Hypertension Research (2017) 40, 947–963

& 2017 The Japanese Society of Hypertension All rights reserved 0916-9636/17
www.nature.com/hr

REVIEW

The relationship between obesity and hypertension: an

updated comprehensive overview on vicious twins
Massimo Leggio1, Mario Lombardi2, Elisa Caldarone2, Paolo Severi1,2, Stefania D’Emidio2, Massimo Armeni3,
Veronica Bravi4, Maria Grazia Bendini5 and Andrea Mazza5

Obesity is a growing global health concern, with a rapid increase being observed in morbid obesity. Obesity is associated with an
increased cardiovascular risk and earlier onset of cardiovascular morbidity. The growing obesity epidemic is a major source of
unsustainable health costs and morbidity and mortality because of hypertension, type 2 diabetes mellitus, dyslipidemia, certain
cancers and major cardiovascular diseases. Similar to obesity, hypertension is a key unfavorable health metric that has
disastrous health implications: currently, hypertension is the leading contributor to global disease burden, and the direct and
indirect costs of treating hypertension are exponentially higher. Poor lifestyle characteristics and health metrics often cluster
together to create complex and difficult-to-treat phenotypes: excess body mass is such an example, facilitating a cascade of
pathophysiological sequelae that create such as a direct obesity–hypertension link, which consequently increases cardiovascular
risk. Although some significant issues regarding assessment/management of obesity remain to be addressed and the underlying
mechanisms governing these disparate effects of obesity on cardiovascular disease are complex and not completely understood,
a variety of factors could have a critical role. Consequently, a comprehensive and exhaustive investigation of this relationship
should analyze the pathogenetic factors and pathophysiological mechanisms linking obesity to hypertension as they provide the
basis for a rational therapeutic strategy in the aim to fully describe and understand the obesity–hypertension link and discuss
strategies to address the potential negative consequences from the perspective of both primordial prevention and treatment for
those already impacted by this condition.
Hypertension Research (2017) 40, 947–963; doi:10.1038/hr.2017.75; published online 5 October 2017

Keywords: cardiovascular risk; obesity

INTRODUCTION factors in overweight and obese patients is therefore of particular

During the past three decades, the worldwide prevalence of obesity has importance.6 Smoking, high blood pressure and elevated serum
nearly doubled, and the mean body mass index (BMI) has increased cholesterol levels represent major cardiovascular risk factors7 that
worldwide by 0.4 kg m−2 per decade for men and 0.5 kg m−2 per are routinely managed in primary care settings. Deficits in risk factor
decade for women.1 Although obesity is merely one of the various detection, treatment and control are well recognized. The ‘rule of
cardiovascular disease risk factors, it has received a lot of medical halves’ has been applied to hypertension management, which suggests
attention lately as the prevalence of obesity continues to increase that half of hypertension may be detected, with half of these treated
globally.2 and half controlled,8 and some studies also suggest that hypertension
Obesity is a growing global health concern, with a rapid increase may be less well controlled in obese patients.9–12
being observed in morbid obesity. Excess body weight is associated The growing obesity epidemic is a major source of unsustainable
with an increased cardiovascular risk and earlier onset of cardiovas- health costs and morbidity and mortality because of hypertension,
cular morbidity.3 It is well established that obesity is associated with type 2 diabetes mellitus, dyslipidemia, certain cancers and major
activation of both the sympathetic nervous system and the renin– cardiovascular diseases. The world is experiencing a real noncommu-
angiotensin system contributing to the emergence of hypertension.4 nicable disease emergency, which has been precipitated by unhealthy
Epidemiological studies have demonstrated the importance of the level lifestyle characteristics (that is, physical inactivity, smoking, unhealthy
and duration of obesity as risk factors for cardiovascular disease.5 diet and excess body mass) and associated poor health metrics
Improving preventive medical care to detect, treat and control of risk (hypertension, dyslipidemia and hyperglycemia).13–16 The American

1
Department of Medicine and Rehabilitation, Cardiac Rehabilitation Operative Unit, San Filippo Neri Hospital—Salus Infirmorum Clinic, Rome, Italy; 2Physical Medicine and
Neurorehabilitation Operative Unit, Salus Infirmorum Clinic, Rome, Italy; 3Institute for Craniosacral Therapies, Norma, Italy; 4Still Osteopathic Institute, Rome, Italy and 5Cardiology
Division, Santa Maria della Stella Hospital, Orvieto, Italy
Correspondence: Dr M Leggio, Department of Medicine and Rehabilitation, Cardiac Rehabilitation Operative Unit, San Filippo Neri Hospital—Salus Infirmorum Clinic, Via della
Lucchina 41, Rome 00135, Italy.
E-mail: [email protected]
Received 2 March 2017; revised 7 April 2017; accepted 14 April 2017; published online 5 October 2017
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Heart Association has clustered these seven key health factors into a often cluster together to create complex and difficult-to-treat pheno-
singular concept, life’s simple 7, with each factor being designated into types. Excess body mass is such an example, facilitating a cascade of
one of the three categories—poor, intermediate or ideal cardiovascular pathophysiological sequelae that create such as a direct obesity–
health.16 We now recognize that improving life’s simple seven hypertension link, which consequently increases cardiovascular
characteristics on a population level is the only way the noncommu- risk.24,28,29
nicable disease crisis can be resolved.17 The United States is currently Although some argue that obesity could be classified as a disease,30
facing a very real obesity epidemic. The most recent National Health some significant issues regarding assessment/management of obesity
and Nutrition Examination Survey indicates that approximately two- remain to be addressed. The first issue is that obesity is measured by
thirds of US adults are presently classified as overweight or obese various means, such as BMI, waist circumference, waist-to-hip ratio or
(BMI ⩾ 25 kg m−2) and one-third as obese (BMI ⩾ 30 kg m−2).18,19 by assessing visceral adiposity by imaging techniques. This means that
Although the numbers alone are formidable, they leave unaddressed the diagnosis of obesity could be influenced by the index used, also
the medical costs associated with obesity and obesity-related comor- given that it is already well established that there are considerable
bidities, not the least of which is obesity-related hypertension. Given variations in the waist circumference and visceral adipose tissue at any
the frequent concurrence of obesity and hypertension, it is no given BMI value.31,32 The second issue is that, although World Health
coincidence that, as the rate of obesity continues to rise, so too does Organization proposed lower BMI cutoff points for obesity among
the rate of hypertension. It is estimated that at least 75% of the Asians,33 cohort studies about the relationships between BMI and
incidence of hypertension is related to obesity.18 It is essential, mortality do not seem to consistently support the need for lower BMI
therefore, to develop treatment strategies for the management of thresholds for the Asian population.34–36 Finally, within the Asian
obesity in order to reduce the development of obesity-related population itself, there may be differences in body composition and
hypertension, as well as to effectively manage high blood pressure, adipose tissue distribution.
in the obese. The more critical issues are the heterogeneity of obesity as a
Body habitus is a key lifestyle characteristic whose current status phenotype as it has been proposed by some investigators and that
and future projections are highly disconcerting.20,21 Much of the world there may even be a healthy form of obesity referred to as
has evolved into a positive caloric balance culture, and excess body ‘metabolically healthy obesity’ (obesity that is characterized by a
mass is the consequence; paradoxically, nearly 800 million people are normal metabolic risk profile).37 In addition, the reported protective
malnourished at the very opposite. Globally, the percentage of the effect of obesity in patients with cardiovascular disease, commonly
population, both children and adults, who are either overweight (that referred to as the ‘obesity paradox’, poses an additional challenge to
is, BMI 25.0–29.9 kg m−2) or obese (that is, BMI ⩾ 30 kg m−2) has the cardiovascular risk assessment and management of the obese
substantially increased over the past three decades; there is no population.38 Finally, the suggested protective role of subcutaneous
indication any country has a solution to this issue.22 In 2014, it was adipose tissue also support the importance of adipose tissue quality
estimated that 1.3 billion adults around the world were overweight and and function rather than just the level of adiposity per se in the
600 million were obese; the worldwide prevalence of obesity doubled regulation of lipid and carbohydrate metabolism and related cardio-
from 1980 to 2014. In the United States, the percentage of individuals metabolic risk profile.2,39–41
who are considered obese has, for the first time, surpassed the Despite the unique characteristics of adipose tissue as an essential
percentage of individuals classified as overweight.20 It is estimated endocrine organ to maintain energy homeostasis, there is no doubt
that obesity was the cause of 18.2% of the deaths between 1986 and that obesity is harmful, is associated with a plethora of health
2006 in the United States.23 Globally, it is estimated that 5% of the problems and definitely leads to increased risk of mortality at the
annual deaths are caused by obesity. In 2010, excess body mass ranked population level.42–44 However, the presence of the obesity paradox in
sixth among 67 risk factors that accounted for global disease burden.24 cardiovascular disease has left some clinicians quite perplexed about
Although lifestyle changes aimed at prevention, especially in child- the ‘identity’ of obesity. On the other hand, although the underlying
hood, are the ultimate solution to the societal problem of obesity and mechanisms governing these disparate effects of obesity on cardiovas-
its complications, the scope of illness caused by obesity demands cular disease are complex and not completely understood, a variety of
immediate attention and therapeutic intervention in the obese factors, such as different anthropometric indices, body fat distribution,
population, also in light of the important role that obesity has in body composition, muscle mass and strength and cardiorespiratory
the pathogenesis of hypertension. fitness, appear to have a critical role in explaining the paradoxical
Similar to obesity, hypertension is a key unfavorable health metric association of obesity with clinical outcomes. Consequently, a com-
that has disastrous health implications if left uncontrolled.21,25 prehensive and exhaustive investigation of complex and disparate
In 2008, it was estimated that 40% of the global adult population effects of obesity on cardiovascular disease should also discuss whether
(⩾25 years) had elevated blood pressure with approximately 1 billion or not metabolically healthy obesity exists and examine factors
cases of uncontrolled hypertension, a 400 million individual increase potentially involved in explaining the obesity paradox, in the aim to
from 1980. In the United States, 32.6% of adults have hypertension, fully describe and understand the obesity–hypertension link and
≈80 million individuals.21 Although 76.5% of these individuals in the discuss strategies to address the potential negative consequences from
United States with hypertension are being treated for this health the perspective of both primordial prevention and treatment for those
metric, only 54.1% are controlled effectively; 17.3% of US adults are already impacted by this condition.
not aware they have hypertension.21 In 2011, 65 123 deaths were
attributable to in the United States, and there were 377 258 any- MECHANISMS AND PATHOPHYSIOLOGY OF OBESITY-
mention deaths for hypertension21; globally, hypertension accounts for RELATED HYPERTENSION
9.4 million deaths annually. Currently, hypertension is the leading The association of obesity and hypertension has been recognized since
contributor to global disease burden,26,27 and the direct and indirect the beginning of the twentieth century when blood pressure was first
cost of treating hypertension in the United States and worldwide is measured in populations, and this relationship between body weight
exponentially growing. Poor lifestyle characteristics and health metrics and blood pressure was demonstrated prospectively in the

