MWEBZA VICTOR - Physiology of the Heart_Arnold M Katz_5th edition.pdf

Arnold M. Katz, MD, D.Med (Hon), FACP, FACC
Professor of Medicine Emeritus
University of Connecticut School of Medicine
Farmington, Connecticut
Visiting Professor of Medicine and Physiology
Dartmouth Medical School
Lebanon, New Hampshire
Visiting Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Physiology of
the Heart
F I F T H E D I T I O N
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Library of Congress Cataloging-in-Publication Data
Katz, Arnold M.
Physiology of the heart / Arnold M. Katz. — 5th ed.
p. ; cm.
Includes bibliographical references and index.
Summary: “Dr. Arnold Katz’s internationally acclaimed classic is now in its thoroughly revised Fifth Edition, in-
corporating the latest molecular biology research and extensively exploring the clinical applications of these findings.
In the single authored, expert voice that is this book’s unique strength, Dr. Katz provides a comprehensive overview
of the physiological and biophysical basis of cardiac function, beginning with structure and proceeding to bio-
chemistry, biophysics, and pathophysiology in arrhythmias, ischemia, and heart failure. Emphasis is on the interre-
lationships of basic processes among the cell, cardiac muscle function, and the biophysics of contractile and electrical
behavior. This edition includes new material on cell signaling and molecular biology”—Provided by publisher.
ISBN-13: 978-1-60831-171-2 (hardback : alk. paper)
ISBN-10: 1-60831-171-6
1. Heart—Physiology. 2. Heart—Pathophysiology. I. Title.
[DNLM: 1. Heart—physiology. 2. Heart Diseases—physiopathology.
WG 202 K19p 2011]
QP111.4.K38 2011
612.17—dc22 2010024639
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To my father
Louis N. Katz
1897–1973
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T
he cardiovascular pandemic is now advancing at an alarming pace in many parts of the
world. Epidemiologists inform us that by 2020, cardiovascular disease will be responsi-
ble for 25 million deaths annually, 36% of all deaths, and for the first time in the history
of our species, it will be the most common cause of death. Thus, cardiovascular disease may
now be considered to be humankind’s most serious health threat. The cardiovascular epidemic
is advancing steadily in developing nations in Asia, Africa and South America with enormous
and rapidly growing populations.
On a more positive note, age-adjusted cardiovascular mortality and morbidity have been de-
clining steadily for more than two decades in North America and Western Europe. These im-
provements, translating into the extension of useful life for millions of persons, result from
advances in cardiovascular science leading to both the prevention and improved treatment of pa-
tients with cardiovascular diseases. A few examples of the latter include the impairment of con-
duction and of automaticity of specialized cardiac tissue, which leads to heart block, and other
serious bradyarrhythmias can be readily corrected with implantation of a cardiac pacemaker;
fatal ventricular fibrillation can be averted with an implanted cardioverter defibrillator; asyn-
chronous ventricular contraction in heart failure can be corrected by biventricular pacing; hy-
pertension secondary to increased activity of the renin-angiotensin-aldosterone axis and of the
adrenergic nervous system can be relieved by pharmacologic blockers; and the imbalance be-
tween myocardial oxygen supply and demand that can lead to debilitating angina pectoris or
fatal myocardial infarction can be relieved by increasing oxygen supply and/or reducing demand.
The age-adjusted incidence of most forms of ischemic heart disease has been declining steadily
with increasing attention to lifestyle—especially the reduction of smoking—and to the widespread
use of statins.
These landmark improvements in cardiac care have resulted directly from the advances in car-
diovascular physiology and pathophysiology that occurred during the first half of the twentieth
century, an era when physiology was devoted largely to the study of the function of the intact
heart. It then became clear that further understanding of cardiovascular function required a
focus on progressively smaller components of the organ. Accordingly, there has been a steady
march from the examination of the whole heart to strips of cardiac muscle, to individual my-
ocytes, to organelles within the myocyte, to the proteins of which these organelles are composed,
and to the genes that encode these proteins. In other words, a reductionist approach has been
dominant in cardiovascular (and other biomedical) sciences for more than 50 years. An impor-
tant next step will be to obtain a clearer understanding of how the individual components affect
the function of the whole heart in the intact human.
This magnificent fifth edition of the classic text, Katz’s Physiology of the Heart, a book that im-
proves with every edition, considers the normal and diseased heart at all of these levels. After an
incisive exposition of cellular, subcellular, molecular, and genetic processes in the first half of the
book, it then goes on to explain how these processes affect the function of the entire organ, both
in health and disease.
What is, of course, so remarkable is that Physiology of the Heart remains a single-authored
comprehensive text, probably among the last of its kind. It is a tour de force that reflects Dr. Katz’s
Foreword
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rich experience as a creative scientist, a gifted educator, and an experienced clinician. It flows
smoothly without the repetition, inconsistencies, gaps, and abrupt changes in style that are char-
acteristic of so many multiauthored texts. The explanatory diagrams are superb. Katz has the
rare gift of explaining complex concepts so that they can be readily understood by students and
physicians without advanced training in cardiovascular science. This book will also be especially
useful to fundamental cardiovascular investigators who today, more than ever before, need to
understand how the brick on which they are laboring fits into and is an integral part of the total
structure. Increasingly, the human is being recognized as a valid model for detailed investigation
by basic scientists. Physiology of the Heart will excite scientists, practitioners, and trainees about
the heart, and it will thereby help to move the field forward.
Eugene Braunwald, MD
Boston, MA
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W
hy write a textbook about the biophysical basis of cardiac function? Of what impor-
tance are the energetics and chemistry of myocardial contraction to anyone but a
physical chemist or a biochemist? Why should electrical potentials at the surface of
the myocardial cell concern those who are not basic electrophysiologists? The answers to all of
these questions lie in the fact that virtually every important physiological, pharmacological, or
pathological change in cardiac function arises from alterations in the physical and chemical
processes that are responsible for the heartbeat.
Although it remains fashionable to consider the heart as a muscular pump, this organ is much
more than a hollow viscus that provides mechanical energy to propel blood through the vascu-
lature. It is an intricate biological machine that contains, within each cell, a complex of control
and effector mechanisms. Both the strength of cardiac contraction and its electrical control are
modulated by alterations in one or more of these cellular mechanisms, which are involved in the
fundamental processes of excitability, excitation-contraction coupling, and contraction.
This text is written for medical students and graduate students in the biological sciences, and
for the physician who would like to find a simplified exposition of our current understanding of
the physiological and biophysical basis of cardiac function. Therefore, this book is intended to
provide a synoptic view of our present knowledge in this rapidly expanding area. The major em-
phasis is on the relationships between the biochemical properties of individual constituents of
the myocardial cell, the biophysics of cardiac muscle function, and the performance of the intact
heart.
The task of relating these different aspects of cardiac function to each other has required
much selectivity, and undoubtedly, an excess of simplification and speculation. There can be no
doubt that much of this conceptual material will become invalid as our knowledge of cardiac
function advances. This is, after all, the lesson taught to us by the history of science. The early neu-
rophysiologists who tried to understand nerve conduction as the passage of fluid down hollow
tubes were trying to explain physiological phenomena in terms of the limited biophysical knowl-
edge of their time. With the development of an understanding of animal electricity, the focus in
neurophysiology shifted to studies of the electrical properties of the nervous system, and at-
tempts were made to explain phenomena such as neuron-to-neuron communication and mem-
ory in terms of electrical circuitry. More recently, the enormous advances in our knowledge of
chemical transmitters and the potential for information storage as newly synthesized macro-
molecules has cast doubt on many of the theories of the great neurophysiologists of the last cen-
tury. Yet these were not unintelligent scientists. They were, however, required to interpret their
observations within the framework of knowledge that existed during their lifetime. It would be
presumptuous indeed for us now to assume that the evolution of new principles of science has
ended. For this reason, no apology is made for the misconceptions and faulty interpretation that
will inevitably accompany the present attempt to organize our knowledge of cardiac function in
terms of the broad principles that are understood today.
The only true “facts” in biology are the results of individual experiments carried out under
controlled conditions by a carefully defined methodology. Yet, it is not the purpose of this book
to catalogue and discuss the biological“facts;”for this, the reader is referred to the large number
Preface to the First Edition
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of reviews, symposia, multi-authored texts, and, most important, individual scientific papers.
Instead, the present text attempts to identify and describe the unifying themes that connect dif-
ferent lines of investigation of the function of the heart and, in so doing, to set out interpreta-
tions of these biological “facts.” The bibliographies to each chapter are intentionally brief and
generally include one or more recent reviews to which the interested student may refer for more
complete lists of references. In some cases,“classic” articles are also cited.
Every effort has been made to keep this book simple—suitable for use as a text for graduate
and undergraduate teaching.Achievement of this goal, however, requires the resolution, more or
less arbitrarily as the case may require, of many serious conflicts, as well as the addition of spec-
ulative material to connect important biochemical, biophysical, physiological, and pathophysi-
ological observations. It is the author’s intention that these departures into the realm of
speculation be clearly identified in the text. Yet the expert in these fields will undoubtedly be
troubled by this attempt to provide a coherent and unified text. While the author is not labor-
ing under the illusion that all of his interpretations will prove correct, it seems especially im-
portant to provide the student with an indication of the significance of the many biological
“facts” describing the heart and its function rather than just to catalogue specific experimental
findings. It is, after all, the pattern on the fabric that holds the interest of most of us, rather than
the threads. For this reason, though with apologies to the protagonists of opposing viewpoints,
the author has chosen the present format for this text.
Arnold M. Katz
Heidelberg, Germany
1976
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T
he material covered in this text has undergone an unprecedented expansion since I began
the first edition of Physiology of the Heart in 1975. Thirty-five years ago I was able to write
from memory virtually all that I felt was essential to understand the physiology of the
heart. Reading a few papers, conversations with colleagues, and attendance at meetings were all
the background that I had needed. What a difference today! The breadth of knowledge needed
to understand cardiovascular physiology now includes topics that did not exist in 1975, and
material that could be summarized in a few sentences even a decade ago is now the subject of
reviews that are dozens of pages long and cite hundreds of references.
This expansion poses a serious challenge to revising Physiology of the Heart as it increases the
difficulty in providing discussions that, while thorough and accurate, are not so detailed as to de-
feat the purpose of this text which, as for the first edition, is to be “simple—suitable for use as a
text for graduate and undergraduate teaching.” In fact, today’s complexity raises the question as
to why anyone should try to summarize all this material in a single-authored book, especially
because virtually all this information is readily available from authoritative sources that can be
located quickly using the Internet. The answer to this question, and the reason that I have spent
much of the past year preparing this new edition, is that there is far more to understanding car-
diovascular physiology than knowing facts—or being able to look them up. It is necessary also
to understand how facts fit together to form patterns. This is because these patterns help physi-
cians and other health care providers to know what is happening to their patients, and allow basic
scientists to understand the relationships between specific areas of biology and human disease.The
importance of physiology in understanding disease is obvious, but it is also true that efforts to un-
derstand heart disease have contributed to our knowledge of normal cardiac physiology. My fa-
ther often quoted his teacher, Carl Wiggers, who observed that “every disease is an experiment
that nature performs, and its signs and symptoms are the manifestations of abnormal function.”
Comparison of the five editions of this text illustrates the extent to which cardiovascular
physiology has expanded during the past 35 years. Progress, however, has been uneven. Fields like
hemodynamics and electrocardiography have advanced within an established framework of
knowledge and so can be viewed as mature sciences. Advances in biochemistry, molecular biol-
ogy, and biophysics have been more significant, notably in understanding energetics and me-
tabolism, excitation–contraction coupling, and cardiac electrophysiology. Most dramatic have
been advances in signal transduction, which is mentioned only briefly in the first edition, pub-
lished in 1977. The second edition, published in 1992, describes two types of regulation that I
called “phasic” and “tonic” because they mediate short-term and long-term responses, respec-
tively; 10 years later, in the third edition, these are called functional and proliferative. The for-
mer, which activates short-term physiological responses, alters interactions between preexisting
structures to modify such physiological variables as heart rate, contractility, and relaxation. Pro-
liferative responses, on the other hand, bring about long-lasting changes in the size, shape, and
composition of the heart by changing myocyte structure, protein synthesis, gene expression, and
other molecular features of the heart. The fourth edition, published in 2006, when signaling ab-
normalities were emerging as a major cause of cardiovascular disease, contains separate chapters
on each of these two types of signal transduction. The importance of cytoskeletal signaling in
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mediating both adaptive and maladaptive proliferative responses to cell deformation led me to
expand a brief discussion of the cytoskeleton in the third edition to a full chapter in the fourth
