Concise Cardiology

Concise Cardiology: An
Evidence-Based Handbook,
1st Edition 2008
Concise Cardiology: An Evidence-Based Handbook, 1st Edition 2008
Table Of Contents
1. cover ......................................................................................................................................... 2
2. Copyright ................................................................................................................................... 4
3. contents .................................................................................................................................... 8
4. Editor......................................................................................................................................... 8
5. Dedication ............................................................................................................................... 13
6. FOREWORD ............................................................................................................................. 14
7. CHAPTER 1 - Physical Examination of the Cardiovascular System .......................................... 14
8. CHAPTER 2 - Stress Testing ..................................................................................................... 37
9. CHAPTER 3 - Chest Pain and the Acute Coronary Syndromes ................................................ 60
10. CHAPTER 4 - Cardiogenic Shock ............................................................................................ 96
11. CHAPTER 5 - Bradyarrhythmias and Pacing ........................................................................ 108
12. CHAPTER 6 - Wide and Narrow Complex Tachyarrhythmias .............................................. 128
13. CHAPTER 7 - Sudden Cardiac Death and ICD Therapy ........................................................ 141
14. CHAPTER 8 - Atrial Fibrillation ............................................................................................ 156
15. CHAPTER 9 - Heart Failure .................................................................................................. 185
16. CHAPTER 10 - Pulmonary Hypertension ............................................................................. 213
17. CHAPTER 11 - Transplant Medicine .................................................................................... 231
18. CHAPTER 12 - Valvular Diseases ......................................................................................... 250
19. CHAPTER 13 - Endocarditis ................................................................................................. 300
20. CHAPTER 14 - Pericardial Disease ....................................................................................... 309
21. Appendix ............................................................................................................................. 313
21.1 APPENDIX A - Central Vascular Access Techniques ...................................................... 313
21.2 APPENDIX B - Clinical Pharmacology ............................................................................ 334
1
1. cover
2
3
2. Copyright
Lippincott Williams & Wilkins
Philadelphia
530 Walnut Street, Philadelphia, PA 19106 USA
978-0-7817-8509-9
0-7817-8509-X
P.iv
© 2008 by Lippincott Williams & Wilkins, a Wolters Kluwer business
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LWW.com
All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any
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Library of Congress Cataloging-in-Publication Data
4
Concise cardiology : an evidence-based handbook / editor, David V. Daniels; associate editors, Stanley
G. Rockson, Randall Vagelos.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-7817-8509-9
1. Cardiology—Handbooks, manuals, etc. 2. Heart—Diseases—Handbooks, manuals, etc. I. Daniels, David
V. II. Rockson, Stanley G. III. Vagelos, Randall.
[DNLM: 1. Heart Diseases—Handbooks. 2. Diagnostic Techniques, Cardiovascular—Handbooks. 3.
Evidence-Based Medicine—Handbooks. WG 39 C755 2008]
RC669.15C66 2008
616.1′2—dc22
2008009965
Care has been taken to confirm the accuracy of the information presented and to describe generally
accepted practices. However, the authors, editors, and publisher are not responsible for errors or
omissions or for any consequences from application of the information in this book and make no
warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the
contents of the publication. Application of this information in a particular situation remains the
professional responsibility of the practitioner.
The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage
set forth in this text are in accordance with current recommendations and practice at the time of
publication. However, in view of ongoing research, changes in government regulations, and the
constant flow of information relating to drug therapy and drug reactions, the reader is urged to check
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employed drug.
Some drugs and medical devices presented in this publication have Food and Drug Administration (FDA)
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to ascertain the FDA status of each drug or device planned for use in their clinical practice.
The publishers have made every effort to trace copyright holders for borrowed material. If they have
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opportunity.
5
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10 9 8 7 6 5 4 3 2 1
6
7
3. contents
4. Editor
Editor
David V. Daniels MD
Fellow in Cardiovascular Medicine
Fellow in Critical Care Medicine
Stanford University Medical Center
Stanford, California
Associate Editors
Stanley G. Rockson MD
Chief of Consultative Cardiology
Randall Vagelos MD
8
Professor of Medicine/Medical Director, CCU
Cardiovascular Medicine
P.ix
CONTRIBUTORS
Amin Al-Ahmad MD
Assistant Professor of Cardiovascular Medicine
Associate Director, Cardiac Arrythmia Services
Stanford University
Euan Ashley MRCP, DPhil
Assistant Professor of Medicine
Stanford University
Todd J. Brinton MD
Instructor of Medicine (Cardiology)
Lecturer in Bioengineering
Interventional Cardiology
Ian Brown MS, MD
Instructor of Surgery (Emergency Medicine)
Stanford University School of Medicine
Kamalendu Chatterjee MB, FRCP, FACC, FCCP, MACP
Ernest Gallo Distinguished Professor of Medicine
Division of Cardiology, Department of Medicine
9
University of California
San Francisco, California
Clarke G. Daniels MD
Cardiologist, Internal Medicine
Doctor's Medical Center—San Pablo
San Pablo, California
David V. Daniels MD
Fellow in Critical Care Medicine
P.x
Ramona L. Doyle MD
Associate Professor
Division of Pulmonary/Critical Care Medicine
Department of Medicine
Stanford University
James V. Freeman MD, MPH
Stanford University
Anurag Gupta MD
Electrophysiology Fellow
Department of Medicine, Division of Cardiology
Stanford University Hospital
François Haddad MD
10
Clinical Instructor of Medicine, Division of Cardiovascular Medicine
Attending Cardiologist
Heart Failure and Transplant Service
Pulmonary Hypertension Service
Henry Hsia MD
Associate Professor, Cardiovascular Medicine
Assistant Director, Arrhythmia Services
Stanford Medical Center
David Kao MD
NASA Ames Research Center
Chief Medicine Resident
Stanford University
Todd L. Kiefer MD, PhD
Fellow, Cardiovascular Medicine
Duke University Medical Center
Durham, North Carolina
David P. Lee MD
Director, Cardiac Catheterization and Coronary Internist
Assistant Professor
P.xi
Juliana C. Liu RN, MSN, ANP
Nurse Practitioner
Vera M. Wall Center for Pulmonary Vascular Disease
Pulmonary and Critical Care Medicine
11
Stanford University
Fred A. Lopez MD, FACP
Associate Professor and Vice Chair
Louisiana State University, Department of Medicine
LSU Health Sciences Center
New Orleans, Louisiana
Kelly Matsuda PharmD
Clinical Pharmacist
(Cardiovascular) Pharmacy
Shriram Nallamshetty MD
Cardiology Fellow
Department of Medicine, Cardiology Division
Massachusetts General Hospital
Boston, Massachusetts
Michael Pham MD, MPH
Instructor, Cardiology Division
Medical Director, Heart Failure and Transplant Program
VA Palo Alto Healthcare System
Palo Alto, California
Stanley G. Rockson MD
Chief of Consultative Cardiology
Donald Schreiber MD, CM
Associate Professor, Surgery (Emergency Medicine)
Attending Physician, Emergency Medicine
Stanford University Hospital
12
P.xii
Randall Vagelos MD
Professor of Medicine/Medical Director, CCU
Stanford University
Paul J. Wang
Director, Cardiac Electrophysiology and Arrythmia Service
Professor of Medicine
Roham T. Zamanian MD, FCCP
Assistant Professor of Medicine
Division of Pulmonary and Critical Care Medicine
Director, Adult Pulmonary Hypertension Clinical Services
5. Dedication
First, to Mom and Dad: You are the best parents anyone could ever hope for and you will always be
with me. I am forever grateful for the infinite lessons, constant patience, and values you have
bestowed upon me. You always had faith in me, often when I was unsure of myself, and I can only
aspire to have the same courage and compassion with my own children someday.
My sister Ana, my brother-in law Bart, and my princess Stefanie: We are family forever, and it is one
of the only things in this world I am truly sure of. I am blessed with best friends that are closer than
many boys are to their own brothers and I hope to never take that for granted.
I want to thank the many great teachers in my life, especially the ones who nurtured a rigorous
academic approach tempered with habitual common sense. These are lessons that no textbook can
confer.
13
6. FOREWORD
To study the phenomenon of disease without books is to sail an uncharted sea, while to study books
without patients is not to go to sea at all.
— Sir William Osler
While we recognize the comprehensive nature of classic textbooks like Braunwald's Heart Disease and
cutting-edge resources like Up-to-Date, a void still remains in the cardiology literature. Residents in
training, cardiology fellows, and those in practice alike operate in a fast-paced environment where
realistically the ability to look something up depends on having a resource that can be consulted in the
time it takes the elevator to go from floor 1 to floor 3. Such a resource must be concise and current,
and must present the most reasonable clinical approach and the landmark evidence to back it up.
Written as a collaborative effort by residents and fellows in training and experienced attending
physicians, Concise Cardiology: An Evidence-Based Handbook will serve a niche in our field. It is a truly
comprehensive handbook that covers topics from acute coronary syndromes to electrophysiology to
valvular heart disease. Each chapter begins with a robust dissection of the clinical problem, starting
with relevant historical and physical exam findings to aid in the diagnostic process. Therapies are
organized in chart format where appropriate, presenting indications, patient selection, and side
effects. Choice of treatment is of course influenced by the best available evidence, and this handbook
delivers—not only with a strong base of recommendations from the ACC/AHA but also with a review of
“landmark clinical trials,” from the historical data to the latest therapies. One of the most unique
aspects of our handbook is this easy-to-use, no-nonsense tabular presentation of the landmark evidence
that shapes cardiology today. The evidence is pared down to the most critical information clinicians
need to make rational treatment decisions, such as level of evidence, patient population studied,
intervention, background therapies, outcomes, and number needed to treat. The initial portion of each
chapter focuses on management and is targeted primarily toward residents, while the landmark
evidence sections will be useful to fellows in training.
Alan Yeung
Professor of Medicine
Division Chief, Cardiology
7. CHAPTER 1 - Physical Examination of the Cardiovascular

System
CHAPTER 1
Physical Examination of the Cardiovascular System
14
Clarke G. Daniels
David V. Daniels
Kamalendu Chatterjee
BACKGROUND AND APPROACH
An 81-year-old patient presented to the emergency room complaining of weakness and fatigue. His
family had noted mild disorientation. Physical exam revealed blood pressure (BP) 113/73, temperature
100°F, and heart rate (HR) 130. The lungs were clear. He was given 2 liters of intravenous normal
saline. The chest x-ray subsequently showed pulmonary congestion, and the patient was found to have
a cardiomyopathy and markedly reduced ejection fraction.
Doctors at all levels of training and experience make errors in diagnosis. Every doctor has made many
mistakes for a variety of reasons; many of these are unavoidable. Failure to recognize heart failure
when physical findings are present is not a rare occurrence. I believe this also applies to other common
cardiovascular disorders. Did the doctor in this hypothetical narrative know how to evaluate the venous
pressure and how to listen for a third heart sound? These are skills that, with practice, can be learned
at an early stage of training.
Accordingly, the emphasis in this section will be limited to physical findings that I think a trainee should
know in detail in order to evaluate the following diseases. Many findings discussed in a standard
textbook of medicine are not covered. The focus will be on physical findings in common diseases and
conditions that demand early recognition because of their serious nature, such as the following:
 Congestive heart failure and left ventricular dysfunction
 Acute and chronic pulmonary hypertension
 Complications of myocardial infarction

 Cardiac tamponade
P.2
 Mitral aortic (pulmonic) and tricuspid valve disease
 Innocent murmurs
 Dilated and hypertrophic cardiomyopathy

 Atrial septal defect (ASD) and ventricular septal defect (VSD)
HEART SOUNDS
15
Normal First and Second Heart Sounds
 Intensity of the first heart sound is related to the rapidity of closure of the mitral valve, which
is dependent on the left ventricular-left atrial pressure gradient in late diastole, the position
of the mitral valve immediately before complete closure, and left ventricular dp/dt.
 The first heart sound is best appreciated at the apical impulse in the left decubitus position.
 Narrow splitting of the S1 representing tricuspid and mitral closure sounds may be heard in
normals.
 A2 and P2 refer to the two components of the second heart sound.
 The intensity of the A2 or P2 is related to the pressures against which aortic and pulmonary
valves close. Because aortic diastolic pressure is normally significantly higher than the
pulmonary artery diastolic pressure, A2 is much louder than the P2 (for abnormal intensity of
heart sounds, see Table 1-1).
 Splitting of S2 is usually heard best at the left sternal border in the second and third interspace
using the diaphragm of the stethoscope.
 Normally, P2 occurs later than A2 because pulmonary artery “hang out time” is longer than the
aortic “hang out time.” The pulmonary hang out normally is about 60 msec and that of the
aorta is about 20 to 30 msec. The difference between these two hang out times explains why
P2 follows A2 and also the differences in normal splitting of the second heart sound. The hang
out times are primarily determined by pulmonary artery and aortic compliance, pulmonary and
aortic pressures and right and left ventricular stroke volumes. 1
 During inspiration, P2 is further delayed as a result of further prolongation of the pulmonary
artery hang out time due to transient increase in right ventricular stroke volume during
inspiration. (Note that decreased impedance decreases ventricular ejection time, and
increased impedance prolongs ventricular ejection time. Normal earlier electrical activation of
the left ventricle causes a minor contribution for earlier A2, and higher LV dp/dt similarly also
contributes, to a rather small extent, to the normal A2-P2 interval.)
 The normal second heart sound is thus usually split with inspiration and single with expiration
in children and younger adults. In older adults (over age 50) it is commonly single in all phases
of respiration.2 (for abnormal splitting of heart sounds, see Table 1-2).
P.3
 A2 is louder than P2 when listening in the second left interspace in 70% of normal subjects
under age 20, and it is always louder than P2 in subjects over age 20. 2
16
 “Normal children, young adults, and trained athletes, may have persistent splitting of S2 when
examined supine, which disappears when they sit or stand owing to decreased venous return.
By contrast, S2 remains audibly split during expiration in pathologic conditions, even when the
patient is examined sitting or standing.”3
TABLE 1-1 Abnormal intensity of heart sounds
Soft Loud
S1 • First degree A-V block • Hyperkinetic circulation as in
children, hyperthyroidism,
anemia, fever, etc.

• Decreased left ventricular
contractility
• Acute severe aortic insufficiency • A short P-R interval
with
premature closure of the mitral • Mitral stenosis when the valve
valve cusps
• Thickening and calcification of are mobile. This is believed to be
the mitral valve resulting in as a result of prolongation of
reduced mobility diastolic flow providing a large
excursion of the valve leaflets and
a loud sound as they strike the
valve ring
• Variability of intensity of S1
occurs when the rhythm is
irregular due to variations in
excursion of the mitral valve
• Variability of intensity of S1, in
17
the presence of regular rhythm,
suggests the presence of A-V
dissociation as in complete heart
block or ventricular tachycardia
S2 • A soft P2 in comparison to A2 may • A loud A2 may be heard in
be heard in valvular pulmonary systemic hypertension or in
stenosis due to valve deformity hyperkinetic states such as
and decreased pulmonary artery thyrotoxicosis or aortic
diastolic pressure regurgitation
• Similarly, A2 is often soft in • A P2 equal in loudness or louder
severe valvular aortic stenosis than A2 is heard in pulmonary
because of relative reduction of hypertension, either chronic such
aortic diastolic pressure as in primary pulmonary
hypertension, or acute as in
pulmonary embolism
• Since this latter condition occurs
frequently in older adults where
the second heart sound is often
single, a single soft second heart
sound may be heard or the second
heart sound may be absent
• In the elderly patients with aortic
stenosis with history of arterial
hypertension, the intensity of A2
may be preserved or even louder
P.4
P.5
18
TABLE 1-2 Abnormal splitting of heart sounds
Persistent Fixed Paradoxical
Wide on expiration and No (or only slight) During inspiration, P2
wider on inspiration phasic variation in the becomes delayed and
splitting during the occurs simultaneously with
respiratory cycle in all A2 or after A2. This results
positions in splitting in expiration
(A2 follows P2) and a single
S2 in inspiration (A2 and P2
occur simultaneously). This
is referred to as
paradoxical splitting
S1 • Right bundle
branch block
• Premature
ventricular
complexes (PVCs)
• Ventricular
tachycardia
• Atrial septal
defects
• Ebstein's anomaly3
S2 • Right bundle • In atrial septal • Left bundle branch
branch block defect, there is block and hence
increased delayed
19
• Type A Wolff- pulmonary activation of the left
Parkinson-White vascular ventricle, A2 may be
syndrome capacitance delayed and occur
presumably as a and increased after P2 in
result of delayed pulmonary expiration
activation blood flow as a
result
of the right of the shunt. • Other causes of
ventricle This results in a paradoxical splitting
delayed P2 and of S2
• Left ventricular wide splitting include left
pacing as during of the second ventricular outflow
biventricular heart sound. tract obstruction
pacing Inspiration does such as hypertrophic
not further obstructive
increase cardiomyopathy
• In valvular pulmonary and severe aortic
pulmonary artery blood flow and valvular stenosis.
stenosis the there is Right ventricular
second heart redistribution PVCs, and right
sound is widely of pulmonary ventricular pacing
split and the and systemic may also cause
degree of splitting blood flow and paradoxical splitting
is directly related hence the due to electrical
to the severity of duration of delay in left
the right splitting is ventricular
ventricular out- relatively fixed activation,
flow obstruction. significant aortic
The splitting of regurgitation due to
the second heart the selective
sound is not increase in left
20
usually fixed until ventricular stroke
the right volume1
ventricular stroke
volume is also
fixed
P.6
The Third Heart Sound (S3 or Ventricular Gallop)
 This sound may normally be heard in children and young adults, pregnant women, and trained
athletes.
 In the context of other evidence of heart disease, an S3 correlates with elevated ventricular
end diastolic pressure and also to elevated B-type natriuretic peptide (BNP) in patients with
systolic heart failure.
 It is best timed by focusing on the second heart sound followed by a brief interval after S2,
followed by S3. The interval is longer than the A2-P2 interval and longer than the S2 opening
snap interval. It may be faint and best heard when focusing on the instant when it is expected;
that is to say, “tuning in.”3
 It is a low-frequency sound, best heard with soft application of the bell over the apical
impulse, with the patient lying on the left side. An outward movement of the apex may be
noted that is synchronous with the S3 (visible and audible). This is further confirmation that
the sound is an S3.
 The most practical way to recognize the S3 or S4 is by listening with the bell of the
stethoscope, which is useful to appreciate these lower frequency sounds, and then to listen
with the diaphragm of the stethoscope, which cuts off the lower frequency sounds. Thus the S3
or S4 becomes muffled or cannot be appreciated.
 This description applies to a left ventricular gallop. A right ventricular S3 gallop is best heard
over the lower left sternal border or rarely below the xiphoid process. It is best heard with the
21
bell and may be heard as the patient inspires. It is heard in patients with right ventricular
systolic or diastolic failure and indicates elevated right ventricular diastolic pressure.
The Fourth Heart Sound (S4 or Atrial Gallop)
 This sound results from forceful atrial contraction against a ventricle with decreased
compliance. “This change in compliance may be related to ventricular hypertrophy, ischemia,
infarction, fibrosis, or increased afterload as in systemic or pulmonary hypertension.” 3
 It is a low-frequency sound occurring just before S1 and best heard with the bell. A left
ventricular S4 is best heard at the apex with the patient lying on the left side and may be
accompanied by a presystolic outward movement of the apex, which is palpable and visible. A
right ventricular S4 may be heard at the left sternal border.
P.7
 It may also be heard in first degree A-V block. It is also commonly heard in acute mitral
insufficiency following rupture of a chorda tendinea. “An Audible S4 is an unusual finding in

the normal heart in patients under fifty years of age except in the presence of A-V block.”3
Close attention is required to differentiate an S4 from a split S1. Proctor Harvey points out the
following distinguishing features:
 A split S1 is heard at the left sternal border and not at the apex or base. In contrast to an S4,
it is of higher frequency and is not affected by pressure with the bell of the stethoscope
whereas an S4 becomes softer with increased pressure.3
 A right-sided S4 may be heard at the left sternal border and becomes more apparent with
inspiration.
 A striking finding which, if present, may help dispel doubt about equivocal ausculatory findings
is the presence of quadruple rhythm that is audible, palpable, and visible at the apex with the
patient lying on the left side. This is the result of an S1, S2, S3, and S4 sequence. Focus should
start with visually observing the overall rhythm rather than individual events and then focus on
each separate sound and apical movement. This finding may be seen in dilated
cardiomyopathy.
 When both an S3 and S4 are present and are close together, as when the heart rate is rapid,
the combined sound closely simulates a diastolic rumble and has been mistaken for the
murmur of mitral stenosis.
22
THE VENOUS PULSE AND VENOUS PRESSURE

Identification of the Venous Pulse
It is important to recognize the jugular venous pulses adequately and properly (take care in being
certain that the pulse is venous in origin). To assess venous pressure it is necessary that the top of the
venous column is appropriately identified. Correct evaluation of venous pulse and pressure often
clarifies the diagnosis. The statement “There was no jugular venous distention (JVD)” is a summary but
a more comprehensive description is optimal.
 The venous pressure should be determined by observing the internal jugular (IJ) pulse that
appears as a diffuse pulsation of the overlying skin.
 The external jugular pulse may be a reliable indicator of venous pressure with attention to
proper technique (see below).
 The pulsations may be more easily seen when their inward and outward movements are
observed with the examiner's line of sight perpendicular to these pulsations.

 With the patient lying down with head elevation at a level to optimize the venous pulse, stand
behind the head and slightly to the right side.

 The patient's chin should be turned slightly to the left when observing the right IJ.
P.8
 Though the right IJ is traditionally examined for a variety of reasons, the left IJ can be
examined as well and may be useful in some patients.
 Shining a penlight tangentially across the neck may also enhance observation.
Distinguishing the Venous from the Carotid Pulse
 The venous pulse has a characteristic sharp inward movement whereas the carotid pulse has a
sharp outward movement and is often the most useful differentiator of the two.
 The height of the venous column will usually vary depending upon degree of head elevation.
 It will often vary with different phases of respiration, normally falling slightly with inspiration.
 It may normally be seen to rise transiently during hand pressure on the periumbilical region.
 The venous pulse is often multi-phasic and rippling and usually not palpable whereas the
carotid pulse is usually mono-phasic with a sharp palpable upstroke, sometimes with a
shoulder.
 The venous pulse is often obliterated or markedly dampened by pressure with the thumb at the
base of the pulsation.
23
 In severe tricuspid regurgitation, the pulsations may be vigorous and difficult to obliterate with
pressure, and the top of the venous column may be difficult to identify. Inward and outward
pulsations of the ear-lobes may be noted. These findings may closely simulate carotid
pulsations. Observing the venous column with the patient sitting on the edge of the bed or
even standing may be helpful in identifying the height of the column and distinguishing it from
the carotid pulse in this setting.
Estimating the Venous Pressure
 Identify the top of the venous column as indicated by the top of the venous pulsations. The
degree of elevation of the patient's head above horizontal is determined by the level at which
the top of the column is best seen and not necessarily by an arbitrary angle such as 45 degrees.
 If the height of the venous column is equal to or lower than the sternal angle the venous
pressure is normal.
 An elevation of the venous pressure is said to be present if the height of the venous column is
two to three cm above the sternal angle.3
Elevation of jugular venous pressure (JVP) reflects an increase in right atrial pressure and occurs in
heart failure, reduced complance of the right ventricle, pericardial disease, hypervolemia, obstruction
of the tricuspid orfice, and obstruction of the superior vena cava.4
P.9
Using the External Jugular (EJ) for Accurate Estimation of Central

Venous Pressure (CVP)6
 JVP can be accurately estimated if the EJ contains venous pulsations.
 Starting at 30 degrees identify the EJ and occlude it at the base of the neck.
 Empty the vein in an inferior to superior direction.
 The height of the column that refills from below is the JVP in centimeters.
 If the EJ cannot be visualized or the column extends above your finger, adjust the bed height
accordingly.
Venous Pulse Waves
 The “A” wave precedes the carotid pulse upstroke and first heart sound and is due to right
atrial systole. It is followed by the “X” descent as the atrium relaxes and the right atrial floor
descends.
24
 The “V” wave begins after the arterial pulse and is due to filling of the right atrium during
systole. The subsequent “Y” descent follows the second heart sound and is related to the fall
in right atrial pressure as blood flows through the tricuspid valve into the right ventricle.
Examples of Abnormalities of the Venous Pulse Waves
 Significant tricuspid regurgitation is characterized by the presence of a prominent “V” wave
followed by a more rapid and prominent “Y” descent.
 A giant “A” wave may be seen in right ventricular hypertrophy, as in pulmonary hypertension.
 Intermittent cannon “A” waves may be seen in complete heart block when sinus rhythm is
present or in ventricular tachycardia and may aid in the diagnosis of a wide complex
tachyarrhythmia.
 The “A” wave is absent in atrial fibrillation.
 An increase or no fall in the venous pressure during inspiration is called the Kussmaul sign and
is observed in patients with constrictive pericarditis, restrictive cardiomyopathy, right
ventricular infarction, and also in patients with partial venacaval obstruction and pulmonary
embolism.
 In constrictive pericarditis or restrictive cardiomyopathy, not only is the jugular venous

pressure elevated but there is also a sharp “Y” descent.
MURMURS
Systolic Murmurs
See Table 1-3.
Innocent Murmurs
THE 4 S's
 Short: Mid-peaking murmur that terminates before S2

 Systolic: Any diastolic murmur should be considered abnormal until proven otherwise
P.10
 Soft: Grade III or louder murmurs require further investigation

 S2 normal: Normal splitting of the second heart sound suggests a physiologic murmur
25
Although these findings are characteristic, the diagnosis of innocent murmur is one of exclusion since a
similar murmur may be heard in pathologic conditions such as atrial septal defect and aortic and
pulmonary stenosis.
The characteristic fixed splitting of the second heart sound in atrial septal defect is not heard with
innocent murmurs. If there is doubt about the presence of fixed splitting when splitting is narrowly split
in expiration, listening with the patient standing may be helpful. When standing, narrow splitting of S2
in expiration may become single and this makes atrial septal defect unlikely.
TABLE 1-3 Pan-systolic murmurs
Ventricular Septal
Mitral Regurgitation Tricuspid Regurgitation Defect
Location Usually best heard at the apex Left lower sternal Left lower
and may radiate to the border or apex sternal
midaxillary line or subscapular border
area and less commonly to the
base
Respiratory Minimal variation or louder on Increased with No change
variation expiration inspiration with
inspiration
Other S3 is often present if S3 if right ventricular Very loud
features hemodynamically significant. diastolic pressure is murmur if
elevated VSD is small
(decompensated) (larger
gradient)
Same intensity after a pause Large V wave, rapid Y Often
(premature atrial contraction descent, (and associated
[PAC], PVC, or aortic stenosis ventricularization of with a thrill
[AS]) which can help the JVP)
differentiate it from AS in
which the intensity after a
26
pause increases
P.11
Systolic Murmur Complicating Myocardial Infarction
Not infrequently, a new systolic murmur will be noted in a patient with a recent myocardial infarction.
The murmur may be detected incidentally or may accompany the onset of hypotension or congestive
heart failure.
The differential diagnosis includes the following:
 Mitral regurgitation secondary to left ventricular dilation or ischemic papillary muscle. In these
conditions, mitral regurgitation is often mild and the murmur may be early or late systolic.
 Mitral regurgitation due to rupture of a papillary muscle head: May not be loud or accompanied
by a thrill at the apex, and the murmur may be absent in patients who develop cardiogenic
shock.
 Ventricular septal defect due to rupture of the interventricular septum. Often accompanied by
a murmur and thrill along the left sternal border.
Both acute VSD and ruptured papillary muscle are frequently accompanied by hypotension and heart
failure. The murmurs may become softer or disappear as arterial pressure falls.
These conditions are often difficult to differentiate at the bedside. The presence of a systolic murmur
in the setting of an acute myocardial infarction (AMI), particularly if new, is an indication to obtain a
transthoracic echocardiogram as an emergency. This is a very useful tool to differentiate these
conditions. It should be emphasized that pulmonary artery catheterization is not required to confirm
the diagnosis of these complications of acute myocardial infarction.
27
Other Systolic Murmurs
See Table 1-4.
Diastolic Murmurs
See Table 1-5.
CARDIAC TAMPONADE
 When a patient is found to have a pericardial effusion, the presence or absence of cardiac
tamponade becomes an immediate crucial issue.
 The hemodynamic consequences of cardiac tamponade such as low cardiac out-put result from
cardiac compression from increased intrapericardial pressure usually due to accumulation of
intrapericardial fluid. There is pandiastolic restriction of ventricular filling, and in advanced

conditions, ventricles can be filled only during atrial systole. With decreasing
P.12
stroke volume, hypotension and reflex tachycardia result. With increasing intrapericardial
pressure, right atrial pressure increases to maintain cardiac filling. This compensatory increase
in right atrial pressure may become inadequate when intrapericardial pressure increases more
than 20 mm Hg. Thus shock syndrome occurs when right atrial pressure approaches 20 mm Hg.
 It has been thought that the gold standard for cardiac tamponade is the invasive demonstration
of elevated and equal intra-pericardial, right atrial, pulmonary artery diastolic, and pulmonary
capillary wedge pressures at the time of pericardiocentesis coupled with a significant increase
in cardiac output post-pericardiocentesis.9 However, in clinical practice it is not necessary.
 Echocardiography is the non-invasive procedure of choice for the detection of pericardial
effusion;9 it is highly sensitive and specific for the diagnosis of tamponade.
 Several echocardiographic findings including systolic right atrial collapse, diastolic right
ventricular collapse, inferior vena caval plethora, and respirophasic exaggeration of flow
velocities across the mitral and tricuspid valves are highly suggestive of cardiac tamponade
when the pre-test probability of tamponade is high.8
 In patients with cardiac tamponade, elevated jugular venous pressure, tachycardia, and pulsus
paradoxus are almost invariably present. Rarely pulsus paradoxus may not be present with
patients in shock; however, in these patient's there is almost always right ventricular collapse
by echocardiography.9 Auscultatory alternans and electrical alternans are occasionally present.
It needs to be appreciated that the patient may have dyspnea; hemodynamic pulmonary
edema is characteristically absent (see Table 1-6).
28
 Tamponade remains a clinical diagnosis and the mere presence of an effusion with some
findings suggesting “hemodynamic compromise,” while certainly meriting close evaluation, is

not synonymous with the diagnosis of tamponade.
P.13
TABLE 1-4 Other systolic murmurs
Murmur HOCM AS PS MVP
Location Heard best at Right second Left second Heard best at
lower left interspace, left interspace, the apex
sternal border sternal border LSB
(LLSB ) or apex (LSB) apex
Radiation Usually not to Usually to Can radiate More to LLSB,
carotids, may carotids, often to to neck less frequently
radiate to right apex with to the axilla
sternal border, musical quality
apex and even
to axilla
Timing Mid-systolic and Mid-systolic, Mid-systolic Late systolic
when secondary later peaking (may be
mitral murmur confused with a
regurgitation is associated with ↑ diastolic
present a long severity of AS murmur)
late systolic
murmur is
superimposed
S2 In severe The second heart Wide Usually normally
outflow sound may be splitting of split
29
obstruction, quite soft, the second
paradoxical single, or heart sound
splitting may paradoxically due to delay
occur split in P2 and
the intensity
of P2 may
be obtunded
Maneuvers Increases in Decreases in Increases in The mid-systolic
intensity during intensity with intensity clicks and the
phase 2 of Valsalva or and onset of the
Valsalva, during standing duration late systolic
post ectopic during murmur is
beat, or inspiration closer to S1 on
standing. standing and
Decreased in during phase 2
intensity during Valsalva as
supine position, ventricular
during volumes are
squatting, and decreased. Click
during phase 4 and murmur
of Valsalva moves → S2
(shorter) during
squatting,
supine position3
Other In contrast to With moderate A prominent Often
notes valvular aortic to severe aortic right introduced by
stenosis, the stenosis, the ventricular single or
carotid upstroke carotid pulse lift multiple systolic
is brisk. may be slowly clicks as the
Occasionally a rising, may have prolapsed valve
bisferiens an anacrotic leaflets and
quality is character, and chordal
appreciated. the amplitude apparatus
30
may decrease. It tenses3
should be
appreciated that
in elderly
patients, even
with severe
calcific aortic
stenosis, the
carotid pulse
features may be
absent
A characteristic The longer the
finding, if murmur, the
present, is a more severe the
triple apical regurgitation
beat (triple
ripple) as a
result of a
presystolic
impulse, normal
apical thrust,
and mid-systolic
outward
movement of
the apex3
An S4 may be
heard at the
apex
accompanied by
a visible and
audible
presystolic
impulse
31
HOCM, hypertrophic obstructive cardiomyopathy; AS, aortic stenosis; PS, pulmonary stenosis;
MVP, mitral valve prolapse; RSB, right sternal border; LSB, left sternal border; LLSB, lower left
sternal border
P.14
P.15
TABLE 1-5 Diastolic murmurs
Murmur MS AR PR Dock Murmur7
Location Apex or just medial RSB or LSB apex. LSB with LSB,
to the apex, best Best heard with diaphragm localized
heard with bell in diaphragm in often to
left lateral seating and second or
decubitus position leaning forward third
(may be very position, during interspace
localized) held expiration
Quality Low pitch, High pitched High pitched High pitched
rumbling
32
Timing Mid-diastolic with Early diastolic Early Early
pre-systolic decrescendo diastolic diastolic
accentuation decrescendo
Maneuvers S2→OS interval Increases in Increases in Increases in
widens with intensity with intensity intensity
standing or exercise or during with hand
Valsalva,2 shortens isometric hand inspiration grip
with tachycardia, grip
in presence of
mitral
regurgitation,
aortic stenosis, and
regurgitation.
Murmur increases
in intensity and
relative duration
with exercise,
during pregnancy,
and with volume
overload
Other Loud S1 in early Diastolic murmur Can increase This murmur
MS, may diminish in identical to MS in intensity is described
advanced disease if may be heard at with in LAD
the mitral valves the apex (Austin inspiration stenosis and
are heavily Flint murmur). represents
calcified and Presystolic turbulent
immobile component is flow through
usually absent the vessel in
(vs. MS),with diastole
vasodilator such
as amyl nitrite
decreasing
intensity and
33
duration of the
Austin Flint
murmur
OS vs. split S2: Very rare,
More likely OS if need to
louder at apex than exclude
base valvular
lesions to
make the
diagnosis
S2→OS interval
shortens with
increasing severity
Associated loud P2,
RV heave of
pulmonary
hypertension and
secondary tricuspid
regurgitation
signify significant
disease
Soft S1 secondary
to premature
closure of the
mitral valve
indicates severe
AR
Diastolic Flow Murmurs: A diastolic rumbling murmur similar to that heard in stenosis of the
tricuspid or mitral valve may be heard because of increased flow in the absence of obstruction.
34
Examples include atrial septal defect and mitral regurgitation. Similarly, a third heart sound or
summation gallop (S3, S4) may simulate a diastolic rumble suggesting a stenotic valve.
MS, mitral stenosis; AR, aortic regurgitation; PR, pulmonary regurgitation; RSB, right sternal
border; LSB, left sternal border
P.16
TABLE 1-6 Cardiac tamponade9
History Sensitivity (%) Physical Finding Sensitivity (%)
Dyspnea 88 Pulsus paradoxus >10 mm Hg 82
Chest pain 20 Tachycardia 77
Fever 25 Elevated JVP 76
Diminished Heart Sounds 28
Hypotension (SBP <120 mm Hg) 30
P.17
35
TABLE 1-7 Operating characteristics of the arterial line pulsus in patients with known
effusion9
Sensitivity (%) Specificity (%) LR + (95% CI) LR - (95% CI)
Pulsus >10 98 70 3.3 (1.8-6.3) 0.03 (0.01-0.24)
Pulsus >12 98 83 5.9 (2.4-14) 0.03 (0-0.21)
In a single study in which patients with a documented pericardial effusion were referred for
pericardiocentesis and had intra-pericardial pressures and cardiac output changes measured, arterial
line pulsus paradoxus were predictive of tamponade. Sensitivity and specificity of pulsus paradoxus are
shown in Table 1-79:
 These sensitivities and specificities predicted tamponade as defined by a >20% increase in
cardiac output post-pericardiocentesis.
 A pulsus of >25 mm Hg was highly predictive of a >50% increase in cardiac output after
pericardiocentesis.
 These patients were known to have a pericardial effusion; thus the stated sensitivity and
specificity may not be applicable to patients who have not yet had an echocardiogram.
 Other conditions resulting in pulsus paradoxus include COPD, congestive heart failure, mitral
stenosis, massive pulmonary embolism, severe hypovolemic shock, obesity, and tense ascites. 8
REFERENCES
1. Topol EJ, et al. Textbook of Cardiovascular Medicine. Lippincott, Williams, & Wilkins. 2006.
2. Constant J. Bedside Cardiology. 5th ed. Philadelphia: Lippincott, Williams, & Wilkins: 1999: 147-148.
3. Chizner MA. Classic Teachings in Clinical Cardiology: A Tribute to W Proctor Harvey M.D. Cedar
Grove, New Jersey: Lannec Publishing, Inc; 1996:125-126:137-139:140-1123.
4. Braunwald E. Heart Disease: A Textbook of Cardiovascular Medicine. 5th ed. Philadelphia: WB
Saunders, 1997:19.
36
P.18
5. Forrester JS, Diamond G,McHugh TJ, et al. Filling pressures in the right and left sides of the heart in
acute myocardial infarction. A reappraisal of central-venous-pressure monitoring. AM J Med.
1971;285(4):190-193.
6. Vinayak AG, Levitt J, Gehlbach B, et al. Usefulness of the external jugular vein examination in
detecting abnormal central venous pressure in critically ill patients. Arch Intern Med.
2006;166(19):2132-2137.
7. Dock W, Zoneraich S. A diastolic murmur arising in a stenosed coronary artery. AM J Med.
1967;42(4):617-619.
8. Curtiss EI, Reddy PS, Uretsky BF, et al. Pulsus paradoxus: definition and relation to the severity of
cardiac tamponade. AM Heart J. 1988;115(2):391-398.
9. Roy CL, Minor MA, Brookhart MA, et al. Does this patient with a pericardial effusion have cardiac
tamponade? JAMA. 2007;297(16):1810-1818.
8. CHAPTER 2 - Stress Testing

CHAPTER 2
Stress Testing
Ian Brown
Donald Schreiber
Stress testing is one diagnostic instrument currently available to medical professionals for the
evaluation and risk stratification of patients with known or suspected coronary artery disease (CAD).
Stress testing may be done with concurrent electrocardiogram (ECG) monitoring, nuclear scintigraphy,
or echocardiography. Indeed, the different tests and the wide variety of patients tested have made
stress testing an increasingly complex and challenging area for practitioners. This chapter is aimed at
providing the reader with an enhanced understanding of the subject. The first portion of this chapter
examines exercise stress testing, describing which patients would benefit from exercise stress tests, the
appropriate timing for these tests, and test protocols. The next section details pharmacologic and
37
imaging alternatives, reviewing the indications for each and comparing the different modalities. The
final section gives guidelines on interpretation of stress test results.
INDICATIONS
Stress tests have two primary indications: to diagnose CAD and to riskstratify patients with known CAD.
Diagnosis of Obstructive CAD
For patients with symptoms of chest pain, or possible anginal equivalent, the medical provider reviews
the history, physical, and ECG to help establish the likelihood that symptoms are due to CAD (Table 2-
1). If the diagnosis is unclear, the physician can use a stress test to assist in the diagnosis of CAD.1
Stress tests are most useful in patients with intermediate pretest probability of CAD. If the patient has
a high pretest probability of CAD, then the results of a stress test are not likely to change the
management. If the patient has a low pretest probability, then the frequency of false positive tests may
lead to overtreatment and/or unnecessary procedures. Note that inTable 2-1, a 40-year-old male with a
clinical diagnosis of nonanginal chest pain is still considered intermediate pretest probability for CAD.
This underscores the limitations of clinical evaluation for ruling out CAD. Table 2-2 lists indications for
exercise stress testing.
P.20
TABLE 2-1 Pretest probability of CAD
Typical/Definitive Atypical/Probable Nonanginal chest
Age Gender angina pectoris angina pectoris pain Asymptomatic
30- Male Intermediate Intermediate Low Very Low
39
Female Intermediate Very Low Very Low Very Low
40- Male High Intermediate Intermediate Low
49
38
Female Intermediate Low Very Low Very Low
59
Female Intermediate Intermediate Low Very Low
69
Female High Intermediate Intermediate Low
From Gibbons RJ, Balady GJ, Timothy Bricker J, et al. ACC/AHA 2002 guideline update for
exercise testing: A report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines).
2002; and from Diamond G, Forrester J. Analysis of probability as an aid in the clinical diagnosis
of coronary-artery disease. N Engl J Med. 1979;300:1350-1358.
Stress tests also play an important role in evaluating CAD in the context of preoperative risk evaluation.
Stress testing is most useful in patients with intermediate clinical cardiac risk who either have poor
functional capacity (<4 METS) or who have better functional capacity (≥4 METS) but are undergoing a
high-risk surgical procedure. Stress testing is also useful in patients who are in a low clinical cardiac risk
group but have poor functional capacity and are undergoing a high-risk surgical procedure. A stepwise
approach to preoperative cardiac risk evaluation for non-cardiac surgery is explored elsewhere.4
Risk Assessment in Patients with Symptoms or History of CAD
In patients with suspected or confirmed CAD, stress tests may be used for risk assessment: to develop a
prognosis, and to help guide treatment. Table 2-3 shows indications for stress tests in these patients.
P.21
39
TABLE 2-2 Indications for exercise testing to diagnose obstructive CAD
Class I (Evidence and/or General Agreement that Procedure is Useful)
• Patients with an intermediate pretest probability of CAD on basis of gender, age, and
symptoms (Table 2-1)
Class IIa (Weight of Evidence/Opinion is in Favor of Usefulness)
• Patients with vasospastic angina
Class IIb (Usefulness Less Well Established)
• Patients with high pretest probability of CAD
• Patients with low pretest probability of CAD
• Patients with <1 mm of baseline ST depression taking digoxin
• Patients with ECG criteria for LVH with <1mm of ST depression
Class III (Evidence/Opinion that Procedure is Not Useful and May be Harmful)
• Patients with any of the following baseline ECG abnormalities:
• Pre-excitation syndrome (e.g., WPW)
• Electronically paced ventricular rhythm
• >1 mm resting ST depression
40
• Complete LBBB
ECG, electrocardiogram; LVH, left ventricular hypertrophy; WPW, Wolff-Parkinson-White; LBBB,
left bundle branch block. From Gibbons RJ, Balady GJ, Timothy Bricker J, et al. ACC/AHA 2002
guideline update for exercise testing: A report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise
Testing Guidelines).
Long-Term Risk Assessment
Stress tests are useful to help predict survival. Risk stratification is improved when the stress test
augments the history of the patient and the description of the pain. There are many risk stratification
schemes based on electrocardiographic, hemodynamic, symptomatic and imaging parameters. These
are reviewed in more detail in the last section of this chapter. High-risk patients may benefit from
angiography, angioplasty, or revascularization.
Short-Term Risk Assessment
For patients presenting with symptoms of acute coronary syndrome (ACS)—that is, with unstable angina
(UA) or myocardial infarct (MI)—stress tests are useful to predict short-term risk.
P.22
TABLE 2-3 Risk assessment in patients with symptoms or history of CAD
41
Class I (Evidence and/or General Agreement that Procedure is Useful)
• Patients undergoing initial evaluation with suspected or known CAD
• Patients with suspected or known CAD who present with significant change in status
• Low-risk UA patients, 8-12 hours after presentation, who have been free of active
ischemic or heart failure symptoms
• Intermediate-risk UA patients, 2-3 days after presentation, who have been free of active
ischemic or heart failure symptoms
Class IIa (Weight of Evidence/Opinion is in Favor of Usefulness)
• Intermediate-risk UA patients who have initial normal cardiac markers, repeat ECG
without significant change, normal cardiac markers 6-12 hours after the onset of
symptoms, and no other evidence of ischemia during observation
Class IIb (Usefulness Less Well Established)
• Patients with any of the following baseline ECG abnormalities:
• Pre-excitation syndrome (e.g., WPW)
• Electronically paced ventricular rhythm
• >1 mm resting ST depression
• Complete LBBB or any IVCD with QRS >120
• Patients with stable clinical course who undergo periodic monitoring to guide treatment
42
Class III (Evidence/Opinion that Procedure is Not Useful and May be Harmful)
• Patients with severe comorbidity likely to limit life expectancy and/or candidacy for
revascularization
• High-risk UA patients
CAD, Coronary artery disease; UA, unstable angina; ECG, electrocardiogram; WPW, Wolff-
Parkinson-White; LBBB, left bundle branch block; IVCD, interventricular conduction defect. From
Gibbons RJ, Balady GJ, Timothy Bricker J, et al. ACC/AHA 2002 guideline update for exercise
testing: A report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines). 2002.
The ability to rule out imminent ischemia is based on the test's negative predictive value. The negative
predictive value of a stress test is dependent upon the specific test used; however, for low to moderate
risk patients who rule out by enzymes and have an adequate negative exercise stress test, the short-
term event rate is generally very low. Gibler et al. showed that only 1 of 1010 patients in a chest pain
unit who ruled out for acute myocardial infarction and had a negative stress test died (cause unknown)
within 30 days.6 In
P.23
another study, 0 of 374 patients had a combined endpoint of death or acute MI at 150 days. 7
CONTRAINDICATIONS
Stress tests are generally safe procedures.8 In a large national survey of exercise stress test facilities,
encompassing both inpatient and outpatients, Stuard et al. enumerated complications including
arrhythmias (<0.05%), infarcts (<0.04%), and death (<0.01%).9 Looking at a higher risk group—632
hospitalized subjects evaluated for unstable angina symptoms—Stein et al. reported the combined
incidence of MI and death within 24 hours of exercise testing as 0.5%. 10 Complications can be reduced by
a careful history and physical, reviewing an ECG, and a pretest chest radiograph. Contraindications for
exercise stress tests are shown in Table 2-4. Most of these contraindications are also applicable to
pharmacologic stress tests.
43
TABLE 2-4 Contraindications to exercise stress tests
Absolute
• Acute myocardial infarction (within 2 d)
• High-risk unstable angina
• Symptomatic or unstable arrhythmia
• Symptomatic severe aortic stenosis
• Uncontrolled symptomatic heart failure
• Acute pulmonary embolus or pulmonary infarction
• Acute myocarditis or pericarditis
• Acute aortic dissection
Relative
• Left main coronary stenosis
• Moderate stenotic valvular heart disease
• Electrolyte abnormalities
• Severe hypertension (>200 mm Hg/100 mm Hg)
44
• Tachyarrhythmias or bradyarrhythmias
• Hypertrophic cardiomyopathy or other outflow tract obstruction
• Mental or physical impairment leading to inability to exercise adequately
• High-degree atrioventricular block
From Gibbons RJ, Balady GJ, Timothy Bricker J, et al. ACC/AHA 2002 guideline update for
exercise testing: A report of the American College of Cardiology/American Heart Association
2002.
P.24
TIMING OF STRESS TESTS
Stress tests should not be performed until the patient is clinically stable. Low-risk outpatients being
evaluated for ACS symptoms should have a stress test within 72 hours.1 The majority of low-risk patients
admitted to the hospital can safely obtain their stress tests as outpatients. Current guidelines
recommend that the stress test be obtained within 72 hours of discharge. 5 In general, outpatient stress
tests for patients presenting via the emergency department (ED) with symptoms should be reserved for
patients who are either at low risk for having ACS or low risk for short-term death or MI.11,12 Outpatient
stress tests are appropriate only for adherent patients.
Observation or chest pain units are increasingly common and provide a middle ground between
inpatient and outpatient testing. Patient selection and management are based on accelerated rule-out
protocols that ideally include stress testing.5, 6, and 7,10,13 These units have been shown to decrease
unnecessary admissions, reduce the rate of missed MIs, reduce costs, and increase patient satisfaction.
STRESS TEST PROCEDURES: PRETEST PREPARATION
The patient should be informed of the purpose, risks, benefits, and details of the stress test
procedure.14 The patient should be instructed not to eat, drink, or smoke for 3 hours before the exam.
45
Patients undergoing an exercise stress test should be instructed to wear comfortable clothing and
footwear.
The physician should review the patient's medication list and decide what medications should be
discontinued for the test. It is usually recommended that patients hold their dose(s) of beta-blocker 24-
48 hours prior to exercise stress testing. A beta-blocker may blunt the chronotropic response to
exercise and prevent the patient from reaching their target heart rates. This limits the diagnostic utility
of the stress test. However, if there is risk involved in discontinuing beta-blocker therapy, there is some
evidence to support that exercise tolerance or diagnostic accuracy is not affected. 15 In addition, the
stress test can be used to test the medical management regimen that may include beta-blockers.
STRESS TEST ALTERNATIVES AND ENHANCEMENTS
Pharmacologic agents can be substituted for physical exercise to cause increased myocardial work and
myocardial oxygen demand. The two major categories of imaging—echocardiography and myocardial
perfusion imaging—can be used as an adjunct to either an exercise or pharmacologic stress test to
delineate the extent, severity, and location of myocardial injury. Figure 2-1 gives an overview of the
clinical context of stress testing, and provides a guide to the type of stress test that may be
appropriate.
P.25
46
47
FIGURE 2-1 Clinical context for exercise testing for patients with coronary heart disease. ACC/AHA
practice guidelines.1 CAD, Coronary artery disease.
P.26
SPECIFIC THERAPIES
Exercise versus Pharmacology
For an exercise stress test, the patient must be able to use the available exercise equipment (usually a
treadmill, or less often in the United States, a cycle ergometer) to elevate the heart rate to ≥85% of
predicted maximum heart rate (HRMax = 220 - age). If the patient is elderly, has significant comorbidity
(e.g., chronic obstructive pulmonary disease [COPD], arthritis), or has other physical or mental
limitation that would limit the ability to exercise, a pharmacologic stress test should be substituted.
Pharmacologic stress tests generally use accompanying imaging.
The two choices for pharmacologic agents are vasodilators or dobutamine (the latter with or without
atropine). Adenosine and dipyridamole are the current vasodilators of choice. Both agents are equally
effective. They increase the heart rate, decrease the blood pressure, and increase myocardial oxygen
demand, but may cause bronchospasm. Caution is warranted if there is a history of asthma or COPD.
They may cause worsening angina. Both are contraindicated in high-degree A-V block and sick sinus
syndrome. The short half-life of adenosine has a theoretical advantage if potential side effects are a
concern. Theophylline and ideally caffeine must be withheld for 24 hours before the procedure.
Calcium channel blockers, and nitroglycerin should ideally be withheld for 24 hours and beta-blockers
for 48 hours, as they decrease the sensitivity of pharmacologic myocardial perfusion imaging. 18, 19, and 20
A dobutamine stress test is preferred in patients with history of bronchospasm or recent use of a
methylxanthine. Dobutamine, an inotropic and chronotropic agent, is usually used in conjunction with
echocardiography imaging but can also be used with myocardial perfusion imaging (MPI). Beta-blockers
should be withheld for 24-48 hours.21,22 unless the indication for the test is to evaluate the effectiveness
of a medical regimen. Specific contraindications to a dobutamine stress test include the following: 18
 Ventricular arrhythmias
 Recent MI (one to three days)
 ACS
 Hemodynamically significant left ventricular outflow tract obstruction
 Aortic aneurysm or aortic dissection
48
 Systemic hypertension.
The accuracy of a dobutamine stress echo is comparable to both adenosine and dipyridamole MPI
(sensitivity ~80%-90% and specificity ~75%-85%). The choice of pharmacologic agent often has more to
do with local expertise and individual patient characteristics rather than the advantages of each
agent.23 Since exercise tolerance and symptoms during exercise are important prognostic factors (see
below), a submaximal exercise test can be combined with a pharmacologic protocol. 18,24, 25, and 26
P.27
Imaging
Moderate-risk patients, and any patients for whom there is a need to localize ischemia or assess the
viability of myocardium, benefit from imaging in addition to ECG testing. For low-risk patients with
normal ECGs who are not on digoxin, a standard (exercise) ECG stress test without imaging is
sufficient.1,27 However, there are guidelines28 that recommend stress imaging in the risk stratification of
low-risk as well as moderate-risk patients with symptoms. A stress test patient who has any of the
following ECG abnormalities that can make ECG interpretation difficult (including low-risk patients)
may benefit from an imaging modality:
 ST depression >1mm
 Left bundle-branch block
 Intraventricular conduction delay with a QRS >120 ms
 Ventricular paced rhythm