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Figure 1 Mechanisms involved in the pathogenesis of obesity-induced hypertension. AgRP, agouti-related peptide; ARC, arcuate nucleus; CRP, C-reactive
protein; ET-1, endothelin-1; FFAs, free-fatty acids; ICAM-1, inter-cellular adhesion molecule-1; IL-6, interleukin-6; IL-1β, interleukin-1β; MC3R, melanocortin
3 receptor; MC4R, melanocortin 4 receptor; NO, nitric oxide; NPY, neuropeptide Y; PAI-1, plasminogen activator inhibitor-1; POMC, proopiomelanocortin;
RAS, renin–angiotensin system; ROS, reactive oxygen species; SNS, sympathetic nervous system; TNFα, tumor necrosis factor-α; Tx-A2, thromboxane A2;
VCAM-1, vascular cell adhesion molecule-1; α-MSH, α-melanocyte-stimulating hormone; Reproduced/modified from Kotsis et al.

Framingham Heart Study in the 1960s.45 The nature of the linkage and reviewed herein as they provide the basis for a rational therapeutic
between blood pressure and body weight remained obscure until the strategy.
mid-1980s when basic clinical and population-based research signifi-
cantly clarified many aspects of the relationship between these two Increased sympathetic nervous system activity, adipokines and
common and complex regulatory disturbances. Appreciation of the insulin
clinical significance of obesity-related hypertension has grown sub- There is an increase in sympathetic nervous system activity in patients
stantially over this same time period, to the point where obesity is with obesity; evidence suggests that high caloric loads increase
recognized as a major cause of high blood pressure, and the peripheral noradrenaline turnover, and high fat and carbohydrate
combination of obesity and hypertension is recognized as a preemi- diets stimulate α1 and β-adrenergic peripheral receptors, which
nent cause of cardiovascular risk. elevates sympathetic nervous system activity.29,60 Elevated free fatty
Clues to the basic mechanisms involved in the link between obesity acid levels, typical of the obesity–hypertension phenotype, increase
and hypertension first appeared in the 1940s and 1950s with the α-adrenergic vascular sensitivity and subsequently arterial tone.
important observations by Vague.46 Based on observations made in his Distribution of body fat also has a role in sympathetic nervous system
own obesity practice, Vague noted that the cardiovascular and variability, with central obesity being associated with greater sympa-
metabolic complications of obesity were more common in patients thetic nervous system activation compared with subcutaneous
with the upper body obesity phenotype, which he called ‘android’, as obesity.61 Finally, baroreflex sensitivity, which when functioning
compared with lower body obesity, which he referred to as ‘gynoid’. normally has a sympathoinhibitory effect in elevated blood pressure
These prescient observations attracted little attention until the 1980s conditions, is diminished in the obesity–hypertension phenotype,
when population-based studies using waist-to-hip ratio as a quantifi- further contributing to enhanced sympathetic nervous system
able surrogate for the upper body phenotype demonstrated significant activity.62
cardiovascular risk (hypertension, myocardial infarction, dyslipidemia The adipocyte as an active endocrine secretory cell, as well as an
and type 2 diabetes mellitus) in association with a high waist-to-hip immune organ, produces many different adipokines to modulate
ratio.47–49 Similar lines of research showed that insulin resistance was inflammation and various metabolic processes.63,64 In normal phy-
also associated with the upper body phenotype50–52 and many siological circumstances, adipocytes release anti-inflammatory factors
subsequent clinical and population-based studies showed an associa- such as adiponectin, transforming growth factor-beta, interleukin-10
tion of insulin levels and/or insulin resistance with hypertension in and nitric oxide, which promote insulin sensitivity and antiatherogenic
both obese and non-obese people.53,54 Thus insulin, hypertension and effects.63,64 At the population level, adiponectin could be found in high
the android or central obesity phenotype tracked together in levels in the blood of lean healthy individuals, whereas its concentra-
population-based and clinical studies. These observations formed the tion was markedly reduced among individuals with type 2 diabetes,
basis for our current understanding of the pathophysiology of obesity- coronary heart disease or with a high-risk form of overweight/
related hypertension.55 There is a clearly established link between obesity.65 As a result, adiponectin has generally been perceived as an
obesity and hypertension.28,29,56,57 The accumulation of excess adipose antidiabetogenic/antiatherosclerotic adipokine; on the contrary, patho-
tissue initiates a cascade of events that give rise to an elevated blood logical hypertrophied adipocytes caused by excessive body weight
pressure; obesity-induced hypertension is a common pathway in both release pro-inflammatory cytokines such as leptin, tumour necrosis
children and adults.29,58,59 Pathogenetic factors and pathophysiological factor-alpha, resistin and interleukin-6, contributing to the develop-
mechanisms linking obesity to hypertension (Figure 1) are described ment of various metabolic diseases.66 These contrasting effects are

