilitation nursing team which assessed patients
with the hospital anxiety and depression scale. Patients waiting the longest to start
rehab had the highest anxiety scores (Harrison 2005). Another study of patients
with coronary artery disease also demonstrated significant reductions in anxiety
following participation in exercise training and rehabilitation (Lavie et al. 2009).
While rehab may help to reduce anxiety, some patients remain anxious during or
after completion of rehab, necessitating psychological intervention. Cognitive
behavior therapy has been demonstrated as useful in alleviating both anxiety and
depression post-MI (Hambridge et al. 2009).
Social Support
Social support impacts on many areas of life including health outcomes. Social
support comprises several elements, including functional/instrumental, emotional,
and perceived support as well as size of network. In the context of recovery from
MI, the ENRICHD trial followed MI patients with either depression or low social
support (Lett et al. 2007) and found that higher levels of perceived social support
were associated with improved outcome for nondepressed patients but not for
patients with high levels of depression. Quality of relationships is often more
important than their mere existence, with marital quality additionally found to be
1104 V. Myers and Y. Gerber
Methodological Considerations
report questionnaire, although some studies stipulate the use of the Beck Depres-
sion Inventory or clinical interview for diagnosis of clinical depression.
Most studies of physical activity in heart patients are observational and thus
preclude drawing of causational conclusions. While consistent evidence supports
the association between exercise and survival, it is possible that selection bias is
involved, with fitter, healthier patients being more active than their more poorly
contemporaries.
Conclusion
Physical activity confers a survival advantage on post-MI patients, yet the majority
of patients are not regularly active. Regular physical activity has been shown to
halve the risk of dying compared with inactive patients, irrespective of pre-MI
habits. The advantages of physical activity clearly outweigh the risks in this
population, and it is up to healthcare professionals to advise their patients on the
importance of exercise and to encourage participation.
Several factors predict uptake of activity post-MI. Patients living in disadvan-
taged neighborhoods have far greater odds of inactivity, regardless of their own
SES. A strong sense of coherence is associated with greater levels of activity after
MI, suggesting that SOC may be involved in the maintenance of health behaviors.
Depressed patients are less likely to be active. Depressed heart patients not only
experience reduced quality of life but indeed have higher mortality risk and are at
risk of reinfarction. Anxiety and depressive symptoms should be identified during
hospitalization and taken into account in this population and efforts made to enroll
patients in exercise-based cardiac rehabilitation.
The low engagement in LTPA in MI patients attests to the difficulties involved in
maintenance of an active lifestyle, particularly in deprived neighborhoods. All MI
patients should be offered exercise-based rehabilitation, and practitioners should
follow up after the official rehabilitation period is over. Beyond rehabilitation, it is
clear that encouraging exercise is not sufficient and that appropriate infrastructure
must be available to put this into practice, providing free or non-expensive facilities
for sports, as well as infrastructure for active commuting. During initial hospital-
ization for MI, patients can be assessed via simple psychological measures to
determine which are less likely to get active and therefore need added support.
Research demonstrates that for heart patients, it is never too late to get active.
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Obesity: Its Relationship with
Cardiovascular Disease and Management
Elizabeth Rieger
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110
The Relationship Between Obesity and Cardiovascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1111
The Management of Overweight and Obesity: Behavioral Interventions . . . . . . . . . . . . . . . . . . . . 1113
The Management of Overweight and Obesity: Pharmacological and Surgical
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1118
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1120
Abstract
The serious worldwide challenge posed by the prevalent, and increasing, prob-
lem of obesity is well known. Obesity places a substantial health burden on
affected individuals, including cardiovascular disease, although the complex
biopsychosocial pathways linking obesity with cardiovascular disease have yet
to be fully explicated. Three primary approaches have been investigated as
treatments for obesity, namely, behavioral (lifestyle) weight-loss programs,
pharmacotherapy, and bariatric surgery. Behavioral weight-loss programs (and
pharmacotherapy) have been found to result in modest weight losses and reduc-
tions in cardiovascular risk factors (e.g., a significantly reduced rate of type
2 diabetes). However, the impact of these programs on cardiovascular morbidity
and mortality has been inadequately investigated, with the few studies conducted
yielding inconsistent results. Any capacity of behavioral weight-loss programs
to reduce cardiovascular disease end points is likely to be limited by the transient
nature of treatment-induced weight losses, with weight regain the normative
response to these programs. Bariatric surgery has been found to yield large and
E. Rieger (*)
Research School of Psychology, ANU College of Medicine, Biology and Environment, Australian
National University, Acton, Canberra, ACT, Australia
e-mail: [email protected]
Keywords
Obesity • Body mass index • Waist circumference • Behavioral weight-loss
program • Lifestyle intervention • Weight loss • Weight-loss maintenance
Introduction
activity, and alcohol intake) for the assessment of absolute cardiovascular disease
risk (National Vascular Disease Prevention Alliance 2012).
While the preceding research relates to adults, childhood overweight/obesity is
also a predictor of increased mortality, primarily as a result of its association with
increased cardiovascular risk. For instance, Franks et al. (2010) found that the
mortality rate from endogenous causes over a 24-year period for children in the
highest BMI quartile was more than twice that of children in the lowest BMI
quartile. Another study reported that, compared to their lean counterparts, male
adolescents who were classified as overweight experienced a relative risk of 2.3 for
mortality from coronary heart disease in the 55-year follow-up period (Must
et al. 1992). Highlighting the importance of interventions for childhood obesity,
the incidence of cardiovascular risk factors in obese children who become nonobese
by adulthood may be comparable to that of individuals who were never obese
(Juonala et al. 2011).
