Physiology of the Heart

592 Pages·2010·16.07 MB·English

by  Arnold M. Katz MD

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Physiology of
the Heart
F I F T H E D I T I O N
Arnold M.Katz,MD,D.Med (Hon),FACP,FACC
Professor ofMedicine Emeritus
University ofConnecticut School ofMedicine
Farmington,Connecticut
Visiting Professor ofMedicine and Physiology
Dartmouth Medical School
Lebanon,New Hampshire
Visiting Professor ofMedicine
Harvard Medical School
Boston,Massachusetts
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Printed in China
Library ofCongress Cataloging-in-Publication Data
Katz,Arnold M.
Physiology ofthe 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 ofthese findings.
In the single authored,expert voice that is this book’s unique strength,Dr.Katz provides a comprehensive overview
ofthe physiological and biophysical basis ofcardiac function,beginning with structure and proceeding to bio-
chemistry,biophysics,and pathophysiology in arrhythmias,ischemia,and heart failure.Emphasis is on the interre-
lationships ofbasic processes among the cell,cardiac muscle function,and the biophysics ofcontractile 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
612.1(cid:2)7—dc22 2010024639
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To my father
Louis N. Katz
1897–1973
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Foreword
The 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% ofall 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 ofpa-
tients with cardiovascular diseases.A few examples ofthe latter include the impairment ofcon-
duction and ofautomaticity ofspecialized 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 ofthe renin-angiotensin-aldosterone axis and ofthe
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 ofmost forms ofischemic heart disease has been declining steadily
with increasing attention to lifestyle—especially the reduction ofsmoking—and to the widespread
use ofstatins.
These landmark improvements in cardiac care have resulted directly from the advances in car-
diovascular physiology and pathophysiology that occurred during the first halfofthe 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 ofwhich 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 ofhow the individual components affect
the function ofthe whole heart in the intact human.
This magnificent fifth edition ofthe classic text,Katz’s Physiology ofthe Heart,a book that im-
proves with every edition,considers the normal and diseased heart at all ofthese levels.After an
incisive exposition ofcellular,subcellular,molecular,and genetic processes in the first halfofthe
book,it then goes on to explain how these processes affect the function ofthe entire organ,both
in health and disease.
What is,of course,so remarkable is that Physiology of the Heartremains a single-authored
comprehensive text,probably among the last ofits kind.It is a tour de force that reflects Dr.Katz’s
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vi Foreword
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 ofexplaining 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 ofthe total
structure.Increasingly,the human is being recognized as a valid model for detailed investigation
by basic scientists.Physiology ofthe Heartwill 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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Preface to the First Edition
Why 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 ofcontrol
and effector mechanisms.Both the strength ofcardiac contraction and its electrical control are
modulated by alterations in one or more ofthese cellular mechanisms,which are involved in the
fundamental processes ofexcitability,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 ofour current understanding of
the physiological and biophysical basis of cardiac function.Therefore,this book is intended to
provide a synoptic view ofour present knowledge in this rapidly expanding area.The major em-
phasis is on the relationships between the biochemical properties ofindividual constituents of
the myocardial cell,the biophysics ofcardiac muscle function,and the performance ofthe intact
heart.
The task of relating these different aspects of cardiac function to each other has required
much selectivity,and undoubtedly,an excess ofsimplification 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 ofscience.The early neu-
rophysiologists who tried to understand nerve conduction as the passage offluid down hollow
tubes were trying to explain physiological phenomena in terms ofthe limited biophysical knowl-
edge oftheir time.With the development ofan understanding ofanimal 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 ofelectrical 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 ofthe theories ofthe great neurophysiologists ofthe last cen-
tury.Yet these were not unintelligent scientists.They were,however,required to interpret their
observations within the framework ofknowledge that existed during their lifetime.It would be
presumptuous indeed for us now to assume that the evolution ofnew principles ofscience 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 ofcardiac function in
terms ofthe broad principles that are understood today.
The only true “facts”in biology are the results ofindividual experiments carried out under
controlled conditions by a carefully defined methodology.Yet,it is not the purpose ofthis book
to catalogue and discuss the biological “facts;”for this,the reader is referred to the large number
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viii Preface to the First Edition
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 ofinvestigation ofthe 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 ofreferences.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 ofthis goal,however,requires the resolution,more or
less arbitrarily as the case may require,ofmany serious conflicts,as well as the addition ofspec-
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 ofmost ofus,rather than
the threads.For this reason,though with apologies to the protagonists ofopposing viewpoints,
the author has chosen the present format for this text.
Arnold M.Katz
Heidelberg,Germany
1976
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Preface
T he material covered in this text has undergone an unprecedented expansion since I began
the first edition ofPhysiology ofthe Heartin 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 ofknowledge 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 ofpages long and cite hundreds ofreferences.
This expansion poses a serious challenge to revising Physiology ofthe Heartas it increases the
difficulty in providing discussions that,while thorough and accurate,are not so detailed as to de-
feat the purpose ofthis 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 ofthe 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 ofbiology and human disease.The
importance ofphysiology in understanding disease is obvious,but it is also true that efforts to un-
derstand heart disease have contributed to our knowledge ofnormal 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 ofabnormal 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 ofthe heart by changing myocyte structure,protein synthesis,gene expression,and
other molecular features ofthe heart.The fourth edition,published in 2006,when signaling ab-
normalities were emerging as a major cause ofcardiovascular disease,contains separate chapters
on each of these two types of signal transduction.The importance of cytoskeletal signaling in
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x Preface
mediating both adaptive and maladaptive proliferative responses to cell deformation led me to
expand a briefdiscussion ofthe 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 briefpassage from “The Catalogue ofthe Ships”in Homer’s Iliadto explain why I describe so
many different proteins.
I am aware that my attempt to discuss a broad range oftopics,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 ofthe 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 ofcardiovascular 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 ofHarvard Medical School in the early 1950s,to the effect that “half
ofwhat the faculty teaches medical students is wrong,but the faculty does not know which half.”
This revision ofPhysiology ofthe Heartchallenges the view that there is a widening gap be-
tween bench and bedside,between understanding the mechanisms ofdisease 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 ofheart 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
halfofthe 20th century made it possible to understand the hemodynamics ofheart 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 ofstructural 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 ofthe
role ofcalcium in regulating cardiac contraction and relaxation led to the development ofnew
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 oftheir energy-sparing effects are ofshort-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