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maintained in balance in a normal state, although increased levels of Alterations in renal function, sodium excretion, pressure
adiponectin have been linked to higher mortality in older adults or natriuresis, salt sensitivity and renin–angiotensin–aldosterone
patients with cardiovascular disease, which is termed as the ‘adipo- system
nectin paradox’,64 and recent data reported that increase in leptin level Obesity is associated with an increased risk for chronic kidney disease,
had conferred some beneficial effects on coronary endothelial as well as end-stage renal disease.80 Initially, blood pressure control
function.67 Adiponectin is secreted by adipose tissue, has a role in through diuresis and natriuresis favors a shift toward hypertension in
regulating energy balance and promotes insulin sensitivity. Increased obese individuals; this occurs prior to glomerular injury and loss of
adipose mass is associated with decreased adiponectin levels and thus renal function.29,59,81 During the initial onset of obesity, an increase in
contributes to insulin resistance. Glucocorticoids, acting within renal tubular reabsorption increases sodium retention. Renal vasodila-
adipose tissue, appear to promote hypertension through increased tion, which increases glomerular filtration and the filtered amount of
renin–angiotensin–aldosterone system activity.29,59 Leptin is secreted both water and electrolytes, occurs in an attempt to compensate for
by adipose tissue, with a direct link between leptin secretion and fat the increase in renal tubular reabsorption. This compensation is
incomplete, however, and extracellular volume is expanded with an
mass.29,59,68 Elevated circulatory leptin levels observed in obesity are
upward pressure recalibration of the pressure natriuresis. Thus the
also implicated in the increased risk of hypertension. Leptin crosses
impact of obesity on the renal system that favors hypertension is
the blood–brain barrier, interacting with the arcuate nucleus and,
consistent with a volume overload model. Obesity predisposes the
similar to insulin, initiating an appetite suppression and increased
kidney to reabsorb sodium by neural (sympathetic nervous system),
energy expenditure signal that is mediated through increased sympa-
hormonal (aldosterone and insulin) and renovascular (angiotensin II)
thetic nervous system activity.69,70 Leptin also has been linked to mechanisms.82 This enhanced sodium avidity shifts the pressure
endothelial dysfunction by negatively impacting nitric oxide synthase natriuresis curve to the right,83 thereby necessitating higher arterial
expression and augmenting sympathetic nervous system activity.29,62 pressure to excrete the day’s salt intake and maintain sodium balance
The relationship of insulin to blood pressure, although controversial and volume homeostasis. This is the basis for the documented salt
at first, has a plausible explanation, and insulin is now generally sensitivity of obesity-related hypertension84 and underlines the need
acknowledged to have a role in the pathophysiology of obesity-related for diuretics in the therapeutic regimen.
hypertension.55 Impaired glucose tolerance, increased insulin levels Obesity is associated with altered/activated renin–angiotensin–
and concomitant reductions in insulin sensitivity are commonplace in aldosterone system function; plasma renin, angiotensinogen, angio-
obese individuals; the clustering of these characteristics defines insulin tensin II, and aldosterone are all elevated with obesity, and aldosterone
resistance/metabolic syndrome.29,56,59,60 As insulin stimulates the levels may be increased out of proportion to the increase in renin
sympathetic nervous system,71,72 and as obese patients have increased activity.85 Several mechanisms have been thought to underlie renin–
sympathetic nervous system activity,73–75 a role for insulin-mediated angiotensin–aldosterone system activation, including sympathetic
sympathetic nervous system stimulation seems a likely factor in the nervous system stimulation of renin release86 with the generation of
pathogenesis of high blood pressure in the setting of central obesity, as angiotensin II; angiotensinogen production in adipose tissue, especially
supported by studies demonstrating concomitant decreases in blood intra-abdominal adipocytes86,87 with the generation of angiotensin II
pressure and sympathetic nervous system activity when insulin is and aldosterone; and effects of free fatty acids, along with other poorly
lowered by low-energy diets in obese patients.76 Insulin also increases defined factors, on aldosterone production and release.85 Increased
sympathetic nervous system activity through both hypoglycemia- levels of renin–angiotensin–aldosterone system constituents favor
induced mechanisms and a possible direct effect on the central vasoconstriction and volume expansion. Although obesity is associated
nervous system. Chronic hyperinsulinemia is also linked to arterial with volume expansion, renin secretion by the kidney persists because
dysfunction, favoring vasoconstriction. Moreover, insulin also has a of the effect of fat accumulation in and around the renal medulla.
direct action on the kidney to stimulate sodium reabsorption and Adipose tissue itself is also a source of all components of the renin–
increase sodium retention through a direct interaction with renal angiotensin–aldosterone system;29,56,88 angiotensinogen produced by
tubules.77 Thus the obesity-induced hyperinsulinemia state contributes adipose cells is released into the circulatory system, increasing the
amount available for conversion along the pressure elevating cascade,
to elevated blood pressure through increased sodium retention and
and renin–angiotensin–aldosterone system receptors are well estab-
volume overload.
lished in adipocytes.88 This cascade of events results in elevated renin–
Finally, plasma endocannabinoids released from the adipose tissue,
angiotensin–aldosterone system activity, which is no longer suppressed
such as anandamide and 2-arachidonoylglycerol, remain a focus of
by the obesity-associated volume expansion. Excess visceral adipose
attention in obesity research. Endocannabinoids involved in feeding
tissue results in physical compression of the kidneys. Compression of
behavior and energy metabolism, as well as glucose and lipid
the renal system impacts both the vascular and tubular systems that
metabolism, are increased via insulin resistance and inflammation in augment renin–angiotensin–aldosterone system activation and sodium
obese individuals, which may stimulate the overexpression of canna- reabsorption.59 The physical stresses that obesity places upon the
binoid receptors in a pathophysiological manner contributing to kidneys initiate a deleterious progression from hyperfiltration to
excessive visceral fat accumulation and decreases in adiponectin glomerulomegaly (that is, enlargement of the glomeruli) to sclerosis
level.78 It is recognized that endocannabinoids may have a key role of the glomeruli wall and nephron, ultimately leading to nephron loss,
in the pathogenesis of obesity-related complications, such as nephro- which negatively impacts pressure natriuresis.58 These structural renal
pathy, atherosclerosis and cardiac dysfunction through inflammation- changes result in higher sodium retention and higher arterial pressure.
mediated reactive oxygen species, and lifestyle interventions leading to
weight loss and loss of visceral adipose tissue have been shown to Other potential mechanisms
reduce anandamide and 2-arachidonoylglycerol levels in the blood of Other factors that may be implicated in the pathophysiology of
abdominally obese, dyslipidemic men with features of the metabolic obesity-related hypertension include a decrease in natriuretic
syndrome.79 peptides85,86 with consequent impairment in salt excretion; a decrease

