Cardiac Mechano-Electric Coupling and Arrhythmias

508 Pages·2011·13.81 MB·English

by  Peter Kohl

Cardiac
Mechano-
Electric
Coupling and
Arrhythmias
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Cardiac
Mechano-
Electric
Coupling and
Arrhythmias
SECOND EDITION
P eter Kohl, F rederick Sachs and
Michael R. Franz
1
1
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Foreword I
Why should basic cardiac
researchers know about stretch
effects on heart rhythm?
Just over 5 years ago, the fi rst edition of this book was published. In will be aware of the benefi ts associated with cardiac resynchroniza-
it the editors compiled a comprehensive series of well-organized, tion therapy, it is intriguing to see the expanding body of insight
well-executed and timely chapters covering important aspects of related to mechanical modulation of arrhythmogenesis and
this subject, from the ion channels and proteins involved in the so- defi brillation. Equally exciting are observations on mechanical
called stretch response of the cardiac cell to the response of the components in the electrocardiogram, the often ignored role of
human heart. In this second edition, these same editors have devel- the pericardium, and the host of remodelling events that occur
oped this by broadening their scope, with a 50 % increase in the in atrial and ventricular overload, or their partial reversal by
number of chapters, contributed by the leading experts in the fi eld, cardiac assist devices. The puzzle for the basic scientist is: why?
and by exploring this subject at even greater depth. Section VIII forms another unique focus in this book. It consists of
W hile many of the original basic science chapters are included, well-written chapters by outstanding clinical investigators
with very signifi cant updates, this volume is characterized by who review the evidence from clinical trials for MEC, again empha-
the additional inclusion of chapters that address the translation sizing to the reader the effects of stretch on cardiac rhythms and
of basic science fi ndings to the electro-mechanical activity of function.
atria and ventricles. These new key chapters are crucial in that O nce again I applaud the editors and contributors for a fi ne job,
they help the basic scientist and the young clinical investigator which illustrates that the fi eld has made considerable progress in
to understand the concept of mechano-electric coupling (MEC), recent years. We are beginning to understand more about ‘what
and approaches towards studying this in ways that are relevant stretch has to do with arrhythmias’, and how mechanisms at the
to human health. Furthermore, in this second edition there are molecular level relate to clinically relevant phenomena. Perhaps
more chapters that are directly related to clinical observations, we are even on our way to the development of a new class of
notably in the new Sections V–VIII. These chapters are a must- anti-arrhythmic drugs.
read for the researcher in that they address the effects of stretch on F or basic scientists, physiological and/or clinical relevance should
myocardial function and electrical activity in both normal and dis- be a key guide for directing research efforts. This book provides a
eased hearts. superb compass for fundamental exploration of cardiac MEC.
Personally, I fi nd the chapters in Section VII on MEC as a mech-
anism involved in therapeutic interventions particularly informa- Penelope A. Boyden
tive. Collectively, these chapters approach control of the mechanical Professor of Pharmacology
environment as an anti-arrhythmic intervention. While readers Columbia University
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Foreword II
Why should clinical
cardiologists know about
stretch effects on
cardiomyocyte
electrophysiology?
In normal hearts, electrical activation occurs by an orchestrated reduced threshold of arrhythmia induction that often accompanies
sequence of selective channel openings and closures, ultimately excessive chamber enlargement (atrial or ventricular), the adverse
delivering a calcium signal to the myofi laments that return the effects of dis-coordinate wall motion in patients with heart failure,
favour by contracting. For cardiologists, arrhythmia most often is and the impact of regional loading of pulmonary veins on atrial
viewed in a similar unidirectional manner, i.e. as stemming from fi brillation. Treatment of arrhythmia-by targeting ion channelopa-
disruption of ion channel function with abnormal ion levels occur- thies had been a mainstay approach for decades, yet has been rather
ring at the wrong place and /or the wrong time, stimulating extra disappointing – the best we generally have to offer is an insurance
contractions and impairing normal intracellular function and policy that shocks you back when needed.
homeostasis. However, as one will learn after reading this extraor- A s clinical cardiologists, we pay most attention to controlling
dinary and newly updated book, this process is far from a one-way electrical abnormalities when they negatively impact heart mechan-
street. Mechanical forces generated by excited muscle can them- ics. The material presented in this volume will make you think
selves trigger changes in ion channel function, calcium–myofi lament about how it can work the other way. Modifying how mechanics
interactions and intercellular communication. These forces may be might impact the electrophysiology has been previously more the-
in the form of dis-coordinated contraction or acute stretch – where oretical than practical – but this is changing. Cardiac resynchroni-
one piece of muscle pulls on the other, or where a whole heart is zation provided a novel way to reduce dis-coordinate motion, and
suddenly loaded. It can also ensue from chronic changes in loading research is yielding surprising insights into how this can improve
such as occur in dilated heart failure, valvular disease, ventricular electrophysiological disease in failing hearts. Ventricular assist
infarction and hypertrophy. devices can profoundly alter chamber loading and with it such
The mechanisms of what is known as mechano-electric feedback, mechanical feedback stimulation. The identity of ‘stretch-activated