 Pre-excitation syndrome
If imaging were not used, these pre-existing ECG abnormalities would limit the ECG diagnosis of
ischemia.1
Myocardial perfusion imaging or echocardiography can be used with an exercise or a pharmacologic
protocol depending on the patient's capability to exercise.
MPI can be done with positron emitting tomography (PET) scanning, single photon emission computed
tomography (SPECT) imaging, or planar imaging. Stress PET imaging, while more sensitive, is
considerably more expensive23 and less readily available than SPECT imaging (Table 2-5). The only class I
recommendation for an adenosine or dipyridamole perfusion PET is for cases where a SPECT scan
produced equivocal results.28 SPECT MPI, while still occasionally referred to as “thallium” MPI, is now
usually done with a technetium isotope—sestamibi, tetrofosmin, or teboroxime—due to shorter half-life
(lower radiation exposure and ability to use higher doses) with technetium, and to the high false-
49
positive rates associated with thallium attenuation in soft tissue. SPECT imaging is considered to be
superior to planar imaging.23,29
Echocardiograms are used to detect the presence of CAD and to risk-stratify patients. An
echocardiogram can localize the area of ischemia by identifying segments with wall motion
abnormalities such as hypokinesis or akinesis. If the echocardiogram is used in conjunction with an
exercise stress test, the patient must move quickly from the point of peak exercise to an exam table
where the echocardiogram can be performed and prior to the resolution of any ischemia that may be
present. Echocardiograms are somewhat quicker to perform and less expensive than MPIs, but are more
dependent on the sonographer's skills.
P.28
TABLE 2-5 Cost and accuracy of imaging modalities
1996 Cost Sensitivity (%) Specificity (%)
PET MPI $1,500 91 82
SPECT MPI $475 88 77
Adenosine 90 75
Dipyridamole 89 65
Dobutamine 82 75
Planar thallium MPI $221 79 73
Stress echocardiography $265 76 88
Adenosine 72 91
50
Dipyridamole 70 93
Dobutamine 80 84
Exercise electrocardiography $100 68 77
Coronary artery bypass graft (CABG) ~$32,500
MI: single admission $7,415
Catheterization with angiogram $1,810
Percutaneous coronary intervention
(PCI) $11,685
Modified from Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the
diagnosis of coronary artery disease. Ann Intern Med. 1999;130:719-728; and Kim C, Kwok YS,
Heagerty P, et al. Pharmacologic stress testing for coronary disease diagnosis: A meta-analysis.
Am Heart J. 2001;142:934-944. These numbers reflect the average taken over all studies in the
meta-analysis.
Patient variables can influence the choice of imaging modalities. In patients with left ventricular
hypertrophy, stress echocardiograms have a superior specificity.31 Vasodilator stress MPI is superior to
exercise stress MPI or stress echo in patients with left bundle branch block or paced ventricular
rhythms.27 MPI is preferred if the patient's body habitus creates a poor echocardiographic acoustic
window.
The choice of imaging modality is usually based on local expertise and availability rather than individual
test characteristics. The sensitivity and
P.29
specificity of these tests are given in Table 2-5. Some studies have shown that SPECT MPI has a higher
sensitivity than echocardiography, while others have shown the two modalities to have comparable
51
sensitivities. As expected, higher sensitivities are found in populations with higher prevalence and/or
severity of disease. The specificity of stress echocardiography is slightly higher than for MPI. 23,31,32 These
two options have similar performance characteristics for risk stratification and predicting outcomes. 33
In addition to these two established imaging modalities, stress testing with magnetic resonance imaging
(MRI) has shown encouraging results. It can be combined with either dobutamine or a vasodilator. In
one study, sensitivity, when compared to dobutamine stress echo, was significantly higher, 86.2% versus
74.3%, and specificity was 85.7% versus 69.8%.34 In addition to being accurate in diagnosing ischemic
heart disease, MRI shows promise of having prognostic power.35
TEST INTERPRETATION
The provider must first determine whether the study was adequate. For the exercise portion of a stress
test, the heart rate ideally should reach 85% or more of the patient's predicted maximum heart rate;
lower heart rates increase the probability of a false negative result. For echocardiographic studies,
satisfactory acoustic windows must be obtained to evaluate cardiac wall motion.
What is considered a positive or negative result on a stress test is somewhat arbitrary and depends on
the desired sensitivity versus specificity of the test.1 Predictors of adverse outcomes can be physiologic,
electrocardiographic, or imaging abnormalities (Table 2-6).36,37 Any one of these findings constitutes a
poor prognosis. Not surprisingly, the inability to exercise is the strongest physiologic predictor of
adverse cardiac outcomes. Downsloping ST segment depression, particularly in lead V5, is the strongest
electrocardiographic predictor. Decreased left ventricular function is the strongest imaging predictor. 1
The provider is not limited to considering these factors individually; there are tools available that allow
prediction of mortality using multiple prognostic factors. Perhaps the best-established of these tools is
the Duke Treadmill Score (DTS), which incorporates the depth of ST depression, the length of time on
the treadmill, and the presence of angina (DTS = exercise time - [5 * ST deviation] - [4 * exercise
angina]) to quantify a 5-year survival rate.38, 39, and 40

The DTS is a well-validated tool that is easy to
use, but has some limits: it considers only three variables, and is somewhat dependent on patient
morphology. It is most useful as a predictor when the score is either particularly high or low. These
scores can be augmented with imaging information. Table 2-7 is an example of a risk stratification
scheme that combines information from various aspects of the stress test, including echocardiographic
imaging and the Duke treadmill score.27
P.30
52
TABLE 2-6 Predictors of adverse cardiac outcomes in stress tests
Exercise
• Poor exercise capacity (<5 METs)
• Exercise-induced angina (particularly if test-limiting)
• Abnormally low peak systolic blood pressure (<130 mm Hg)
• Fall in the systolic blood pressure during exercise
• Chronotropic incompetence (<85 % of the age-predicted max HR)
Echocardiography
• Rest images
• New wall motion abnormality
• Stress images
• Stress-induced left ventricular abnormality
• Reversible dyssynergy
• Decreased wall thickening
• Decreased global left ventricular ejection fraction
53
• Increased LV end-systolic volume
• Reversible (or biphasic) segmental wall motion abnormality
Myocardial Perfusion
• Number and/or location of reversible defects
• Magnitude (severity and extent) of stress defects
• Lung uptake of isotope
• Transient ischemic left ventricle cavity dilation after exercise
• Delayed redistribution
EKG
• ≥1 mm horizontal or down sloping ST depression or elevation
• ≥2 mm of ischemic ST depression at a low workload (HR ≤130 bpm, or stage 2 or less)
• Early onset (stage 1) or prolonged duration (>5 min) of ST depression
• Multiple leads (>5) with ST depression
• ST segment elevation (in leads without pathologic Q waves and not in a VR)
• Ventricular couplets or tachycardia at a low workload or during recovery
54
• ST/HR slope (6 microV/beat per min)
Combined Exercise and EKG
• Elevated treadmill score (e.g., Duke)
Adapted from Weiner D. Exercise ECG testing to determine prognosis of coronary heart disease.
In: UpToDate; 2006.
P.31
TABLE 2-7 Prognosis based on Duke treadmill score and echocardiographic findings
High Risk (>3% Annual Mortality)
• Severe resting left ventricular dysfunction (LVEF <35%)
• High-risk treadmill score (score ≤-11)
• Severe exercise left ventricular dysfunction (exercise LVEF <35%)
• Echocardiographic wall motion abnormality (involving >2 segments) developing at low
dose of dobutamine (≤10 mg/kg/min) or at a low heart rate (<120 bpm)
• Stress echocardiographic evidence of extensive ischemia
Intermediate Risk (1%-3% Annual Mortality)
55
• Mild/moderate resting left ventricular dysfunction (LVEF = 35%-49%)
• Intermediate-risk treadmill score (-11 < score <5)
• Limited stress echocardiographic ischemia with a wall motion abnormality only at
higher doses of dobutamine involving ≤2 segments
Low Risk (<1% Annual Mortality)
• Low-risk treadmill score (score ≥5)
• Normal stress echocardiographic wall motion or no change of limited resting wall
motion abnormalities during stress (unless high treadmill score)
LVEF, left ventricular ejection fraction adapted from Gibbons RJ, Chatterjee K, Daley J, et al.
ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: A
report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Committee on Management of Patients With Chronic Stable Angina). J Am Coll
Cardiol. 1999;33:2092-2197.
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2. Gibbons LW, Mitchell TL, Wei M, et al. Maximal exercise test as a predictor of risk for mortality from
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3. Diamond G, Forrester J. Analysis of probability as an aid in the clinical diagnosis of coronary-artery
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11. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA guideline update for the management of
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12. Meyer MC, Mooney RP, Sekera AK. A critical pathway for patients with acute chest pain and low risk
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13. Amsterdam EA, Kirk JD, Diercks DB, et al. Exercise testing in chest pain units: Rationale,
implementation, and results. Cardiol Clin. 2005;23:503-16, vii.
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14. Pina IL, Balady GJ, Hanson P, et al. Guidelines for clinical exercise testing laboratories. A statement
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15. Herbert WG, Dubach P, Lehmann KG, et al. Effect of beta-blockade on the interpretation of the
exercise ECG: ST level versus delta ST/HR index. Am Heart J. 1991;122:993-1000.
16. Fletcher GF, Balady G, Froelicher VF, et al. Exercise standards. A statement for healthcare
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17. Gibbons RJ, Balady GJ, Timothy Bricker J, et al. ACC/AHA 2002 Guideline update for exercise
testing: Summary Article: A Report of the American College of Cardiology/American Heart Association
Circulation. 2002;106:1883-1892.
18. Heller GV. Pharmacologic stress myocardial perfusion imaging in the diagnosis and prognosis of
coronary heart disease. In: Up-To-Date, ed. 15.1 ed; 2007.
19. Taillefer R, Ahlberg AW, Masood Y, et al. Acute beta-blockade reduces the extent and severity of
myocardial perfusion defects with dipyridamole Tc-99m sestamibi SPECT imaging. J Am Coll Cardiol.
2003;42:1475-1483.
20. Sharir T, Rabinowitz B, Livschitz S, et al. Underestimation of extent and severity of coronary artery
disease by dipyridamole stress thallium-201 single-photon emission computed tomographic myocardial
perfusion imaging in patients taking antianginal drugs. J Am Coll Cardiol. 1998;31:1540-1546.
21. Heller GV, Kapetanopoulos A. Pharmacologic stress myocardial perfusion imaging: Testing
methodologies and safety. In: UpToDate. 15.3 ed; 2007.
22. Shehata AR, Gillam LD, Mascitelli VA, et al. Impact of acute propranolol administration on
dobutamine-induced myocardial ischemia as evaluated by myocardial perfusion imaging and
echocardiography. Am J Cardiol. 1997;80:268-272.
23. Garber AM, Solomon NA. Cost-effectiveness of alternative test strategies for the diagnosis of
coronary artery disease. Ann Intern Med. 1999;130:719-728.
24. Casale PN, Guiney TE, Strauss, HW, et al. Simultaneous low level treadmill exercise and intravenous
dipyridamole stress thallium imaging. Am J Cardiol. 1988;62:799-802.
25. Pennell DJ, Mavrogeni SI, Forbat SM, et al. Adenosine combined with dynamic exercise for
myocardial perfusion imaging. J Am Coll Cardiol. 1995;25:1300-1309.
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26. Thomas GS, Prill NV, Majmundar H, et al. Treadmill exercise during adenosine infusion is safe,
results in fewer adverse reactions, and improves myocardial perfusion image quality. J Nucl Cardiol.
2000;7:439-446.
27. Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of
patients with chronic stable angina: A report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee on Management of Patients With Chronic
Stable Angina). J Am Coll Cardiol. 1999;33:2092-2197.
28. Klocke FJ, Baird MG, Lorell BH, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac
radionuclide imaging—Executive Summary: A report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995
Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). Circulation. 2003;108:1404-1418.
29. Fintel DJ, Links JM, Brinker JA, et al. Improved diagnostic performance of exercise thallium-201
single photon emission computed tomography over planar imaging in the diagnosis of coronary artery
disease: Areceiver operating characteristic analysis. J Am Coll Cardiol. 1989;13:600-612.
30. Kim C, Kwok YS, Heagerty P, et al. Pharmacologic stress testing for coronary disease diagnosis: A
meta-analysis. Am Heart J. 2001;142:934-944.
31. Marwick T, D'Hondt A, Baudhuin T, et al. Optimal use of dobutamine stress for the detection and
evaluation of coronary artery disease: Combination with echocardiography or scintigraphy, or both? J
Am Coll Cardiol. 1993;22:159-167.
32. Fleischmann KE, Hunink MG, Kuntz KM, et al. Exercise echocardiography or exercise SPECT imaging?
A meta-analysis of diagnostic test performance. JAMA. 1998;280: 913-920.
33. Olmos LI, Dakik H, Gordon R, et al. Long-term prognostic value of exercise echocardiography
compared with exercise 201Tl, ECG, and clinical variables in patients evaluated for coronary artery
disease. Circulation. 1998;98:2679-2686.
34. Nagel E, Lehmkuhl HB, Bocksch W, et al. Noninvasive diagnosis of ischemia-induced wall motion
abnormalities with the use of high-dose dobutamine stress MRI: Comparison with dobutamine stress
echocardiography. Circulation. 1999;99:763-770.
35. Jahnke C, Nagel E, Gebker R, et al. Prognostic value of cardiac magnetic resonance stress tests:
Adenosine stress perfusion and dobutamine stress wall motion imaging. Circulation. 2007;115:1769-
1776.
59
36. Weiner D. Exercise ECG testing to determine prognosis of coronary heart disease. In: UpToDate;
2006.
37. Yao S-S, Rozanski A. Principal uses of myocardial perfusion scintigraphy in the management of
patients with known or suspected coronary artery disease. Prog Cardiovasc Dis. 2001;43:281-302.
P.35
38. Mark D, Shaw L, Harrell F, et al. Prognostic value of a treadmill exercise score in outpatients with
suspected coronary artery disease. N Engl J Med. 1991;325:849-853.
39. Kwok JMF, Miller TD, Christian TF, et al. Prognostic value of a treadmill exercise score in
symptomatic patients with nonspecific ST-T abnormalities on resting ECG. JAMA. 1999;282:1047-1053.
40. Mark DB, Hlatky MA, Harrell FE, et al. Exercise treadmill score for predicting prognosis in coronary
artery disease. Ann Intern Med. 1987;106:793.
9. CHAPTER 3 - Chest Pain and the Acute Coronary Syndromes

CHAPTER 3
Chest Pain and the Acute Coronary Syndromes
David V. Daniels
Todd J. Brinton
David P. Lee
There are over 5 million emergency department visits each year in the United States for acute chest
pain.1 Annually, over 800,000 people experience an acute myocardial infarction (AMI), of which 213,000
die and half do so before reaching the hospital. In-hospital mortality in the pre-CCU era reached >30%.
With the advent of the coronary care unit (CCU), mortality dropped to 15%, and in the modern era of
percutaneous coronary intervention (PCI) with stenting, combination antithrombotic therapy, and
routine use of adjunctive medical treatment, in-hospital mortality of ST segment elevation MI (STEMI)
has reached a low of 6%-7%. In this chapter we review the initial recognition, triage, acute
management, and definitive therapy across the spectrum of the acute coronary syndromes (ACS).
CLINICAL PRESENTATIONS
60
Acute Coronary Syndrome
The spectrum of acute ischemia-related syndromes ranges from unstable angina to acute myocardial
infarction (MI), with or without ST elevation (see Figure 3-1), that are secondary to acute plaque
rupture or plaque erosion. The clinical diagnosis relies on the combination of at least two of the
following:
 History (angina or anginal equivalent)
 Acute ischemic electrocardiogram (ECG) changes
 Typical rise and fall of cardiac markers

 Absence of another identifiable etiology
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FIGURE 3-1 Spectrum of ACS.
Unstable Angina
Angina pectoris or ischemic symptoms with at least one of the following:
 Occurring at rest or with minimal exertion and usually lasting >20 minutes (if not interrupted
by nitroglycerin)
 Severe pain of new onset (i.e., <1 month)
 Occurring with a crescendo pattern (i.e., more severe, prolonged, or frequent than previously)
 No evidence of myocardial infarction by biomarkers
61
Myocardial Infarction 2
The typical rise and fall of troponin or creatinine kinase MB fraction (CK-MB) with at least one of the
following:
 Ischemic symptoms
 Development of pathologic Q waves on the ECG
 ST elevation, depression or evolutionary EKG changes consistent with ischemia

 Post PCI (CK-MB 3× upper limit of normal)
Non-ST Segment Elevation MI (NSTEMI)

Criteria for MI in the absence of or with only transient ST elevation
ST Segment Elevation MI (STEMI)
Criteria for MI in the presence of persistent ST elevation indicative of myocardial injury
NQWMI/QWMI
The older literature makes reference to Q wave MI (QWMI) and Non-Q wave MI (NQWMI). The
implication was that Q wave MI was associated with transmural infarction and Non-Q wave MI was
limited to the subendocardium. Pathology studies have shown that Q waves are neither sensitive nor
specific for transmural infarction. While there may be prognostic value in the identification of Q waves
in patients with myocardial infarction, the modern terms STEMI and NSTEMI are preferred as they have
more immediate implications with regard to acute management strategies (i.e., STEMI is triaged toward
emergent reperfusion)
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Causes of ST Elevation Other than AMI
Normal Variants
 Normal male pattern: Often with 1-3 mm of concave sinus tachycardia (ST) elevation greatest
lead V2
 Early repolarization: Often with 1-3 mm of concave ST elevation, often with notching at the J
point in V4
 Variant ST elevation with T wave inversion: Seen often in young black men, convex ST
elevation, T wave inversion, thought to represent persistent juvenile T wave inversion + early
repol, may look like STEMI
62
Other Pathology
 Left bundle branch block (LBBB): Typical pattern of LBBB present with anterior ST elevation
 Pericarditis: Diffuse ST elevation and PR depression, PR elevation in AVR, the ratio of ST
elevation: T wave height (> 0.25 measured using PR segment as the baseline in this case) in V6
is highly sensitive and specific for the diagnosis of pericarditis
 Left ventricular hypertrophy with strain
 Hyperkalemia: Downsloping ST elevation associated with wide QRS, peaked T waves
 Pulmonary embolism: Sinus tachycardia, often anterior T wave inversions
 Takotsubo cardiomyopathy (apical ballooning syndrome)

 Brugada syndrome: Right bundle, downsloping ST elevation >2mm isolated to V1 and V2
DIFFERENTIAL DIAGNOSIS OF CHEST DISCOMFORT

See Tables 3-1, 3-2, 3-3.
TABLE 3-1 Immediately life-threatening causes (must consider these every time)
Disorder History Classic Findings
ACS Substernal pressure with radiation to jaw, - Tachycardia, S4, new
shoulder, arm, nausea, diaphoresis, often MR murmur or
similar in character to previous angina. normal exam
History of CAD, HTN, DM, hyperlipidemia,
smoker, advanced age
Aortic Acute onset, tearing CP, radiation to - Classic clinical ACS
dissection back, may be associated with stroke with normal ECG
symptoms. History of HTN, Marfan
syndrome
- May see ST
elevation, classically
inferior from RCA
dissection
- Widened
mediastinum
63
- Good positive
predictors of the
diagnosis: Pulse
deficits and focal
neuro findings with
CP3
- New AI murmur
- Poor negative
clinical predictors—if
you think about it,
exclude it
Pulmonary Acute onset, sharp, pleuritic CP, dyspnea, - Always consider with
embolism tachypnea. History/family history of hypoxia and a nl
DVT/PE/thrombophilia, malignancy, chest x-ray
pelvic surgery, trauma, prolonged bed
rest, travel, smoking, OCP

- ECG most commonly
sinus tach, also
anterior TWI, new
RBBB, RAD
- S1Q3T3 uncommon
Pneumothorax Unilateral, sharp CP, pleuritic. History of - Tracheal shift
trauma, asthma, COPD, mechanical
ventilation, tall and skinny

- Lucency of chest x-
ray
- Shock if under
tension
P.40
64
TABLE 3-2 Urgent causes
Disorder History Classic Findings
Pericarditis Sharp, localized, relief - Friction rub
with sitting forward
- Diffuse PR depression and/or ST
elevation
- PR elevation in AVR
- ST elevation: T wave amplitude ratio in
V6≥ 0.25 very high sensitivity/specificity
for acute pericarditis (baseline is end of
the PR segment)4
Pulmonary DOE, anginal-like pain - Elevated JVP, loud P2, parasternal lift,
HTN (? RV ischemia), S4
history-middle age
women>men
- Stigmata of R sided HF
- CXR with increased PA markings
- See chapter on PH
Myocarditis CP, fever, malaise, - Can elevate troponins and focal
viral prodrome myocarditis can even cause WMAs
Esophageal Pleuritic CP, History of - Chest x-ray with mediastinal air
rupture violent vomiting,
65
esophagitis
- Hamman crunch on exam
Biliary tract RUQ pain, - Murphy sign
disease postprandial, fever,
history of gallstones,
n/v
- Jaundice if common duct
- Abnormal LFTs
Pancreatitis Epigastric, radiates to - LFTs in gallstone pancreatitis, Lipase
back, alcoholic, History
of pancreatitis or
gallstones
Pneumonia Pleuritic, fever, cough, - Elevated WBC, fever
sputum production
- Rhonchi, rales
- Chest x-ray with infiltrate
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TABLE 3-3 Other causes
66
Disease History Classic findings
GERD Long rest episodes with neg cardiac - Esophagitis on
markers, burning, worse with recumbency, EGD
chocolate, caffeine, alleviated by antacids
- Promptly
relieved with GI
cocktail (be
careful here)
PUD/Gastritis Epigastric burning, worse after meals, - Epigastric
caffeine, stress tenderness
- Guaiac positive
stools
Esophageal spasm Substernal pain, aggravated with cold - Often relieved
liquids with NTG
(remember it's
smooth muscle
too!)
Costochondritis or Localized pain, history of trauma or recent - Tender to
chest wall trauma viral illness palpation
Herpes Zoster Unilateral local pain, immunosuppression, - Pain often
HIV precedes rash
- Make sure you
look at the
chest!
Anxiety History of panic attacks, GAD, Depression, - This has to be a
67
PTSD, recent traumatic event, on diagnosis of
antidepressants/benzodiazepines exclusion
ACS, acute coronary syndrome; CAD, coronary artery disease; HTN, hypertension; DM, diabetes
mellitus; MR, mitral regurgitation; CP, chest pain; RCA, right coronary artery; DVT, deep venous
thrombosis; PE, pulmonary embolism; OCP, oral contraceptive pill; CXR, chest x-ray; TWI, t wave
inversion; RBBB, right bundle branch block; RAD, right axis deviation; COPD, chronic obstructive
pulmonary disease; AVR, aortic value replacement; JVP, jugular venous pressure; P2, pulmonic
second sound; DOE, dyspnea on exertion; RV, right ventricle; PA, pulmonary artery; RUQ, right
upper quadrant; LFT, liver function test; WBC, white blood count; GERD, gastroesophageal reflux
disease; EGD, esophagogastroduodenoscopy; PUD, peptic ulcer disease; NTG, hitroglycerin; GAD,
general anxiety disorder; PTSD, post-traumatic stress disorder.
P.42
Other Disorders Presenting with Chest Discomfort and ECG

Changes (+/- Biomarker)
 Takotsubo cardiomyopathy (apical ballooning syndrome)
 Coronary vasospasm (Prinzmetal angina)

 Coronary dissection
HISTORY
The history should be methodically taken and may be aided by remembering the “SOCRATES”
mnemonic.
 Severity: The 1-10 scale is useful, functional limitations should be sought
 Onset: Be specific, can affect decisions about thrombolysis and PCI
 Character: Pressure versus sharp, pleuritic, tearing (aortic dissection)
 Radiation: Shoulder, jaw, arm, back
 Associated symptoms: shortness of breath (SOB), nausea/vomiting (N/V), palpitations, syncope
 Tempering factors: Rest, particular position (pericarditis—relief sitting forward)
 Exacerbating factors: Exertion, emotional state versus particular position
 Self assessment: Knowing the patient's fears is important for many reasons
68
 Also look for history of CAD, details of prior angiography, CABG or percutaneous coronary
intervention (PCI), recent stress tests or echoes, other risk factors (DM, smoking, HTN,
hyperlipidemia, cocaine use)
P.43
PHYSICAL EXAM
The physical exam in someone having an ACS may be entirely normal. Its purpose is to identify early
complications of ACS as well as other possible etiologies of CP.
Look for:
 Hypotension/hypertension
 Arrhythmias
 Tachypnea or hypoxia
 Fever
 Bilateral SBP difference >15 mm Hg (think of aortic dissection)
 Asymmetric pulses and/or a focal neurologic exam (aortic dissection)
 Signs of heart failure (elevated JVP, S3, crackles, hemoptysis)
 New MR murmur (? papillary muscle ischemia)
 A new S4 in a patient with active CP is highly suggestive of ischemia
 Murmur of aortic stenosis, pulsus parvus et tardus
 Abdominal tenderness (biliary tract/pancreatic disease)
 Rectal exam—evaluate for melena or guaiac positive stool (? how aggressive to anticoagulate)
 Rash on the chest (Zoster), make sure to examine the chest on hospital day 2, the pain often
precedes the skin findings!
LABORATORY EXAMS AND IMAGING

Cardiac Biomarkers
 Troponin I or T may be detectable as early as 2 hours after injury and CK-MB become
detectable around 6 hours and are most sensitive at 10 hours
 Myoglobin may rise somewhat sooner but is nonspecific
 Must obtain serial tests q4-6 h for at least 10 hours after the start of CP to definitively r/o MI
 False positive in heart failure, significant hypertension, PE
 Look for typical rise and fall of enzymes in the context of CP and the ECG to make a diagnosis
of NSTEMI
69
 Heart failure can be responsible for persistent low-grade elevation of troponin thought to be
from elevated LVEDP leading to subendocardial necrosis often with normal CKs
Additional Labs
 WBC: Likely mildly elevated in AMI but may also establish infectious etiology for current state
 Hemoglobin: Anemia contributes to patients presenting with shortness of breath or angina
 Platelets: Severely depressed <50k levels may be a contraindication to PCI
 Electrolytes: Monitor for potassium and calcium abnormalities which may alter the ECG,
Evaluate for infectious etiologies, electrolyte abnormalities
P.44
contributing to arrhythmias, biliary tract disease, or pancreatitis, if indicated
 Creatinine: Usually elevated in patients with longstanding HTN and DM. Elevated creatinine is a
relative contraindication to angiography because of the risk of renal failure secondary to
contrast nephropathy
 LFTs: Elevated in cases of hypotension due to shock or passive congestion due to elevated
right-sided filling pressures. Also serum glutamic oxaloacetic transaminase/aspartate
aminotransferase (SGOT/AST) can be elevated from an acute coronary syndrome as it is
released from myocardial necrosis
 Urine toxicology: Should be obtained for all young or at-risk patients with concerning chest
pain (cocaine-induced MI can result from thrombosis in addition to vasospasm and therefore
reperfusion may be indicated)
 B-type natriuretic peptide (BNP): May be helpful in establishing the diagnosis of congestive
heart failure (CHF) (see chapter on complications of AMI)
ECG
 Should be obtained within 5 minutes of arrival within the emergency department
 Make sure to label each ECG with the degree of pain
 Comparison to an old ECG can be helpful
 Repeat every 15 minutes ×2 if nondiagnostic, this has been shown to increase sensitivity
 Dynamic T wave and ST changes should greatly increase your suspicion for ACS
 Reoccurrence of CP should be re-evaluated with additional ECG recordings prior to giving NTG
 Obtain right-sided leads in those with inferior distribution injury to evaluate for RV injury or
infarct
 Obtain posterior leads in patients with only anterior ST depression to r/o posterior wall STEMI
70
Chest X-ray
 Assess for a widened mediastinum and always consider aortic dissection
 Examine lung fields for evidence of a pneumonic process, pulmonary congestion, or
pneumothorax
 Assess ribs and soft tissues for evidence of trauma

 Hypoxia/tachypnea with a clear CXR? Consider PE
Echo
 Useful test for evaluating systolic function, regional WMAs, effusion, valvular lesions, and to
assess for complications of MI
 May be helpful in a high risk patient with ongoing CP and a nondiagnostic ECG or when the
diagnosis of STEMI is in doubt
P.45
Helical CT of the Chest
 Used to assess for proximal PE and aortic dissection and to assess for other noncardiac
etiologies of CP such as pneumonia or pulmonary mass
 Sensitivity and specificity are institutional and reader dependent
 Consider MRI if patient has CRI or is high risk for contrast nephropathy
 Different phase of contrast often needed for optimal evaluation of PE and aortic dissection
MANAGEMENT—NSTE ACS VERSUS STEMI

Differentiation of STEMI from non-ST-segment-elevation acute coronary syndrome (NSTE ACS) is critical
to optimal management. These two entities have vastly different priorities as STEMI often involves a
completely occluded artery and clinical data indicate that revascularization is both an emergency and
that outcomes are tied to time to reperfusion. Management of NSTE ACS, both from a pathophysiologic
and a clinical outcomes perspective focus on initial treatment with drugs that inhibit thrombosis and
platelet aggregation usually in conjunction with a nonemergent early interventional approach and early
adjunctive medical therapies. The major difference is the prioritization of treatments and the
recognition of STEMI as a time-critical emergency.
TABLE 3-4 TIMI risk score (TRS) for UA/NSTEMI11
71
Score calculation (1 point each) Score D/MI/Revasc @ 14 days
Age ≥65 0-1 5%
≥3 risk factors for CAD 2 8%
Known CAD (>50% stenoses) 3 13%
ASA use in past 7 d 4 20%
≥2 episodes of angina in 24 h 5 26%
ST deviation ≥0.5 mm 6-7 41%
(+) cardiac enzymes
Add total points 0-7
P.46
INITIAL EVALUATION AND RISK STRATIFICATION
See Figure 3-2 and Tables 3-4, 3-5 and 3-6.
72
FIGURE 3-2 Approach to antithrombotic therapy in suspected ACS.
P.47
73
TABLE 3-5 UA/NSTEMI ACS risk stratification
High risk (≥1 of:) Low risk (all of:)
History Prolonged anginal CP or CP relieved only New CCS II-IV angina in the past
with maximal medical treatment 2 weeks but NO CP >20 min
ECG ST ↓≥0.5 mm in two contiguous leads or No ST ↓ or TWI
Deep TWIs >2mm excluding AVR and V1
Troponin (+) Troponin (-) Troponin
TIMI risk ≥3 ≤2
score
TABLE 3-6 Immediate NSTEMI ACS treatment strategies checklist
Low High
risk risk
ASA 162-325 mg5 (If allergy use Clopidogrel instead) X X
O2 (To keep SaO2>90%) X X
B-Blockers6 X X
Lopressor 5 mg IVP q 5 min ×3 then 50 mg po q6h and titrate as tolerated. Harm
likely in pts with significant CHF (see COMMITT CCS-2 below)
(Contraindicated HR <55, SBP <110mm Hg, PR >0.24 S or advanced heart block,
74
mod-severe CHF, severe asthma, cocaine ACS. If actively wheezing, consider
Diltiazem for significant tachycardia)
Nitroglycerin X X
SL, Paste, IV
(Contraindicated in severe AS, HOCM, RV infarct, and Viagra/Levitra/Cialis use)
Morphine X X
Prn pain, anxiety
K>4.0 meq/dL, Mg>2.0 meq/dL X X
Decreases risk of arrhythmias
DVT prophylaxis X X
(SQ heparin or LMWH prophylaxis for those not already on full anticoagulation)
Enoxaparin or UFH7 X
Enoxaparin 1 Mg/Kg SC q 12 hr, UFH may be favored if urgent cath
(If Cr > 2.5, CrCl < 30 ml/min, or weight > 150 kg use UFH, relative
contraindication: significant anemia, low plts)
Clopidogrel8 X
600 mg po load then 75 mg daily
75
(Contraindicated with thrombocytopenia and caution with guaiac positive
patients, caution if high likelihood of CABG, consult fellow/attending)
GPIIB/IIIA inhibitor9 X
(Start immediately for STEMI. In NSTEMI benefit probably only in troponin +
patients, PCI, and greatest benefit in diabetics, consult fellow/attending for
guidance)
High dose statin10 X
Lipitor 40-80 mg po daily or Simvastatin 40-80 mg po qhs (check baseline LFTs,
lipid panel in am on all ACS patients)
ACE inhibitor before discharge for ↓ EF or HF X
Captopril 6.25 mg po tid and titrate to goal 50 mg tid Ramipril 2.5 mg po and
titrate to goal 5 mg po bid (Especially with anterior MI or ↓ EF, contraindicated
if hypotensive, ARF or ↑ K+)
Early coronary angiography and reperfusion X
(See chapter on angiography and PCI)
Adapted from the ACC/AHA 2002/2004 practice guidelines. (TIMI), thrombolysis in myocardial
infarction
P.48
STEMI MANAGEMENT
76
As mentioned above, STEMI is often associated with a completely occluded coronary artery (>90%) and
outcomes are directly tied to timeliness and adequacy of revascularization. The goal of reperfusion
using PCI is a door-to-balloon time of <90 minutes in an experienced center and is preferred over
thrombolysis when possible. If thrombolysis is employed the goal is a door-to-needle time of <30
minutes in the absence of contraindications (see below). Additional antithrombotic, antiplatelet, and
adjunctive medical therapies are indicated in STEMI as above in NSTEMI ACS but should not delay
reperfusion in any way.
PCI versus Thrombolysis in STEMI
See Table 3-7.
P.49
TABLE 3-7 PCI versus thrombolysis in STEMI
Angiography with directed PCI preferred Thrombolysis preferred
Skilled PCI lab with surgical backup available (Door- Early presentation (<3 h from onset of
to-balloon time <90 min) or rapid transport (<2 h) symptoms) with a delay (>2 h) to an
available to an experienced center invasive strategy
Cardiogenic shock No appropriate PCI lab available
Contraindications to thrombolysis No contraindications to thrombolysis
Late presentation: >3 h from pain onset
Diagnosis of STEMI is in question
Adapted from the ACC/AHA 2004 practice guidelines.
SPECIFIC THERAPIES
77
Thrombolytic Regimens
See Table 3-8.
Rescue PCI
Thrombolysis success is associated with resolution of chest pain, >50% resolution of ST elevations,
hemodynamic stability, and reperfusion rhythms such as an accelerated idioventricular rhythm (do not
treat unless unstable). Indications of thrombolysis failure include ongoing chest pain, hemodynamic
instability <50% resolution of ST elevations, and malignant ventricular tachycardia. In such cases rescue
PCI is the optimal management strategy, and if not locally available, arrangements for critical care air
or ground transport to a tertiary center should be arranged.
Contraindications to Thrombolysis and Combination

Antithrombotic Therapy
Antithrombotic therapy is associated with increases in the risk of major and minor bleeding and
therefore decisions about appropriateness of therapy should also take into account relative
contraindications so that a decision about the relative risks and benefits can be made. Remember that
most patients with these contraindications were excluded from major clinical trials of advanced
antithrombotic/antiplatelet therapy, and therefore bleeding rates in these trials likely underestimate
bleeding in our population.
P.50
TABLE 3-8 Thrombolytic regimens
78
Drug Dose Notes Adjunctive Therapy
Streptokinase 1.5 million units Inferior to TPA, patient ASA, +/- heparin
over 30-60 min may be refractory if prior
exposure
Alteplase - TPA 15 mg bolus IV push Better outcomes ASA: 325 mg/d
compared to
Then 0.75 mg/kg streptokinase (30 Heparin:
over 30 min (max day mortality 60 U/kg (max
4000 U), then
50 mg) 6.3 vs. 7.3% in 12 U/kg/h (max
1000 U/h)
Then 0.50 mg/kg GUSTO-1) Clopidogrel:
over the next <75 years old
60 min (max 300 mg load
then 75 mg/d
35 mg) >74 years old
75 mg/d
Tenecteplase - Single bolus IV push As effective as alteplase
TNK in
<60 kg = 30 mg ASSENT -2 with
79
60-69 kg = 35 mg less noncerebral
70-79 kg = 40 mg bleeding, single
80-89 kg = 45 mg bolus easier to
>90 kg = 50 mg administer
Reteplase 10 units over 2 min Similar outcomes to
then repeat 10 unit alteplase
bolus at 30 min
Also consider that patients with acute anemia, significant hyper- or hypotension, superimposed severe
aortic stenosis, and other factors known to alter myocardial supply-demand relationships may not have
plaque rupture as an etiology of myocardial infarction.Therefore, they may derive less benefit, and
potentially more harm, from these therapies. The following are generally considered contraindications
to thrombolytic therapy and should be considered individually for patients getting multiple
antithrombotic and antiplatelet agents as well:
See Tables 3-9, 3-10, 3-11.
P.51
TABLE 3-9 Contraindications to thrombolytic therapy
80
Absolute Relative
• Any prior intracranial hemorrhage • History of chronic severe HTN
• Known cerebrovascular malformation • Severe HTN on presentation, systolic
(e.g., arteriovenous malformation blood pressure (SBP) >180, DBP >110
[AVM]) • History of ischemic stroke >3 mo, other
• Known malignant intracranial intracranial pathologies
neoplasm
• Prior ischemic stroke from >3 h to 3 • Prolonged CPR >10 min
mo
• Suspected aortic dissection • Surgery <3 weeks prior
• Active bleeding diatheses (excluding • Recent <2-4 weeks of internal bleeding
menses)
• Significant closed head or facial • Noncompressible vascular punctures
trauma
w/in 3 mo • Thrombocytopenia
• Pregnancy
• Active peptic ulcer
• Current use of oral anticoagulation
Adapted from the ACC/AHA 2004 practice guidelines.
81
TABLE 3-10 TIMI Risk Score (TRS) for STEMI
Score Calculation Points Score In-Hospital Mortality (%)
History of DM, HTN, or angina 1 0 0.8
Anterior STEMI or LBBB 1 1 1.6
Time to treatment >4 h 1 2 2.2
Weight <67 kg 1 3 4.4
HR >100 2 4 7.3
Killip class II-IV 2 5 12.4
Age ≥ 65-74 2 6 16.1
Age ≥ 75 3 7 23.4
SBP <100 mm Hg 3 8 26.8
>8 35.9
TABLE 3-11 Post MI discharge checklist
82
Intervention Comments
Cardiac Phase II as an outpatient with restrictions as indicated
rehabilitation
ASA 81-162 mg All patients without ASA allergy or contraindication
daily
Stress testing For patients who are not revascularized: Submaximal
Plavix 75 mg At least 9-12 months after NSTEMI or STEMI w/o PCI. predischarge stress
daily test or symptom limited ETT at 14-21
Minimum 2 weeks s/p bare metal stent and 3 months s/p d post MI drug
eluting stent Lifelong therapy probably if tolerated
Post-discharge At 1 mo post d/c: Important especially in those with LV tolerated.
echo dysfunction to assess for ICD criteria (EF <35%)
Statin Target LDL <70 mg/dl w/LFTs and repeat lipid profile in 1 month
Beta Blocker To target HR of 55-65 @ rest, consider Carveidolol if EF <40% post MI
ACE -I or ARB Probably most useful with large anterior infarcts or those with post MI LV
dysfunction (EF <40%). Target BP <130/80 for DM or CRI. Check BMP in 1-
2 weeks2
Nitroglycerin NTG Sl for occasional angina. Isordil, Imdur, or nitro patch for patients
with recurrent angina or medically treated obstructive CAD
Aldosterone Indicated in post MI patients with an EF <40% and CHF. Must monitor K
antagonist and renal function carefully or don't prescribe! at 1 week and 4 weeks
83
Coumadin For patients with AF or documented LV thrombus. INR 2.0-3.0
Diabetes Target HbA1C <7.0%
management
Smoking All patients
cessation
Cardiac Phase II as an outpatient with restrictions as indicated
Rehabilitation
Stress testing For patients who are not revascularized: Submaximal predischarge stress
test or symptom limited ETT at 14-21 days post MI
Post-discharge At 1 month post d/c: Important especially in those with LV dysfunction
Echo to assess for ICD criteria (EF < 35%)
Adapted from the ACC/AHA 2002/2004 practice guidelines.
P.52
LANDMARK CLINICAL TRIALS
See Tables 3-12, 3-13, 3-14, and 3-15.
P.53
TABLE 3-12 PCI and thrombolysis in STEM1
84
Intervention Trial Details
Streptokinase (S) vs. GISSI-1 (Lancet, Streptokinase → 18% RRR (P 13% S 10.7%)
Placebo (P) Streptokinase 198612) ISIS -2 death 21 d, most benefit if tx w/in 1 h of
+ ASA (S+A) vs. Placebo (Lancet, 198813) symptomsNNT = 44 Streptokinase + ASA
(P) → 42% RRR (P 13.2% S + A 8.0%) death @ 5
weeks NNT = 20
Primary PTCA (P) vs. Metanalysis PTCA → 34% RRR of (T 6.5% P 4.4%) death
Thrombolysis (T) (JAMA, 199714) n @ 30 d NNT = 48
= 2606
Primary PCI w/stenting Danami 2 PCI w/stenting → 45% RRR (T 13.7% P 8.0)
(P) vs. Thrombolysis (T) (NEJM, 200315) n of death/MI/stroke @ 30 d compared with
= 1572 thrombolysis in patients transported from
community hospitals w/in 2 h NNT = 18
Primary PCI w/Sirolimus STRATEGY Sirolimus stent → 65% RRR (B 20% D 7%)
drug eluting stent (D) + (JAMA, 200516) n TVR @ 8 mo NNT = 8
tirofiban vs. bare metal = 175
stenting (B) + abcixamab
TABLE 3-13 PCI in NSTEM1
85
Meta- Early invasive → 25% RRR (S 6.5% E 4.9%) of death at 2 y
analysis NNT = 63
(JACC,
200617)
Early invasive Meta- Early invasive → 15% RRR (S 12.2% S 14.4%) D/MI @ 17 mo
(E) vs. analysis NNT = 46
selectively (JAMA,
200518) n =
9212
invasive (S) ICTUS (Troponin positive subgroup) Early invasive → 30% RRR
(NEJM, D/MI @ 17 mo NNT = 25
200519) n =
1200
No difference between early invasive and selectively
invasive groups.
n.b.: Both groups received background Enoxaparin and
most got Clopidogrel and high dose statins up front.
Crossover rate to diagnostic cath in the selectively
invasive group was 53% during the index hospitalization
and they remained in hospital for up to 12 days before
stress testing.
P.54
P.55
86
TABLE 3-14 Antiplatelet and antithrombotics
Aspirin vs. Canadian multicenter ASA → 43% RRR all cause death @ 18 mo
placebo trialua/nstemi (NEJM, 1985

5
) n = 555
RISC80% ua/nstemi (Lancet, ASA → 64% RRR of D/MI @ 3 mo NNT = 9
199020) n = 796
ISIS-256% STEMI (Lancet, ASA → 23% RRR of death @ 5 weeks NNT = 42

198813) n = 17, 871 (Cost per life saved = $13!!)
Heparins (UFH Metanalysis (Lancet, 47% RRR of D/MI at 1 week (background: ASA)
or LMWH vs. 2000 21) n = 17, 157 NNT = 35
placebo)
Enoxaparin vs. ESSENCEua/nstemi (NEJM, Enox → 16% RRR of D/MI/Angina @ 14 d NNT =
UFH* 19977) n = 3, 171 32 (30% revascularization rate, background
ASA)
INTERACTua/nstemi (Circ, Enox → 56% RRR of D/MI @ 30 d in high risk
2003 22) n = 746 ACS patients receiving eptifibatide NNT = 25
(30% revascularization rate, background: asa,
eptifibatide)
SYNERGYua/nstemi (JAMA, No difference between Enox vs. UFH at 30 d in
2004 22) n = 10, 027 patients managed with an early invasive
approach. Small increase in major bleeding
with Enox in those patients who crossed over
from UFH → Enox. (Background: ASA,
Clopidogrel - 66%, 2b/3a - 57%)
87
Clopidogrel CUREua/nstemi (NEJM, 20% RRR of D/MI/Stroke @ 9 mo (80% medical
vs. placebo *
2001 ) n = 12, 562
8
management) NNT = 48
Increase in major bleeding but NOT life
threatening bleeds NNH = 100
PCI-CURE (PCI treated Clopidogrel 300 mg loading dose and 75
subgroup of CURE) ua/nstemi

mg/day vs. placebo → 34% RRR (P 4.4% C
(Lancet, 200123) n = 2, 2.9%) of D/MI @ 30 d in patients undergoing
658 PCI for UA/NSTEMI (Average 6 d pretreatment
prior to stent. Open label
Clopidogrel was used from PCI to 30 d in 80%
of patients, hence difference pretreatment)
NNT = 67
CREDOua/nstemi (JAMA, Clopidogrel 300 mg loading dose prior to PCI
2002 ) n = 2, 116
24
vs. placebo strong trend (p = 0.051) of 39%
RRR of D/MI/uTVR at 28 d if pretreated >6 h
pre-pci. (All got open label Clopidogrel for 30
d poststenting, background: ASA, heparin,
gp2b/3a 45%)
67% RRR if pretreated for >15 h NNT = 16
Clopidogrel PCI-Clarity (JAMA, 2005 Clopidogrel pretreatment vs. loading after
vs. placebo 25
) n = 1, 863 angiography in 3 d postthrombolysis STEMI →
46% RRR (P 6.2% C 3.6%) of d/mi/stroke at 30
d (30% got GPIIB/IIIA inhibitor with PCI,
additive benefit in this group rather than
reduction in benefit) NNT = 39
GPIIB/IIIA vs. ADMIRALstemi (NEJM, Abciximab (A) → 60% RRR (P 14.6% A 6%) of
88
placebo *
2001 26) n = 300 D/MI/uTVR @ 30 d NNT = 12
PURSUITua/nstemi (NEJM, Eptifibatide → 9% RRR of D/MI @ 30 d NNT =
1998 9) n = 11, 000 67
Metanalysisua/nstemi 2b/3a → 9% RRR (P 11.8% 2b/3a 10.8%) of
(Lancet, 200227) n = 31, D/MI @ 30 d NNT = 100 (Benefit limited to +
400 Trop or those that underwent
revascularization within 30 days)
Metanalysis of 2b/3a → 25 % RRR (P 6.2% 2b/3a 4.6%) of
diabeticsua/nstemi death in all pts @ 30 d NNT = 63
(Circulation, 2001 ) n 28
= 6, 458
2b/3a → 70% RRR of death in those undergoing
PCI @ 30 d NNT = 26
*
Studies showed benefit primarily in patients stratified as “High risk”
stemi
Primarily STEMI patient population
nstemi
Primarily NSTEMI patient population
RRR, relative risk reduction; NNT, number needed to treat; D/MI, death/MI
P.56
TABLE 3-15 Adjunctive medical therapy
89
Acute beta Goteborg study Metoprolol 15 mg IV, then total 100 mg po bid →
blockade vs. (Lancet, 198129) n 36% RRR (P 8.9% M 5.7%) of death @ 90 d NNT = 32
placebo = 1, 395
ISIS-1 (Lancet, Atenolol 5-10 mg IV then 100 mg po daily → 15%
198630) n = 16, 027 RRR of death @ 7 d NNT = 143
TIMI 2B Metoprolol 15 mg IV then total 100 mg po bid vs.
(Circulation, metoprolol po starting day 6 → No difference in
199131) n = 1, 434 mortality or LV function, 50% RRR (P 5.1% M 2.7%)
in re-infarction at 6 d
COMMITT- CCS 2 Metoprolol 15 mg IV then total 200 mg po a day →
(Lancet, 200532) n No mortality benefit, minimal reinfarction and VF
= 45, 852 benefit, increased risk of cardiogenic shock
Reinfarction and VF NNT = 200 Cardiogenic shock
overall NNH = 91 HR >110 NNH = 30 BP <110 NNH =
42 Killip III NNH = 18
Secondary CAPRICORN Pts with EF <40% post-MI, Carvedilol → 20% RRR (P
prevention (Lancet, 200133) n 15% C 12%) mortality at 1.3 y NNT = 34
= 1, 959
Metanalysis
(NEJM, 1998)
βBs → 40% RRR of death @ 2 y NNT = 11
Statins 4S (Lancet, 199434) In patients with CHD Simvastatin (S) → 30% RRR (P
secondary n = 4, 444 12% S 8%) of death at 5 y NNT = 25
prevention
90
TNT (NEJM, 200535) Atorvastatin 80 mg vs. Atorvastatin 10 mg → 22%
n = 10, 001 RRR (10 mg 10.9% 80 mg 8.7%) of
death/MI/resuscitated cardiac arrest/stroke at 5
y. Avg ldl in 80 mg group = 77 mg/dL vs. 10 mg
group = 101 mg/dL. AST/ALT elevations 1.2% in 80
mg group vs. 0.2% in 10 mg group.
Statins post PROVE IT - TIMI 22 Atorvastatin → RRR 15% (P 26% A 22%) of
ACS Atorvastatin (A) 80 D/ACS/PCI/stroke @ 2 y NNT = 26
mg vs. pravastatin
(P) 40 mg
(NEJM, 200436) n =
4, 162
MIRACL Atorvastatin → 16% RRR (P 17.4% A 14.8%) of
Atorvastatin (A) 80 death/mi/cardiac arrest/rehospitalization for
mg vs. placebo ischemia at 16 weeks. Driven primarily by
(JAMA, 2001 ) n =
10
ischemia. NNT = 39
3, 086
ACE inhibitor SAVE - EF <40%stemi Captopril (S) 50 mg TID vs. placebo → 19% RRR (P
(NEJM, 199237) 25% C 20%) death @ 42 mo NNT = 20
ACE inhibitor SAVE - EF <40%stemi Captopril (S) 50 mg TID vs. placebo → 19% RRR (P
(NEJM, 199237) 25% C 20%) death @ 42 mo NNT = 20
SMILE - Anterior RRR 46% of Severe HF @ 6 weeks RRR 29% of death
MIstemi (NEJM, @ 1 y NNT = 25
1995 )
38
AIRE (Lancet, Ramipril vs. placebo → 27% RRR (P 23% R 17%) of
1993 ) n = 2, 006
39
death at 15 mo NNT = 17
91
Aldosterone EPHESUS (NEJM, Patients with EF <40% and clinical HF or DM,
antagonist - 2003 )
40
Eplerenone (E) 25 mg → 15% RRR (P 16.7% E 14.4%)
Eplerenone of death @ 18 mo NNT = 44
K and Mg GISSI-2 (Am J OR 1.97 for VF if K <3.6
replacement Card, 1998)
stemi
Primarily STEMI patient population
nstemi
Primarily NSTEMI patient population
RRR, relative risk reduction
OR, odds ratio
NNT, number needed to treat
P.57
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31. Roberts R, Rogers WJ, Mueller HS, et al. Immediate versus deferred beta-blockade following
thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in
Myocardial Infarction (TIMI) II-B Study. Circulation. 1991;83(2):422-437.
32. Chen ZM, Pan HC, Chen YP, et al. Early intravenous then oral metoprolol in 45,852 patients with
acute myocardial infarction: Randomised placebo-controlled trial. Lancet. 2005;366(9497):1622-1632.
33. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-
ventricular dysfunction: The CAPRICORN randomised trial. Lancet. 2001;357(9266):1385-1390.
34. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease:The
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-1389.
35. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with
stable coronary disease. N Engl J Med. 2005;352(14):1425-1435.
36. Cannon CP, Braunwald E, McCabe CH,et al. Intensive versus moderate lipid lowering with statins
after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
37. Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients
with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular
enlargement trial. The SAVE Investigators. N Engl J Med. 1992;327(10):669-677.
95
38. Ambrosioni E, Borghi C, Magnani B. The effect of the angiotensin-converting-enzyme inhibitor
zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial
Infarction Long-Term Evaluation (SMILE) Study Investigators. N Engl J Med. 1995;332(2):80-85.
39. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with
clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.
Lancet. 1993;342(8875):821-828.
40. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left
ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309-1321.
10. CHAPTER 4 - Cardiogenic Shock