edition. This chapter became so detailed in the present edition that I decided to introduce it with
a brief passage from “The Catalogue of the Ships” in Homer’s Iliad to explain why I describe so
many different proteins.
I am aware that my attempt to discuss a broad range of topics, which range from molecular
biology, through biochemistry and physiology, to clinical cardiology, might be viewed as pre-
sumptuous. Because I am not an expert in all of the fields covered in this text, it is inevitable that
this book contains errors. In spite of this limitation, I have prepared this new edition because I
believe it important that readers have access to an integrated discussion of cardiovascular physi-
ology that is written in a single voice. I find some comfort in a statement attributed to Dr. C.
Sidney Burwell,who was Dean of Harvard Medical School in the early 1950s,to the effect that“half
of what the faculty teaches medical students is wrong, but the faculty does not know which half.”
This revision of Physiology of the Heart challenges the view that there is a widening gap be-
tween bench and bedside, between understanding the mechanisms of disease and how to treat
patients. History shows that this is not correct, and that new knowledge has been filling, rather
than widening the gap. The ancient Greeks and Romans, who viewed health as a balance be-
tween opposing principles (the four humors), believed that the heart generated heat that it
distributed throughout the body in the blood; it is largely for this reason that bleeding was viewed
as a logical way to treat fever. It was not until 1628, when William Harvey showed that the heart
is a pump and not a furnace, that it became possible to recognize the hemodynamic basis for the
signs and symptoms of heart failure, a syndrome that had been described many times during the
preceding 2000 years. However, the gap between science and medicine was so wide that this dis-
covery was to have little impact on patient care for the next 300 years. Throughout the 19th cen-
tury, when efforts to understand the causes of heart failure centered on cardiac hypertrophy,
correlations between clinical syndromes and autopsy findings led to the view, elegantly stated in
1892 by William Osler, that hypertrophy begins as an adaptive response to overload but eventu-
ally causes the heart to deteriorate.
Ernest Starling’s description of the “Law of the Heart” and Carl Wiggers’ work in the first
half of the 20th century made it possible to understand the hemodynamics of heart disease. This
narrowed the gap between bench and bedside and contributed to a revolution in patient care
when, in the 1940s, cardiac catheterization—pioneered by Werner Forssmann,André Cournand,
and Dickinson Richards—made possible the precise diagnoses of structural heart disease needed
to allow surgeons to repair structurally damaged hearts. In the 1950s, Stanley Sarnoff’s descrip-
tion of “families of Starling curves” clarified the concept of myocardial contractility, which a
decade later led Eugene Braunwald to demonstrate that contractility is depressed in failing hearts.
The gap between bench and bedside continued to narrow in the 1960s, when recognition of the
role of calcium in regulating cardiac contraction and relaxation led to the development of new
inotropic drugs.
The widely held view that heart failure is largely a hemodynamic disorder began to unravel
in the early 1990s, when clinical trials showed that although inotropic drugs cause an immedi-
ate improvement in symptoms, they shorten long-term survival. At the same time, direct-acting
vasodilators, which because of their energy-sparing effects are of short-term benefit in patients
with heart failure, were found to have serious adverse effects on long-term prognosis. Explana-
tions for these and other unexpected findings began to emerge when maladaptive consequences
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of overload-induced cardiac hypertrophy were recognized to contribute to the poor prognosis
in heart failure. The practical importance of these discoveries became apparent in the 1990s
when -adrenergic receptor blockers, whose negative inotropic effects transiently worsen symp-
toms, were found to improve long-term outcome in part by inhibiting maladaptive proliferative
signaling. Today, as we enter the 21st century, insights from the emerging fields of signal trans-
duction and molecular biology, supplemented by discoveries in new fields such as epigenetics,
are stimulating an interplay between clinical cardiology and molecular biology that encompasses
the pathophysiology, treatment, and prevention not only of heart failure, but also arrhythmias,
sudden cardiac death, and vascular disease.
Even though the gap between bench and bedside is narrowing, the flood of new information
is making it difficult to find individuals who can teach basic science to students of the clinical sci-
ences, and who can teach students of biology the relevance of basic science to patient care. The
problem is especially serious in medical schools, where an already overcrowded curriculum is
generating pressures to shorten the time allocated for teaching the mechanisms of disease. Be-
cause this threatens to lead to the graduation of practitioners who lack the foundation needed
to deliver optimal care to their patients, a major goal of this revision is to help medical educa-
tors explain the interplay between basic science and patient care in managing cardiac patients.
The importance of a scientific foundation in medical practice was noted by William Osler,
who in 1902 wrote: “A physician without physiology practices a sort of pop-gun pharmacy, hit-
ting now the disease and again the patient, he himself not knowing which.” Osler’s observation
is of even greater relevance today because physicians have access to powerful physiologically
based therapy that, when used properly, is of immeasurable value to the patient, whereas treat-
ment lacking a solid basis in physiology often does more harm than good.
The division of the fourth edition into four parts seemed to work well and so has not been
changed. Part I, Structure, Biochemistry, and Biophysics, reviews the structure, biochemistry, and
biophysics of the normal heart, the functions of the cytoskeleton, and the chemistry of cardiac
contraction, relaxation, and excitation–contraction coupling. Part II, Signal Transduction and
Regulation, contains an expanded discussion of the functional signal transduction systems that
bring about short-term responses, and the proliferative signaling systems that control long-
term changes in cardiac size, shape, and composition. The physiology of the cardiac pump and
the electrical signals that maintain the homogeneity necessary for efficient contraction are de-
scribed in Part III, Normal Physiology. Part IV, Pathophysiology, begins with a description of the
physiological basis for the normal electrocardiogram, a marvelous diagnostic tool that uses
physiological principles to define pathophysiology, and concludes with chapters on arrhythmias,
ischemic heart disease, and heart failure, the major types of heart disease encountered in de-
veloped societies.
Although there have been no changes in overall organization, virtually the entire text of this
edition has been rewritten, new figures have been added, and many of the older figures revised.
Much of the“mature”science has been condensed and material that no longer seems important
has been removed. The discussions of arrhythmias, ischemic heart disease, and heart failure that
end this text have been updated to reflect the growing impact of molecular biology on our un-
derstanding of the pathophysiology and management of these syndromes. As this book is de-
signed primarily for the nonexpert, no attempt has been made to document the many details;
instead, bibliographies are included to identify sources for further reading. I have kept a few ref-
erences to classical papers because these contain clear descriptions of important concepts and,
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perhaps more important, they provide students with an understanding as to how we got to where
we are today.
My major goal in preparing this fifth edition of Physiology of the Heart, as for previous edi-
tions, is to provide a readable and comprehensive text that explains normal cardiac function and
how altered function causes disease. This text is not a reference book to be consulted to verify facts
but instead is intended to be read from cover to cover. Stated simply, my goal is to help physicians
and other health care professionals understand the basic sciences, and basic scientists to appre-
ciate how specific areas of research relate to the broad sweep of cardiac physiology.
Norwich, Vermont
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M
ore than 35 years have passed since I had planned to coauthor a textbook on cardiac
physiology with my father, to whom this book is dedicated. Dad’s death in 1973 made
this impossible, but those who remember him will, I hope, recognize his forthright and
lucid approach in this text.
The 1st edition of this book was published when I was Philip J. and Harriet L. Goodhart
Professor of Medicine (Cardiology) at the Mount Sinai School of Medicine of the City of New
York; most of the text was written at the Max-Planck-Institut-für Medizinische Forschung in
Heidelberg, Germany, and was supported in part by the Alexander von Humboldt Stiftung. The
2nd edition was written in the Dana Medical Library at Dartmouth Medical School during a
sabbatical year when I was Professor of Medicine (Cardiology) at the University of Connecticut.
The 3rd, 4th, and present editions were written on our hilltop in Norwich, Vermont, after I had
retired from the University of Connecticut. I thank Dartmouth Medical School for providing
me with library privileges and an Internet link that allowed me to work from my home. I thank
Indu Jawwad and her team at Aptara for dealing patiently with my many fussy corrections. I am
especially grateful to Frances DeStefano and Lippincott Williams Wilkins for their confidence
in asking me to write this 5th edition.
I warmly acknowledge the probing questions posed by the students I have taught over the past
45 years at Columbia University, the University of Chicago, the Mount Sinai School of Medi-
cine, the University of Connecticut, Dartmouth Medical School, and most recently Harvard
Medical School where I teach in a 2nd-year course that I took as a student in 1953. These stu-
dents continue to serve as gentle but firm critics of my efforts to explain things.
The understanding of my children and their families when I disappeared during their visits
to work on this edition is gratefully acknowledged, as are Eurykleia (“Kleia”), our Springer
Spaniel, who took me from my desk for walks in the woods that restored my circulation and
recharged my intellectual batteries, and Pyrrhus, our long-haired ginger cat who occasionally
sat in my inbox while I wrote this text. Above all, I thank Phyllis, my wife, for her steadfast and
loving support during the past 51 years and for providing an intellectually stimulating and tran-
quil environment without which this text could not have been written.
Professor of Medicine Emeritus,
University of Connecticut School of Medicine,
Visiting Professor of Medicine and Physiology,
Dartmouth Medical School,
Visiting Professor of Medicine,
Harvard Medical School
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Chapter 1 • Structure of the Heart and Cardiac Muscle xiii
Acknowledgments
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Foreword v
Preface to the First Edition vii
Preface ix
Acknowledgments xiii
PA R T O N E :
STRUCTURE, BIOCHEMISTRY, AND BIOPHYSICS
1 Structure of the Heart and Cardiac Muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2 Energetics and Energy Production . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3 Energy Utilization (Work and Heat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
4 The Contractile Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5 The Cytoskeleton . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
6 Active State, Length-Tension Relationship, and Cardiac Mechanics . . . . . . . . . . . . 125
7 Excitation-Contraction Coupling: Extracellular and Intracellular
Calcium Cycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
PA R T T W O :
SIGNAL TRANSDUCTION AND REGULATION
8 Signal Transduction: Functional Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
9 Signal Transduction: Proliferative Signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
10 Regulation of Cardiac Muscle Performance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
PA R T T H R E E :
NORMAL PHYSIOLOGY
11 The Heart as a Muscular Pump . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
12 The Working Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313
13 Cardiac Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343
14 The Cardiac Action Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
PA R T F O U R :
PATHOPHYSIOLOGY
15 The Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
16 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431
17 The Ischemic Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
18 Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 510
INDEX 551
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Chapter 1 • Structure of the Heart and Cardiac Muscle xv
Contents
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Structure, Biochemistry,
and Biophysics
P A R T O N E
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It has been shown by reason and experiment that blood by the beat of the ventricles
flows through the lungs and heart and is pumped to the whole body . . . the blood in the
animal body moves around in a circle continuously, and . . . the action or function of the
heart is to accomplish this by pumping. This is the only reason for the motion and beat of
the heart.
—William Harvey (1628).
Exercitatio Anatomica de Moto Cordis et Sanguinis in Animalibus.
H
arvey’s proof that the heart is a muscular pump, which overthrew the ancient view that
the heart is the source of the body’s heat, along with increasing use of human autopsies,
made it possible to understand the pathogenesis of heart disease in terms of abnormal
organ structure (Katz, 2008). Virchow’s founding of pathology in the 19th century supple-
mented this anatomical knowledge with histological pathology. In the 20th century, develop-
ment of electron microscopy and new insights into the biochemistry and biophysics of cardiac
function further extended knowledge of the causes of heart disease. Today, rapid advances in
molecular biology are providing additional insights into the ultrastructural and molecular basis
of cardiovascular disease.
ORGAN STRUCTURE
Mammalian hearts can be viewed as two pumps that operate in series: the right atrium and the
right ventricle, which pump blood from the systemic veins into the pulmonary circulation, and
the left atrium and the left ventricle, which pump blood from the systemic veins into the pul-
monary circulation (Fig. 1-1).Within the heart, atrioventricular (AV) valves prevent blood from
flowing backward from the ventricles into the atria: on the right the tricuspid valve and on the
left the mitral valve (Fig. 1-2). Semilunar valves, named for their crescent-shaped cusps, sepa-
rate each ventricle from its great artery: the pulmonic valve between the right ventricle and the
pulmonary artery, the aortic valve between the left ventricle and the aorta. All four of these
valves lie in a plane within a connective tissue “skeleton” that separates the atria and ventricles
in which the mitral,tricuspid,and aortic valves surround a fibrous triangle,called the central fibrous
body (Fig. 1-3). This connective tissue skeleton can be viewed as an insulator that prevents electri-
cal impulses from being conducted between the atria and the ventricles. The AV bundle (also called
the common bundle or bundle of His), a strand of specialized cardiac muscle that penetrates this
insulator, normally provides the only conducting pathway between the atria and the ventricles.
Damage to this critical conducting structure is an important cause of AV block (Chapter 16).
3
Structure of the Heart and
Cardiac Muscle
C H A P T E R
1