There are multiple and complex pathways through which excess body fat is
thought to influence cardiovascular health (for an overview see, e.g., Eckel
et al. 2005; Gustafson 2010; Lau et al. 2005; Van Gaal et al. 2006). Research
suggests that obesity contributes to elevated cardiovascular disease risk both
independently and through the development of other cardiovascular disease risk
factors (Caterson et al. 2004). Regarding the latter, overweight and obesity result in
adverse metabolic effects leading to hypertension, dyslipidemia (i.e., increased
levels of triglycerides, small low-density lipoprotein [LDL] particles, and very
low-density lipoprotein [VLDL] cholesterol, as well as reduced levels of high-
density lipoprotein [HDL] cholesterol), and insulin resistance, all of which are risk
factors for coronary heart disease and stroke (WHO 2011). While adipose tissue
was traditionally conceptualized as a passive depository for triglycerides and a store
for excess free fatty acids to be released as needed, it is now known to be an active
endocrine organ (Lau et al. 2005). The increased adipose tissue mass of obesity
(especially abdominal obesity) secretes elevated levels of numerous bioactive
molecules (e.g., interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) and
can impede the secretion of others (e.g., adiponectin), thereby having a negative
impact on cardiovascular health through altered lipid levels, insulin resistance,
vascular tone, coagulation, fibrinolysis, inflammation, and atherosclerosis (Van
Gaal et al. 2006). Much research continues to be undertaken in order to clarify
the complex biological pathways through which overweight and obesity contribute
to cardiovascular disease.
Relative to the abundant research on the biological mechanisms underpinning
the obesity-cardiovascular disease link, investigating potential psychosocial mech-
anisms mediating this relationship has been neglected. However, it has been
proposed that the stigmatization experienced by obese individuals comprises a
chronic stressor that may lead to adverse cardiovascular health outcomes
(Gearhardt et al. 2012; Puhl and Latner 2007). Certainly, the widespread experience
of stigmatization of obesity has been extensively documented in overweight and
obese children, adolescents, and adults, occurring in the media and interpersonal,
educational, employment, and healthcare settings. While studies have highlighted
Obesity: Its Relationship with Cardiovascular Disease and Management 1113
Obesity has humbled one research group after another. Some of the field’s brightest
scientists have attempted to subdue obesity by treating it, but now, after decades of work,
treatment gains remain small, maintenance is poor, and the field produces effects far below
what patients want or expect. (p. 717)
How best to proceed based on this summation of the field has generated some
controversy, with four (not necessarily mutually exclusive) discernable views. The
first has been to view obesity as a chronic condition, requiring long-term, even
lifelong, treatment (Latner et al. 2000; Mauro et al. 2008). There is certainly
evidence to support the maintenance of weight losses in obese adults who have
participated in extended behavioral programs. Unfortunately, extending treatment
beyond the usual 6–12 months of intervention usually only serves to delay (until
after treatment ends) rather than prevent weight regain (Perri and Corsica 2002) and
can suffer from the limitation of being associated with declining patient attendance
(e.g., one study reported an average attendance of 72 % of sessions during the first
6 months of weight-loss treatment but only 49 % over the subsequent 12 months of
maintenance treatment) (West et al. 2011). There is some evidence that highly
intensive and extended interventions are capable of yielding maintenance of lost
weight. In this regard, a unique study found that a six-week day patient program
followed by 4 years of weekly sessions (and readmission to the day patient program
as needed, with 63 % of patients being readmitted at least once) resulted in weight
losses being maintained over the subsequent 10–12-year period (Björvell and
Rössner 1985, 1992). However, extended, intensive interventions are limited by
the substantial demands (and, indeed, unrealistic demands given the prevalence of
obesity) placed on healthcare services.
A second viewpoint is to conclude that behavioral approaches are ineffective for
the treatment of obesity and to recommend that this line of psychological research
be abandoned to instead focus on prevention (Cooper et al. 2010). Preventative
efforts highlight the environmental factors (i.e., the high availability and accessi-
bility of energy-dense foods combined with conditions that encourage sedentary
behavior) underpinning the obesity epidemic and, hence, suggest strategies such as
1116 E. Rieger
targeting food and physical activity policies in schools and food marketing to
prevent weight gain (Brownell 2010; Gearhardt et al. 2012). Yet given the high
prevalence of overweight/obesity, and the fact that medical interventions have
limitations in the treatment of obesity and also require behavior change, there is
still a strong need for developing effective behavioral interventions alongside
prevention-oriented research.
Hence, the third view is to encourage innovative approaches in order to develop
behavioral weight-loss programs that support long-term weight control while still
being realistic and cost-effective solutions translatable to existing healthcare sys-
tems. As advocates of this perspective, Jeffery and Levy (2010) state that, “behav-
ioral research specifically on the issue of weight loss maintenance is young, and in
our view has barely scratched the surface of possible research questions” (p. 715).
