Ebook Harrison''s cardiovascular medicine (2nd edition): Part 1

2nd Edition

HARRISON’S

TM

Cardiovascular
Medicine


Derived from Harrison’s Principles of Internal Medicine, 18th Edition

Editors
Dan L. Longo, md

Professor of Medicine, Harvard Medical School;
Senior Physician, Brigham and Women’s Hospital;
Deputy Editor, New England Journal of Medicine,
Boston, Massachusetts

Dennis L. Kasper, md

William Ellery Channing Professor of Medicine,
Professor of Microbiology and Molecular Genetics,
Harvard Medical School; Director, Channing Laboratory,
Department of Medicine, Brigham and Women’s Hospital,
Boston, Massachusetts

J. Larry Jameson, md, PhD

Robert G. Dunlop Professor of Medicine;
Dean, University of Pennsylvania School of Medicine;
Executive Vice-President of the University of Pennsylvania
for the Health System, Philadelphia, Pennsylvania

Anthony S. Fauci, md

Chief, Laboratory of Immunoregulation;
Director, National Institute of Allergy and Infectious Diseases,
National Institutes of Health,
Bethesda, Maryland

Stephen L. Hauser, md

Robert A. Fishman Distinguished Professor
and Chairman, Department of Neurology,
University of California, San Francisco,
San Francisco, California

Joseph Loscalzo, md, PhD

Hersey Professor of the Theory and Practice of Medicine,
Harvard Medical School; Chairman, Department of Medicine;
Physician-in-Chief, Brigham and Women’s Hospital,
Boston, Massachusetts


2nd Edition

HARRISON’S

TM

Cardiovascular
Medicine
Editor
Joseph Loscalzo, MD, PhD
Hersey Professor of the Theory and Practice of Medicine, Harvard Medical School;
Chairman, Department of Medicine; Physician-in-Chief, Brigham and Women’s Hospital,
Boston, Massachusetts

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Contents
Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

13 Diagnostic Cardiac Catheterization and
Coronary Angiography . . . . . . . . . . . . . . . . . . 117
Jane A. Leopold, David P. Faxon

SECTION I

SECTION III

Introduction to Cardiovascular
Disorders

Heart Rhythm Disturbances
14 Principles of Electrophysiology. . . . . . . . . . . . . 128
David D. Spragg, Gordon F. Tomaselli

  1 Basic Biology of the Cardiovascular System. . . . . . 2
Joseph Loscalzo, Peter Libby, Jonathan Epstein

15 The Bradyarrhythmias. . . . . . . . . . . . . . . . . . . 137
David D. Spragg, Gordon F. Tomaselli

  2 Epidemiology of Cardiovascular Disease. . . . . . . 20
Thomas A. Gaziano, J. Michael Gaziano

16 The Tachyarrhythmias. . . . . . . . . . . . . . . . . . . 151
Francis Marchlinski

  3 Approach to the Patient with Possible
Cardiovascular Disease. . . . . . . . . . . . . . . . . . . . 28
Joseph Loscalzo

SECTION IV

Disorders of the heart

SECTION II

Diagnosis of Cardiovascular

Disorders

17 Heart Failure and Cor Pulmonale. . . . . . . . . . . 182
Douglas L. Mann, Murali Chakinala

  4 Chest Discomfort . . . . . . . . . . . . . . . . . . . . . . . 34
Thomas H. Lee

18 Cardiac Transplantation and
Prolonged Assisted Circulation. . . . . . . . . . . . . 201
Sharon A. Hunt, Hari R. Mallidi

  5 Dyspnea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Richard M. Schwartzstein

19 Congenital Heart Disease in the Adult . . . . . . . 207
John S. Child, Jamil Aboulhosn

  6 Hypoxia and Cyanosis. . . . . . . . . . . . . . . . . . . . 49
Joseph Loscalzo

20 Valvular Heart Disease. . . . . . . . . . . . . . . . . . . 219
Patrick O’Gara, Joseph Loscalzo

  7 Edema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Eugene Braunwald, Joseph Loscalzo

21 Cardiomyopathy and Myocarditis. . . . . . . . . . . 248
Lynne Warner Stevenson, Joseph Loscalzo

  8 Palpitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Joseph Loscalzo

22 Pericardial Disease. . . . . . . . . . . . . . . . . . . . . . 273
Eugene Braunwald

  9 Physical Examination of
the Cardiovascular System. . . . . . . . . . . . . . . . . 63
Patrick T. O’Gara, Joseph Loscalzo

23 Tumors and Trauma of the Heart. . . . . . . . . . . 284
Eric H. Awtry, Wilson S. Colucci

10 Approach to the Patient with a Heart Murmur. . . 76
Patrick T. O’Gara, Joseph Loscalzo

24 Cardiac Manifestations of Systemic Disease. . . . 289
Eric H. Awtry, Wilson S. Colucci

11 Electrocardiography. . . . . . . . . . . . . . . . . . . . . . 89
Ary L. Goldberger

25 Infective Endocarditis . . . . . . . . . . . . . . . . . . . 294
Adolf W. Karchmer

12 Noninvasive Cardiac Imaging:
Echocardiography, Nuclear Cardiology,
and MRI/CT Imaging. . . . . . . . . . . . . . . . . . . 101
Rick A. Nishimura, Panithaya Chareonthaitawee,
Matthew Martinez

26 Acute Rheumatic Fever. . . . . . . . . . . . . . . . . . 309
Jonathan R. Carapetis
27 Chagas’ Disease. . . . . . . . . . . . . . . . . . . . . . . . 316
Louis V. Kirchhoff, Anis Rassi, Jr.

v


Contents

vi

28 Cardiogenic Shock and Pulmonary Edema. . . . 320
Judith S. Hochman, David H. Ingbar

38 Diseases of the Aorta. . . . . . . . . . . . . . . . . . . . 467
Mark A. Creager, Joseph Loscalzo

29 Cardiovascular Collapse, Cardiac Arrest, and
Sudden Cardiac Death. . . . . . . . . . . . . . . . . . . 328
Robert J. Myerburg, Agustin Castellanos

39 Vascular Diseases of the Extremities. . . . . . . . . 476
Mark A. Creager, Joseph Loscalzo

SECTION V

Disorders of the vasculature
30 The Pathogenesis, Prevention, and

Treatment of Atherosclerosis . . . . . . . . . . . . . . 340
Peter Libby
31 Disorders of Lipoprotein Metabolism. . . . . . . . 353
Daniel J. Rader, Helen H. Hobbs
32 The Metabolic Syndrome . . . . . . . . . . . . . . . . 377
Robert H. Eckel
33 Ischemic Heart Disease . . . . . . . . . . . . . . . . . . 385
Elliott M. Antman, Andrew P. Selwyn,
Joseph Loscalzo
34 Unstable Angina and Non-ST-Segment
Elevation Myocardial Infarction. . . . . . . . . . . . 407
Christopher P. Cannon, Eugene Braunwald

40 Pulmonary Hypertension. . . . . . . . . . . . . . . . . 490
Stuart Rich
SECTION VI

Cardiovascular Atlases
41 Atlas of Electrocardiography. . . . . . . . . . . . . . . 500
Ary L. Goldberger
42 Atlas of Noninvasive Cardiac Imaging . . . . . . . 517
Rick A. Nishimura, Panithaya Chareonthaitawee,
Matthew Martinez
43 Atlas of Cardiac Arrhythmias. . . . . . . . . . . . . . 526
Ary L. Goldberger
44 Atlas of Percutaneous Revascularization. . . . . . 539
Jane A. Leopold, Deepak L. Bhatt,
David P. Faxon

35 ST-Segment Elevation Myocardial Infarction. . . 415

Elliott M. Antman, Joseph Loscalzo

Appendix
Laboratory Values of Clinical Importance. . . . . . . . 549
Alexander Kratz, Michael A. Pesce,
Robert C. Basner, Andrew J. Einstein

36 Percutaneous Coronary Interventions and
Other Interventional Procedures . . . . . . . . . . . 434
David P. Faxon, Deepak L. Bhatt

Review and Self-Assessment. . . . . . . . . . . . . . . 575
Charles Wiener, Cynthia D. Brown,
Anna R. Hemnes

37 Hypertensive Vascular Disease. . . . . . . . . . . . . 443
Theodore A. Kotchen

Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 615


CONTRIBUTORS
Numbers in brackets refer to the chapter(s) written or cowritten by the contributor.
UCLA Adult Noninvasive Cardiodiagnostics Laboratory, Ronald
Reagan-UCLA Medical Center, Los Angeles, California [19]