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in adiponectin;89 obstructive sleep apnea, which stimulates the epidemic extending into its third decade, prevalence rates of hyperten-
sympathetic nervous system;90–93 low birth weight, which is associated sion, which had been falling in the 1970s and 1980s, are again rising.
with excessive weight gain in childhood and adolescence, along with Numerous studies have also demonstrated the important role of
increased risk of hypertension and stimulation of the sympathetic weight gain in blood pressure elevation and of weight reduction in
nervous system94–96 in adulthood; and endothelial dysfunction with blood pressure lowering. As a general rule, in Western societies,
consequent blunting of physiological vasodilation.97,98 Particularly systolic blood pressure and diastolic blood pressure tend to rise with
about endothelial function and structure, obesity creates a state of age beginning at around age 25 in most adults.105,106 This is a
insulin resistance and systemic inflammation that promotes endothe- ‘normative’ process of aging, but it may not be inevitable or ‘normal’.
lial dysfunction and hypertension.29,59 Insulin resistance decreases In fact, recent data suggest that these ‘age-related’ increases in systolic
nitric oxide synthesis and hyperinsulinemia promotes vasoconstriction blood pressure and diastolic blood pressure may be avoided in young
through increased endothelin-1 levels. A host of proinflammatory and adults who maintain stable BMI during long-term follow-up into
inflammatory compounds secreted by adipose tissue, including inter- middle age. In the Coronary Artery Risk Development in Young
leukin-1β, interleukin-6, tumor necrosis factor and C-reactive protein, Adults study, young adults (mean age 25 years at baseline) who
also promote endothelial dysfunction and thus hypertension.29 Obesity maintained a stable BMI (within 2 kg m−2 of baseline) at six
is also associated with increased carotid artery thickness, intima media examinations during 15 years had no significant changes in systolic
thickness and arterial remodeling and stiffening.99 Chronic hypergly- or diastolic blood pressure, whereas those who had an increase in their
cemia, as well as increased renin–angiotensin–aldosterone system BMI ⩾ 2 kg m−2 had substantial increases in blood pressure.107 For
activation and sympathetic nervous system activity, contributes to example, women who maintained stable BMI in this study had
changes in vascular structure that favor blood pressure increase and nonsignificant declines in systolic blood pressure, whereas women
development of hypertension. whose BMI increased had statistically significant average increases in
systolic blood pressure of 9.8–12.5 mm Hg. Of note, this weight gain
EPIDEMIOLOGY AND PREVALENCE OF OBESITY-RELATED was more important than the baseline weight, as the same patterns
HYPERTENSION were observed for those who were at normal weight or overweight at
In the United States, more than 40% and 25% of the obese and baseline. Hence, age-related changes in blood pressure may not be
overweight population, respectively, also have hypertension. This, inevitable and may be caused more by age-related weight gain than
compared with a hypertension prevalence of approximately 15% in aging per se. These data have important implications for health care
normal-weight individuals,4 clearly demonstrates a stepwise increase in and public health, as weight maintenance may be a strategy that is
easier to achieve than substantial weight loss for preventing or
hypertension risk with increasing body mass. It is estimated that 78%
controlling hypertension.107 The influence of weight gain on blood
of the risk for developing essential hypertension in men and 65% of
pressure and the benefits of maintaining stable weight or losing weight
the risk for developing essential hypertension in women is attributed
extend down even to young children. One large birth cohort study of
to excess body mass.59 Evaluating the relationship from the reverse
children examined BMI at ages 5 and 14 years and the association with
perspective (that is, the hypertension population exclusively), 470%
systolic and diastolic blood pressure at age 14 years. Children who
of individuals with hypertension are overweight or obese.100 In those
were overweight at age 5 years but had normal BMI at age 14 years
with type II diabetes mellitus, the prevalence of the obesity–hyperten-
had similar mean systolic and diastolic blood pressure to those who
sion phenotype is variable by country and defining blood pressure
had a normal BMI at both time points. Conversely, children who were
threshold, ranging from 33% to 93%.101 Collectively, these data
overweight at both ages or who had a normal BMI at age 5 years and
indicate a high prevalence for the obesity–hypertension phenotype, were overweight at age 14 years had higher systolic and diastolic blood
warranting a focus on prevention and treatment. pressure at age 14 years than those who had a normal BMI at both
Data from recent US National Health and Nutrition Examination ages, even after adjustment for potential confounders.108
Surveys (NHANES) from 2005 to 2008 indicate that the prevalence of
hypertension among adults aged 418 years in the United States was JOINT EFFECTS OF OBESITY AND HYPERTENSION ON
30.9%, or nearly 1 in 3 adults. In the context of the entire population, CARDIOVASCULAR RISK
476 million US adults are estimated to have hypertension; at the Hypertension is a complex phenotype that arises from numerous
same time, nearly 70% of American adults are overweight or obese.102 genetic, environmental (including air pollution26), behavioral and even
Thus we can expect a significant increase in the prevalence of social origins, and obesity is one of the most prevalent risk factors for
hypertension in the coming years if trends of increasing weight in its development. Regardless of its etiology, however, hypertension is a
the population are not stabilized and reversed. Epidemiological data highly prevalent and highly significant risk factor for the development
unequivocally support the link between body weight and blood of all manifestations of cardiovascular disease, including coronary
pressure, thus indicating greater body weight as one of the major risk heart disease, stroke, heart failure, aortic and peripheral arterial
factors for high blood pressure. Recent data from NHANES indicate disease, and valvular heart disease. The association of hypertension
that the prevalence of hypertension among obese individuals, with a with cardiovascular risk in the short and long term is unequivocally
BMI ⩾ 30 kg m−2, is 42.5% compared with 27.8% for overweight established. The association of obesity with short-term cardiovascular
individuals (BMI 25.0–29.9 kg m−2) and 15.3% for those with disease event rates (for example, in the next 10 years) is more difficult
BMIo25 kg m−2.103 Likewise, higher BMI is also associated with to establish, largely because the major effects of obesity appear to act
increased risk for development of hypertension over time. Data from through more proximal risk factors, such as diabetes, dyslipidemia and
the long-standing Framingham Heart Study revealed that, compared hypertension. However, longer-term studies of obesity and cardiovas-
with normal-weight adult men and women, the multivariable-adjusted cular disease do indicate risk for cardiovascular disease associated with
relative risks for development of hypertension in long-term follow-up obesity independent of these other risk factors. In addition, several
were 1.48 and 1.70 for overweight men and women and 2.23 and 2.63 lines of evidence data suggest that obesity and hypertension may have
for obese men and women, respectively.104 With the current obesity additive effects in increasing risk for cardiovascular disease over long-

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term follow-up.109 Data from the long-standing Chicago Heart factor affecting the study results. Most studies supporting the existence
Association Detection Project in Industry,110 which enrolled of metabolically healthy obese phenotype have had a relatively short
438 000 individuals from 1967 to 1973, serve as an example to follow-up period of o10 years, whereas data by Arnlöv et al.117 have
highlight these joint risks. As reported, 32-year cardiovascular disease shown that there was an increased risk for cardiovascular disease
death rates were higher (and increased in a stepwise manner) for events in metabolically healthy obese subjects when a follow-up period
patients with higher BMI at baseline and no hypertension. For those beyond 10 years and up to 30 years was used. Similarly, Lee et al.125
with hypertension at baseline, cardiovascular disease death rates were demonstrated that the metabolically healthy obese group showed a
substantially higher overall and increased in a stepwise manner for similar risk of incident hypertension during the first 4-year follow-up
patients with higher baseline BMI levels. A similar pattern of results compared with metabolically healthy normal-weight controls.
was observed for individual outcomes of coronary heart disease death However, an increased risk of developing hypertension began to be
and stroke death rates, as well as for hospitalizations for coronary observed only after 6-year follow-up. In addition, the authors refuted
heart disease, stroke and heart failure during follow-up using the concept of ‘benign obesity’ by demonstrating that a higher
Medicare data. proportion of metabolically healthy obese group deteriorated meta-
An additional important factor in the cardiovascular risk associated bolically over time.126 Indeed, they observed a progressive conversion
with obesity and hypertension is the role played by obesity in the of metabolically healthy obese subjects from being healthy to becom-
development of type 2 diabetes. Obesity, and particularly central ing unhealthy over the follow-up period.125 Thus these results
adiposity, is the dominant risk factor for the development of type 2 emphasize the long-term cardiovascular hazards of being characterized
diabetes, which routinely clusters with hypertension because of by an apparently benign obesity phenotype and the necessity to follow
common underlying pathophysiology. Diabetes exerts a substantial these patients over the long term. In other words, although younger
independent and amplifying effect on the cardiovascular risks asso- individuals may have metabolically healthy obesity, they may never-
ciated with both obesity and hypertension.111,112 Efforts aimed at theless develop insulin resistance, diabetes, dyslipidemia and arterial
diminishing the incidence and impact of diabetes, therefore including hypertension called metabolic syndrome with increasing age.
both lifestyle changes and the appropriate use of antihypertensive and Recently, two meta-analyses concluded that the metabolically
antiobesity therapies, are an essential part of the overall healthy obese phenotype should no longer be considered as a benign
therapeutic plan. condition. One analysis, including 8 studies in 61 386 people with a
follow-up period of 410 years, reported that metabolically healthy
METABOLICALLY HEALTHY OBESITY AND OBESITY PARADOX obesity was associated with an increased risk for all-cause mortality
Although being overweight and obese are well-established risk factors and cardiovascular disease events.126 Another study also demonstrated
for cardiovascular disease, there are substantial individual differences similar findings: in a meta-analysis of 14 studies involving 299 059
observed in the cardiometabolic risk profile of subjects within the individuals, a 100% increased risk for cardiovascular disease events
same BMI category. Based on favorable metabolic features observed in was observed in the metabolically healthy obese group.127 The risk of
some obese patients such as high levels of insulin sensitivity and high- clinical outcomes was much worse when only considering studies with
density lipoprotein-cholesterol as well as low levels of fasting 415-year follow-up. Accordingly, by labeling a subset of obese people
triglycerides and fasting glucose, a unique obesity phenotype known as metabolically healthy, a strategy of only offering treatment to obese
as ‘metabolically healthy obesity’ was introduced.113,114 Early studies patients with overt metabolic derangements would seem to provide a
suggested that metabolically healthy obesity was not associated with an short-sighted view to the current obesity epidemic.128 In addition,
increased risk of cardiovascular mortality compared with normal- according to a recent study by Ortega et al.,129 when physical activity
weight individuals.115 Such early data have been interpreted by some or fitness was considered as one of the confounders, the adverse effect
as providing evidence that these apparently metabolically healthy obese of metabolically healthy obese phenotype on all-cause and cardiovas-
people would not need to receive preventive therapies, because they cular disease mortality was significantly attenuated or even not
would appear unlikely to experience long-term morbidity on the basis observed. In other words, as a high level of cardiorespiratory fitness
of their seemingly normal cardiometabolic risk profile.116 However, was associated with a low incidence of metabolic syndrome and
considerable controversy exists about the criteria and levels to be used attenuated the magnitude of the relationship between the metabolic
to define metabolically healthy obesity and whether obesity can be syndrome and mortality regardless of weight status,130 these results
healthy. Recent studies with long-term follow-up information have suggest that the metabolically healthy obese phenotype is clearly
refuted the existence of metabolically healthy obesity by demonstrating associated with a higher level of cardiorespiratory fitness.131 These
that these individuals are nevertheless associated with an increased risk findings could provide useful information to physicians in assessing
of cardiovascular disease.117 In addition, a series of cross-sectional the risk stratification of obese individuals. Thus the prevalence of the
studies have shown that metabolically healthy obesity was associated metabolically healthy obesity phenotype is probably much lower than
with subclinical target organ changes, including increased carotid expected and levels of physical activity/cardiorespiratory fitness are
intima media thickness and coronary artery calcium scores, subtle probably some of the key factors, in addition to body composition and
impairment of left ventricular structure and function and impaired level of visceral adiposity/ectopic fat, to explain this phenomenon. Our
vasoreactivity.118–121 Several potential explanations for these conflict- suggestion would be to define metabolically healthy not only on the
ing results have been proposed in recent years. First of all, there is basis of absence of any criteria of the metabolic syndrome but rather
no standard definition for metabolically healthy obesity. Although as having all usual risk factors being at optimal levels; otherwise, any
Hinnouho et al.122 suggested that metabolically healthy obese indivi- slight increase in any of the risk factors increases the risk of
duals were at increased risk of mortality, irrespective of various cardiovascular disease.
definitions used, and these different definitions still make the Clinical research reveals an obesity paradox, where overweight/
comparison of findings among studies, such as prevalence rates and obese patients with hypertension, heart failure, coronary heart disease
the long-term health effects, difficult.123,124 Second, the issue of a and peripheral arterial disease have perhaps even a more favorable
difference in the follow-up duration between studies is another crucial short- and long-term prognosis. Notably, a large cohort study of