Among just some of the innovative lines of research being pursued with the aim of
yielding improved weight-loss maintenance in a cost-effective manner are training
individuals from the obese person’s social network to provide effective weight
management support so that continued support is available to the obese person after
treatment cessation (Rieger et al. 2014), the use of technological approaches (e.g.,
text messaging, Internet-based treatment programs, e-mail contact, and prerecorded
webinars) that can increase the intensity and duration of interventions without the
need for intensive involvement by health professionals (Neve et al. 2010; Svetkey
et al. 2008), and, given the finding that intrinsic motivation for weight control
predicts weight-loss maintenance (Williams et al. 1996), the use of motivational
interviewing (Hardcastle et al. 2013).
The fourth and final response to the data on weight regain following the
cessation of behavioral programs is to propose that these outcomes nevertheless
have some merit. Specifically, individuals who eventually return to their baseline
weight after participating in a behavioral weight-loss program may still weigh less
than they would have without treatment given that many adults are prone to weight
gain over time. For instance, one study found that Australian adults gained a mean
1.4 kg during a 5-year period, with participants in the 25–34-year age group gaining
a mean 3.5 kg over this time (Barr et al. 2006). As Jeffery and Levy (2010)
maintain, “we find the idea appealing that in a society where weight gains of half
a kilogram per year are normative in adults through much of their life span,
stabilization of weight for several years is a good clinical result” (p. 715). It should
be noted, however, that it remains to be determined if weight cycling (i.e., weight
loss followed by weight regain) itself poses a risk to health, although one study
found no increase in the risk of developing hypertension among women who had
experienced severe weight cycling in the context of intentional weight loss (Field
et al. 1999).
In contrast to the data on obese adults, there is stronger evidence for the
effectiveness of behavioral interventions in producing long-term weight-loss main-
tenance in obese children. Specifically, family-based behavioral programs – in
which the eating and physical activity patterns of both the child and parent are
targeted, and parents are taught techniques to support behavior change in their
children – have been consistently found to be efficacious in the long term
Obesity: Its Relationship with Cardiovascular Disease and Management 1117
(Epstein et al. 2007). A recent study also reported promising findings for the
maintenance of weight loss 2 years after a 16-week cognitive-behavioral program
among obese adolescents (Lloyd-Richardson et al. 2012). The greater success of
behavioral programs in obese children is likely contributed to by the fact that it is
easier to mobilize family support for children, unhealthy eating and physical
activity patterns are less entrenched in children, youth are generally more physi-
cally active than adults, and weight stabilization (rather than weight loss) may be a
sufficient treatment goal given increases in height throughout childhood
(Katzmarzyk et al. 2014).
The effectiveness of behavioral programs in terms of improved cardiovas-
cular outcomes. While dissatisfaction with the weight outcomes attained through
behavioral programs has been expressed by obese individuals and researchers alike,
there is evidence to suggest that such programs can yield noteworthy improvements
in medical indices, including cardiovascular disease risk factors (Douketis
et al. 2005; Galani and Schneider 2007; Shaw et al. 2005). For instance, the
Diabetes Prevention Program demonstrated significant reductions in the incidence
of type 2 diabetes in high-risk individuals after they participated in a behavioral
weight-loss intervention, namely, the prevention of 58 % of new cases after 4 years
(Diabetes Prevention Program Research Group 2002) and 34 % of new cases after
10 years (Diabetes Prevention Program Research Group 2009) relative to the
control group. Significant reductions after 10 years were also evident in systolic
and diastolic blood pressure, LDL cholesterol, and triglycerides, along with a
significant increase in HDL cholesterol; these positive changes in cardiovascular
disease risk factors were comparable in the behavioral, medication, and control
groups despite the fact that those in the behavioral intervention used significantly
less blood pressure and lipid-lowering medication (Diabetes Prevention Program
Outcomes Study Research Group 2013). The beneficial effect of a behavioral
weight-loss program on weight and cardiovascular disease risk factors has also
been found in overweight and obese patients with established type 2 diabetes, both
immediately after the 1-year intervention and 4 years later (Look AHEAD Research
Group 2007, 2010).
However, these significant reductions in risk factors for the behavioral interven-
tion did not translate to decreased cardiovascular morbidity and mortality compared
to the control group after a median follow-up of 10 years (Look AHEAD Research
Group 2013). One possible explanation for this unexpected finding is that there was
insufficient difference in weight loss between the behavioral and control interven-
tions at the 10-year follow-up (mean weight loss of 6 % of initial body weight
versus 3.5 %, respectively) to yield differential rates in cardiovascular events. In
addition, the significantly higher use of statins in the control group and medical
management during the period following the intervention may have diminished
differences in cardiovascular disease end points between the behavioral and control
groups.
There has been some research suggesting that behavioral weight-loss programs
result in reduced rates of morbidity and mortality. For instance, in a study on older
overweight and obese older adults, participation in an 18-month weight-loss
1118 E. Rieger
program was associated with a reduced risk of overall mortality (Shea et al. 2010),
suggesting that the increased mortality rate associated with weight loss found in
some studies on older adults may be due to unintentional (e.g., illness-induced)
weight loss (Stevens et al. 2015). In addition, a review reported significantly fewer
fatal and nonfatal cardiovascular events for individuals with type 2 diabetes or
hypertension following a lifestyle intervention (Ebrahim et al. 2011). Yet, since the
reviewed studies included interventions targeting multiple risk factors (i.e., weight
loss, diet, physical activity, smoking, alcohol use, stress management, and/or
medication compliance), the precise role of weight loss in achieving these reduc-
tions in cardiovascular morbidity and mortality remains unknown. Clearly, research
is needed to determine whether behavioral weight-loss programs in obese individ-
uals are effective in reducing cardiovascular disease beyond their effects on weight
and cardiovascular disease risk factors.