Jamil Aboulhosn, MD
Assistant Professor, Departments of Medicine and Pediatrics,
David Geffen School of Medicine, University of California,
Los Angeles, Los Angeles, California [19]

Wilson S. Colucci, MD
Thomas J. Ryan Professor of Medicine, Boston University School
of Medicine; Chief of Cardiovascular Medicine, Boston Medical
Center, Boston, Massachusetts [23, 24]

Elliott M. Antman, MD
Professor of Medicine, Harvard Medical School; Brigham and
Women’s Hospital, Boston, Massachusetts [33, 35]

Mark A. Creager, MD
Professor of Medicine, Harvard Medical School; Simon C. Fireman
Scholar in Cardiovascular Medicine; Director, Vascular Center,
Brigham and Women’s Hospital, Boston, Massachusetts [38, 39]

Eric H. Awtry, MD
Assistant Professor of Medicine, Boston University School of
Medicine; Inpatient Clinical Director, Section of Cardiology,
Boston Medical Center, Boston, Massachusetts [23, 24]

Robert H. Eckel, MD
Professor of Medicine, Division of Endocrinology, Metabolism and
Diabetes, Division of Cardiology; Professor of Physiology and
Biophysics, Charles A. Boettcher, II Chair in Atherosclerosis,
University of Colorado School of Medicine, Anschutz Medical
Campus, Director Lipid Clinic, University of Colorado Hospital,
Aurora, Colorado [32]

Robert C. Basner, MD
Professor of Clinical Medicine, Division of Pulmonary, Allergy, and

Critical Care Medicine, Columbia University College of Physicians
and Surgeons, New York, New York [Appendix]
Deepak L. Bhatt, MD, MPH
Associate Professor of Medicine, Harvard Medical School; Chief
of Cardiology, VA Boston Healthcare System; Director, Integrated
Interventional Cardiovascular Program, Brigham and Women’s
Hospital and VA Boston Healthcare System; Senior Investigator,
TIMI Study Group, Boston, Massachusetts [36, 44]

Andrew J. Einstein, MD, PhD
Assistant Professor of Clinical Medicine, Columbia University
College of Physicians and Surgeons; Department of Medicine,
Division of Cardiology, Department of Radiology, Columbia
University Medical Center and New York-Presbyterian Hospital,
New York, New York [Appendix]

Eugene Braunwald, MD, MA (Hon), ScD (Hon) FRCP
Distinguished Hersey Professor of Medicine, Harvard Medical
School; Founding Chairman, TIMI Study Group, Brigham and
Women’s Hospital, Boston, Massachusetts [7, 22, 34]

Jonathan A. Epstein, MD, DTMH
William Wikoff Smith Professor of Medicine; Chairman,
Department of Cell and Developmental Biology; Scientific Director,
Cardiovascular Institute, University of Pennsylvania, Philadelphia,
Pennsylvania [1]

Cynthia D. Brown, MD
Assistant Professor of Medicine, Division of Pulmonary and Critical
Care Medicine, University of Virginia, Charlottesville, Virginia

[Review and Self-Assessment]

David P. Faxon, MD
Senior Lecturer, Harvard Medical School; Vice Chair of Medicine
for Strategic Planning, Department of Medicine, Brigham and
Women’s Hospital, Boston, Massachusetts [13, 36, 44]

Christopher P. Cannon, MD
Associate Professor of Medicine, Harvard Medical School; Senior
Investigator, TIMI Study Group, Brigham and Women’s Hospital,
Boston, Massachusetts [34]

J. Michael Gaziano, MD, MPH
Professor of Medicine, Harvard Medical School; Chief, Division of
Aging, Brigham and Women’s Hospital; Director, Massachusetts
Veterans Epidemiology Center, Boston VA Healthcare System,
Boston, Massachusetts [2]

Jonathan Carapetis, PhD, MBBS, FRACP, FAFPHM
Director, Menzies School of Health Research, Charles Darwin
University, Darwin, Australia [26]
Agustin Castellanos, MD
Professor of Medicine, and Director, Clinical Electrophysiology,
Division of Cardiology, University of Miami Miller School of
Medicine, Miami, Florida [29]

Thomas A. Gaziano, MD, MSc
Assistant Professor, Harvard Medical School; Assistant Professor,
Health Policy and Management, Center for Health Decision
Sciences, Harvard School of Public Health; Associate Physician in

Cardiovascular Medicine, Department of Cardiology, Brigham and
Women’s Hospital, Boston, Massachusetts [2]

Murali Chakinala, MD
Associate Professor of Medicine, Division of Pulmonary and
Critical Care Medicine, Washington University School of Medicine,
St. Louis, Missouri [17]
Panithaya Chareonthaitawee, MD
Associate Professor of Medicine, Mayo Clinic College of Medicine,
Rochester, Minnesota [12, 42]

Ary L. Goldberger, MD
Professor of Medicine, Harvard Medical School; Wyss Institute for
Biologically Inspired Engineering, Harvard University; Beth Israel
Deaconess Medical Center, Boston, Massachusetts [11, 41, 43]

John S. Child, MD, FACC, FAHA, FASE
Streisand Professor of Medicine and Cardiology, Geffen School of
Medicine, University of California, Los Angeles (UCLA); Director,
Ahmanson-UCLA Adult Congenital Heart Disease Center; Director,

Anna R. Hemnes, MD
Assistant Professor, Division of Allergy, Pulmonary, and Critical
Care Medicine, Vanderbilt University Medical Center, Nashville,
Tennessee [Review and Self-Assessment]

vii


viii

Contributors

Helen H. Hobbs, MD
Professor of Internal Medicine and Molecular Genetics, University
of Texas Southwestern Medical Center, Dallas, Texas; Investigator,
Howard Hughes Medical Institute, Chevy Chase, Maryland [31]
Judith S. Hochman, MD
Harold Snyder Family Professor of Cardiology; Clinical Chief,
Leon Charney Division of Cardiology; Co-Director, NYU-HHC
Clinical and Translational Science Institute; Director, Cardiovascular
Clinical Research Center, New York University School of
Medicine, New York, New York [28]
Sharon A. Hunt, MD, FACC
Professor, Division of Cardiovascular Medicine, Stanford University,
Palo Alto, California [18]
David H. Ingbar, MD
Professor of Medicine, Pediatrics, and Physiology; Director,
Pulmonary Allergy, Critical Care and Sleep Division, University of
Minnesota School of Medicine, Minneapolis, Minnesota [28]
Adolf W. Karchmer, MD
Professor of Medicine, Harvard Medical School; Division of
Infectious Diseases, Beth Israel Deaconess Medical Center,
Boston, Massachusetts [25]
Louis V. Kirchhoff, MD, MPH
Professor of Internal Medicine (Infectious Diseases) and Epidemiology,
Department of Internal Medicine, The University of Iowa,
Iowa City, Iowa [27]
Theodore A. Kotchen, MD
Professor Emeritus, Department of Medicine; Associate Dean for

Clinical Research, Medical College of Wisconsin, Milwaukee,
Wisconsin [37]
Alexander Kratz, MD, PhD, MPH
Associate Professor of Pathology and Cell Biology, Columbia
University College of Physicians and Surgeons; Director, Core
Laboratory, Columbia University Medical Center, New York,
New York [Appendix]
Thomas H. Lee, MD, MSc
Professor of Medicine, Harvard Medical School; Network President,
Partners Healthcare System, Boston, Massachusetts [4]
Jane A. Leopold, MD
Associate Professor of Medicine, Harvard Medical School;
Brigham and Women’s Hospital, Boston, Massachusetts [13, 44]
Peter Libby, MD
Mallinckrodt Professor of Medicine, Harvard Medical School;
Chief, Cardiovascular Medicine, Brigham and Women’s Hospital,
Boston, Massachusetts [1, 30]
Joseph Loscalzo, MD, PhD
Hersey Professor of the Theory and Practice of Medicine,
Harvard Medical School; Chairman, Department of Medicine;
Physician-in-Chief, Brigham and Women’s Hospital, Boston,
Massachusetts [1, 3, 6–10, 20, 21, 33, 35, 38, 39]
Hari R. Mallidi, MD
Assistant Professor of Cardiothoracic Surgery; Director of
Mechanical Circulatory Support, Stanford University Medical
Center, Stanford, California [18]
Douglas L. Mann, MD
Lewin Chair and Chief, Cardiovascular Division; Professor of
Medicine, Cell Biology and Physiology, Washington University
School of Medicine, St. Louis, Missouri [17]