CHAPTER 4
Cardiogenic Shock
David V. Daniels
Todd J. Brinton
Randall Vagelos
BACKGROUND
Cardiogenic shock is a state of inadequate tissue perfusion and dysoxia due to primary cardiac
dysfunction clinically manifest by systemic hypotension and end-organ compromise.
 Historical mortality approaches 80% without revascularization1
 Current era mortality remains as high as 60%2
 Complicates 7%-9% of all acute myocardial infarctions (AMI)3,4
 Shock criteria often absent on admission (<10% of patients) but usually develops early in the
hospitalization (mean time MI to onset 5.5 hours in the SHOCK trial registry)
 Multifactorial etiologies (LV failure - 79%, Severe MR - 7%, acute ventricular septal defect (VSD)
- 4%, isolated right ventricular (RV) failure - 2%, tamponade - 1.4%2)
 Majority of cases secondary to AMI present with ST segment elevation myocardial infarct
(STEMI)
FEATURES OF CARDIOGENIC SHOCK 5
 Persistent systemic hypotension: systolic blood pressure (SBP) <90mm Hg or mean arterial
pressure (MAP) >30 mm Hg below baseline
96
 Cardiac index <1.8 liters/min/m2 or inotrope dependence to maintain cardiac output and blood
pressure (BP)
 Pulmonary artery wedge pressure (PAWP) >18 mm Hg

 Signs of systemic hypoperfusion (cool extremities, oliguria, lactic acidosis)
HISTORY
 Rapid diagnosis essential: history and physical exam should be focused and brief with
simultaneous initial resuscitation
 Inquire about time course of symptoms, new or changing angina, shortness of breath (SOB),
paroxysmal nocturnal dyspnea (PND), orthopnea, edema, weight changes, or fatigue
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 History of MI, heart failure (HF), or valvular disease

 Recent changes in medication dose or type
PHYSICAL EXAM
Look for the following:
 Absolute or relative hypotension (SBP >30 mm Hg below baseline)
 Check bilateral blood pressures if hypotension suspected as unilateral subclavian or axillary
stenosis may falsely classify patients as centrally hypotensive.
 Narrow pulse pressure (pulse pressure <25% of the SBP has a sensitivity and specificity of 91%
and 83% for a cardiac index of <2.2 L/min/m2)4
 Cool underperfused extremities, altered mental status, low urine output
 Pulmonary edema and respiratory distress
 Signs of HF: Elevated JVP, S3, S4, tachycardia, hypoxia, crackles
 Peripheral edema suggests some component of chronic HF and can be absent with acute HF
 New systolic murmur suggests acute mitral regurgitation (MR) or VSD, assess for a thrill
 Listen with patient leaning forward to detect the diastolic murmur of AI

 Asymmetric pulses and a focal neurologic exam (aortic dissection)

Labs
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 Complete blood count (CBC) w/ diff, comprehensive metabolic panel (CMP), cardiac enzymes,
APTT/PT, BNP
 Serial lactate measurements and ABGs useful in following tissue perfusion and response to
therapy
ECG
 Rapid assessment of potential acute coronary syndrome (ACS), arrhythmia, or heart block
 Although most ACS associated with cardiogenic shock presents as a STEMI, significant ST
depression or other signs of ischemia should prompt consideration of early angiography in the
setting of shock
 Inferior ST elevation should prompt R sided leads to assess for RV injury or infarct
 Isolated anterior ST depression should prompt posterior leads to assess for true posterior STEMI
Chest X-ray
 Assess mediastinum and always consider aortic dissection
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 Pulmonary edema (1/3 of patients without pulmonary edema in the SHOCK trial)
 Clear lungs with hypotension +/- hypoxia, consider massive PE
Echo
 An extremely useful test for systolic function, regional WMAs, RV infarct, mechanical
complications of MI, tamponade, and valvular lesions
 Transesophageal echocardiography (TEE) may be necessary for technically suboptimal
transthoracic echocardiogram (TTE), on ventilator, or to evaluate for aortic dissection

(especially in unstable patients who can't go to computed tomography (CT))
Helical CT of the Chest
 Useful to assess for proximal pulmonary embollism (PE) and aortic dissection (sensitivity only
83% for proximal dissection in one study)
 Sensitivity and specificity probably institutional and reader dependent
 Even if patient is in acute renal failure (ARF) the benefits of IV contrast likely outweigh the
risks in this patient population and may need to consider dialysis
98
 Different phase of contrast needed for optimal PE and aortic dissection evaluations
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TABLE 4-1 Etiology of cardiogenic shock
Etiology Findings
Acute severe LV failure (most - Often from massive anterior infarct
common cause of cardiogenic
shock)
- ST elevation often seen
- Consider in aggressive titration of HF meds →
decompensation
Mechanical complications of Papillary muscle rupture or dysfunction w/ severe MR
AMI
- Classically 2-7 days post-MI
- More common with inferior/posterior infarct because
of single blood supply to posterior papillary muscle
via the RCA
- Often with an early systolic murmur vs. classic
holosystolic murmur because of early systolic
equalization of LV → LA pressure
- Echo with severe MR, +/- flail leaflet
Acute ventricular septal defect (vsd)
99
- Higher risk with “wrap around LAD” should be alerted
to this complication when anterior STEMI presents
with concomitant inferior lead ST elevation (OR 17)8
- Anterior MI → apical VSD
- Inferior MI → basal VSD
- Holosystolic murmur radiating to R sternal border
often with a thrill
- PO2 step-up from RA to RV/PA (use the swan that's
in!)
- Echo dx by color Doppler
cardiac tamponade (free wall rupture or hemorrhagic
effusion)
- Beck's triad: hypotension, distant heart sounds, JVD
- Pulsus paradoxus
- Echo support of dx by effusion + RA/RV diastolic
collapse, PW Doppler
- Swan: Equalization of diastolic pressures - RA = RVD =
PAD Can see as an early complication of PCI (coronary
rupture)
RV infarct - Seen most often with concomitant inferior wall MI
100
- Check R sided leads
- JVD, + Kussmaul's sign, hypotensive response to NTG
and diuretics, responds to fluids, generally clear lungs
- May see bradycardia, heart block, GI symptoms from
RCA ACS
- Echo will show RV dilation, hypokinesis
- Swan: RA pressure >10 mm Hg and RA:PCWP >0.8
Stress cardiomyopathy (Tako - Consider as a cause of cardiogenic shock in ST
tsubo) Or “broken heart elevation with normal epicardial coronary arteries
syndrome”
- Preponderance of post menopausal females, often
significant “life stressor” is identifiable
- Look for apical or more rarely basal ballooning
- Consider acute LVOT obstruction as an etiology of
shock; if present, trial of phenylephrine
RV failure secondary to - Signs and symptoms of acute RV failure in the
massive PE absence of AMI
- Echo with dilated RV
- Diagnosis by Helical CT angiography
Proximal aortic dissection - Pulse deficits and focal neuro exam
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- Suspect with widened mediastinum on CXR
- Severe AI with extension to the root on Echo
- Cardiac tamponade
- May see inferior STEMI because the RCA is most often
compromised by dissection
Tachyarrhythmias - AF/Atrial flutter w/ RVR, VT
Bradyarrhythmias - Anterior infarct → Mobitz II or CHB with slow
ventricular escape
- Inferior infarct → sinus bradycardia, Mobitz I → CHB
usually with junctional escape
Myocarditis - Acute LV dysfunction, positive enzymes, +/- fever
and viral prodrome
Endocarditis - Acute valvular regurgitation in the setting of septic
picture and vegetations
- Positive blood cultures
Hemorrhagic shock - Either as a primary presentation or as a complication
of thrombolytics and anticoagulants
- Shock with low filling pressures
Septic shock - Can see LV dysfunction in severe sepsis
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- Can see positive cardiac enzymes
LV, left ventricular; LAD, left anterior descending; LVOT, left ventricular outfloor tract.
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INITIAL EVALUATION AND TREATMENT
See Figure 4-1 and Table 4-1.
SPECIFIC THERAPIES
Antithrombotic Therapy and Anticoagulation
 Patients with STEMI or ACS should be treated with ASA, heparin, GPIIB/IIIA inhibitors (see
chapter on CP and ACS)
 Strongly consider withholding Clopidogrel if early angiography planned and patient is a surgical
candidate (lack of comorbidities and multiorgan system disease) as up to 40% of patients may
benefit from emergent CABG and bleeding may complicate an already critically ill patient
 Retrospective subgroup data from PURSUIT suggests benefit of eptifibatide in cardiogenic
shock complicating non-ST elevation ACS (NSTE ACS)5
 Improvement in TIMI 3 flow with the use of GPIIB/IIIA inhibitors in TIGER-PA trial prior to PCI
versus during would suggest improvements in microvascular obstruction as a possible

mechanism6
Revascularization
 Associated with significant mortality benefit in AMI complicated by cardiogenic shock
 Timing of reperfusion is highly correlated with outcomes: 44% mortality if admitted within 3
hours from symptom onset versus 58% from 12-24 hours7
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 TIMI flow grade of infarct related artery (IRA) highly correlated with mortality: 27% in IRAs
with TIMI grade 3 flow versus 47% with TIMI grade 0/1 flow8
 In the landmark, “SHould we emergently revascularize Occluded Coronaries for cardiogenic
shocK” (SHOCK) randomized trial, successful angioplasty (TIMI grade 2 or 3 flow) associated
with 38% 30 day mortality versus 79% in unsuccessful angioplasty (TIMI grade 0 or 1 flow),
lending support to the open artery hypothesis9
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104
FIGURE 4-1 Initial evaluation and treatment of cardiogenic shock. Markers of poor tissue perfusion
include altered mentation, oliguria, cool extremities, azotemia, and lactic acidosis.
Initial Medical Therapy versus Emergent Revascularization
 SHOCK trial mortality 50% with emergent revascularization (60% PCI, 40% CABG) versus 63% at
6 months with initial medical therapy and subsequent targeted revascularization9
 Number needed to treat of eight to prevent one death
 Benefit is probably beyond thrombolysis as 63% of initial medical therapy group and 49% of
revascularization group got thrombolytic therapy
 More benefit in those <75 years old

 Sustained benefits at 6 years6
Thrombolysis + IABP
 Suggestion of mortality benefit with thrombolytic therapy (TT) in post-hoc analysis of the
SHOCK trial in the medical treatment group 60% mortality with versus 78% without TT though
assignment to TT was not randomized and results may represent selection bias10
 Strongly consider IABP placement by an experienced operator as substantial mortality benefit
with the use of an IABP + TT,11 and there is NO proven benefit with TT alone (see Figure 4-2)
 Given high rate of thrombolysis in the early revascularization arm of SHOCK (and lack of harm),
it is reasonable to employ a strategy of IABP placement and thrombolysis followed by emergent

transfer to a facility capable of PCI if such a transfer is likely to be delayed >90 minutes
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105
FIGURE 4-2 Effect of IABP added to thrombolysis on mortality in cardiogenic shock (GUSTO I, JACC
1997).
Percutaneous Ventricular Assist Device (PVAD)-Tandem Heart
 Placed in the cath lab with a left atrial inflow catheter (via transeptal puncture) and a femoral
artery return catheter
 Initial study in cardiogenic shock showed improvement of cardiac index from 1.7 → 2.4
L/m/m2 and significant improvements in CVP and PCWP12
 Randomized trial of PVAD versus intra-aortic balloon pump (IABP) revealed improvement in
hemodynamic parameters in the PVAD group but with higher bleeding and leg ischemia
complications and no difference in mortality13
 Can consider PVAD as an aggressive support intervention if IABP support is inadequate in the
setting of refractory cardiogenic shock
REFERENCES
1. Holmes DR, Berger PB, Hochman JS, et al. Cardiogenic shock in patients with acute ischemic
syndromes with and without ST-segment elevation. Circulation. 1999;100(20):2067-2073.
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106
2. Hochman JS, Buller CE, Sleeper LA, et al. Cardiogenic shock complicating acute myocardial
infarction—etiologies, management and outcome: A report from the SHOCK Trial Registry. Should we
emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol. 2000;36(3
Suppl A):1063-1070.
3. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in
chronic heart failure. JAMA. 1989;261(6):884-888.
4. Hasdai D, Harrington RA, Hochman JS, et al. Platelet glycoprotein IIb/IIIa blockade and outcome of
cardiogenic shock complicating acute coronary syndromes without persistent ST-segment elevation. J
Am Coll Cardiol. 2000;36(3): 685-692.
5. Fuster V, Alexander RW, O'Rourke RA. Hurst's the Heart. 11th ed. New York: McGraw-Hill Medical
6. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization and long-term survival in
cardiogenic shock complicating acute myocardial infarction. JAMA. 2006;295(21):2511-2515.
7. Zeymer U, Vogt A, Zahn R, et al. Predictors of in-hospital mortality in 1333 patients with acute
myocardial infarction complicated by cardiogenic shock treated with primary percutaneous coronary
intervention (PCI): Results of the primary PCI registry of the Arbeitsgemeinschaft Leitende
Kardiologische Krankenhausärzte (ALKK). Eur Heart J. 2004;25(4):322-328.
8. Wong SC, Sanborn T, Sleeper LA, et al. Angiographic findings and clinical correlates in patients with
cardiogenic shock complicating acute myocardial infarction: A report from the SHOCK Trial Registry.
SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? J Am Coll Cardiol.
2000;36(3 Suppl A):1077-1083.
9. Hochman JS, Sleeper LA, Webb JG, et al. Early revascularization in acute myocardial infarction
complicated by cardiogenic shock. SHOCK Investigators. Should we emergently revascularize occluded
coronaries for cardiogenic shock? N Engl J Med. 1999;341(9):625-634.
10. French JK, Feldman HA, Assmann SF, et al. Influence of thrombolytic therapy, with or without intra-
aortic balloon counterpulsation, on 12-month survival in the SHOCK trial. Am Heart J. 2003;146(5):804-
810.
11. Hayashi T, Hirano Y, Takai H, et al. Usefulness of ST-segment elevation in the inferior leads in
predicting ventricular septal rupture in patients with anterior wall acute myocardial infarction. Am J
Cardiol. 2005;96(8):1037-1041.
107
12. Thiele H, Lauer B, Hambrecht R, et al. Reversal of cardiogenic shock by percutaneous left atrial-to-
femoral arterial bypass assistance. Circulation. 2001;104(24):2917-2922.
13. Thiele H, Sick P, Boudriot E, et al. Randomized comparison of intra-aortic balloon support with a
percutaneous left ventricular assist device in patients with revascularized acute myocardial infarction
complicated by cardiogenic shock. Eur Heart J. 2005;26(13):1276-1283.
11. CHAPTER 5 - Bradyarrhythmias and Pacing

CHAPTER 5
Bradyarrhythmias and Pacing
James V. Freeman
Paul J. Wang
BACKGROUND
Bradyarrhythmias result from abnormalities of sinus node function or A-V conduction. In this chapter we
review the initial recognition, triage, acute management, and definitive therapy for the
bradyarrhythmias.
DEFINITIONS
Bradycardia
Bradycardia is defined as a ventricular heart rate <60 beats per minute (bpm), and sinus bradycardia
exists when each QRS complex is preceded by a P wave of sinus node origin on the electrocardiogram
(ECG).
Sinus Node Dysfunction
Sinoatrial blocks: Sinoatrial (S-A) blocks are uncommon and occur when there is disturbance of the
conduction of the electrical impulse from the heart's normal pacemaker, the S-A node, to the
surrounding atrium. (See Figure 5-1.) The severity of dysfunction can vary widely and there are many
ECG findings associated with S-A blocks (also called S-A exit blocks).1 The S-A blocks can be categorized
as first, second, and third degree based on the characteristics of the conduction disturbance.
First Degree
In first-degree S-A block, there is an increased time for the S-A node's impulse to reach and depolarize
the rest of the atrium and form a P wave on ECG (Figure 5-1). There are no abnormalities seen on the
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12-lead tracing with first-degree S-A block because impulse origination from the S-A node still produces
a normal P wave on the 12-lead ECG.2
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FIGURE 5-1 Sinoatrial (S-A) block. Normal sinus rhythms with various degrees of S-A block. Sinus
impulses not seen on the body surface ECG are represented by the vertical lines. With first-degree S-A
109
block, although there is prolongation of the interval between the sinus impulses and the P wave, such a
delay cannot be detected on the ECG. A: Persistent 2:1 S-A block cannot be distinguished from marked
sinus bradycardia. B: The diagnosis of second-degree S-A block depends on the presence of pause or
pauses that are the multiple of the basic P-P interval. C: When there is a Wenckebach phenomenon,
there is gradual shortening of the P-P interval before the pause. With third-degree S-A block, the ECG
records only the escape rhythm. (Used with permission from Suawicz B, Knilans TK. Chou's
electrocardiography in clinical practice. 5th ed. Philadelphia: WB Saunders; 2001:321.)
Second Degree
Type I (Wenkebach): In second-degree S-A block type I, there is a progressively increasing interval for
each S-A nodal impulse to depolarize the atrial myocardium and produce a P wave on ECG (Figure 5-1).
This
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interval continues to lengthen until the S-A node's impulse does not depolarize the atrium at all, which
is manifested on ECG by a gradual shortening of the P-P interval with an eventual dropping of a P wave.
It can be recognized by grouped beatings of the P waves, with sinus pauses.
Type II: In second-degree S-A block type II, there is a fixed interval between the S-A node impulse and
the depolarization of the atrium with an intermittent S-A nodal impulse that fails to conduct to the
atrium (Figure 5-1). This manifests on ECG as a dropped P wave with a P-P interval surrounding the
pause that is two to four times the length of the baseline P-P interval.3
Second-degree S-A Block with 2:1 Conduction
In second-degree S-A block with 2:1 conduction, every other impulse from the S-A node causes atrial
depolarization while the other is dropped. It is impossible to differentiate this from sinus bradycardia
on ECG unless the beginning or termination of the S-A block is recorded, in which case it manifests as a
distinct halving (beginning) or doubling (termination) of the baseline heart rate.
Third Degree
In third-degree S-A block, none of the S-A nodal impulses depolarize the atrium, which appears on ECG
as either atrial stand-still or P waves retrogradely conducted from a junctional rhythm (Figure 5-1).
Sometimes there can be a long pause on the ECG until a normal sinus rhythm is resumed, which can be
difficult to distinguish from sinus pause or arrest due to abnormalities of sinus impulse formation.
110
Sinus pause/sinus arrest: Sinus pause and sinus arrest are characterized by the failure of the S-A node
to form an impulse, manifesting on the ECG as a sinus pause of varying length. 1 Some sinus pauses
follow the spontaneous termination of atrial fibrillation because of the overdrive suppression of the
sinus node.
Sick sinus syndrome: Sick sinus syndrome includes a range of S-A node dysfunction that includes
inappropriate sinus bradycardia, sinus arrhythmia, sinus pause/arrest, S-A block, A-V junctional
(escape) rhythm, and the tachycardia-bradycardia syndrome (covered in the tachyarrhythmias
chapter).4
Atrioventricular Conduction Dysfunction
Atrioventricular block: In atrioventricular block, electrical conduction is disturbed between the atrium
and the ventricle. As with S-A blocks, A-V blocks are categorized into first-, second-, and third-degree
blocks based on the characteristics of the conduction disturbance.
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First Degree
First-degree A-V block is defined as a prolonged P-R interval, greater than 200 milliseconds, which
remains constant. (See Figure 5-2.) On ECG, the P wave and QRS complex have normal morphology, and
a P wave precedes each QRS complex. The lengthening of the P-R interval results from a conduction
delay from within the atrium, the A-V node, or the His-Purkinje system.
Second Degree
Mobitz Type I (Wenckebach): Second-degree A-V block Mobitz type I is characterized by a P-R interval
that lengthens progressively until an impulse fails to conduct to the ventricles and a QRS complex is
dropped. (See Figure 5-3.) This block usually occurs at the level of the A-V node and above the His
bundle. The patient's QRS complex is usually narrow (less than or equal to 120 milliseconds) although
there may be a concomitant lower conduction disturbance leading to bundle branch block. On ECG, the
P-R interval lengthens as the R-R interval shortens, and the R-R interval that contains the dropped beat
is less than the sum of two of the shortest R-R intervals seen on the ECG. Also, on the ECG rhythm strip,
a grouping of beats can be seen.2,7 A consistent and diagnostic feature of Wenkebach is that the PR
interval after the dropped beat is shorter than those immediately preceding the AV block.
Mobitz Type II: Second-degree A-V block Mobitz type II is defined by a constant P-R interval that may be
normal or prolonged (>0.20 s) and periodic abrupt failure of the atrial impulse to conduct to the
ventricles. (See Figure 5-4.) The QRS complex is nearly always widened, since development of Mobitz
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Type II block almost always follows development of bundle branch block. This rule is so strong that
apparently abrupt A-V block without measurable preceding P-R prolongation in a patient with a narrow
QRS complex is more likely to be at the level of the A-V node and thus be an atypical Mobitz Type I A-V
block rather than actually representing Mobitz Type II A-V block.
FIGURE 5-2 First degree AV block: The PR interval here is > 200 ms with a 1:1 relationship of P waves to
QRS complexes. (With permission: Goldberger: Clinical Electrocardiography: A Simplified Approach.
2006, Mosby.)
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FIGURE 5-3 Mobitz Type I (Wenkebach) Second degree AV block: Fixed P-P interval with progressive PR
prolongation with development of AV block. Note the PR interval on the beat after the pause is the
shortest which is diagnostic of Wenkebach. (With permission: Goldberger: Clinical Electrocardiography:
A Simplified Approach. 2006, Mosby.)
Second-degree A-V block with 2:1 conduction: In second-degree A-V block with 2:1 conduction, every
other QRS complex is dropped, causing two P waves for each QRS complex. Since there is no way to
determine on ECG if the P-R interval lengthens before the dropped QRS complex, the primary method
of determining the level of the block is examining the QRS width. If the QRS complex is narrow, the 2:1
A-V block almost certainly exists at the level of the A-V node. If the QRS complex is widened, the level
of the block could be either at the level of the A-V node or infrahisian.
FIGURE 5-4 Second degree type II AV block: Fixed P-P interval with fixed PR interval and development
of AV block. Note the PR interval on the beat after the pause is identical to the one prior. This is in
contradistinction to Wenkebach. (With permission: Goldberger: Clinical Electrocardiography: A
Simplified Approach. 2006, Mosby.)
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Third Degree
Third-degree A-V block, or complete heart block, occurs when no electrical impulses from the atria
conduct through to the ventricles. (See Figure 5-5.) The atria and ventricles thus depolarize and beat
113
independently. An escape rhythm originating from the A-V junction or the ventricles below the level of
the block maintains the ventricular rate. In third-degree A-V block, the P waves march out regularly and
independently of the regular ventricular depolarization (QRS complexes). The atrial rate is generally
faster than the ventricular rate, because the latter is an escape rhythm, and the ventricular rate can
vary depending upon where the ventricular depolarization originates. 1 In some cases, the P-P interval
encompassing the escape QRS complex may be shorter than otherwise in the tracing, a phenomenon
called “ventriculophasic phenomenon.”
Escape Rhythms
When electrical impulses fail to conduct to the ventricles from the atria, whether due to S-A block or A-
V block, ventricular depolarization can originate from more distal locations in the conduction system
that also possess automaticity. Generally the more distal the site of impulse origination, the slower the
rate generated. The ventricular rate is generally 40 to 60 bpm with a narrow QRS complex when it is
driven by a junctional pacemaker within the A-V node or above the His bundle. A ventricular pacemaker
is characterized by a widened QRS and a rate less than 40 bpm (except an accelerated idioventricular
rhythm with a rate >40 bpm). These rhythms originate in the His-Purkinje system and are usually
associated with a poorer prognosis.7 If no escape impulse is generated, then the result is an asystolic
arrest.
FIGURE 5-5 Third degree (Complete) AV block: Fixed P-P interval with AV dissociation: No relationship
between P waves and the QRS complexes. In this case the escape pacemaker is junctional and hence
the QRS is narrow and rate is relatively faster than a ventricular escape. (With permission: Goldberger:
Clinical Electrocardiography: A Simplified Approach. 2006, Mosby.)
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CAUSES
Intrinsic abnormalities of conduction may occur as the result of many complex changes in the cardiac
conduction system:
 Congenital
o Related to maternal lupus
o Related to congenital heart disease
o L-transposition of the great arteries
 Genetic abnormalities
 Immunologic
o Lyme disease
 Infectious
o Endocarditis
o Lyme disease
 Idiopathic degeneration and fibrosis
 Ischemia or infarction
 Infiltrative diseases
o Sarcoidosis
o Amyloidosis
 Trauma
o During valve replacement surgery
o During radiofrequency catheter ablation
o Extra-cardiac causes:
 Electrolyte abnormalities
 Hypothyroidism
 Hypothermia
 Increased intracranial pressure
 Vasovagal reactions
 Drugs, for example: lithium, amiodarone, digoxin, beta-adrenergic receptor

antagonists, calcium channel antagonists9
Bradycardia can result in cerebral hypoperfusion leading to symptoms such as presyncope, syncope,
confusion, memory loss, and, rarely, seizure activity. Inability of the heart rate to increase in response
to increased physiologic demand, called chronotropic incompetence, can occur even when true
bradycardia is not present and can result in subjective effort intolerance, fatigue, weakness, and
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dyspnea.10 Sometimes, patients with advanced A-V block appear to be asymptomatic. Patients with
sinus node dysfunction and atrial arrhythmias, the tachycardia-bradycardia syndrome, can present with
complaints of palpitations as well as symptoms related to bradycardia.
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It is extremely important to take a careful medication history with particular focus on medications that
may impair sinus node and A-V nodal function.
PHYSICAL EXAM
 Bradycardia, regular or irregular, depending on specific arrhythmia
 Systemic hypotension in the absence of concomitant vasodilation or vasodepressor

phenomenon may not be present; the systolic pressure generated after a pause may be higher
than the average systolic blood pressure
 Evidence of impaired alertness or cognitive function may be due to cerebral hypoperfusion
 If some P waves are blocked, there will be a lack of coordination of the A wave in the jugular
venous waves with the carotid impulse. With complete A-V block or prolongation of the P-R
interval to more than 300 milliseconds, asynchronous atrial and ventricular contraction can
result in cannon A waves.
 Pulmonary congestion, and in severe cases peripheral
 Typical rash of Lyme disease
 Manifestations of underlying congenital heart disease or cardiomyopathy such as murmurs or

gallops
LAB EXAMS AND IMAGING

Lab
 Cardiac enzymes to rule out myocardial infarction or ischemia as the predisposing condition
 Electrolyte abnormalities
 BNP if there is evidence of heart failure
 Drug levels of agents such as digoxin, lithium, and anti-arrhythmics
 Thyroid function tests
 Lyme titers if Lyme disease is suspected

 Blood cultures if infection is suspected
Chest X-ray
116
 Examine lung fields for evidence of pulmonary congestion and abnormal chamber size
Echocardiogram
 Useful to evaluate for wall motion abnormalities, effusions, or valvular lesions secondary to
ischemia/infarction, infiltrative process, and congenital abnormalities

 Evidence of cardiac vegetations due to endocarditis
P.77
MRI/CT
 May play a role in identifying areas of ischemia/infarction and in ruling out rare infiltrative
processes such as amyloidosis or tumors
INITIAL MANAGEMENT
Initial management of patients with bradycardia should be directed at identifying and treating
reversible causes and at providing rate support for those that are symptomatic. Temporary pacing is
generally indicated in patients with symptomatic bradycardia that is likely to recur, particularly in the
setting of syncope. Pacing may be performed initially transcutaneously, but this method is not well
tolerated due to pain and is unreliable for prolonged periods. Thus, transvenous pacing is generally
preferred. For mild degrees of bradycardia, particularly in reversible settings, acutely, sinus
bradycardia or A-V block with a narrow QRS complex may be treated with intravenous atropine, usually
0.5 to 1.0 mg. For a wide QRS complex, atropine may worsen the degree of A-V block since it may
increase the sinus rate but not improve A-V block below the level of the His bundle. Isoproterenol or
epinephrine is generally used in this setting. Figure 5-6 also indicates that IV dopamine may be used.
117
FIGURE 5-6 ACLS bradycardia treatment algorithm. (From 2005 American Heart Association Guidelines
for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care; Part 7.3: Management of
Symptomatic Bradycardia and Tachycardia. Circulation. 2005;112: IV-67-IV-77.)
P.78
Oral theophylline has been used with some success in the treatment of sinus bradycardia that is likely
to be transient.11
INDICATION FOR HOSPITALIZATION
118
All patients with a severe or symptomatic bradycardia should be admitted to a monitored setting to
ensure prompt diagnosis and treatment. Patients who require temporary or permanent pacemaker
therapy according to the American College of Cardiology/American Heart Association Task Force
guidelines should be hospitalized for pacemaker implantation. (See Tables 5-1, 5-2, 5-3, and 5-4.)
Patients should be admitted to the cardiac intensive care unit (CCU) or an intermediate cardiac care
unit if the cause of the bradyarrhythmia necessitates admission (e.g., acute coronary syndrome), or if
temporary pacemaker support is needed while awaiting definitive therapy. 10
TABLE 5-1 Common indications for temporary cardiac pacing
1. Therapeutically, for symptomatic bradycardia
a. Persistent bradycardia, until permanent pacemaker implantation can be
accomplished
b. Transient bradycardia (e.g., acute myocardial infarction)
2. Prophylactically, for potential bradycardia that may produce symptoms or
hemodynamic embarrassment in acute myocardial infarction
a. New bundle-branch block
b. New bi- or trifascicular block with first-degree A-V block
c. Type I second-degree A-V block with wide QRS complexes at slow rate
d. Type II second-degree A-V block or higher degrees of A-V block
e. Prophylactically, to prevent pause-dependent ventricular tachyarrhythmias
Adapted from Hongo RH, Goldschlager NF. Bradycardia and pacemakers. In Wachter RM,
Goldman L, Hollander H, eds. Hospital Medicine. 2nd ed. Philadelphia: Lippincott Williams &
119
Wilkins. 2005.10
P.79
TABLE 5-2 Indications for permanent pacing in sinus node dysfunction
Class I (conditions for which there is evidence and/or general agreement that a given procedure
or treatment is useful and effective)
1. Sinus node dysfunction with documented symptomatic bradycardia, including frequent
sinus pauses that produce symptoms; in some patients, bradycardia is iatrogenic and
occurs as a consequence of essential long-term drug therapy of a type and dose for
which there are no acceptable alternatives (Level of evidence C*)
2. Symptomatic chronotropic incompetence (Level of evidence C)
Class II (conditions for which there is conflicting evidence and/or divergence of opinion about
the usefulness/efficacy of a procedure or treatment)
Class IIa (weight of evidence/opinion is in favor of usefulness/efficacy)
120
1. Sinus node dysfunction, occurring spontaneously or as a result of necessary drug
therapy, with heart rate <40 bpm when a clear association between significant
symptoms consistent with bradycardia and the actual presence of bradycardia has not
been documented (Level of evidence C)
2. Syncope of unexplained origin when major abnormalities of sinus node function are
discovered or provoked in electrophysiologic studies (Level of evidence C)
Class IIb (usefulness/efficacy is less well established by evidence/opinion)
1. In minimally symptomatic patients, chronic heart rate <40 bpm while awake (Level of
evidence C)
Class III (conditions for which there is evidence and/or general agreement that a
procedure/treatment is not useful/effective and in some cases may be harmful)
1. Sinus node dysfunction in asymptomatic patients, including those in whom substantial
sinus bradycardia (heart rate <40 bpm) is a consequence of long-term drug treatment
2. Sinus node dysfunction in patients with symptoms suggestive of bradycardia and clearly
documented as not associated with a slow heart rate
3. Sinus node dysfunction with symptomatic bradycardia due to nonessential drug therapy
*
The weight of the evidence was ranked highest (A) if the data were derived from multiple
randomized clinical trials that involved large numbers of patients and intermediate (B) if the
data were derived from a limited number of randomized trials that involved small numbers of
patients or from careful analyses of nonrandomized studies or observational registries. A lower
rank (C) was given when expert opinion was the primary basis for the recommendation.
Adapted with permission from Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002
guideline update for implantation of cardiac pacemakers and antiarrhythmia devices—summary
121
article. J Am Coll Cardiol. 2002;40:1703-1719. Copyright 2002 by the American College of
Cardiology and American Heart Association, Inc.13
P.80
TABLE 5-3 Indications for permanent pacing in acquired atrioventricular block
Class I
1. Third-degree and advanced second-degree A-V block at any anatomic level, associated
with any one of the following conditions:
a. Bradycardia with symptoms (including heart failure) presumed to be due to A-V
block (Level of evidence C)
b. Arrhythmias and other medical conditions that require drugs that result in
symptomatic bradycardia (Level of evidence C)
c. Documented periods of asystole ≥3.0 s or any escape rate <40 bpm in awake,
symptom-free patients (Level of evidence B, C)
d. After catheter ablation of the A-V junction
122
e. Postoperative A-V block that is not expected to resolve after cardiac surgery
(Level of evidence C)
f. Neuromuscular diseases with A-V block (e.g., myotonic muscular dystrophy,
Kearns-Sayre syndrome, Erb limb-girdle dystrophy, and peroneal muscular
atrophy) with or without symptoms, because there may be unpredictable
progression of A-V conduction disease (Level of evidence B)
2. Second-degree A-V block with associated symptomatic bradycardia, regardless of the
type or site of block (Level of evidence B)
Class IIa
1. Asymptomatic third-degree A-V block at any anatomic site with average awake
ventricular rates of >40 bpm, especially if cardiomegaly or left ventricular dysfunction is
present (Level of evidence B, C)
2. Asymptomatic type II second-degree A-V block with narrow QRS; when type II second-
degree A-V block occurs with a wide QRS, pacing becomes a Class I recommendation
(Level of evidence B)
3. Asymptomatic type I second-degree A-V block at intra- or infra-His levels found at
electrophysiologic study performed for other indications (Level of evidence B)
4. First- or second-degree A-V block with symptoms similar to those of pacemaker
syndrome (Level of evidence B)
Class IIb
1. Marked first-degree A-V block (>0.30 s) in patients with left ventricular dysfunction and
symptoms of congestive heart failure in whom a shorter A-V interval results in
hemodynamic improvement (Level of evidence C)
123
2. Neuromuscular disease (e.g., myotonic muscular dystrophy, Kearns-Sayre syndrome, Erb
limb-girdle dystrophy, and peroneal muscular atrophy) with any degree of A-V block
(including first-degree A-V block) with or without symptoms, because there may be
unpredictable progression of A-V conduction disease (Level of evidence B)
Class III
1. Asymptomatic first-degree A-V block (Level of evidence B)
2. Asymptomatic type I second-degree A-V block at the supra-His (A-V node) level or not
known to be intra- or infra-Hisian (Level of evidence B, C)
3. A-V block expected to resolve and/or unlikely to recur (e.g., drug toxicity, Lyme
disease, or during hypoxia in sleep apnea syndrome in absence of symptoms) (Level of
evidence B)
See Table 5-2 for definitions of classes and levels of evidence.
a
A symptom complex of fatigue, weakness, dizziness, hypotension, effort intolerance, and
pulmonary and central venous hypertension caused by inappropriate relationships between atrial
and ventricular depolarization-contraction sequences.
Adapted with permission from Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002
guideline update for implantation of cardiac pacemakers and antiarrhythmia devices—summary
article. J Am Coll Cardiol. 2002;40:1703-1719. Copyright 2002 by the American College of
Cardiology and American Heart Association, Inc.13
P.81
TABLE 5-4 Indications for permanent pacing after the acute phase of a myocardial
124
infarction
Class I
1. Persistent second-degree A-V block in the His-Purkinje system with bilateral bundle-
branch block or third-degree A-V block within or below the His-Purkinje system (Level
of evidence B)
2. Transient advanced (second- or third-degree) infranodal A-V block and associated
bundle-branch block; if the block site is uncertain, an electrophysiologic study may be
necessary (Level of evidence B)
3. Persistent and symptomatic second- or third-degree A-V block (Level of evidence B)
Class IIa
None
Class IIb
1. Persistent second- or third-degree A-V block at the A-V node level (Level of evidence B)
Class III
1. Transient A-V block in the absence of intraventricular conduction defects (Level of
evidence B)
2. Transient A-V block in the presence of isolated left anterior fascicular block (Level of
evidence B)
3. Acquired left anterior fascicular block in the absence of A-V block (Level of evidence B)
125
4. Persistent first-degree A-V block in the presence of bundle-branch block that is old or
age-indeterminate (Level of evidence B)
See Table 5-2 for definitions of classes and levels of evidence. (Adapted with permission from
Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for
implantation of cardiac pacemakers and antiarrhythmia devices—summary article. J Am Coll
Cardiol. 2002;40:1703-1719. Copyright 2002 by the American College of Cardiology and American
Heart Association, Inc.13)
See Table 5-5.
P.82
TABLE 5-5 Pacemaker placement
Dual chamber pacing vs. VPS (J Am Coll Cardiol 199914) Dual chamber pacing with
medical management N = 54 rate-drop response → 85.4%
for vasovagal syncope RRR in first recurrence of
syncope. NNT = 2
Pacing with rate drop VPS II (Card Electrophysiol Pacing with rate drop sensing
sensing vs. sensing alone Rev 200315) N = 100 → 23% RRR in risk of syncope
and the risk of vasovagal at 6 mo. NNT = 11
syncope
Atrial vs. ventricular Prospective randomized trial Atrial pacing → 69% RRR of
126
pacing in sick-sinus of atrial vs. ventricular pacing thromboembolic events at 5y.
syndrome in sick-sinus syndrome NNT = 8
(Lancet 199416) N = 225
REFERENCES
1. Ufberg JW, Clark, JS. Bradydysrhythmias and atrioventricular conduction blocks. Emerg Med Clin
North Am. 2006;24:1-9.
2. Olgin JE, Zipes DP. Specific arrhythmias: Diagnosis and treatment. In: Braunwald E, Zipes DP, Libby
P, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia: WB
Saunders; 2001:815-889.
3. Sandoe E, Sigurd B. Arrhythmia—a Guide to Clinical Electrocardiology. Verlags GmbH: Bingen
Publishing Partners; 1991:278-290.
4. Shaw DB, Southall DP. Sinus node arrest and sino-atrial block. Eur Heart J. 1984;5(Suppl A):83-87.
5. Suawicz B, Knilans TK. Chou's Electrocardiography in Clinical Practice. 5th ed. Philadelphia: WB
Saunders; 2001:321.
6. AnaesthesiaUK. ECG Interpretation: Conduction Abnormalities, 2006.
http://www.frca.co.uk/article.aspx?articleid=
7. Rardon DP, Miles WM, Zipes DP. Atrioventricular block and dissociation. In: Zipes DP, Jalife J, eds.
Cardiac Electrophysiology: From Cell to Bedside. 3rd ed. Philadelphia: WB Saunders; 2000:451-459.
8. Denes P, Levy L, Pick A, et al. The incidence of typical and atypical A-V Wenckebach periodicity. Am
Heart J. 1975;89:26-31.
9. Bradycardia. ClinicalResource@Ovid Clin-eguide
10. Hongo RH, Goldschlager NF. Bradycardia and pacemakers. In Wachter RM, Goldman L, Hollander H,
eds. Hospital Medicine. 2nd ed. Philadelphia: Lippincott Williams & Wilkins. 2005.
127
P.83
11. Benditt DG, Benson DW Jr, Kreitt J, et al. Electrophysiologic effects of theophylline in young
patients with recurrent symptomatic bradyarrhythmias. Am J Cardiol.1983 Dec 1;52(10):1223-1229.
12. 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency
Cardiovascular Care; Part 7.3: Management of Symptomatic Bradycardia and Tachycardia. Circulation.
2005;112:IV-67-IV-77.
13. Gregoratos G, Abrams J, Epstein AE, et al. ACC/AHA/NASPE 2002 guideline update for implantation
of cardiac pacemakers and antiarrhythmia devices—summary article. J Am Coll Cardiol. 2002;40:1703-
1719.
14. Connolly SJ, Sheldon R, Roberts RS, et al. The North American Vasovagal Pacemaker Study (VPS). A
randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope. J Am Coll
Cardiol. 1999 Jan;33(1):16-20.
15. Sheldon R, Connolly S, Vasovagal Pacemaker Study II Investigators. Second Vasovagal Pacemaker
Study (VPS II): Rationale, design, results, and implications for practice and future clinical trials Card
Electrophysiol Rev. 2003 Dec;7(4):411-415.
16. Andersen HR,Thuesen L, Bagger JP, et al. Prospective randomized trial of atrial versus ventricular
pacing in sick-sinus syndrome. Lancet. 1994 Dec 3;344(8936):1523-1528.
12. CHAPTER 6 - Wide and Narrow Complex Tachyarrhythmias

CHAPTER 6
Wide and Narrow Complex Tachyarrhythmias
David V. Daniels
Amin Al-Ahmad
The tachyarrhythmias presented in this chapter and the approach to their differential diagnosis,
workup, and treatment are among the most common problems encountered in inpatient cardiology.
These entities range in gravity from arrhythmias that are a nuisance, allowing for careful consideration
as to the best approach, to life-threatening emergencies demanding decisive action.
128
DEFINITIONS
 Narrow complex tachycardia: QRS duration <120 milliseconds
 Wide complex tachycardia: QRS duration >120 milliseconds with or without pre-excitation
 Pre-excitation: Initial “slurring” of the QRS complex implying manifest antegrade conduction
down an accessory bypass tract (e.g., WPW pattern); may see in sinus rhythm atrial fibrillation
(AF), or antidromic reciprocating tachycardia (ART)
 Supraventricular tachycardia (SVT): A tachycardia arising from or involving the atria,
specialized atrial conduction tissue, or compact A-V node
 Though technically SVT includes AF, some exclude AF as a separate entity for the purposes of
nomenclature for multiple reasons
P.86
 Ventricular tachycardia (VT): A tachycardia arising from and exclusively involving the tissue
beneath the compact portion of the AV node, including the His bundle, bundle branches, and
ventricular myocardium
 VT most commonly associated with CAD and/or structural heart disease
 10% of VT occurs in structurally normal hearts arising both from the endocardium1,2 and
epicardium3
HISTORY
 Symptoms include palpitations, dyspnea, chest pain, presyncope, syncope
 History of myocardial infraction (MI), congestive heart failure (CHF) increase the risk of
malignant arrhythmias such as VT
 Implantable cardioverter-defibrillator (ICD) → consider VT
 Drop attack (sudden syncope without prodrome) is suggestive of cardiac mediated syncope but
its absence should not dissuade you from considering the diagnosis4
 Palpitations are also commonly felt in the recovery phase of neurocardiogenic syncope
 Consider the patient's medications as an etiology of arrhythmias:
o A-V nodal agents—see bradyarrhythmias
o Antiarrhythmics—particularly those that prolong the QTc, IC agents (Flecainide,
encainide (not available in the United States), propafenone), dofetilide, sotalol,
amiodarone
o QTc-prolonging nonantiarrhythmics—macrolides, fluoroquinolones, antipsychotics,
etc.
129
o Digoxin toxicity
PHYSICAL EXAM
 Hypotension or clinical instability does not distinguish between SVT and VT!
 Cannon A waves may be observed in the jugular venous pulse and in the setting of a wide
complex tachycardia are indicative of A-V dissociation and highly suggestive of ventricular
tachycardia
 Crackles or wheezes may suggest heart failure but also consider concomitant pulmonary
disease that may be associated with atrial tachycardias
 Examine chest wall for the presence of an ICD or pacemaker that you can interrogate to reveal
the atrial rhythm in difficult cases
 Murmurs may point to cardiac disease in general, which is useful, but an S3 is suggestive of
decompensated heart failure and can be the cause or result of an arrhythmia
P.87
130
FIGURE 6-1 Algorithm for initial approach to tachyarrhythmias. DDX, differential diagnosis; VT,
ventricular tachycardia; SVT, supraventricular tachycardia; AVRT, atrioventricular reentrant
tachycardia; ART, antidromic reciprocating tachycardia; ORT, orthodromic reciprocating tachycardia;
AVNRT, A-V nodal reentrant tachycardia; AT, atrial tachycardia; JET, junctional ectopic tachycardia.
INITIAL MANAGEMENT
 Always consider cardioversion for unstable arrhythmias. (See Figure 6-1.)
 Obtain a baseline ECG for comparison whenever possible!
 Attention to electrolyte abnormalities, especially ↓ K+ and Mg2+
 If the patient has an ICD or pacemaker (particularly dual chamber), consider interrogation to
help with workup of the arrhythmia
WIDE COMPLEX TACHYCARDIA (WCT)
131
 Differential diagnosis includes VT versus SVT with aberrancy or pre-excited tachycardias. (See
Table 6-1.)
o Unselected population 80% of WCT = VT

o Post-MI or structural heart disease 95% of WCT = VT5
P.88
o Consider AF with antegrade conduction down an accessory pathway (pre-excited AF) if
irregular with wide complex—avoid A-V nodal blockers can → VF
 Misdiagnosis of a WCT as SVT when it is VT can have several consequences:
o Acute progressive pump failure possible with incessant VT
o Drugs: Verapamil, diltiazem, adenosine are potentially dangerous in VT

o Failure to consider acute ischemia as an etiology of new onset VT
TABLE 6-1 Wide complex tachycardia: Differentiating VT from SVT
Diagnostic Features Ventricular Tachycardia SVT with Aberrancy
Prior MI or structural heart More likely Less likely
disease
WCT different in More likely Less likely
morphology from baseline
QRS widening
Right superior QRS axis More likely Less likely
A-V dissociation Diagnostic
Fusion or capture beats Diagnostic
132
Negative or positive >90% specific6
concordance
V1 positive WCT (RBBB V1: rsR' (second R wave taller)
pattern) 7
>50:1 LR for VT V6: rS (small r,
large S) >50:1 LR for VT
V1 negative WCT (LBBB V1: Broad initial R wave >40 ms Absence of an R
pattern)7 favors VT wave or <40 ms
favors SVT
V1: Nadir of S wave >60 ms after Nadir of S wave <60
initiation of QRS ms after initiation of
QRS
V6: Q or QS favors VT LR >50:1 Absence of Q wave
favors SVT
P.89
Therefore, approach WCT with a prejudice toward the diagnosis of VT and consider SVT w/ aberrancy
less likely unless supported by strong evidence.
Approach to Wide Complex Tachycardias: Specific VT syndromes
 Polymorphic VT with normal QT interval: Strongly consider acute ischemia as the etiology
 Torsade de pointes
o Polymorphic VT in the presence of a prolonged QT
o Etiologies: drugs (www.torsades.org), ischemia, familial
 Idiopathic VT: VT in the absence of structural heart disease
o RVOT VT, ILVT, LVOT VT, epicardial VT, aortic cusp VT
 Arrhythmogenic right ventricular dysplasia (ARVD): Epsilon wave
 Brugada syndrome: Characteristic atypical RBBB with ST elevation (leads to VF rather than VT)
 Bidirectional VT: Associated with digoxin toxicity
133
NARROW COMPLEX TACHYCARDIA