4 Part One • Structure, Biochemistry, and Biophysics
The free margins of the semilunar aortic and pulmonary valve cusps are supported by thick
tendinous edges. Sinus of Valsalva lie behind each of the three aortic valve cusps; the anterior
and left posterior sinuses contain the orifices of coronary arteries (see below), whereas the right
posterior sinus does not give rise to a coronary artery and so is often called the “noncoronary”
sinus (see Fig. 1-3). The larger cusps of the mitral and tricuspid valves are tethered at their free
margins by fibrous chordae tendinae that attach to“fingers”of myocardium called papillary mus-
cles that project into the right and left ventricular cavities (see Fig. 1-2). Much as the strands of
a parachute arise from a skydiver’s harness, several chordae tendinae fan out from each papillary
muscle to support the valve margins (Becker and deWit, 1979). Laxity of the connective tissue
supporting the mitral valve can allow the leaflets to move backward (prolapse) into the left atrium
when left ventricular pressure rises during systole. In some patients, abrupt opening of these ab-
normal valves causes an audible “click”; if blood subsequently leaks from the left ventricle into
the left atrium (mitral regurgitation), a late systolic murmur can be heard. This syndrome, called
mitral valve prolapse, is often of no hemodynamic significance (although leaky valves are sus-
ceptible to bacterial infection); when severe, however, laxity of the chordae tendinae can cause
significant mitral regurgitation. Rupture of a papillary muscle, which can occur when coronary
SYSTEMIC
CIRCULATION
PULMONARY
CIRCULATION
Pulmonary
Artery
Venae
Cavae Aorta
LV
LA
RA
RV
Pulmonary
Veins
FIG. 1-1: Circulation of the blood. Light shading: deoxy-
genated blood; dark shading: oxygenated blood. RA, right
atrium; LA, left atrium; RV, right ventricle; LV, left ventricle.
(Adapted and modified from Starling, 1926).

Chapter 1 • Structure of the Heart and Cardiac Muscle 5
Superior vena cava
Right atrium
Tricuspid valve
Mitral valve
Chordae tendinae
Aortic valve
Chordae tendinae
Papillary muscle
Right ventricle
Left ventricle
Right ventricle
Right atrium
Coronary ostia
Aorta
Aorta
Pulmonary artery
Pulmonary veins
Left atrium
Papillary muscle
Interventricular septum
Interventricular septum
FIG. 1-2: Major structures in a human heart opened after transection slightly anterior to the midline. (Adapted and mod-
ified from Berne and Levy, 1967.)
RP
“Acute margin” “Obtuse margin”
Tricuspid valve Mitral valve
AV bundle
RIGHT LEFT
ANTERIOR
POSTERIOR
Central fibrous body
Aortic valve
Pulmonic valve
LP
A
RCA
LM
FIG. 1-3: Schematic diagram of the connective tissue skeleton of the heart, viewed from above, showing the four valves
and the atrioventricular (AV) bundle that crosses this insulating structure through the central fibrous body. Sinuses of Val-
salva lie behind the aortic valve cusps, two of which give rise to coronary arteries. The ostium of the left main (LM) lies in
the left posterior (LP) sinus, while the right coronary artery (RCA) originates in the anterior sinus (A); the third sinus of Val-
salva, the right posterior (RP), is called the “noncoronary” sinus because it does not give rise to a coronary artery. The
sharper right border of the heart forms the “acute margin,” the more rounded left border is the “obtuse margin.”

