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Cardiac Adaptation in Heart Failure
Supplement to
Basic Research in Cardiology, Vol. 87, Suppl. 2 (1992)
Editors:
G. Heusch (Essen), R. Jacob (Tiibingen), Th. Kenner (Graz)
J. Holtz, H. Drexler, H. Just (Eds.)
Cardiac Adaptation in
Heart Failure
Risks due to myocardial
phenotype changes
.~
Steinkopff Verlag Darmstadt
Springer-Verlag New York ~
The Editors:
Prof. Dr. med. J. Holtz PD Dr. H. Drexler
Martin-Luther-U niversitat Prof. Dr. H. Just
Halle-Wittenberg Albert-Ludwigs-Universitat
Medizinische Fakultat Medizinische Universitatsklinik
Institut fUr Pathophysiologie Innere Medizin III, Kardiologie
Magdeburger Str. 6 Hugstetter StraBe 55
0-4020 Halle/Saale, FRG W-7800 Freiburg, FRG
Basic Res. Cardiol, ISSN 0300-8428
Indexed in Current Contents.
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ISBN-13: 978-3-642-72479-4 e-ISBN-13: 978-3-642-72477-0
DOl: 10.1007/978-3-642-72477-0
Copyright © 1992 by Dr. Dietrich Steinkoplf Verlag GmbH & Co. KG, Darmstadt
Medical Editor: Sabine Muller - English Editor: James C. Willis - Production: Heinz J. Schafer
Softcover reprint of the hardcover 1st edition 1992
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Introduction
Traditionally, cardiac hypertrophy is regarded as an adaptation of the heart to
permanent mechanical overload. Regardless of the fact that many different and often
unknown primary causes can result in heart failure, mechanical overload and
myocardial hypertrophy is found in almost all forms of manifest chronic heart failure
(apart from failure due to extramyocardial hindrances to inflow or to relaxation).
However, the reactive enlargement of myocardial mass in response to an enhanced
hemodynamic burden appears to be a double-edged sword.
Obviously, the hypertrophy helps to reduce the enhanced ventricular wall stress in
heart failure by adding contractile units to the overdistended chamber wall. However,
in recent years it became clear that this adaptive hypertrophic process is rather
complex and may include problematic facets. The adaptive hypertrophy includes
proliferation of the nonmyocyte cardiac cells as well as substantial alterations in the
phenotype of the growing myocytes due to differential changes in gene expression.
Presently open issues in this context are: What is the pathophysiological relevance of
this altered phenotype of the myocardial tissue in overload hypertrophy? Does it
explain the disturbed diastolic function ofthe failing myocardium? Does it contribute
to the enhanced risk of complex ventricular arrhythmias? What is the relevance of a
disproportionate increase in myocardial mass relative to the growth of the coronary
vascular tree? Are there hypertrophy-specific alterations in coronary vascular func
tion, even in absence of arteriosclerotic coronary heart disease? Facts, concepts and
opinions on these questions are under intensive discussion and research in car
diology, worldwide.
Within this volume, three questions out of the complex problem of cardiac
adaptation in heart failure will be considered by international experts in clinical and
experimental cardiology:
- What do we know about the cellular transduction mechanisms triggering myocyte
hypertrophy and phenotype alterations in response to hemodynamic overload?
- Is the fragile Ca + + -homeostasis of hypertrophied cardiocytes a common basis for
disturbed diastolic function and for the susceptibility to complex ventricular
arrhythmias in heart failure?
- Is there a specific trophic role of the renin-angiotensin-system in cardiac adapta-
tion to chronic overload?
The contributions to this volume resulted from the lectures and discussions of
an international symposium devoted to these questions, which took place in
Freiburg/Breisgau, Germany, December 5-7, 1991. This symposium was under the
auspices of the European Society of Cardiology (Working group: Drug Therapy in
Cardiology), of the Deutsche Gesellschaft fUr Herz- und Kreislaufforschung (Arbeits-
VI Introduction
gemeinschaft Vasodilatantien), and of the Society for Cooperation in Medical
Sciences, Freiburg. We are very grateful for the generous financial support by Bristol
Myers-Squibb, Munich, and by Schwarz-Pharma, Monheim, which made this
symposium possible.