For those obese individuals (or overweight individuals with a BMI > 27 and
medical comorbidities) for whom behavioral weight-loss programs alone are inef-
fective, the addition of weight-loss medications and/or bariatric surgery may be
considered (National Health and Medical Research Council [NHMRC] 2013).
Pharmacological interventions. The mechanism of action of obesity medica-
tions entails either appetite suppression (e.g., phentermine) or reduced absorption of
ingested fat (e.g., orlistat). In their systematic review, Yanovski and Yanovski
(2013) reported that, in combination with lifestyle interventions, medications
induced additional weight losses relative to placebo of 3–9 % of initial body weight
after 1 year. At this time, an estimated 35–70 % of patients treated with medication
experienced a clinically meaningful weight loss (i.e., at least 5 % of initial body
weight), together with greater reductions in cardiovascular risk factors compared to
patients receiving placebo. In adolescents, a meta-analysis found that medication
compared to placebo yielded an additional 2–13 % loss of initial body weight after
at least 6 months (Czernichow et al. 2010).
However, to date, no weight-loss medication has been shown to significantly
reduce cardiovascular morbidity and mortality (Yanovski and Yanovski 2013).
Furthermore, the adverse side effects of medications, combined with their modest
effects on weight loss, may result in their discontinued use. For example, while
orlistat is one of the few obesity medications approved for long-term use (Anthes
2014; NHMRC 2013), few patients continue its use over time. Specifically, less
than 10 % of patients prescribed orlistat have been found to take it for at least
1 year, with this medication potentially producing considerable gastrointestinal side
effects (Yanovski and Yanovski 2013).
Surgical interventions. Bariatric (weight loss) surgery for obesity is considered
when all other measures have emphatically failed (NHMRC 2013). Various surgi-
cal procedures entailing modification of the gastrointestinal system have been
Obesity: Its Relationship with Cardiovascular Disease and Management 1119
utilized, which aim to reduce weight and maintain these weight losses through
restriction of food intake (e.g., adjustable gastric banding entails placing a
constricting ring around the upper part of the stomach) possibly in combination
with malabsorption of food (e.g., along with restricted food intake, gastric bypass
results in the lower stomach, duodenum, and first portion of the jejunum being
bypassed). Each procedure necessitates postsurgical changes to eating behavior,
although these changes are greater for purely restrictive procedures compared to
those with a malabsorption component. Hence, behavioral techniques for assisting
obese patients to alter their eating behavior are also essential in the surgical context.
This assistance is particularly important for patients who engage in binge eating and
other forms of disordered eating, with postsurgical disordered eating a robust
predictor of significantly lower weight losses (Colles et al. 2008; Niego et al. 2007).
Bariatric surgery has been consistently found to result in greater weight-loss than
nonsurgical interventions (Colquitt et al. 2009) and to produce substantial weight
loss in obese adults. One study reported the loss of 20–32 % of initial body weight
(depending on the type of procedure) 1–2 years after surgery and, importantly,
given the challenges of weight-loss maintenance, losses of 14–25 % of baseline
weight over a 10-year period (Sjöström et al. 2007).
In addition to the large and sustained weight losses that can be attained by
obese adults following bariatric surgery, there are also improvements in cardio-
vascular disease risk factors, including significant reductions in hypertension and
improvements in lipid profiles, some of which remain unchanged after 10 years
(Sjöström et al. 2007). As is the case with research on behavioral weight-loss
programs and pharmacotherapy for obesity, studies evaluating the effects of
surgery on cardiovascular events are lacking but the preliminary findings are
promising (for a systematic review and meta-analysis, see Kwok et al. 2014).
For example, one study found that, after a median follow-up of 15 years, there was
more than a 50 % reduction in cardiovascular deaths in surgical compared to
nonsurgical obese patients (Sjöström et al. 2012). There were also significantly
fewer first time cardiovascular events (myocardial infarction or stroke) in the
surgical patients.
Yet despite the sustained weight loss and subsequent improvements in cardio-
vascular disease risk factors, morbidity, and mortality evident in surgical patients,
bariatric surgery also has several noteworthy limitations. Bariatric surgery is a
major surgical intervention that carries a risk of early and late morbidity (which
may necessitate a revision or reversal of the procedure) and perioperative mortality.