Every EKG has a differential diagnosis and the various mechanisms below should be listed as a definitive
diagnosis which is usually difficult by EKG.
 Almost always SVT
 AVNRT is the most common cause of paroxysmal SVT in adults (50%), followed by AVRT (40%)
and AT/SNRT (10%)8
 If irregular, likely AF or multifocal atrial tachycardia (MAT)
 If regular, rhythm useful to divide into short R-P, long R-P, or no R-P where the “R-P” interval
is defined as the onset of the R wave → P wave
o Short R-P tachycardia: R-P interval < P-R interval: AVNRT, AVRT, atypical atrial
tachycardia (AT)
o Long R-P tachycardia: R-P interval > P-R interval: Sinus tachycardia, SNRT, AT,
atypical AVRT and AVNRT
o No R-P tachycardia (no visible P waves): AVNRT most likely, atrial flutter, rarely AT or
JET
 Rarely fascicular VT can present with minimally prolonged QRS, also can terminate with
verapamil or diltiazem and therefore mimic SVT9
Approach to Narrow Complex Tachycardias: Notes on Valsalva

and Carotid Massage
 In an unselected population Valsalva followed by carotid sinus massage terminated PSVT in 28%
of patients10
P.90
 In the absence of carotid bruits, history of stroke, MI within 6 months, history of VT or VF 11
neurologic complications in 16,000 occurrences of carotid sinus massage (CSM) and only 2 had
permanent disability11
134
FIGURE 6-2 Algorithm for the management of wide complex tachycardias. * VT can occasionally be
irregular especially during initiation = If WCT is actually VT, adenosine can precipitate VF, have
defibrillation immediately available
P.91
135
FIGURE 6-3 Algorithm for the management of narrow complex tachycardias. A-V block, atrioventricular
block; AT, atrial tachycardia; AVNRT, atrioventricular nodal reentrant tachycardia; AVRT,
atrioventricular reentrant tachycardia; JET, junctional ectopic tachycardia; SNRT, sinus node reentrant
tachycardia
*
Caution with WPW pattern on baseline ECG, can→ AF → VF (have defibrillator immediately available)
† Contraindicated with carotid bruits, history of stroke, MI within 6 months, history of VT or VF
P.92
PHARMACOLOGIC THERAPY OF TACHYARRHYTHMIAS
See Table 6-2.
136
TABLE 6-2 Pharmacologic therapy of tachyarrhythmias
Arrhythmia Drug Dose Notable side effects
VT Amiodarone 150 mg IV over 10 ↓ BP (though less significant
min, then 1 than CCB and βB), HB, ↓HR,
mg/min infusion, ventricular arrhythmia
consider reduction (attention to QTc), phlebitis
to 0.5 mg/min with prolonged peripheral
when stable or the infusion, pulmonary toxicity,
patient develops hepatotoxicity, hyper- or
sinus node hypothyroidism, ocular
supression toxicity, skin discoloration,
warfarin and digoxin
interaction
Lidocaine 1-1.5 mg/kg IVP, Tremor, insomnia, drowsiness,
may repeat in 5-10 dysarthria, ataxia, seizures
min up to max 3
mg/kg
1-4 mg/min Sinus slowing, asystole Nausea,

infusion vomiting
Therapeutic level:
1.5-5.0 µg/mL
Procainamide 15-18 mg/kg over ↓BP, torsade de pointes,
30 min, then 1-4 nausea, vomiting, diarrhea
mg/min
Renal impairment Cross allergy
(RI) reduce load to
12 mg/kg and
infusion 1/3 mild Avoid with QTc >500 ms
137
and 2/3 severe RI
Torsade Magnesium 1-2 g over 10 min
de pointes
Lidocaine As above
Isoproterenol 2 µg/min (range 2- PVCs, VT, tachycardia,
Consider for TdP 10 µg/min) worsening of ischemia, tremor
associated with (the “Isuprel shakes”), nausea,
significant vomiting, hypokalemia,
bradycardia hyperglycemia
SVT Adenosine 6 mg IVP, repeat ↓BP, asystole, AF, facial
without with 12 mg if no A- flushing (up to 45%, warn
pre- V block patients of this!),
excitation bronchospasm, chest pain,
dyspnea
Give rapidly via
proximal peripheral
IV with rapid flush
Central line
preferred if
already in place
Esmolol 0.5 mg/kg IV over 1 ↓BP, HB, ↓HR, bronchospasm,
min; may repeat q HF; exercise extreme caution
4 min while if used despite HF or
titrating infusion: hypotension though very short
50-200 µg/kg/min half-life
Metoprolol 2.5 to 5 mg IV over ↓BP, HB, ↓HR, bronchospasm,
2 min; may repeat HF; exercise extreme caution
138
q 5 min up to 3 if used despite HF or
doses hypotension
Diltiazem 0.25 mg/kg (~20 ↓BP, HB, HF; exercise extreme
mg) IV over 2 min; caution if used despite HF or
may repeat in 15 hypotension
min at dose of 0.35
mg/kg (~25 mg) IV
over 2 min
infusion: 5-15
mg/h
Verapamil 0.075 to 0.15 ↓BP, HB, HF; contraindicated
mg/kg (~5-10 mg) in HF or hypotension
IV over 2 min; may
repeat in 15-30 min
infusion: 0.125
mg/min
SVT with Procainamide As above As above
pre-
excitation
Amiodarone As above, not FDA As above
approved but
reasonable
SVT with Amiodarone As above, not FDA As above
heart approved but
failure reasonable
AF See chapter on AF
Modified from Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the
Management of Patients with Atrial Fibrillation: A report of the American College of
139
Cardiology/American Heart Association Task Force on Practice Guidelines and the European
Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001
Guidelines for the Management of Patients With Atrial Fibrillation): Developed in collaboration
with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation.
2006;114(7):e257-354.12
P.93
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8. Josephson ME. Clinical Cardiac Electrophysiology: Techniques and Interpretations. 3rd ed.
Philadelphia: Lippincott Williams & Wilkins; 2002.
9. Elswick BD, Niemann JT. Fascicular ventricular tachycardia: An uncommon but distinctive form of
ventricular tachycardia. Ann Emerg Med. 1998;31(3):406-409.
10. Lim SH, Anantharaman V, Teo WS, et al. Comparison of treatment of supraventricular tachycardia
by Valsalva maneuver and carotid sinus massage. Ann Emerg Med. 1998;31(1):30-35.
11. Davies AJ, Kenny RA. Frequency of neurologic complications following carotid sinus massage. Am J
Cardiol. 1998;81(10):1256-1257.
12. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of
Patients with Atrial Fibrillation: A report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for
Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients
With Atrial Fibrillation): Developed in collaboration with the European Heart Rhythm Association and
the Heart Rhythm Society. Circulation. 2006;114(7):e257-354.
13. CHAPTER 7 - Sudden Cardiac Death and ICD Therapy

CHAPTER 7
Sudden Cardiac Death and ICD Therapy
David V. Daniels
Henry Hsia
BACKGROUND
Sudden cardiac death (SCD) is defined as death from cardiovascular causes shortly after the onset of
symptoms in a person without a condition that would otherwise appear fatal.1 Estimates as to the
impact of SCD on our health care system put the total annual mortality up to 450,000, which is 63% of
all deaths from cardiovascular causes.2 Mechanisms of arrhythmic SCD include3,4:
 Ventricular arrhythmia (60% to 80%): Most commonly VT → VF, also primary VF, or torsade de
pointes
 Bradyarrhythmia/asystole
 Pulseless electrical activity (PEA)
141
In a series of young sudden death patients <40 years old without known heart disease, the most
common etiology was still cardiac (73%). Coronary heart disease (CHD) was the most common cause in
those >30 (58%), while myocarditis (22%), hypertrophic cardiomyopathy (HCM) (22%), and conduction
system disease (13%) were more common in those <20 years of age.5 (See Table 7-1.)
P.96
TABLE 7-1 Etiologies of sudden death
Structural (up to 75%) Primary electrical (5%-10%) Noncardiac (10%-35%)
• Coronary heart disease • Congenital or • Intracranial
acquired long QT hemorrhage (most
syndrome common)
• Dilated cardiomyopathy
• Hypertrophic • Idiopathic • Pulmonary
obstructive polymorphic VT and embolism
cardiomyopathy VF
(HOCM)
• Trauma
• Coronary anomalies • Brugada syndrome • Bleeding
• Valvular disease • WPW • Drug intoxication
• Hypertensive heart • Proarrhythmia • Near drowning
associated
disease and LVH with drugs • Central airway
• Arrhythmogenic right • Toxic/metabolic obstruction
142
ventricular dysplasia • Commotio cordis
(ARVD)
• Short QT syndrome
• Inflammatory and
infiltrative myocardial
disease
• Ventricular
noncompaction
• Congenital heart
disease
OUTCOMES
SCD is associated with a high incidence of mortality, and the ability to rescue the patient probably
depends most on timely interventions that restore perfusion to and protect vital organs. Unfortunately,
many patients will die in the prehospital setting or early in the resuscitative effort. For out-of-hospital
sudden death, 20% make it to the hospital, half of them will die in the hospital, and only about half of
the survivors will have any “meaningful” survival. Hence in total only about 5% of patients who sustain
an out-of-hospital sudden death in the absence of ICD therapy will have a good outcome. In contrast,
the survival with early defibrillation when the initial rhythm is VT or VF is substantially higher with up
to 40% of those being discharged with a good neurologic outcome and is the single factor most strongly
associated with a good outcome.4,6 Those that regain a sustained perfusing rhythm are candidates for
further therapy as outlined in Figure 7-1.
INITIAL PREDICTORS OF POOR PROGNOSIS
 Prolonged resuscitation time (>20 minutes)
 Survival decreases by ~10% for each minute of lapsed time before restoration of a viable
rhythm
P.97
143
 Asystole (0% to 2% survival) or pulseless electrical activity (PEA) (11% survival) as the initial
rhythm
 End tidal CO2 by capnography <10mm Hg after 20 minutes of resuscitation in patients with PEA
predicts death with 100% sensitivity and specificity7
FIGURE 7-1 Approach to sudden cardiac death. ACLS, advanced cardiac life support; ABC, airway,
breathing, circulation; VF, ventricular fibrillation; PCI, percutaneous coronary intervention; ICD,
internal cardioverter defibrillator; CCU, coronary care unit; DVT, deep venous thrombosis
144
*
See above for details.
‡ Especially if planned angiography. Intracranial hemorrhage is the most common noncardiac cause of
sudden death. Also trauma secondary to cardiac arrest may → bleeding which can be complicated by
therapeutic anticoagulation.
**
See following for details.
P.98
SPECIFIC ACUTE THERAPIES
Coronary Angiography and Directed Revascularization 8
 High degree of obstructive coronary artery disease (CAD) (71%) in an unselected population of
SCD
 Up to 50% have a totally occluded coronary artery
 ST elevation+chest pain are highly predictive of recent coronary occlusion (87%), ST elevation
alone (63%)
 Up to 25% of those with recent total coronary occlusions have NO pathologic ST elevation
 Successful angioplasty is an independent predictor of survival (Odds ratio 5.2)
 Therefore, coronary angiography is reasonable in all survivors of SCD, especially in those with
persistent ST elevation or antecedent chest pain, but should be considered on an individual

basis for all patients given the significant pretest probability of obstructive CAD and potential
for decreasing further arrhythmic events
Induced Hypothermia Protocol
 Consider for patients who do not regain consciousness immediately after cardiac arrest
 Well validated in combination with primary PCI after resuscitation9
 Induced hypothermia 32-34 degrees Celsius by cooling blankets, ice packs, or central venous
cooling catheter for 24 hours followed by passive rewarming 10,11
 Monitor temperature with bladder or central venous temperature probe
 Sedation with midazolam or Diprivan, analgesia with fentanyl, paralysis with nondepolarizing
neuromuscular blocking agent to prevent shivering

 Bradycardia is common during hypothermia but seldom requires treatment 11
Further Testing
145
In the absence of CHD, other less common structural, metabolic, and primary electrical etiologies
should be considered. The following provide a framework for this investigation:
Review of History
 History of known structural heart disease: prior myocardial infarct/coronary artery disease
(MI/CAD), hypertrophic cardiomyopathy (HCM), rheumatic heart disease, valvular CM, dilated
cardiomyopathy (DCM)
 Family history: FH of SCD, LQT syndrome, FH of CAD, WPW, etc.

 Medication list: drugs known to cause long QT
P.99
Evaluation of the 12-Lead ECG for Primary Electrical Etiologies of SCD
 Look for evidence of structural heart disease:
o Q waves for transmural scar from prior MI
o Evidence of LVH, sarcoidosis (blocks)
o Amyloidosis (low volts), epsilon wave for arrhythmogenic right ventricular dysplasia
(ARVD)
o Consider congenital or acquired long QT syndrome in a patient with significantly
prolonged QTc, risk of torsade is low with a QTc <500 milliseconds12
 Pre-excitation suggestive of a bypass tract which could → rapid A-V conduction and VF
 Brugada syndrome:
o Atypical ST elevation in V1-V3, right bundle branch block pattern13
o Associated with polymorphic VT and VF
 Congenital short QT syndrome:

o Very rare, manifest by QTc <300 milliseconds14
Echocardiography
 Looks for anatomical correlates of the underlying substrate: Wall motion abnormalities,
aneurysm for scar-based arrhythmic substrate (Table 7-1)
 May reveal evidence of left ventricular hypertrophy (LVH), dilated cardiomyopathy (DCM),
HCM, significant valvular disease, pulmonary hypertension, acute RV failure suggestive of
possible pulmonary embolism
 While often performed early, should consider repeating if abnormal LV function >48 hours after
resuscitation because early myocardial stunning may improve11
146
Cardiac MRI
 Useful for evaluation of myocarditis, ARVD, infiltrative cardiomyopathies, and occult
myocardial infarction and scar
 Correlates with increased progression of disease and risk factors for sudden death in patients
with hypertrophic cardiomyopathy (HCM)15
 Late gadolinium enhancement correlates with risk of SCD in patients with nonischemic
cardiomyopathy16
 Contraindicated with pacemakers, ICD, or ferromagnetic medical devices
Electrophysiology Study
 Primarily indicated in those with an accessory pathway (WPW pattern) to assess the
anterograde properties of the accessory pathways,
P.100
shortest RR during pre-excited AF, ERP of the pathway, followed by RFA
 Recurrent refractory ventricular arrhythmias, myocardial scar
 In pts who had a SCD and sustained monomorphic VT is suspected, in a setting of MI, to induce
VT and determine the number, morphology, rate of VT and its response to antitachycardia
pacing (ATP) → for future ICD programming
 Except in the case of a clear link to an accessory pathway → sudden death, most patients
should still get an ICD despite RF ablation
SECONDARY PREVENTION
ICD Therapy
 Significant mortality benefit in survivors of SCD when compared to amiodarone 17
 Likely greater benefit in those with left ventricular ejection fraction (LVEF) <35%17
 Careful consideration of contraindications including:
o Noncardiac disease associated with high short-term mortality

o Active proarrhythmic illegal drug use
Beta Blockers
 Beta blockade is associated with significant reductions in mortality in systolic heart failure
from both reductions in progressive pump failure and sudden death. 18,19
147
Amiodarone
 In contrast to most other antiarrhythmic drugs (see Table 7-2), amiodarone is not pro-
arrhythmic and not associated with increased mortality20
 Meta-analysis confirms no statistically significant mortality benefit in post-MI, LV dysfunction
and postcardiac arrest versus placebo21
 Should not replace beta blockers if indicated for heart failure as they have proven mortality
benefit and careful combination therapy is generally safe22
 Should not replace ICD therapy but may consider as an adjunct to reduce shocks
 Toxicities and intolerance → discontinuation or dose reduction in up to 50% long term23
 800 to 1200 mg/day in divided doses while in hospital, 400 mg/day for 3 to 4 weeks, 200
mg/day maintenance
 Attention to toxicities: Baseline and interval TSH, PFTs (w/ DLCO), chest X-ray, LFTs, Optho
exam
P.101
TABLE 7-2 Antiarrhythmic therapy of aborted sudden cardiac death
Arrhythmia Drug Dose Notable acute side effects
Monomorphic Amiodarone If pulseless 300 mg Relatively contraindicated
VT or VF IVP, then 1 mg/min with congenital or
acquired long QT
syndrome
If cardioverted and
stable, 150 mg IV ↓BP (though less
over 10 min, then 1 significant than CCB and
mg/min, consider βB), HB, ↓HR, ventricular
reduction to 0.5 arrhythmia (attention to
mg/min when QTc), phlebitis with
148
stable prolonged peripheral
infusion
Lidocaine 1-1.5 mg/kg IVP, Tremor, insomnia,
may repeat drowsiness, dysarthria,
0.5/0.75 mg/kg in ataxia, seizures
5-10 min up to max
3 mg/kg
Sinus slowing, asystole
1-4 mg/min
infusion
Nausea, vomiting
Therapeutic level:
1.5-5.0 µg/mL
Procainamide 15-18 mg/kg over ↓BP, torsade de pointes,
30 min, then 1-4 nausea, vomiting,
mg/min diarrhea
Cross allergy with
Renal impairment ester-type local
(RI) reduce load to anasthetics
12 mg/kg and Avoid with QTc >500 ms
infusion 1/3 mild
and 2/3 severe RI
149
Torsade de Magnesium 1-2 g IV over 10
pointes (TdP) min
Isoproterenol 2 µg/min (range 2- PVCs, VT, tachycardia,
Consider for TdP 10 µg/min) worsening of ischemia,
associated with tremor, nausea, vomiting,
significant hypokalemia,
bradycardia hypoglycemia
Transvenous HR 80-100,
pacing especially useful
for TdP associated
with bradycardia
P.102
See Table 7-3.
TABLE 7-3 Landmark clinical trials
Acute therapies
Coronary angiography with Spaulding et al. (N Odds ratio 5.2 (95% CI 1.2-24.5) for
directed PCI Engl J Med 19978) n= survival in patients with successful
angioplasty
Induced moderate Bernard et al. (N Engl Hypothermia → 53% RRR (N 49% H
150
hypothermia (H) in J Med 200211) n= 26%) of bad neurologic outcome
postarrest patients with
persistent coma vs.

NNT = 5
normothermia (N)
Combined PCI and induced Knafelj et al. Hypothermia combined with PCI in
hypothermia (H) in (Resuscitation 2007 ) 9

patients with STEMI and cardiac
survivors of cardiac arrest n= arrest → 71% RRR (N 16% H 55%) of
vs. normothermia (N) bad neurologic outcome
NNT = 3
Antiarrhythmics
Amiodarone vs. EPS CASCADE24 (Am J Amiodarone → 50% RRR of death at
guided antiarrhythmic Cardiol 1993) n= 6 y vs. conventional therapy (most
therapy in survivors of often type 1A antiarrhythmics
SCD in the absence of AMI which are associated with ↑
mortality) Avg. EF 35%
NNT = 5
Amiodarone vs. placebo in EMIAT25 (Lancet 1997) Amiodarone → 35% RRR of
post-MI patients with EF n = 1,486 arrhythmic death (A 2.2%, P 3.3%)
<40% at 21 mo
NNT = 91
NO difference in mortality
Amiodarone vs. placebo in CAMIAT26 (Lancet Amiodarone → 49% RRR of
post-MI patients with 1997) n= arrhythmic death (A 4.5%, P 6.9%)
151
frequent PVCs at 1.8 y
NNT = 42
NO difference in mortality
Amiodarone vs. placebo Meta-analysis21 Amiodarone → no statistically
(Circulation 1997) n= significant difference in all cause
mortality
ICD Therapy
Secondary prevention
ICD vs. amiodarone in AVID27 (N Engl J Med ICD → 24% RRR of total mortality (A
patients resuscitated from 1997) n= 24% I 15.8%) at 18 mo
SCD or with
hemodynamically
NNT = 13
significant VT
ICD vs. amiodarone or CASH28 (Circulation ICD → 23% RRR of total mortality
metoprolol in survivors of 2000) n= (A/M 44.4% I 36.4%, P 0.08) at 57
SCD secondary to mo. P value not significant. N.b.
ventricular arrhythmias procedural mortality was high (4%)
early in the ICD group and trial was
significantly underpowered
ICD vs. amiodarone Meta-analysis ICD → Hazard ratio 0.72 for total
(AVID/CASH/CIDS)17 mortality (Annual mortality A 12.3%
(Eur Heart J) n= I 8.8%) ICD vs. amiodarone
NNT = 29
152
Primary prevention
ICD vs. conventional MADIT II29 (N Engl J ICD → 31% RRR of total mortality (C
therapy for primary Med 2002) n= 19.8% I 14.2%) at 20 mo. Avg EF 23%
prevention of SCD in post-
MI with EF <30%
NNT = 18
ICD vs. amiodarone vs. SCD-HeFT20 (N Engl J ICD 23% RRR of total mortality (P
placebo with EF <35% and Med 2005) n= 29% A 28% I 22%) at 4 y. Avg EF 25%
NYHA II or III CHF
No difference between amiodarone
and placebo
NNT = 15
P.103
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1 hour of the onset of acute symptoms. Am Heart J. 1982;103(1):156-159.
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2. Zheng ZJ, Croft JB, Giles WH, et al. Sudden cardiac death in the United States, 1989 to 1998.
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arrest patients resuscitated from ventricular fibrillation by early defibrillation. Mayo Clin Proc.
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7. Levine RL, Wayne MA, Miller CC. End-tidal carbon dioxide and outcome of out-of-hospital cardiac
arrest. N Engl J Med. 1997;337(5):301-306.
8. Spaulding CM, Joly LM, Rosenberg A, et al. Immediate coronary angiography in survivors of out-of-
hospital cardiac arrest. N Engl J Med. 1997;336(23):1629-1633.
9. Knafelj A, Radsel A, Ploj A, et al. Primary percutaneous coronary intervention and mild induced
hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial
infarction. Resuscitation. 2007;74(2):227-234.
10. Al-Senani FM, Graffagnino C, Grotta JC, et al. A prospective, multicenter pilot study to evaluate the
feasibility and safety of using the CoolGard System and Icy catheter following cardiac arrest.
Resuscitation. 2004;62(2):143-150.
11. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac
arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563.
12. Bednar MM, Harrigan EP, Anziano RJ, et al. The QT interval. Prog Cardiovasc Dis. 2001;43(5 Suppl
1):1-45.
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conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association.
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14. Gaita F, Giustetto C, Bianchi F, et al. Short QT Syndrome: A familial cause of sudden death.
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15. Moon JCC, McKenna WJ, McCrohon JA, et al. Toward clinical risk assessment in hypertrophic
cardiomyopathy with gadolinium cardiovascular magnetic resonance. J Am Coll Cardiol.
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16. Assomull RG, Prasad SK, Lyne J, et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in
dilated cardiomyopathy. J Am Coll Cardiol. 2006;48(10):1977-1985.
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17. Connolly SJ, Hallstrom AP, Cappato R, et al. Meta-analysis of the implantable cardioverter
defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable
Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart
J. 2000;21(24):2071-2078.
18. Goldstein S, Fagerberg B, Hjalmarson AJ, et al. Metoprolol controlled release/extended release in
patients with severe heart failure: Analysis of the experience in the MERIT-HF study. J Am Coll Cardiol.
2001;38(4):932-938.
19. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in
patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med.
1996;334(21):1349-1355.
20. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for
congestive heart failure. N Engl J Med. 2005;352(3):225-237.
21. Sim I, McDonald KM, Lavori PW, et al. Quantitative overview of randomized trials of amiodarone to
prevent sudden cardiac death. Circulation. 1997;96(9):2823-2829.
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metoprolol and xamoterol in combination with amiodarone for resistant ventricular tachycardia
associated with impaired left ventricular function. Am Heart J. 1992;124(5):1233-1240.
23. Bokhari F, Newman D, Greene M, et al. Long-term comparison of the implantable cardioverter
defibrillator versus amiodarone: Eleven-year follow-up of a subset of patients in the Canadian
Implantable Defibrillator Study (CIDS). Circulation. 2004;110(2):112-116.
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CASCADE Investigators. Am J Cardiol. 1993;72(3):280-287.
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Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349(9053):667-674.
26. Cairns JA, Connolly SJ, Roberts R, et al. Randomized trial of outcome after myocardial infarction in
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27. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated
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Investigators. N Engl J Med. 1997;337(22):1576-1583.
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28. Kuck KH, Cappato R, Siebels J, et al. Randomized comparison of antiarrhythmic drug therapy with
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29. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with
myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877-883.
14. CHAPTER 8 - Atrial Fibrillation

CHAPTER 8
Atrial Fibrillation
Anurag Gupta
Paul J. Wang
BACKGROUND
Atrial fibrillation (AF) is the most common chronic cardiac dysrhythmia. The estimated prevalence of
atrial fibrillation and atrial flutter is greater than 2.2 million individuals in the United States, with
estimated incidence of greater than 75,000 cases per year.1 The median age of individuals with AF is
approximately 75 years. The estimated lifetime risk for the development of AF, when studied in all
individuals age 40 years or older free of AF in the Framingham Heart Study, was estimated to be
approximately 1 in 4.2 The morbidity and mortality attributable to AF is significant as its presence
confers an increased risk for congestive heart failure (CHF), embolic events including stroke, and death.
ELECTROPHYSIOLOGIC FEATURES
AF is supraventricular arrhythmia characterized by seemingly disorganized atrial depolarizations
consequently accompanied by ineffectual atrial contraction. The mechanisms contributing to AF are
under investigation with proposed, possibly coexisting, models that include the following:
 Multiple-wavelet reentry, in which AF is maintained via multiple coexisting wave fronts of
electrical activity that propagate randomly throughout the atria
156
 Focal activation at areas of enhanced automaticity, with rapid discharge leading to
heterogeneous, fibrillatory conduction. Of note, numerous foci have been identified though
the region of the pulmonary veins in the left atrium appears to be most common 3
 Small reentrant sources (rotors) that lead to a hierarchical distribution of frequencies

throughout the atria that maintain AF
P.108
 Heterogeneity of autonomic innervation likely plays a further role in the initiation and
maintenance of AF
AF appears to be initiated by atrial premature beats (most commonly), as well as by atrial flutter and
other supraventricular tachycardias.

ELECTROCARDIOGRAPHIC FEATURES 4
The ECG appearance of AF is most immediately suggested by an irregular ventricular rhythm with no
discrete P waves. More specifically,
 Atrial activity: P waves are replaced by f waves, typically smaller waves characterized by
variable morphology, amplitude, and intervals, with rapid rate generally between 350 and 600
beats per minute (bpm).
 Ventricular response: The ventricular response (R-R interval) is generally irregular with rate of
90 to 170 bpm in an untreated individual. The ventricular rate is significantly less than the
atrial rate due to block at the A-V node and possibly due to collision of fibrillatory wave fronts.
However, the ventricular rate varies significantly depending upon multiple factors including
o action of drugs
o electrophysiological properties of the A-V node and conducting tissue
o autonomic tone
 Accessory pathways? Assess for the possible presence of an accessory pathway(s) capable of
antegrade conduction, as ventricular rates can be greater than 300 bpm and deteriorate into
lethal ventricular fibrillation. The presence of an accessory pathway may be suggested by
typical appearance on an electrocardiogram during sinus rhythm (namely, short P-R interval
with delta wave), by extremely rapid ventricular rates greater than 200 bpm during AF, and/or
by wide-QRS complexes during AF (although aberrant conduction or pre-existing conduction

abnormality can also lead to wide complexes).
INITIAL MANAGEMENT
157
 Attempt to identify and address underlying etiologies, risk factors, and/or triggers for AF,
including potentially reversible causes of AF
 Initiate appropriate antithrombotic therapy, if indicated and safe, based on an individualized
assessment of overall stroke risk
 Control the ventricular rate, if needed
 Assess the acute and/or chronic effects of AF including associated symptoms and its
hemodynamic consequences. This will help guide decisions of whether or not to pursue a
strategy of attempting to restore and maintain sinus rhythm.
P.109
CLINICAL CONSEQUENCES
Hemodynamic Compromise
The hemodynamic derangements in AF may or may not be accompanied with symptoms, most commonly
palpitations, dyspnea, decreased exercise tolerance, lightheadedness, syncope, and chest discomfort.
The factors leading to hemodynamic deterioration include the following:
 Loss of effective atrial contraction and thus atrioventricular (A-V) synchrony; this may be
especially detrimental in those dependent upon diastolic ventricular filling
 Irregularity of ventricular response
 Inappropriately elevated heart rate. Chronically elevated atrial rates may lead to adverse
atrial remodeling (including atrial dilatation), and persistently elevated ventricular rates may
lead to the development of a tachycardia-induced cardiomyopathy. Excessive ventricular rates

may also compromise diastolic ventricular filling.
Thromboembolic Risk
Multiple factors contribute to increased thromboembolic events in individuals with AF, although static
flow within the left atrial appendage (LAA) appears most significant. The rate of ischemic stroke varies
significantly depending upon the presence of associated stroke risk factors, but on average is estimated
to be approximately 5% per year in individuals with nonvalvular AF (that is, AF not associated with
rheumatic mitral valve disease, valve replacement, or valve repair). This represents an approximately
sixfold increase in the risk of thromboembolic events in individuals with nonvalvular AF as compared to
individuals without AF. The attributable risk of stroke in individuals with AF increases significantly with
advancing age.5
CLASSIFICATION 6
158
The following definitions apply to episodes of AF lasting longer than 30 seconds without a reversible
cause. It is useful to identify a first-detected episode of AF, acknowledging that the duration of that
episode is generally unknown and prior undetected episodes may have been present. When AF has been
detected at least 2 times, it is termed recurrent AF.
First-detected or recurrent AF can be further classified as the following:
 Paroxysmal: AF episode(s) usually lasts 7 days or less (and most less than 24 hours) and
terminates spontaneously
 Persistent: AF episode(s) usually lasts greater than 7 days and does not terminate
spontaneously
 Permanent: Cardioversion has failed and/or attempts have been foregone
P.110
ETIOLOGIES
The delineation of the following risk factors for AF is somewhat arbitrary, overlap exists, and multiple
etiologies are often present in one individual. Nonetheless, “secondary” AF is intended to draw
attention to cases in which AF may not be the primary problem, and may be ameliorated or terminated
by treatment of the underlying disorder.
“Primary” AF
Established risk factors for the development of AF include the following:
 Advancing age
 Hypertension (systemic and/or pulmonary), especially when accompanied by left ventricular
hypertrophy
 Coronary heart disease, especially when complicated by history of myocardial infarction (MI) or
CHF
 Valvular heart disease, especially mitral regurgitation, mitral stenosis, and tricuspid
regurgitation. In developed nations, this etiology is decreasing in frequency due to the reduced
incidence of rheumatic heart disease.
 Heart failure
 Other factors, possibly including hypertrophic cardiomyopathy, congenital heart disease,
intracardiac (or adjacent) tumors or thrombi, obstructive sleep apnea, and obesity
 Lone or “idiopathic” AF is said to be present in individuals younger than 60 years of age with
no known cardiopulmonary disease (including hypertension) per clinical and echocardiographic
159
assessment. The risk profile, including thromboembolic complications and death, is typically
lower, though these individuals generally progress beyond the lone AF category with time.
Multiple factors including genetic determinants, “sick sinus” syndrome, degenerative
conduction disease, and other electrophysiologic abnormalities likely account for a significant
proportion of incident AF but their role remains incompletely defined at present.
“Secondary” AF
Potentially reversible, “acute” causes and/or triggers for AF include the following:
 Acute MI (usually as a complication of transmural ST segment elevation MI [STEMI])
 Pericarditis
 Myocarditis
 Endocrine disorders including uncontrolled hyperthyroidism and pheochromocytoma
 Infection
 Postoperative state, especially with cardiac, pulmonary, or esophageal interventions
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 Acute pulmonary disease, such as pulmonary embolus, pneumonia, and exacerbation of
obstructive lung disease
 Neurogenic disease, such as major stroke and subarachnoid hemorrhage
 Toxins, such as alcohol, cocaine, amphetamines, and caffeine, including withdrawal states
 Medications, such as theophylline or positive inotropes
 Electrolyte disturbance, such as hypokalemia and hypomagnesemia
 Other supraventricular arrhythmias

 Enhanced sympathetic or parasympathetic tone
EVALUATION
It is critical to carefully consider in every single patient potential etiologies and risk factors
predisposing one to AF. This provides an opportunity to identify and modify significant concomitant
medical disease. However, one must be cognizant that even despite correction of a suspected
reversible cause of AF, a patient may have underlying paroxysmal AF necessitating long-term therapy.
To evaluate possible etiologies of AF and to guide management decisions, it is reasonable to obtain the
following diagnostics, with further studies guided by the clinical scenario.
History and Physical Examination
160
Characterize the patient's pattern of AF; define her symptoms; document her response to prior
therapies; identify possible etiologies, risk factors, and triggers; and assess for clinical evidence of
heart failure.
ECG
Verify the presence of AF, assess for accessory pathways, determine ventricular rate, document
concomitant cardiac disease (e.g., atrial size, left ventricular hypertrophy [LVH], prior MI), monitor
intervals in response to pharmacologic therapy, and assess for other arrhythmias.
Transthoracic Echocardiogram (TTE)
Determine LV size and function, screen for valvular and pericardial disease, measure atrial size, assess
for LVH, and estimate pulmonary pressure. The sensitivity for detection of LA thrombus is low for TTE
as opposed to TEE.
Laboratory Tests
Tests include thyroid panel, serum electrolytes, complete blood count (CBC), renal and hepatic
function, and coagulation tests in part to assess for possible risk factors for AF and to guide
pharmacologic therapy.
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Additional tests may be indicated. This notably may include but is not limited to the following:
 Chest imaging
 Holter monitoring or event recording (in part to assess rate control, confirm diagnosis of AF,
assess concomitant arrhythmias, and correlate symptoms)
 Exercise testing (in part to evaluate for ischemia prior to using Class 1C antiarrhythmic drugs,
assess rate control, define exercise tolerance, and possibly reproduce exercise-induced AF)
MANAGEMENT—OVERALL STRATEGY
While the management of patients with AF is highly individualized, principal components include the
following:
 Carefully consider and address the potential etiologies, risk factors, and/or triggers for AF
 Control the ventricular rate, if needed
 Initiate appropriate antithrombotic therapy, if safe, based primarily on assessment of overall
stroke risk
161
 Consider employing measures to restore and maintain sinus rhythm, if indicated, generally via
cardioversion and antiarrhythmic drugs. If the patient's condition is unstable, urgent

cardioversion should be performed.
Specific guidelines regarding each of these components are discussed in depth for the remainder of the
chapter.
In all stable patients with atrial fibrillation of any clinical pattern, it is recommended that they be
started on appropriate antithrombotic therapy (if safe) and rate control (if needed). However, the
issue of whether or not attempts should also be made to maintain sinus rhythm is debatable. Despite
the hypothesized benefits of maintaining sinus rhythm over rate control alone, randomized clinical
trials comparing these two strategies have failed to show a statistically significant difference in
mortality, stroke, or quality of life (see “Landmark Clinical Trials” section for further details).7, 8, 9, 10,
and 11
Importantly, regardless of the strategy pursued, appropriate antithrombotic therapy is generally
warranted.
MANAGEMENT—RATE CONTROL
Acute Setting
 The goal for the ventricular rate will vary significantly depending upon the clinical scenario.
 As outlined below, amiodarone may be an acceptable agent for rate control despite its
multiple toxicities, if other measures are unsuccessful or contraindicated. The additional
antiarrhythmic potential of amiodarone for facilitating conversion to sinus rhythm must be

considered prior to use. (See Table 8-1.)
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TABLE 8-1 Selected agents for rate control in the acute setting
162
Selected Side Effects and
Drug Loading Dose Maintenance Dose Comments
Patients without accessory pathways and no acute heart failure
Esmolol 0.5 mg/kg IV 50-200 ↓BP, HB, ↓HR,
over 1 min; may µg/kg/min IVCI bronchospasm, HF;
repeat q 4 min exercise extreme
while titrating caution if used despite
IVCI HF or hypotension
though very short half-
life
Metoprolol 2.5 to 5 mg IV No IVCI ↓BP, HB, ↓HR,
βB over 2 min; may available bronchospasm, HF;
repeat q 5 min exercise extreme
up to 3 doses caution if used despite
HF or hypotension
Propranolol 0.15 mg/kg (~1 No IVCI ↓BP, HB, ↓HR,
mg) IV q 2 min available bronchospasm, HF;
exercise extreme
caution if used despite
HF or hypotension
Diltiazem 0.25 mg/kg (~20 5-15 mg/h IVCI ↓BP, HB, HF; exercise
mg) IV over 2 extreme caution if used
min; may repeat despite HF or
in 15 min at hypotension
CCB dose of 0.35
mg/kg (~25 mg)
IV over 2 min
Verapamil 0.075 to 0.15 0.125 mg/min ↓BP, HB, HF; exercise
163
mg/kg (~5-10 IVCI extreme caution if used
mg) IV over 2 despite HF or
min; may repeat hypotension
in 15-30 min
Patients with accessory pathway: Rate control may be appropriate though conversion to sinus
rhythm and/or catheter ablation of the accessory pathway is generally recommended. Agents
that slow conduction across the A-V node (including nondihydropyridine CCB, β-blockers, and
digoxin) are not recommended as they may lead to rapid antegrade conduction across the
accessory pathway during AF.
Amiodarone 150 mg IV over 0.5-1 mg/min ↓BP (though less
10 min IVCI significant than CCB and
βB), HB, ↓HR,
ventricular arrhythmia
(attention to QTc),
pulmonary toxicity,
hepatotoxicity, hyper-
or hypothyroidism,
ocular toxicity, skin
discoloration, warfarin
and digoxin interaction
Patients with heart failure and without accessory pathway
Digoxin 0.25 mg IV; may 0.125-0.375 mg Digitalis toxicity, HB,
repeat IV or PO daily ↓HR, amiodarone
cautiously q 2 h (reduce dosage interaction; the onset of
up to 1.5 mg if used in renal digoxin is slow (over 60
(reduce dosage insufficiency) min or greater)
if used in renal
insufficiency)
Amiodarone 150 mg IV over 0.5-1 mg/min (see above)
164
10 min IVCI
Consult pharmacopoeia/manufacturer recommendations for most accurate and complete
listings, and for additional appropriate drugs.
↓BP, hypotension; IVCI, intravenous continuous infusion; HB, heart block; HF, heart failure; ↓HR,
bradycardia; NA, not applicable; and QTc, corrected QT interval
Modified from Fuster et al. ACC/AHA/ESC 2006 guidelines for the management of patients with
atrial fibrillation. Circulation. 2006;114:700-752.6
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Chronic Setting
 It is reasonable to pursue a goal ventricular rate of 60 to 80 bpm at rest and 90 to 115 bpm
during moderate exercise.
 It is reasonable to consider using a 24-hour Holter monitor (with a goal overall average rate of
approximately ≤100 bpm) and/or exercise testing as an adjunct in assessing the adequacy of
rate control therapy.
 In selected patients with symptomatic, medically refractory atrial fibrillation,
nonpharmacologic attainment of rate control via catheter ablation of the A-V node in
conjunction with permanent ventricular pacing has been demonstrated to be effective and is
associated with improvement in symptoms.12
See Table 8-2.
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TABLE 8-2 Selected agents for rate control in the nonacute and/or chronic setting
165
Drug Dosing Regimen Onset Major Side Effects and Comments
Metoprolol 25-100 mg PO twice a day 4-6 ↓BP, HB, ↓HR, bronchospasm, HF
Propranolol 80-240 mg PO total daily, 60- ↓BP, HB, ↓HR, bronchospasm, HF
divided in 2-4 doses per day 90
min
Diltiazem 120-360 mg PO total daily, in 2-4 ↓BP, HB, HF
divided doses depending h
upon formulation
Verapamil 120-360 mg PO total daily, in 1-2 ↓BP, HB, HF, digoxin interaction
divided doses depending h
upon formulation
Amiodarone Multiple dosing regimens are Days ↓BP (though less significant than
possible. One example is to CCB and βB), HB, ↓HR,
load (in divided doses) with ventricular arrhythmia
800 mg PO daily for 1 wk, (attention to QTc), pulmonary

then 600 mg PO daily for 1 toxicity, hepatotoxicity, hyper-
wk, then 400 mg PO daily for or hypothyroidism, ocular
4-6 wk, then 200 mg PO daily toxicity, skin discoloration,
as maintenance dose warfarin and digoxin interaction
Digoxin May load with 0.5 mg PO 2 Digitalis toxicity, HB, ↓HR,
daily up to 1.5 mg, then days amiodarone interaction;
0.125-0.375 mg daily as consider monitoring digoxin
maintenance dose (reduce serum levels. Not recommended
dosage if used in renal as sole agent for rate control in
insufficiency) paroxysmal AF.
166
↓BP, hypotension; IVCI, intravenous continuous infusion; HB, heart block; HF, heart failure; ↓HR,
bradycardia; NA, not applicable; and QTc, corrected QT interval
MANAGEMENT—RHYTHM CONTROL
Restoring Sinus Rhythm
Direct-current (DC) cardioversion is generally more effective and reliable than pharmacologic
cardioversion and is typically preferred. The primary
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disadvantage of DC cardioversion is the requirement for conscious sedation or anesthesia.
Pharmacologic cardioversion is an acceptable option in some scenarios, including for recent-onset AF
(especially <48 hours).
 Direct-Current Cardioversion
o Immediate DC cardioversion (as initial therapy or promptly after failed pharmacologic
therapy) is suggested in unstable individuals, including those with symptomatic
hypotension, myocardial ischemia, heart failure, or accessory pathways associated
with hemodynamic compromise and/or rapid ventricular rate.
o See section entitled “Management—Antithrombotic Therapy” for suggested
anticoagulation therapy.
o Pretreatment with some antiarrhythmic drugs may increase the likelihood of
successful DC cardioversion, reduce the energy requirement needed for DC
cardioversion, and enhance the likelihood of maintaining sinus rhythm.
o The patient should be fasting with electrolytes and drug levels (including digoxin)
within normal limits.
o DC cardioversion should be synchronized to the R-wave. Although the required energy
is variable and may need to be adjusted, it may be reasonable to use ≥200J
167
monophasic (or 200J biphasic) as the initial shock for external cardioversion in most
patients, based on higher rates of cardioversion.13
o The operating team should be equipped for cardiopulmonary resuscitation.
Prophylactic pacing measures should be available, especially in individuals with
conduction system disease including sick sinus syndrome who are at risk for prolonged
asystole or bradycardia following cardioversion.
 Pharmacologic Cardioversion
o Although facilitation of cardioversion with medications increases the probability of
restoring sinus rhythm, the spontaneous rate of cardioversion for recent-onset AF
(especially within 24 hours) is greater than 50% in some series. 14
o Class IC drugs, such as propafenone and flecainide, are thought to be more effective
than agents such as amiodarone (Class III) in effecting cardioversion for recent-onset
AF. However, Class IC agents are thought to be less effective than Class III agents for
pharmacologic cardioversion if the AF episode has been present for more than 7
days.15
o IV preparations are associated with greater success rates than oral preparations.
o Of the wide array of pharmacologic agents available for cardioversion, five of the
more studied and well proven agents are included in Table 8-3.
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TABLE 8-3 Selected agents for cardioversion of AF of up to 7 days
168
Drug (Vaughan
Williams Class) Dosing Regimen Selected Side Effects
Flecainide Oral: 200-300 mg • ↓BP, atrial flutter with rapid
(Class 1C) ventricular rate (consider use with
β-blocker or nondihydropyridine
CCB)
IV: 1.5-3 mg/kg over 10-20
min
• Ventricular arrhythmiaa (avoid if
CAD, HTN with LVH, or CHF; see
below)
Propafenone Oral: 600 mg • ↓BP, atrial flutter with rapid
(Class 1C) ventricular rate (consider use with
β-blocker or nondihydropyridine
CCB)
IV: 1.5-2 mg/kg over 10-20
min
• Ventricular arrhythmiaa (avoid if
CAD, HTN with LVH, or CHF; see

below)
Amiodarone Oral: Load 1.2-1.8 g per day • ↓BP, HB, ↓HR, GI upset,
(Class III) in divided dose until 10 g constipation, phlebitis (IV),
total, then maintenance pulmonary toxicity, hepatotoxicity,
dose 200-400 mg daily hyper- or hypothyroidism, ocular
toxicity, skin discoloration,
warfarin and digoxin interaction
IV: Load 5-7 mg/kg over 30- • QT prolongation, torsade de
60 min then 0.5-1 mg/min pointes/ventricular arrhythmia
IVCI (rare)b (see below)
169
Dofetilide Oral: 500 µg BID if creatinine • QT prolongation, torsade de
(Class III) clearance >60 mL/min pointes/ventricular arrhythmiab
(reduce dosage if used in (see below)
renal insufficiency;
contraindicated if creatinine
• Use restricted and need for
clearance <20 mL/min)
continuous monitoring given
significant risk of torsade de
pointes
• IV formulation not available in
United States
Ibutilide IV: 1 mg over 10 min; may • QT prolongation, torsade de
(Class III) repeat 1 mg IV when pointes/ventricular arrhythmiab
necessary (see below)
significant risk of torsade de
pointes
↓BP, hypotension; HB, heart block; HF, heart failure; ↓HR, bradycardia; HTN, hypertension; QTc,
corrected QT interval; CAD, coronary artery disease; HTN, hypertension; LVH, left ventricular
hypertrophy; CHF, congestive heart failure; GI, gastrointestinal
a
Factors that predispose one to ventricular proarrhythmia with Class IC agents include, but are
not limited to, structural heart disease (including CAD, CHF, HTN with substantial LVH), QRS >
120 ms, concomitant VT, depressed LV function, rapid ventricular response rate, rapid dose
increase, high dose (drug accumulation), and addition of other drugs with negative inotropic
properties.
170
b
Factors that predispose one to ventricular proarrhythmia with Class III agents include, but are
not limited to, QTc >460 ms, long QT interval syndrome, excessive QT lengthening after drug
initiation, structural heart disease (notably, substantial LVH), depressed LV function,
hypokalemia, hypomagnesemia, female sex, renal insufficiency, bradycardia, previous
proarrhythmia, rapid dose increase, high dose (drug accumulation), and addition of other QT-
prolonging drugs, diuretics, or drugs listed in http://www.torsades.org/.
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FIGURE 8-1 Antiarrhythmic drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal
or persistent atrial fibrillation. Within each box, drugs are listed alphabetically and not in order of
suggested use. The vertical flow indicates order of preference under each condition. The seriousness of
heart disease proceeds from left to right, and selection of therapy in patients with multiple conditions
depends on the most serious condition present. LVH indicates left ventricular hypertrophy. (From Fuster
et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Circulation.
171
2006;114:700-752.)6
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Maintenance of Sinus Rhythm
Pharmacologic and nonpharmacologic options (including catheter ablation) are available if a strategy of
rhythm control is attempted (Figure 8-1). Catheter ablation is not discussed here, as published long-
term outcomes and larger trial data are lacking at present. However, it represents a promising
treatment modality with a growing clinical experience. Although treatment decisions must be
individualized, Figure 8-1 represents a framework for safely initiating therapy based on the
proarrhythmic risks of these agents. Table 8-4 presents the maintenance dosing for some of the more
commonly used agents. Drug guidelines must be consulted for safely initiating and monitoring
antiarrhythmic therapy.
TABLE 8-4 Selected agents for maintenance of sinus rhythm
Drug Total Daily Oral Dosage Selected Side Effects
Flecainide 200-300 mg (generally • ↓BP, atrial flutter with rapid
divided in BID doses) ventricular rate (consider use with β-
blocker or nondihydropyridine CCB)
• Ventricular arrhythmiaa (avoid if CAD,
HTN with LVH, or CHF; see below)
Propafenone 450-900 mg (generally in • ↓BP, atrial flutter with rapid
divided doses depending ventricular rate (consider use with β-
upon formulation) blocker or nondihydropyridine CCB)
• Ventricular arrhythmiaa (avoid if CAD,
HTN with LVH, or CHF; see below)
172
Amiodarone 100-400 mg (generally • ↓BP, HB, ↓HR, GI upset, constipation,
preceded by loading phlebitis (IV), pulmonary toxicity,
regimen) hepatotoxicity, hyper- or
hypothyroidism, ocular toxicity, skin
discoloration, warfarin and digoxin
interaction
• QT prolongation, (rare) torsade de
pointes/ventricular arrhythmiab (see
below)
Dofetilide 500-1000 µg (generally • QT prolongation, torsade de
divided in BID doses); pointes/ventricular arrhythmiab (see
adjust dose for renal below)
function and QT-interval
response during in-hospital

initiation phase
significant risk of torsade de pointes
• IV formulation not available in United
States
Sotalol 160-320 mg (generally in • QT prolongation, torsade de
divided doses); adjust dose pointes/ventricular arrhythmiab (see
for renal function and QT- below)
interval response; often
requires in-hospital
• Additionally with β-blocking
initiation phase
properties including exacerbation of
bronchospastic disease
173
↓BP, hypotension; HB, heart block; HF, heart failure; ↓HR, bradycardia; HTN, hypertension; QTc,
corrected QT interval; CAD, coronary artery disease; HTN, hypertension; LVH, left ventricular
hypertrophy; CHF, congestive heart failure; GT, gastrointestinal
a
Factors that predispose one to ventricular proarrhythmia with Class IC agents include, but are
not limited to, structural heart disease (including CAD, CHF, HTN with substantial LVH), QRS
>120 ms, concomitant VT, depressed LV function, rapid ventricular response rate, rapid dose
increase, high dose (drug accumulation), and addition of other drugs with negative inotropic
properties.
b
Factors that predispose one to ventricular proarrhythmia with Class III agents include, but are
not limited to, QTc >460 ms, long QT interval syndrome, excessive QT lengthening after drug
initiation, structural heart disease (notably, substantial LVH), depressed LV function,
hypokalemia, hypomagnesemia, female sex, renal insufficiency, bradycardia, previous
proarrhythmia, rapid dose increase, high dose (drug accumulation), and addition of other QT-
prolonging drugs, diuretics, or drugs listed in http://www.torsades.org/.
Modified from Fuster et al. ACC/AHA/ESC 2006 guidelines for the management of patients
withatrial fibrillation. Circulation. 2006;114:700-752.6
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MANAGEMENT—ANTITHROMBOTIC THERAPY
Risk Factors for Ischemic Stroke and Systemic Embolism in AF
See Table 8-5.
TABLE 8-5 Risk factors for ischemic stroke and systemic embolism in AF
174
Less Validated or Weaker
Risk Factors Moderate-risk Factors High-risk Factors
Female sex Age ≥75 y Previous stroke, transient
ischemic attack (TIA), or
embolism
Age 65-74 y Hypertension Mitral stenosis
Coronary artery Heart failure Prosthetic heart valve
disease
Thyrotoxicosis Left ventricular (LV) ejection Hypertrophic cardiomyopathy
fraction ≤35% Diabetes mellitus
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Long-term Antithrombotic Therapy Guidelines
Decisions regarding appropriate antithrombotic therapy in patients with AF must be individualized
based on overall risk versus benefit of therapy with specific attention to (a) assessment of one's overall
stroke risk, (b) assessment of one's bleeding risk, and (c) patient preference, including ability to comply
with proposed therapy. Notably, current practice places less emphasis on guiding decisions regarding
antithrombotic therapy based on the pattern of AF—that is, paroxysmal, persistent, or permanent.
Unless contraindications exist, antithrombotic therapy is generally recommended in all individuals with
AF unless they have lone AF. Despite considerable debate among providers, particularly regarding
individuals at intermediate risk for stroke, a framework for individualizing decisions based on
assessment of stroke risk (see Table 8-5) is presented in Table 8-6.
ANTICOAGULATION IN SPECIAL POPULATIONS/SCENARIOS
175
Electrical or Pharmacologic Cardioversion
 In patients with AF episode of known duration <48 hours undergoing cardioversion,
thromboembolic risk is mitigated, though present; whether or not antithrombotic therapy is
needed must be individualized and is in part based on assessment of stroke risk.
 In patients with AF for ≥ 48 hours or of unknown duration:
o In hemodynamically unstable patients, cardioversion should be performed
immediately with concomitant administration of IV heparin (if not contraindicated).
At least 4 weeks of anticoagulation is suggested following successful cardioversion due
to persistent thromboembolic risk, in part related to slow return of mechanical
function (“stunning”) of the left atrium (LA) and left atrium appendage (LAA). Given
the propensity of AF to recur, prolonged anticoagulation following cardioversion is
often advisable.
o In hemodynamically stable patients, one may consider either (a) the conventional
approach of empiric anticoagulation with warfarin for at least 3 weeks preceding
cardioversion (with strict documentation of consistent therapeutic INR values between
2 and 3) or (b) a TEE-guided approach.19 For further details describing these two
approaches, refer to Figure 8-2 as well as the “Landmark Trials” section. In either
scenario, a minimum of 4 weeks of anticoagulation is suggested following successful

cardioversion.
TABLE 8-6 Antithrombotic therapy in AF
Risk Category (See Table 8-5) Suggested Therapy
No risk factors Aspirin (81-325 mg PO daily); need for aspirin is
unclear though if lone AF and <60 y
One moderate risk factor (or ≥1 less Aspirin (81-325 mg PO daily), or warfarin (INR 2-3
validated/weaker risk factor, though with target 2.5)
more debated)
Any high-risk factor or more than 1 Warfarin (INR 2-3 with target 2.5); if a mechanical
moderate risk factor prosthesis is present, the INR should be at least
≥2.5 depending upon the prosthesis
176
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177
FIGURE 8-2 Figure 1 study protocol published by Klein AL, et al. (From Klein AL, Grimm RA, Murray RD,
et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial
fibrillation. N Engl J Med. 2001;344:1411-1420.)
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Surgical or Diagnostic Procedures Associated with Bleeding Risk
In patients without high-risk for stroke (notably including mechanical prosthetic heart valve; see Table
8-5), it may be reasonable to interrupt anticoagulation for up to 1 week without using heparin.
Percutaneous Coronary Intervention
178
No clear data exist to guide optimal therapy. One potentially reasonable strategy is to use warfarin and
clopidogrel for maintenance therapy with duration depending upon the type of stent implanted (aspirin
may be added acutely until the INR is therapeutic); again, in the absence of data, this is an area of
considerable debate and variability in practice.
See Tables 8-7 and 8-8.
TABLE 8-7 Rate versus rhythm control in AF
Trial Details Results/Comments
AFFIRM7 • 4,060 patients with • Primary endpoint of overall mortality
paroxysmal or comparable: 26.7% in rhythm control
persistent AF; average vs. 25.9% in rate control (p = 0.08)
f/u 3.5 y
• Patients ≥65 y/o (mean • Rate of ischemic stroke comparable:
age 69.7) with other 7.1% in rhythm control vs. 5.5% in rate
risk factors for stroke control (p = 0.79)
or death (70.8%
with hypertension) • Majority of strokes occurred in
individuals
• Myriad antiarrhythmic who discontinued warfarin or had
interventions, though subtherapeutic INR; more individuals
amiodarone most in rhythm control group discontinued
common (used by 62.8% warfarin
in rhythm control at
some point)
RACE8 • 522 patients with • Primary composite endpoint of
persistent AF or atrial cardiovascular (CV) death, HF,
179
flutter; average f/u 2.3 thromboembolic complications,
y bleeding, pacemaker implantation,
and severe adverse drug reaction
comparable: 17.2% in rate control vs.