Francis Marchlinski, MD
Professor of Medicine; Director, Cardiac Electrophysiology, University
of Pennsylvania Health System, Philadelphia, Pennsylvania [16]
Matthew Martinez, MD
Lehigh Valley Physician Group, Lehigh Valley Heart Specialists,
Allentown, Pennsylvania [12, 42]
Robert J. Myerburg, MD
Professor, Departments of Medicine and Physiology, Division of
Cardiology; AHA Chair in Cardiovascular Research, University of
Miami Miller School of Medicine, Miami, Florida [29]
Rick A. Nishimura, MD, FACC, FACP
Judd and Mary Morris Leighton Professor of Cardiovascular Diseases;
Professor of Medicine; Consultant, Division of Cardiovascular
Diseases and Internal Medicine, Mayo Clinic College of Medicine,
Rochester, Minnesota [12, 42]
Patrick T. O’Gara, MD
Professor of Medicine, Harvard Medical School; Director, Clinical
Cardiology, Brigham and Women’s Hospital, Boston, Massachusetts
[9, 10, 20]
Michael A. Pesce, PhD
Professor Emeritus of Pathology and Cell Biology, Columbia
University College of Physicians and Surgeons; Columbia
University Medical Center, New York, New York [Appendix]
Daniel J. Rader, MD
Cooper-McClure Professor of Medicine and Pharmacology,
University of Pennsylvania School of Medicine, Philadelphia,
Pennsylvania [31]
Anis Rassi, Jr., MD, PhD, FACC, FACP, FAHA
Scientific Director, Anis Rassi Hospital, Goiânia, Brazil [27]

Stuart Rich, MD
Professor of Medicine, Department of Medicine, Section of
Cardiology, University of Chicago, Chicago, Illinois [40]
Richard M. Schwartzstein, MD
Ellen and Melvin Gordon Professor of Medicine and Medical
Education; Associate Chief, Division of Pulmonary, Critical Care,
and Sleep Medicine, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts [5]
Andrew P. Selwyn, MD, MBCHB
Professor of Medicine, Harvard Medical School; Brigham and
Women’s Hospital, Boston, Massachusetts [33]
David D. Spragg, MD
Assistant Professor of Medicine, Johns Hopkins University,
Baltimore, Maryland [14, 15]
Lynne Warner Stevenson, MD
Professor of Medicine, Harvard Medical School; Director,
Heart Failure Program, Brigham and Women’s Hospital,
Boston, Massachusetts [21]
Gordon F. Tomaselli, MD
Michel Mirowski, MD Professor of Cardiology; Professor of Medicine
and Cellular and Molecular Medicine; Chief, Division of Cardiology,
Johns Hopkins University, Baltimore, Maryland [14, 15]
Charles M. Wiener, MD
Dean/CEO Perdana University Graduate School of Medicine,
Selangor, Malaysia; Professor of Medicine and Physiology, Johns
Hopkins University School of Medicine, Baltimore, Maryland
[Review and Self-Assessment]


PREFACE

it. As knowledge about these complex systems expands,
the opportunity for identifying unique therapeutic targets
increases, holding great promise for definitive interventions in the future. Regenerative medicine is another area
of cardiovascular medicine that is rapidly achieving translation. Recognition that the adult human heart can repair
itself, albeit sparingly with typical injury, and that cardiac
precursor (stem) cells reside within the myocardium to do
this can be expanded, and can be used to repair if not
regenerate a normal heart is an exciting advance in the
field. These concepts represent a completely novel paradigm that will revolutionize the future of the subspecialty.
In view of the importance of cardiovascular medicine to
the field of internal medicine, and the rapidity with which
the scientific basis for the discipline is advancing, Harrison’s
Cardiovascular Medicine was developed. The purpose of this
sectional is to provide the readers with a succinct overview
of the field of cardiovascular medicine. To achieve this
goal, Harrison’s Cardiovascular Medicine comprises the key
cardiovascular chapters contained in the eighteenth edition
of Harrison’s Principles of Internal Medicine, contributed by
leading experts in the field. This sectional is designed not
only for physicians-in-training on cardiology rotations, but
also for practicing clinicians, other health care professionals,
and medical students who seek to enrich and update their
knowledge of this rapidly changing field. The editors trust
that this book will increase both the readers’ knowledge of
the field, and their appreciation for its importance.
The first section of the book, “Introduction to Cardiovascular Disorders,” provides a systems overview,
beginning with the basic biology of the cardiovascular system, followed by epidemiology of cardiovascular
disease, and approach to the patient. The integration
of pathophysiology with clinical management is a hallmark of Harrison’s, and can be found throughout each
of the subsequent disease-oriented chapters. The book

is divided into six main sections that reflect the scope of
cardiovascular medicine: (I) Introduction to the Cardiovascular System; (II) Diagnosis of Cardiovascular Disorders; (III) Heart Rhythm Disturbances; (IV) Disorders
of the Heart; (V) Disorders of the Vasculature; and (VI)
Cardiovascular Atlases.
Our access to information through web-based journals and databases is remarkably efficient. Although
these sources of information are invaluable, the daunting
body of data creates an even greater need for synthesis
by experts in the field. Thus, the preparation of these
chapters is a special craft that requires the ability to distill

Harrison’s Principles of Internal Medicine has been a respected
information source for more than 60 years. Over time,
the traditional textbook has evolved to meet the needs of
internists, family physicians, nurses, and other health care
providers. The growing list of Harrison’s products now
includes Harrison’s for the iPad, Harrison’s Manual of Medicine, and Harrison’s Online. This book, Harrison’s Cardiovascular Medicine, now in its second edition, is a compilation
of chapters related to cardiovascular disorders.
Our readers consistently note the sophistication of
the material in the specialty sections of Harrison’s. Our
goal was to bring this information to our audience in
a more compact and usable form. Because the topic is
more focused, it is possible to enhance the presentation
of the material by enlarging the text and the tables. We
have also included a Review and Self-Assessment section
that includes questions and answers to provoke reflection
and to provide additional teaching points.
Cardiovascular disease is the leading cause of death in
the United States, and is rapidly becoming a major cause
of death in the developing world. Advances in the therapy and prevention of cardiovascular diseases have clearly
improved the lives of patients with these common, potentially devastating disorders; yet, the disease prevalence

and the risk factor burden for disease (especially obesity
in the United States and smoking worldwide) continue to
increase globally. Cardiovascular medicine is, therefore, of
crucial importance to the field of internal medicine.
Cardiovascular medicine is a large and growing subspecialty, and comprises a number of specific subfields,
including coronary heart disease, congenital heart disease,
valvular heart disease, cardiovascular imaging, electrophysiology, and interventional cardiology. Many of these
areas involve novel technologies that facilitate diagnosis
and therapy. The highly specialized nature of these disciplines within cardiology and the increasing specialization
of cardiologists argue for the importance of a broad view
of cardiovascular medicine by the internist in helping to
guide the patient through illness and the decisions that
arise in the course of its treatment.
The scientific underpinnings of cardiovascular medicine have also been evolving rapidly. The molecular
pathogenesis and genetic basis for many diseases are now
known and, with this knowledge, diagnostics and therapeutics are becoming increasingly individualized. Cardiovascular diseases are largely complex phenotypes, and
this structural and physiological complexity recapitulates
the complex molecular and genetic systems that underlie

ix


x

Preface

core information from the ever-expanding knowledge
base. The editors are, therefore, indebted to our authors,
a group of internationally recognized authorities who
are masters at providing a comprehensive overview

while being able to distill a topic into a concise and
interesting chapter. We are indebted to our colleagues at

McGraw-Hill. Jim Shanahan is a champion for Harrison’s and these books were impeccably produced by Kim
Davis. We hope you find this book useful in your effort
to achieve continuous learning on behalf of your patients.
Joseph Loscalzo, MD, PhD


NOTICE
Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are
required. The authors and the publisher of this work have checked with
sources believed to be reliable in their efforts to provide information that is
complete and generally in accord with the standards accepted at the time of
publication. However, in view of the possibility of human error or changes
in medical sciences, neither the authors nor the publisher nor any other party
who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or
complete, and they disclaim all responsibility for any errors or omissions or
for the results obtained from use of the information contained in this work.
Readers are encouraged to confirm the information contained herein with
other sources. For example and in particular, readers are advised to check
the product information sheet included in the package of each drug they
plan to administer to be certain that the information contained in this work
is accurate and that changes have not been made in the recommended dose
or in the contraindications for administration. This recommendation is of
particular importance in connection with new or infrequently used drugs.