In one study, perioperative complications (such as bleeding, thromboembolism, and
abdominal infection) were experienced by 13 % of patients, with 2.2 % of patients
requiring reoperation (Sjöström et al. 2007). There were also five deaths (0.25 %) in
the 90 days following surgery. Over the subsequent 10-year period, 17–31 % of
patients (depending on the type of surgical procedure) required reoperations or
reversals. Moreover, the rate of adverse events reported from surgical centers of
excellence may be an underestimate of those occurring in the general medical
community (NHMRC 2013). There is also the suggestion in the literature that
bariatric surgery is associated with an elevated rate of completed suicide
1120 E. Rieger
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Part VII
The Summing Up: From
Evidence to Practice
Psychocardiology Now and Where the
Evidence Promises to Take Us in the Future:
A Summing Up
Contents
The Evidence Now: Presentations in the Handbook of Psychocardiology . . . . . . . . . . . . . . . . . . . 1127
Signposts for Future Research and Practice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1138
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1142
Keywords
Cardiovascular disease (CVD) • Psychocardiology • Cardiac Psychology •
Stress, Psychopathology and Cardiovascular Disease • Anxiety • Personality •
Psychobiological mechanisms • Psychological management of, patients • Life
style of, cardiac patients • Depression
The link between heart and mind is now so well established that it can no longer be
considered a farfetched speculation; rather there is now a robust body of respectable
empirical and clinical evidence which strongly asserts the nature of this relationship
as both congruous and complimentary. It is now clear that strong emotional distress,
whether in the context of acute or chronic stress or from mental illness, is commonly
reciprocated by elevated risk factors for cardiovascular disease (CVD) and increased
cardiac morbidity and even cardiac mortality. The Handbook of Psychocardiology is
the first fully comprehensive volume examining this now accepted heart/mind nexus.
The book showcases a unique collaboration between research scientists and clini-
cians across the fields of behavioral medicine and psychology, neuroscience, cardi-
ology, and psychiatry. It was by bringing together such a seemingly diverse and
eclectic mix of scientists and practitioners that we have been able to fully highlight
the commonalities and complimentary aspects of this relationship.
In examining the contents of this volume, readers will note that we have
categorized the book into six sections. The first section looks at The Foundations
of Cardiac Psychology. Here the needs and motivations for the Handbook are
eloquently outlined in chapters “▶ Psychogenesis and Heart Disease Now: The
Thinking Heart in Action” and “▶ Cardiac Psychology: Ancient and Modern
History”, moving from the poetic observations of yesteryear to Esler and Schwarz’s
journey to the modern day picture of cardiac psychology. This is indeed a journey
which takes us from the anecdotal to empirical research and to the origins of
behavioral medicine in CVD research. The Handbook then moves to provide us
with an overview of the principal organ at the center of our exploration, namely, the
heart, by giving a detailed outline of its anatomy and mechanics and providing us
with an intricate yet gentle introduction to cardiology for the non-cardiologist,
which comprehensively covers current trends in cardiology as well as a clinically
relevant discussion of cardiovascular disorders.
The seminal work of the Framingham studies, which led to the identification of
risk factors, both behavioral (such as a sedentary lifestyle and smoking) and
biological (such as hypercholesterolemia, hypertension, and diabetes), has given
way to an increased awareness of ways to lower the risk factors responsible for the
development of heart disease. The worldwide framework for tobacco control and
other public health measures such as collaboration with the food industry are
proposed solutions (Reid, chapter “▶ Epidemiology of Cardiovascular Disease”)
as are such individual approaches as reducing “sitting time” and “screen time”
during our day (Vaddadi, chapter “▶ Cardiovascular Risk Factors: Role of Life-
style”). Evidence suggests that over 80 % of cardiovascular risk factors have a
behavioral component (Oldenburg et al., chapter “▶ Changing Lifestyle Behaviors
to Improve the Prevention and Management of Cardiovascular Disease”). Close
examination of the motivations for taking up and maintaining chronic tobacco
consumption is therefore undertaken by looking at the origins of smoking in
adolescence (chapters “▶ Cardiovascular Risk Factors: Role of Lifestyle,”
“▶ Smoking and Cardiovascular Risk: Role of Stress in the Genesis of Smoking
Behavior” and “▶ Smoking and Cardiovascular Risk: Role of Personality in Ado-
lescent Smoking”). There is a plethora of work which highlights late adolescence
and early adulthood as the most pivotal period in life to develop mental illnesses
(AIHW 2003; Rotter and Smith 1995), and it could very well be that it is here that
the onset of other behaviors which place the individual at an increased risk of heart
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1129
(Lifestyle of Our Kids) study makes a predictive estimate of risk factors associated
with the development of CVD in later life by tracing insulin resistance and fitness
deficits to early distress and depression in young children. Olive et al. (chapter
“▶ Childhood Stress, Emotional Distress, and Cardiovascular Function in Adoles-
cents”) shift the focus from childhood to adolescence by examining the effect of
psychosocial stress and depression on endothelial function and the measure of
arterial stiffness, both predictive markers of future heart disease. These two chap-
ters highlight the need for primary prevention health strategies at the level of
childhood and adolescence, with the message essentially being that looking after
the mental well-being of children and adolescents today translates to ensuring
future adults are at lower risk of CVD.
At the other end of the lifespan, stress associated with the sense of loss also
significantly affects cardiac health. As the proportion of older persons increases,
examining the effect of bereavement and its impact on their heart becomes more
significant. Bartrop et al. (chapter “▶ Bereavement and the Risk of Cardiovascular
Disease”) highlight the effect that the loss of a loved one has on the surviving spouse,
giving yet again an appreciation of the neurobiological processes and mechanisms
associated with one of life’s greatest stressors, normally experienced at the later
stages of life. This very pertinent chapter highlights the importance of identifying
even culturally expected, indeed universal, psychological distress in cardiac practice.