• Mean age 68 y/o
22.6% in rhythm control (90%
confidence interval of -11 to 0.4%)
PIAF9 • 252 patients with • Primary endpoint of improvement in
persistent AF; average symptoms related to AF comparable:
f/u 1 y 60.8% in rate control vs. 55.1% in
rhythm control (p = 0.317)
• Mean age 61 y/o
• Diltiazem first-line
agent in rate control
group; amiodarone
first-line agent in
rhythm control group
HOT • 205 patients with first • Primary composite endpoint of death,
CAFÉ10 clinically overt episode thromboembolic events, and major
of AF; average f/u 1.7 y bleeding comparable: <5 events in
each group with odds ratio between
rate and rhythm control of 1.98 (p

• Mean age 60.8 y/o
>0.71)
STAF11 • 200 patients with • Primary composite endpoint of death,
persistent AF; average cardiopulmonary resuscitation,
f/u 1.6 y cerebrovascular event and systemic
embolus comparable: 5.54% per year
in rhythm control vs. 6.09% per year in

• Mean age 66
rate control (p = 0.99)
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180
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TABLE 8-8 Antithrombotic strategies in AF
Strategy Comments/Findings
Adjusted-dose warfarin • Six trials using an intention-to-treat analysis of 2,900
vs. placebo: meta- patients with nonvalvular AF
analysis16
• 62% overall relative RR of stroke with warfarin (95% CI of
48%-72%); statistically significant in 4 of 6 individual trials
• 2.7% per year absolute RR of stroke with warfarin in the
five primary prevention trials analyzed (to prevent 1
stroke per year, NNT = 37]
• 8.4% per year absolute relative risk (RR) of stroke with

warfarin in the one secondary prevention trial analyzed
(NNT = 12)
• Nine total intracranial hemorrhages among the 2,900
patients (6 in the warfarin group [0.3% per year] vs. 3 in
the placebo group [0.1% per year]; not statistically
significantly different)
• Significantly more extracranial hemorrhages per year in
the warfarin group (0.9%) compared to the placebo group
(0.6%) in the 5 studies included for analysis
181
• Significant reduction in all-cause mortality with warfarin
• Caveat that these clinical trials excluded patients at high
risk for bleeding, and, as opposed to actual clinical
practice, involved generally shorter time of follow-up
(mean 1.6 y), younger patients (mean 69 y), and more
stringent monitoring of anticoagulation
Aspirin vs. placebo: • Six trials using an intention-to-treat analysis of 3,337
meta-analysis16
patients with nonvalvular AF
• 22% overall relative RR of stroke with aspirin (95% CI of 2%-
38%)
• 1.5% per year absolute RR of stroke with aspirin for
primary prevention (NNT = 67)
• 2.5% per year absolute RR of stroke with aspirin for
secondary prevention (NNT = 40)
• No significant differences between intracranial
hemorrhage, extracranial hemorrhage, nor mortality
• Caveat: Modest benefit for stroke prevention with aspirin
in this meta-analysis questioned due to (a) favorable
results being largely driven by the Stroke Prevention in
Atrial Fibrillation (SPAF) study,17 the only trial of the six
demonstrating a statistically significant benefit with
aspirin therapy; and (b) apparent statistically significant
advantage of aspirin in nondisabling stroke only, and not
disabling stroke, per a subanalysis of the three largest
trials reporting data on stroke severity
182
Aspirin AND Clopidogrel • 3,335 patients with AF and ≥1 stroke risk factor
vs. vitamin K antagonist randomized to clopidogrel 75 mg QD + aspirin 75-100 mg
QD versus oral anticoagulation with vitamin K antagonist
(VKA)
ACTIVE W18 • Trial stopped prematurely given evidence of clear
superiority of VKA in reducing the primary composite
outcome of stroke, non-CNS systemic embolic event, MI,
and vascular death (3.93% annual risk with VKA vs. 5.6%
with clopidogrel + ASA; p = 0.0003)
• Major bleeding rates not significantly different
• Separate question examining the role of dual antiplatelet
therapy versus aspirin monotherapy in patients unable or
unwilling to take warfarin currently being studied in the
ACTIVE A arm
Use of TEE to guide • (see preceding text for flow sheet of study design)
duration of
anticoagulation prior to
• In 1,222 patients with AF for >2 d scheduled for elective
elective cardioversion in
cardioversion, comparable safety of a conventional
patients with AF19
approach (3 wk empiric anticoagulation with warfarin) to a
TEE-guided approach (cardioversion performed shortly
after brief anticoagulation therapy if patients with no
detected thrombi): composite primary end point of CVA,
TIA, and peripheral embolism within 8 wk was 0.8% in TEE
group vs. 0.5% in conventional-treatment group (p = 0.50)
• In TEE group, significantly lower hemorrhage rate (2.9%)
than in the conventional approach, (5.5%, p = 0.03)
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183
REFERENCES
1. Thom T, Haase N, Rosamond W, et al. American Heart Association. Heart disease and stroke
statistics: 2006 Update. Circulation. 2006;113:85-151.
2. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation.
Circulation. 2004;110:1042-1046.
3. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation of atrial fibrillation by ectopic beats
originating in the pulmonary veins. N Engl J Med. 1998;339:659-666.
4. Olgin JE, Zipes DP. Specific arrhythmias: Diagnosis and treatment. In: Zipes DP, Libby P, Bonow RO,
Braunwald E, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed.
Philadelphia: Elsevier Saunders;2005:803-863.
5. Wolf PA, Abbott RD, Kannell WB. Atrial fibrillation as an independent risk factor for stroke: The
Framingham Study. Stroke. 1991;22:983-988.
6. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients
with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines
(Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial
Fibrillation). Circulation 2006;114:e257-e354.
7. Wyse DG, Waldo AL, DiMarco JP, et al. Atrial fibrillation follow-up investigation of rhythm
management (AFFIRM) investigators. A comparison of rate control and rhythm control in patients with
atrial fibrillation. N Engl JMed. 2002;347:1825-1833.
8. Van Gelder IC, Hagens VE, Bosker HA, et al., for the Rate Control versus Electrical Cardioversion for
Persistent Atrial Fibrillation Study Group (RACE). A comparison of rate control and rhythm control in
patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347:1834-1840.
9. Hohnloser SH, Kuck KH, Lilienthal J, for the PIAF Investigators. Rhythm or rate control in atrial
fibrillation—pharmacological intervention in atrial fibrillation (PIAF): A randomized trial. Lancet.
2000;356:1789-1794.
10. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs. rhythm control in patients with nonvalvular
persistent atrial fibrillation: The results of the Polish How to Treat Chronic Atrial Fibrillation (HOT
CAFÉ) study. Chest. 2004;126:476-486.
184
11. Carlsson J, Miketic S, Windeler J, et al., for the STAF Investigators. Randomized trial of rate-control
versus rhythm-control in persistent atrial fibrillation: The Strategies of Treatment of Atrial Fibrillation
(STAF) study. J Am Coll Cardiol. 2003;41:1690-1696.
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12. Wood MA, Brown-Mahoney C, Kay GN, et al. Clinical outcomes after ablation and pacing therapy for
atrial fibrillation. Circulation. 2000;101:1138-1144.
13. Joglar JA, Hamdan MH, Ramaswamy K, et al. Initial energy for elective external cardioversion of
persistent atrial fibrillation. Am J Cardiol. 2000;86:348-350.
14. Hersi A, Wyse G. Medical management of atrial fibrillation. Curr Cardiol Rep. 2006;8:323-329.
15. Rudo T, Kowey P. Atrial fibrillation: Choosing an antiarrhythmic drug. Curr Cardiol Rep. 2006;8:370-
376.
16. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with
atrial fibrillation: A meta-analysis. Ann Intern Med. 1999;131:492-501.
17. Stroke Prevention in Atrial Fibrillation (SPAF) investigators. Stroke Prevention in Atrial Fibrillation
study. Final results. Circulation. 1991:84:527-539.
18. The ACTIVE Writing Group. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation
in the atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events (ACTIVE W): A
randomized controlled trial. Lancet. 2006:367:1903-1912.
19. Klein AL, Grimm RA, Murray RD, et al. Use of transesophageal echocardiography to guide
cardioversion in patients with atrial fibrillation. N Engl J Med. 2001;344:1411-1420.
15. CHAPTER 9 - Heart Failure

CHAPTER 9
Heart Failure
David Kao
David V. Daniels
Euan Ashley
185
Approximately 5 million people throughout the United States have heart failure (HF); 550,000 are
diagnosed each year, and it represents the primary diagnosis in over 1 million hospitalizations
annually.1,2 We will focus our efforts on the recognition and management of HF as an inpatient problem
with the understanding that encounters may be prompted by everything from new onset HF,
decompensation of patients with known HF, to refractory HF. We will make recommendations on
reasonable strategies of acute HF management and initialization of chronic therapies known to have
long-term benefit in terms of morbidity and mortality.
DEFINITION
Failure of the heart to pump blood forward at a sufficient rate to meet the metabolic demands of
peripheral tissues, or the ability to do so only at the expense of abnormally high cardiac filling
pressures.3
CLINICAL PRESENTATIONS OF HEART FAILURE
See Table 9-1.
P.130
Type
 Up to 44% isolated diastolic dysfunction, often mixed diastolic and systolic dysfunction
Systolic Dysfunction
 Most commonly secondary to ischemic heart disease (50%-75%) or primary valvular disease
 Differential diagnosis for nonischemic dilated cardiomyopathy (DCM) is very broad including
toxins, medications, autoimmune, viral and bacterial infection, nutritional, familial,

endocrine, pregnancy, isolated ventricular noncompaction
Diastolic Dysfunction
 Associated most commonly with chronic hypertension (HTN), left ventricular hypertrophy
(LVH), and metabolic syndrome
 Infiltrative etiologies include hemochromatosis, sarcoidosis, and amyloidosis
 Can be seen acutely with ischemia as well as chronic coronary artery disease (CAD) after
multiple myocardial infarctions (MI)
186
TABLE 9-1 Clinical presentations of heart failure
Volume overload Acute pulmonary edema Low output state
• Gradual • Acute dyspnea at rest • Signs of
worsening of hypoperfusion
symptoms • Generally hypoxemic including relative
• Increased respiratory failure hypotension, altered
weight,
edema • Often older patients, mentation,
azotemia,
• Dyspnea women > men, isolated oliguria, cool
increased extremities
often with diastolic function common • Generally severely
minimal
pulmonary • Triggers can be med impaired ejection
edema
• Signs of right- noncompliance, pain, fraction
sided
volume infection/fevers, or • May be volume
overload often dietary indiscretions overloaded or rarely
present
including ↑
187
JVP, peripheral • Significant and intravascularly
edema, ascites, hypertension and high depleted and in a
pleural catecholamine state low output state as a
effusions common result of
• Elevated • Frank pulmonary edema overdiuresis
creatinine often
often improves on CXR • Invasive
with hemodynamics
diuresis • Often not totally body may have a role in
volume overloaded and diagnosis and
neck veins may not be stabilization
elevated
• Generally responds quickly • Often requires
to CPAP/BIPAP and positive inotropic or
vasodilator therapy with vasodilator therapy
minimal diuresis
P.131
COMMON CAUSES OF ACUTE ON CHRONIC EXACERBATIONS
Forgotten meds (most common cause)
Anemia/Arrhythmias
Ischemia/Infection
Lifestyle (dietary indiscretion, non-steroidal anti-inflammatories [NSAID])
Upregulation of cardiac output (e.g., thyrotoxicosis, cocaine)
Renal failure
188
Embolism (PE)
HISTORY
 Recent chest pains (CP) or symptoms of ischemia
 Recent palpitations
 History of congestive heart failure (CHF), CAD, HTN
 Prior cardiac workup (i.e., echo, stress test, cardiac catheterizations)
 Functional status/exercise capacity (e.g., flights of stairs or number of blocks before having to
rest)
 Changes in weight (e.g., clothes or rings not fitting recently), dependent edema, nocturia,
paroxysmal nocturnal dyspnea (PND), orthopnea (most sensitive symptom of elevated
pulmonary capillary wedge pressure (PCWP))1
 Recent changes in medications or missed doses—be specific about timing
 Recent changes in eating habits such as dining out, special events (e.g., holidays and
weddings)
PHYSICAL EXAM
SIGNS OF RIGHT VENTRICULAR (RV) FAILURE
 Elevated jugular venous pressure (JVP) or + hepatojugular reflex
 Hepatomegaly or pulsatile liver
 Dependent peripheral edema
 Ascites
 Parasternal heave
 S3 or S4 at lower R sternal edge
SIGNS OF LEFT VENTRICULAR (LV) FAILURE
 Tachypnea, diaphoresis
 Enlarged or displaced point of maximal impulse (PMI)
 Early inspiratory rales (often not present in chronic failure) and hypoxemia
 Decreased breath sounds with decreased tactile fremitus at lung bases
 S3 (specific if present but not very sensitive) or summation gallop

 Murmur/thrill suggestive of severe valvular regurgitation or septal defect
P.132
SIGNS OF LOW CARDIAC OUTPUT
189
 Cool extremities
 Oliguria
 Altered mental status
 Narrow pulse pressure (pulse pressure <25% of the systolic blood pressure (SBP) has a
sensitivity and specificity of 91% and 83% for a cardiac index of <2.2 L/min/m 2)4
 Tachypnea with normal oxygen saturation

 Pulsus alternans (ominous)

CARDIAC ENZYMES
 Always exclude ischemia/infarct as etiology of acute HF
 Rule out with serial enzymes, as in acute myocardial infarction (AMI)
 Low-grade troponin may be detectable and even expected with significantly elevated left
ventricular end diastolic pressure (LVEDP), CKMB often negative, and enzymes do not follow
the typical rise and fall seen in an acute coronary syndrome
CREATININE AND THE CARDIO-RENAL SYNDROME
 Chronic renal failure is often associated with CHF, termed the “cardio-renal syndrome”
 Acute renal failure often due to further worsening of cardiac output
 Remember that decreased cardiac output (CO) is one cause of prerenal azotemia
 Rising creatinine during treatment of acute HF is associated with worse in-hospital and long-
term outcomes
 Often “volume overload” presentations associated with creatinine improvement in the face of
diuresis …? Improved CO versus lowering venous back pressure/congestion on kidneys
B-TYPE NATRIURETIC PEPTIDE (BNP)
 Most useful for excluding CHF as a contributor to clinical presentation
 >150 pg/mL had a sensitivity and specificity of 85% and 83% and LR (+) of 5.3, LR (-) 0.18 for
the diagnosis of heart failure in the Breathing Not Properly trial3
 Elevated BNP in the setting of intact systolic function (nl EF) is highly suggestive of diastolic
dysfunction5
 BNP >400 pg/mL is virtually diagnostic of LV failure contributing to symptoms6
P.133
190
 May be normal in cases of restrictive or constrictive physiology
 Use caution in interpreting test in patients with chronic renal insufficiency (CRI), where brain
natriuretic peptide (BNP) elevation may be exaggerated
 Pro-NT BNP had a higher cutoff but similar operating characteristics7:
o Optimal cutoff for age:
o <50 = 450 pg/mL
o 50 to 75 = 900 pg/mL
o >75 = 1800 pg/mL

o above cutoffs yield a sensitivity of 90%, specificity of 84%
URINE TOXICOLOGY
 Rule out cocaine or amphetamine use as an etiology of heart failure in suspected patients
ECG
 Useful for rapidly detecting ST segment elevation MI (STEMI) as a cause of new onset HF but
beware “strain” can be an effect of HF
 Arrhythmias such as A fib or high-grade A-V block as a precipitant of HF
 Q waves and left bundle branch block (LBBB) are good predictors of systolic dysfunction. QRS
>220 milliseconds portends a poor prognosis

 Nonspecific intraventricular conduction delay >160 milliseconds suggests cardiomyopathy
CHEST X-RAY
 May demonstrate pulmonary edema, cardiomegaly, pleural effusions
 Useful for excluding other etiologies of symptoms

 If rapid change in heart size, consider pericardial effusion/tamponade
ECHO
 Universally the single most important test in the evaluation of new onset HF
 Rapidly differentiates among many etiologies listed above
 Can be difficult to identify restrictive or constrictive physiology

 Markers of diastolic dysfunction controversial and difficult in A fib
REST-STRESS ECHO, MRI OR PET SCANNING
 ALWAYS evaluate for ischemia in new-onset CHF, consider angiography as below
 Useful for assessing viability of myocardium and potential for response to revascularization
191
 Dobutamine echo may help determine response to aortic valve replacement (AVR) in critical
aortic stenosis
P.134
PULMONARY ARTERY CATHETERIZATION
 May be helpful in titration of inotropes and vasodilators

 No benefit in large-scale randomized trials
CORONARY ANGIOGRAPHY
 Definitely if evidence of acute ischemia/infarct as cause of HF
 Consider in newly diagnosed systolic dysfunction as the gold standard for evaluation of
coronary disease and potentially treatable lesions
CARDIOPULMONARY FUNCTIONAL VO MAX TESTING 2
 Infrequently used in acute setting, can be useful for determining a cardiac or pulmonary cause
of dyspnea when the etiology is unclear

 Used in severe HF in making objective assessments about transplantation
GENERAL APPROACH TO ACUTE MANAGEMENT OF HF

(See Figure 9-1.)
Pearls on Diuresis
 In a hemodynamically stable patient who is volume overloaded, your goal should be at least 1
to 2 liters/day
 In patients with renal insufficiency, consider continuous furosemide infusion rather than bolus
dosing8
 Strict I/Os and/or daily weights are essential to monitor diuresis
 Cardiac monitoring and frequent electrolyte checks (particularly magnesium and potassium)
with aggressive replacement is essential to prevent arrhythmias
 Encourage the patient to take an active role by asking the nursing staff their weight daily
 Most patients respond to aggressive diuresis despite theoretical concerns of decreasing cardiac
output
 Diuretics alone rarely cause serious hypotension
192
 Clinical deterioration with diuresis suggest preload-dependence such as severe pulmonary
hypertension/RV failure, aortic stenosis, LV outflow tract obstruction, tamponade, constrictive
pericarditis, or restrictive cardiomyopathy
 If diuresis is inadequate consider adding metolazone (limited data),9 chlorothiazide, or
nesiritide
 Double the dose when switching from IV to oral furosemide to achieve equivalent diuretic
effect
 Consider oral bumetanide as an alternative to oral furosemide (better absorption in CHF but
shorter elimination half-life)10
FIGURE 9-1 General approach to the acute management of HF.
P.135
193
Noninvasive Positive Pressure Ventilation
 Consider continuous positive airway pressure (CPAP) as a bridge while diuresing and has
recently been shown to have significant mortality benefit and decreases need for intubation in
a large meta-analysis11
 Strongly consider in patients with increased work of breathing or persistent hypoxia despite
initial therapy
 CPAP probably preferred to bilevel positive airway pressure (BIPAP) as there is some evidence
of a trend toward increased AMI with BIPAP in comparison to CPAP11
 Reasonable to start with 8 cm H2O and titrate to effect
 Contraindications: Inability to protect airway, craniofacial deformities limiting mask fit,
hemodynamic instability, high oxygen requirement that cannot be achieved with BIPAP,
nausea/vomiting due to risk of aspiration, and significant arrhythmias
SPECIFIC THERAPIES FOR SYSTOLIC DYSFUNCTION

GOALS
 Optimize preload, minimize afterload via vasodilator and diuretic therapy
 Prevent worsening of ejection fraction (EF) via ischemic events, tachyarrhythmia, excess
afterload
 Reduce risk of life-threatening arrhythmia
ACE Inhibitors and ARBs
 Multiple trials that show mortality benefit (see below). ACE-I12,13,14 or ARBs15 > nitrates and
hydralazine16
P.136
 ACE-Is are the preferred vasodilator and should be given a trial before hydralazine and nitrates
 Enalapril, losartan, and candesartan best studied, but presumed to be class-effect
 Start ACE-Is low and titrate while watching K and renal function closely
 The lower the EF, the more benefit from ACE-I/ARB if tolerated
 Allow for a 30% increase in creatinine with therapy before considering the patient intolerant
Hydralazine/Nitrates
 First vasodilator therapy to show survival benefit versus placebo16
194
 Subsequently found to be inferior to ACE-I/ARBs,17 though best alternative for patients
intolerant to ACE-I/ARB
 Goal dose in VHeFT-I: hydralazine 300 mg/day + 160 mg isosorbide dinitrate/day16
 May have an additive benefit to ACE-I/ARB, though only studied in self-identified “African
descent” patients so far18
Beta Blockers
 Multiple trials show mortality benefit19,20,21,22,23
 Some patients may have dramatic improvement in EF with therapy

 Not all beta-blockers are created equal!24
CHOICE OF AGENT
 Carvedilol (use caution in severe asthma because nonselective) > metoprolol succinate for
increasing EF but both show mortality benefit25
 Metoprolol succinate (long acting) is the type of metoprolol best studied in CHF 25
 Patients with low BP may tolerate metoprolol better and those who are hypertensive may get
more BP-lowering effects from carvedilol25
 Metoprolol may worsen insulin resistance, carvedilol has neutral effect26
 Consider compliance when selecting regimen (once versus twice daily dosing—Coreg XR now
available however)
INITIATION, TITRATION, AND SIDE EFFECTS
 Start at low dose if stable off inotrope therapy
 See landmark trials section below for starting doses in clinical trials
 Symptomatic benefit may take months and patients may complain of initial worsening of
symptoms
 Titrate primarily as an outpatient, increase dose to highest tolerated by blood pressure (BP),
heart rate (HR)
 Side effects include increased fatigue, hypotension, water retention, azotemia, decreased
libido/impotence, theoretically exacerbation of reactive airway disease
 Consider maintaining beta blockade while intensifying diuresis in patients treated for >3
months with increased congestive symptoms
P.137
195
 Decrease or hold in patients presenting with severe acute-HF, especially with low output
symptoms or significant azotemia
Aldosterone Antagonists (Spironolactone/Eplerenone)
 Indicated for NYHA class III-IV HF (RALES)27 and post-MI heart failure (EPHESUS)
 Best-studied in patients already on ACE-I or ARB27
 Significant reduction in mortality and hospitalization27
 Contraindicated with K >5.0 mEq/L, Cr >2.5 mg/dL, or CrCl <30 mL/min
 Extreme caution in patients with Cr >1.5 mg/dL or CrCl <50 mL/min
 Also consider in patients with resistant hypokalemia on standard therapy
 Close monitoring for hyperkalemia is critical, especially in setting of CRI 28,29
 Stop exogenous K replacement and monitor serum K and Cr at 3 days, 1 week, and monthly
after initiation of therapy for at least the first 3 months

 Eplerenone is alternative to spironolactone that does not produce gynecomastia30
Digoxin
 May be considered after first-line therapies including RAAS inhibition, beta blockers, and
aldosterone antagonists are maximized or in conjunction with A-V nodal agents for improving
rate control in atrial fibrillation
 Can be considered as an adjunct especially in patients with AF with RVR, decreases
hospitalizations and improves symptoms31
 Post hoc analysis of the DIG trial suggests serum dig concentration (SDC) of 0.5 to 0.8 ng/mL
may be associated with mortality benefits as well32
 Consider no more than 0.125 mg daily in all patients
 Do not load unless being used as an adjunct for rate control

 Close attention to prevention of hypokalemia which can promote toxicities
Nesiritide
 Natriuretic that reduces preload and afterload without effect on contractility
 More rapid improvement in PCWP and dyspnea over placebo but similar when compared to
nitroglycerin (NTG),33 milrinone, or dobutamine34
 Clinically may be a useful adjunct to standard therapy in refractory HF and as bridge to
transplant
 Optional 2 µg/kg bolus, followed by infusion at 0.01 to 0.03 µg/kg/min

 Less likely to promote ventricular arrhythmias compared to dobutamine 35
Anticoagulation
196
 All patients with ischemic cardiomyopathy should at least be on aspirin36
 Patients in AF should be on Coumadin (INR 2.0-3.0) if there is no contraindication
 Those with severely depressed EF (<30%), large territory of akinetic LV, or evidence of LV
thrombus probably benefit from anticoagulation as well36
P.138
Internal Cardioverter Defibrillators
 See chapter on sudden death
Revascularization Therapy
 Evaluate for contribution of ischemia; see chapter on CAD for indications and strategy.
P.139
P.140
TABLE 9-2 Heart failure treatment strategies checklist
Stage A; At risk Stage B; Stage C; Stage D;
for HF but no Structural Structural Refractory HF
symptoms or heart disease heart disease despite
structural without with current or maximal
abnormalities symptoms or past symptoms conventional
signs of HF of HF therapy
Aggressive BP control
• Goal <130/80 X X X X
197
Aggressive lipid management
• Goal LDL <100 and <70 X X X X
with CAD or DM
• Statins generally
preferred
Lifestyle modifications
• Facilitate cessation of
smoking, alcohol, illicit
drugs
• Emphasize importance X X X X
of patient role in daily
monitoring of status
(e.g., weight, diet,
symptoms)
• Encourage exercise to
the point of developing
sx
Avoid NSAIDS, calcium
channel blockers, and
antiarrhythmics except B-
blockers
• Aspirin OK, particularly
if ischemic CM
198
• Most antiarrhythmics X X X
a/w increased mortality
except amiodarone and
dofetilide
• Calcium channel
blockers a/w increased
mortality in patients
with ↓ EF except
dihydropyridine which
can be used as a BP
control adjunct if other
treatment maximized
Na restriction
• Goal: <2 G Na per day X X
• Refer to nutrionist,
compliance very
difficult
ACE Inhibitors/ARB
• Goal: Highest dose
tolerated by BP, RF but
most benefit in low dose
range
• Contraindications: Cr Consider Consider
>3.0, history of in in
X X
angioedema, prior selected selected
episode of ARF with patients patients
199
drug, or pregnancy
• Caution: known bilateral
RAS, SBP <80 mm Hg,
acute renal failure, K
>5.5 meq/L
Beta-blockers
• Metoprolol succinate or
carvedilol best studied
• Goal: Highest dose Consider X X
tolerated by BP, HR, in
side effect selected
patients
• Caution: HR <60,
symptomatic
hypotension, low output
state, heart block,
reactive airway disease
especially with a
significant reversible
component
Hydralazine/Nitrates
• Alternative to ACE-I or
ARB
• May have value as Consider X X
adjunct to ACE-I/ARB in
200
selected
patients
• Goal: Highest doses
tolerated by BP, sx
• Contraindications: Use
of PDE-5 inhibitors (e.g.,
Viagra)
Aldosterone antagonists
• Consider as adjunct to
ACE-I/ARB
• Goal: Spironolactone 25 X X
mg or eplerenone 50 mg
qd
• Caution: Renal failure,
hyperkalemia
Loop diuretics
• Cornerstone of volume,
sx management X X
• Bumetanide or
torsemide an alternative
to furosemide if concern
for bowel edema
201
Digoxin
• Consider as adjunct if
first-line therapy
insufficient
• Goal: low dose (≤0.125 Consider Consider
mg daily, ideally to level in select in
0.5-0.8 ng/ml patients selected
patients
• Contraindicated with
significant renal failure
Nesiritide
• Comparable to
combined diuretics +
NTG
• Goal: 0.01-0.03 Consider Consider
mcg/kg/min +/- 2 in in
mcg/kg bolus selected selected
patients patients
• Caution: Hypotension,
active ischemia
P.141
Heart Failure with a Normal EF and No Valvular Disease

(Diastolic Dysfunction)
202
Not nearly as well studied and the jury is still out on optimal treatment.
Rate Control
 Attractive physiologically though yet unproven to alter end points clinically
 Carvedilol shown in one study to improve hemodynamics in diastolic HF37

 No hard end points studied
ACE-I
 Results from an analysis of the HOPE study suggests ACE-Is have beneficial effects on structure
and function in patients with diastolic dysfunction and normal BP38
ARB
 See CHARM-Preserved below
P.142
Spironolactone
 Recent study suggests spironolactone improves hemodynamics in isolated diastolic HF, 39 though
no hard end-point data yet

See Table 9-3.
P.143
P.144
TABLE 9-3 Landmark clinical trials related to heart failure
203
Drug Trial and design Results
Digoxin DIG Trial - NEJM, 199731 6,800 pts 22% RRR of hospitalization NNT =
- EF <45% in NSR Digoxin 0.25 13
mg/d vs. placebo
No sig diff in all-cause mortality
Digoxin level and outcomes in Dig level of 0.5-0.8 ng/mL:
DIG Trial - JAMA, 2003 Post hoc

32
analysis stratified by dig level

28% RRR of death NNT = 16
Nitrates + V-HeFT I - NEJM, 198616 642 men - Mortality same in prazosin vs.
hydralazine NYHA 2-4 Hydralazine 300 mg/d + placebo
isosorbide dinitrate 160 mg/d vs.
prazosin 20 mg/d vs. placebo

34% RRR of death at 2, 3 y with
H/N NNT = 11 at 2 y, 9 at 3 y
A-HeFT - NEJM, 200418 1,050 pts - Stopped early due to mortality
NYHA 3-4 on “standard therapy” benefit
including ACE-I, ARB, or B-
blockers x >3 mo 37.5-225 mg

40% RRR all-cause death NNT = 25
hydralazine + 20-120 mg
isosorbide dinitrate vs. placebo

33% RRR of first CHF admit NNT =
13
Angiotensin- CONSENSUS - NEJM, 198713 253 27% RRR of death at 1 y NNT = 7
Converting- pts - NYHA class IV Enalapril 2.5-
Enzyme 40 mg/d vs. placebo
Inhibitors
SOLVD - NEJM, 199114 2,569 pts - 16% RRR of all-cause death NNT =
EF <35%, NYHA 2-3 Enalapril 2.5- 25
204
20 mg/d vs. placebo 26% RRR of death/CHF admit NNT
= 10
SOLVD - NEJM, 199212 4,228 pts - No mortality benefit
EF <35%, NYHA 1 Enalapril 2.5-20
mg/d vs. placebo

RRR 37% of developing CHF NNT =
10
V-HeFT II - NEJM, 199117 804 men 28% RRR of death at 2 y NNT = 25
- NYHA 2-3 on dig/diuretics
Enalapril 20 mg/d vs. hydralazine

Difference mostly in sudden death
300 mg/d + isosorbide dinitrate
in pts with less severe sx
160 mg/d
Angiotensin ELITE - Lancet, 199740 722 pts - EF 8% ARR of d/c meds due to side
Receptor <40%, NYHA 2-4 Losartan 50 mg/d effects
Blockers vs. captopril 150 mg/d
RRR 46% all-cause mortality NNT =
25 (unexpected result!)
ELITE II - Lancet, 200041 3,152 pts No difference in all-cause
- EF <40%, NYHA 2-4 Losartan 50 mortality
mg/d vs. captopril 150 mg/d
5% ARR of med d/c due to side
effects
CHARM-Overall - Lancet, 200342 No difference in all-cause death
7,601 pts - NYHA 2-4 x at least 4
weeks Candesartan 4-32 mg/d vs.

18% RRR of CV death/admit NNT =
placebo
23
CHARM-Added - Lancet, 200343 No difference in all-cause death
205
2,548 pts - EF <40%, NYHA 2-4, 15% RRR of CV death/admit NNT =
already on ACE-inhibitor 23
Candesartan 4-32 mg/d vs.
placebo
CHARM-Alternative - Lancet, 13% RRR of death NNT = 33
2003 2,028 pts - EF <40%, NYHA

15
2-4, intolerant of ACE-inhibitor

30% RRR for CV death/admit NNT =
Candesartan 4-32 mg/d vs.
14
placebo
CHARM-Preserved - Lancet, RRR of all-cause death
200344 3,023 pts - EF >40%, NYHA nonsignificant
2-4 Candesartan 4-32 mg/d vs.
placebo
16% RRR of admit for CHF NNT =
41
VALHeFT - NEJM, 200145 5,010 pts No difference in all-cause death
- EF <40%, NYHA 2-4 on either
diuretics, ACE-I, dig, B-blockers,

13% RRR of death, cardiac arrest
or combo Valsartan 160 mg bid vs.
with resuscitation, CHF admit or
placebo
output IV tx NNT = 30
Subgroup suggests RR of death 1.4
in pts on ACE-I and B-blockers
Aldosterone RALES - NEJM, 199927 1,663 pts - Stopped early due to mortality
antagonists EF <35%, NYHA III-IV, on diuretics benefit
(100%) and ACE-I (95%)
Spironolactone 25-50 mg/d vs.

placebo
10% men had gynecomastia/breast
206
pain
EPHESUS - NEJM, 200330 6,632 pts 15% RRR of death NNT = 44
- EF <40% 3-14 d post-AMI, NYHA
3-4 most on ACE-I (86%)

Effect seen mostly in sudden death
Eplerenone 25-50 mg/d vs.
0.5% men had gynecomastia Death
placebo
in placebo arm lower than RALES
(16.6% vs. 46%), EF higher (33% vs.
25%)
Beta-Blockers CIBIS - Circulation, 199419 641 pts All-cause mortality not stat
- EF <40%, NYHA 3 (95%)-4 (5%) on significant
vasodilator and diuretic Bisoprolol
1.25-5 mg/d vs. placebo

31% RRR of all CHF events NNT = 6
40% RR of NYHA improvement NNT
= 20
55% RRR of death in pts with
idiopathic dilated cardiomyopathy
NNT = 9
CIBIS II - Lancet, 199920 2,647 pts - Stopped early due to mortality
EF <35%, NYHA 3-4, on diuretics, benefit
ACE-inhibitors Bisoprolol 1.25-10
mg/d vs. placebo

44% RRR of sudden death NNT = 37
US Carvedilol Study - NEJM, Stopped early due to mortality
199621 1,094 pts - EF <35%, NYHA benefit 65% RRR of death NNT =
2-4 on diuretics and ACE-I 22
207
Carvedilol 6.25-25 mg bid vs. 27% RRR of CV admit NNT = 18
placebo
MERIT-HF Lancet, 199923 3,391 pts Stopped early due to mortality
- NYHA 2-4 on diuretics, ACE-I benefit
Metoprolol XL 12.5-200 mg/d vs.
placebo
33% RRR of death NNT = 26 / pt y
49% RRR of death of CHF NNT = 38
41% RRR of sudden death NNT = 71
BEST - NEJM, 200124 2,708 pts - EF No overall mortality benefit
<35% NYHA 3-4 Bucindolol 3-100
mg bid vs. placebo

14% RRR of CV death NNT = 25
COPERNICUS - NEJM, 200122 2,289 33% RRR of death NNT = 18
pts - EF <25% NYHA 3-4 Carvedilol
3.125-25 mg bid vs. placebo

24% RRR of death or admit NNT =
13
COMET - Lancet, 200325 3,029 pts - 17% RRR of death NNT = 17
EF <35%, NYHA II-IV, on diuretics +
ACE-I unless not tolerated

1 y mortality in both arms higher
Carvedilol 3.125-25 mg bid vs.
than in MERIT-HF, CIBIS-II - Used
metoprolol tartrate 5-50 mg bid
lower doses of metoprolol than
MERIT-HF
Nesiritide VMAC - JAMA, 200233 489 pts - At 3 hrs: PCWP -5.8 vs -3.8 vs -2
acute decompensated CHF, NYHA
4 Nesiritide 2 mcg/kg bolus then

SOB improved vs placebo, not vs
208
0.01-0.03 mcg/kg/min vs NTG gtt NTG
vs placebo gtt
At 24 hrs: PCWP -8.2 vs -6.3 NTG
SOB same as with NTG
Global clinical status not sig
different
RR, relative risk; RRR, relative risk reduction; ARR, absolute risk reduction; NNT, number needed
to treat = 1/ARR
P.145
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4. Stevenson LW, Perloff JK. The limited reliability of physical signs for estimating hemodynamics in
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Alternative trial. Lancet. 2003;362:772.
16. Cohn JN, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure.
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17. Cohn JN, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of
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18. Taylor AL, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N
Engl J Med. 2004;351:2049-2057.
19. CIBIS Investigators. A randomized trial of beta-blockade in heart failure: The Cardiac Insufficiency
Bisoprolol Study (CIBIS). Circulation. 1994;90:1765-1773.
20. CIBIS-II Investigators. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): A randomized trial.
Lancet. 1999;353:9-13.
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morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349-1355.
22. Packer M,et al., for the Carvedilol Prospective Randomized Cumulative Survival Study Group
(COPERNICUS).Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med.
2001;344:1651-1658.
23. Goldstein S, et al. Metoprolol controlled release/extended release in patients with severe heart
failure. Analysis of the experience in the MERIT-HF study. J Am Coll Cardiol. 2001;38:932.
24. The BEST Trial Investigators. A trial of the beta-blocker bucindolol in patients with advanced
chronic heart failure. N Engl J Med. 2001;344:1659-1667.
25. Poole-Wilson PA, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients
with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET):Randomised
controlled trial. Lancet. 2003;362:7-13.
26. Bakris GL, et al. Metabolic effects of carvedilol vs. metoprolol in patients with type 2 diabetes
mellitus and hypertension. JAMA. 2004;292:2227-2236.
27. Pitt B, Zannad F, Remme WJ, et al., for The Randomized Aldactone Evaluation Study (RALES)
Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart
failure. N Engl J Med. 1999;341:709.
28. Shah KB, et al. The adequacy of laboratory monitoring in patients treated with spironolactone for
congestive heart failure. J Am Coll Cardiol. 2005;46:845-849.
29. Juurlink DN, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation
Study. N Engl J Med. 2004;351:543-551.
30. Neaton J. et al., for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and
Survival Study (EPHESUS) Investigators. Eplerenone, a selective aldosterone blocker, in patients with
left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.
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31. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with
heart failure. N Engl J Med. 1997;336:525.
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32. Rathore SS, Curtis JP, Wang Y, et al. Association of serum digoxin concentration and outcomes in
patients with heart failure. JAMA. 2003;289:871.
33. Publication Committee for the Vasodilation in the Management of Acute CHF (VMAC) Investigators.
Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: A
randomized controlled trial. JAMA. 2002;287:1531-1540.
34. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the
treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med.
2000;343:246.
35. Burger AJ, Elkayam U, Neibaur MT, et al. Comparison of the occurrence of ventricular arrhythmias
in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide
therapy. Am J Cardiol. 2001;88:35.
36. Hunt SA, et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart
Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and
Management of Heart Failure). Circulation. 2005;112:e154.
37. Palazzuoli A, Carrera A, Calabria P, et al. Effects of carvedilol therapy on restrictive diastolic filling
pattern in chronic heart failure. Am Heart J. 2004 Jan;147(1):E2.
38. Lonn E, et al. Effects of ramipril on left ventricular mass and function in cardiovascular patients
with controlled blood pressure and with preserved left ventricular ejection fraction: A substudy of the
Heart Outcomes Prevention Evaluation (HOPE)Trial. J Am Coll Cardiol. 2004 Jun 16;43(12):2200-2206.
39. Mottram PM,et al. Effect of aldosterone antagonism on myocardial dysfunction in hypertensive
patients with diastolic heart failure. Circulation. 2004 Aug 3;110(5):558-565.
40. Pitt B, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure
(Evaluation of Losartan in the Elderly Study, ELITE). Lancet. 1997;349:747-752.
41. Pitt B, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic
heart failure: Randomized trial—the Losartan Heart Failure Survival Study ELITE II. Lancet.
2000;355:1582-1587.
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42. Pfeffer MA, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart
failure: The CHARM-Overall programme. Lancet. 2003;362:759-766.
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43. McMurray JJV, et al. Effects of candesartan in patients with chronic heart failure and reduced left-
ventricular systolic function taking angiotension-converting enzyme inhibitors: The CHARM-Added trial.
Lancet. 2003;362:767-771.
44. Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-
ventricular ejection fraction: The CHARM-preserved trial. Lancet. 2003;362:777-781.
45. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial (ValHeFT) Investigators. A Randomized
trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med.
2001;345:1667-1675.
16. CHAPTER 10 - Pulmonary Hypertension