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22 576 treated hypertensive patients with known coronary heart concept of being fat and fit has recently come into the spotlight as a
disease demonstrated that all-cause mortality was 30% lower in potential reason for the obesity paradox.138
overweight/obese compared with normal-weight patients.132 More-
over, the landmark Systolic Hypertension in Elderly Program showed THE METABOLIC SYNDROME
decreased stroke and total mortality among overweight compared with Obesity-related hypertension frequently occurs in association with
lean patients.133 Therefore, although obesity is a powerful risk factor other cardiovascular risk factors, forming a constellation referred to as
for hypertension and left ventricular hypertrophy, obese hypertensive the metabolic syndrome.140 Although the concept of a metabolic
patients may paradoxically have a better prognosis compared with lean syndrome has achieved widespread acceptance over the past two
patients.134 Similarly, with heart failure, obese patients may have a decades, no consensus has developed over the precise definition of the
better event-free survival.135 There is strong and powerful evidence syndrome nor over the criteria required to establish the diagnosis. No
showing that an elevated BMI predisposes individuals to most less than five sets of diagnostic criteria have been proposed by different
cardiovascular disease and has been associated with a greater risk of international and national panels, including the International Diabetes
mortality. In a 10-year follow-up study of 527 265 US men and Federation, the World Health Organization and the US National
women in the National Institutes of Health-American Association of Cholesterol Education Program Adult Treatment Panel III (NCEP-
Retired Persons cohort between the ages of 50 and 71 years,42 a ATP III), among others.141 The differences in criteria, although small
J-shaped relationship between BMI and the risk of death was observed, and overlapping, point to the imprecision in defining the metabolic
showing that underweight and excess body weight, including over- syndrome and to the differences in the perceived importance of the
weight, were associated with higher rates of death than normal weight. various manifestations. Using the NCEP-ATP III criteria and the
On the other hand, a recent meta-analysis from prospective studies of NHANES III survey, it has been estimated that about 30% of the US
general populations reported a statistically significant 6% lower all- population has the metabolic syndrome.142 The prevalence increases
cause mortality in overweight persons compared with normal-weight with age so that by 60 years, 440% of people meet criteria for the
subjects. Although the mortality risk was increased in overall obesity diagnosis.
including all classes (class I, II and III combined) and class II (BMI The four fundamental components of the metabolic syndrome are
35–40 kg m−2) and class III obesity (BMI ⩾ 40 kg m−2), class I obesity central obesity, insulin resistance, hypertension and a characteristic
dyslipidemia (high triglycerides and low high-density lipoprotein
(BMI 30–35 kg m−2) was not associated with higher mortality
cholesterol). Reaven141 has identified the importance of insulin
compared with normal-weight individuals;136 however, considering
resistance as a critical component of the syndrome, which he originally
the fact that the mortality rate for a BMI between 19 and 20 kg m−2 is
designated ‘syndrome x’ and which was also called the ‘insulin
higher than a BMI between 24 and 25 kg m−2 where the lowest
resistance syndrome’, although these earlier designations have given
mortality is observed, the use of a wide range of BMI between 18.5 and
way to the term metabolic syndrome. Central or android obesity is the
25 kg m−2 as the presumably ‘normal weight’ reference group could
usual although not the exclusive cause of the insulin resistance. Insulin
explain the protective effect conferred by overweight and class I
resistance and the consequent hyperinsulinemia drive the hypertension
obesity in the general population. Recent data from the Antihyper-
(as described above) and the dyslipidemia (stimulation of hepatic very
tensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
low-density lipoprotein production). In addition to the four principal
confirmed that the protective effect of obesity on all-cause mortality
components, a variety of other abnormalities have been associated
was not observed after excluding individuals with BMIo22 kg m−2
with the metabolic syndrome, including type 2 diabetes mellitus,
who are clearly at increased risk compared with subjects in a normal impaired glucose tolerance, renal functional impairment and micro-
but higher BMI range such as 22–25 kg m−2.137 Nevertheless, there is albuminuria, hyperuricemia, prothrombotic coagulation diatheses,
accumulating evidence that obesity in patients with established small dense low-density lipoprotein cholesterol and markers of
cardiovascular disease, including coronary heart disease, heart failure, inflammation.143 All of these abnormalities have been associated with
hypertension and atrial fibrillation, has a protective role against both increased cardiovascular risk.
all-cause and cardiovascular mortality, findings which contributed to Although abdominal obesity and insulin resistance are the major
feed the ‘obesity paradox’ hypothesis in the field of cardiology.138 threads that connect the various features of the metabolic syndrome,
However, because this obesity paradox is being reported in a variety of two other factors of potential importance should be mentioned:
chronic diseases including end-stage renal disease, chronic obstructive dietary fructose and disordered sleep. The consumption of high
pulmonary disease and type 2 diabetes mellitus, it does not appear to fructose corn syrup has increased dramatically in the past three
be specific for only cardiovascular disease. decades, paralleling the increase in obesity and hypertension. Swee-
A variety of mechanisms have been proposed to explain the obesity tened beverages, such as non-diet soda, account for 70% of the intake
paradox in patients with cardiovascular disease.138 Among potential of high fructose corn syrup,144,145 and recent evidence suggests a link
causes for the obesity paradox, spontaneous weight loss, which is between sweetened sodas, hyperuricemia and the manifestations of the
observed after the development of heart failure, is known to cause a metabolic syndrome.146,147
bias associated with the timing of weight measurement. However, Another recently described factor that may contribute to the
because a recent study from the Atherosclerosis Risk In Communities development of the metabolic syndrome is shortened or interrupted
has suggested that the protective effect of obesity paradox is driven by sleep. Obstructive sleep apnea, a well-recognized complication of
preexisting obesity,139 cardiac cachexia due to advanced heart failure obesity, is associated with increased sympathetic nervous system
does not appear to fully explain the obesity paradox in patients with activity, which persists during daytime wakefulness.90,92 The sympa-
established heart failure, although this phenomenon certainly con- thetic nervous system overactivity is associated with hypertension.
tributes to the high mortality risk of very lean heart failure patients. Both the sympathetic nervous system stimulation and the hyperten-
Given that the obesity paradox is usually observed in the elderly with sion are reversed with effective treatment of the sleep apnea. Sleep
cardiovascular disease, age-related changes of body fat distribution and debt, a consequence of shortened or disordered sleep, or night shift
also sarcopenia may be clues to the obesity paradox.2 Accordingly, the work, is also associated with obesity, insulin resistance and