Review and self-assessment questions and answers were taken from Wiener CM,
Brown CD, Hemnes AR (eds). Harrison’s Self-Assessment and Board Review, 18th ed.
New York, McGraw-Hill, 2012, ISBN 978-0-07-177195-5.

The global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine
throughout the world.
The genetic icons identify a clinical issue with an explicit genetic relationship.


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SECTION I

Introduction to
Cardiovascular
Disorders


CHaPter 1

BASIC BIOLOGY OF THE CARDIOVASCULAR
SYSTEM
Joseph loscalzo

■

Peter libby

■

Jonathan epstein

sandwiched between layers of smooth-muscle cells
(Fig. 1-1E ). Larger arteries have a clearly demarcated
internal elastic lamina that forms the barrier between
the intima and the media. An external elastic lamina
demarcates the media of arteries from the surrounding
adventitia.

tHe Blood Vessel
VaSCulaR ulTRaSTRuCTuRE
Blood vessels participate in homeostasis on a momentto-moment basis and contribute to the pathophysiology
of diseases of virtually every organ system. Hence,
an understanding of the fundamentals of vascular biology
furnishes a foundation for understanding the normal
function of all organ systems and many diseases.
The smallest blood vessels—capillaries—consist of a
monolayer of endothelial cells apposed to a basement
membrane, adjacent to occasional smooth-muscle-like
cells known as pericytes (Fig. 1-1A). Unlike larger vessels, pericytes do not invest the entire microvessel to
form a continuous sheath. Veins and arteries typically
have a trilaminar structure (Fig. 1-1B–E). The intima
consists of a monolayer of endothelial cells continuous
with those of the capillaries. The middle layer, or
tunica media, consists of layers of smooth-muscle cells;
in veins, the media can contain just a few layers of
smooth-muscle cells (Fig. 1-1B). The outer layer,
the adventitia, consists of looser extracellular matrix
with occasional fibroblasts, mast cells, and nerve
terminals. Larger arteries have their own vasculature,
the vasa vasorum, which nourishes the outer aspects
of the tunica media. The adventitia of many veins

surpasses the intima in thickness.
The tone of muscular arterioles regulates blood
pressure and flow through various arterial beds. These
smaller arteries have a relatively thick tunica media in
relation to the adventitia (Fig. 1-1C). Medium-size
muscular arteries similarly contain a prominent tunica
media (Fig. 1-1D); atherosclerosis commonly affects
this type of muscular artery. The larger elastic arteries
have a much more structured tunica media consisting
of concentric bands of smooth-muscle cells, interspersed with strata of elastin-rich extracellular matrix

ORIgIN OF VaSCulaR CEllS
The intima in human arteries often contains occasional
resident smooth-muscle cells beneath the monolayer
of vascular endothelial cells. The embryonic origin of
smooth-muscle cells in various types of arteries differs.
Some upper-body arterial smooth-muscle cells derive
from the neural crest, whereas lower-body arteries generally recruit smooth-muscle cells from neighboring
mesodermal structures during development. Derivatives of the proepicardial organ, which gives rise to the
epicardial layer of the heart, contribute to the vascular
smooth-muscle cells of the coronary arteries. Recent
evidence suggests that bone marrow may give rise to
both vascular endothelial cells and smooth-muscle cells,
particularly under conditions of injury repair or vascular
lesion formation. Indeed, the ability of bone marrow to
repair an injured endothelial monolayer may contribute
to maintenance of vascular health, whereas failure to
do so may lead to arterial disease. The precise sources
of endothelial and mesenchymal progenitor cells or
their stem cell precursors remain the subject of active

investigation.

VaSCulaR CEll bIOlOgy
Endothelial cell
The key cell of the vascular intima, the endothelial cell,
has manifold functions in health and disease. Most obviously, the endothelium forms the interface between

2


A. Capillary

B. Vein

3

C. Small muscular artery

Pericyte

Endothelial cell

Basic Biology of the Cardiovascular System

D. Large muscular artery

E. Large elastic artery

Internal elastic
lamina

External elastic
lamina

Adventitia

Figure 1-1
Schematics of the structures of various types of blood
vessels. A. Capillaries consist of an endothelial tube in contact with a discontinuous population of pericytes. B. Veins
typically have thin medias and thicker adventitias. C. A small
muscular artery features a prominent tunica media. D. Larger

tissues and the blood compartment. It therefore must
regulate the entry of molecules and cells into tissues in a
selective manner. The ability of endothelial cells to serve
as a selectively permeable barrier fails in many vascular
disorders, including atherosclerosis and hypertension.
This dysregulation of permeability also occurs in pulmonary edema and other situations of “capillary leak.”
The endothelium also participates in the local regulation of blood flow and vascular caliber. Endogenous
substances produced by endothelial cells such as prostacyclin, endothelium-derived hyperpolarizing factor, nitric
oxide (NO), and hydrogen peroxide (H2O2) provide
tonic vasodilatory stimuli under physiologic conditions
in vivo (Table 1-1). Impaired production or excess
catabolism of NO impairs this endothelium-dependent
vasodilator function and may contribute to excessive
vasoconstriction in various pathologic situations. By
contrast, endothelial cells also produce potent vasoconstrictor substances such as endothelin in a regulated
fashion. Excessive production of reactive oxygen species, such as superoxide anion (O2−), by endothelial or
smooth-muscle cells under pathologic conditions (e.g.,
excessive exposure to angiotensin II) can promote local

oxidative stress and inactivate NO.

CHAPTER 1

Vascular
smooth-muscle cell

muscular arteries have a prominent media with smoothmuscle cells embedded in a complex extracellular matrix.
E. Larger elastic arteries have cylindrical layers of elastic tissue
alternating with concentric rings of smooth-muscle cells.

The endothelial monolayer contributes critically
to inflammatory processes involved in normal host
defenses and pathologic states. The normal endothelium resists prolonged contact with blood leukocytes;
however, when activated by bacterial products such as
endotoxin or proinflammatory cytokines released during
infection or injury, endothelial cells express an array of
­leukocyte adhesion molecules that bind various classes of
Table 1-1
Endothelial Functions in Health and Disease
Homeostatic
Phenotype

Dysfunctional
Phenotype

Vasodilation

Impaired dilation,
­vasoconstriction

Antithrombotic,
profibrinolytic

Prothrombotic,
­antifibrinolytic

Anti-inflammatory

Proinflammatory

Antiproliferative

Proproliferative

Antioxidant

Prooxidant

Permselectivity

Impaired barrier function


4

SECTION I
Introduction to Cardiovascular Disorders

leukocytes. The endothelial cells appear to recruit selectively different classes of leukocytes in different pathologic conditions. The gamut of adhesion molecules and

chemokines generated during acute bacterial infection
tends to recruit granulocytes. In chronic inflammatory
diseases such as tuberculosis and atherosclerosis, endothelial cells express adhesion molecules that favor the
recruitment of mononuclear leukocytes that characteristically accumulate in these conditions.
The endothelium also dynamically regulates thrombosis
and hemostasis. Nitric oxide, in addition to its vasodilatory properties, can limit platelet activation and aggregation. Like NO, prostacyclin produced by endothelial
cells under normal conditions not only provides a vasodilatory stimulus but also antagonizes platelet activation
and aggregation. Thrombomodulin expressed on the
surface of endothelial cells binds thrombin at low concentrations and inhibits coagulation through activation
of the protein C pathway, inactivating clotting ­factors
Va and VIIIa and thus combating thrombus formation. The surface of endothelial cells ­contains heparan
sulfate glycosaminoglycans that furnish an endogenous
antithrombotic coating to the vasculature. Endothelial cells also participate actively in fibrinolysis and its
regulation. They express receptors for plasminogen and
­plasminogen activators and produce tissue-type plasminogen activators. Through local generation of plasmin,
the normal endothelial monolayer can promote the lysis
of nascent thrombi.
When activated by inflammatory cytokines, bacterial endotoxin, or angiotensin II, for example, endothelial cells can produce substantial quantities of the major
inhibitor of fibrinolysis, plasminogen activator inhibitor
1 (PAI-1). Thus, in pathologic circumstances, the endothelial cell may promote local thrombus accumulation
rather than combat it. Inflammatory stimuli also induce
the expression of the potent procoagulant tissue factor, a
contributor to disseminated intravascular coagulation in
sepsis.
Endothelial cells also participate in the pathophysiology of a number of immune-mediated diseases. Lysis
of endothelial cells mediated by complement provides
an example of immunologically mediated tissue injury.
The presentation of foreign histocompatibility complex
antigens by endothelial cells in solid-organ allografts can
trigger immunologic rejection. In addition, immunemediated endothelial injury may contribute in some