artery occlusion interrupts the blood supply to these vital muscular structures (see Chapter 17),
generally causes severe mitral regurgitation and can be fatal.
Architecture of the Walls of the Heart
When the heart is viewed from above, the rounded margin of the left ventricle forms an above
obtuse angle, whereas the margin of the right ventricle is sharper, like an acute angle (see Fig. 1-3);
this explains the terms “obtuse marginal” and “acute marginal” used in naming branches
of the coronary arteries (see below). The thin-walled atria, which develop much lower pressures
than do the ventricles, contain ridges of myocardium called pectinate muscles that may provide
preferential conducting pathways, often referred to as internodal tracts or sinoatrial (SA) ring
B
Pulmonic
valve
Aortic
valve
Mitral valve
(anterior (posterior
leaflet) leaflet)
Tricuspid
valve
INFLOW
TRACT OUTFLOW
TRACT
INFLOW
TRACT
Right ventricle
Right ventricle Right ventricle Left ventricle
Left ventricle
Left ventricle
A
FIG. 1-4: A: Schematic anterior views of the right and left ventricular chambers. The inflow (tricuspid) and outflow (pul-
monic) valves in the U-shaped right ventricle are widely separated, whereas in the conical left ventricle, the mitral and aor-
tic valves lie side-by-side, where they are separated by the anterior leaflet of the mitral valve. B: Casts of canine right and
left ventricles showing approximate locations of the pulmonic (PV) and tricuspid (TV) valves in the right ventricle, and the
aortic (AV) and mitral (MV) valves in the left ventricle. Left: anterior view. Right: superior view.

bundles, that link the SA and AV nodes (Hayashi et al., 1982). The ventricles, which develop
much higher pressures than do the atria, have thicker muscular walls. The left ventricle, which
has approximately three times the mass and twice the thickness of the right ventricle, can be
viewed as a “pressure pump” whose cavity resembles an elongated cone in which the mitral
valve, through which blood flows into the ventricle, and the aortic valve, through which blood
leaves the ventricle, lie side-to-side in the wider end (Fig. 1-4). Peak systolic pressure in the left
ventricle is normally about three times higher than that in the right ventricle; the latter, which
represents a “volume pump,” is shaped like a crescent with inflow through the tricuspid valve
at one end and outflow through the pulmonic valve at the other (see Fig. 1-4). During systole,
the interventricular septum normally moves toward the left ventricular free wall and so partic-
ipates in left ventricular ejection. In chronic right ventricular overload, for example, in patients
with pulmonary hypertension, the septum can move paradoxically away from the left ventric-
ular cavity during systole to aid right ventricular ejection.
The left ventricular cavity, which is conical in shape during diastole, assumes a more spher-
ical shape as intraventricular pressure rises at the end of isovolumic contraction (Hawthorne,
1961, 1969) (Fig. 1-5). During left ventricular ejection, its cavity again assumes its conical shape.
Because ejection propels blood superiorly (toward the head), according to Newton’s third Law—
which states that for every action there is an equal and opposite reaction—the base of the heart
moves inferiorly (toward the feet). This movement, called “decent of the base,” explains the
prominent “x descent” seen in the normal venous pulse during ventricular ejection.
The heart, along with a small amount of fluid, is contained within a noncompliant fibrous
sac called the pericardium whose inner surface, the parietal pericardium, is continuous with
the epicardium (see below). The cavities of the atria and the ventricles, along with the valves, are
lined with another connective tissue layer called the endocardium (Brutsaert, 1989). Because the
heart is contained within the rigid pericardium (see below), the ventricles interact with one an-
other. Ventricular interactions are especially important in diastole, when dilatation of one ven-
tricle can impair filling of the other (Yacoub, 1995; Santamore and Dell’Italia, 1998; Williams
and Frenneaux, 2006).
The muscular walls of the ventricles are made up of overlapping fiber bundles, sometimes
called bulbospiral and sinuspiral muscles, that follow spiral paths as they sweep from the fibrous
skeleton at the base of the heart to its apex (Grant, 1965; Lower, 1669; Streeter et al., 1969;
End of diastole
LA
LV
Ao
End of Isovolumic
Contraction
End of Ejection
FIG. 1-5: Schematic diagrams of the canine left ventricle at the ends of diastole, isovolumic contraction, and ejection. The
broad lightly shaded arrow in the right-hand side of the diagram shows the “decent of the base” in an inferior direction as
blood is ejected in a superior direction in to the aorta (darkly shaded arrow). Ao, aorta; LA, left atrium; LV, left ventricle.
(Adapted and modified from Hawthorne, 1961.)

Fenton et al., 1978; Sengupta et al., 2006). The bundles at the epicardial surface of the left ven-
tricle are oriented as a right-handed helix that tends to parallel the base-apex axis of the heart,
whereas those at the endocardial surface form a left-handed helix and are oriented more cir-
cumferentially (Cheng et al., 2008) (Fig. 1-6).
Electrical Activation
The heartbeat is initiated and controlled by electrical impulses that are generated and con-
ducted by specialized myocardial cells in different regions of the heart. Activation normally
begins in the SA node (Fig. 1-7), a band of spontaneously depolarizing cells derived from the
embryonic right sinus venosus that lies between the superior vena cava and the right atrium
(Oosthoek et al., 1993a; Anderson and Ho, 1998; Verheijck et al., 1998). Because the firing rate
of the SA node is more rapid than that of the other regions of the heart, this structure normally
serves as the cardiac pacemaker (see Chapter 15).
The wave of depolarization initiated by the SA node is propagated through atrial myocardial
cells to the right atrium, and then to the left atrium. After encountering a delay in the slowly
A
B C
FIG. 1-6: Spiral musculature of the ventricular walls. A: Spiral bundles in the left ventricle. Left: anterior view, Right: in-
ferior view. (Modified from Lower, 1669.). B: Schematic drawing of the spiral bundles that sweep from the fibrous skele-
ton at the base of the heart (above) to the apex (below). C: Schematic diagram showing the different helical orientations
of the fiber bundles in the subendocardium (left) and the subepicardium (right).

conducting cells of the AV node, which is derived from the embryonic left sinus venosus, the
wave of depolarization enters the AV bundle (Oosthoek et al., 1993b). The latter, a rapidly con-
ducting structure made up of Purkinje cells (see below), bifurcates into right and left bundle
branches at the top of the interventricular septum. The right bundle branch crosses the right
ventricular cavity within the moderator band, a muscular bundle that extends from the inter-
ventricular septum to the base of the papillary muscle that supports the anterior leaflet of the tri-
cuspid valve (Fig. 1-7). The left bundle branch is often pictured as bifurcating into anterior and
posterior fascicles, but this branching is highly variable (see Chapter 15). The impulses conducted
through the bundle branches reach the ventricular myocardium via the His-Purkinje system, a
subendocardial network of rapidly conducting cells that synchronizes ventricular activation.
THE CORONARY CIRCULATION
Major Epicardial Coronary Arteries
Large epicardial coronary arteries carry virtually all of the blood that supplies the heart.
Although a few layers of endocardial myocytes are perfused from the ventricular cavities via
arteriosinusoidal and arterioluminal vessels, this auxiliary blood supply is of no clinical impor-
tance when a large coronary artery becomes occluded (Chapter 17). The major coronary arter-
ies are the left main coronary artery (LEFT MAIN), right coronary artery (RCA), left anterior
descending (LAD), circumflex (CIRC), and posterior descending artery (PDA) (Fig. 1-8). All lie
FIG. 1-7: Conducting system of the human heart (capitalized labels at right) and major anatomical features (lower case
labels at left). AV, atrioventricular; SA, sinoatrial. (Modified from Benninghoff, 1944.)

in grooves between the heart’s chambers: the RCA and the CIRC between the atria and the ven-
tricles, the LAD and the PDA between the left and right ventricles.
The anatomy of these vessels can be summarized by the statement three out of two makes
four. Two coronary arteries arise from the aorta (RCA and LEFT MAIN) and, after the LEFT
MAIN divides into the LAD and CIRC, continue as three vessels (RCA, LAD, and CIRC). The
PDA is a continuation of either the RCA or the CIRC, so that the myocardium is supplied by four
major arteries (RCA, LAD, CIRC, and PDA).
The LEFT MAIN, which originates in the left posterior sinus of Valsalva (see Fig. 1-3), con-
tinues as a single vessel of variable length before dividing into its two major branches: the LAD
and the CIRC (see Fig. 1-8). The LAD, which courses down the anterior interventricular groove,
gives rise to septal perforating arteries that supply the anterior two-thirds of the interventricu-
lar septum, diagonal branches that supply the anterior wall of the left ventricle, and right ven-
tricular branches that provide blood to the anterior wall of the right ventricle. After crossing
the apex of the heart, the LAD usually turns upward, toward the base, to run a short distance
in the posterior interventricular groove (see Fig. 1-8; Fig. 1-9). The CIRC, which courses to the
left in the anterior AV groove, gives rise to obtuse marginal branches that supply the lateral wall
of the left ventricle. In most human hearts, the CIRC, after reaching the back of the left ventri-
cle, runs only a short distance down the posterior interventricular groove to end near the crux
of the heart, where the plane of the interventricular septum crosses the plane of the AV groove
(Fig. 1-9B).
SA node artery
LEFT MAIN
CIRCUMFLEX
Obtuse marginal branch
LEFT ANTERIOR DESCENDING
Septal perforating branches
Diagonal branches
Right ventricular branches
POSTERIOR DESCENDING
RIGHT CORONARY
Acute marginal branches
AV node artery
Septal perforating branches
AV NODE
SA NODE
AV
BUNDLE
LEFT
BUNDLE
BRANCH
ANTERIOR
FASCICLE
RIGHT
BUNDLE
BRANCH
POSTERIOR
FASCICLE
FIG. 1-8: Major coronary arteries and their branches (labels at right and left) and key elements of the cardiac conduction
system (labels above and below). AV, atrioventricular; SA, sinoatrial.