CHAPTER 10
Pulmonary Hypertension
François Haddad
Ramona L. Doyle
Juliana C. Liu
Roham T. Zamanian
BACKGROUND
Pulmonary hypertension (PH) refers to a state in which pulmonary artery pressure is elevated. By expert
consensus, PH is defined as a mean pulmonary arterial pressure (mPAP) greater than 25 mm Hg at rest
or greater than 30 mm Hg with exercise as measured by right heart catheterization. 1 Pulmonary arterial
hypertension (PAH) refers to disease states that localize to small pulmonary muscular arterioles. It is
characterized as PH in the presence of (a) a pulmonary capillary wedge pressure (PCWP) <15 mm Hg,
(b) pulmonary vascular resistance (PVR) >240 dynes/s/cm5 (3 Wood units), and (c) a transpulmonary
gradient >10 mm Hg (mPAP-PCWP).2
GRADING THE SEVERITY OF PH
213
The severity of PH may be described in terms of pulmonary arterial pressure (Table 10-1), pulmonary
vascular resistance or impedance, or pulmonary pathological vascular changes (Heath-Edwards
classification [Table 10-2]). When assessing the severity of PH using levels of pulmonary arterial
pressure, it is important to always consider cardiac output (CO). In fact, lower pulmonary arterial
pressure may reflect a failing right ventricle and more advanced pulmonary vascular disease. Pulmonary
vascular resistance (PVR) takes into account pulmonary pressure and flow and is measured as the
difference between mean PAP and wedge pressure divided by cardiac output (PVR = (mPAP-PCWP)/CO).
PVR is considered a better marker of pulmonary vascular disease. A normal value of PVR is 1 Wood unit
or 80 dynes/s/cm5 while PVR values higher than
P.152
10 Wood units in PAH or value of PVR higher than 6 Wood units in left heart failure are considered
severe. Pulmonary vascular histological changes of the media and intima have also been associated with
the severity and reversibility of pulmonary arterial hypertension (PAH) associated with congenital heart
disease or idiopathic PAH (Table 10-3).3
DEFINING PULMONARY VASCULAR REACTIVITY
Pulmonary vascular reactivity refers to the decrease in PAP in response to vasodilators. Several agents
are of value in assessing acute vasoreactivity including oxygen, inhaled nitric oxide (usually 20 ppm),
epoprostenol (Flolan), adenosine, or nitroprusside (especially in pre-heart transplant evaluations).
Pulmonary vascular reactivity studies provide useful prognostic information and guide the choice of
therapy in PAH, help predict the reparability of complex congenital heart disease, and help stratify the
risk of acute right failure after heart transplantation. A positive vasodilator response in PAH is defined
as a reduction of mPAP by at least 10 mm Hg to a value of 40 mm Hg or less. Significant response is
found in about 5% to 6% of PAH patients. These patients have a better response to calcium channel
blockers.2 A significant response in advanced heart disease undergoing a pretransplantation evaluation
is defined by a decrease in PVR to a value of 3 Wood units or less.
TABLE 10-1 Hemodynamic grading of PH
214
Severity Mean PA (mm Hg) Systolic PA (mm Hg) Relative PA (mm Hg)
Mild 25-35 40-50 0.33-0.50
Moderate 35-50 50-80 0.50-0.66
Severe >50 >80 >0.66
TABLE 10-2 Heath-Edwards classification of PH3
Pathologic grade Pathology
Grade I Hypertrophy of small muscular arteries and arterioles
Grade II Grade I + intimal cell proliferation
Grade III Obliterative arteriopathy
Grade IV Plexiform lesion
Grade V Complex plexiform, cavernous and angiomatous
Grade VI Necrotizing arteritis
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TABLE 10-3 Classification of pulmonary hypertension1
215
1. Pulmonary arterial hypertension (PAH)
1.1. Idiopathic (IPAH)
1.2. Familial (FPAH)
1.3. Associated with (APAH):
1.3.1. Collagen vascular disease
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension
1.3.4. HIV infection
1.3.5. Drugs and toxins
1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary
hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders,
splenectomy)
1.4. Associated with significant venous or capillary involvement
1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary hemangiomatosis (PCH)
1.5. Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension with left heart disease
216
2.1. Left-sided atrial or ventricular heart disease
2.2. Left-sided valvular heart disease
3. Pulmonary hypertension associated with lung diseases and/or hypoxemia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep-disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities
4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease
4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
5. Miscellaneous
Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy,
tumor, fibrosing mediastinitis)
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217
WHO CLASSIFICATION OF PH
The World Health Organization (WHO) classifies patients with PH into five groups based on etiology and
pathobiology. Pulmonary arterial hypertension (PAH) describes group 1 PAH; group 2 describes patients
with pulmonary venous hypertension; group 3 refers to PH associated with lung disease and/or
hypoxemia; group 4 describes PH associated with chronic thrombotic and/or embolic disease and group
5 refers to miscellaneous causes of PH.1 This revised classification provides a useful framework for the
diagnosis and management of PH patients. Modifications to this classification have been made at the
latest WHO meeting in 2008. Formal publication of the classifications is still pending.
PATHOPHYSIOLOGY OF PH
Multiple molecular pathways have been implicated in the pathogenesis of PAH. These include nitric
oxide, prostacyclin, endothelin-1, and serotonin pathways.A dysfunction in these pathways can lead to
an imbalance between vasodilatation and vasoconstriction,and between apoptosis and proliferation,
which leads to progressive vascular disease. In patients with pulmonary venous hypertension, PH can be
explained by left ventricular diastolic failure, left-sided valvular heart disease, or pulmonary vein
stenosis. In patients with lung disease, PH can be explained by hypoxemic vasoconstriction and/or by
the loss of pulmonary vascular bed. In chronic thromboembolic PH (CTEPH), in situ thrombosis and/or
failure of resolution of thromboemboli contribute to disease progression. The development of
pulmonary hypertensive arteriopathy in unobstructive lung regions as well as in vessels distal to
partially occluded proximal pulmonary arteries also contributes to the pathophysiology of CTEPH.
One of the most important consequences of PH is right ventricular (RV) failure. Survival in PH is closely
related to RV failure. RV adaptation to disease depends on the time of onset of PH (congenital or
acquired), setting (acute versus chronic), and specific cause of PH. Hypoxemia can be seen in PH as a
result of right-to-left shunting through a patent foramen ovale or congenital defect, ventilation-
perfusion mismatches, or decreased diffusion capacity. Hemoptysis, although rare, can be associated
with significant morbidity and mortality. Hemoptysis may originate from a rupture of a bronchial artery
or pulmonary trunk.
Most patients initially experience exertional dyspnea and fatigue, which reflects low cardiac output
during exercise (low exercise reserve). As the PH progresses and RV failure develops, peripheral edema,
exertional syncope, exertional chest pain, and passive liver congestion may occur. Less common
symptoms of PH include cough, hemoptysis, and hoarseness (Ortner
P.155
218
syndrome, which is due to compression of the left recurrent laryngeal nerve by a dilated main
pulmonary artery). Other symptoms may also reflect the specific underlying cause.
Signs of RV failure are commonly found in patients with advanced PH; these include elevated jugular
veins, distended liver, peripheral edema, and occasionally ascites. An increased intensity of the
pulmonic component of the second heart sound is an initial physical finding in PH. Other signs include a
right-sided S3 gallop, a holosystolic parasternal murmur of tricuspid regurgitation, and in more severe
disease, a diastolic pulmonic regurgitation murmur.The right-sided murmurs and gallops are augmented
with inspiration.4
LAB EXAMS AND IMAGING
A comprehensive workup is necessary in order to confirm the presence of PH, assess its severity and
identify its cause.1,2,5 Echocardiography is very helpful in estimating pulmonary artery pressure and
assessing RV function. Signs of RV pressure overload may include D-shape left ventricle, tricuspid
regurgitation, decreased systolic performance, and RV hypertrophy (>5 mm wall thickness). Right heart
catheterization (RHC) is the most reliable method for measuring pulmonary arterial pressure,
pulmonary vascular resistance, and pulmonary vascular reactivity. RHC is often obtained to confirm the
diagnosis, assess pulmonary vascular reactivity, and evaluate the response to therapy.
Electrocardiography may reveal signs of RV or right atrial dilatation, right bundle branch block, or
arrhythmias. A comprehensive laboratory workup includes complete blood count, a comprehensive
metabolic panel, B-type natriuretic peptide (BNP), troponins, collagen vascular disease workup,
assessment for hypercoagulable states, hepatic serologies, and HIV screening. Functional studies such
as 6-minute walk test or cardiopulmonary exercise test are important for the assessment of functional
capacity and response to therapy. The diagnostic evaluation may also include a pulmonary function
test, a sleep study, chest x-ray, ventilation-perfusion scanning, and/or CT-angiography. Magnetic
resonance imaging is useful in studying RV function and in modeling pulmonary circulation.
HISTORY OF PH AND PROGNOSTIC FACTORS
Untreated idiopathic PAH (IPAH) is associated with a very poor prognosis with a 5-year survival rate of
34% according to the NIH registry.6 PH is also recognized to be a bad prognostic factor in heart failure,
valvular heart disease, pulmonary disease, and in systemic diseases such as scleroderma. 7 In PAH,
factors associated with poor outcome include (a) low exercise capacity (NYHA: IV, 6 Minute Walk
Distance <300m [984 feet]); (b) markers of severe RV dysfunction including high right atrial
P.156
pressure (RAP >15 mm Hg), low cardiac index, significant RV dysfunction, elevated BNP, and troponins;
219
(c) rapid progression; (d) pericardial effusion; (e) poor response to prostacyclin therapy (persistence of
NYHA III or IV); and (f) persistent supraventricular arrhythmias or sudden death. 2,8 In chronic
thromboembolic PH, patients who are not considered suitable for pulmonary endarterectomy are
considered at higher risk of mortality.9
MANAGEMENT OF PH
The management of pulmonary hypertension should be tailored to its cause, hemodynamic consequence
(degree of RV failure), and vascular reactivity. Patients with significant PH should follow a low sodium
diet (<2 grams of sodium), participate in graded physical activity, and avoid isometric activities such as
weight lifting as well as medications that can exacerbate heart failure such as nonsteroidal anti-
inflammatory medication. Pregnancy is also not advisable as maternal and fetal mortality can exceed
50%.
This revised WHO classification provides a useful framework for the management of PH patients.
Patients with PAH (WHO class I) may benefit from prostanoid therapy (epoprostenol, treprostinil,
iloprost), phosphodiesterase inhibitors (sildenafil), or an endothelin receptor antagonist (bosentan,
ambrisentan). Anticoagulation with a goal INR between 1.5 to 2.5 is also recommended. 10 The minimal
dose of diuretics is used to prevent fluid retention. The role of cardiac glycoside in pulmonary
hypertension is controversial with only one study showing short-term hemodynamic benefits. The value
of beta-blockade, angiotensin converting enzyme inhibitors, and spironolactone in chronic RV failure
associated with PH has not been comprehensively studied. In patients presenting with acute
decompensation, inhaled nitric oxide and vasopressor/inotropic support (usually with dobutamine 2 to 5
µg/kg/min) may be required (Figure 10-1 and Table 10-4). Atrial septostomy should only be considered
a palliative procedure in refractory patients. Double-lung or heart-lung transplantation should be

considered in selected patients.
In patients with pulmonary venous hypertension (WHO class II), optimization of left-sided heart failure
and valvular disease management is the most important component of therapy. Small studies also
suggest that sildenafil may be beneficial in selected patients with pulmonary hypertension.11 In patients
with PH secondary to lung disease and/or hypoxemia (WHO class III), primary therapy consists of oxygen
therapy and ventilatory support (CPAP, BIPAP) as required. These patients usually do not benefit from
treatment with pulmonary vasodilators. In patients with chronic thromboembolic disease (WHO class
IV), therapy consists of anticoagulation and careful evaluation for candidacy for pulmonary
endarterectomy.
P.157
220
FIGURE 10-1 Algorithm for the management of PAH. Please refer to text for the definition of pulmonary
reactivity and the description of higher risk patients. ETRA indicates endothelin receptor inhibitors;
PDE-5, phosphodiesterase 5; CCB, calcium channel blockers.Prostanoid therapy includes intravenous
epoprostenol, intravenous or subcutaneous treprostinil, and inhaled iloprost.(Adapted from McLaughlin
VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006 September 26;114[13]:1417-1431.)
P.158
TABLE 10-4 Characteristics of agents used in the treatment of PAH1,2,4
221
Group Studied Dose and
Agent and Evidence Effects Characteristics Significant Side Effects
Prostanoids
Epoprostenol PAH 1. ↑ 6MWT Continuous Jaw pain
IV
(Flolan) NYHA III-IV 2. Better Initiate: 1 Hypotension
HD ng/kg/min
Randomiz 3. ↑ Usual: 30- May ↑ V/Q

ed Survival 40
ng/kg/min
PC trials (historical Half-life: 6 mismatch
12 weeks control) min Catheter sepsis,
thrombosis
Rebound PH if
D/C
Thrombocytopen
ia
Treprostinil PAH 1. ↑ 6MWT SQ or IV Same as above
except less
rebound PH
(Remodulin) NYHA III-IV 2. Better Initiate: 1
Possible ↑
HD ng/kg/min
incidence Gram -
catheter sepsis
Randomiz Usual: 40-
Site pain with SQ
ed 60
form
ng/kg/min
PC trials Half-life 3-
222
12 weeks 4h
Iloprost PAH NYHA ↑ in Inhalation Compliance
(Ventavis) III-IV composite (USA) 2.5-5 difficult
Randomiz end point µg/inhalati Variation PAP
ed PC of on 6 to 9
trials 12 improveme inhalations
weeks nt ↑ 6MWT /d
Endothelin
receptor
blockers
Bosentan PAH 1. ↑ 6MWT 125 mg po Teratogenic ↑
(nonselective) (Group 1) bid Liver enzymes
NYHA III-IV (10%)
Randomiz
2. Better
ed PC
HD
trials; 12
weeks
Ambrisentan Under 1. ↑ 6MWT To be Teratogenic ↑
(selective) review by determined Liver enzymes
FDA 06/07 (3%)
2. Better
HD
Phosphodiester
ase inhibitors
Sildenafil PAH NYHA 1. ↑ 6MWT 20 mg po Hypotension
II-III tid Headache NAION
223
Randomiz 2. Better (<1%) CI with
ed PC HD nitrates
trials
Calcium PAH- 1. ↑ Higher Hypotension
channel vasoreacti Survival in doses Non-
blockers ve (<5%) responders Nifedipine dihydropyridine
Prospectiv &thkap; → negative
e trials 180 mg po inotropy
daily
2. Better
HD
3. ↑ QL life
Inhaled nitric PH Better HD, 20 ppm Methemoglobine
oxide Prospectiv oxygenatio mia Rebound PH
e studies n
PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; PC, placebo
controlled; 6MWT, 6-minute walk test; HD, hemodynamic; NYHA, New York Heart
Association Functional Class; NAION, nonarteritic anterior ischemic optic neuropathy
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See Table 10-5.
P.160
224
TABLE 10-5 Summary of selected studies in pulmonary arterial hypertension
Medication Study Population n Outcome
Prostacyclin The Primary PH IPAH NYHA III-IV 81 1. ↑ 6MWT by 31
(epoprostenol) Study Group12 meters (60
continuous Randomized, 12 meters
intravenous weeks comparative) in
the prostacyclin
group
2. HD
improvement
3. Survival
benefit
Badesch et al.13 Scleroderma 113 1. ↑ 6MWT by 63
Randomized, 12 spectrum of meters (99
weeks disease meters
comparative) in
the prostacyclin
group
2. HD
improvement
3. No survival
benefit
Sitbon et al.14 IPAH 178 Survival benefit
Observational compared to the
long term historical control
225
McLaughlin et IPAH 162 Survival benefit
al. 15
compared to the
Observational historical control
long term
Rosenweig et CHD 20 Improvement in
al. 16
HD and exercise
Observational capacity (NYHA)
Treprostinil Subcutaneous PAH NYHA II-IV 470 1. Modest ↑
Subcutaneous Simonneau et 6MWT by 16
intravenous al. Randomized

17
meters
12 weeks
2. Dose-related
improvement
Intravenous PAH III-IV 16 1. ↑ 6MWT by 82
Tapson et al. 18
meters
Open-label
prospective 12
2. Improvement
weeks
in HD
Intravenous PAH NYHA II-III 31 27 pts completed
Gomberg- Transition Study the transition and
Maitland et al.19 4 were
Open-label transitioned back
to epoprostenol
Iloprost Inhaled Olschewski et IPAH PAH-CTD 207 Improvement in
(6-9 times daily) al.20 PAH-stim. CTEPH composite end
Randomized, 12 (inoperable) point of clinical
weeks NYHA III-IV improvement
226
Beraprost (not Galie et al.21 PAH NYHA II-III 130 1. ↑ 6MWT by 82
FDA approved) Randomized, 12 meters
weeks
2. No
improvement in
HD
Barst et al.22 PAH NYHA II-III 116 No significant
Randomized 1 improvement in
year 6MWT at 9 and 12
meters
Bosentan BREATHE-15 IPAH PAH- CTD 213 1. ↑ 6MWT by 36
(endothelin Randomized trial NYHA III-IV meters (44
receptor blocker) 12 weeks meters
comparative)
2. Improvement
in time to clinical
worsening
McLaughlin et IPAH PAH- CTD 169 First-line
al. 23
NYHA III-IV bosentan ↑
Observational survival
Long term compared to NIH
historical control
BREATHE-524 CHD- 54 1. ↑ 6MWT by 53
Randomized 16 Eisenmenger meters
weeks syndrome
2. HD
improvement
227
3. No
compromise
peripheral oxygen
saturation
Sitaxsentan (ETA STRIDE-125 PAH- 178 1. ↑ Maximum VO2
selective Randomized 12 IPAH,CTD,CHD 3.1%, sitaxsentan
antagonist) (not weeks NYHA II-IV 300 mg, but
FDA approved) unchanged 100
mg group
2. ↑ 6MWT
SRIDE-226 PAH- 247 1. ↑ 6MWT by 31
Randomized 18 IPAH,CTD,CHD meters (100 mg
weeks dose)
Ambrisentan Galie et al.27 PAH 64 1. ↑ 6MWT by 36
Randomized 12 meters
weeks
2. HD
improvement
Sildenafil SUPER28 PAH-IPAH,CTD, 278 1. ↑ 6MWT by 45
Randomized 12 repaired CHD meters placebo-
weeks corrected
treatment effect
2. HD
improvement
P.161
228
REFERENCES
1. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll
Cardiol. 2004 June 16;43 (12 Suppl S):5S-12S.
2. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006 September
26;114(13):1417-1431.
3. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease; a description of six
grades of structural changes in the pulmonary arteries with special reference to congenital cardiac
septal defects. Circulation. 1958 October;18 (4 Part 1):533-547.
4. Rubin JR, Hopkins W. Overview of pulmonary hypertension. In: Rose BD, ed. Up to Date. Waltham,
MA: 2007.
5. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J
Med. 2002 March 21;346(12):896-903.
6. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension.
Results from a national prospective registry. Ann Intern Med. 1991 September 1;115(5):343-349.
7. Haddad F, Doyle RL, Murphy DJ, et al. Right Ventricular Function in Cardiovascular Disease, Part II
Pathophysiology, clinical importance and management of RV failure. Circulation. 2007. In press.
8. Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricular
tachyarrhythmias in pulmonary hypertension. Am Heart J. 2007 January;153(1): 127-132.
P.162
9. Hoeper MM, Mayer E, Simonneau G, et al. Chronic thromboembolic pulmonary hypertension.
Circulation. 2006 April 25;113(16):2011-2020.
10. McLaughlin VV, Rich S. Pulmonary hypertension. Curr Probl Cardiol. 2004 October;29(10):575-634.
11. Lewis GD, Lachmann J, Camuso J, et al. Sildenafil improves exercise hemodynamics and oxygen
uptake in patients with systolic heart failure. Circulation. 2007 January 2;115(1):59-66.
12. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol
(prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary
Hypertension Study Group. N Engl J Med. 1996 February 1;334(5):296-302.
229
13. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary
hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern
Med. 2000 March 21;132(6):425-434.
14. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary
pulmonary hypertension: Prognostic factors and survival. J Am Coll Cardiol. 2002 August 21;40(4):780-
788.
15. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension:The impact of
epoprostenol therapy. Circulation. 2002 September 17;106(12):1477-1482.
16. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with
associated congenital heart defects. Circulation. 1999 April 13;99(14):1858-1865.
17. Simonneau G, Barst RJ, Galie N, et al. Continuous subcutaneous infusion of treprostinil, a
prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized,
placebo-controlled trial. Am J Respir Crit Care Med. 2002 March 15;165(6):800-804.
18. Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al. Safety and efficacy of IV treprostinil for
pulmonary arterial hypertension: A prospective, multicenter, open-label, 12-week trial. Chest. 2006
March;129(3):683-688.
19. Gomberg-Maitland M, Tapson VF, Benza RL, et al. Transition from intravenous epoprostenol to
intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med. 2005 December
15;172(12):1586-1589.
20. Olschewski H, Simonneau G, Galie N, et al. Inhaled iloprost for severe pulmonary hypertension. N
Engl J Med. 2002 August 1;347(5):322-329.
21. Galie N, Humbert M, Vachiery JL, et al. Effects of beraprost sodium, an oral prostacyclin analogue,
in patients with pulmonary arterial hypertension: A randomized, double-blind, placebo-controlled trial.
J Am Coll Cardiol. 2002 May 1;39(9):1496-1502.
P.163
22. Barst RJ, McGoon M, McLaughlin V, et al. Beraprost therapy for pulmonary arterial hypertension. J
Am Coll Cardiol. 2003 June 18;41(12):2119-2125.
23. McLaughlin VV, Sitbon O, Badesch DB, et al. Survival with first-line bosentan in patients with
primary pulmonary hypertension. Eur Respir J. 2005 February;25(2):244-249.
230
24. Galie N, Beghetti M, Gatzoulis MA, et al. Bosentan therapy in patients with Eisenmenger syndrome:
A multicenter, double-blind, randomized, placebo-controlled study. Circulation. 2006 July 4;114(1):48-
54.
25. Barst RJ, Langleben D, Frost A, et al. Sitaxsentan therapy for pulmonary arterial hypertension. Am J
Respir Crit Care Med. 2004 February 15;169(4):441-447.
26. Barst RJ, Langleben D, Badesch D, et al. Treatment of pulmonary arterial hypertension with the
selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006 May 16;47(10):2049-
2056.
27. Galie N, BadeschD,Oudiz R, et al.Ambrisentan therapy for pulmonary arterial hypertension. J Am
Coll Cardiol. 2005 August 2;46(3):529-535.
28. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial
hypertension. N Engl J Med. 2005 November 17;353(20):2148-2157.
17. CHAPTER 11 - Transplant Medicine

CHAPTER 11
Transplant Medicine
Michael Pham
BACKGROUND
The first human heart transplant was performed in South Africa in 1967, followed by the first U.S.
procedure in 1968 by Dr. Norman Shumway at Stanford University. Over 4,000 heart transplants are
performed worldwide each year; the number of procedures is currently limited by the availability of
organ donors. Survival rates are 81%, 74%, 68%, and 50% at 1, 3, 5, and 10 years. 1
INDICATIONS FOR TRANSPLANTATION
 Systolic heart failure with severe functional limitation and/or refractory symptoms despite
maximal medical therapy
o Left ventricular ejection fraction (LVEF) usually <35%, but a low LVEF is not an
adequate indication for transplantation
o NYHA Functional Class III-IV
o Maximum oxygen uptake (VO2 max) of > 12 to 14 cc/kg/min on exercise testing
 Cardiogenic shock not expected to recover
o Acute myocardial infarction
o Myocarditis
231
 Ischemic heart disease with intractable angina
o Not amenable to surgical or percutaneous revascularization
o Refractory to maximal medical therapy
 Intractable ventricular arrhythmias, uncontrolled with antiarrhythmic medications, ICD
therapy, and/or ablation
 Severe symptomatic hypertrophic or restrictive cardiomyopathy
 Congenital heart disease

 Cardiac tumors with low likelihood of metastasis
P.166
CONTRAINDICATIONS
 Irreversible severe pulmonary arterial hypertension: Considered an absolute contraindication
by most programs
o Pulmonary vascular resistance (PVR) >4 to 5 Wood units
o Pulmonary vascular resistance index (PVRI) >6
o Transpulmonary gradient (mean PA - PCWP) >16 to 20 mm Hg
o PA systolic pressure >50 to 60 mm Hg or >50% of systemic pressures
 Advanced age: Many programs are moving away from “absolute” age limits and considering
rehabilitation potential, end-organ function, and presence of comorbid conditions when
evaluating older patients. Some programs still have an age cutoff between 65 and 70 years of
age.
 Active systemic infection: Patients can typically be listed after the infection has been
identified and adequately treated (i.e., absence of fever, leukocytosis, and bacteremia).
 Active malignancy or recent malignancy with high risk of recurrence. Exceptions include
nonmelanoma skin cancers, primary cardiac tumors restricted to the heart, and low-grade
prostate cancers. Consultation with an oncologist is recommended.
 Diabetes mellitus with either poor glycemic control (variable definitions, but usually HbA1c
>7.5) or end-organ damage (neuropathy, nephropathy, and proliferative retinopathy)
 Marked obesity (body mass index [BMI] >30 kg/m2 or >140% of ideal body weight). Most
programs will have variable cutoffs for BMI.
 Severe peripheral arterial disease not amenable to revascularization
 Systemic process with high probability of recurrence in the transplanted heart
o Amyloidosis
o Sarcoidosis
o Hemochromatosis
232
 Irreversible severe renal, hepatic, or pulmonary disease. Occasional combined heart/kidney,
heart/lung, or heart/liver transplants are done at selected centers.
 Recent or unresolved pulmonary infarction due to the high probability of progression into
pulmonary abscesses after initiating immunosuppression
 Psychosocial factors that may impact on patient's ability to receive posttransplant care
o History of poor compliance with medications or follow-up appointments
o Lack of adequate support system
o Uncontrolled psychiatric illness

o Active or recent substance abuse (alcohol, tobacco, or illicit drugs)
P.167
PRETRANSPLANT EVALUATION
History
 Does patient meet indications for transplantation?
 Has adequate medical, device, and/or surgical therapy been attempted?

 Does patient have significant contra-indications to transplantation?
Psychosocial Evaluation
 Assess patient's understanding of transplant procedure and willingness to undergo lifelong
immunosuppression and follow-up
 Assess adequacy of social support system
 Assess for uncontrolled psychiatric illness or active/recent substance abuse that may impact
posttransplant care.
Lab Exams and Imaging
 Blood tests: Complete blood count, electrolytes, renal and hepatic function, ABO typing;
human leukocyte antigens (HLA) antibody screen against panel of common antigens (PRA);
hepatitis, syphilis, and HIV serologies
 Chest x-ray
 Electrocardiogram
 Echocardiogram
 Coronary angiography (or review most recent study) if known coronary artery disease (CAD) or
if patient has risk factors for CAD
233
 Right heart catheterization to document pulmonary artery pressures. Pharmacologic
intervention with vasodilators (intravenous nitride or inhaled nitric oxide) may be used to
document reversibility of pulmonary hypertension.
 Pulmonary function testing
 Carotid ultrasound and lower extremity ABIs
 Age and sex-appropriate cancer screening (PAP smear, mammogram, colonoscopy, prostate-
specific antigen (PSA) with DRE)
Most candidacy determinations are made after review of patient's history and workup by a
multidisciplinary Transplant Selection Committee comprising cardiologists, surgeons, social

workers, and/or psychologists.
ORGAN MATCHING AND PRIORITIZATION
 Recipient waiting list maintained by United Network of Organ Sharing (UNOS)
 Recipients and donors are matched by blood type, weight, priority status (Table 11-1), and
time accrued on waiting list.
 Prospective HLA matching between donor and recipient is typically not performed unless a
recipient has high levels of preformed antibodies (PRA >20%).
 Waiting times range from days to years and are dependent upon priority status (shortest for
1A, longest for 2), blood type (longest for blood group O), weight (longer for large recipients),
and geographic location.
P.168
TABLE 11-1 UNOS prioritization of heart transplant recipients
234
Status Criteria Location
Mechanical circulatory support, or
• ventricular assist device (VAD) (first 30 days) or total
artificial heart (TAH)
• intra-aortic balloon pump (IABP) or extracorporeal Transplant center
membrane oxygenation (ECMO)
1A Mechanical ventilation
Inotropic requirement with HD monitoring
• 1 high-dose (Dob ≥7.5, mcg/kg/min milrinone ≥0.5
mcg/kg/min)
• 2 inotropes (IV vasodilators do not count)
Exceptional provision (life expectancy <14 d)
1B • 1 inotrope, or
• VAD after 30 days Hospital or
outpatient
2 Not meeting criteria for 1A or 1B listing (stable)
7 On hold (infection, insurance, clearance too well)
SURGICAL TECHNIQUE
235
 Most donor hearts are implanted in the orthotopic position (i.e., in the same position as the
explanted heart).
 The original technique involved anastomosis of the donor heart at the level of the atria
(biatrial technique), leaving a cuff of donor atria. In recent years, the biatrial technique has
been modified to make the anastomoses at the level of the superior and inferior vena cavae
and pulmonary veins (bicaval technique). This results in less A-V valve regurgitation, decreased
incidence of atrial arrhythmias, and decreased incidence of donor sinus node dysfunction and
heart block requiring permanent pacemaker implantation.

 Ischemic times of 3 to 4 hours are preferred.
P.169
PHYSIOLOGY OF TRANSPLANTED HEART
 The transplanted heart is initially completely denervated. Cardiac denervation has several
important clinical implications:
o Patients exhibit a faster resting heart rate (usually between 95 to 110 bpm)
o Many patients will not experience angina. Typical presentations of ischemia include
congestive heart failure, myocardial infarction, or sudden death.
o Drugs that act through the autonomic nervous system (e.g., atropine) will have little
to no effect on a transplanted heart.
IMMUNOSUPPRESSION
General Principles
 The risk of rejection is highest immediately after transplantation and decreases over time.
Most rejection episodes occur during the first year; therefore, immunosuppression is highest
during this time.
 The goal of immunosuppression is to use the lowest doses of drugs to prevent rejection while
minimizing toxicities (particularly renal insufficiency) and immunosuppression-related

complications (infection and cancer).
Induction Therapy
 Currently, induction is used by 50% of transplant centers to provide a period of intense
immunosuppression in the early (first 6 months) posttransplant period, when the risk of
rejection is highest.
236
 Advantages: Decreases the incidence of rejection during the first 6 months, allows delayed
initiation of nephrotoxic immunosuppressive drugs in patients with compromised renal function
after surgery
 Disadvantages: May simply be shifting rejection to the late period (6-12 months) after
transplantation; may increase the risk of infection and malignancy
 Agents used for induction include
o Cytolytic agents are antibodies that result in near complete depletion of T-
lymphocytes (OKT3, Thymoglobulin)
o Interleukin-2 receptor antagonists are antibodies that inhibit IL-2 mediated

proliferation of activated T-lymphocytes (daclizumab, basiliximab).
Maintenance Immunosuppression
Most maintenance protocols employ a two- to three-drug regimen with no more than one agent from
each class to avoid overlapping toxicities (see Table 11-2). The dosing, target drug levels, and side
effect profile of each agent is shown in Table 11-3.
P.170
TABLE 11-2 Typical immunosuppressive regimens
Era Pre-1980s Typical CAV Renal sparing
Calcineurin Cyclosporine or Cyclosporine
inhibitor tacrolimus or tacrolimus
Antiproliferative Imuran Mycophenolate Mycophenolate
agent mofetil mofetil
mTOR inhibitor Sirolimus Sirolimus
Corticosteroids Prednisone Prednisone
(lifelong) (first 6-12 mo)
237
TABLE 11-3 Immunosuppressive agents used in heart transplantation
Drug Dosing Target Levels Major Toxicities
Calcineurin inhibitors
Cyclosporine 4-8 mg/kg/d in 0-6 Months: Renal insufficiency
two divided 250-350 ng/mL
doses, titrated
Hypertension
to keep target 6-12 Months: Dyslipidemia
12-h trough
levels
200-250 ng/mL Hypokalemia and
>12 Months: hypomagnesemia
100-200 ng/mL Hyperuricemia
Neurotoxicity
(encephalopathy, seizures,
tremors, neuropathy,
posterior reversible
encephalopathy syndrome
[PRES])
Gingival hyperplasia
Hirsutism
Tacrolimus 0.05-0.1 0-6 Months: 10- Renal dysfunction
mg/kg/d in two 14 ng/mL
divided doses,
Hypertension
238
titrated to keep 6-12 Months: 7- Hyperglycemia and diabetes
target 12-h 10 ng/mL mellitus
trough levels
>12 Months: 5- Dyslipidemia
10 ng/mL
Hyperkalemia
Hypomagnesemia
Neurotoxicity (tremors,
headaches, PRES)
Antiproliferative agents
Azathioprine 1.5-3.0 None Bone marrow suppression
mg/kg/d,
titrated to keep
Hepatitis (rare)
WBC ~3,000
Pancreatitis
Malignancy
Mycophenolate 1,000-3,000 Mycophenolic Gastrointestinal disturbances
mofetil mg/d in two acid (MPA): (nausea, diarrhea)
divided doses 2.5-4.5 µg/mL
Leukopenia
mTOR inhibitors
239
Sirolimus 1-3 mg/d, 5-10 ng/mL Oral ulcerations
titrated to keep
therapeutic 24-h
Hypercholesterolemia and
trough levels
hypertriglyceridemia
Poor wound healing
Lower extremity edema
Pneumonitis
Leukopenia, anemia, and
thrombocytopenia
Potentiation of CNI
nephrotoxicity
Corticosteroids
Prednisone 1 mg/kg/d in None Weight gain
two divided
doses, tapered
Hypertension
to 0.05 mg/kg/d
by 6-12 mo
Hyperlipidemia
Osteopenia
Hyperglycemia
Poor wound healing
240
Salt and water retention
Proximal myopathy
Cataracts
Peptic ulcer disease
Growth retardation
P.171
 Calcineurin inhibitors: Block calcineurin-dependent signal transduction, thus inhibiting IL-2
production and preventing both T- and B-cell differentiation and proliferation. They are the
cornerstone of immunosuppression in heart transplantation.
o Cyclosporine (Sandimmune, Neoral, Gengraf) was introduced in the 1980s and led to a
dramatic decrease in acute rejection and subsequent increase in life expectancy after
heart transplantation.
o Tacrolimus (Prograf) is similar in efficacy to cyclosporine but has a more favorable

metabolic profile (less hypertension and dyslipidemia)
P.172
and lacks cyclosporin-specific side effects such as hirsutism and gingival
hyperplasia.2,3 In the kidney transplant literature, use of tacrolimus is associated with
a higher incidence of posttransplant diabetes compared to cyclosporine, and a similar

trend has been noted in heart transplant patients.
 Antiproliferative agents: Block purine synthesis and inhibit proliferation of both T- and B-
lymphocytes
o Mycophenolate mofetil (CellCept) has replaced the older agent, azathioprine (Imuran)
as the preferred antiproliferative agent in recent years. 4
241
 Mammalian Target of Rapamycin (mTOR) inhibitors5,6 are a newer class of agents that block
proliferation of T-cells, B-cells, and vascular smooth muscle cells by causing cell cycle arrest
at the G1 to S phase. They are used in patients with cardiac allograft vasculopathy (CAV) due
to their antiproliferative effects on vascular smooth muscle cells and in patients with renal
insufficiency because they have no intrinsic nephrotoxic effects.
o Sirolimus (Rapamune)
o Everolimus (Certican) is used in Europe and undergoing Phase III clinical trials in the
United States.
 Glucocorticoids are nonspecific agents that are typically used in high doses in the early
posttransplant period and then tapered to low doses or discontinued altogether after the first
6 to 12 months.
DRUG INTERACTIONS
Many drugs can alter the metabolism of the immunosuppressive agents, and vice versa (Table 11-4).7
REJECTION
Even with modern immunosuppressive regimens, acute rejection is still experienced by 30% to 50% of
patients during the first year after transplantation.
Types of Rejection
 Hyperacute rejection: Very rare and may occur immediately after transplantation in the
setting of high levels of preformed antibodies to the ABO blood group (in cases of
incompatibility) or to major histocompatibility antigens in the donor.
 Acute cellular rejection (ACR): The most common form of rejection and mediated by T-
lymphocytes. It is detected by identifying lymphocytic infiltration, inflammation, and myocyte

damage on heart
P.173
biopsy samples. ACR is graded according to a standardized classification system developed by

the International Society of Heart and Lung Transplantation (ISHLT). (Table 11-5).8
 Acute antibody mediated rejection (AMR) is mediated by B-lymphocytes and characterized by
immunoglobulin deposition on the cardiac allograft microvasculature, causing complement
activation, myocardial injury, and eventual graft dysfunction. Compared to ACR, AMR is more
likely to cause hemodynamic instability and is associated with a worse prognosis. It is detected
by a combination of histologic evidence of capillary injury, positive immunohistochemistry
staining for C4d (a complement split product), or immunofluorescence staining for
242
immunoglobulin deposition on heart biopsy specimens, clinical evidence of graft dysfunction,
and by measuring HLA antibodies in the circulation that are directed against known donor
antigens.
TABLE 11-4 Important drug interactions
Increase levels of cyclosporine, tacrolimus, and sirolimus
Calcium channel blockers Diltiazem
Nifedipine
Nicardipine
Verapamil
Antifungal drugs Itraconazole
Fluconazole
Ketoconazole
Voriconazole
Posaconazole
Macrolide antibiotics All
Fluoroquinolone antibiotics Ciprofloxacin
HIV-protease inhibitors All
243
Antiarrhythmic agents Amiodarone
Gastrointestinal agents Metoclopramide
Miscellaneous Grapefruit juice
Decrease levels of cyclosporine, tacrolimus, and sirolimus
Antitubercular drugs Rifampin
Antiseizure drugs Phenytoin
Phenobarbital
Gastrointestinal drugs Octreotide
Miscellaneous Saint-John's-wort
Drugs with synergistic nephrotoxicity when used with cyclosporine or tacrolimus
Aminoglycoside antibiotics
Amphotericin B
Colchicine
Nonsteroidal anti-inflammatory agents (NSAIDs)
Drugs whose concentrations are increased when used with with cyclosporine or tacrolimus
244
Lovastatin
Simvastatin
Atorvastatin
Ezetimibe
P.174
TABLE 11-5 Acute rejection grading and treatment
Acute cellular rejection (ACR)
Old
(1990) Revised
ISHLT (2004) ISHLT
Severity Grade Grade Pathologic Features Treatment
No 0 0R Normal myocardium None
rejection
Mild 1A, 1R Interstitial and/or None; optimize
1B, perivascular maintenance
2 mononuclear cell immunosuppression
infiltrate with up to one
focus of myocyte damage
Moderate 3A 2R Two or more foci of No hemodynamic
245
mononuclear cell compromise Pulse
infiltrate with associated steroids
myocyte damage (methylprednisolone
500-1,000 mg IV daily × 3
days) Hemodynamic
compromise Pulse
steroids and/or cytolytic
antibody therapy (OKT3,
ATGAM, or
Thymoglobulin)
Severe 3B, 3R Diffuse mononuclear Pulse steroids and/or
4 and/or mixed cytolytic antibody
inflammatory cell therapy (OKT3, rATG)
infiltrates with multiple
foci of myocyte damage,
with or without edema,
hemorrhage, or vasculitis
Antibody-mediated rejection (AMR)
Absent or AMR 0 Absence of cellular Pulse steroids

present (absent) infiltrate; prominent Plasmapheresis
or 1 endothelial cells lining Photopheresis IV
(present) microvasculature; immunoglobulin
presence of intravascular Cytolytic antibody
histiocytes; interstitial therapy (OKT3, rATG)
edema; positive Rituximab
immunofluorescence or
immunoperoxidase
staining (CD68, C4d)
P.175
246
Treatment
 Rejection episodes are treated by augmentation of immunosuppression. The specific treatment
depends upon the type of rejection, histologic severity of rejection episode, and presence of
graft dysfunction or hemodynamic compromise (defined as a decrease in left ventricular
systolic function, decrease in cardiac output, or signs of hypoperfusion) (Table 11-5).
 Any rejection episode should prompt an investigation for precipitating causes (CMV infection,
noncompliance, drug interactions resulting in subtherapeutic immunosuppressive drug levels).
 A biopsy should be repeated 2 weeks after completion of treatment to document resolution of
a rejection episode.
 Recurrent or recalcitrant rejection can be treated with total lymphoid irradiation.
CARDIAC ALLOGRAFT VASCULOPATHY (CAV)

CAV is a major cause of late graft failure and death in heart transplant patients. It is noted
angiographically in 10% of patients by the first postoperative year and in 30% to 50% of patients by the
fifth posttransplant year.
P.176
CAV Pathogenesis
The pathogenesis of CAV is not completely understood, but it is thought to involve both immune and
nonimmune mechanisms. It manifests as diffuse coronary intimal thickening with tapering or pruning of
distal vessels. However, focal stenoses can also be present.
CAV Diagnosis
CAV is detected on the basis of surveillance coronary angiography, although the disease can be difficult
to detect due to its diffuse nature. Some centers use intravascular ultrasound (IVUS) as a more sensitive
tool for early CAV detection. Dobutamine stress echocardiography (DSE) provides a reasonable
alternative to yearly coronary angiography when used to screen for CAV. In this setting, a normal DSE
predicts a low risk of major adverse cardiac events over the next year. 9
CAV Treatment
The mTOR inhibitors (sirolimus and everolimus) have been shown to slow progression of the disease. 5,6
PCI with stenting can be effective for focal lesions. 10 Outcomes following coronary artery bypass graft
(CABG) for CAV have been poor.11 The most definitive form of treatment is retransplantation and is
typically reserved for patients with severe, symptomatic CAV and graft failure. 12
247
EVALUATION AND MANAGEMENT OF A HEART TRANSPLANT

PATIENT WITH HEART FAILURE
 New onset of heart failure signs or symptoms in a transplant patient constitutes a medical
emergency.
 Heart failure can be caused by both systolic and diastolic dysfunction. The echocardiogram can
be useful to document a reduction in LV systolic function, but a normal LVEF does not exclude
the possibility of graft dysfunction.
 The etiology of heart failure varies according to time posttransplant
o Early period (years 1-2): Acute rejection >> CAV resulting in silent ischemia or
infarction
o Late period (years 2 and beyond): CAV >> acute rejection
Workup includes an echocardiogram, electrocardiogram, right heart catheterization, heart biopsy (if
rejection is suspected), and coronary angiography (if CAV is suspected).
 The patient's transplant team should be contacted immediately, and prompt transfer to a
transplant center should be arranged if the patient presents to an outside hospital.
 In the early period (years 1-2 after transplantation), consider administration of high-dose
steroids (methylprednisolone 1 gm IV) to pre-emptively treat for possible rejection until

additional testing can be performed.
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OPPORTUNISTIC INFECTIONS
Infections are a major cause of death during the first year and remain a threat throughout the life of a
chronically immunosuppressed patient. Effective therapy requires an aggressive approach to obtaining
specific microbiological diagnosis (i.e., bronchoscopy with bronchoalveolar lavage for pneumonias, fine
needle aspiration for pulmonary nodules, detection of CMV viremia via quantitative PCR of the serum).
 Bacterial pathogens are more likely to cause disease in the first month and are typically
associated with indwelling catheters and surgical wounds.
 Viral pathogens include cytomegalovirus (CMV) and herpes simplex virus (HSV).
 Fungal pathogens include Aspergillus, Candida, and Pneumocystis.

 Atypical pathogens include Mycobacterium, Nocardia, and Toxoplasma.
REFERENCES
248
1. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung
Transplantation: Twenty-third official adult heart transplantation report—2006. J Heart Lung
Transplant. Aug 2006;25(8):869-879.
2. Taylor DO, Barr ML, Radovancevic B, et al. A randomized, multicenter comparison of tacrolimus and
cyclosporine immunosuppressive regimens in cardiac transplantation: Decreased hyperlipidemia and
hypertension with tacrolimus. J Heart Lung Transplant. Apr 1999;18(4):336-345.
3. Reichart B, Meiser B, Vigano M, et al. European Multicenter Tacrolimus (FK506) Heart Pilot Study:
One-year results—European Tacrolimus Multicenter Heart Study Group. J Heart Lung Transplant. Aug
1998;17(8):775-781.
4. Kobashigawa J, Miller L, Renlund D, et al. A randomized activecontrolled trial of mycophenolate
mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators. Transplantation. Aug 27
1998;66(4):507-515.
5. Keogh A, Richardson M, Ruygrok P, et al. Sirolimus in de novo heart transplant recipients reduces
acute rejection and prevents coronary artery disease at 2 years: A randomized clinical trial.
Circulation. Oct 26 2004;110(17):2694-2700.
6. Eisen HJ, Tuzcu EM, Dorent R, et al. Everolimus for the prevention of allograft rejection and
vasculopathy in cardiac-transplant recipients. N Engl J Med. Aug 28 2003;349(9):847-858.
7. Page RL II, Miller GG, Lindenfeld J. Drug therapy in the heart transplant recipient: Part IV: Drug-drug
interactions. Circulation. Jan 18 2005;111(2):230-239.
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8. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the
standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. Nov
2005;24(11):1710-1720.
9. Spes CH, Klauss V, Mudra H, et al. Diagnostic and prognostic value of serial dobutamine stress
echocardiography for noninvasive assessment of cardiac allograft vasculopathy: A comparison with
coronary angiography and intravascular ultrasound. Circulation. Aug 3 1999;100(5):509-515.
10. Bader FM, Kfoury AG, Gilbert EM, et al. Percutaneous coronary interventions with stents in cardiac
transplant recipients. J Heart Lung Transplant. Mar 2006;25(3):298-301.
11. Halle AA III, DiSciascio G, Massin EK, et al. Coronary angioplasty, atherectomy and bypass surgery in
cardiac transplant recipients. J Am Coll Cardiol. Jul 1995;26(1):120-128.
249
12. Topkara VK, Dang NC, John R, et al. A decade experience of cardiac retransplantation in adult
recipients. J Heart Lung Transplant. Nov 2005;24(11):1745-1750.
18. CHAPTER 12 - Valvular Diseases

CHAPTER 12
Valvular Diseases
Shriram Nallamshetty
Stanley G. Rockson
AORTIC STENOSIS
Background
 The normal aortic valve orifice area (AVA) is 3 to 4 cm2; clinically significant gradients occur
when AVA is reduced by one half, and symptoms usually arise when AVA is one fourth of normal
size.
 Grading severity is based on valve area, gradients, and aortic jet velocity. 1,2 (See Table 12-1.)
 Gradients are less predictive (a mean gradient > 50 mm Hg has >90% positive predictive value
for severe AS, but there is no clear cutoff for a good negative predictive value 3).
Etiology
 Most common etiologies: Congenital, rheumatic, and calcific (degenerative) (See Table 12-2.)
 Under 70 years: >50% congenital; over 70 years: ~ 50% degenerative4
Pathophysiology
 Pressure gradient between the left ventricle (LV) and aorta (increased afterload)
 Initially, cardiac output is maintained through compensatory mechanisms of left ventricular
hypertrophy (LVH), increased preload, and increased myocardial contractility.
 If preload reserve is exceeded or if LV function declines, cardiac output fails to increase (fixed
cardiac output).
History
 Cardinal manifestations: Classic triad of angina, exertional syncope, and congestive heart
failure (CHF).
 Angina is due to increased myocardial demand/decreased coronary flow reserve.6
250
 Syncope can be due to exercise-related vasodilation in the setting of fixed cardiac output, 7 as
well as a vasodepressor response.8
 CHF results from diastolic dysfunction, systolic dysfunction, or both.
 Sudden cardiac death occurs in a minority of patients (less than 1% of asymptomatic patients;
higher rates among symptomatic patients).2,9,10
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TABLE 12-1 Grading of severity of AS
Severity of AS AVA Velocity
Mild >1.5 cm2 2.6-3.0 m/s
Moderate 1.0-1.5 cm2 3.0-4.0 m/s
Severe <1.0 cm2 >4.0m/s
TABLE 12-2 Etiology of AS
Etiology Notes
Congenital
1. Congenital aortic Can occur with unicuspid, bicuspid, tricuspid valve
stenosis
2. Congenital bicuspid Commonly associated with aortic coarctation, dissection, or
valve aneurysm. Onset of symptoms in third to fifth decade
251
Acquired
1. Degenerative Onset of symptoms in seventh to eighth decade. Higher
calcification incidence of risk factors for coronary artery disease (CAD)
2. Rheumatic heart Adhesions and fusion of commissures and cusps
disease
3. Rare causes Infectious vegetations, Paget disease, SLE, RA, Postradiation
(typically occurs 11.5-16.5 years after radiation5)
Natural History
 Progression of AS is poorly understood; the latent phase is prolonged.
 Rate of progression
o - Mild AS to severe AS: 8% in 10 years, 22% in 20 years, and 38% in 25 years11
o - Decrease in valve area of 0.1 to 0.3 cm2/year and increase in peak pressure gradient
of 10 to 15 mm Hg/year12, 13, and 14
o - Faster progression in calcific AS than in congenital malformations15
 The onset of symptoms marks an important transition with a marked decline in survival (50%
survival over 2, 3, and 5 years for patients with CHF, syncope, and exertional angina,
respectively).16
 Presence of symptoms may be difficult to gauge, especially in sedentary/elderly individuals.
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252
FIGURE 12-1 Management algorithm: aortic stenosis.
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Physical Exam
 Systolic ejection murmur is heard best in the aortic area/apex radiating to neck and right
clavicle.
 Gallavardin phenomenon (disappearance of the murmur over the sternum and reappearance
over the apex, mimicking mitral regurgitation (MR))
 Intensity of murmur does not accurately reflect severity of stenosis.
 Later peaking murmur is associated with worsening severity of stenosis.
 S2 is absent, single, paradoxically split in severe AS.

 Pulsus parvus et tardus (slow rising arterial pulse with reduced peak) in severe AS
253
 Brain natriuretic peptide (BNP) may be useful in differentiating symptomatic from
asymptomatic patients (BNP >66 pg/mL has predictive accuracy of 84% for symptomatic AS). 17,18
 Chest x-ray can show dilated proximal ascending aorta (poststenotic dilatation) and
calcification of cusps on lateral films.
 Electrocardiogram
o - Usually normal sinus rhythms (NSR), but AF is common in elderly AS patients
o - Complete heart block may occur in calcific AS
o - Left atrial enlargement present in 80% of patients
o - LVH with secondary ST-T changes
 Echo
o - Useful for diagnosis, determining severity (AVA, velocity, gradient; see Table 12-1)
o - AVA is determined using the continuity equation (conservation of mass).
o - Peak pressure gradient is determined using Continuous Wave (CW) Doppler.
o - Accuracy compared to cardiac catheterization:19 Valve area is within ±0.3 cm;2 Peak
gradient is within ±10mm Hg; Gradients usually higher than cath due to pressure
recovery20
 Recommendations for serial studies (in the absence of symptoms)1
 Mild: Every 5 years
 Moderate: Every 2 years

 Severe: Every 6 months to 1 year
Provocative Testing
EXERCISE TESTING
 Contraindicated in symptomatic patients
 Should be considered in patients severe AS, with unclear symptom status
 Guidelines recommend consideration for surgery in asymptomatic patients with abnormal
response to exercise (symptoms, <20 mm Hg increase in BP, ST depression, and/or complex

ventricular arrhythmias).21
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DOBUTAMINE STRESS ECHOCARDIOGRAPHY (DSE)
 Employed in patients with AS, depressed LVEF with two primary goals
 DSE can help distinguish severe stenosis from pseudo (flow dependent) AS.22
254
 DSE can help to identify patients with pre-operative cardiac reserve (increase in stroke volume
by >20%, or in mean transvalvular gradient of 10 mm Hg) as this subset of patients with low EF
tends to have better outcomes (surgical mortality of 6% vs. 33%). 23
CARDIAC CATHETERIZATION AND ANGIOGRAPHY
 Catheterization is used to assess coronary anatomy (prior to surgery).
 Catheterization used to confirm/clarify diagnosis, severity by determining transvalvular
gradient (simultaneous aortic, LV pressures are most accurate) and calculation of AVA by
Gorlin formula or Hakki formula.
 The gradient is dependent on transvalvular flow, so errors occur in patients with low cardiac
output.
 Dobutamine can be used to distinguish pseudostenosis from true anatomically severe AS.
Management: General Principles
 Identify patients that warrant surgery with close monitoring for onset of symptoms.
 Medical therapy has a limited role in providing a survival benefit or slowing progression.
 Symptomatic severe AS should be referred for surgery: Mortality high without surgery16; age-
corrected survival after surgery is near normal.24
 Patients with asymptomatic severe AS generally have a good prognosis, 25 but there is a risk of
sudden death (~ 2%) and of irreversible myocardial damage. 25,26
 Identify subset of asymptomatic severe AS patients at risk for SCD and/or onset symptoms that
would require surgery in the near future.
 Patients at highest risk for symptom onset/needing surgery in the short term include: Peak
aortic velocity >4m/s;24 Severe calcification of the aortic valve;10 Rapid progression of aortic
velocity (increase of >0.3 m/s per year).10
 Exercise testing: A negative test has a strong negative predictive value (85%-87%) for event-
free survival20 but is positively predictive (79%) only in physically active patients <70 years
old.21
 No randomized controlled data support the strategy of referring “high-risk” patients with
asymptomatic severe AS for AVR, but this is a Class II recommendation (see Table 12-3).
Medical Therapy
 Antibiotic prophylaxis is indicated if high risk for endocarditis (see Chapter 13).26
 Afterload agents are considered to be contraindicated because of concern over hemodynamic
collapse (supporting data is lacking).
 Considered to be contraindicated because of concern over hemodynamic collapse (supporting
data is lacking)
255
 Afterload reducing agents have been shown to be beneficial in patients with severe AS and bw
EF27 and decompensated CHF.28
 ACE inhibitors are well tolerated.29
 Studies on effect of ACE inhibitors on progression of AS have yielded conflicting results.31,32
 Data on the role of statins in slowing progression of AS is conflicting.
 Recent retrospective data suggest statins may slow progression of AS. 33, 34, and 35
 A single randomized controlled trial showed no effect of statins on progression of AS.36

 Several randomized controlled trials of statins in AS are pending.
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TABLE 12-3 Indications for AVR in AS
Class I
1. Symptomatic patients with severe AS
2. Patients with severe AS undergoing CABG, or surgery on aorta/other valves
3. Patients with severe AS and depressed LVEF (<50%)
Class II
Patients with moderate AS undergoing CABG, surgery of the aorta, or other heart valves
1. (IIa)
2. Asymptomatic patients with severe AS and
- Abnormal response to exercise (symptoms or hypotension) (IIb)
- Critical AS (valve area <0.6 cm2, mean gradient >60mm Hg, aortic jet velocity
256
>5m/s)
- High likelihood of rapid progression (age, calcification, CAD)
Adapted from AHA/ACC 2006 Guidelines on Management of Patients with Valvular Heart
Disease.1
Surgical Management: Aortic Valve Replacement (AVR)
 AVR is the only effective treatment for symptomatic AS.
 Symptoms/high risk features are the chief indications for AVR.
 Operative mortality for AVR ~5% to 30% depending on the patient population
 Age itself is not an absolute contraindication to AVR. 37,38
 Predictors of higher operative mortality and lower late survival: CHF, low LVEF, chronic kidney
disease, urgent procedures, and need for concomitant CABG or MVR39
 Outcomes similar in patients with preserved LV function and with moderate LV dysfunction
 Patients with low EF/low gradient AS have higher operative mortality (20%).40,41
 Provocative testing (DSE) can identify patients with contractile reserve; this subgroup may
have better surgical outcomes.23
P.185
 Surgical mortality is very high (30%-50%) in patients with severe AS and decompensated heart
failure who are taken directly to surgery42 (balloon valvuloplasty and medical optimization are
important bridge therapies).
 In patients with severe AS who need surgical intervention, but are poor candidates,
percutaneous AVR may represent a safe, viable alternative.43
AORTIC REGURGITATION
Background
 Aortic regurgitation (AR) is due to ineffective coaptation of aortic cusps.
257
 The prevalence of chronic AR increases with age; the majority of patients with AR have trace
or mild AR.44
 Grading of severity is based on several qualitative and/or quantitative measures. (See Table
12-4.)
Etiology
 AR can be due to primary valvular disease and/or aortic pathology (see Table 12-5).
 AR can be acute or chronic, and the clinical presentation of each entity is distinct.
 Chronic AR is more common than acute AR.
 Acute AR is commonly caused by endocarditis, aortic dissection, and trauma.