patients with thrombotic thrombocytopenic purpura
and patients with hemolytic-uremic syndrome. Thus,
in addition to contributing to innate immune responses,
endothelial cells participate actively in both humoral
and cellular limbs of the immune response.
Endothelial cells regulate growth of the subjacent
smooth-muscle cells as well. Heparan sulfate glycosaminoglycans elaborated by endothelial cells can hold
smooth-muscle proliferation in check. In contrast,

when exposed to various injurious stimuli, ­endothelial
cells can elaborate growth factors and chemoattractants, such as platelet-derived growth factor, that can
promote the migration and proliferation of vascular
smooth-­muscle cells. Dysregulated elaboration of these
­growth-stimulatory molecules may promote smoothmuscle accumulation in atherosclerotic lesions.
Clinical assessment of endothelial function
Various invasive and noninvasive approaches can be
used to evaluate endothelial vasodilator function in
humans. Either pharmacologic agonists or increased
flow stimulates the endothelium to release acutely
molecular effectors that alter underlying smooth-­muscle
cell tone. Invasively, infusion of the cholinergic agonists acetylcholine and methacholine stimulates the
release of NO from normal endothelial cells. Changes
in coronary diameter can be quantitatively measured
in response to an intracoronary infusion of these shortlived, rapidly acting agents. Noninvasive assessment of
endothelial function in the forearm circulation typically
involves occlusion of brachial artery blood flow with
a blood pressure cuff, which elicits reactive ­hyperemia
after release; the resulting flow increase normally causes
endothelium-dependent vasodilation, which is measured as the change in brachial artery blood flow and
diameter by ultrasound (Fig. 1-2). This approach depends

on shear stress–dependent changes in endothelial release of
NO after restoration of blood flow, as well as the effect of
adenosine released (transiently) from ischemic tissue in
the forearm.
Typically, these invasive and noninvasive approaches
detect inducible vasodilatory changes in vessel diameter
of ∼10%. In individuals with atherosclerosis or its risk
factors (especially hypertension, hypercholesterolemia,
diabetes mellitus, and smoking), such studies can detect
endothelial dysfunction as defined by a smaller change
in diameter and, in the extreme case, a so-called paradoxical vasoconstrictor response owing to the direct
effect of cholinergic agonists on vascular smooth-muscle
cell tone.
Vascular smooth-muscle cell
The vascular smooth-muscle cell, the major cell type
of the media layer of blood vessels, also ­contributes
actively to vascular pathobiology. Contraction and
relaxation of smooth-muscle cells at the level of the
muscular arteries controls blood pressure, and, hence,
regional blood flow and the afterload experienced
by the left ventricle (see later). The vasomotor tone
of veins, which is governed by smooth-muscle cell
tone, regulates the capacitance of the venous tree and
influences the preload experienced by both ventricles. Smooth-muscle cells in the adult vessel seldom


Vascular smooth-muscle cells govern vessel tone. Those
cells contract when stimulated by a rise in intracellular calcium concentration by calcium influx through
the plasma membrane and by calcium release from
intracellular stores (Fig. 1-3). In vascular smoothmuscle cells, voltage-dependent L-type calcium channels open with membrane depolarization, which is

Basic Biology of the Cardiovascular System

replicate. This homeostatic quiescence of smoothmuscle cells changes in conditions of arterial injury or
inflammatory activation. Proliferation and migration of
arterial smooth-muscle cells, which is associated with
a change in phenotype characterized by lower content

Vascular smooth-muscle cell function

5

CHAPTER 1

Figure 1-2
Assessment of endothelial function in vivo using blood
pressure cuff-occlusion and release. Upon deflation of
the cuff, changes in diameter (A) and blood flow (B) of the
brachial artery are monitored with an ultrasound probe (C).
(Reproduced with permission of J. Vita, MD.)

of contractile proteins and greater production of extracellular matrix macromolecules, can contribute to the
development of arterial stenoses in atherosclerosis,
­arteriolar remodeling that can sustain and propagate
hypertension, and the hyperplastic response of arteries injured by angioplasty or stent deployment. In the
pulmonary circulation, smooth-muscle migration and
proliferation contribute decisively to the pulmonary
vascular disease that gradually occurs in response to sustained high-flow states such as left-to-right shunts. Such
pulmonary vascular disease provides a major obstacle to
the management of many patients with adult congenital heart disease. Elucidation of the signaling pathways

that regulate the reversible transition of the vascular
smooth-muscle cell phenotype remains an active focus
of investigation. Among other mediators, microRNAs
have emerged as powerful regulators of this transition,
offering new targets for intervention.
The activated, phenotypically modulated smooth-muscle
cells secrete the bulk of vascular extracellular matrix.
Excessive production of collagen and glycosaminoglycans contributes to the remodeling and altered biology
and biomechanics of arteries affected by hypertension
or atherosclerosis. In larger elastic arteries, the elastin
­synthesized by smooth-muscle cells serves to maintain
not only normal arterial structure but also hemodynamic function. The ability of the larger arteries, such
as the aorta, to store the kinetic energy of systole promotes tissue perfusion during diastole. Arterial stiffness
associated with aging or disease, as manifested by a
­widening pulse pressure, increases left ventricular afterload
and portends a poor outcome.
Like endothelial cells, vascular smooth-muscle cells
do not merely respond to vasomotor or inflammatory
stimuli elaborated by other cell types but can themselves
serve as a source of such stimuli. For example, when
exposed to bacterial endotoxin or other proinflammatory stimuli, smooth-muscle cells can elaborate cytokines
and other inflammatory mediators. Like endothelial
cells, upon inflammatory activation, arterial smoothmuscle cells can produce prothrombotic mediators such
as tissue factor, the antifibrinolytic protein PAI-1, and
other molecules that modulate thrombosis and fibrinolysis. Smooth-muscle cells also elaborate autocrine
growth factors that can amplify hyperplastic responses to
arterial injury.


6

NE, ET-1, Ang II

NO

SECTION I

VDCC
PIP2

PLC

K+ Ch

Na-K ATPase

G

GTP

AC
ATP

SR

RhoA

Introduction to Cardiovascular Disorders

IP3R

RyrR

IP3

G

pGC
sGC

DAG

BetaAgonist

ANP

Plb
ATPase

cGMP

cAMP

PKG

PKA

Calcium

PKC
Rho

Kinase

MLCK

Caldesmon
Calponin

MLCP

Figure 1-3
Regulation of vascular smooth-muscle cell calcium
­concentration and actomyosin ATPase-dependent contraction. AC, adenylyl cyclase; Ang II, angiotensin II;
ANP, antrial natriuretic peptide; DAG, diacylglycerol; ET-1,
­endothelin-1; G, G-protein; IP3, inositol 1,4,5-trisphosphate;
MLCK, myosin light chain kinase; MLCP, myosin light
chain phosphatase; NE, norepinephrine; NO, nitric oxide;

pGC, particular guanylyl cyclase; PIP2, phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein
kinase C; PKG, protein kinase G; PLC, phospholipase C;
sGC, soluble guanylyl cyclase; SR, sarcoplasmic reticulum;
VDCC, voltage-dependent calcium channel. (Modified from
B Berk, in Vascular Medicine, 3rd ed, p 23. Philadelphia,
Saunders, Elsevier, 2006; with permission.)