The PDA, which can arise from either the CIRC or the RCA, runs inferiorly in the posterior
interventricular groove where it supplies septal perforating branches that perfuse the posterior
third of the interventricular septum. In approximately 90% of human hearts the PDA is sup-
plied by the RCA (called“right dominant”); in the remaining approximately 10% the CIRC turns
downward at the crux to supply the PDA (“left dominant”) (Fig. 1-9A).
The RCA, which arises from the anterior sinus of Valsalva, courses toward the right in the
anterior AV groove where it gives rise to right ventricular (acute marginal) branches that supply
the free wall of the right ventricle.The RCA then crosses the acute margin of the heart,turns to the
left in the posteriorAV groove,and,after reaching the crux of the heart,usually continues in the pos-
terior interventricular groove as the PDA (“right dominant” coronary circulation, Fig. 1-9B).
Coronary occlusive disease is often described as“one-vessel,”“two-vessel,”and“three-vessel”
disease, terms that describe how many of the three major arteries (RCA, LAD, and CIRC) are nar-
rowed significantly. Obviously, the more vessels that are narrowed, the worse is the clinical prog-
nosis. LEFT MAIN disease is especially dangerous because this vessel supplies both of the arteries
that supply blood to the left ventricle (LAD and CIRC).
Collateral Vessels
Occlusion of a large epicardial artery generally causes an infarct (defined as an area in which cells
have died because of inadequate blood supply) whose borders are sharply demarcated from the
adjacent normally perfused myocardium supplied by other, nonoccluded arteries. Intracoronary
collateral vessels can connect the vascular beds supplied by different large epicardial arteries, such
as the RCA, LAD, and CIRC. Although collateral vessels are usually poorly developed in younger
individuals, in older patients, especially those with long-standing coronary atherosclerosis, intra-
coronary collaterals can enlarge and provide blood flow to regions of the heart downstream from
FIG. 1-9: Posterior view of the human heart showing left dominant (A) and right dominant (B) coronary artery distri-
bution. In the left dominant distribution, the posterior descending artery (PDA) is a continuation of the circumflex branch
of the left coronary artery (CIRC) that runs from the crux of the heart down the posterior interventricular groove; more com-
monly, in the right dominant distribution, the posterior descending artery is a continuation of the right coronary artery
(RCA). The left anterior descending (LAD) coronary artery, after wrapping around the inferior surface of the heart, usually
courses upward for a short distance in the posterior interventricular groove. LA, left atrium; RA, right atrium; LV, left ven-
tricle; RV, right ventricle; SVC, superior vena cava, crux; point at which the plane of the interventricular septum crosses that
of the atrioventricular groove.

an occluded coronary artery. However, collaterals are not found at the level of the microcircula-
tion, so that there is usually little or no “border zone,” defined as a region where a limited blood
supply is preserved at the edge of a myocardial infarct (Factor et al., 1981).
Blood Supply to the Ventricular Myocardium
Blood from the epicardial arteries reaches the myocardium via muscular branches that traverse
the walls of the ventricles (Fig. 1-10); normal compression of these muscular branches during
systole explains why virtually all nutrient coronary flow occurs during diastole, and why the
subendocardial regions of the thick-walled left ventricle are especially vulnerable to coronary
artery narrowing.
The left ventricular papillary muscles receive their blood supply from large penetrating ves-
sels called perforators. The anterolateral papillary muscle, which supports the anterior leaflet of the
mitral valve, has a dual blood supply derived from branches of the CIRC and the LAD. The pos-
teromedial papillary muscle, which supports the posterior leaflet, receives its blood supply from
the RCA or the CIRC via the PDA.
Blood Supply to the Conduction System
The SA node is perfused by the SA node artery (see Fig. 1-8), which in slightly more than half
of human hearts is a branch of the RCA; in the remainder, this artery arises from the CIRC. The
AV node is usually supplied by an AV node artery that is a branch of the PDA, so that the blood
supply to the AV node is derived from the RCA in approximately 90% of human hearts and the
CIRC in approximately 10%.
FIG. 1-10: X-ray microphotograph of a cross section of a left ventricle following injection of the coronary arteries with
radiopaque dye. The large coronary arteries that course over the epicardial surface of the ventricle give rise to muscular
branches that penetrate the myocardium and reach the endocardium after traversing the thick ventricular wall (retouched).

TheAV bundle,along with proximal portions of both right and left bundle branches,is perfused
by septal perforators that arise from both the LAD and the PDA. Because these critical conducting
structures have a dual blood supply, the appearance of a conduction block in the AV bundle or
bundle branches in a patient with an acute myocardial infarction implies that more than one major
coronary artery is occluded. The anterior division of the left bundle branch and midportion of the
right bundle branch are supplied by septal perforators arising from the LAD, whereas the posterior
division of the left bundle branch is perfused by septal perforators supplied by the PDA.
Coronary Venous Drainage
The venous effluent of the heart is collected in large veins that parallel the epicardial coronary
arteries. Most venous drainage of the left ventricle enters the coronary sinus, which parallels the
CIRC in the left posterior AV groove before emptying into the floor of the right atrium. A por-
tion of the venous drainage of the left ventricle, along with much of that derived from the right
ventricle, enters the right atrium through anterior cardiac veins. A small fraction of the venous
drainage of the ventricular myocardium flows directly into the cavities of the right and left ven-
tricles by way of Thebesian veins.
Because the coronary sinus passes to the left behind the heart in the left AV groove, an elec-
trode catheter inserted into this venous channel can be used to record the electrical activity of
the left atrium and ventricle, stimulate these structures, and perform ablation therapy on the
left side of the heart.
FRACTAL ANATOMY OF THE HEART
Many structures in the heart, including the coronary blood vessels, chordae tendinae, and inter-
ventricular conduction system, form networks whose seemingly disorganized branching actu-
ally follows complex rules. The latter can be described mathematically as fractals, which define
the order often found in seemingly random biological structures (Goldberger et al., 1990).
Goldberger et al. (2002) note that disease and aging are often associated with a “breakdown of
fractal physiological complexity [that] may be associated with excessive order (pathological
periodicity) on the one hand, or uncorrelated randomness on the other.”
LYMPHATICS
Fluid that is transudated across the capillary endothelium and enters the cardiac interstitium is
returned to the circulation via the lymphatic system. In the heart, the larger lymphatic vessels
run alongside the coronary arteries and veins in the AV and interventricular grooves. Most car-
diac lymphatic channels cross the anterior surface of the pulmonary artery to reach pretracheal
lymph nodes and a cardiac lymph node situated between the superior vena cava and the right
innominate artery. The lymph ultimately drains into the thoracic duct (Miller, 1982).
INNERVATION
The heart is innervated by both sympathetic and parasympathetic nerves. Most postganglionic
sympathetic fibers reach the heart from the fourth and fifth thoracic segments of the spinal
cord after forming synaptic connections in the cervical and thoracic cervical ganglia (often

called stellate ganglia) and in the cardiac plexus, a network of sympathetic fibers located at the
base of the heart. Once they arrive at the heart, postsynaptic sympathetic nerves do not form
specialized junctions but instead lie in plasma membrane depressions on the surface of car-
diac myocytes where they release norepinephrine, the sympathetic neurotransmitter. The
heart’s parasympathetic innervation originates in the dorsal efferent nuclei of the medulla
oblongata and reaches the heart via the cardiac branches of the vagus nerve. Preganglionic
parasympathetic fibers impinge on postganglionic cells in the SA and AV nodes, the atria,
and the heart’s blood vessels; parasympathetic innervation of the ventricular myocardium is
more limited.
Sensory fibers that originate in the heart reach the brain stem via the cardiac plexus. Activa-
tion of these fibers in patients with coronary artery occlusive disease causes a chest discomfort,
called angina pectoris. Like other visceral pain, the discomfort caused by cardiac ischemia is
poorly localized and perceived differently by different individuals.
Stretch receptors located in the inferior and posterior walls of the left ventricle can evoke a
powerful vagal response, called the von Bezold-Jarisch reflex, that slows the SA node pacemaker,
inhibits conduction through the AV node, and causes peripheral vasodilatation (Dawes and
Comroe, 1954). This parasympathetic reflex is commonly activated in inferior and posterior wall
myocardial infarction (see Chapter 17).
HISTOLOGY
The outer surfaces of the atria and the ventricles are lined by the epicardium, a layer of squamous
cells that overlies a network of fibroelastic connective tissue, that is continuous with the inner
layer of the pericardium. The endocardium, which lines the heart’s chambers, is made up of squa-
mous cells, a mesh of collagen and elastic fibers, and a rudimentary layer of smooth muscle.
The myocardium, which makes up the vast majority of the heart’s thickness, contains both my-
ocytes and connective tissue. Although cardiac myocytes represent most of the myocardial mass,
approximately 70% of the cells are smaller nonmyocytes, which include vascular smooth muscle,
endothelial cells, and fibroblasts. The latter secrete and maintain the connective tissue fibers that
contribute to the heart’s tensile strength and stiffness. This connective tissue framework is organ-
ized into the endomysium, which surrounds individual cardiac myocytes, the perimysium, which
supports groups of myocytes, and the epimysium, which encases the entire muscle (Fig. 1-11).
Several types of cardiac myocytes are found in the adult human heart (Fig. 1-12). Working
myocytes, which are specialized for contraction, are found in the atria and the ventricles; atrial
myocytes are smaller than those of the ventricles. Purkinje fibers, found in the AV bundle, bundle
branches, and ventricular endocardium, are large, pale, glycogen-rich cells that are specialized for
rapid conduction and have few myofilaments. Nodal cells in the SA and AV nodes, which are re-
sponsible for pacemaker activity and an AV conduction delay, respectively, are small pale cells that
also contain few myofilaments. Additional heterogeneity is seen at the molecular level (Katz and
Katz, 1989); for example, in human atria, different cardiac myocyte molecular phenotypes are
distributed in a mosaic pattern (Fig. 1-13) (Sartore et el., 1981; Bouvagnet et al., 1984).
The many different types of cardiac myocytes form a branched network that was once be-
lieved to represent an anatomical syncytium. However, the intercalated discs, which are densely
staining transverse bands that characteristically appear at right angles to the long axis of the
cardiac myofibers, are now known to represent specialized cell–cell junctions that form strong
mechanical linkages between cells. The intercalated discs also contain pores that reduce internal

electrical resistance (see below). Although the heart is not a true anatomical syncytium, all of its
myocytes are in free electrical communication.
Working cardiac myocytes are filled with cross-striated myofibers and mitochondria and
usually contain a single centrally located nucleus (Fig. 1-12A). The rapidly conducting Purkinje
fibers are large pale cells that contain more glycogen but fewer contractile filaments and mito-
chondria (Fig. 1-12B). Cells intermediate in appearance between the Purkinje fibers and the
working cardiac myocytes are called transition cells (Fig. 1-12E). The myocytes in the SA node
(Fig. 1-12C) and the AV node (Fig. 1-12D), like Purkinje fibers, are rich in glycogen and contain
few contractile filaments; however, nodal cells conduct slowly in part because of their small size.
A
W
W
W
P
B
W
S
S
FIG. 1-11: Connective tissue framework of
the human heart showing groups of my-
ocytes surrounded by the perimysium (P). A
weave of endomysium that surrounds the in-
dividual myocytes (W) forms lateral struts (S)
that connect adjacent cells. Collagen struts
also connect myocytes to microvessels (thin
arrow) and to the perimysium (thick arrow).
(From Rossi et al., 1998, by permission of
the American Heart Association.)