Chapter “▶ Anxiety and Cardiovascular Disease: Epidemiology and Proposed
Mechanisms” examines the other main psychiatric disorder associated with cardiac
morbidity and mortality, namely, anxiety. Patients with CVD tend to manifest
intense anxiety, particularly after recovering from acute cardiac events. Yet the
role of anxiety in heart disease has not received as much attention in the literature as
has depression. Epidemiological studies indicate that there is an increased risk of
sudden death and myocardial infarction in patients experiencing panic anxiety and
the pathophysiologic correlates of anxiety appear to contribute logically and casu-
ally to an increase in cardiac risk, leading to the appreciation that anxiety disorders
might in fact constitute a risk to life. Explanatory mechanisms of cardiac risk once
again point to the established link between anxiety and heart disease being medi-
ated by stress and giving way to increased cardiac sensitivity and reactivity.
Vaccarino and Bremmer (chapter “▶ Posttraumatic Stress Disorder and Risk of
Cardiovascular Disease”) elaborate on the anxiety-heart disease relationship by
drawing special attention to the role of posttraumatic stress disorder as both a cause
and consequence of acute, life-threatening cardiovascular events. They highlight
the evidence that individuals with trauma tend to engage in adverse lifestyle
behaviors, such as smoking, which can worsen existing heart disease or predispose
individuals to the development of cardiac disorders. The pathophysiology of the
anxiety/heart disease relationship elaborates on and follows from the proposed
explanatory models outlined in chapter “▶ Anxiety and Cardiovascular Disease:
Epidemiology and Proposed Mechanisms” earlier. An understanding of the psy-
chobiological mechanisms involved in the development of CVD provides a plat-
form for appreciating the phenomena of sudden cardiac death as seen during and
right after experiencing natural disasters of one kind or another. Mulder and Zarifeh
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1131
post diagnosis is now seen as necessary. Chessa et al. (chapter “▶ Congenital Heart
Diseases”) and Callus and Quadri (chapter “▶ Psychosocial Aspects of Adults with
Congenital Heart Disease”) explain that this condition manifests behavioral and
psychiatric abnormalities in sufferers, leading these authors to suggest that psycho-
logical interventions should be commenced early and ideally, from childhood
(chapter “▶ Congenital Heart Diseases”), and should be continued throughout life
(chapter “▶ Psychosocial Aspects of Adults with Congenital Heart Disease”) to
ensure patients feel psychologically well adjusted to their condition. In valvular
heart disease (Gooley et al., chapter “▶ The Interaction Between Psychological
Health and Valvular Heart Disease: Pathogenesis, Clinical Course, and Treat-
ment”), where the patient is usually older as well as physically and emotionally
frail, psychological support and psychotherapeutic interventions, if appropriately
applied, can ensure a better quality of care for this cohort. Again, these suggestions
are important for improving current clinical practice in cardiac care.
Another condition receiving much attention is that of psychogenic syncope.
Vaddadi and Alvarenga (chapter “▶ The Psychosocial Impact of Syncope”) review
the psychosocial impact of this condition and point that cardiologists need to be
mindful of mental status in these patients as a key component in their management.
Indeed, the ability to bounce back (resilience) after having experienced an adverse
cardiac event is crucially important. Turner and O’Neil (chapter “▶ Psychological
Responses to Acute Coronary Syndrome”) examine the aftermath of surviving an
acute coronary syndrome and outline the role of attitudinal responses as clear
indicators of recovery or clinical deterioration. Murphy et al. (chapter “▶ Anxiety,
Depression, and Psychological Adjustment After an Acute Cardiac Event”) go on to
outline important considerations in the screening of depression and anxiety in
cardiac patients. Here we appreciate the importance of psychological input in
cardiac clinical practice, where elucidating patient’s beliefs and understanding
around illness assists in modifying any maladaptive beliefs which can act as a
barrier to treatment. Of course, being aware of psychological aspects is not merely a
matter of achieving clinical end points but it also assists in ensuring a higher quality
of life, both general and health related, in cardiac patients. Lazarewicz
et al. (chapter “▶ Quality of Life in Survivors of Myocardial Infarction”) propose
this and highlight the evidence that psychosocial characteristics (such as self-
esteem, self-efficacy, dispositional optimism, sense of coherence, and social sup-
port) can reliably predict improvements in survivors of myocardial infarction. The
importance of quality of life issues in cardiac patients has also been highlighted in
patients with implantable cardioverter defibrillators (Sears et al., chapter “▶ Psy-
chological Consultation for Patients with Implantable Cardioverter Defibrillator:
Confounding Challenges of Cardiac Disease, Technology, and the Patient Experi-
ence”) and after cardiac surgery and cardiac transplantation (Ackerman and Sha-
piro, chapter “▶ Psychological Effects of Invasive Cardiac Surgery and Cardiac
Transplantation”). Indeed, it is crucial to ensure that patients who undergo these
quite intrusive and invasive procedures feel psychologically adapted on board with
their treatment and better focused on their recovery, particularly as postsurgical
psychopathology is both conspicuously associated with impaired cognition (Bruce
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1133
In light of the evidence presented in the first three sections of the handbook, the
case for a clear psychogenic component to CVD is indeed strong. The fourth section
of this book, Psychology and Cardiovascular Biology – the Linking Mechanisms,
then offers a series of chapters which now go to specific explanatory psychobio-
logical mechanisms for the heart/mind relationship.
There is no doubt whatsoever that the cardiovascular system is under the direct
influence of the autonomic nervous system. At times of stress, such as during the
fight/flight response, there is acute activation of the sympathetic nervous system
(SNS) which normally returns to homeostasis once external stressors have passed.