regulated by energy-dependent ion pumps such as
the Na+,K+-ATPase pump and ion channels such as
the ­Ca2+-­sensitive K+ channel. Local changes in intracellular ­calcium concentration, termed calcium sparks,
result from the influx of calcium through the voltagedependent calcium channel and are caused by the coordinated activation of a cluster of ryanodine-sensitive
­calcium release channels in the sarcoplasmic reticulum
(see later). ­Calcium sparks directly augment intracellular calcium concentration and indirectly increase intracellular calcium concentration by activating chloride

channels. In addition, calcium sparks reduce smoothmuscle contractility by activating large-conductance
calcium-sensitive K+ channels, hyperpolarizing the cell
­membrane and thereby limiting further voltage-dependent
increases in intracellular calcium.
Biochemical agonists also increase intracellular calcium
concentration, in this case by receptor-­dependent activation of phospholipase C with hydrolysis of phosphatidylinositol 4,5-bisphosphate, resulting in generation of

diacylglycerol (DAG) and inositol 1,4,5-trisphosphate
(IP3). These membrane lipid derivatives in turn activate
protein kinase C and increase intracellular calcium concentration. In addition, IP3 binds to specific receptors
on the sarcoplasmic reticulum membrane to increase
calcium efflux from this calcium storage pool into the
cytoplasm.
Vascular smooth-muscle cell contraction is ­controlled
principally by the phosphorylation of myosin light
chain, which in the steady state depends on the ­balance
between the actions of myosin light chain kinase and
myosin light chain phosphatase. Calcium activates
myosin light chain kinase through the formation of a
­calcium-calmodulin complex. Phosphorylation of myosin light chain by this kinase augments myosin ATPase
activity and enhances contraction. Myosin light chain
phosphatase dephosphorylates myosin light chain,
reducing myosin ATPase activity and contractile force.
Phosphorylation of the myosin-binding ­subunit (thr695)
of myosin light chain phosphatase by Rho kinase


The tone of vascular smooth-muscle cells is governed
by the autonomic nervous system and by the endothelium in tightly regulated control networks. Autonomic
neurons enter the blood vessel medial layer from the

adventitia and modulate vascular smooth-muscle cell
tone in response to baroreceptors and chemoreceptors
within the aortic arch and carotid bodies and in response
to thermoreceptors in the skin. These regulatory components include rapidly acting reflex arcs modulated
by central inputs that respond to sensory inputs (olfactory, visual, auditory, and tactile) as well as emotional
stimuli. Three classes of nerves mediate autonomic
regulation of vascular tone: sympathetic, whose principal neurotransmitters are epinephrine and norepinephrine; ­parasympathetic, whose principal neurotransmitter
is acetylcholine; and nonadrenergic/noncholinergic, which
include two ­subgroups—nitrergic, whose principal neurotransmitter is NO, and peptidergic, whose principal
­neurotransmitters are substance P, vasoactive intestinal
peptide, ­calcitonin gene-related peptide, and ATP.

Basic Biology of the Cardiovascular System

Control of vascular smooth-muscle cell tone

Each of these neurotransmitters acts through spe- 7
cific receptors on the vascular smooth-muscle cell to
modulate intracellular calcium and, consequently, contractile tone. Norepinephrine activates α receptors,
and epinephrine activates α and β receptors (adrenergic
receptors); in most blood vessels, norepinephrine activates postjunctional α1 receptors in large arteries and
α2 receptors in small arteries and arterioles, leading to vasoconstriction. Most blood vessels express
­β2-adrenergic receptors on their vascular smooth-muscle
cells and respond to β agonists by cyclic ­AMP–dependent
relaxation. Acetylcholine released from parasympathetic
neurons binds to muscarinic receptors (of which there are
five subtypes, M1–5) on vascular smooth-muscle cells to
yield vasorelaxation. In addition, NO stimulates presynaptic neurons to release acetylcholine, which can stimulate the release of NO from the endothelium. Nitrergic
neurons release NO ­produced by neuronal NO synthase,
which causes vascular smooth-muscle cell relaxation via

the cyclic GMP–dependent and –independent mechanisms described earlier. The peptidergic neurotransmitters all potently vasodilate, acting either directly or
through endothelium-dependent NO release to decrease
vascular smooth-muscle cell tone.
The endothelium modulates vascular ­smooth-muscle
tone by the direct release of several effectors, ­including
NO, prostacyclin, hydrogen sulfide, and ­endothelium-­
derived hyperpolarizing factor, all of which cause
­vasorelaxation, and endothelin, which causes vasoconstriction. The release of these endothelial effectors
of ­vascular smooth-muscle cell tone is stimulated by
mechanical (shear stress, cyclic strain, etc.) and biochemical mediators (purinergic agonists, muscarinic
agonists, peptidergic agonists), with the biochemical
mediators acting through endothelial receptors specific
to each class. In addition to these local paracrine modulators of vascular smooth-muscle cell tone, circulating
mediators can affect tone, including norepinephrine and
epinephrine, vasopressin, angiotensin II, bradykinin, and
the natriuretic peptides (ANP, BNP, CNP, and DNP),
as discussed earlier.

CHAPTER 1

inhibits phosphatase activity and induces calcium sensitization of the contractile apparatus. Rho kinase is itself
activated by the small GTPase RhoA, which is stimulated by guanosine exchange factors and inhibited by
GTPase-activating proteins.
Both cyclic AMP and cyclic GMP relax vascular
smooth-muscle cells through complex mechanisms.
β  agonists, acting through their G-protein-coupled
receptors activate adenylyl cyclase to convert ATP
to cyclic AMP; NO and atrial natriuretic peptide acting directly and via a G-protein-coupled receptor,
respectively, activate guanylyl cyclase to convert GTP
to cyclic GMP. These agents in turn activate protein kinase A and protein kinase G, respectively, which

inactivate myosin light chain kinase and decrease vascular smooth-muscle cell tone. In addition, protein
kinase G  can interact directly with the myosin-binding
substrate subunit of myosin light chain phosphatase,
increasing phosphatase activity and decreasing vascular tone. Finally, several mechanisms drive NO-dependent, ­protein kinase G–mediated reductions in vascular
smooth-muscle cell calcium concentration, including
phosphorylation-dependent inactivation of RhoA;
decreased IP3 formation; phosphorylation of the IP3
receptor–associated cyclic GMP kinase substrate, with
subsequent inhibition of IP3 receptor function; phosphorylation of phospholamban, which increases calcium
ATPase activity and sequestration of calcium in the sarcoplasmic reticulum; and protein kinase G–dependent
stimulation of plasma membrane calcium ATPase activity, perhaps by activation of the Na+,K+-ATPase pump or
hyperpolarization of the cell membrane by activation of
calcium-dependent K+ channels.

Vascular Regeneration
Growth of new blood vessels can occur in response
to conditions such as chronic hypoxemia and tissue
­ischemia. Growth factors, including vascular endothelial growth factor (VEGF) and forms of fibroblast
growth factor (FGF), activate a signaling cascade that
stimulates endothelial proliferation and tube formation,
defined as angiogenesis. The development of ­collateral
vascular networks in the ischemic myocardium reflects
this process and can result from selective activation
of endothelial progenitor cells, which may reside in
the blood vessel wall or home to the ischemic ­tissue


8

Table 1-2

Genetic Polymorphisms in Vascular Function and Disease Risk

SECTION I

Gene

Introduction to Cardiovascular Disorders

Polymorphic Allele

Clinical Implications

`1A

Arg492Cys

None

`2B

Glu9/G1712

Increased CHD events

`2C

A2cDcl3232-325

Ethnic differences in risk of hypertension or heart failure

Angiotensin-converting
enzyme (ACE)

Insertion/deletion polymorphism in intron 16

D allele or DD genotype-increased response to ACE inhibitors;
inconsistent data for increased risk of atherosclerotic heart
­disease, and hypertension

Ang II type I receptor

1166A → C Ala-Cys

Increased response to Ang II and increased risk of pregnancy-­
associated hypertension

Ser49Gly

Increased HR and DCM risk

Arg389Gly

Increased heart failure in blacks

Arg16Gly

Familial hypertension, increased obesity risk

Glu27Gln

Hypertension in white type II diabetics

Thr164Ile

Decreased agonist affinity and worse HF outcome

B2-Bradykinin receptor

Cys58Thr, Cys412Gly,
Thr21Met

Increased risk of hypertension in some ethnic groups

Endothelial nitric oxide
synthase (eNOS)

Nucleotide repeats
in introns 4 and 13,
­Glu298Asp

Increased MI and venous thrombosis

Thr785Cys

Early coronary artery disease

`-Adrenergic Receptors

a-Adrenergic Receptors
β1

β2

Abbreviations: CHD, coronary heart disease; HR, heart rate; DCM, dilated cardiomyopathy; HF, heart failure; MI, myocardial infarction.
Source: Derived from B Schaefer et al: Heart Dis 5:129, 2003.

s­ubtended by an occluded or severely stenotic ­vessel
from the bone marrow. True arteriogenesis, or the
development of a new blood vessel that includes all
three cell layers, normally does not occur in the cardiovascular system of adult mammals. The molecular
mechanisms and progenitor cells that can recapitulate
blood vessel development de novo are under rapidly
advancing study.

with differences in vascular response often (but not
invariably) relate to functional differences in the activity or expression of the receptor or enzyme of interest.
Some of these ­polymorphisms appear to have different
allele frequencies in specific ethnic groups. A summary
of recently identified polymorphisms defining these
vascular ­pharmacogenomic differences is provided in
Table 1-2.

