PATHOGENESIS OF HEART FAILURE

CONTENTS

Editorial: Pathogenesis of Heart Failure

Jagat Narula and James B. Young

xi

Preface
Roger J. Hajjar and Federica del Monte

xiii

Cardiogenesis and the Regulation of Cardiac-Specific Gene Expression

Jau-Nian Chen, Douglas B. Cowan, and John D. Mably

157

Development and maturation of the embryonic vertebrate heart is an exquisitely conducted ensemble of cell movements, interactions, and morphologic transformations.
Proper heart morphogenesis is important to normal embryonic development because the
heart is the first organ formed. All subsequent events depend on the ability of the heart
to supply oxygen and nutrients to fulfill the metabolic requirements of the organism.
Abnormalities in the formation of the heart often lead to abnormal function and embryonic lethality or may manifest later in life, causing severe health issues. This article
reviews the molecular events and mechanisms regulating heart formation, focusing on
the recently identified members of the cardiogenic repertoire.

The Failing Cardiomyocyte

Sian E. Harding

171

This article presents an integrated account of the subcellular alterations underlying each
of the main observed defects in function of the ventricular cardiomyocytes from failing
human heart: poor contraction, slow relaxation, -adrenoceptor desensitization, and tendency to arrhythmia. The key role of the -adrenoceptor system is highlighted: loss of
tonic support from cyclic AMP-stimulated pathways contributes to the contraction and
relaxation defects observed, but it is residual -adrenoceptor function that exacerbates
arrhythmias. Most of the alterations are acquired during the process of adaptation of
the heart to cell loss, and are common to various etiologies of heart failure. Information
gained from studies on genetic causes of cardiomyocyte malfunction, however, has been
instructive in the interpretation of the functional effects of subcellular alterations.

-Adrenergic Receptors in Heart Failure

Stefan Engelhardt

183

This review provides a brief overview of the -adrenergic signal transduction system in
the mammalian heart and its alterations in heart failure. Furthermore, the mechanisms

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underlying the detrimental effect of chronic -adrenergic stimulation, the beneficial effects
of -blockade in heart failure, and the emerging role of pharmacogenomics in this field will
be discussed.

Sodium Current and Arrhythmogenesis in Heart Failure

Luis F. Santana, Harol Nez-Durn, Keith W. Dilly, and W. Jonathan Lederer

193

The low sodium arrhythmic mechanism hypothesis is demonstrated in normal cells with
unmodified Na+ and Ca2+ channels, in long QT syndrome models, and in heart failure
model systems. The authors propose that the changes in Ca2+ influx during the early part
of the action potential and during the plateau and repolarization phases of the action
potential sum to influence contractility and arrhythmogenesis. The importance of both
of these changes is supported by their present work, which suggests that antiarrhythmic
agents should be examined for their actions on low sodium arrhythmic mechanism and
action potential duration.

Role of Phospholamban in the Pathogenesis of Heart Failure

Jason R. Waggoner and Evangelia G. Kranias

207

A common characteristic of the failing cardiomyocyte is abnormal calcium homeostasis,

which is linked to depressed sarcoplasmic reticulum calcium cycling. Calcium cycling
is controlled by a cardiac-specific Ca2+-ATPase, SERCA2a, whose activity is regulated by
a small phosphoprotein called phospholamban (PLN). The authors discuss the role of PLN
in the pathogenesis of heart failure and the significant advancements over the past 15 years
that have helped in understanding the role of PLN in controlling heart contractility
through its regulation of SERCA2a. The functional effects of several naturally occurring
PLN mutations in humans are examined, and the potential of PLN as a therapeutic target
in human heart failure is assessed.

Transgenic Models of Heart Failure: Elucidation of the Molecular Mechanisms

of Heart Disease
Djamel Lebeche, Rishikesh Dalal, Monica Jang, Federica del Monte,
and Roger J. Hajjar

219

Several animal models of heart failure have been generated recently. There are two types
of animal models: naturally occurring models and experimentally induced models. This
article focuses on the most potentially and widely used gene-based murine models of
cardiac failure with the purpose of identifying the major functional classes of altered
genes and outlining the results of experiments using these transgenic models.