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hypertension, raising the possibility that disturbances of normal sleep physical and health education programs as well as healthy food choices
patterns may have a role in the pathogenesis of the metabolic in schools, well-designed worksite health and wellness programming,
syndrome.93,148–150 Insufficient sleep may also antagonize weight loss health insurance incentives for maintenance of a healthy lifestyle, and
in response to caloric restriction.151 broad adoption of healthy lifestyle assessments and interventions in
Considerable debate has centered on whether the metabolic health-care systems. The aforementioned policy statement encourages
syndrome is in fact a discrete entity. Although the abnormalities creativity in developing healthy lifestyle initiatives, allowing stake-
characteristic of the metabolic syndrome are relatively common in the holders to capitalize on resources and infrastructure at the local level.
population at large, there is no doubt that these traits occur together Moving forward, prevention of unhealthy lifestyle characteristics,
much more commonly than predicted by chance alone. This, however, including obesity, from ever developing must become a primary focus.
may reflect the central role of insulin resistance and hyperinsulinemia The childhood origins of obesity-related hypertension are well
in the pathogenesis of the different manifestations, rather than a direct illustrated in a study of 260 000 overweight and obese children in
linkage of the associated traits. The argument has been advanced, with Germany and Switzerland, in which 35% had hypertension with
some merit, that the concept of a metabolic syndrome may alert increased ventricular mass or arterial stiffness.162 Studies of the
clinicians to look for associated manifestations when obesity and Bogalusa childhood cohort who were prehypertensive or mildly
hypertension coexist and to recognize the cardiovascular risk asso- hypertensive in adulthood showed that when they were tracked back
ciated with this constellation. to as young as 4–8 years, they had higher blood pressures and were
heavier and more insulin resistant than their normotensive
PREVENTION AND TREATMENT OPTIONS FOR THE counterparts.163 This is in accord with prospective studies showing
MANAGEMENT OF OBESITY AND HYPERTENSION tracking of adiposity, obesity and blood pressures from childhood into
The obesity–hypertension phenotype works synergistically to expo- adult life. In a recent analysis of four cohort studies followed for a
nentially increase cardiovascular disease risk, chronic renal disease mean of 23 years, overweight or obese children who remained obese as
and associated adverse events.4,21,81,152–161 Given the incidence and adults had substantially increased risk of hypertension, diabetes,
prevalence, poor clinical outcome and quality of life as well as negative dyslipidemia and carotid atherosclerosis.164 Importantly, patterns of
financial implications of the obesity–hypertension phenotype, aggres- food consumption and physical activity also track from childhood to
sive prevention and treatment strategies are imperative. adulthood.165 Stemming from the work by Barker,94 there is sub-
stantial evidence for effects of intrauterine growth and early postnatal
Lifestyle changes in the management of obesity-related weight gain on adiposity and high blood pressure.166 These effects are
hypertension not restricted to low birth weight infants, as shown by the clustering of
The importance of lifestyle management in the treatment of patients adiposity and blood pressure along with impaired glucose tolerance
with obesity-related hypertension cannot be misunderstood. Adoption and dyslipidemia in 8- and 14-year olds born from the lowest and
of a healthy lifestyle facilitates weight loss, increases responsiveness to highest birth weight quintiles.167,168 Excessive postnatal weight gain in
antihypertensive medications and produces independent beneficial early childhood dominated over effects of birth weight,168 especially in
effects on cardiovascular risk factors. children of mothers who smoked in pregnancy or did not
Promoting the maintenance of a life-long normal body weight is breastfeed.168 In the same Australian cohort, the trajectories for
the optimal approach to preventing the deleterious consequences of adolescent obesity were well established by the age of 5 years.169 For
the obesity–hypertension phenotype. If obesity were removed from the all of these reasons, a consensus is developing that it may be necessary
equation, the risk of developing hypertension would be minimized for to tackle lifestyle-induced obesity-related hypertension at its source: in
a significant proportion of the population. The prevention of obesity infancy and early childhood and in the parents.
from occurring requires a multipronged approach by numerous There are an increasing number of randomized controlled trials
stakeholders working together toward a common goal. The focus is attempting to modify and/or prevent childhood obesity at a popula-
to encourage adoption of a healthy lifestyle from the individual to tion level rather than in clinic settings. Most of these have been school
population level across the lifespan. The core tenets of a healthy based. Few have also examined the effects of the programs on blood
lifestyle as it relates to maintenance of a normal body weight include pressure. An extensive Cochrane review of lifestyle interventions to
sufficient levels of physical activity and consuming a nutritious, prevent obesity in childhood included 55 studies. A meta-analysis of
calorically balanced diet. The American Heart Association has defined 37 of these involved 27 946 children, of whom the majority were aged
ideal physical activity and dietary characteristics that all individuals 6–12 years,170 concluding that the ‘programs overall were effective at
should strive toward.25 Recently, the American Heart Association, reducing adiposity, although not all individual interventions were
European Society of Cardiology, European Association for Cardiovas- effective, and there was a high level of observed heterogeneity and
cular Prevention and Rehabilitation and American College of possible bias’. Moreover, the effect was relatively small with children in
Preventive Medicine published a policy statement that proposed a the intervention group ‘showing a small standardized mean difference
nonhierarchical connectivity model for key stakeholders who must in adiposity of − 0.15 kg m−2’. Given the unexplained heterogeneity
collaboratively work together to address the noncommunicable disease and the likelihood of small study bias, however, these findings must
crisis through healthy lifestyle interventions.17 be interpreted cautiously. The authors were unable to distinguish
Professional organizations, educational systems, government on all which of the program components contributed to the beneficial effects
levels, health-care organizations, the insurance industry, nonprofit and and suggested that ‘childhood obesity prevention research must now
community organizations, media outlets and mobile health and move towards identifying how effective intervention components can
technology companies and employers were all identified as healthy be embedded within health, education and care systems and achieve
lifestyle stakeholders in this policy statement. With respect to long term sustainable impacts’. None of the above studies reported
promoting maintenance of a healthy body weight across the lifespan, effects on blood pressure or cardiovascular risk phenotypes other than
numerous collaborative strategies can be implemented. Examples obesity. However, two large randomized controlled trials of effects of
include: creation of walker-/biker-friendly public spaces, robust K-12 home- and school-based nutrition and physical activity programs on