The success of the symposium came from the excellent lectures of the invited
ex~erts and from the lively and intensive discussions, which were inspired and
directed by the distinguished chairmen of the sessions: W. Kubler (Heidelberg,
Germany), A.H. Henderson (Cardiff, United Kingdom), F. Burkart (Basel, Switzer
land), H. Krayenbuhl (Zurich, Switzerland) and H. Scholz (Hamburg, Germany).
Indispensable, however, were the excellent symposium organization in the hands of
Mrs. Hedy Woeste, Bristol-Myers-Squibb, Munich, and the skillful help by Mrs. S.
Muller, Steinkopff-Verlag, in preparing this volume.
Freiburg, summer 1992
J. Holtz H. Drexler, H. Just
Institute of Pathophysiology Klinikum der Albert-Ludwigs-Universitat
Martin-Luther UniversiHit Abteilung Innere Medizin III - Kardiologie
Halle/Saale Freiburg
Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
Biological adaptation of the myocardium to a permanent change in loading
conditions
Swynghedauw, B. ................................. .
Role of protein kinase system in the signal transduction' of stretch-mediated
myocyte growth
Yazaki, Y., I. Komuro. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Sympathetic modulation of the cardiac myocyte phenotype: studies with a
cell-culture model of myocardial hypertrophy
Long, e.S., K. Kariya, L. Karns, P.e. Simpson. . . . . . . . . . . . . . . . 19
Growth factors, growth factor response elements, and the cardiac phenotype
Schneider, M.D., W.R. McLellan, F.M. Black, T.G. Parker. . . . . . . . . . 33
Signaling mechanisms for the activation of an embryonic gene program during
the hypertrophy of cardiac ventricular muscle
Chien, R. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
Endothelial modulation of myocardial contraction:
mechanisms and potential relevance in cardiac disease
Shah, A.M., MJ. Lewis ................ . 59
The regulation of calcium cycling in stressed hearts
Alpert, N.R., M. Periasamy, M. Arai, H. Matsui, L.A. Mulieri, G. Hasenfuss 71
Energetics of calcium cycling in nonfailing and failing human myocardium
Hasenfuss, G., L.A. Mulieri, e. Holubarsch, B. Pieske, H. Just, N. R. Alpert 81
Spontaneous sarcoplasmic reticulum Ca2 + release leads to heterogeneity of
contractile and electrical properties of the heart
Lakatta, E.G., A. Talo, M.e. Capogrossi, H.A. Spurgeon, M.D. Stern 93
Afterdepolarizations and triggered activity
Fozzard, H.A ........................................ 105
VIII Contents
The contribution of nonreentrant mechanisms to malignant ventricular
arrhythmias
Pogwizd, S.M., R Corr. . . . . . . . . . . . . . . . . • . . . . . . . . . . 115
The potential role of Ca2 + for electrical cell-to-cell uncoupling and conduction
block in myocardial tissue
Kleber, G.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 131
Failure of myocardial inactivation: a clinical assessment in the hypertrophied
heart
Paulus, W.J., M.A. Goethals, S.U. Sys . . . . . . . . . . . . . . . . . . . . . .. 145
Diastolic dysfunction in pressure-overload hypertrophy and its modification by
angiotesin II: current concepts
Lorell, RH.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
Mechanisms of cardiac growth. The role of the renin-angiotensin system
Fernandez-Alfonso, M.S., D. Ganten, M. Paul . . . . . . . . . . . . ... . . 173
Cardiac fibroblasts: function, regulation of gene expression, and phenotypic
modulation
Eghbali, M.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
Modulation of myocardial sarcoplasmic reticulum Ca + + -ATPase in cardiac
hypertrophy by angiotensin converting enzyme?
Holtz, J., R. Studer, H. Reinecke, H. Just, H. Drexler 191
Subject index. . . . . . . . . . . . . . . . . . . 205
Biological adaptation of the myocardium to a permanent
change in loading conditions
B. Swynghedauw
U 127-INSERM, Hopital Lariboisiere, Paris, France
Summary: Cardiac hypertrophy due to permanent mechanical overloading is only one ex
ample among thousands of the general process of biological adaptation. The process is
randomly governed and results in at least one thermodynamical benefit: to be adaptational
and to induce several changes in gene expression. Some of these changes are detrimental, some
can ev.en be useless. The cascade of events which finally leads to a permanent modification of
the genetic expression involves an initial signal, likely to be the stretch, a pathway which
transducts the signal, and a transient change in genetic expression which transmits competence
to the cell to be transformed. The permanent modifications occur at all cellular levels including
the sarcomere, sarcolemma, energy metabolism, and extra-cellular matrix, but they are species
specific and differ in the ventricles and the atria.