or coupling, are many, and they are authoritatively presented in channels’ has long been mysterious and, in an important way, this
Sections I–III of this book. The fi rst section, dedicated to the sub- has limited progress in the fi eld. However, this too is rapidly chang-
cellular mechanisms of cardiac mechano-sensitivity, is followed by ing, with new data revealing putative proteins such as members of
one that explains cellular correlates. In the third section, multi- the non-selective cation transient receptor potential channel super-
cellular manifestations of cardiac mechano-electric coupling are family. This opens up opportunities for targeted translational stud-
reviewed. Together, they are believed to play a major role in numer- ies (as highlighted in Section IV), and may even have future
ous clinical heart diseases (see Sections V–VIII). Examples are the potential for novel treatment approaches, such as via selective
viii foreword
stretch-channel blockers that maybe particularly relevant in the The clinician, in particular, will learn about an area rarely dealt
setting of abnormal mechanics (see Section IX). Better understand- with in traditional medical education, yet one with the potential to
ing of how wall stretch translates into electrical instability could profoundly impact how we view arrhthmogenicity and, hopefully,
yield an entirely new class of mechano-sensitive drugs. how we can improve our ability to treat it. If you are looking for a
T his book fi lls a unique position in the fi eld, bringing together an place to explore the mechanisms and implications for cardiac
outstanding group of basic, translational and clinician scientists to mechano-electric responses, you have found it.
explore cardiac mechano-electric coupling phenomena in a broad
and comprehensive manner. The chapters are lucid and accessible, David A. Kass
and the book impresses by how well it links basic science (Sections Abraham and Virginia Weiss Professor of Cardiology
I–III), via translational studies (IV) to clinically relevant scenarios Johns Hopkins University
(V–VIII) with an outlook towards future developments (IX).
Foreword to the 1st
Edition (Reprinted)
Stretching our views
of cardiac control
E xcitation–contraction coupling (ECC), the transduction of These include some of the most common forms of heart disease
electrical impulses into changes in the rate and mechanical force of such as dilative failure, atrial fi brillation and post-infarction scar-
muscle contraction, is a fundamental concept essential to both a ring. Although we now suspect MEF effects are likely to play a role
basic and clinical understanding of the heart. Modulators of ECC, in both electrical and mechanical pathological remodelling, direct
and hence of cardiac muscle performance, include neuro-humoral evidence for this has remained elusive. Thus while much basic
transmitters such as catecholamines, as well as many other regula- information is becoming available on topics such as how MEF
tors, notably those that affect intracellular Ca handling. This affects effects may facilitate normal physiological processes, we still have
the actin–myosin interactions, and adjusts the haemodynamics in few clues on how they may be applied in prevention or reversal of
accord with changing requirements, on a beat by beat, year by year disease.
basis. T his book represents an important step in documenting the elu-
T he complementary concept that changes in cardiac mechanical sive yet important role of MEF. Here, assembled in one source, are
function which occur in response to neural and hormonal infl u- the current thoughts and fi ndings of many, if not most of the lead-
ences impact back on the excitatory and conductive electrical ing investigators in the fi eld. As one reviews the pages that follow,
properties of the heart, i.e. mechano-electric coupling or feedback it becomes apparent that progress in MEF research is indeed a topic
(MEF), is a less established idea whose role in normal and patho- whose ‘time to shine’ has arrived and that this volume contributes
logical physiology has become an exciting new chapter in contem- much to lighting this path. The three editors are among the fi eld’s
porary biology. Mechanisms and pathways whereby mechanical pioneers and their selection of topics has resulted in an excellent
events, changes in tension, force and spatial displacement, alter the summary of much of the world’s current thinking. The book con-
heart’s electrical properties are now recognized as an important tinues the momentum established though their leadership in
dimension for development of new approaches in therapeutic car- organizing a number of important international symposia on MEF
diac control. that have addressed many of the fi eld’s outstanding questions in
The fi gure provides a simplifi ed, but conceptually useful view of forums encompassing most of its working investigators. The syn-
this emerging bi-directional dynamic. While the left-to-right path- thesis and distillation from these efforts have contributed much to
way, ECC, appears a familiar element in current therapeutic strate- the pages that follow, in providing coverage of important concepts
gies, the right-to-left pathway, MEF, has only recently begun to be proceeding from basic physiology towards an integrated under-
explored as a topic of medical interest. However, while it has standing of cardiac control, and the exploration of new targets of
become well established that dysfunction in pathways of ECC is largely unexplored therapeutic potential.
important in a number of cardiac pathologies (e.g. in various car- Classical studies on MEF and how it might contribute to well-
diomyopathies), there are as yet only a few clues for a parallel infl u- established events such as the Bainbridge response, or the function
ence of factors involved in pathways of MEF. This situation appears of stretch-activated channels, or the fatal phenomenon of
likely to change, however, as greater attention is given to mechanisms Commotio cordis, are all discussed. In addition, new approaches by
involved in acute and chronic processes of cardiac remodelling. many of today’s cutting edge MEF exponents employ a wide range