However, chronic SNS activation is associated with initiation of disease processes
such as hypertension, atherosclerosis, insulin resistance, and cardiac dysfunction,
as may be seen, for example, in left ventricular hypertrophy and diastolic dys-
function. Lambert and Esler (chapter “▶ Role of the Sympathetic Nervous System
in Cardiovascular Disease”) present evidence for the pivotal role of the SNS in
generating cardio-metabolic illness. Examining how hypothalamic and amygda-
loid projections induce sympathetic nervous activation, it becomes clear that
sustained SNS influences hypothalamic signaling which not only increases glu-
cose production but also insulin resistance, leading to an increase in fat mass and
lipolysis (chapter “▶ Role of the Sympathetic Nervous System in Cardiovascular
Disease”), which in turn increase the risk of fatal and nonfatal CVD (Levitan
et al. 2004).
Keegan and Naumovski (chapter “▶ Insulin Resistance, Glucose Regulation,
Obesity, and Mood”) further examine this relationship while drawing parallels with
the effect depression and its influence on the SNS have on the development of Type
II diabetes, itself a powerful risk marker for CVD. Adriaanse and Pouwer (chapter
“▶ Diabetes, Depression, and Cardiovascular Risk”) also highlight the evidence
that depression can lead to cardiovascular complications in people with diabetes,
both through behavioral pathways and, again, through biological mechanisms
which implicate the role of the SNS. These chapters concur in that where obesity
is present, insulin resistance appears to be heightened, in turn influencing hypotha-
lamic signaling, such as can be seen in acute stress, leading to insulin resistance,
hyperglycemia, and eventually CVD. Clearly then, psychosocial stress and its
immediate psychobiological sequelae appear to be a fundamental aspect mediating
the heart/mind link. However, more work needs to be done in expanding our current
knowledge of the link between emotion, the development of Type II diabetes, and
eventual CVD.
Lambert and Esler (chapter “▶ Role of the Sympathetic Nervous System in
Cardiovascular Disease”) and Sverrisdottir (chapter “▶ Sympathetic Nerve Activ-
ity, Stress, and Cardiovascular Risk”) focus on the role of SNS overactivity and its
impact on the development of cardiac pathologies, particularly cardiomyopathy.
Immune dysregulation, and in particular, inflammation, is another area of focus
which can explain the effect that mental illnesses may have on cardiovascular
pathology (chapter “▶ Immunology, Inflammation, Mental Disorders, and Cardio-
vascular Risk”). Baune (chapter “▶ Immunology, Inflammation, Mental Disorders,
and Cardiovascular Risk”) examines immune dysregulation in clinical depression,
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1135
The phrase which comes immediately to our minds in summing up the Handbook of
Psychocardiology then is “Unity in Diversity.” It is perhaps a hackneyed phrase,
but it is one we think is particularly apt – the confluence of widely diverse
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1139
a similar magnitude to, say, cigarette smoking. And there is emerging evidence,
though perhaps somewhat more complex in its nature, that psychosis also consti-
tutes a CVD risk factor. Clearly, the field of mental illness and CVD risk is a field
ripe for further investigations of an intensive kind. But there is another issue here. It
now challenges clinical psychologists and psychiatrists, traditionally the front line
for the diagnosis and treatment of mental illness, to be well aware that their patients
may also be at risk of CVD – and to consider referral to cardiologists if there is any
indication that this may be the case.
The role of the psychosocial environment – commonly operationalized as stress –
in elevating CVD risk has always been just a little controversial, not so much because
the case in evidence does not exist for the link but because of the difficulties in
measuring stress and its psychosocial antecedents. Some of this controversy has now
been resolved with the development of more finely tuned psychometric instruments
and in the use of more novel technologies such as stress interview techniques. There
is also increasing evidence from technically sophisticated studies both in the field and
in the laboratory that stress defined in various ways (exposure to social stressors,
difficult cognitive challenges, and the like) can result in significant changes to
cardiovascular activity which may be prodromal to cardiac dysfunction. We will
note a little further on that the psychobiological links between the mind and heart are
now being extensively investigated in more and more sophisticated ways – but this is
part and parcel of what now seems very clear, that a continuing investigation into the
role of the psychosocial environment in clarifying links between the mind and heart is
now very definitely justified.
And on the matter of the psychosocial environment, there is increasing evidence
that particular domains of psychosocial stressors constitute particular risks for
CVD. One obvious example here is that of the unique stressors inherent in the
occupational environment; another confronts the neglected role of gender in deter-
mining the varying nature and impact of psychosocial stressors more broadly. It is
therefore concerning to us, as we evaluate the evidence here, that the definitive
prospective epidemiological study of psychosocial stress and CVD (in any of its
clinical manifestations) – a study with a sample size sufficient to endow strong
statistical power, using state-of-the-art-measures on all levels, and a long enough
follow-up period to allow the emergence of clear outcome variance – has yet to be
done. It would be a mammoth undertaking, expensive and time consuming, but it
would resolve – one way or another – one of the most longstanding controversies in
psychocardiology.