Vascular Pharmacogenomics
The last decade has witnessed considerable progress
in efforts to define the genetic differences underlying individual variations in vascular pharmacologic
responses. Many investigators have focused on receptors and enzymes associated with neurohumoral
modulation of vascular function as well as hepatic
enzymes that metabolize drugs that affect vascular
tone. The genetic polymorphisms thus far associated

Cellular Basis of Cardiac
Contraction
Cardiac Ultrastructure
About three-fourths of the ventricular mass is composed
of cardiomyocytes, normally 60–140 μm in length and
17–25 μm in diameter (Fig. 1-4A). Each cell contains
multiple, rodlike cross-banded strands (myofibrils) that


9

CHAPTER 1

Myofiber
A

Myocyte

10 µm

Ca2+
enters
Ca2+
Pump
Ca2+
“trigger”

Myofibril

Myocy

te

T tubule

Ca2+
leaves
Free
Ca2+

Myofibril
Mitochondrion

SR

Contract Relax

B

Systole
Myofibril

Z
C

Diastole

Actin

Head

Titin

Myosin
M

43 nm

Z

Figure 1-4 
A shows the branching myocytes ­making
up the cardiac myofibers. B illustrates the
critical role played by the changing [Ca2+] in
the myocardial cytosol. Ca2+ ions are schematically shown as entering through the calcium channel that opens in response to the
wave of depolarization that ­travels along the
sarcolemma. These Ca2+ ions “trigger” the
release of more calcium from the sarcoplasmic reticulum (SR) and thereby initiate a contraction-relaxation cycle. Eventually, the small
quantity of Ca2+ that has entered the cell
leaves predominantly through an Na+/Ca2+
exchanger, with a lesser role for the sarcolemmal Ca2+ pump. The varying actin-­myosin
overlap is shown for (B) systole, when [Ca2+]
is maximal, and (C) diastole, when [Ca2+] is
­minimal. D. The myosin heads, attached to
the thick filaments, interact with the thin actin
filaments. (From LH Opie, Heart ­Physiology,
reprinted with permission. Copyright LH Opie,
2004.)

D

run the length of the cell and are composed of serially
repeating structures, the sarcomeres. The cytoplasm
between the myofibrils contains other cell constituents,
including the single centrally located nucleus, numerous
mitochondria, and the intracellular membrane ­system,
the sarcoplasmic reticulum.
The sarcomere, the structural and functional unit of
contraction, lies between adjacent Z lines, which are
dark repeating bands that are apparent on transmission electron microscopy. The distance between Z lines
varies with the degree of contraction or stretch of the
muscle and ranges between 1.6 and 2.2 μm. Within
the confines of the sarcomere are alternating light and
dark bands, giving the myocardial fibers their striated
appearance under the light microscope. At the center of the sarcomere is a dark band of constant length

(1.5 μm), the A band, which is flanked by two lighter
bands, the I bands, which are of variable length. The
­sarcomere of heart muscle, like that of skeletal muscle, consists of two sets of interdigitating myofilaments.
Thicker filaments, composed principally of the protein myosin, ­traverse the A band; they are about 10 nm
(100 Å) in diameter, with tapered ends. Thinner filaments, composed primarily of actin, course from the
Z lines through the I band into the A band; they are
approximately 5 nm (50 Å) in diameter and 1.0 μm in
length. Thus, thick and thin filaments overlap only within
the (dark) A band, whereas the (light) I band contains
only thin filaments. On electron-microscopic examination, bridges may be seen to extend between the thick and
thin filaments within the A band; these are myosin heads
bound to actin filaments.

Basic Biology of the Cardiovascular System

Na+
Exchange


10

SECTION I
Introduction to Cardiovascular Disorders

molecules are laid down in an orderly, polarized manner, leaving the globular portions projecting outward so
that they can interact with actin to generate force and
shortening (Fig. 1-4B).
Actin has a molecular mass of about 47,000 Da. The
thin filament consists of a double helix of two chains
of actin molecules wound about each other on a
larger molecule, tropomyosin. A group of regulatory
­proteins—troponins C, I, and T—are spaced at regular intervals on this filament (Fig. 1-5). In contrast to
myosin, actin lacks intrinsic enzymatic activity but does
combine reversibly with myosin in the presence of
ATP and Ca2+. The calcium ion activates the myosin
ATPase, which in turn breaks down ATP, the energy
source for contraction (Fig. 1-5). The activity of ­myosin
ATPase determines the rate of forming and breaking of
the actomyosin cross-bridges and ultimately the ­velocity
of muscle contraction. In relaxed muscle, tropomyosin
inhibits this interaction. Titin (Fig. 1-4D) is a large,

The Contractile Process
The sliding filament model for muscle contraction rests
on the fundamental observation that both the thick and

the thin filaments are constant in overall length during
both contraction and relaxation. With activation, the
actin filaments are propelled farther into the A band.
In the process, the A band remains constant in length,
whereas the I band shortens and the Z lines move
toward one another.
The myosin molecule is a complex, asymmetric fibrous
protein with a molecular mass of about 500,000 Da; it
has a rodlike portion that is about 150 nm (1500 Å) in
length with a globular portion (head) at its end. These
globular portions of myosin form the bridges between
the myosin and actin molecules and are the site of
ATPase activity. In forming the thick myofilament,
which is composed of ∼300 longitudinally stacked
myosin molecules, the rodlike segments of the myosin

ADP

ATP

Pi

1. ATP hydrolysis

Relaxed
4. Dissociation of

Relaxed, energized
Actin

Actin

actin and myosin

ATP

2. Formation of
active complex
Pi

ADP

ADP

3. Product
dissociation
Rigor complex

Figure 1-5
Four steps in cardiac muscle contraction and relaxation.
In relaxed muscle (upper left), ATP bound to the myosin
cross-bridge dissociates the thick and thin filaments. Step 1:
Hydrolysis of myosin-bound ATP by the ATPase site on the
myosin head transfers the chemical energy of the nucleotide
to the activated cross-bridge (upper right). When cytosolic
Ca2+ concentration is low, as in relaxed muscle, the reaction cannot proceed because tropomyosin and the ­troponin
complex on the thin filament do not allow the active sites
on actin to interact with the cross-bridges. Therefore, even
though the cross-bridges are energized, they cannot interact with actin. Step 2: When Ca2+ binding to troponin C has
exposed active sites on the thin filament, actin interacts

with the myosin cross-bridges to form an active complex
(lower right) in which the energy derived from ATP is
retained in the actin-bound cross-bridge, whose orientation

Active complex

has not yet shifted. Step 3: The muscle contracts when ADP
dissociates from the cross-bridge. This step leads to the formation of the low-energy rigor complex (lower left) in which
the chemical energy derived from ATP hydrolysis has been
expended to perform mechanical work (the “rowing” motion
of the cross-bridge). Step 4: The muscle returns to its resting
state, and the cycle ends when a new molecule of ATP binds
to the rigor complex and dissociates the cross-bridge from the
thin filament. This cycle continues until calcium is dissociated
from troponin C in the thin filament, which causes the contractile proteins to return to the resting state with the cross-bridge
in the energized state. ATP, adenosine triphosphate; ATPase,
adenosine triphosphatase; ADP, adenosine diphosphate. (From
AM Katz: Heart failure: Cardiac function and dysfunction, in
Atlas of Heart Diseases, 3rd ed, WS Colucci [ed]. ­Philadelphia,
Current Medicine, 2002. Reprinted with permission.)


into the myocardial fiber along the Z lines, i.e., the ends
of the sarcomeres.

