Table Of ContentADVANCES IN
ORGAN BIOLOGY
HEART METABOLISM IN FAILURE
Series Editor: E. EDWARD BITTAR
Department of Physiology
University of Wisconsin
Guest Editors: RUTH A. ALTSCHULD
Department of Medical Biochemistry
The Ohio State University
ROBERT A. HAWORTH
Department of Surgery
University of Wisconsin
VOLUME 4A 1998
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LIST OF CONTRIBUTORS
Norman R. Alpert Department of Molecular Physiology and
Biophysics
University of Vermont
Burlington, Vermont
Ruth A. Altschuld Department of Medical Biochemistry
The Ohio State University
Columbus, Ohio
Kenneth M. Baker Weis Center for Research
Geisinger Clinic
Danville, Pennsylvania
Robert D. Bernstein Department of Physiology
New York Medical College
Valhalla, New York
Marvin Boluyt Gerontology Research Center
Laboratory of Cardiovascular Science
Baltimore, Maryland
Maria Carles Integrated Physiology Research Laboratories
Boston University, School of Medicine
Cambridge, Massachusetts
David €. Dostal Weis Center for Research
Geisinger Clinic
Danville, Pennsylvania
Rainer W. Gulch Institute of Physiology II
University of Tiibingen
Tubingen, Germany
IX
X LIST OF CONTRIBUTORS
Iudith K. Cwathrney Integrated Physiology Research Laboratories
Boston University, School of Medicine
Cambridge, Massachusetts
Roger 1. Hajjar Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Sian €. Harding Cardiac Medicine
National Heart and Lung Institute
Imperial College
London, England
Thomas H. Hintze Department of Physiology
New York 'Medical College
Valhalla, NY
loanne S. lngwall NMR Laboratory for Physiological Chemistry
Cardiovascular Division
Harvard Medical School
Boston, Massachusetts
Ruthard lacob Institute of Physiology II
University of Tubingen
Tubingen, Germany
Helmut Kammermeier Medical Faculty
Institute of Physiology
Aachen, Germany
Daniel P. Kelly Department of Molecular Biology and
Pharmacology
Washington University School of Medicine
St. Louis, Missouri
Cerolf Kissling Institute of Physiology I1
University of Tubingen
Tubingen, Germany
Edward C. Lakatta Gerontology Research Center
Laboratory of Cardiovascular Science
Baltimore, Maryland
xi
List of Contributors
Sarra K. Laycock Department of Physiology
New York Medical College
Valhalla, NY
Carl V. Leier Division of Cardiology
The Ohio State University Medical Center
Columbus, Ohio
Rebecca Liebes Department of Human Nutrition
The Ohio State University
Columbus, Ohio
A. )ames Liedtke Cardiology Section
University of Wisconsin Hospital and Clinics
Madison, Wisconsin
Denis Medeiros Department of Human Nutrition
The Ohio State University
Columbus, Ohio
Andrew R. W. Money-Kyrle Cardiac Medicine
National Heart and Lung Institute
Imperial College
London, England
Louis A. Mulieri Department of Molecular Physiology and
Biophysics
University of Vermont
Burlington, Vermont
Ulrich Schmidt Integrated Physiology Research Laboratories
Boston University, School of Medicine
Cambridge, Massachusetts
Nahid Seyedi Department of Physiology
New York Medical College
Valhalla. NY
Randall C. Starling Department of Cardiology
Cleveland Clinic Foundation
Cleveland, Ohio
xii LIST OF CONTRIBUTORS
Arnold W. Strauss Department of Pediatrics
Washington University School of Medicine
St. Louis, Missouri
Matthew R. Wolff Department of Medicine
University of Wisconsin Medical School
Madison, Wisconsin
Xaioping Zhang Department of Physiology
New York Medical College
Valhalla, NY
Gong Zhao Department of Physiology
New York Medical College
Valhalla, NY
PREFACE
It is with great pleasure that we present this collection of chapters on metabolism in
heart failure, contributed by a distinguished panel of authors all of whom are lead-
ers in their field.
Heart failure continues to be a major public health problem in the United States
with close to half a million new cases diagnosed each year. Moreover, deaths from
heart failure are on the increase, in part because of advances in the treatment of
other fatal diseases, and in part from the prevalence of lifestyles indifferent to the
risk factors for heart disease. This is not to say that no progress has been made in the
treatment of heart failure. While for many years treatment was confined to the man-
agement of the symptoms, in recent years with the advent of ACE inhibitor and p
blocker therapies, real improvements in cardlac function and life expectancy have
been achieved (Volume 4B,L eier). On a more basic level, enormous advances have
been made in describing many of the changes in structure and function of the heart
and the parallel neurohumoral and circulatory adaptations that occur during the on-
set of failure. These advances have been made not only by using various animal
models of heart failure, but also using fresh failing human heart tissue, which has
become readily available for experimental investigation since the advent of cardiac
transplantation.