But no association between the mind and the heart, however statistically com-
pelling, can be sustained in the absence of clear, replicable, and ideally causal
evidence establishing the psychobiological mechanisms leading from one to the
other. The evidence presented in the Handbook has indicated not just one but three
very plausible and scientifically cogent pathways through which, with the benefit of
further accumulating research, this link may be confidently confirmed. The central
role of the autonomic nervous system when faced with both acute and chronic
stress, or in the presence of psychopathology, is perhaps first and foremost among
these. Another is the role of immunology and inflammation, again following the
Psychocardiology Now and Where the Evidence Promises to Take Us in the. . . 1141
so often that young people do not see the salience of modifying CVD risk at an
early age where even early signs of CVD are not present – but the evidence from
social psychology tells us quite clearly that these barriers can be overcome if only
we were to intelligently apply that evidence. The field of health risk behavior
modification and its potential for CVD prevention are just too compelling to be
left to drift along.
And then, there is the now incontrovertible evidence linking mental illness – and
particularly depression – with elevated risk for CVD. That evidence applies not
only to the initial clinical episode of CVD (typically but not always a myocardial
infarction) but also to the clinical course of the condition once the acute episode has
occurred and passed. Yet we are, as clinicians, not giving sufficient emphasis, we
believe, to researching the management of mental illness in the context either of
elevated CVD risk or of those patients having already experienced a clinical event
of CVD. And this is an area of research which so self-evidently requires more – and
better funded – research attention.
Finally, and as we have identified a little earlier, the issue of the psychobiolog-
ical mechanisms linking the mind with the heart is absolutely central to intervention
and patient management. A clearer specification of those mechanisms – and this is
well within what we could expect in the very near future, given appropriate
attention by high level research of an ongoing kind – has the inescapable potential
to provide direct and targeted guidelines for the management of those both with
elevated CVD risk and with already manifest clinical CVD. Systematic clinical
trials based on evidence coming from research into the psychobiological mecha-
nisms linking the mind and heart do not seem to us to be very far into the future – or
at least they should not be.
These are, of course, not the only domains of potential translation into practice
which we can see as emerging from the contributions offered in the Handbook of
Psychocardiology. Our readers will no doubt see more – we have simply identified
some meta-themes and we hope that you, the readers of this book, will draw your
own links between research and practice. It is our fervent wish, however, that we
have at least been able to provide you with the organizational framework, the
source material, the wealth of evidence, and so importantly the critical and schol-
arly accounts which the contributors of individual chapters have offered up, to
allow you then to draw your own conclusions and to take those conclusions – if it is
appropriate to do so – into your own work as scientists and clinicians.
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Index
Hypertension, 68, 669, 675, 748, 751–752, Interpersonal relationships, 501–503, 671–675,
885–888, 1034–1035 679
aversive stressors, 366 Interpersonal therapy, 967
brain norepinephrine turnover, 367 Interruption of the aortic arch (IAA), 433
clinical studies, 363 Intervention, 308–309, 312
early animal models of, 884 behavioural, 310
epidemiological evidence of, 884 face-to-face intervention, 311
epidemiological studies, 364 lifestyle, 310–312
epinephrine, 368 multimodal, 311
genetic makeup, role of, 884–885 psychological and psychotherapeutic, 312
neurogenic, 371–372 telephone-based intervention, 311
plasma cortisol, 368 Intervention, ICD
stress biomarkers, 366, 368 cognitive-behavioral therapy interventions,
stress-induced, 363, 365–366 985–988
sympathetic nerve cotransmitter, 368 non-traditional interventions, 989–991
sympathetic nervous system, 367, 369–370 pharmacological interventions, 988–989
Hypothalamic-pituitary-adrenal (HPA)-axis,
151, 811–819
J
Jenkins Activity Survey (JAS), 648, 658
I Job strain, 320–327
Illness perceptions, 491, 493–494, 503
Immune changes, bereavement, 236–238
Implantable cardioverter defibrillator (ICD), L
552–555, 968 Left atrial appendage, 35
anxiety, 984 Leisure time physical activity (LTPA), 1098
brief cognitive-behavioral interventions, Life events, 166
985 Life experiences, 444
cardiac rehabilitation, 990 Lifestyle, 310–311
cognitive, affective and behavioral and behavior change, 1079–1081
avoidance, 984 cardiac patients, 1137–1138
implantation, 982 change in CVD risk, 1078–1079
patient referral, 983 interventions, 1113–1114, 1118
pharmacological interventions, 988–989 Lifestyle of our Kids (LOOK) study, 197
quality of life, 985 CVD risk profile, 220
support groups, 989 health investigation, 218
technology-based treatments, 990–991 metabolic factors, 220
traditional cognitive-behavioral stress and depression, 223–224
interventions, 987–988 timeline and progress, 218
yoga and mindfulness, 989–990 types, 217
Index of microcirculatory resistance Lipids, 53–55
(IMR), 390 Locus of, control, 109
Inflammation, 770
depression and, 774
obesity and, 779–780 M
stress and, 777 Mechanisms depression vs. cardiovascular
and type 2 diabetes, 777 risk, 837–839
Insulin resistance, 753 Median sternotomy, 589
and brain involvement, 854–857 Meditation. See Mindfulness and meditation
and glucose regulation, 851–853 Mental disorders, 770
and obesity, 853 and cardiovascular risk factors, 771–772
Intermittent explosive disorder (IED), 669 in refugees, 716–717
Interpersonally sensitive disposition, 635–636 prevalence of, 715–716
1152 Index
U
Unstable angina (UA), 29–30 Y
Uplifts Scale, 153 Yoga, 1026, 1029–1031, 1033, 1035