Key Words: Cardiac hypertrophy; I!lolecular iJiology; myosin; 1!Iembrane proteins; gncogenes;
~egulation of gene supression; iJiological ctdaptation
Biological adaptation
Biological adaptation is a very general process by which a cell, an organ, an organism
or a group of individuals adapt to a change in environmental conditions (40). There
are roughly three types of biological adaptation (Table 1).
Biological changes which do not involve the expression or the structure of the
genome. A good example is the increased oxygen consumption or catecholamine
excretion during exercise. This type of adaptation usually constitutes the chapter
called "adaptation" in the textbook of physiology.
Changes in genetic expression. A good example is the hypertrophied biceps of a
well-trained athlete or the compensatory hypertrophy of the kidney following
unilateral nephrectomy. The modifications of the genomic expression are usually
both quantitative and qualitative. This chapter is usually forgotten in the physiology
textbooks for at least two different reasons. From a linguistic point of view, the gap
existing between physiologists and molecular biologists is increasingly wide. Sec
ondly, because this type of adaptation is frequently associated with pathological
manifestations and is not attributed to pure "physiology".
Changes in the genome itself, including mutations. This type of adaptation is
supposed to be the one which was put into play during evolution. For example,
thousands years ago a mutation allowed one gazelle to have a longer neck than its
neighbors, which facilitated eating leaves on a tree in a country where the grass was
becoming scarce due to climatic changes. This particular gazelle was able to survive
and reproduce more easily and, finally, this resulted in a new, more adapted species:
the giraffe. Nobody can ever prove or contradict this theory, at least for this
particular example, because these examples belong to the history oflife. Nevertheless,
we can easily reproduce in vitro this kind of biological adaptation and, indeed, we do
2 B. Swynghedauw
Table 1. 'Biological adaptation.
1) Biological adaptation without any changes in gene expression resulting from the triggering
of a neural reflex or hormonal stimulation. Example: the enhanced uptake of substrate during
exercise
2) Biological adaptation due to changes in gene expression. Usually, several genes are involved
and the changes are both quantitative and qualitative. Example: muscle hypertrophy during
training
3) Biological adaptation due to changes in the structure of genes. This is likely to be the
process involved during evolution, e.g., a mutation occurs randomly in a fish, and the fish
becomes adapted to the atmosphere instead of water. Genetic manipulations reproduce this
type of adaptation when one introduces, for example, a gene which renders a cell resistant to
antibiotics.
that in our laboratory every week when we have to amplify a clone. The clone is
introduced into a plasmid and then in a bacteria together with a gene coding for a
protein which renders the bacteria insensitive to a given antibiotic. The addition of
the antibiotic to the medium will kill most of the bacteria except the few which
possess the antibiotic resistance gene and which can therefore reproduce and replace
the others. This is a typical example of in vitro genetic manipulation, very similar to
what we call gene therapy.
Cardiac hypertrophy due to mechanical overload belongs to the second type of
adaptation. Gene therapy theoretically can be applied to this particular condition,
but, obviously, one needs to know not only all the adaptational changes which occur
during a permanent cardiac overload, but also which one is beneficial, which one is
detrimental, i.e., what is the physiological significance of a given change on the
phenotype? Because scientific research is self-reproducible, we can easily predict that
soon we should know in detail every tiny change in the amount of even the most
minor transcript, while it will become impossible to estimate the physiological
function of the corresponding gene or to really quantitate a force/velocity curve.
The function of the heart is not only to synthesize mRNAs, but, incidently, also to
eject the blood into the large vessels!
Main characteristics of biological adaptation are due to changes
in genetic expression
The process is randomly governed and, as such, has three characteristics.
The final result has to be at least initially beneficial. In other words, the resulting
thermodynamic status has to be improved when compared to the initial conditions. If
not, the heart submitted to a permanent overload would have failed immediately and
nobody would have survived.
An important point is that the concept has a statistical basis. The resulting change
is obtained by modifications of the expression of not only one, but several genes. The
initiation of the new program renders a better adapted thermodynamic status more
probable. There are indeed several examples showing that very small modifications in
this program may entirely modify the expected benefit. From this point of view