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cardiovascular risk factors have been provided from Australia. The first for the prevention of hypertension but also for improving overall
1147 10–12-year olds from 30 schools found improved blood pressure, prognosis in most groups with cardiovascular diseases.186–188 The
a reduction in fatness and improved physical fitness.171 Decline in literature convincingly demonstrates that individuals with an excess
systolic blood pressure was significantly greater with a fitness inter- body mass experience significant weight loss through participation in
vention for the boys and with a home nutrition intervention for the healthy lifestyle interventions that ideally includes a structured exercise
girls. The greatest improvements overall were with the combined program, nutritional counseling and promotion of increased physical
fitness and home nutrition program. The second study used cluster activity throughout the day.189–195 Ensuring these programs are
analysis to identify 29% of 800 11-year-old children at increased prescribed in a way that creates an appropriate, daily, negative caloric
cardiovascular/metabolic risk. The children in both high- and low-risk balance (that is, 500–1000 kcal deficit per day) is essential for weight
clusters were then randomized to two semesters of family nutrition loss and its maintenance.195,196 With respect to the structured exercise
and school-based physical activity programs.172 High-risk children program, combining aerobic and resistance training is considered
responded better in terms of fatness, fitness, nutrition and blood advantageous with respect to facilitating weight loss while preserving
cholesterol than did low-risk children. Boys responded better than the lean mass.192,195 Behavioral counseling is also considered an important
girls during the program but effects were more sustained after a component of healthy lifestyle interventions directed toward promot-
further 6 months in girls. The lifestyle factors contributing to the rising ing weight loss,197–199 ensuring individuals are properly motivated to
epidemic of obesity, and hence obesity-related hypertension, are lose weight and maintain improvements in body habitus over the long
embedded in changes in society worldwide: increased sedentariness term. Research has shown that individuals who lose weight through
from the car, television and computers; parental protectiveness in exercise and nutritional interventions demonstrate significant reduc-
seemingly hostile urban environments; and increased consumption of tions in blood pressure, as well as improvements in the pathophysio-
calorie-rich foods in the form of soft drinks, fast foods and sugar- logical cascade associated with the obesity–hypertension phenotype,
enriched low-fat dairy products. Clustering of unhealthy behaviors in including improved arterial structure and function.56,60,200–202 In
obese children, such as poor nutritional habits, high salt consumption, individuals in the early stages of hypertension, exercise training in
low levels of physical activity and smoking and alcohol consumption and of itself, after controlling for baseline body weight and weight loss
(by adolescence)173 dictate the need for multifaceted national-, school- following an intervention, reduced the risk of developing left
and family-based programs to tackle global cardiovascular risk at an ventricular hypertrophy.186,202,203 Exercise training also significantly
early stage. Many such programs are underway worldwide, and are reduces left ventricular mass in those with hypertension where cardiac
addressing issues relating to infancy, childhood, parents and the structural abnormalities have already developed.202,203 Also, increased
community, and through international networks.174–178 physical activity and exercise is particularly important for long-term
Lifestyle changes tend not to occur in isolation. Those who are weight maintenance.204
obese tend to show clustering of behaviors predisposing to higher
blood pressure including not only disturbed energy balance but less Weight loss and choice of weight-reducing diet
healthy diets with higher salt intake, less fruit and vegetable intake, less Systematic reviews consistently report a decrease in systolic blood
low-fat dairy products and increased saturated fat intake,173,179 pressure of about 1 mm Hg per kg of weight loss with follow-up of
sedentary behaviors and in many communities high alcohol con- 2–3 years.205–208 There is attenuation in the longer-term, with a
sumption. These pro-hypertensive behaviors add to the effects of decrease of about 6 mm Hg in systolic blood pressure per 10 kg of
obesity per se. In industrialized communities, low socioeconomic weight loss.206 Intervention programs appropriate for obesity–hyper-
status is a further factor predisposing to obesity,180 while in developing tension combine diet, physical activity and behavioral modification
nations, rising urbanization and westernization with fast-food patterns and aim to achieve long-term change in health-related behaviors. In
and decreased physical activity create obesogenic environments.181 the short term, many variations on reduced-energy diets can achieve
Long-term weight gain is insidious, arising from the cumulative effect weight loss. Diets include very low calorie, balanced deficit (reduction
of excess intake, which may be as little as 50–100 kcal day − 1.182 In a in protein, fat and carbohydrates), changes in a specific nutrient (low
longitudinal analysis,105 weight gain in US adults was positively fat, low carbohydrate, low glycemic index, high protein) and those
associated with small changes that included increased consumption popularized through publications or commercial weight-reduction
of sugars, starches, refined grains and processed foods, as well as plans.209,210 Meta-analyses and systematic reviews that compare these
increased alcohol intake, time spent watching television and decreased various dietary approaches do not favor a specific diet for weight
physical activity; weight change related inversely to consumption of reduction.211,212
fruit and vegetables, whole grains, nuts and yogurt. These authors In the management of obesity-related hypertension, a palatable diet
suggest that the small daily changes associated with weight gain could rich in components that may lower blood pressure and low in salt is
be prevented by small changes in lifestyle adhered to in the long term. supported by clinical trials.213 Such information has been incorporated
Long-term behavior change, however, will need recognition of in the Dietary Approaches to Stop Hypertension (DASH) diet214 for
effective strategies from population studies and clinical trials as well management of blood pressure, endorsed by the Seventh Report of the
as the cooperation of governments and industry.183 Effects of low Joint National Committee on Prevention, Detection, Evaluation and
socioeconomic status and ethnic differences, with greater predisposi- Treatment of High Blood Pressure. This approach focuses on a
tion to obesity and hypertension in blacks and obesity in Hispanics, ‘prudent diet’ rather than the effects of specific nutrients. Appropriate
will need particular attention.180,184 diets for the management of obesity-related hypertension are rich in
Although we must plan for the future and initiate primordial potassium, calcium and magnesium and fiber and low in salt and
prevention strategies for life-long maintenance of a normal body saturated fat. In terms of foods, these diets promote consumption of
weight, the obesity crisis that currently is upon us must also be vegetables, fruits, low-fat dairy products, whole grains, nuts, poultry
addressed.185 Weight loss is a key goal for treating patients presenting and fish and discourage salt, red meats, sweet foods and sugary drinks.
with the obesity–hypertension phenotype. Additionally, increasing Mediterranean215 and lactoovovegetarian216 diets are also associated
levels of cardiorespiratory fitness has major implications not only with benefits in relation to cardiovascular risk, weight control and

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blood pressure, but vegetarian diets are not widely acceptable. In US reduction, sodium restriction and the combination of both were
adults, long-term weight gain was related to foods that are discouraged compared with usual care in obese participants. The relative hazard
in a prudent diet, while foods promoted in a DASH-type diet were ratio was 0.60 for reduced sodium alone, 0.64 for weight loss alone
associated with better weight control.179 It is important then to and 0.47 for the combined intervention. The within-groups rate of
consider diets for weight management in obesity–hypertension in a adverse events was similar.
wider context than energy restriction to ensure an adequate content of
foods that may ameliorate blood pressure.213 Several trials have shown Physical activity
early but not sustained benefits of combining DASH-type diets with Aerobic exercise can reduce weight and blood pressure, but when
other modification of lifestyle.217–221 One study222 found significant exercise is the only intervention, weight losses are small, with an
differences between white, African American, Chinese and Hispanic estimated change of 1.6 kg in moderate-intensity programs continued
groups in conforming to a DASH diet assessed in the Multi-Ethnic for 6–12 months.186,217,232,233 In a meta-analysis that included
Study of Atherosclerosis, indicating that responses may improve if assessment of ambulatory blood pressure,234 it was reported that in
ethnicity is taken into account in delivery of lifestyle programs that studies lasting 4–52 weeks with physical activity as the only interven-
include DASH guidelines. The Arthritis, Diet, and Activity Promotion tion, aerobic exercise reduced blood pressure by 3/2.4 mm Hg.
Trial223 included a 3-year follow-up evaluation of a behaviorally based, The change affected daytime (3.3/3.5 mm Hg) but not nighttime
multifactorial lifestyle program compared with usual care in over- (0.6/1.0 mm Hg) blood pressure. The effect on blood pressure was
weight or obese individuals being treated with not more than two independent of the estimated weight loss of 1.2 kg. However, when
antihypertensive drugs. The 4-month intervention promoted weight aerobic exercises combined with calorie restriction for weight control,
loss using a low-sodium DASH-style diet224 with the inclusion of at the effects on ambulatory blood pressure can be substantial.235 A few
least four fish meals weekly, moderate-intensity physical activity with studies234 also examined the effects of resistance training on blood
increased incidental activity, not more than two standard alcoholic pressure. The estimated decrease in blood pressure (3.2/3.5 mm Hg)
drinks daily and quitting smoking. In the intervention group, weight was similar to the effects of aerobic exercise, although not statistically
loss and reduction in waist girth were significantly greater with the significant for systolic blood pressure and without statistically sig-
intervention after 4 months and 1 year, but decrease in blood pressure nificant weight change. A more recent meta-analysis236 found that
was greater only at 4 months. Improvements in diet, notably in fat, resistance training of at least 4 weeks resulted in an estimated decrease
sodium, fish and vegetables, persisted to 1 year in the intervention of 3.9/3.9 mm Hg in normotensive or prehypertensive individuals, but
group. Two years later, physical activity was greater in the intervention a decrease of 4.1/1.5 mm Hg in hypertensive patients was not
group and some dietary improvements were maintained but with no statistically significant. The place of resistance training in programs
significant between-group difference in weight change or blood for management of hypertension is not established. Comparison of
pressure. high- and low-intensity exercise programs with 3.5–12-month follow-
Salt sensitivity is commonly associated with obesity.225 Salt restric- up favored the higher-intensity programs with a difference in weight
tion decreases the risk of hypertension with or without weight loss as loss of about 1.5 kg.237 Higher levels of activity may be difficult to
well as reducing the incidence of cardiovascular events.226 In the maintain in the long term, although the maintenance of 10% weight
Hypertension Prevention Trial,227 participants with diastolic blood loss for 2 years in women whose activity increased by 275 min per
pressure 78–89 mm Hg were followed for 3 years after being rando- week from baseline values has been reported.238,239 Physical activity
mized to one of the five groups: control, decreased energy intake, encourages maintenance of weight loss and offers additional benefits
decreased sodium intake, decreased sodium and energy intake, or in improving cardiovascular risk factors.239 A systematic review of
decreased sodium and increased potassium intake. Blood pressure longitudinal studies of sedentary behaviors in adults found insufficient
decreased in all the groups, with the greatest decrease in patients evidence for an association between sedentary behaviors and measures
assigned to reduced energy only. The groups with reduced sodium of adiposity or cardiovascular risk factors, including self-reported
intake had a significantly lower rate of hypertension. In the Trials of hypertension, but there was moderate evidence for an association with
Hypertension Prevention phase I study,228 participants with high type 2 diabetes and strong evidence for an association with all-cause
normal blood pressure were randomized to one of the four groups and cardiovascular disease mortality.240 However, longitudinal analysis
for 18 months: control, weight loss, sodium restriction, or stress of data from US adults179 showed that an increase in time spent in
management. In the weight reduction group, weight decreased by watching television predicted weight gain, possibly mediated by lack of
3.9 kg and blood pressure by 2.9/2.3 mm Hg. Sodium restriction physical activity, adverse food choices and eating snacks while watch-
resulted in a decrease in blood pressure of 1.7/2.9 mm Hg. Seven ing television. Although there is some variation in the relationships
years later, the odds ratio for hypertension among 181 participants was identified, evidence points to the need to incorporate measures to
lower by 77% with weight loss and 35% with sodium restriction. modify sedentary behavior in lifestyle intervention programs.203
Phase II of Trials of Hypertension Prevention examined the effects of
weight loss, sodium restriction or both on blood pressure and the Alcohol
incidence of hypertension.229,230 At 6, 18 and 36 months, weight loss A very recent study demonstrated that alcohol abuse increases the risk
favored the weight reduction intervention over usual care, although of incident atrial fibrillation, myocardial infarction and congestive
weight loss was attenuated over time, and change in blood pressure heart failure, exhibiting magnitudes of risk similar to other well-
showed a similar pattern. In the sodium reduction group, a decrease established risk factors, suggesting that alcohol in excess should not be
in blood pressure was greater at each time point and also considered cardioprotective but rather cardiotoxic.241 The pressor
became attenuated with time, from 5.1/4.4 mm Hg at 6 months to effect of alcohol has also been established in clinical trials, with an
0.7/3.0 mm Hg at 3 years. The Trial of Nonpharmacologic Interven- estimated increase in systolic blood pressure of 1 mm Hg per 10 g of
tions in the Elderly study231 investigated weight loss and salt restriction alcohol.242 Alcohol provides 29 kJ g − 1, and although weight gain from
and the need for antihypertensive drugs in treated hypertensive excess intake might be expected, meta-analysis has not shown a
patients during follow-up to a median of 29 months. Weight consistent relationship between alcohol and weight gain.243 In US