Unlike working cardiac myocytes, which rely on oxidative metabolic pathways to generate adeno-
sine triphosphate (ATP), the myocytes that make up the heart’s conduction system are capable
of significant anaerobic energy production (Henry and Lowry, 1983).
Atrial cardiac myocytes contain granules that represent stores of biologically active natriuretic
peptides, which are natriuretic and diuretic and relax vascular smooth muscle. These peptides are
released when the walls of the heart are stretched, which helps the body defend against expanded
A
Nucleus
Nucleus
Nucleus
Nucleus
Purkinje fibers
Transition
cell Working
myocardium
Intercalated
disc
Intercalated
disc
B
C
D
E
FIG. 1-12: Human cardiac myocytes. A: Working ventricular myocytes contain cross striations, central nuclei, and inter-
calated discs. B: Purkinje fibers are large, poorly staining cells with sparse cross striations. The sinoatrial node (C) and atrio-
ventricular node (D) are networks of small, sparsely cross-striated cells. E: Transition cells are seen where Purkinje fibers
(left) impinge on the working myocardium (right). (Modified from Benninghoff, 1944).

blood volume (see Chapter 8). This means that the heart is not only a pump but also an en-
docrine organ!
ULTRASTRUCTURE
The contractile proteins, which make up almost half the volume of working cardiac myocytes
(Table 1-1), are organized in a regular array of cross-striated myofibrils (Figs. 1-14 through 1-16).
Most of the remaining cell volume is occupied by mitochondria, which generate the large
A B C
FIG. 1-13: Microphotographs of serial sections from human right atrium stained with two different immunofluorescent
antiventricular human myosin antibodies (A, B) and a histochemical marker for myosin ATPase activity (C). One antibody
binds to all atrial myosin isoforms (A), the second binds selectively to some cells (B). The arrowheads in (B) and (C) show
a fiber that binds the second antibody (B) but exhibits weak ATPase activity (C) while the arrows show a cell that binds
weakly to the second antibody but exhibits high ATPase activity. Bar 20 m. (Reprinted from Bouvagnet et al., 1984,
by permission of the American Heart Association, Inc.)
TABLE 1-1
Components of a Working Myocardial Cell
(Rat Left Ventricle)
Percentage of
Component Cell Volume
Myofibrils 47
Mitochondria 36
Sarcoplasmic reticulum 3.5
Subsarcolemmal cisternae 0.35
Sarcotubular network 3.15
Nuclei 2
Other (mainly cytosol) 11.5
Modified from Page (1978).

M
M
D
L
N
∗
FIG. 1-14: Electron microphotograph of
two normal human left ventricular myocytes
(above and below) that are separated by a
narrow extracellular space (oriented from
right to left in the center of the figure).
Sarcomeres are aligned both within and
between cells. Arrowheads: endomysium
between cells. M, mitochondria; Z, Z-lines; D,
intercalated disc; L, lipid droplet; *, t-tubule.
Scale bar 2 M. (Reproduced with per-
mission from Gerdes et al., 1995.)
amounts of high-energy phosphate required for contraction. Key membrane systems that reg-
ulate the performance of cardiac myocytes include the plasma membrane, which separates the
cytosol from the surrounding extracellular space, extensions of the plasma membrane called t-
tubules that penetrate the interior of these cells, and the intracellular membranes of the sar-
coplasmic reticulum (Table 1-2).
Myofibrils
The cross-striated pattern in working atrial and ventricular cardiac myocytes reflects the highly
ordered distribution of two types of filaments: thick filaments, which extend the length of the
A-band, and thin filaments, which extend from the Z-lines toward the center of the sarcomere
(see Chapters 4 and 6). The fundamental unit of striated muscle, the sarcomere, is defined as
the region between two Z-lines; each sarcomere therefore includes a central A-band and the
two adjacent half I-bands. The darkly staining striations contain a parallel array of thick and
thin filaments that strongly rotate polarized light and so are highly birefringent (anisotropic),
hence their designation A-bands. The lightly staining striations, which contain only thin
filaments, are less birefringent (more isotropic) and so are called I-bands. Both thick and

FIG. 1-15: Ultrastructure of a working cardiac myocyte. Contractile proteins are arranged in a regular array of thick and
thin filaments (seen in cross section at the left). The A-band represents the region of the sarcomere occupied by the thick
filaments into which thin filaments extend from either side. The I-band contains only thin filaments that extend toward the
center of the sarcomere from Z-lines that bisect each I-band. The sarcomere, the functional unit of the contractile appara-
tus, lies between two Z-lines and contains one A-band and two half I-bands. The sarcoplasmic reticulum, an intracellular
membrane system that surrounds the contractile proteins, consists of the sarcotubular network at the center of the sarcomere
and the subsarcolemmal cisternae. The latter form specialized composite structures with the transverse tubular system
(t-tubules) called dyads. The t-tubular membrane is continuous with the sarcolemma, so that the lumen of the t-tubules con-
tains extracellular fluid. Mitochondria are shown in the central sarcomere and in cross section at the left. (Modified from
Katz, 1975).
FIG. 1-16: Electron microphotograph of a sarcomere in normal human left ventricle. A grazing section on the left side of
the sarcomere shows the sarcotubular network (S) overlying the I-band. Three mitochondria are seen above the sarcomere.
M, M line; A, A-band; I, I-band; Z, Z-line; T, t-tubule. Scale bar 2 M. (Reproduced with permission from Gerdes et al.,
1995).

thin filaments, along with the darkly staining Z-line that bisects each I-band, contain several
cytoskeletal proteins (see Chapter 5).
In cross section, the A-band is a hexagonal array of thick filaments, each of which is sur-
rounded by six thin filaments that lie at the trigonal points between adjacent thick filaments
(Figs. 1-17 and 1-18). In the I-band, which lacks thick filaments, the thin filaments are less or-
dered. Radial cross-links, formed by myosin-binding protein C, link the thick filaments in a
hexagonal array at the center of the A-band.
The thick filaments are composed largely of myosin polymers (see Chapter 4) and a huge cy-
toskeletal protein called titin. The central regions of the thick filaments contain several addi-
tional cytoskeletal proteins, including myosin-binding protein C, M-protein, myomesin, and the
MM isoform of creatine phosphokinase (see Chapter 5). Cross-bridges that project from the thick
filaments and interact with the thin filaments represent the heads of myosin molecules. The thin
filaments are double-stranded actin polymers that include tropomyosin and the three proteins of
the troponin complex. The Z lines, in which the thin filaments are interwoven with a number of
cytoskeletal proteins, link adjacent sarcomeres to one another and to the extracellular matrix
(see Chapter 5).
FIG. 1-17: Schematic cross sections at three regions of the sarcomere. A: In the A-band thin filaments lie at the trigonal
points in a hexagonal array of thick filaments. I: In the I-band, where thick filaments are absent, the thin filaments are less
ordered. M: In the M-band at the center of the A-band thin radial filaments made up of myosin-binding protein C connect
adjacent thick filaments.
TABLE 1-2
Membrane Surface Areas in a Working Myocardial
Cell (Rat Left Ventricle)
m2
Membrane Area Per
Membrane m3
Cell Volume
Plasma membrane 0.465
Sarcolemma 0.31
t-Tubules 0.15
Nexus 0.005
Total sarcoplasmic reticulum 1.22
Subsarcolemmal cisternae 0.19
Sarcotubular network 1.03
Mitochondria 20
Modified from Page (1978).

One of most important discoveries in muscle physiology was that the lengths of the thick and
thin filaments remain constant during contraction and relaxation (Hanson and Huxley, 1953;
Huxley,1953).These findings demonstrated that muscle contraction is not brought about by fold-
ing of elongated contractile protein filaments but indicated instead that muscle shortening is caused
by changes in the extent of overlap between thick and thin filaments (Fig. 1-19) (see Chapter 6).
The Plasma Membrane and Transverse Tubules
Cardiac myocytes are surrounded by a plasma membrane (sarcolemma) that separates the intra-
cellular and extracellular spaces (see Fig. 1-15). This membrane contains channels, carriers, and
pumps that regulate cell composition and function; receptors and enzymes that participate in
cell signaling; and cytoskeletal molecules that link cells to each other and to the extracellular
matrix. Extensions of the plasma membrane, called transverse tubules (t-system), penetrate the
cell where they play a key role in excitation–contraction coupling by transmitting action poten-
tials deep into the cell interior (see Chapter 7). The t-tubules, which are open to and commu-
nicate freely with the extracellular space, contain extracellular fluid.
Intracellular Membrane Structures
Cardiac myocytes, like all eukaryotic cells, contain intracellular membrane-delimited
organelles (see Fig. 1-15; Figs. 1-20 through 1-22). These include the nucleus, which contains
the genetic material that determines cell structure (Chapter 9), mitochondria, which catalyze
FIG. 1-18: Cross section of a cat right ventricular pap-
illary muscle, showing mitochondria (Mito) and my-
ofilaments cut at the level of the A-band (A), I-band (I),
and M-band (M); in the latter, radial filaments link ad-
jacent thick filaments (Compare with Fig. 1-17). The
Z-line (Z) appears as a dense network. (From McNutt
and Fawcett, 1974.)