Understanding the significance of many of these changes that occur during the
transition to failure and the role they play in the etiology of failure is, however, a
much more difficult task. These are exciting times in heart failure research. It is as
though many of the pieces of the jigsaw puzzle are available but the puzzle has yet to
xiii
xiv PREFACE
be assembled. The objective of these volumes is to bring together some advances
that have been made in recent years in defining one aspect of the failing heart, that
is, the role of altered metabolism, in order to facilitate assembly of the puzzle.
Seeking to understand the events important in the progression of heart failure
has several difficulties. Firstly, there are clearly many initial etiologies as failure is
the common end-point for hearts that have suffered any one of a variety of initial in-
sults. These have in common an initial supply/demand imbalance of cardiac output
that is rectified immediately by inotropic mechanisms but that also set in motion an
adaptive hypertrophic response. This normalizes cardiac output, at least for a time,
before progression to failure occurs by mechanisms that as yet are unclear. One dif-
ficulty is that, although there are many similarities in the progression to failure of
hearts with different initial insults, it is unclear if this is indicative of a common
mechanism of demise from the well-compensated hypertrophic state. Different
events could precipitate failure in hearts set on the path to failure by different
causes. Even if there is a common final pathway to failure, it could be multifactorial,
involving the interaction of a number of different factors. Secondly, the elucidation
of changes that occur in the failing heart has uncovered such a broad spectrum of
changes that could well have impact on cardiac function that there seems to be an
oversupply of possible causes of dysfunction, many of which appear to be poten-
tially sufficient. The problem has become one of seeking to evaluate the impact of
each change, to distinguish which of the many changes have pathological conse-
quences and which are adaptive, and to distinguish essential causes from less sig-
nificant consequences.
A role for energy exhaustion in the altered systolic and diastolic function of the
failing heart has been championed by Katz (J. Am. Coll. Cardiol. (1989). 13,513-
523), based on evidence for increased intercapillary distances, increased myofi-
bril/mitochondria ratio, and decreased levels of high-energy phosphate compounds
found in failing hearts. Changes in gene expression were interpreted as an adapta-
tion for greater efficiency in the face of these constraints. Ten years later, these argu-
ments are still valid. More evidence is now available for changes in gene expression
adaptive for greater efficiency (Volume 4B, Alpert and Mulieri), and changes in j3
adrenergic regulation (Volume 4A, Harding and Money-Kyrle) may also have this
effect (Volume 4B, Wolff). Changes adaptive for greater efficiency are also likely to
limit work rates (Volume 4B, Alpert and Mulieri). Evidence for an energy sup-
plyldemand imbalance in failing hearts is reviewed in Volume 4A by Starling and
colleagues. Levels of the high energy intermediates ATP (Volume 4A, Starling et
al.) and phosphocreatine (Volume 4A, Ingwall) are reduced in failure, the latter
mainly reflecting a reduced level of creatine (Volume 4A, Ingwall). The ability to
quickly restore a high phosphate potential via the creatine phosphokinase reaction
is compromised in failure (Volume 4A, Ingwall), and maintaining a high phosphate
potential is key to maintaining function (Volume 4A, Kammermeier). Indeed, un-
der conditions where a decline in phosphate potential is imposed, function appears
to adjust so as to keep phosphate potential high (Volume 4A, Kammermeier). Thus,
Preface xv
limitations in energy supply could contribute to the upper limit of function observed
in failing hearts. The role of altered coronary blood flow regulation in failure is con-
sidered in Volume 4A by Laycock and colleagues, and especially the role of altered
nitric oxide production. Even though agonist-induced vascular NO production is
severely depressed in pacing-induced failure in dogs (Volume 4A, Laycock et al.),
there is also evidence that blood flow in the failing heart is not limiting energy pro-
duction in this model (Volume 4B, Wolff). There is, however, evidence for a possi-
ble role for transient ischemic events in the transition to failure, which may be
demand-induced. The upregulation of superoxide dismutase at the expense of cyto-
chrome oxidase seen in failure could be evidence of transient ischemia (Volume 4A,
Starling et al.). Distinguishing cause and consequence is difficult. In a model of
myocardial stunning, a chronic limitation of coronary reserve, which has little ef-
fect on resting blood flow, induces a substrate shift toward glucose oxidation and a
significant loss of contractility (Volume 4B, Liedtke). On the other hand, hearts fail-
ing after other initial insults exhibit a significant loss of contractility (Volume 4A,
Jacob et al.), a substrate shift towards glucose oxidation (Volume 4B, Strauss and
Kelly), and a chronic limitation of coronary reserve (Volume 4A, Laycock et al.).