 Chronic AR is usually due to degenerative, aortic root, congenital abnormalities.
Pathophysiology
ACUTE AR
 Large regurgitant volume into a nondilated LV leads to an abrupt increase in LV end diastolic
pressure (LVEDP).
 Compensatory tachycardia usually insufficient to maintain cardiac output
 Poor hemodynamic tolerance: LVEDP equalizes with diastolic aortic pressure with subsequent
pulmonary edema and cardiogenic shock.
TABLE 12-4 Grading of severity of AR
Severity of AR Mild Moderate Severe
Qualitative
Angiographic grade 1+ 2+ 3+
Doppler central jet width <25% LVOT 25%-65% LVOT >65%
Vena contracta width (cm) <0.3 0.3-0.6 LVOT >0.6
Quantitative
258
Regurgitant volume (mL/beat) <30 30-59 >60
Regurgitant fraction <30% 30-49 >50
Regurgitant orifice area (cm2) <0.1 0.1-0.29 >0.3
Adapted from AHA/ACC 2006 Guidelines on Management of Patients with Valvular Heart Disease. 1
P.186
TABLE 12-5 Etiology of AR
Etiology Notes
Primary valve disease
1. Degenerative AR Associated with ascending aortic aneurysm
2. Congenital Bicuspid valve (increased risk of aortic coarctation, root
abnormalities dilatation, and dissection)
VSD
Subvalvular AS
Rare abnormalities: Congenital valve fenestration,
unicommissural/quadricusp valve
259
3. Rheumatic heart Thick, retracted leaflets with central regurgitation
disease
4. Endocarditis Leaflet perforation/tears, perivalvular abscess with
abnormal aorta-LV communication
5. Rare causes Complications of valvuloplasty, balloon dilation
- Trauma Appetite suppressants (fenfluramine)
- Drugs Including antiphospholipid syndrome
- Connective
tissue disease
- Chest radiation
Primary aortic disease
1. Annulus/Aortic root
dilatation
- Idiopathic root Isolated aortic root pathology
dilatation
- Annulo-aortic Dilation present in ~80%, AR present in ~30%45
ectasia
- Marfan syndrome Dilation present in ~30%45
- Ehlers-Danlos
260
syndrome
- Osteogenesis
imperfecta
2. Aortitis
- Infectious Syphilitic aortitis now a rare etiology
- Inflammatory Ankylosing spondylitis, RA, SLE, Behcet disease, giant cell
diseases and Takayasu arteritis, relapsing polychondritis, Reiters
syndrome
3. Aortic dissection
CHRONIC AR
 Combined volume and pressure overload on the LV
 Volume overload due to regurgitant volume
 Pressure overload due to increased afterload (hypertension [HTN] from increased aortic stroke
volume)
 Three compensatory mechanisms initially preserve cardiac output: Increased LV end diastolic
volume; increased chamber compliance; LVH (eccentric/concentric).
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 Compensated phase can last for years/decades.

 Eventually, progressive LV dilation and LV systolic dysfunction lead to CHF.
History
 Patients with acute AR present with marked dyspnea and pulmonary edema.
 Patients with chronic AR can be asymptomatic for many years.
261
 Angina without structural coronary artery disease is due to decreased coronary perfusion (due
to high LVEDP).
 Exertional dyspnea is the most common presenting symptom in chronic AR (late stage).
 Syncope and sudden cardiac death are rare in absence of other symptoms.
Natural History
 Progression of AR results from complex interplay of multiple variables.
 Mild AR: Minimal data on natural history; Most patients with mild AR probably do not progress
to severe AR.
 Moderate to severe AR
o Asymptomatic patients with normal systolic function
 - Rate of progression (decrease in EF, symptoms, death) of 4% to 6% per
year46,47
 - Up to one fourth develop systolic dysfunction or die suddenly. 46, 47, 48, and 49
 - Predictors of progression: Age, LV dimensions at end systole (LVIDs) and LV
dimension at end diastole (LVIDd), and LVEF during exercise46,47,48,49, 50, and 51
 - Unlike AS, onset of symptoms is not the only important factor
o Asymptomatic patients with systolic dysfunction
 - Rate of progression to symptoms of ~ 25%/year52, 53, and 54
 - Majority will need AVR in 2 to 3 years
o Symptomatic patients
 - No contemporary studies, but outcomes are poor with medical therapy
 - High mortality rates: Angina - mortality of ~ 10%/year; heart failure -

mortality of ~ 25%/year55, 56, and 57
Physical Exam
 The high-frequency decrescendo blowing diastolic murmur is heard best over the left lower
sternal border (LLSB) through stethoscope's diaphragm with patient sitting upright during
forced expiration.
 Murmurs that are louder over right lower scapular border (RLSB) are more likely due to aortic
root/ascending aorta pathology, rather than primary valve abnormalities.
 Duration of murmur correlates with severity (mild AR - short murmur; severe AR - typically
holodiastolic).
 In acute AR, the diastolic murmur and peripheral signs (see Table 12-6) may be absent (the
only clue may be absent S2 with hypotension/pulmonary edema).
 Austin Flint murmur (mid-late diastolic rumble that resembles MS - due to vibration from AR
jet striking the mitral valve)
262
 Pulse: High-amplitude, rapidly collapsing pulse (waterhammer pulse)
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FIGURE 12-2 Management algorithm: aortic regurgitation
 Chest x-ray can be normal or demonstrate pulmonary edema, cardiomegaly, or dilated aorta.
 ECG shows LAD, LVH and signs of LV diastolic volume overload (high QRS amplitude and tall T
waves with ST depression), and conduction abnormalities.
263
Echocardiography
 Assessment of anatomy of aortic leaflets, aortic root, LV size/function, and severity of AR
 Estimation of severity is based on color flow and Doppler parameters (Table 12-4)
 Supportive findings:
o - Early mitral valve closure by M-Mode (can be masked by tachycardia)
o - AR pressure half time: Mild >500 milliseconds and severe <200 milliseconds
(confounded by filling volumes and diastolic function)
o - Holodiastolic flow reversal in descending aorta reflective of at least moderately
severe AR
 Recommendations for serial studies in asymptomatic patients
o - Mild AR and normal LV size and function: Every 2 to 3 years
o - Patients with LV dilation: Every 6 to 12 months
o - Patients with advanced LV dilation (LVIDs >50 mm, LVIDd >70 mm): Risk of
progression 10%-20%/year;46 studies every 4-6 mos.

o - Associated aortic root disease: Monitoring of aortic root size
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TABLE 12-6 Auscultatory and peripheral findings in severe AR: A glossary of eponyms
Sign Description
Austin Flint murmura Low-pitched apical mid-diastolic rumble
Corrigan pulsea High-amplitude, abruptly collapsing pulse
Duroziez signa To-and-fro bruit over femoral artery
Hill signa >40 mm HgΔ between popliteal and brachial pressures
Mayne sign >15mm Hg drop in SBP with arm elevation pressure
264
Traube sign Loud systolic “pistol shots” over the femoral artery
Quincke pulse Exaggerated reddening and blanching of nail beds
Mueller sign Visible pulsations of the uvula
de Musset sign Visible bobbing of the head
a
Signs identified in a recent review of physical findings in AR as the most significant findings
based on a review of available literature (peer-reviewed journals and classic text books). Babu
A, et al. Ann Intern Med. 2003;138:736-742.58
Cardiac Catheterization and Angiography
 Useful in initial assessment if echocardiography is suboptimal1
 Aortography provides semiquantitative estimates of severity of AR
 Coronary angiogram pre-operatively to diagnose co-existing CAD

 Routinely performed in men >35 years and premenopausal women >45 years with risk factors
 Close monitoring for onset of symptoms and evidence of changes in LV size and function
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 Appropriate for referral for surgery
 Unlike AS, monitoring for onset of symptoms alone is NOT sufficient.
 LV size and systolic function have a significant impact on prognosis.
 Surgery is indicated in symptomatic patients, and in patients with severe LV chamber dilation
and/or LV dysfunction (even in the absence of symptoms).
 Medical therapy has limited role.

 The optimal surgical option depends on the etiology of AR and aortic pathology.
Medical Therapy
265
 Antibiotic prophylaxis is indicated in high risk patients with AR (prosthetic valves, prior
endocarditis, unrepaired congenital heart disease— please see Chapter 1326).
 Acute AR
o - The role of medical therapy is limited if there is evidence of heart failure.
o - Negative chromotropes should be avoided; they lengthen diastole and may increase
regurgitant fraction and precipitate hemodynamic collapse.
o - Nitroprusside and inotropic agents can serve as temporizing measures.
o - Intra-aortic balloon pulsation (IABP) is contra-indicated.
 Chronic severe asymptomatic AR with preserved LV function and size
o - The goal of medical therapy is to reduce systolic blood pressure and mitigate the
afterload mismatch.
o - Vasodilator therapy with hydralazine59 and nifedipine60 have been shown in small
randomized control trials to decrease LVIDd and increase LVEF.
o - Nifedipine delayed surgery when compared with digoxin,61 but recent trials showed
no effect of nifedipine or enalapril on timing of surgery. 62
Surgical Management: Aortic Valve Replacement (AVR)
 Acute AR requires emergent surgical intervention.
 In chronic AR, AVR is the only effective treatment for symptomatic patients.
 Indications for AVR in asymptomatic patients:
o - Depressed LVEF (<50%)63
o - If LVEF is normal, excessive ventricular dilation (marker of incipient systolic
dysfunction): LVIDs >55 mm64 or LVIDd >70mm65
o - In patients with established LV dysfunction, the majority of patients improve
although some may have irreversible dysfunction: In short-term follow-up (14-18
months), 72% of patients with severe asymptomatic AR and LV dysfunction who

underwent AVR had stable or improved LVEF.66
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TABLE 12-7 Indications for AVR in AR
266
Class I
1. Symptomatic patients with severe AR
2. Patients with severe AR undergoing CABG, or surgery on aorta/other valves
3. Asymptomatic patients with severe AR and LV dysfunction (LVEF <50%)
Class II
1. Asymptomatic patients with severe AR with normal LVEF but severe LV dilation (LVIDd
70-75 mm and LVIDs 50-55 mm)
2. Patients with moderate AR undergoing CABG or surgery of the aorta or other heart
valves
Disease.1
MITRAL REGURGITATION
Background
 Dysfunction of any part of the valve apparatus (leaflets, annulus, chordae tendineae, papillary
muscles, LV) can lead to mitral regurgitation (MR).
 Prevalence of MR increases with age (1.3-fold increase per decade).44

 Acute MR leads to rapid decline; chronic MR is tolerated for prolonged period (see Table 12-8).
Etiology
 MR can be due either to primary disease of the valve apparatus or to cardiac/systemic/genetic
diseases that affect the valve apparatus.
 The most common etiologies in patients with chronic severe MR include mitral valve prolapse
(MVP), ischemic MR, rheumatic heart disease, and endocarditis.67, 68, 69, 70, 71, and 72 (see Table
12-9)
267
 Acute MR can result from structural (papillary muscle dysfunction/rupture, chordal rupture due
to myxomatous changes) and infectious (endocarditis, acute rheumatic fever) etiologies.
Pathophysiology
ACUTE MR
 The regurgitant volume in LV produces an abrupt increase in LVEDP and left atrial pressure.
 Higher preload (abrupt volume overload), lower afterload (systolic runoff into LA) 73 and
compensatory increased LV contractility.
 There is a modest increase in cardiac output, but overall LV function declines: Majority of the
stroke volume is directed to the LA.

 Pulmonary edema, cardiogenic shock can develop due to poor forward flow.
CHRONIC MR
 MR causes pure volume overload, unlike AR (combined volume/pressure load).
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 Compensatory mechanisms (LVH and increased contractility/compliance) initially preserve
cardiac output.
 The compensated phase can persist for years, with high-normal LVEF.
 LA dilation, RV dilation/dysfunction due to pulmonary hypertension

 Over time, progressive LV dysfunction, LV dilation leads to CHF. 74,75
TABLE 12-8 Grading of severity of MR
268
Severity of MR Mild Moderate Severe
Qualitative
Angiographic grade 1+ 2+ 3+-4+
Doppler central jet width <20% LA area 20%-40% LA area >40% LA area
Vena contracta width (cm) <0.3 0.3-0.69 >0.7
LA/LV size Enlarged
Quantitative
Regurgitant volume <30 30-59 >60
(mL/beat)
Regurgitant fraction <30% 30-49 >50
Regurgitant orifice area (cm2) <0.2 0.2-0.39 >0.4
TABLE 12-9 Etiology of MR
269
Etiology Notes
Primary mitral apparatus disease
1. MVP (myxomatous disease)
2. Rheumatic heart disease Acute rheumatic fever and chronic rheumatic
valvular disease
3. Endocarditis MR due to perforation, incomplete coaptation,
chordal rupture
4. Congenital lesions Cleft anterior leaflet (associated with ASD and
other congenital heart disease)
Leaflet fenestration
Parachute mitral valve (associated with
endocardial cushion defects and transposition)
5. Mitral annular calcification Degenerative changes of leaflets
Increased annular rigidity
6. Idiopathic chordal rupture Associated MR is typically mild to moderate
7. Trauma Surgical/percutaneous valvuloplasty
8. Drugs Methysergide
9. Radiation therapy
270
Secondary MR
1. Cardiac disease
- CAD Papillary muscle rupture
Transmural myocardial infarction (MI)
Ischemic regional dysfunction
Global ventricular dysfunction
- Dilated cardiomyopathy Incomplete closure due to annular dilation from
LV chamber dilation
- Hyphertrophic Systolic anterior motion (SAM) leads to MR with
cardiomyopathy (HCM) elongated leaflets
- Endomyocardial fibrosis
2. Systemic disease
- Systemic lupus
erythematosus (SLE)
- Hypereosinophilic
syndrome
- Amyloidosis 25% have significant MR
- Rheumatoid arthritis
271
- Marfan syndrome
- Ehlers Danlos (Type I and
III)
- Scleroderma
- Pseudoxanthoma
elasticum
- Ankylosing spondylitis Anterior leaflet long/redundant with MR
P.193
History
 Clinical history depends on the etiology and acuity of onset of MR.
 Symptoms include the insidious onset of dyspnea on exertion and exercise intolerance and
progress to overt CHF.
 MR may manifest symptoms in the context of hemodynamic stress such as pregnancy,
infection, and new onset AF with rapid ventricular response.

 Acute MR (due to chordal rupture or endocarditis) presents with acute decompensated CHF.
Natural History
 The clinical course depends on the etiology of MR, the status of both ventricles and of the left
atrium.
 The compensated phase of MR may last for several years (up to 10-15 years).76
 There are limited data on the progression of mild/moderate MR, with wide individual
variability.77
 In MVP/MR, the 5-year event-free rates are 85% to 95% for mild-moderate MR.78
 There is a high likelihood (5%-10%) of developing symptoms/LV dysfunction in severe

asymptomatic MR.79, 80, 81, and 82
272
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 Patients with asymptomatic severe MR have a mortality rate of ~ 5%/year. 76,79
 LVEF is the best validated predictor of outcome.
 When LVEF <60%, survival after MVR is lower.83

 When symptoms develop, survival is improved with surgical intervention. 76,84
Physical Exam
 Auscultation
 Soft S1 with normal S2 early on; later a loud P2 appears when pulmonary HTN develops.
 S3 may be present independent of presence of LV failure.
 The holosystolic murmur is loudest over apex.
 Posterolateral jets (radiating to axilla/back) are heard with ischemic disease, anterior leaflet
abnormalities, and dilated cardiomyopathy.
 Anterior jets (radiating to sternum/base/carotids mimicking AS) are heard with posterior
leaflet prolapse.
 Maneuvers to distinguish from AS: Handgrip (increased afterload) augments MR and softens AS
(lower transvalvular gradients); AS murmer increases post PVC while MR murmer changes; AS
but not MR heard over right clavicle.
 In chronic MR, the intensity of the murmur correlates with severity.
 In acute MR, 50% of patients have no murmur.85

 Midsystolic and late systolic murmur if mitral valve prolapse is present
 Chest x-ray can be normal early, shows left atrial enlargement and cardiomegaly later in the
course of disease.
 ECG findings are nonspecific (LAE, LVH, AF).
 Echocardiography is useful for assessing:
o - Severity (See Table 12-8.)
o - Anatomic mechanism of MR
o - Assessment of anatomy of mitral valve apparatus (especially 3-D echo)
o - Evaluation of LV size and systolic function
o - Evaluation of left atrial size and pulmonary artery pressures
o - Assessment of options for valve repair versus replacement
273
 TEE is useful if TTE images are suboptimal, and pre-operatively for mapping to determine type
of repair and likelihood of successful repair.
 Estimation of severity is based on a combination of color flow and Doppler (see table).
 Systolic flow reversal in pulmonary veins indicates moderate-to-severe MR.
 Recommendations for serial studies (in the absence of symptoms): mild MR and normal LV size
and function, Every 2 to 3 years; severe MR, Every 6 to 12 months
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274
FIGURE 12-3 Management algorithm: mitral regurgitation
Exercise Testing
 Provides objective data on symptoms and change in exercise tolerance
 Measurement of PA pressures and severity of MR during exercise is useful.
 The precise role of exercise testing in determining need for surgery is not clearly defined
because many of the patients studied were already symptomatic.
 Useful if there is a discrepancy between clinical and noninvasive data1
 Performed pre-operatively to screen for CAD if cardiac risk factors are present
 Ventriculography provides semiquantitative estimates of MR severity.

 Right heart catheterization is performed to assess right-sided filling pressures, PA pressures,
and PCWP.
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 Close monitoring for onset of symptoms and evidence of changes in LV size and function
 Appropriate referral for surgery (see Table 12-10)
 LV size and systolic function have a significant impact on prognosis (see Table 12-11).
 Surgery is indicated in symptomatic patients, and patients with LV chamber dilation and/or LV
dysfunction (even in the absence of symptoms).
 Medical therapy has limited role.

 Optimal surgical option depends on the etiology of MR.
Medical Therapy
 Antibiotic prophylaxis if indicated (see endocarditis chapter) 26
 Acute MR
o - The role of medical therapy is limited to stabilization prior to surgery.
o - Main goals: (a) ↓ MR; (b) ↑ forward cardiac output; (c) ↓ pulmonary congestion
o - Normotensive patients: Nitroprusside86
o - Hypotensive patients: Nitroprusside and inotropic agent (dobutamine)
275
o - IABP to decrease afterload and increase forward CO
 Chronic severe asymptomatic MR with preserved LV function and size
o - There has been sustained interest in vasodilator therapy, but there are no data to
support its clinical efficacy in delaying surgery.87
o - Vasodilator therapy is most effective in MR secondary to LV dilation.88 Nitroprusside
and hydralazine have been shown to decrease MR, LV, and increase forward cardiac
output.
o - ACE inhibitors do not consistently reduce severity of primary MR. 88, 89, and 90
Surgical Intervention
 Acute MR requires emergent surgical intervention.
 In chronic MR, surgery is the only effective treatment for symptomatic patients.
 Three types of MV operations are possible for correction of MR:
o - MV repair
o - MV replacement with preservation of chordal preservation
o - MV replacement (MVR)
 Indications for surgical intervention in chronic severe MR:
o Symptomatic patients (NHYA Class II-IV): LVEF 30-60%; no severe LV dysfunction (LVEF
< 30% or LVIDs < 55 mm)
o Asymptomatic patients: LVIDs > 40 mm and/or LVIDd > 75 mm; new onset AF;
pulmonary HTN( >50mm Hg at rest or >60mm with exercise)
 MV repair preserves the native valve apparatus, although technically more difficult, leads to
better post-operative LV function and survival.91, 92, 93, 94, 95, 96, and 97
 Reoperation rates are similar to MVR (10% at 10 years).98
 MVR is associated with higher operative mortality and less favorable outcomes compared to
surgery for AS, AR, or MS, as well as MV repair.
 Overall surgical mortality with MVR is 5-10%(higher for ischemic than for rheumatic/
myxomatous MR) and overall survival rates poor (5-85% at 5 years).99
 MVR with preservation of chordal apparatus is better post-operative LV function and survival.99,
100
, and ,
101 102
 MVR with resection of chordal apparatus is rarely performed given the better outcomes with
preserved chordal apparatus (necessary in rheumatic cases where the valve apparatus is
deformed).
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276
TABLE 12-10 Indications for surgical intervention in MR
Class I
1. Acute symptomatic severe MR
2. Chronic severe MR
- Symptomatic patients (NYHA Class II-IV) in absence of severe LV dysfunction (LVEF
<30% and/or LVIDs >55 mm)
- Asymptomatic patients with mild-moderate LV dysfunction (LVEF 30%-60%, LVIDs
>40 mm)
3. MV repair preferable to MVR if repair is feasible
Class II
1. Asymptomatic chronic severe MR
- New onset AF
- Pulmonary HTN ( >50 mm Hg at rest, >60 mm Hg with exercise)
- MV repair in patients with preserved LV function (LVEF >60% and LVIDs <40 mm) if
likelihood of successful repair >90%
- MV repair in patients with severe LV dysfunction (LVEF <30% and/or LVIDs >40
mm) if likelihood of successful repair >90%
277
Disease.1
TABLE 12-11 Severity of MS
Severity of MR Mild Moderate Severe
Parameter
Mean gradient (mm Hg) <5 5-10 >10
PA systolic pressure (mm Hg) <30 30-50 >50
Valve area (cm2) >1.5 1.0-1.5 <1.0
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MITRAL STENOSIS
Background
 The normal MV area is 4 to 6 cm2.
 A diastolic transmitral gradient and symptoms appear at valve areas <2 cm2.103
278
 Rheumatic carditis is the predominant cause of MS.
 MS found in ~ 40% of patients with chronic rheumatic heart disease. 104,105
 The ratio of women to men in isolated MS is 2:1.104,105

 Grading severity is based on valve area, gradient, and degree of pulmonary HTN.
Etiology
 Rheumatic heart disease is the major cause of acquired MS; congenital MS is rare (see Table
12-12).
 Other rare causes of acquired mitral inflow obstruction include atrial myxoma, valve thrombus,
mucopolysaccharidosis, and severe mitral annular calcification.
Pathophysiology
 Obstruction leads to increased diastolic pressure between the left atrium and LV.
 Transmitral gradients increase with more severe obstruction and higher flow rates across the
MV (fever, anemia, exercise, and co-existing MR).
 Progressive limitation of cardiac output with rise in left atrial pressure (LAP) and pulmonary
HTN.
 Increased LAP leads to chamber enlargement and low-velocity flow.
 AF develops due to high LAP and rheumatic insults to the left atrium.
 AF further reduces flow velocity (especially in LA appendage), leading to a very high risk of
thrombus.
 Pulmonary HTN develops due to high LAP and pulmonary vascular remodeling.
 Chronic pulmonary HTN can lead to RVH, RV dilation, and RV failure.
 LV systolic function is typically preserved, but forward stroke volume may be impaired due to
impaired diastolic filling from the MS or RV overload.
History
 Insidious onset of fatigue and exercise intolerance due to decreased forward cardiac output
 Dyspnea on exertion, paroxysmal nocturnal dyspnea (PND), and pulmonary edema from
accompanying elevated LAP
 Right heart failure (edema, ascites) can arise from pulmonary HTN.
 AF and/or embolic events can be the first manifestations of MS.
 Less common presentations include hemoptysis (severe MS) and hoarseness (compression of the
recurrent laryngeal nerve from a giant LA)
 Recurrent pulmonary infections are common in severe MS.

 Hemodynamic stresses (anemia, infection, pregnancy) are common precipitants.
279
P.199
TABLE 12-12 Etiology of MS
Etiology Notes
Acquired causes
1. Rheumatic heart Rheumatic heart disease is the most common
disease
2. Carcinoid heart disease cause of acquired MS. Fusion of one/both commissures,
3. Fabry disease with thickening/fibrosis calcification
4. Mucopolysaccharidosis of valves. Other valves involved in rheumatic
5. Rheumatoid arthritis heart disease in one third of cases (tricuspid
6. SLE disease and AR most frequently)
7. Atrial tumor
8. Large vegetation
9. Whipple disease
10. Gout
Congenital
280
1. Supravalvular ring Congenital abnormalities frequently associated
2. Mitral valve with other left ventricular outflow tract (LVOT)
abnormalities obstruction and ventricular septal defect (VSD)
Natural History
 Stable course initially, followed by accelerated progression in later life 104, 105, and 106
 Rate of progression 0.09 to 0.32 cm2/year (slower in United States and Europe107,108)
 The interval between acute rheumatic fever and symptomatic MS is ~15 years. 109
 Once symptoms develop, another ~10 years before symptoms become disabling 104
 Overall, the 10-year survival of untreated patients is 50% to 60%,105,106 but 0% to 15% once
disabling symptoms develop.104, 105, and 106,110,111
 Mortality in MS is due to progressive systemic/pulmonic congestion, thromboembolism, and

infection (higher rates of pneumonia).
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281
FIGURE 12-4 Management algorithm: aortic stenosis. PBMV, perculaneous balloon mitral valvuloplasty;
PASP, pulmonary artery systolic pressure; MVG, mitral valve gradient.
Physical Exam
 JVP: Normal or elevated with prominent CV wave from TR
 Loud snapping S1
 Opening snap (medium-high pitch) not heard with heavy calcification, mixed mitral disease,
pulmonary HTN, RV dilation
 A shorter S2-OS interval indicative of more severe disease
 The diastolic rumbling murmur is best heard in the midprecordial area.
 In severe MS, the murmur is pandiastolic.
282
 TR and pulmonic regurgitation murmur (Graham-Steele murmur) if pulmonary HTN is present
 Chest x-ray is normal early in disease but LAE and pulmonary HTN develop later.
 ECG commonly shows LAE and AF (RVH, RAD if pulmonary HTN).
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 Echocardiography
o Quantification of stenosis severity (see Table 12-11) based on valve area, transmitral
gradient, and pulmonary HTN
o Valve morphology (restricted leaflet opening and doming of anterior
leaflet/immobility of posterior leaflet) and evaluation for MR, as well as other valve
disease (associated rheumatic AS in 17%, AR in 8%, and TR in 38%) 112
o Rule out other causes of obstruction (LA myxoma, parachute MV, Cor triatrium).
 Wilkins valve score (leaflet thickening, calcification, mobility, subvalvular involvement) to
determine suitability for balloon valvulotomy
 Formal exercise testing with measurement of transmitral gradient and PA pressures may help
determine timing of intervention.
 Serial follow-up of asymptomatic patients: Severe MS - yearly TTE; moderate MS - TTE every 1
to 2 years; mild MS - every 3 to 5 years

 TEE if TTE is inadequate or to rule out thrombus prior to percutaneous intervention.
 Useful if there is discrepancy between clinical and noninvasive data
 Gorlin formula can be used to determine MVA and PVR.

 Angiography pre-operatively to screen for CAD if cardiac risk factors present
 Identification of patients who will benefit from intervention (see Table 12-13)
 Periodic evaluation: Subjective assessment of symptom status and objective assessment of LV
function/size and exercise tolerance
 Annual follow-up with the indication for chest x-ray, ECG, or TTE based on severity of MS
 Holter monitoring in patients with palpitations in the absence of documented AF
283
Medical Therapy
 Medical therapy cannot address mechanical obstruction to mitral inflow.
 Asymptomatic patients with mild MS in sinus rhythm need no specific therapy.
 Patients with AF or atrial flutter (30%-40%) have high risk for thromboembolism and need
anticoagulation, but data specific to MS is limited.113, 114, and 115
 Patients with MS/AF should have efforts to restore sinus rhythm (balloon valvulotomy or
cardioversion with adjunctive antiarrhythmic therapy).
 Anticoagulation may be considered for asymptomatic patients with severe MS NSR, if LA
dimension >55 mm Hg even in sinus rhythm.1
 Endocarditis and rheumatic fever prophylaxis
 Avoidance of strenuous activity (increases in HR lead to high LAP) but low-level aerobic activity
is recommended to prevent deconditioning
 Beta blockers are useful for patients with exertional symptoms (blocks tachycardia).
 Salt restriction and diuretics for patients with pulmonary congestion
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TABLE 12-13 Indications for intervention in MS
Indications for percutaneous mitral balloon valvulotomy
Class I
1. Moderate/severe MS with NYHA II-IV symptoms with favorable morphology if no atrial
thrombus or moderate/severe MR
2. Asymptomatic moderate/severe MS with pulmonary HTN (>50 mm Hg at rest, >60 mm Hg
with exercise) if morphology is favorable and no concomitant left atrial
thrombus/significant MR
Class II
284
1. Symptomatic (NYHA II-IV) moderate/severe MS with nonpliable calcified valve if NOT a
candidate for surgical intervention or high risk for surgery
2. Symptomatic patients (NYHA II-IV) with valve area >1.5 cm2 if there is evidence of
pulmonary HTN (>50 mm Hg at rest and >60 mm Hg with exercise)
3. Asymptomatic patients with moderate/severe MS with favorable morphology with new
onset AF (if no left atrial thrombus/significant MR)
Class III
1. Mild MS
2. Mild MS with left atrial thrombus, significant MR
Indications for surgery
Class I
1. Symptomatic moderate/severe MS with acceptable operative risk when (a) percutaneous
mitral valvulotomy is not available or contraindicated or (b) unfavorable anatomy is
present
2. Symptomatic patients with moderate/severe MS with concomitant severe MR
Class II
1. MV replacement for symptomatic patients with severe MS and severe pulmonary HTN
who are not candidates for percutaneous intervention or surgical commisurotomy
2. MV repair for asymptomatic patients with moderate or severe MS who have had
285
recurrent embolic events while receiving adequate anticoagulation with favorable
anatomy for repair
Class III
1. MV repair is not indicated in mild MS
Disease.1
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Percutaneous Intervention: Mitral Balloon Valvulotomy
 The preferred procedure in select patients with pliable, noncalcified valves and minimal fusion
of the subvalvular apparatus
 In these patients, immediate and long-term results (3-7 years) are comparable to surgical
commissurotomy.116, 117, and 118
 The mean valve area usually doubles, with a 50% decrease in transmitral gradient in the
immediate postprocedure period.
 Long term follow-up (3-7 years): 90% of patients free of events remain in NYHA I-II.
 Outcomes are heavily dependent on operator experience.
 Complications include severe MR (2%-10%), large residual ASD (5%), LV perforation (0.5%-4 %),
embolic events (0.5%-3%), and MI (0.5%).103
 Postprocedure: Baseline TTE at 72 hours and consideration for immediate surgery if either
severe MR or large residual ASD is present
 Relative contraindications to PMV include: Significant (3-4+) MR; Left atrial thrombus;
Unfavorable valve anatomy (calcied valve, high Wilkins score)
Surgical Intervention
 Surgical commissurotomy or MVR are options.
 Surgical commissurotomy can be done open or closed.
286
 Closed procedures are procedures of choice in developing countries whereas open procedures
are preferred in developed countries.
 Open procedures allow direct inspection of the valve.
 Commissurotomy is usually combined with left atrial appendage resection.
 Long-term outcomes are clearly better for commissurotomy than for medical therapy. 118, 119, 120,
and 121
 Five-year event-free survival rates of 80% to 90% with re-operation rate of 4% to 7%
 MVR is an acceptable option in patients who are not candidates for surgical commissurotomy or
percutaneous valvulotomy.
 The risk of surgery is lower in young patients with normal LV function, good functional status,
and no comorbid diseases such as CAD.
 Peri-operative mortality ranges from less than 5% to 20%.
 Preservation of the mitral valve apparatus is preferable (to preserve LVEF) but often not
possible in rheumatic MS.

 Complications include valve thrombosis, valve dehiscence, valve malfunction, and embolic
events.
RIGHT-SIDED VALVE DISEASE

Background
 Due to primary valve disease or pulmonary HTN
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 Primary valve abnormalities are usually congenital and diagnosed early.
 In adults, right-sided valve disease is usually due to pulmonary HTN.
 Less common acquired causes include trauma, endocarditis, and drugs.
 Difficult to assess impact on the RV (complex RV dimensions make quantification of the RV

function difficult)
TRICUSPID VALVE DISEASE

Tricuspid Regurgitation
 Primary TR is due to primary valve abnormalities.
 Secondary TR is due to conditions that affect the RV (pulmonary HTN, chronic obstructive
pulmonary disease (COPD), RV dysplasia, ischemia, posttransplant state).
287
 Primary causes include congenital etiologies (Ebstein anomaly) and acquired conditions
(rheumatic heart disease, myxomatous degeneration, endocarditis, carcinoid, endomyocardial
fibrosis, trauma, and iatrogenic causes).
 Secondary causes are more common.
 Moderate-to-severe TR is frequently well tolerated.
 There is little information on natural history.
 Patients s/p TV resection tolerate severe TR well for several years. 122
 Other concomitant valve disease is usually present and usually dictates clinical course.
 Isolated severe TR presents with fatigue, exercise intolerance, and RV failure.
 Physical exam: Prominent jugular V wave, jugular venous distension, hepatomegaly +/-
pulsatility, a classic holosystolic murmur at the LLSB that increases with inspiration (murmur
heard only 20% of cases)123,124
 Echocardiography: Severe TR with systolic flow reversal in hepatic veins
 Patients with mild-to-moderate TR do not require any specific therapy.

 Medical therapy is designed to control peripheral venous congestion with diuretics.
 Surgical intervention considered for patients with severe TR
 The most common procedure is annuloplasty (surgical plication vs. complete ring vs.
semicircular ring).
 Many patients have residual TR, and 40% develop TS.125
 TV replacement is performed only if annuloplasty is not feasible or fails.
 Variable outcomes
 Heart block is the main complication.

 High risk of valve thrombosis with mechanical valves (4%-30%)126
Tricuspid Stenosis
 Primarily due to rheumatic heart disease127; only 3% to 5% of patients with rheumatic heart
disease have tricuspid stenosis (TS)
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 Rare etiologies: Carcinoid, congenital defects, endocarditis, and Whipple disease
 Majority of patients have concomitant mitral disease and TR
 There are limited data on natural history, but TS usually takes a slowly progressive course.
 Clinical presentation with fatigue, dyspnea, edema
 Physical exam notable: OS, diastolic murmur at RLSB (murmur often inaudible)
288
 ECG shows AF in 90% of cases
 Chest x-ray: RAE
 Rheumatic involvement with commissural fusion and diastolic doming
 Findings can be subtle.
 Doppler evaluation
 Medical therapy with diuretics often ineffective

 Optimal surgical intervention for severe TS: Direct tricuspid commissurotomy +/- annuloplasty
Pulmonic Stenosis
 The majority of cases (95%) are due to congenital abnormalities; 85% occur as an isolated
defect, but can occur in association with other congenital defects (tetralogy of Fallot,
pulmonary artery aneurysms).
 Other rare etiologies include carcinoid disease and rheumatic heart disease.
 Patients with mild PS (gradient <50 mm Hg) are rarely symptomatic, and outcomes are good
without surgical intervention.128, and 129
 Severe PS (>80 mm Hg) typically leads to fatigue and dyspnea on exertion, and right heart
failure and surgery may be beneficial.129
 Clinical outcomes for patients with moderate stenosis (50-80 mm Hg)
 Overall survival at 25 years was 96% in a natural history study,129 and predictors of poor
outcome include presence of symptoms, cardiomegaly on chest x-ray, hypotension, and
elevated right sided pressures.
 Physical examination
 Crescendo-decrescendo systolic murmur loudest at left upper sternal border (LUSB)
 Radiation to the suprasternal notch and left neck
 Loud late-peaking murmur is suggestive of severe obstruction.
 An ejection click may be heard.
 Thickened pulmonic leaflets with doming in systole
 Severity based on transpulmonic velocity and gradient (severe: Velocity >1.2m/s and gradient
>80mm Hg)
 Pulmonary HTN
 Cardiac catheterization is not typically required unless clinical data and noninvasive data are
discordant.
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289
 There is a limited role for medical therapy.
 The intervention of choice for severe PS is balloon valvuloplasty, which has low morbidity and
mortality and generally leads to decrease in gradient by two thirds.

 Accompanying subvalvular stenosis often regresses after valvuloplasty.
Pulmonary Regurgitation
 Small degrees of PR present in normal adults.
 Pathologic PR occurs after intervention for congenital heart disease (tetralogy of Fallot), and
can also be due to rheumatic heart disease, carcinoid disease, or endocarditis.
 PA/annular dilatation due to pulmonary HTN, Marfan syndrome, or volume overload (as seen in
renal failure) can also lead to PR.

 Patients with mild PR have a benign course.
 Patients with moderate/severe PR can develop chronic RV volume overload, dilation, and
failure.
 Physical exam
 The soft, diastolic, decrescendo diastolic murmur over LUSB may be difficult to hear.
 May be accompanied by PS murmur
 Echocardiogram
 Abnormal diastolic flow in right ventricular outflow tract (RVOT)
 Holodiastolic flow reversal in PA
 Severity graded qualitatively (0-4+) on extent of color flow

 RV dilation and dysfunction
 No specific therapy is required for mild PR.
 Surgical intervention should be considered for severe PR with evidence of progressive RV
dilation/dysfunction.
 Surgical procedure of choice is placement of a homograft conduit, although a prosthetic valve
can be used as well.

 RV size and functional status can improve after surgery. 130
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19. CHAPTER 13 - Endocarditis

CHAPTER 13
Endocarditis
Todd L. Kiefer
Fred A. Lopez
Randall Vagelos
NATIVE VALVE ENDOCARDITIS
Etiologies , 1 2
 Staphylococcus aureus: Increasing prevalence; Streptococcus viridans; Streptococcus species:
S. mitis, S. mutans, S. bovis, S. sanguis; Coagulase-negative Staphylococcus species:
Staphylococcus lugdunensis is quite virulent;Enterococcus species; Gram-negative bacilli;
Fungi: Candida and Aspergillus species
 Other less common organisms, which are often “culture negative”: HACEK organisms
(Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis,
Eikenella corrodens, Kingella kingae), Abiotrophia species, Bartonella quintana, Bartonella
300
henselae, Tropheryma whipplei, Legionella, Coxiella burnetii, Brucella species, Chlamydia

psittaci, Mycoplasma, Neisseria gonorrhoeae
Clinical Presentation 3
Fever, weight loss, fatigue, anorexia, arthritis/arthralgias, myalgias, skin manifestations, cough, mental
status changes, headache
Risk Factors
Mitral valve prolapse (most common), other valvular abnormalities, hemodialysis, indwelling vascular
catheters, intravenous drug use
Differential Diagnosis/Endocarditis Mimics 4
Atrial myxoma, carcinoid valve disease, myxomatous valve degeneration, papillary fibroelastoma,
Lambl excrescence, ruptured chordae, thrombus or stitch after valvular surgery, eosinophilic heart
disease, acute rheumatic fever, pulmonary embolus, CVA.
PHYSICAL EXAM
Cardiac auscultation for evidence of new heart murmur (in particular, murmur of valvular
regurgitation), Janeway's lesions, Osler's nodes (painful), splinter hemorrhages, Roth spots, skin
petechiae, oral petechiae, conjunctival hemorrhage, splenomegaly, clubbing, S3 gallop, lung crackles.
P.216
Electrocardiogram (ECG)
Evaluate for prolonged P-R interval or high-grade A-V block suggestive of aortic perivalvular abscess, or
evidence of other new conduction abnormalities
DIAGNOSIS5
Modified Duke Criteria for definite infective endocarditis: 2 major criteria or; 1 major and 3 minor
criteria or; 5 minor criteria
Major criteria: blood culture positive for typical organism from two separate blood cultures or
persistent culture positive from specimens greater than 12 hours apart or all of 3 or a majority of
greater than 4 separate cultures with an organism consistent with endocarditis, new valvular
regurgitation, echocardiogram positive for endocarditis (oscillating mass, abscess, or partial dehiscence
301
of prosthetic valve), evidence of endocardial involvement, blood culture positive for Coxiella burnetti
or IgG titer > 1:800.
Minor criteria: temperature > 38°C, vascular ( Janeway's lesions, emboli, mycotic aneurysm),
immunologic (Osler's nodes, Roth's spots, glomerulonephritis, positive rheumatoid factor), positive
blood culture not meeting major criteria or serological data supporting infection with organism known
to cause endocarditis, predisposing heart condition or intravenous drug use.
Laboratory evaluation:6 Blood cultures prior to antibiotics; if initial cultures are negative
(approximately 10%) and diagnosis is still suspected, alert lab to hold for fastidious organisms (HACEK
organisms); May also be associated with leukocytosis, anemia, and/or microscopic hematuria
Chest radiograph: May reveal septic pulmonary emboli from right-sided endocarditis
Echocardiography7, 8, and 9: Transsthoracic echo: Starting point for suspected native valve
endocarditis: Sensitivity: 32% to 63%; Specificity: 98% to 100%; Transesophageal echo: Next step if
transthoracic echocardiogram (TTE) nondiagnostic and endocarditis is still suspected; First step in
evaluation of patient with prosthetic valve (see section below), high clinical suspicion, or anticipated
difficulty imaging with TTE; Also perform pre-operatively if patient will undergo valve surgery:
Sensitivity: 94% to 100%; Specificity: 98% to 100%; Additional considerations for transesophageal
echocardiography (TEE): Enhanced ability to detect myocardial abscess, aneurysm, fistula
TREATMENT 10
Early cardiothoracic surgery consultation and evaluation with coordination of care involving infectious
diseases and cardiology consultants.
Antibiotic regimens: See reference 10 for dosing regimens.
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 Penicillin-sensitive Streptococcus viridans and S. bovis: Penicillin G or ceftriaxone for 4 weeks
OR Vancomycin for 4 weeks with penicillin allergy
 Penicillin-resistant Streptococcus viridans and S. bovis: Penicillin G or ceftriaxone for 4 weeks
with the addition of gentamicin for 2 weeks OR Vancomycin for 4 weeks with penicillin allergy
 Penicillin-sensitive Enterococcus: Ampicillin for 4-6 weeks with the addition of gentamicin for
4-6 weeks; penicillin G for 4-6 weeks with the addition of gentamicin for 4-6 weeks;
vancomycin and gentamicin for 6 weeks with penicillin allergy
 Oxacillin-sensitive Staphylococcus: Nafcillin or oxacillin for 6 weeks +/-3-5 days of gentamicin;
cefazolin for 6 weeks with penicillin allergy (not ananphylaxis)
302
 Oxacillin-resistant Staphylococcus: Vancomycin for 6 weeks
 HACEK endocarditis: Ceftriaxone or ampicillin/sulbactam or ciprofloxacin
(ampicillin/ceftriaxone allergy) for 6 weeks
 Inpatient parenteral antibiotics first 2 weeks of treatment when risk of embolism and other
complications is highest, then selection of lower-risk patients for outpatient parenteral
therapy based on published guidelines8
 High risk for outpatient therapy: congestive heart failure (CHF), arrhythmia, altered mental
status, perivalvular abscess, aortic valve disease, prosthetic valve disease, infection with S.
aureus, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides or N.

gonorrhoeae, betahemolytic Strep, gram-negative organisms, or fungal organism11
Indications for surgery:10 Class I: heart failure secondary to valve stenosis or insufficiency, aortic or
mitral insufficiency with elevated left ventricular end-diastolic or left atrial pressures, aortic
insufficiency with mitral valve preclosure, fungal endocarditis, infection with highly resistant organism,
heart block, abscess, fistula formation, or mitral leaflet perforation. Class IIa: recurrent embolic
events, persistent vegetation with appropriate antimicrobial therapy. Class IIb: mobile vegetation > 10
mm.
OUTCOMES
Overall mortality of 10% to 20% for hospitalized patients, 30% to 40% 1-year mortality12
 Right-sided endocarditis: Mortality less than 10%13
 Significant increase in 6-month survival with valve replacement surgery for left-sided
endocarditis using current criteria for valve replacement (16% vs. 33%); most significant
decrease in mortality seen in patients with evidence of moderate to severe CHF (14% vs. 51%)14
P.218
Five Predictors of 6-Month Mortality with Left-sided

Endocarditis 12
 Comorbid medical conditions, Altered mental status, Moderate to severe CHF, Organism other
than S. viridans, Medical therapy without valve replacement
Predictors of Early In-hospital Mortality (based on data 15
collected during initial 7 days of hospitalization)
 Diabetes mellitus, S. aureus endocarditis, Embolic event, Elevated APACHE II score
303
Complications , , 4 16 17
 Embolism: 20% to 40% of cases of endocarditis, of these cerebral - 62%, splenic - 49%, renal -
22%, coronary - 2%
 Risk of embolization increases with the size and mobility of the vegetation and mitral valve
presents a greater risk than aortic valve vegetation
 Abscess (local cardiac or metastatic)
 Vertebral osteomyelitis
 Septic arthritis
 Immune-complex glomerulonephritis
 Renal infarction
 Mycotic aneurysm
 Fistula: Most commonly between paravalvular infection and sinuses of Valsalva, aorta, or
pulmonary artery: Associated with > 50% mortality
 Valvular perforation
 Congestive heart failure
 Cardiogenic shock
 Arrhythmias (A-V block): Increased mortality associated with infranodal conduction block
 Sepsis
Relapse Rate 1
Most common in 4 weeks following termination of antibiotics: Higher relapse rates with Enterococcus, S.
aureus, Gram-negative bacilli, fungal pathogens
INFECTIVE ENDOCARDITIS ASSOCIATED WITH INTRAVENOUS DRUG

USE 13
 Etiologies: Staphylococcus species, Pseudomonas species, Fungi (Candida species)
 Clinical presentation: Fever, cough, pleuritic chest pain, hemoptysis

 Most commonly involves right-sided valves, can be left-sided or both leftand right-sided
P.219
 Chest radiograph: May demonstrate multiple pulmonary infiltrates suggestive of septic
pulmonary emboli
304
 Treatment:13 Two-week duration of nafcillin and gentamicin for uncomplicated right-sided
infection (i.e., absence of aortic/mitral valve involvement, not MRSA, no high-level gentamicin
resistance, no extrapulmonary evidence of metastatic infection, no renal insufficiency
 Predictors of worse outcome:13 HIV infection

 Increasing mortality with low CD4 levels (<200 cells/mL3)
PACEMAKER OR IMPLANTED CARDIOVERTER DEFIBRILLATOR (ICD)-

ASSOCIATED ENDOCARDITIS , , , and 18 19 20 21
 Etiology: S. aureus (most common less than 1 month postplacement), coagulase-negative
Staphylococci, Streptococci, Candida, Peptostreptococcus species, Propionibacterium acnes,
Enterobacteriaceae, Pseudomonas
 Cleveland Clinic series of device endocarditis in 123 patients with pacemaker or ICD: 68%
coagulase-negative Staphylococcus, 24% S. aureus, 17% Gram-negative rods, 13%
polymicrobial18
 Clinical Presentation: May have erythema or pain over device pocket, fever, chills, malaise,
anorexia
 Treatment: Complete system explant and antibiotic therapy
 In one series, 41% mortality with antibiotic therapy alone compared with 19% mortality with
antibiotics and pacemaker removal
 Duration: At least 4 to 6 weeks of parenteral antibiotics based on sensitivity of specific
organism isolated
 Timing of reimplantation of device: Literature varies with recommendations of 1 to 6 weeks
delay with patient remaining afebrile and with negative repeat blood cultures. Plan for
reimplantation on contralateral side.
 If pacemaker dependent, place temporary pacing wire with change every 5-10 days until
permanent device can be placed as outlined above
 If at high risk for lethal arrhythmia, patient may wear external defibrillator vest until ICD can
be replaced.
PROSTHETIC VALVE ENDOCARDITIS 22
 4% risk infectious endocarditis with mechanical prosthetic valve >5 years
 Higher incidence of early prosthetic valve endocarditis with surgery performed during active
infective endocarditis
 Aortic PVE more common than mitral PVE
 Early: Within 2 months of surgery up to 1 year (nosocomial)
 Etiologies: S. aureus, coagulase-negative Staphylococci, Gram-negative bacilli, fungi,

Enterococci, diphtheroids: Late—After 2 to 12 months postoperation (community-acquired)
305
P.220
 Etiologies: Streptococcus species, coagulase-negative Staphylococci, S. aureus, Enterococci
(i.e., similar to non-IVDU associated native valve endocarditis microbiology)
 Predisposing factors: Wound infection, intravascular catheter-associated infection, urinary
tract infection, pneumonia
o Treatment:10 Early cardiothoracic surgery consultation and evaluation with
coordination of care involving infectious diseases and cardiology consultants;
ACC/AHA antibiotic table
 HACEK endocarditis: Ceftriaxone or ampicillin/sulbactam 4 weeks or ciprofloxacin

(ampicillin/ceftriaxone allergy) for 6 weeks
Indications for surgery10: Class I: heart failure, dehiscence of prosthetic valve, increasing obstruction
or insufficiency of the infected prosthetic valve, paravalvular abscess. Class IIa: persistent bacteremia
or recurrent emboli in setting of appropriate antimicrobial therapy, relapsed infection following
therapy.
 Fungal prosthetic valve endocarditis will require surgery plus long-term antifungal therapy.
 Anticoagulation: Switch from warfarin to heparin given possibility of urgent surgery,
discontinue aspirin. Discontinue heparin if focal neurologic symptoms develop and image brain
 Outcomes:22 60% overall 10-year survival, 20% need repeat operation
 Predictors of worse outcome:22 With surgery for PVE
 Early mortality: Older age, female, longer bypass times, emergency surgery, Staph etiology,
positive intraoperative culture, severity of preoperative congestive heart failure
 Late mortality: Older age, male, decreased ejection fraction, fungal etiology, extent of
infection, and complexity of operative procedure
 Complications:22 Similar to native valve endocarditis
 One series reported a 36% incidence of myocardial abscess and a 63% incidence of paravalvular
abscess with prosthetic valve endocarditis. Relapse rate:1 10% to 15%
MARANTIC ENDOCARDITIS , , and 23 24 25
 Libman-Sacks: Patients with systemic lupus erythematosus: Most commonly involves mitral
valve
 Increased prevalence in lupus patients with positive anticardiolipin and/or lupus anticoagulant
antibodies
306
 Suggestion of predisposition to bacterial endocarditis from valvular damage and need for
antibiotic prophylaxis
 Lack of controlled trials to guide management
 Case reports of valve replacement

 No objective data demonstrating altered course with steroids
P.221
 Anticoagulation recommended for patients with valvulopathy and thromboembolic event
 No recommendation for primary prevention anticoagulation at this time
 Underlying neoplasm:25 Anticoagulation recommended for nonbacterial thrombotic endocarditis
and systemic or pulmonary emboli

 Anticoagulation also recommended for patients with disseminated cancer or debilitating
disease and marantic vegetations on echo25
INDICATIONS FOR ENDOCARDITIS PROPHYLAXIS AND ANTIBIOTIC