FIG. 1-20: Electron micrograph of rat ventricular
muscle showing the sarcotubular network (SR) in a
“grazing” section overlying a sarcomere (center).
The dark granules are glycogen. A faint linear struc-
ture, composed of two parallel lines, that crosses
the sarcotubular network over a Z line at the lower
right is probably a microtubule. Mito, mitochon-
dria; A, A-band; I, I-band; Z, Z-line. Scale l m.
(Courtesy of Mrs. Judy Upshaw-Earley and Dr.
Ernest Page.)
Thick filament Thin filament Z-line
A
B
C
FIG. 1-19: Schematic diagram of a sarcomere showing length-dependent changes in the overlap between thick and thin
filaments. A: At long sarcomere lengths in resting muscle, the myosin cross-bridges are at right angles to the thick filament
and the thin filaments are pulled away from the center of the A-band. B: During contraction, the thin filaments, which
are attached to thin filaments, are drawn toward the center of the sarcomere by a shift in the orientation of the myosin
cross-bridges. C: As the sarcomere shortens further, the thin filaments of adjacent I-bands pass in the center of the A-band
(“double overlap”).

FIG. 1-21: Cross section of dyad in rat ventricu-
lar muscle. The transverse tubular system (t), seen
in cross section, is adjacent to the subsarcolemmal
cisternae (sc). Electron-dense “feet” (arrows) can be
seen in the cytosol between the membranes of the
t-tubule and subsarcolemmal cisterna. Mito, mito-
chondria; A, A-band; I, I-band; Z, Z-line. Scale
0.1 m. (Courtesy of Mrs. Judy Upshaw-Earley and
Dr. Ernest Page.)
t-tubule
Plasma membrane
calcium channel
(dihydropyridine receptor)
Sarcoplasmic reticulum
calcium release channel
(ryanodine receptor)
Subsarcolemmal
cisterna
Foot
Channel openings
within subsarco-
lemmal cisterna
Cytosol
Channel openings
to cytosol
FIG. 1-22: Schematic diagram of a dyad showing sarcoplasmic reticulum calcium release channels (“ryanodine receptors”)
adjacent to plasma membrane calcium channels (“dihydropyridine receptors”) in the t-tubule. The former, which form the
“feet,” have a single opening into the cytosol and four openings into the lumen of the subsarcolemmal cisterna.

the oxidative reactions that generate most of the ATP used by the heart (Chapter 2), and the
sarcoplasmic reticulum, which plays a central role in excitation–contraction coupling and
relaxation (Chapter 7).
Mitochondria originated as microorganisms that, hundreds of millions of years ago, crept
into the cells of our progenitors where, in return for a nutrient-filled environment, these sym-
biotic invaders provide eukaryotic cells with a generous supply of ATP (Margulis, 1970). Mam-
malian mitochondria, which contain circular DNA characteristic of prokaryotes, are surrounded
by outer and inner membranes; infoldings of the latter, called cristae, contain enzymes that par-
ticipate in oxidative phosphorylation. Phase contrast studies show that mitochondrial shape
changes rapidly in living cardiac myocytes, enlarging and contracting, branching, and fusing
with one another. In hearts fixed under conditions that do not permit oxidative phosphorylation
(e.g., low oxygen tension), the cristae appear as stacks of flat membrane sheets, whereas in hearts
fixed when the mitochondria are carrying out oxidative phosphorylation, the cristae are angu-
lated in an “energized” configuration.
The sarcoplasmic reticulum, which takes up, stores, and releases the calcium that regulates
contraction and relaxation (Chapter 7), is a specialized form of the endoplasmic reticulum found
in virtually every mammalian cell. The endoplasmic reticulum generally includes a rough en-
doplasmic reticulum whose outer surface is studded with ribosomes that carry out protein syn-
thesis and a smooth endoplasmic reticulum that participates in such processes as lipid metabolism
and drug detoxification. In muscle, the major function of these internal membranes, some-
times referred to as the sarcoendoplasmic reticulum (SERCA), is to regulate cytosolic calcium
concentration.
The cardiac sarcoplasmic reticulum consists of two regions (see Figs. 1-15 and 1-21). The
sarcotubular network, a network of tubules that surrounds the myofilaments, contains ATP-
dependent calcium pump molecules that relax the heart by pumping calcium out of the cy-
tosol. Subsarcolemmal cisternae, which contain channels that activate contraction by releasing
calcium from the sarcoplasmic reticulum into the cytosol in response to plasma membrane
depolarization, are flattened structures that form composite structures, called dyads, in which
the sarcoplasmic reticulum and plasma membranes approach one another but do not fuse.
The narrow cytosolic space between these membranes contains huge electron-dense proteins,
often called feet because they resemble the feet of a caterpillar (Franzini-Armstrong and
Nunzi, 1983) (see Figs. 1-21 and 1-22). These proteins (called “ryanodine receptors” because
they bind with high affinity to this chemical) contain the calcium release channels whose
opening initiates cardiac contraction by allowing calcium to flow out of the sarcoplasmic retic-
ulum into the cytosol (Chapter 7). The sarcoplasmic reticulum calcium release channels dif-
fer from the L-type calcium channels (called “dihydropyridine receptors”) found in the
plasma membrane.
Cytoskeletal Proteins
Cells contain a network of proteins, called the cytoskeleton, that maintains cellular architecture,
forms mechanical linkages between cells and with the extracellular matrix, organizes enzymes
that participate in integrated catalytic cycles, maintains functionally important spatial relation-
ships between membrane pumps and channels that regulate key ion fluxes, and plays an impor-
tant role in cell signaling (see Chapter 5). The heart’s cytoskeleton contains three types of fila-
ments: microfilaments, microtubules, and intermediate filaments. Microfilaments, which have an

actin backbone, include sarcomeric actin filaments, which are the thin filaments of the sarcomere
(see above), and cortical actin filaments. The latter form a network beneath the plasma mem-
brane, link various cell structures to one another and to the extracellular matrix, and, along with
members of an extended family of myosin molecules, transport membrane vesicles to and from
the cell surface. Microtubules, which have a tubulin backbone, transport cell organelles and par-
ticipate in cell division and the movements of cilia and flagella. Microtubular transport runs
along polymers of tubulin, rather than actin, and uses kinesins and dyneins, rather than myosin,
as“motor proteins.”The third type of cytoskeletal filament, the intermediate filaments, are desmin
polymers that form strong rivet-like structures, called desmosomes, which link cells to one
another and attach cells to the extracellular matrix. Unlike microfilaments and microtubules,
intermediate filaments are not motile.
Intercalated Discs
Specialized cell-to-cell junctions, called intercalated discs (Fig. 1-23), form mechanical and elec-
trical connections between cardiac myocytes (Table 1-3) (Gallicano et al., 1998; Perriard et al.,
2003). The mechanical linkages are provided by the fascia adherens, in which sarcomeric actin
filaments are connected to networks of cytoskeletal actin filaments, and by desmosomes that
connect intermediate filaments in adjacent cardiac myocytes. A third structure, the gap junc-
tion, contains large nonselective connexin channels that allow ions and other small molecules to
diffuse freely between the cytosol of adjacent cells. By providing low-resistance connections
between cells, gap junction channels allow electrical impulses to be conducted rapidly through-
out the heart (see Chapter 13).
FIG. 1-23: Electron microphotographs of
the intercalated disc. Top: Transverse section
of cat ventricular myocardium, showing in-
sertions of sarcomeric actin microfilaments
into the fascia adherens of the intercalated
disc (FA), which is made up of cortical actin
microfilaments (AM). At the right the inter-
calated disc continues as a nexus, or gap
junction (N). Bottom: Oblique section of in-
tercalated disc in the mouse ventricle show-
ing cortical actin myofilaments (AM), fascia
adherens (FA), a nexus (N), and two desmo-
somes or maculae adherens (MA). (Modified
from McNutt and Fawcett, 1974.)

MEMBRANE STRUCTURE AND FUNCTION
Biological membranes are made up of a phospholipid bilayer in which a lipid core is lined by
two hydrophilic surfaces (Fig. 1-24). The hydrophobic core provides a barrier to the passage of
charged molecules, while various charged “head groups” that line the hydrophilic surfaces
interact with the aqueous media on the two sides of the membrane. Proteins that are imbedded
in the bilayer serve various transport, signaling, and other functions.
TABLE 1-3
Cell-to-Cell Communication Across the Intercalated Disc
Type of Transmembrane Cytoplasmic
Structure Connection Proteins Proteins Cellular Structure
Fascia Mechanical N-cadherin -Catenin Microfilament (actin,
adherens -actinin)
-1D integrin Plakoglobin
Vinculin
Desmosome Mechanical Desmoglein-2 Desmoplakin Intermediate filament
(desmin)
Desmocollin-2 Plakophilins
Plakogloblin
Gap junction Electrical Connexin 43 Ion channel
Head group
regions
Hydrophobic
core
Tightly
packed
regions
Phospholipid
molecules
Cholesterol
Head groups
Fatty acyl chains Glycerol
FIG. 1-24: The membrane bilayer showing phospholipid molecules and cholesterol. The hydrophobic core, which is made
up of uncharged (apolar or hydrophobic) fatty acyl chains and cholesterol, is lined by charged (polar or hydrophilic) “head
groups.”