This suggests that the limitation of coronary reserve seen with hypertrophy could
potentially set in motion changes that result in failure.
The component other than oxygen which is critical to energy supply is substrate.
The importance of fatty acid oxidation for the maintenance of normal cardiac func-
tion is evident from the cardiomyopathy resulting from genetic defects that specifi-
cally reduce the activity of enzymes needed for fatty acid oxidation (Volume 4B,
Strauss and Kelly). This is surprising since, in normal isolated hearts, the oxidation
of other substrates can substitute for fatty acid oxidation without loss of function
even though fatty acids are the substrate of choice. Since this cardiomyopathy arises
from a genetic defect, however, there is no question about causality: the defect
causes the disease. Thus, evidence exists for a critical role for the regulation of both
fuel and oxygen in the transition to failure, though the nature and mechanism of the
link remains obscure. Even if the failing heart is an energy-starved heart, a causative
role for energy supply/demand imbalance in the onset of failure cannot yet be con-
sidered established. Since the control of blood flow relative to oxygen demand is
central to theories of energy supplyldemand imbalance, elucidation of the role of
such an imbalance in the progression to failure may be predicated upon elucidation
of these control mechanisms. While the observation of autoregulation in the heart is
longstanding, it is not yet clear whether even the major players involved in this
mechanism have been identified.
Even though the focus of these volumes is on the role of altered metabolism in
heart failure, we thought it was important to set this topic in the context of other
changes occurring in the myocardium that impact metabolism. Thus we begin with
a section on contractile function, since cardiac function and metabolism are so inti-
mately related. This includes discussion of structural changes in relation to function
(Volume 4A, Jacob et al.), changes in the force-frequency relation (Volume 4A,
xvi PREFACE
Mulieri and Alpert), changes in calcium regulation (Volume 4A, Schmidt et al.),
and regulation by adrenergic agonists (Volume 4A, Harding and Money-Kyrle) in
the transition from hypertrophy to failure. Compelling arguments are also made in
this section for failure paradigms that do not invoke an energy supplyldemand im-
balance: the catastrophic functional consequences when excessive ventricular dila-
tion is combined with reduced contractility (Volume 4A, Jacob et al.) or when the
normal force-frequency relation is lost (Volume 4A, Mulieri and Alpert). The latter
is attributed by the authors to downregulation of SERCA2 Ca pump expression by
overexposure to catecholamines (Volume 4A, Mulieri and Alpert). The importance
of the role of catecholamine overexposure, which results in receptor downregula-
tion and desensitization to catecholamine stimulation, is also discussed in Volume
4A by Harding and Money-Kyrle. The other possible contributory cause of failure
which has received much attention is activation of the renirdangiotensin system,
which initiates myocyte remodeling and collagen synthesis by fibroblasts (Volume
4B, Dostal and Baker). The importance of the role played by these systems in the
etiology of failure is underscored by the therapeutic effectiveness of ACE inhibitors
and p blockers (Volume 4B, Leier). A paracrine function of the heart is emerging
the role of which is not yet clear (Volume 4B, Dostal and Baker). Desensitization to
catecholamines, collagen synthesis, and other changes observed during adaptation
to increased load are also observed with aging, however, and without necessarily a
progression to failure (Volume 4B, Boluyt and Lakatta). This suggests that these
changes do not trigger failure, but they may well accelerate the transition to failure
(Volume 4A, Harding and Money-Kyrle). Also, since the changes observed with
aging utilize many of the mechanisms by which the heart adapts to increased load
and because the adaptive reserve of the aged heart to chronic stress is reduced, aging
can be viewed as a risk factor for failure (Volume 4B, Boluyt and Lakatta). Atten-
tion has also turned to the possible role of cytokines, especially tumor necrosis fac-
tor alpha (TNFa), in the transition to failure because failure is accompanied by
increased levels of TNFa in the blood. Failure mechanisms can be constructed
around any one of the above, as for a theory of supply/demand imbalance, but the
challenge remaining is to progress from observed correlation to established cause.
Robert A. Haworth and Ruth A. Altschuld
Guest Editors