RECOMMENDATIONS 26
 Prosthetic heart valve
 Prosthetic material used for valve repair
 History of prior infectious endocarditis
 Patients with cardiac transplant valvulopathy
 Cyanotic congenital heart disease-unrepaired
 Cyanotic congenital heart diasease—surgically or percutaneously repaired in the first six
months following repair
 Surgically or percutaneously repaired congenital heart disease with residual defect that
impairs endothelialization process26
 Prophylaxis is recommended for dental procedures that will disrupt gingival or periapical tissue
or oral mucosa.26
 Prophylaxis is no longer indicated for gastrointestinal or genitourinary procedures.24
REFERENCES
1. Mylonakis E, Calderwood SB. Infective endocarditis in adults. N Engl J Med. 2001;345:1318-1330.
2. Hoen B, Epidemiology and antibiotic treatment of infective endocarditis: an update. Heart. 92:1694-
1700, 2006.
307
3. Crawford MH, Durack DT. Clinical presentation of infective endocarditis. Cardiology Clinics. 21:159-
166, 2003.
4. Baddour LM, et al. Infective endocarditis. Circulation. 111:394-434, 2005.
5. Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke criteria for the diagnosis of
infective endocarditis. Clin Infect Dis. 2000;30:633-638.
6. Moreillon P, Que Y, Infective endocarditis. Lancet. 363:139-149, 2004.
7. Erbel R, Rohmann S, Drexler M, et al. Improved diagnostic value of echocardiography in patients with
infective endocarditis by transesophageal approach. A prospective study. Eur Heart J. 1988;9:43-53.
8. Shively BK, Gurule FT, Roldan CA, et al. Diagnostic value of transesophageal compared with
transthoracic echocardiography in infective endocarditis. J Am Coll Cardiol. 1991;18:391-397.
P.222
9. Fowler VG, Li J, Corey GR, et al. Role of echocardiography in evaluation of patients with
Staphylococcus aureus bacteremia: Experience in 103 patients. J Am Coll Cardiol. 1997;30:1072-1078.
10. Bonow RO, et al. ACC/AHA 2006 Guidelines for the management of patients with valvular heart
disease. Am J Cardiol. 48:1-148, 2006.
11. Andrews MM, von Reyn CF. Patient selection criteria and management guidelines for outpatient
parenteral antibiotic therapy for native valve infective endocarditis. Clin Infect Dis. 2001;33:203-209.
12. Hasbun R, Vikram HR, Barakat LA, et al. Complicated left-sided native valve endocarditis in adults.
JAMA. 2003;289:1933-1940, 2003.
13. Moss R, Munt B. Injection drug use and right sided endocarditis. Heart. 2003;89:577-581.
14. Vikram HR, Buenconsejo J, Hasbun R, et al. Impact of valve surgery on 6-month mortality in adults
with complicated, left-sided native valve endocarditis: A propensity analysis. JAMA. 2003;290:3207-
3214.
15. Chu VH, Cabell CH,Benjamin DK,et al.Early predictors of in-hospital death in infective endocarditis.
Circulation. 2004;109:1745-1749.
16. Habib G. Management of infective endocarditis. Heart. 2006;92:124-130.
17. Sexton DJ, Spelman D. Current best practices and guidelines. Cardiol Clin. 2003;21:273-282.
308
18. Chua JD, Wilkoff BL, Lee I, et al. Diagnosis and management of infections involving implantable
electrophysiologic cardiac devices. Ann Intern Med. 2000;133:604-608.
19. Karchmer AW, Longworth DL. Infections of intracardiac devices. Cardiol Clin. 2003;21:253-271.
20. Darouiche RO. Treatment of infections associated with surgical implants. N Engl J Med.
2004;350:1422-1429.
21. Cacoub P, Leprince P, Nataf P, et al. Pacemaker infective endocarditis. Am J Cardiol 82:480-484,
1998.
22. Mahesh B, Angelini G, Caputo M, et al. Prosthetic valve endocarditis. Ann Thorac Surg.
2005;80:1151-1158.
23. Gonzalez-Juanatey C, Gonzalez-Gay MA. Libman-Sacks endocarditis and primary antiphospholipid
syndrome. J Heart Valve Dis. 2005;14:700-702.
24. Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome:
Recommendations for treatment. Committee consensus report. Lupus. 2003;12:518-523.
25. Salem DN, Daudelin DH, Levine HJ, et al. Antithrombotic therapy in valvular heart disease. Chest.
2001;119:207-219.
26. Wilson W, et al. Prevention of infective endocarditis: Guidelines from the American Heart
Association. Circulation. 116:1736-1754, 2007.
20. CHAPTER 14 - Pericardial Disease

CHAPTER 14
Pericardial Disease
Todd L. Kiefer
Randall Vagelos
ACUTE PERICARDITIS , 1 2
 Etiologies: Idiopathic, viral, tuberculosis (TB), coccidiomycosis, uremia, collagen vascular
diseases, neoplasm, trauma, post-myocardial infarction—two types: 1 to 3 days post-
transmural infarct and weeks to months postinfarction (Dressler syndrome), prior external
beam radiation, HIV
309
 Clinical presentation: Substernal chest pain, pleuritic in nature, +/- radiation to left arm,
often radiates to trapezius, pain diminished with sitting up and leaning forward, pain
exacerbated with lying supine
o Patient may provide history of fever or recent viral illness
 Differential diagnosis: Myocardial infarction, pulmonary embolism, aortic dissection,
pneumothorax, pleurisy, costochondritis, gastroesophageal reflux
 Physical exam: Triphasic (ventricular systole, early diastole, and atrial contraction) friction
rub in 85% of patients, radiates from left lower sternal border to apex, exam often fluctuates
 Electrocardiogram (ECG): Diffuse ST segment elevation with the exception of leads avR and V1
FOUR STAGES OF ECG ABNORMALITIES 1
 Diffuse concave S-T elevation and P-R depression
 Normalization S-T and P-R segments
 Diffuse T wave inversions

 Normalization of T waves
 Laboratory evaluation: +/- Elevated white blood cell count with lymphocyte predominance,
elevated ESR suggests TB or autoimmune etiology, may see minimal troponin elevation (greater
elevation suggests
P.224
myocardial infarction or myocarditis), blood cultures if fever and elevated WBC, pericardial
fluid culture if purulent pericarditis is suspected and pericardiocentesis is performed
 Echocardiography: Usually normal, may see pericardial effusion
 Treatment: Nonsteroidal anti-inflammatory drugs—ibuprofen 600 to 800 mg p.o. tid for 2
weeks
 Prednisone taper over weeks to a month if no improvement with ibuprofen
 Consider evaluation for underlying etiology if recurrent
 Colchicine (COPE Trial):3 One hundred twenty patients with first episode pericarditis from
connective tissue disease, postpericardiotomy, or idiopathic etiology were randomized to
aspirin+colchicine versus aspirin alone, and the aspirin+colchicine treatment arm resulted in
significantly decreased symptoms at 3 days and recurrent symptoms at 18 months.
 Predictors of worse outcome:1 Temperature >38°C, symptoms of several weeks duration in an
immunosuppressed patient, traumatic etiology, development of pericarditis while on oral
anticoagulation, large effusion greater than 20 mm, evidence of purulent pericarditis without
310
antibiotic treatment >24 hours, postradiation pericarditis often progresses to
effusive/constrictive pericarditis
 Complications: Enlarging effusion progressing to cardiac tamponade, development of chronic

constrictive pericarditis
PERICARDIAL EFFUSION , 1 2
 Etiologies: Neoplasm (lung, breast, lymphoma, melanoma), pericarditis, postradiation therapy,
trauma, infection (bacterial, fungal, HIV, mycobacterium), uremia, collagen vascular disease,
hypothyroidism
 Cardiac tamponade: Pericardium exquisitely sensitive to fluctuations in volume over time and
will not hemodynamically tolerate rapid accumulation of fluid
 Right heart low-pressure system which is susceptible to compression
 Clinical presentation: +/- Chest pain, dyspnea
 Physical exam: Tachycardic, jugular venous distention, decreased heart sounds, paradoxical
pulse: >10mm Hg decrease in systolic arterial pressure with inspiration (can have absent
brachial or radial pulse on palpation with inspiration)
 ECG: Low voltage, electrical alternans (beat to beat variation in voltage)
 Invasive hemodynamic data:4 Characteristic fall in aortic pressure with inspiration and right
atrial pressure tracing pattern with steep x-descent and lack of y-descent
 Echocardiography:1 Right atrial collapse with expiration (sensitive)

o Right ventricular collapse greater than one third of diastole (specific)
P.225
 Mitral inflow velocity: With inspiration mitral valve inflow velocity decreases and tricuspid
valve inflow velocity increases
o Treatment: If tamponade physiology is present administer IV fluids to temporize until
pericardiocentesis is performed.
 Use caution with intubation and initiation of mechanical ventilation as positive end-expiratory
pressure may induce cardiovascular collapse from further decrease in preload.
PERICARDIAL CONSTRICTION , , , , and 4 5 6 7 8
 Etiologies: Postpericarditis, postradiation therapy, postcardiac surgery, TB pericarditis
 Clinical presentation: Consistent with low cardiac output state manifested by decreased
exercise tolerance, cardiac cachexia/wasting, ascites, edema
311
 Physical examination: Jugular venous distention with rapid x and y descent
Kussmaul's sign: Lack of fall or increase in jugular venous distention (RA pressure) with
inspiration due to pericardial limitation preventing transmission of intrathoracic pressure

variation to the cardiac chambers
Pericardial knock: High-pitched, early diastolic sound due to sudden cessation of right
ventricular filling from rigid pericardium
 Laboratory evaluation: Transaminitis (“cardiac cirrhosis”), BNP <200 usually
 ECG: P waves with evidence of intra-atrial conduction delay
 Chest radiograph: Globular heart, calcified pericardium, pleural effusions, rarely pulmonary
edema
 Imaging: Transthoracic echocardiography, transesophageal echocardiography (increased
sensitivity compared with transthoracic), computed tomography scan, magnetic resonance

imaging—pericardium greater than 2 mm supports diagnosis; echocardiographic evidence of
marked respiratory variation of greater than 25% in the mitral inflow E wave velocity
(decreases with inspiration and increases with expiration)1
 Echocardiographic evidence of marked respiratory variation of greater than 25% in the mitral
inflow E wave velocity (decreases with inspiration and increases with expiration)
 Clinical pericardial constriction can occur without evidence of calcification or thickening on
imaging.
 Hemodynamic evaluation:7, and 8 Equalization of diastolic pressure in all four cardiac
chambers with the pericardial pressure due to the rigid pericardium
o Hemodynamic data to support a diagnosis of constriction:7,8

 LV/RV interdependence
 LVEDP-RVEDP < 5 mm Hg
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 Pulmonary artery systolic pressure < 55 mm Hg
 RVEDP/RVSP > 1/3
 Inspiratory decrease in right atrial pressure <5 mm Hg
 LV rapid filling wave >7 mm Hg
 PCWP/LV respiratory gradients >5 mm Hg
 “Dip and plateau” or “square root sign” waveform of ventricular diastolic pressure due to
limitation of rapid early diastolic filling from the rigid pericardium
312
 Simultaneous left and right heart catheterization demonstrates ventricular interdependence
(discordance) with increased right ventricular and decreased left ventricular systolic pressure
during inspiration.
 Treatment: Pericardiectomy (mortality 6%-12% in various series)
REFERENCES
1. Little WC, Freeman GL. Pericardial disease. Circulation. 2006;113:1622-1632.
2. LeWinter MM, Kabbani S. Pericardial diseases. In: Zipes DP, Libby P, Bonow RO, Braunwald E, eds.
Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed. Philadelphia: Elsevier
Saunders; 2005:1757-1779.
3. Imazio M, et al. Colchicine in addition to conventional therapy for acute pericarditis: results of the
colchicine for acute pericarditis (COPE) trial. Circ. 112:2012-2016, 2005.
4. Sharkey SW. Beyond the wedge: Clinical physiology and the Swan-Ganz catheter. Am J Med.
1987;83:111-122.
5. Hancock EW. Differential diagnosis of restrictive cardiomyopathy and constrictive pericarditis. Heart.
2001;86:343-349.
6. Nishimura RA. Constrictive pericarditis in the modern era: A diagnostic dilemma. Heart. 2001;86:619-
623.
7. Talreja DR, et al. Constrictive pericarditis in the modern era: Novel criteria for diagnosis in the
catheterization laboratory. Jrnl. of Am Coll Cardio. 51:315-319, 2008.
8. Higano ST, et al. Hemodynamic Rounds Series II: Hemodynamics of constrictive physiology: Influence
of respiratory dynamics on ventricular pressures. Cath. Cardio. Interven. 46:473-486, 1999.
21. Appendix
21.1 APPENDIX A - Central Vascular Access Techniques
APPENDIX A
Central Vascular Access Techniques
Ian Brown
ASEPTIC PROCEDURES
When performing elective central venipuncture, the provider must follow sterile procedures. Once the
skin is grossly clean, scrub a wide area with 2% chlorhexidine for 30 to 60 seconds. Chlorhexidine is
313
preferred over povidone-iodine (Betadine) or alcohol because it reduces catheter-related infection.1,2
The provider should wash hands with antibacterial soap and water or an alcohol-based waterless
product.3,4 For elective central venous catheter (CVC) placement, the provider should use surgical cap,
gown, sterile gloves, mask with face shield, and full-body drape.5 Scheduled line changes and reducing
the number of lumens of a catheter are not useful for preventing infection.1,6
Tips
 Have all instruments, kits, and tubes ready at bedside, such that they can be opened in sterile
fashion if needed.
THE SELDINGER TECHNIQUE

See Table A-1.
PREPARE
Most hospitals stock prepared kits containing the basic required equipment for placement of a central
venous catheter (CVC) except for sterile gloves, saline flushes, and needleless saline-lock hubs.
Equipment Needed
 Preparation and drape: chlorhexidine (2% solution with applicator), full-body fenestrated
drape, sterile gloves, gown, mask, and surgical cap
 Anesthetic: 1% lidocaine, 5-mL syringe, and 26-gauge needle
 Placement: needle capable of passing guidewire, 10-mL syringe, guidewire, 11-blade scalpel,
skin dilator, and catheter of desired size
 Flushing: saline flushes and saline-lock hubs
 Securing the catheter: needle driver, 4-0 or larger nonabsorbable suture material or stapler,
suture scissors, and transparent dressing

 Other: antibiotic ointment, gauze pads, and IV tubing
P.228
TABLE A-1 General overview of Seldinger Technique
314
General Indications Relative Contraindications General Risks
Arterial
Emergency access Distorted anatomy puncture
Hematoma
Inadequate peripheral IV Overlying lesions (e.g., infection,
sites burn, abrasion) Air embolism
Extended need for IV access Risks for sclerosis or thrombosis (e.g., Infection
Frequent blood draws prior long-term cannulation,
Nerve injury
Special procedures (e.g., PA radiation therapy) Pain
catheter, CVP monitoring, Proximal vascular injury Aberrant
placement
transvenous pacemaker) Severe coagulopathy Arrhythmia
Uncooperative patient Failure of
procedure
Inexperienced provider Vessel
thrombosis
Arteriovenous
fistula
PA, pulmonary artery; CVP, central venous pressure.
PROCEDURE
315
 Preparation and drape: use aseptic technique
 Anesthetic: in conscious patients apply lidocaine. Superficially, use a skin wheal. Anesthetize
deeper layers including clavicular periosteum if subclavian vein is used.
 Catheter placement (see Figure A-1): While applying negative pressure (i.e., pulling back on
syringe plunger) advance needle into vessel (A) until flash of blood in the syringe. Pass the
guidewire through the needle (B) into the vessel. Remove the needle (C) while the guidewire
remains. Placing the flat edge of an 11-blade scalpel parallel to the wire (D), push down to
incise the skin. Depending on the kit used, dilation is either performed by a catheter-over-
dilator method (as with a Cordis introducer sheath kit), or a separate dilator and catheter. The
combined equipment is depicted in Figure A-1. The catheter-over-dilator is threaded onto the
guidewire (E). With a firm twisting motion, the dilator and catheter are advanced into the vein
(F). Then the dilator is removed with the catheter remaining in the vessel (G). (If a separate
dilator is used, after dilation, the dilator is removed while the wire remains. Then place the
catheter over the wire into the vessel.) Advance the catheter such that the tip is in the desired
position, usually in the vena cava near the right atrium. Remove the wire. Never let go of the
wire as long as it is in the patient.
P.229
 Flush - Perform phlebotomy as needed. Attach saline-lock hub. Attach flush-syringe and pull
back and confirm good blood flow into syringe. Flush with 10 mL of saline.
 Secure the catheter to the skin with sutures or staples. Depending on the kit used, there is
often a butterfly clip and a locking cap that can be used for securing the catheter. Clean, dry,
and cover with antibiotic ointment and transparent dressing.
316
FIGURE A-1 Catheter placement in the Seldinger Technique.9
P.230
TIPS
 Watch the New England Journal of Medicine procedure video on CVC.7
317
 Always order postprocedure chest radiograph after upper body CVC insertion. Specifically
review for pneumothorax, hemothorax, and line position.
 If unsure whether catheter is in vein or artery, consider color and pressure of blood. If readily
available, check arterial blood gas (ABG) or use pressure transducer. Never dilate the vessel if
the wire may be in the artery.
 If using an upper extremity site, prepare both the neck and ipsilateral chest for all jugular and
subclavian approaches.
 Always aspirate before injection of an anesthetic.
 Multiple sticks increase likelihood of complications.
 If multiple sticks are used, be sure to flush, or replace, needle after each stick (lidocaine can
be used).
 When treating severe sepsis, consider placement of CVC capable of measuring central venous
oxygen saturation for use in early goal-directed therapy.8
Infraclavicular Approach to the Subclavian Vein

See Table A-2.
Pros: Low rate of infection. Easily identifiable landmarks. Maximizes patient mobility.
Cons: Higher rate of pneumothorax. Noncompressible vessels. Painful.
Position: The patient should be supine to 15-degree Trendelenburg's position, as tolerated, to decrease
chance of air embolism. The head should face forward. A small rolled towel can be placed between the
scapulae. The right side is preferred9 because of a lower pleural dome and avoidance of the thoracic
duct, except when placing an introducer sheath for procedures (e.g., transvenous pacing or PA catheter
placement).
P.231
TABLE A-2 The infraclavicular (IC) approach to the subclavian vein
318
Specific Indications Relative Contraindications Specific Risks
Routine use of CVC Chest wall deformities Pneumothorax
Special procedures Contralateral pneumothorax Hemothorax
CVP Enlarged lung fields (e.g., COPD, Arterial puncture of
monitoring positive pressure ventilation) noncompressible
Temporary Hypoxemia artery
pacemaker
Emergency venous Coagulopathy/anticoagulation Vessel thrombosis
access
Concurrent CPR Brachial plexus injury
Hemodialysis access
Ipsilateral pacemaker or ICD
ICD, implantable cardioverter defibrillator.
Procedure: Identify and palpate the landmarks—clavicle and sternal notch (Figure A-2). Prepare and
drape the patient. In the conscious patient, apply lidocaine, including to the periosteum of the clavicle
at point of intersection.
A preferred method9 is to enter the skin just caudal to the middle of the clavicle. Advance the needle
toward the sternal notch until it hits the clavicle at the junction of the medial two thirds. While
maintaining negative pressure, gently “walk” the needle down the clavicle until it passes directly
beneath it. Advance slowly with the needle horizontal to the plane of the patient. Blood “flash” is
often obtained at a depth of 1 to 2 inches. If the first approach does not yield blood, pull back to skin,
fan the needle cephalad, and reinsert. Keeping the needle bevel pointing caudal, pass the guidewire
and place catheter as described above.
319
NOTES
 A straight-tip guidewire is best when entering a straight vessel.
 Needle insertion at the medial aspect of the delta-pectoral groove (at the anterior clavicular
tubercle at the junction of the lateral two thirds of the clavicle), may make a technically
easier procedure than does midclavicle insertion, but increases the risk of complications
including pneumothorax, arterial puncture, and brachial plexus injury.9,10
 Don't be afraid to hit the clavicle; the attached vein is directly beneath it. Going too deep
increases risk of arterial puncture, brachial plexus injury, or pneumothorax.
 Place the provider's nondominant index finger on the sternal notch (and thumb on clavicle) and
aim underneath the index finger, staying horizontal to the plane of the patient. Alternatively,
place a fingerprint of blood or povidone-iodine on the drape as a landmark.
P.232
320
FIGURE A-2 Anatomy for infraclavicular approach to subclavian vein.34
P.233
Central Approach to the Internal Jugular (IJ) Vein
321
See Table A-3.
Pros: Low risk of pneumothorax. Good landmarks. Common.
Cons: Difficult in obese patients. Interferes with patient neck movement. Interferes with intubation.
Slower than IC. Higher infection rate than IC.
Position: The patient should be supine to 30-degree Trendelenburg's position, as tolerated. The head
should face approximately 45 degrees away from the procedure site. If the patient is awake, humming
or Valsalva is helpful to engorge the jugular system.11 The right side has a more direct path to the
superior vena cava and avoids the thoracic duct; thus, it is preferred, particularly if placing a Cordis
introducer sheath for transvenous pacing.
Procedure: Ultrasound guidance techniques are superior to landmark techniques alone, particularly in
IJ placement. Ultrasound decreases time of placement, increases chances of successful placement, and
reduces mechanical complications.12, 13, 14, 15, 16, 17, and 18

It is the method of choice for nonemergent
CVC when training and equipment permits. , Ultrasound should be used in conjunction with the
1 12
landmark technique as described below.
Identify and palpate the landmarks:The clavicle, the sternocleidomastoid muscle, and the carotid
artery. Prepare and drape the patient. The IJ courses down the middle of the triangle formed by the
two straps of the sternocleidomastoid muscle heading toward the clavicle (Figure A-3A and B). Because
the IJ lies just lateral to the carotid artery, placing fingers from the provider's nondominant hand along
the carotid maintains identification of landmarks and decreases chances of arterial puncture.
Apply a wheal of lidocaine at the apex of the cephalad end of the triangle formed by the
sternocleidomastoid muscle. Aim at the ipsilateral nipple, while keeping the needle at a 20-degree
angle above the plane of the body. While maintaining negative pressure, puncture at this place.
Depending on body habitus, expect blood at about 0.5-inch depth. If the vessel is not successfully
cannulated, pull back to the skin and fan the needle to a point more medial. Some physicians prefer to
start with a 22-gauge “finder needle” attached to a 5-mL syringe to identify the IJ and then use this as
a guide for the larger needle through which the wire can be passed as described above.
TABLE A-3 Central approach to the internal jugular (IJ) vein
322
Subclavian vein not accessible Contralateral pneumothorax Carotid puncture
Routine use of CVC Contralateral subclavian Pneumothorax
attempt
Special procedures (e.g., CVP Obese neck Hemothorax
monitoring, transvenous pacemaker)
Coagulopathy/anticoagulation Tracheal
perforation
Concurrent intubation
Neck trauma
P.234
323
FIGURE A.3, A&B Anatomy for internal jugular (IJ) vein.6,34
P.235
NOTES
 The right side of the neck is generally easier for right-hand-dominant physicians.
324
 If the carotid artery is punctured, simply hold pressure with the nondominant hand and
continue the procedure.
 The finder needle can be used for lidocaine injection.
 If using a finder needle, the provider can place the procedure needle parallel to the finder
needle, or when removing the finder needle, drip a thin line of blood to mark the course of the
IJ.
The Femoral Vein

See Table A-4.
Pros: Good landmarks. Quick to place. Easy to apply pressure if artery is punctured.
Cons: Risk of infection and thrombosis. CPR can cause femoral vein pulsation.
Position: The patient should be in supine position. If the physician is right-hand dominant, the patient's
right side is usually a technically easier approach.
Procedure: Identify and palpate landmarks. Prepare and drape patient. Place the provider's
nondominant hand over the femoral artery pulsation just distal to the inguinal crease. The femoral vein
is directly medial to the artery. Apply lidocaine to the conscious patient. Enter the skin at
approximately a 45-degree angle. Advance the needle, with negative pressure, until a dark blood flash
is returned. Insert catheter via the Seldinger technique.
TABLE A-4 Femoral vein
Emergency venous Ambulatory patient Infection
access
Coagulopathy Grossly contaminated groin area Thrombosis
Neck trauma Penetrating abdominal trauma Bowel
perforation
No palpable femoral pulse Bladder
perforation
325
Known lower extremity deep venous
thrombosis (DVT)
P.236
TABLE A-5 External jugular (EJ) approach to subclavian vein
Special procedures (e.g., CVP monitoring, Inability to visualize Failure of
hemodialysis catheter) EJ vein procedure
Emergency venous
access
Unclear length of stay Introducer sheath
needed
Pain- or risk-averse patient Inexperienced
provider
Pros: The complication rate of an EJ is almost zero; compare to ~13% complication rate for IJ, including
very serious complications.19 For an experienced physician who can visualize the EJ, the excellent risk
profile may make the EJ an ideal line for the critically ill patient for whom a complication may be life
326
threatening.20 An EJ peripheral line can later be converted to a CVC line, if needed. No pain from deep
puncture.
Cons: Extra time required for inexperienced physicians to manipulate the wire intrathoracically.
Uncommon. The rate of successful EJ placement is only ~76%, compared to ~91% for IJs. 19
Position: The patient should be supine to 30-degree Trendelenburg's position, as tolerated. The head
should face approximately 45 degrees away from the procedure site. If the patient is awake, humming
or Valsalva is helpful to engorge the jugular system.11
Procedure: In one version of this procedure, an 18-gauge angiocatheter can be placed in the EJ as a
peripheral line using sterile precautions. Later, if central venous access is indicated, the line can be
converted into a CVC. The site is sterilized, and the IV tubing and saline-lock are removed. A “J” tipped
wire21 is passed via the angiocatheter until an intrathoracic position is presumed (the length of the
guidewire must extend past the clavicle). The angiocatheter is then removed. A standard CVC can be
passed over the wire via the Seldinger technique.
Supraclavicular Approach to the Subclavian Vein
See Table A-6.
Pros: No need to stop CPR or intubation.9 Only possible CVC for sitting patient.
Cons: Uncommon. Poor landmarks.
Position: The patient can be in any position from sitting up to 30-degree Trendelenburg's position, as
tolerated.
P.237
TABLE A-6 The supraclavicular (Super C) approach to the subclavian vein
327
Inability to lie supine Inexperienced provider Pneumothorax
CPR Hemothorax
328
FIGURE A.4 Anatomy for supraclavicular approach to subclavian vein. 34
P.238
TABLE A-7 Comparison of complication incidence by CVC method; Ease of use in code
329
situation
IC IJ Femoral EJ Super C
Unsuccessful 6%-26% 5%-25% 15% 4%-24% 5%
placement25, 26, 27, 28
Mechanical
complications6,25,26
Arterial 3%-5% 5%-9% 5%-9% 0% 1%
puncture
Hematoma 1%-2% 0%-2% 4% 0% 1%-2%a
Pneumothorax 2%-3% 0% 0% 0% 1%
Infection22,27,29, 30, 31 2- 8/1,000 16- 0- 2-
4/1,000 d 20/1,000 2/1,000 4/1,000
d d d da
Thrombosis27,29,32,33 0%-15% 0%-40% 21%-25% 0% 0%-15%a
Ease of use in code + - ++ -- ++
situation
a
Most articles that give complication rate for subclavian vein cannulation do not delineate
approach.
Data given are for all subclavian.
Procedure: Identify and palpate landmarks. Prepare and drape the patient. The needle is inserted
above and behind the medial clavicle (Figure A-4). The syringe bisects the angle formed by the clavicle
330
and the sternal head of the sternocleidomastoid muscle. Aim just caudal to the contralateral nipple.
While pulling back on the syringe plunger, insert the needle initially horizontal to the body. If no blood
is returned, withdraw the needle to the surface and tilt it such that it is aiming slightly posterior.
Cannulation of the bulb where the subclavian vein meets the internal jugular is usually achieved when
the syringe is at 15 to 20 degrees above the plane of the body.
COMPLICATIONS OF CVC
Methods for decreasing complications include maximizing physician experience, minimizing catheter
indwelling time, using maximum sterile precautions, and choosing a clinically appropriate line with
minimal complications (Table A-7). Antibiotic-impregnated catheters have been shown to decrease CVC
colonization and catheter-related infections.1,6,22, 23, and 24

Please refer to the footnoted references for
details on reducing complications. ,1 6
P.239
REFERENCES
1. O'Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-
related infections. Infect Control Hosp Epidemiol. 2002;23:759-769.
2. Maki DG, Alvarado CJ, Ringer M. Prospective randomised trial of povidone-iodine, alcohol, and
chlorhexidine for prevention of infection associated with central venous and arterial catheters. Lancet.
1991;338: 339-343.
3. Larson EL. APIC guideline for handwashing and hand antisepsis in health care settings. Am J Infect
Control. 1995;23:251-269.
4. Mimoz O, Pieroni L, Lawrence C, et al. Prospective, randomized trial of two antiseptic solutions for
prevention of central venous or arterial catheter colonization and infection in intensive care unit
patients. Crit Care Med. 1996;24:1818-1823.
5. Raad I, Hohn DC, Gilbreath BJ, et al. Prevention of central venous catheter-related infections by
using maximal sterile barrier precautions during insertion. Infect Control Hosp Epidemiol. 1994;15:231-
238.
6. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med.
2003;348:1123-1133.
7. Graham AS, Ozment C, Tegtmeyer K, et al. Central venous catheterization. N Engl J Med. 2007.
Available at: http://content.nejm.org/cgi/content/short/356/21/e21/.
331
8. Rivers E, Nguyen B, Havstad S, et al., for the Early Goal-Directed Therapy Collaborative Group. Early
goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345:1368-
1377.
9. Mickiewicz M, Dronen S, Younger J. Central venous catheterization and central venous pressure
monitoring. In: Roberts J, Hedges J, eds. Roberts: Clinical Procedures in Emergency Medicine. 4th ed.
Philadelphia: WB Saunders; 2004.
10. Simon RR. A new technique for subclavian puncture. JACEP. 1978;7:417.
11. Lewin MR, Stein J, Wang R, et al. Humming is as effective as Valsalva's maneuver and
Trendelenburg's position for ultrasonographic visualization of the jugular venous system and common
femoral veins. Ann Emerg Med. 2007.
12. Guidance on the use of ultrasound locating devices for placing central venous catheters. In:
Technology Appraisals. 49th ed. London: National Institute for Clinical Excellence (NICE); 2002.
13. Teichgraber U, Benter T, Gebel M, et al. A sonographically guided technique for central venous
access. AJR Am J Roentgenol. 1997;169:731-733.
14. Bailey PL, Whitaker EE, Palmer LS, et al. The accuracy of the central landmark used for central
venous catheterization of the internal jugular vein. Anesth Analg. 2006;102:1327-1332.
P.240
15. Randolph AG, Cook DJ, Gonzales CA, et al. Ultrasound guidance for placement of central venous
catheters: A meta-analysis of the literature. Crit Care Med. 1996;24:2053-2058.
16. Leung J, Duffy M, Finckh A. Real-time ultrasonographically-guided internal jugular vein
catheterization in the emergency department increases success rates and reduces complications: A
randomized, prospective study. Ann Emerg Med. 2006;48:540-547.
17. Hind D, Calvert N, McWilliams R, et al. Ultrasonic locating devices for central venous cannulation:
Meta-analysis. BMJ. 2003;327:361.
18. Rothschild J. Ultrasound guidance of central venous catheterization. In: Wachter R, ed. Evidence
Report/Technology Assessment No. 43, Making Health Care Safer: A Critical Analysis of Patient Safety
Practices. Rockville, MD: Agency for Healthcare Research and Quality; 2001.
19. Belani K, Buckley J, Gordon J, et al. Percutaneous cervical central venous line placement: A
comparison of the internal and external jugular vein routes. Anesth Analg. 1980;59:40-44.
332
20. Byth PL. Evaluation of the technique of central venous catheterisation via the external jugular vein
using the J-wire. Anaesth Intensive Care. 1985;13:131-133.
21. Blitt CD, Wright WA, Petty WC, et al. Central venous catheterization via the external jugular vein. A
technique employing the J-WIRE.JAMA. 1974;229:817-818.
22. Heard S, Wagle M, Vijayakumar E, et al. Influence of triple-lumen central venous catheters coated
with chlorhexidine and silver sulfadiazine on the incidence of catheter-related bacteremia. Arch Intern
Med. 1998;158:81-87.
23. Raad I, Darouiche R, Dupuis J, et al. Central venous catheters coated with minocycline and rifampin
for the prevention of catheter-related colonization and bloodstream infections: A randomized, double-
blind trial. Ann Intern Med. 1997;127:267-274.
24. Maki DG, Stolz SM, Wheeler S, et al. Prevention of central venous catheter-related bloodstream
infection by use of an antiseptic-impregnated catheter: A randomized, controlled trial. Ann Intern Med.
1997;127:257-266.
25. Brahos G. Central venous catheterization via the supraclavicular approach. J Trauma. 1977;17:872-
877.
26. Eisen LA, Narasimhan M, Berger JS, et al. Mechanical complications of central venous catheters. J
Intensive Care Med. 2006;21:40-46.
27. Cho SK, Shin SW, Do YS, et al. Use of the right external jugular vein as the preferred access site
when the right internal jugular vein is not usable. J Vasc Interv Radiol. 2006;17:823-829.
28. Sterner S, Plummer DW, Clinton J, et al. A comparison of the supraclavicular approach and the
infraclavicular approach for subclavian vein catheterization. Ann Emerg Med. 1986;15:421-424.
P.241
29. Merrer J, De Jonghe B, Golliot F, et al., for the French Catheter Study Group in Intensive Care.
Complications of femoral and subclavian venous catheterization in critically ill patients: A randomized
controlled trial. JAMA. 2001;286:700-707.
30. McKinley S, Mackenzie A, Finfer S, et al. Incidence and predictors of central venous catheter related
infection in intensive care patients. Anaesth Intensive Care. 1999;27:164-169.
31. Torok-Both CJ, Jacka MJ, Brindley PG. Best evidence in critical care medicine: Central venous
catheterization: The impact of insertion site. Can J Anaesth. 2006;53:524-525.
333
32. Timsit J, Farkas J, Boyer J, et al. Central vein catheter-related thrombosis in intensive care
patients: Incidence, risk factors, and relationship with catheter-related sepsis. Chest. 1998;114:207-
213.
33. Trottier SJ, Veremakis C, O'Brien J, et al. Femoral deep vein thrombosis associated with central
venous catheterization: Results from a prospective, randomized trial. Crit Care Med. 1995;23:52-59.
34. Knopp R, Dailey RH. Central venous cannulation and pressure monitoring. JACEP. 1977;6:358-366.
21.2 APPENDIX B - Clinical Pharmacology
TABLE B-1 Vasopressors, inotropes, and vasodilators
PCW Cautions/cli
Drug Dose α β Dop CO P SVR BP HR ARR nical effects
Dopa 1-2 + + + ↑ ? ? ? ? ? Stimula
mine µg/kg + ? tes
/min + dopami
not nergic
reco DA1
mme recepto
nded rs in
the
renal
mesent
eric
and
coronar
y beds
resultin
g in
vasodil
ation
2-10 + + + ↑ ? 0 ? ↑ ↑ Causes
µg/kg + + + NE
334
/min release
from
nerve
termin
als
10-20 + + + ↑ ? ↑ ↑ ↑ ↑ ↑ MVO2
µg/kg + + 0
/min +
Epine 1-20 + + 0 ↑ ↑ ↑ ↑ ↑ ↑ May
phrin µg/mi + induce
e n + tachyar
rhythm
+ ias
Norep 1-30 + + 0 ↔ ↔ ↑ ↑ ↔ + May
ineph µg/mi + + / / induce
rine n + ↑ - tachyar
rhythm
ias and
myocar
dial
ischemi
Pheny 40- + 0 0 ↓ ? ↑ ↑ ↓ ↑ May
lephri 180 + cause
ne µg/mi + reflex
n bradyc
ardia
Vasop 0.01- 0 0 0 ↔ ↔ ↑ ↑ ↔ ↑ Direct
ressin 0.04 stimula
335
units tion
/min smooth
muscle
V1
recepto
rs
Myocar
dial
ischemi
a,
cardiac
dysfunc
tion,
arrhyth
mias
reporte
Dobut 2-20 + + 0 ↑ ↓ ↓ ↓ ↑ ↑ Tachya
amine µg/kg ↑ / / / ↑ rrhyth
/min + 0 0 0 mias
Milrin 0.375 0 0 0 ↑ ↓ ↓ ↓ ↑ ↑ Noncat
one - ↑ ↓ echola
0.75µ mine,
g/kg/ PDI, PI,
min VD,
ARR,
adjust
dose in
renal
failure
336
Nesiri 0.01 0 0 0 ↑ ↓ ↓ ↓ 0 0 Hypote
tide µg/kg ↓ ↓ ↓ nsion,
/min VD
Nitrog 5-400 0 0 0 ↑ ↓ ↓ ↓ ↑ 0 VD,
lyceri µg/mi ↓ ↓ / hypote
n n 0 nsion,
toleran
ce
Nitro 0.5-2 0 0 0 ↑ ↓ ↓ ↓ ↑ 0 VD,
prussi µg/kg ↓ ↓ ↓ hypote
de /min ↓ ↓ ↓ nsion,
reflex
tachyca
rdia,
caution
in renal
insuffic
iency
second
ary
accumu
lation
of
thiocya
nate
and
cyanide
toxiciti
es
α, alpha agonist; β, beta agonist; Dop, dopaminergic-1 agonist; CO, cardiac output; PCWP,
pulmonary capillary wedge pressure; SVR, systemic vascular resistance; BP, blood pressure; HR,
337
heart rate; ARR, arrhythmias; min, minutes; NE, norepinephrine; PDI, phosphodiesterase
inhibitor; PI, positive inotrope; VD, vasodilation.
P.246
P.247
P.248
P.249
P.250
TABLE B-2 Antiarrhythmic medication properties
338
Adverse
Effects, Drug
Mechanism of Pharmacokin Contraindicatio Interactio Dosing by
Drug Action etics ns ns Indication Comments
Quinidin Strong t1/2 = 5-9 AE: Warfa Afib TR = 6-9
e vagolytic, h Nausea, rin mainten mg/L
anticholi vomiting, ance:
nergic diarrhea Sulfate
propertie (30%), 200-400
s, Na +
proarrhyth mg q6h
channel mic, Glucona
blockade cinchonis te 324

m HF mg q8-
exacerbati 12h
ons
Procain Na+ (SA) t1/2 AE: — Afib TR = 4-
amide channel = 5-6 h Decrease conversi 15
blockade (FA) t1/2 dose in on (IV):
= 2-3 h renal and 1 g over
liver 30 min,
dysfunctio then 2-4
n, active mg/min
metabolit Afib
e NAPA mainten
accumulat ance: 1-
es, 2 g/d in
lupuslike divided
syndrome doses
in 30% of VT
patients if (preserv
>6 months ed LVEF
of >40%):
treatment 20
339
, mg/min
hypotensi loading
on (IV) dose
30% infusion
until 17
mg/kg,
arrhyth
mia
ceases,
or QRS
widens
>50% VT
mainten
ance: 2-
mg/min
Disopyra Potent t1/2 = 4-8 AE: — Afib TR = 2-6
mide Na and
+
h Anticholin conversi
M2 ergic side on: 200
blockade, effects: mg po
strong Urinary q4h
negative retention, (max
inotropic constipati 800 mg)
effects on, Mainten
tachycardi ance
a, dry 400-600
eyes CI: mg/d in
Glaucoma divided
doses
Lidocain Inactive t1/2 = 1-3 AE: CNS — VT/VF Dose
e Na+ h symptoms conversi adjust in
channel , on: patients
blocker periorbital Pulseles with
340
numbness, s VT/VF liver,
seizures, or renal, or
confusion, stable heart
blurry VT with failure
vision, LVEF and in
tinnitus >40%: 1- elderly
CI: Third- 1.5 TR = 1.5-
degree A- mg/kg 5
V heart IVP ×2;
block 0.5-0.75
mg/kg
q3-5
min
thereaft
er max
3 mg/kg
VT
mainten
ance: 1-
mg/min
Mexileti Inactive (PM) t1/2 AE: VT TR = 0.8-
ne Na+ = 12-20 psychosis, mainten 2
channel h (EM) aggravatio ance:
blocker t1/2 = 7- n of 200-300
11 h underlying mg q8h
conductio
disturbanc
es,
ventricula
arrhythmi
as
341
CI: Third-
degree A-
V heart
block
Propafe Na+ and (PM) t1/2 AE: Digoxi Afib Can use
none Ca2+
= 10-25 Metallic n ↑ by conversi in NYHA
channel h (EM) taste, 70%; on: 600 class I
blocker, t1/2 = 3-7 dizziness warfa mg po and II
β-blocker h CI: HF rin ↑ ×1 Afib safely
(causes by mainten
exacerbati 50% ance:
on), liver 150-300
disease, mg po
valvular q8-12h
disease
(torsade
de
pointes)
Flecaini Strong (PM) t1/2 AE: HF Digoxi Afib TR = 0.3-
de Na +
= 14-20 exacerbati n ↑ by conversi 2.5
channel h (EM) on, 25% on: 300
blockade; t1/2 = 10- dizziness, mg po ×
vagolytic, 14 h tremor, 1 Afib
anticholi bronchosp mainten
nergic, asm CI: HF ance:
and (causes 50-150
negative exacerbati mg q12h
inotropic ons), CAD,
effects valvular
disease,
LV
hypertrop
hy,
342
(torsade
de
pointes)
Amiodar Na+, K+, t1/2 = 15- AE: Warfa Afib Does not
one Ca2+ 100 d Pulmonary rin, conversi increase
channel Inhibits fibrosis digoxi on IV: mortality
blocker, cytochro (3%-17%); n, 300 mg in heart
β-blocker me P450 hypothyroi pheny IV over failure
(CYP) dism (30%- toin ↑ 60 min, patients
metaboli 50%); ≥ 50% then 20 TR = 1-
sm neurologic mg/kg 2.5
CYP2C9, toxicity over 24
CYP (20%-40%); h PO:
2D6, blue-gray 400 mg
CYP3A4 skin (15%); tid ×5 to
Inhibits torsade de 7 days
glycopro pointes (8 to 10
tein in (<1%); A-V g) Afib
GI tract block mainten
to (14%); ance:
increase hypotensi 100-200
digoxin on, mg/d
bioavail phlebitis Pulseles
ability (IV) CI: s VT/VF
Iodine conversi
hypersensi on: 300
tivity, mg IVP
hyperthyr × 1,
oidism, repeat
heart 150 mg
block IVP q 3-
5 min
(ARREST
trial), or
343
(ALIVE
trial): 5
mg/kg
IVP,
repeat
2.5
mg/kg
Stable
VT: 150
mg IVP
× 1 over
10
minutes
VT/VF
mainten
ance: 1
mg/min
× 6h
then 0.5
mg/min
(max =
2.2 g/d)
Sotalol Blocks β1, t1/2 = 10- HF exacerbation, Not Double
β2 20 h bradycardia, effectiv dose
receptors wheezing; torsade e for q3d; NTE
,K +
(3%-8%) within 3 days Afib QTc >440
channels of initiation; conversi ms or
bronchospasm CI: on Afib CrCL <20
Baseline QTc>440 ms mainten mL/min
or CrCL <40 mL/min in ance: Mandato
atrial arrhythmias CrCL 80 ry
mg bid hospitali
>60 zation
mL/min for
344
80 mg initiation
q36-48h
10-30
mL/min
80 mg >
q48h
<10
mL/min
Dofetili Pure K+ t1/2 = 6- Torsade de pointes Afib Does not
de channel 10h (0.8%-4%); if no real conversi increase
blocker adjustments, on: mortality
only dizziness, diarrhea CI: 500µg in HF
Baseline QTc>440 ms po bid if patients
or CrCL <20 mL/min CrCL Mandato
DI: 3A4 inhibitors or >60 ry
drugs secreted by mL/min hospitali
kidney: cimetidine, 250 mg zation
ketoconazole, po bid if for
verapamil, CrCL 40- initiation
trimethoprim, 60 ECG
prochlorperazine, mL/min after
megestrol 125µg each
po bid if dose
CrCL 20- while
40 hospitali
mL/min zed
(efficac
y 12% at
1 mo)
Afib
mainten
ance:
Titrate
upward
345
based
on QTc
NTE 500
ms or
>15% ↑
in QTc
after
each
dose
Ibutilide Strong K+ t1/2 = 3-6 AE: Torsade risk (8%) Conversi Requires
blocker; h CI: Receiving on: 1 ECG
also Na +
concomitant mg × 1 monitori
and β- antiarrhythmics or QTc IV (≥ 60 ng
blocking > 440 ms before kg), during
effects initiation DI: 3A4 repeat and
inhibitors or QT- in 10 after
prolonging drugs min if cardiove
ineffecti rsion
ve
(efficac
y 47% at
90 min)
t1/2, half-life; AE, adverse effects; TR, therapeutic range; HF, heart failure; CI, contraindications;
CrCL, creatinine clearance; Afib, atrial fibrillation; NTE, not to exceed; LV, left ventricular; DI,
drug interactions; IV, intravenous; CAD, coronary artery disease; PM, poor metabolizers; EM,
extensive metabolizers.
P.251
P.252
346
TABLE B-3 Pharmacological rate control with atrial fibrillation: Acute setting (without
accessory pathway)
Adverse
Reactions, Drug
Interactions,
Mechanism of Pharmacokinetic Contraindication
Drug Action s s Dosing Comments
Esmolol β1 Onset: 5 ↓BP, ↓HR, 500 µg/kg Beta blocker

blockade min t1/2 = 9 HF, HB CI: IV bolus toxicity use
min Asthma DI: over 1 intravenous
Beta min Then atropine,
agonist 25-50 pressors
µg/kg/mi (dopamine,
n infusion dobutamine,
To epinephrine,
maximum isoproterenol)
200 , or glucagon
µg/kg/mi bradycardia,
n and asystole
intravenous
atropine,
pressors
(dopamine,
dobutamine,
epinephrine,
isoproterenol)
, or glucagon
and/or
temporary
ventricular
pacing may
347
be initiated
Metoprolo β1 Onset: 5 ↓BP, ↓HR, 2.5-5 mg Beta blocker
l blockade min t1/2 = HF, HB CI: IV q5min toxicity use
3-7 h Asthma DI: × 3 doses intravenous
Beta atropine,
agonist pressors
(dopamine,
dobutamine,
epinephrine,
isoproterenol)
, or glucagon
bradycardia,
and asystole
intravenous
atropine,
pressors
(dopamine,
dobutamine,
epinephrine,
isoproterenol)
, or glucagon
and/or
temporary
ventricular
pacing may
be initiated
Diltiazem ↓S-A and Onset 2-7 HB, ↓BP, 0.25 Ca2+ overdose,
↓A-V node min t1/2 = ↓HR mg/kg IV use IV
conductio 4-10 h over 3 calcium 1-2 g
n min then to reverse
5-15 hypotension
mg/h IV Use
continuou intravenous
348
s atropine,
pressors
(dopamine,
dobutamine,
epinephrine,
isoproterenol)
, or glucagon
bradycardia,
and asystole
intravenous
atropine,
pressors
(dopamine,
dobutamine,
epinephrine,
isoproterenol)
, or glucagon
and/or
temporary
ventricular
pacing may
be initiated
Verapamil ↓S-A and Onset 3-5 HB, ↓BP, 0.075- Ca2+ overdose,
↓A-V node min t1/2 = ↓HR 0.15 use IV
conductio 4-12 h mg/kg IV calcium 1-2 g
n over 2 to reverse
min hypotension
Use
intravenous
atropine,
pressors
(dopamine,
dobutamine,
epinephrine,
349
isoproterenol)
, or glucagon
for
bradycardia,
asystole,
and/or
temporary
ventricular
pacing may
be initiated
t1/2, half-life; ADR, adverse drug reactions; BP, blood pressure; HR, heart rate; HF, heart failure;
HB, heart block; CI, contraindications; DI, drug interactions. From Fuster V, Ryden LE, Cannom
DS, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation:
Executive summary. A report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines and the European Society of Cardiology Committee for
Practice Guidelines. Circulation. 2006;114:700-752.
P.253
TABLE B-4 Heart rate control without accessory pathway with heart failure
Adverse Drug
Reactions,
Mechanism of Pharmacokineti Contraindications,
Drug Action cs Drug Interactions Dosing Comments
Digoxin Negative Onset: 60 ADR: Digitalis 10 Monitor
chromotro min or toxicity, HB, ↓ µg/kg renal
pe Positive longer t1/2 HR IV function,
inotrope = 1.8-2.2 loadin digoxin will
350
d g accumulate
based in renal
on dysfunction
lean Some
body subgroup
wt. evidence to
then target dig
0.125- level <1.2
0.25
mg
daily
IV
Symptomati
c digoxin
toxicity, use
Digoxin
Immune Fab
(Digibind)
Amiodaro Na+ Onset: ADR: ↓BP, HB, 150 Caution:
ne channel Days t1/2 = pulmonary mg Concentratio
blockade, 50 d toxicity, skin over n for central
beta discoloration, 10 line
blockade, hypothyroidis min, administrati
Ca2+
m, then on vs.
channel hyperthyroidis 0.5-1 peripheral
blockade, m, corneal mg/mi line
K+ channel deposits, optic n administrati
blockade, neuropathy, on
and sinus (phlebitis)
vasodilator bradycardia
y effects DI: Warfarin,
digoxin
351
t1/2, half-life; ADR, adverse drug reactions; HB, heart block; HR, heart rate; BP, blood pressure;
DI, drug interactions.
P.254
TABLE B-5 Heart rate control with accessory pathway
Adverse Drug
Mechanism of Pharmacokineti Reactions, Drug
Drug Action cs Interactions Dosing Comments
Amiodaron Na+ Onset: ADR: ↓BP, HB, 150 Caution:
e channel Days t1/2 = pulmonary mg Concentratio
blockade, 50 d toxicity, skin over n for central
beta discoloration, 10 line
blockade, hypothyroidism min, administrati
Ca2+ , then on vs.
channel hyperthyroidis 0.5-1 peripheral
blockade, m, corneal mg/mi line
K+ channel deposits, optic n administrati
blockade, neuropathy, on
and sinus (phlebitis)
vasodilato bradycardia DI:
ry effects Warfarin,
352
digoxin
t1/2, half-life; ADR, adverse drug reactions; BP, blood pressure; HB, heart block; DI, drug
interactions.
353

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Concise Cardiology: An

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G. Rockson, Randall Vagelos.

Includes bibliographical references and index.

1. Cardiology—Handbooks, manuals, etc. 2. Heart—Diseases—Handbooks, manuals, etc. I. Daniels, David

V. II. Rockson, Stanley G. III. Vagelos, Randall.

[DNLM: 1. Heart Diseases—Handbooks. 2. Diagnostic Techniques, Cardiovascular—Handbooks. 3.

Evidence-Based Medicine—Handbooks. WG 39 C755 2008]

professional responsibility of the practitioner.

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Fellow in Cardiovascular Medicine

Fellow in Critical Care Medicine

Stanford University Medical Center

Chief of Consultative Cardiology

Stanford University Medical Center

Professor of Medicine/Medical Director, CCU

Stanford University Medical Center

Assistant Professor of Cardiovascular Medicine

Associate Director, Cardiac Arrythmia Services

Euan Ashley MRCP, DPhil

Assistant Professor of Medicine

Instructor of Medicine (Cardiology)

Ian Brown MS, MD

Instructor of Surgery (Emergency Medicine)

Stanford University School of Medicine

Kamalendu Chatterjee MB, FRCP, FACC, FCCP, MACP

Ernest Gallo Distinguished Professor of Medicine

Division of Cardiology, Department of Medicine

San Francisco, California

Cardiologist, Internal Medicine

Doctor's Medical Center—San Pablo

San Pablo, California

Fellow in Cardiovascular Medicine

Fellow in Critical Care Medicine

Stanford University Medical Center

Division of Pulmonary/Critical Care Medicine

James V. Freeman MD, MPH

Fellow in Cardiovascular Medicine

Department of Medicine, Division of Cardiology

Stanford University Hospital

Clinical Instructor of Medicine, Division of Cardiovascular Medicine

Heart Failure and Transplant Service

Pulmonary Hypertension Service

Stanford University School of Medicine

Associate Professor, Cardiovascular Medicine

Assistant Director, Arrhythmia Services