Cardiac Activation

Basic Biology of the Cardiovascular System

In the inactive state, the cardiac cell is electrically polarized; i.e., the interior has a negative charge relative to

the outside of the cell, with a transmembrane potential
of −80 to −100 mV (Chap. 14). The sarcolemma, which
in the resting state is largely impermeable to Na+, has a
Na+- and K+-stimulating pump energized by ATP that
extrudes Na+ from the cell; this pump plays a critical role
in establishing the resting potential. Thus, intracellular
[K+] is relatively high and [Na+] is far lower; conversely,
extracellular [Na+] is high and [K+] is low. At the same
time, in the resting state, extracellular [Ca2+] greatly
exceeds free intracellular [Ca2+].
The action potential has four phases (Fig. 14-1B).
During the plateau of the action potential (phase 2),
there is a slow inward current through L-type Ca2+
channels in the sarcolemma (Fig. 1-7). The depolarizing current not only extends across the surface of
the cell but penetrates deeply into the cell by way of
the ramifying T tubular system. The absolute quantity
of Ca2+ that crosses the sarcolemma and the T system
is relatively small and by itself appears to be insufficient
to bring about full activation of the contractile apparatus. However, this Ca2+ current triggers the release of
much larger quantities of Ca2+ from the SR, a process
termed Ca2+-induced Ca2+ release. The latter is a major
­determinant of intracytoplasmic [Ca2+] and therefore of
myocardial contractility.
Ca2+ is released from the SR through a Ca2+ release
channel, a cardiac isoform of the ryanodine receptor
(RyR2), which controls intracytoplasmic [Ca2+] and,
as in vascular smooth-muscle cells, leads to the local
changes in intracellular [Ca2+] called calcium sparks.
A number of regulatory proteins, including calstabin
2, inhibit RyR2 and thereby the release of Ca2+ from

the SR. PKA dissociates calstabin from the RyR2,
­enhancing Ca2+ release and thereby myocardial contractility. Excessive plasma catecholamine levels and
cardiac sympathetic neuronal release of norepinephrine
cause hyperphosphorylation of PKA, leading to calstabin
2–depleted RyR2. The latter depletes SR Ca2+ stores
and thereby impairs cardiac contraction, leading to heart
failure, and also triggers ventricular arrhythmias.
The Ca2+ released from the SR then diffuses
toward the myofibrils, where, as already described,
it combines with troponin C (Fig. 1-6). By repressing this inhibitor of contraction, Ca2+ activates the
myofilaments to shorten. During repolarization, the
activity of the Ca2+ pump in the SR, the SR Ca2+
ATPase ­(SERCA2A), reaccumulates Ca2+ against
a concentration ­gradient, and the Ca2+ is stored in
the SR by its attachment to a protein, calsequestrin.

11

CHAPTER 1

flexible, myofibrillar protein that connects myosin to
the Z line; its stretching contributes to the elasticity
of the heart. Dystrophin is a long cytoskeletal protein
that has an amino-terminal actin-binding domain and a
carboxy-terminal domain that binds to the dystroglycan
complex at adherens junctions on the cell ­membrane,
thus tethering the sarcomere to the cell membrane at
regions tightly coupled to adjacent contracting myocytes. Mutations in components of the ­dystrophin
complex lead to muscular dystrophy and associated
cardiomyopathy.

During activation of the cardiac myocyte, Ca2+
becomes attached to one of three components of the
heterotrimer troponin C, which results in a conformational change in the regulatory protein tropomyosin;
the latter, in turn, exposes the actin cross-bridge interaction sites (Fig. 1-5). Repetitive interaction between
myosin heads and actin filaments is termed cross-bridge
cycling, which results in sliding of the actin along the
myosin filaments, ultimately causing muscle shortening and/or the development of tension. The splitting of ATP then dissociates the myosin cross-bridge
from actin. In the presence of ATP (Fig. 1-5), linkages
between actin and myosin filaments are made and broken cyclically as long as sufficient Ca2+ is present; these
linkages cease when [Ca2+] falls below a critical level,
and the troponin-tropomyosin complex once more
prevents interactions between the myosin cross-bridges
and actin filaments (Fig. 1-6).
Intracytoplasmic Ca2+ is a principal determinant of
the inotropic state of the heart. Most agents that stimulate myocardial contractility (positive inotropic ­stimuli),
including the digitalis glycosides and β-adrenergic
­agonists, increase the [Ca2+] in the vicinity of the myofilaments, which in turn triggers cross-bridge cycling.
Increased impulse traffic in the cardiac adrenergic
nerves stimulates myocardial contractility as a consequence of the release of norepinephrine from cardiac
adrenergic nerve endings. Norepinephrine activates
myocardial β receptors and, through the Gs-­­stimulated
guanine nucleotide-binding protein, activates the
enzyme adenylyl cyclase, which leads to the formation
of the intracellular second messenger cyclic AMP from
ATP (Fig. 1-6). Cyclic AMP in turn activates protein
kinase A (PKA), which phosphorylates the Ca2+ channel in the myocardial sarcolemma, thereby enhancing
the influx of Ca2+ into the myocyte. Other functions of
PKA are discussed later.
The sarcoplasmic reticulum (SR) (Fig. 1-7), a complex
network of anastomosing intracellular channels, invests

the myofibrils. Its longitudinally disposed tubules closely
invest the surfaces of individual sarcomeres but have no
direct continuity with the outside of the cell. However,
closely related to the SR, both structurally and functionally, are the transverse tubules, or T system, formed
by tubelike invaginations of the sarcolemma that extend


12

Ca2+

β - Adrenergic agonist

SECTION I

β
αs

γ

Adenyl
cyclase

P

SL

Ca2+
+

+

SR

cAMP

+

Via protein kinase A

P

Metabolic
• glycolysis
• lipolysis
• citrate cycle

Ca2+
ADP + Pi
+
ATP

+

Troponin C
+
2

Myosin
ATPase

+

ADP + Pi

β

cAMP
via Tnl
cAMP
via PL

1

Increased
1. rate of contraction
2. peak force
3. rate of relaxation

3

+
Control

Force

Introduction to Cardiovascular Disorders

GTP

β

Receptor

Time

Pattern of contraction

Figure 1-6 
Signal systems involved in positive inotropic and lusitropic
(enhanced relaxation) effects of a-adrenergic stimulation.
When the β-adrenergic agonist interacts with the β receptor, a
series of G protein–mediated changes leads to ­activation of adenylyl cyclase and the formation of cyclic adenosine monophosphate (cAMP). The latter acts via protein kinase A to stimulate
metabolism (left) and phosphorylate the Ca2+ channel protein
(right). The result is an enhanced opening probability of the
Ca2+ channel, thereby increasing the inward movement of Ca2+
ions through the sarcolemma (SL) of the T tubule. These Ca2+
ions release more calcium from the sarcoplasmic reticulum (SR)
to increase cytosolic Ca2+ and activate troponin C. Ca2+ ions

also increase the rate of breakdown of adenosine triphosphate
(ATP) to adenosine diphosphate (ADP) and inorganic phosphate
(Pi). Enhanced myosin ATPase activity explains the increased
rate of contraction, with increased activation of troponin C
explaining increased peak force development. An increased
rate of relaxation is explained by the fact that cAMP also activates the protein phospholamban, situated on the membrane
of the SR, that controls the rate of uptake of calcium into the
SR. The latter effect explains enhanced relaxation (lusitropic
effect). P, phosphorylation; PL, phospholamban; TnI, troponin I.
(Modified from LH Opie, Heart Physiology, reprinted with permission. Copyright LH Opie, 2004.)

This reaccumulation of Ca2+ is an energy (ATP)-requiring

process that lowers the ­cytoplasmic [Ca2+] to a level
that inhibits the ­actomyosin interaction responsible
for contraction, and in this manner leads to myocardial relaxation. Also, there is an exchange of Ca2+ for
Na+ at the sarcolemma (Fig. 1-7), reducing the cytoplasmic [Ca2+]. Cyclic ­AMP–dependent PKA phosphorylates the SR ­protein ­phospholamban; the latter,
in turn, permits activation of the Ca2+ pump, thereby
increasing the uptake of Ca2+ by the SR, accelerating

the rate of relaxation and providing larger quantities of
Ca2+ in the SR for release by subsequent depolarization, thereby stimulating contraction.
Thus, the combination of the cell membrane,
­transverse tubules, and SR, with their ability to ­transmit
the action potential and release and then reaccumulate
Ca2+, plays a fundamental role in the rhythmic contraction and relaxation of heart muscle. Genetic or
­pharmacologic alterations of any component, whatever
its ­etiology, can disturb these functions.