Membrane Lipids
Membrane bilayers contain a mixture of lipids, most of which are amphipathic in that they are
made up of both hydrophilic (polar) and hydrophobic (apolar) moieties. Most membrane
lipids are built upon glycerol, a 3-carbon sugar that is generally esterified to a hydrophilic “head
group” and one or two hydrophobic fatty acyl chain “tails” (Fig. 1-25). Other membrane lipids
include sphingolipids, which are built upon the 3-carbon amino acid serine, instead of glycerol.
Most head groups contain charged anionic phosphate compounds, and so are called phospho-
lipids. Cholesterol, which is found in the plasma membrane (see Fig. 1-24), reduces fluidity and
“stiffens” the bilayer.
Virtually all of the fatty acids in membrane lipids contain an even number of carbon atoms;
in mammalian membranes these are mainly palmitic and stearic acids (saturated C16 and C18),
and oleic, linoleic, and linolenic acids (unsaturated C18 fatty acids that contain one, two, and
three double bonds, respectively). Saturated fatty acids form relatively ordered regions in mem-
brane bilayers, whereas regions made up of unsaturated fatty acids are more fluid (Klausner
et al., 1980). Natural unsaturated membrane fatty acids are cis-isomers; trans-fatty acids, which
occur in artificially hydrogenated fats, are unnatural molecules that can have adverse effects on
membrane function (Mozaffarian and Willett, 2007).
Hydrolysis of membrane lipids by enzymes called phospholipases can contribute to mem-
brane damage in a number of diseases. Phospholipases A1 and A2 hydrolyze the ester bonds link-
ing fatty acids to glycerol carbons 1 and 2, respectively (Fig. 1-26). (Phospholipase B is a mixture
of phospholipases A1 and A2 that hydrolyzes both of these ester bonds.) Phospholipase C cleaves
the phosphate head group from the glycerol “backbone,” whereas phospholipase D removes or-
ganic structures from the head group leaving the phosphatidic acid moiety attached to carbon
3 of glycerol.
Small amounts of membrane lipids released by phospholipases often serve as signaling mol-
ecules (see Chapters 8 and 9). For example, two intracellular messengers, diacyl glycerol (DAG)
and inositol trisphosphate (InsP3), are released when phospholipase C hydrolyzes the membrane
Phosphate head group
Glycerol
Fatty acyl chains
OR
O P O
H H O
H C C C H
O O H
O C C O
(H C) (CH )
n n
2 2
3 3
H C C H
1 3
2
FIG. 1-25: Structure of a phospholipid, oriented with the surface of the bilayer at the top, showing the glycerol “backbone”
that is esterified to a head group and two fatty acyl chains. Left: Atomic structure, in which the glycerol carbons are num-
bered 1, 2, and 3. The fatty acids in most phospholipids are esterified to carbons 1 and 2 and the head group, which can
be linked to various compounds (R), is esterified to carbon 3. Right: Molecular model as shown in Figure 1-24.

phospholipid phosphatidylinositol 4,5-bisphosphate. Arachidonic acid, a polyunsaturated 20-
carbon fatty acid released from membrane phospholipids by phospholipase A2, is the precursor
of several extracellular messengers including prostaglandins, thromboxanes, and leukotrienes.
Surface Charge and Transmembrane Potential
Anionic moieties in the head groups of membrane lipids give rise to a negative surface charge that
attracts cations in the aqueous media toward the membrane surface. The result is a gradual
change in surface potential as one moves away from the membrane (Fig. 1-27). The potential at
Phospholipase D
Phospholipase C
Phospholipase A2
Phospholipase A1
OR
O P O
H H O
H C C C H
O O H
O C C O
(H C) (CH )
n n
2 2
3 3
H C C H
FIG. 1-26: Phospholipases A1 and A2 release the fatty acids esteri-
fied to glycerol at carbons 1 and 2, respectively, whereas phospholi-
pases C and D release all or part of the head groups from glycerol
carbon 3. Diacylglycerol also serves as a second messenger.
FIG. 1-27: Distribution of electrical potential at the surface of a membrane composed of phospholipids with negatively
charged head groups. Left: Surface charge falls sharply with increasing distance from the membrane when ions are absent
in the surrounding medium. Right: When salts are included in the medium adjacent to the membrane, attraction of the
cations to the anionic surface causes a more gradual fall in surface charge. Some of these cations remain associated with
the membrane when it is moved through to the surrounding medium, giving rise to a “plane of shear” outside of which
ions move freely. The potential at the plane of shear is the zeta potential.

the plane of shear when the membrane moves through the surrounding aqueous medium is
called the zeta potential.
Biological membranes often separate regions of different electrical potential; cardiac
Purkinje fibers, for example, have a potential difference of about 90 mV across the resting plasma
membrane. Changes in the magnitude, and often the polarity, of this potential difference exert
forces that modify the conformations of intrinsic membrane proteins such as voltage-gated ion
channels (Chapter 13). Although the absolute potential differences across the plasma membrane
are small, they create enormous electrical potential gradients because they occur across a very thin
surface. A resting potential of 90 mV (90 103
V viewed from within the cell) across the
sarcolemma, which is approximately 30 Å (30 108
cm) thick, represents a potential gradient
of 300,000 V/cm (90 103
V 30 108
cm). During depolarization, this potential differ-
ence reverses to 30 mV, so that the gradient becomes 100,000 V/cm. This means that the
change in transmembrane potential gradient is approximately 400,000 V/cm! These large changes
in potential gradient explain how what seem to be small changes in transmembrane potential
generate forces that can open and close ion channels.
Membrane Proteins
Most of the important activities of biological membranes are mediated by intrinsic membrane pro-
teins that are imbedded in one or both leaflets of the bilayer (Fig. 1-28). In the plasma membrane
these include receptors, ion channels, carriers, pumps, exchangers, and cell adhesion molecules
that span the phospholipid bilayer. Some cytosolic proteins mediate signal transduction after they
are incorporated into aggregates along the inner surface of the plasma membrane. Membrane
proteins can make up more than half of the weight of a membrane. Their extracellular portions
often contain covalently bound lipid (lipoproteins) or carbohydrate (glycoproteins).
The fluid nature of the lipid bilayer allows membrane proteins to move in the plane of the
bilayer, much as icebergs float in the sea. The lipids that surround the hydrophobic surfaces of
membrane proteins, sometimes called the boundary layer lipids or annulus, play an important role
in regulating the activity of these proteins (Katz and Messineo, 1981). Many cardioactive drugs
are amphipathic molecules that can reach binding sites on the hydrophobic surfaces of mem-
brane proteins after they enter the hydrophobic core and diffuse through the plane of the bi-
layer (Herbette and Mason, 1991).
B
A C D
FIG. 1-28: Membrane proteins (shaded) can span the bilayer (A), be incorporated into one leaflet of the bilayer (B), or
adsorbed to the membrane surface (C and D). A and B represent intrinsic membrane proteins. C and D illustrate an ag-
gregate, sometimes called a “scaffold,” formed when regulatory proteins become organized along the inner surface of a mem-
brane to form a signaling complex.

Membrane Transport
Transport of materials across membranes can be effected by two fundamentally different mech-
anisms. The first utilize the pumps and exchangers described in Chapters 7 and 8 and the chan-
nels discussed in Chapter 13 to move ions and other substances across membrane bilayers. A
second, entirely different, mechanism uses membrane-lined vesicles for the bulk movement of
various substances. These transport mechanisms begin when a membrane invaginates and then
pinches off to form a vesicle that carries materials through the cytosol. In exocytosis, intracellu-
lar membrane vesicles transport substances manufactured within cells to the surface where the
vesicles fuse with the plasma membrane, thereby releasing the substances into the extracellular
fluid by a process called trafficking. Bulk transport in the opposite direction occurs by endocy-
tosis in which molecules, often bound to a specific receptor, enter cells within vesicles formed
by invagination of the plasma membrane. These bulk transport processes utilize cytoskeletal
“molecular motors” that are powered by interactions between cortical actin filaments and non-
muscle myosin, and tubulin with kinesins and dyneins (see above).
Endocytosis can be effected by several mechanisms, including pinocytosis, where vesicles
formed from plasma membrane invaginations enclose small amounts of extracellular fluid that
is then transported into the cell. Receptor-mediated endocytosis occurs when selected molecules
in the extracellular fluid (ligands) bind to specific receptors on the outer surface of the plasma
membrane; the ligand-bound receptors then stimulate the adjacent plasma membrane to in-
vaginate. These invaginations, which are called coated pits because their cytosolic surfaces are
lined by proteins such as clathrin and caveolin, form sealed coated vesicles that contain the
receptor-bound ligands. These vesicles then fuse with other intracellular vesicles, called endo-
somes, that can be transported within cells.
■ BIBLIOGRAPHY
Anderson RH, Becker AE. The heart. Structure in health and disease. London: Gower Medical Publishing,
1992.
Colicci WS, ed. Atlas of heart failure, 5th ed. New York: Springer, 2007.
Finean JB, Coleman R, Michell RH. Membranes and their cellular functions. Oxford: Blackwell, 1978.
Goldstein MA, Schroeter JP. Ultrastructure of the heart. In: Page E, Fozzard HA, Solara RJ, eds. The car-
diovascular system, Vol. I, The heart. Oxford: Oxford University Press, 2002:3–74.
Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology, 4th ed. Basingstoke: Freeman, 1999.
Quinn PJ. The molecular biology of cellular membranes. Baltimore: University Park Press, 1976.
Robertson RN. The lively membranes. Cambridge: Cambridge University Press, 1983.
Sommer JR, Dolber PC. Cardiac muscle: ultrastructure of its cells and bundles. In: de Carvalho AP,
Hoffman BF, Lieberman M, eds. Normal and abnormal conduction in the heart. Mt Kisco, NY: Futura,
1982:1–28.
■ REFERENCES
Anderson RH, Ho SY. The architecture of the sinus node, the atrioventricular conduction axis, and the
internodal atrial myocardium. J Cardiovasc Electrophysiol 1998;9:1233–1248.
Becker AE, deWit APM. Mitral valve apparatus. A spectrum of normality relevant to mitral valve pro-
lapse. Br Heart J 1979;42:680–689.
Benninghoff A. Lehrbuch der Anatomie des Menschen. Munich: JF Lehmanns, 1944.

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