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adults, however, increased alcohol intake was associated with greater warranted given the importance of healthy lifestyle medicine for this
long-term weight gain.179 Moderation of heavier daily alcohol intake population.
to no more than one standard drink in women and two standard
drinks in men appears prudent,213 with potential benefits for both Pharmacological interventions and comorbid disease
weight gain and blood pressure. In a factorial trial of independent and Healthy lifestyle interventions and bariatric surgery both can result in a
combined effects of alcohol moderation and weight reduction in significant reduction in blood pressure in patients with the obesity–
overweight and obese hypertensive drinkers, effects on blood pressure hypertension phenotype; significant weight loss is central to achieving
were additive over a 3-month period, with the combined modalities blood pressure reductions. Where healthy lifestyle interventions are
achieving a 14/9 mm Hg blood pressure reduction compared with unsuccessful in producing weight loss and an individual is not a
controls who maintained usual weight and drinking habits.244 candidate for bariatric surgery, pharmacological options are available.
There are currently six antiobesity drugs approved by the Food and
Smoking and behavioral modification techniques Drug Administration; other pharmacological options are under
Although smokers tend to have lower body weight, they may gain development.261 Moreover, for those individuals in whom hyperten-
weight because of clustering of adverse health behaviors.245 Smoking sion persists following front-line weight loss interventions, pharma-
increases blood pressure acutely, with an associated rise in arterial cological blood pressure control options should be considered, and
stiffness that lasts longer in hypertensive men.246 There is an there are a host of options available.56 As obese individuals generally
important window of opportunity for lifestyle programs to prevent have a relative volume overload state and often have low plasma renin
the weight gain (and blood pressure rise) often seen with smoking hypertension,187,188,262 they typically respond particularly well to
cessation.179 diuretics and calcium entry blocking agents. However, considering
Behavioral modification techniques are considered an essential part the adverse renal effects in the obesity–hypertension phenotype,
of programs to achieve and maintain weight loss.247 Social and angiotensin-converting enzyme inhibitors and angiotensin receptor
professional support, goal-setting, self-monitoring, stimulus control, blockers may provide renal protection in addition to lowering blood
changing the environment and problem solving, daily self-weighing pressure; these agents also produce a 25–30% reduction in the
and prevention of relapse are strategies that have had some success in development of type 2 diabetes mellitus and are the best agents to
improving adherence to weight loss programs.247–249 In the Weight reduce left ventricular hypertrophy, which is highly prevalent in the
Loss Maintenance Randomized Controlled Trial,250 improvement in obesity–hypertension phenotype.263–265 Although β-adrenergic block-
maintenance at 30 months was associated with monthly personal ers are not currently considered a first-line treatment for hypertension
contact with the program staff and regular use of an internet-based (except in those with coronary heart disease, heart failure, atrial
intervention.251 Contact by telephone, including text messaging, mail fibrillation or other conditions helped by beta blocking agents), these
or email, have been used to maintain contact with staff,248 but rapid agents, especially the vasodilating β-blockers,266 may also be useful in
changes in technology with availability of, for example, social the obesity–hypertension phenotype, particularly given their heigh-
networking and applications for mobile phones offer new opportu- tened sympathetic nervous system responses. In summary, managing
nities. At this time, there is no consensus about the most effective blood pressure is a key goal and should be achieved through all
behavioral strategies for lifestyle modification, particularly in the long clinically available means possible.
term. Trials that are in progress may clarify the best options for Individuals presenting with obesity are also at higher risk for
encouraging the maintenance of lifestyle change that is so critical to obstructive sleep apnoea, a condition that elevates blood pressure and
weight control. increases cardiovascular risk.56,267 As such, individuals who are obese
should be screened for obstructive sleep apnoea and receive appro-
Bariatric surgery priate treatment (that is, continuous positive airway pressure) when
Significant weight loss is achieved in individuals who undergo bariatric identified.267
surgery, and it should therefore be considered in those who are Furthermore, many of the medications available to treat type 2
eligible.252,253 Bariatric surgery is also associated with a significant diabetes are associated with weight gain and increased fat deposition.
reduction in blood pressure and improvements in the pathophysio- For overweight and obese patients with diabetes, however, there are
logical alterations (for example, sympathetic nervous system, renal Food and Drug Administration-approved medications that have been
system and systemic inflammation) precipitated by obesity.56,252,254,255 associated with weight loss and reduced blood pressure. The effects of
In patients undergoing bariatric surgery, healthy lifestyle interventions these agents on weight, and especially on blood pressure, are rather
(that is, exercise training and nutritional counseling) are vital modest but stand in contrast to the gain in weight frequently seen with
components of the overall care plan to further promote weight loss insulin, thiazolidinediones and insulin secretagogues.
and maintain a healthy body weight; improve functional capacity and
quality of life; and further improve abnormalities in the sympathetic CONCLUSIONS
nervous system, renal, hemodynamic, vascular and systemic inflam- Obesity-related hypertension is an important public health issue. As
matory profile associated with the obesity–hypertension the prevalence of obesity increases, the prevalence of hypertension
phenotype.56,60,200,254,256–259 Behavioral counseling should also be with its associated cardiovascular risk will increase as well. Although
integrated into the healthy lifestyle intervention plan for patients primary and even primordial prevention is the long-term goal for
undergoing bariatric surgery. Arena and Lavie260 recently proposed diminishing the prevalence of obesity, control of both obesity and
broadly embedding healthy lifestyle teams (for example, exercise hypertension in the population at risk is the overriding current
scientist, registered dietician, behavioral counselor and so on) into challenge. Treating hypertension in the obese requires addressing the
the clinical setting to deliver individually tailored healthy lifestyle obesity as part of the therapeutic plan. Lifestyle management is
medicine to those requiring these services. Integrating a healthy required in every case, with a focus on weight loss and risk reduction.
lifestyle team into clinical practices caring for patients undergoing Some have likened the treatment of obesity with caloric restriction
bariatric surgery, both preoperatively and postoperatively, is certainly alone to the treatment of hypertension with sodium restriction: it

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