Protein Unfolding in Cardiomyopathies

Luisa Gorza and Federica del Monte

237

This article provides an overview of the role and mechanisms of molecular chaperones in
protein folding in the different cellular compartments and attempts to coordinate the
nomenclature of the proteins as they have been described in different organisms with the
corresponding proteins in mammals. Recent knowledge of the relevance of the unfolding
protein response and degradation pathways and the role of the chaperone proteins in the
development of human diseases is explored. Although most of the disease entities caused
by protein misfolding have been described for other organs, this article more specifically
addresses the consequences of protein misfolding for cardiovascular diseases.

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Role of Apoptosis in Heart Failure

Luanda P. Grazette and Anthony Rosenzweig

251

Investigators have identified biochemical and morphologic hallmarks of apoptosis in a

wide variety of heart diseases; however, delineating the functional and anatomic contribution of apoptosis to the pathogenesis of heart disease has been challenging. Studies in
cardiomyocytes and genetically engineered mice suggest that this contribution is likely
to be substantial and may be greater than initially anticipated because of the observation
that common signaling mechanisms regulate not only cardiomyocyte apoptosis but also the
function of surviving cardiomyocytes. This article reviews mechanisms and implications of
apoptotic signaling and evidence that these pathways contribute to cardiac dysfunction
and heart failure. Consideration is given to whether these pathways represent an opportunity for therapeutic intervention.

Mechanisms of Cardiac Hypertrophy

Giulio Selvetella and Giuseppe Lembo

263

Cardiac hypertrophy is a response of myocardium to various physiologic and pathologic

stimuli, mechanical and hormonal, that causes the heart to work harder under conditions
of increased workload. The hypertrophic response can be maladaptive or compensatory
depending on the specific signaling pathways involved. This article reports recent findings
in the molecular pathways involved in cardiac hypertrophic mechanism, distinguishing
between adaptive and maladaptive pathways to direct future therapeutic intervention to
stimulate positive hypertrophic patterns and prevent molecular pathways that lead to
heart failure.

Nitric Oxide and Cardiac Remodeling

Jonathan Passeri and Kenneth D. Bloch

275

Cardiac remodeling occurs as an adaptive response to chronic increases in hemodynamic

load and neurohormonal stimulation but may become maladaptive over time, leading to
deleterious structural and functional alterations and manifesting clinically as congestive
heart failure. On a cellular level, cardiac myocyte hypertrophy and apoptosis, fibroblast
proliferation, and changes in the extracellular matrix are some of the principal alterations
underlying the remodeling process. In recent years, nitric oxide (NO) has been recognized
to modulate contractile function, myocardial oxygen metabolism, ventricular hypertrophy
and apoptosis, and fibrosis. The identification of the different isoforms of NO synthase and
the generation of genetically modified mice lacking or overexpressing these enzymes have
provided new insights into the complexity of NO biology and its multifaceted role in
cardiac remodeling and heart failure.

Targeting Genes and Cells in the Progression to Heart Failure

Motoki Sato, Stephen J. Fuller, Roger J. Hajjar, and Sian E. Harding

287

The limited success of pharmacologic treatment to reverse the progression of heart failure
has let to an exploration of new therapeutic strategies. Gene transfer using viral vectors is
successful in restoring function in isolated human ventricular myocytes and animal models,
with Ca2+ halding, -adrenoceptor signaling, and apoptosis as promising targets. Cell transfer to repair damaged myocardium using autologous bone marrow stem cells or skeletal
myoblasts is already under clinical evaluation, and such sources as embryonic stem cells
are being developed. Common problems must be overcome, such as optimal methods for
delivery and the prevention of arrhythmias, so that experiences in the gene and cell
transfer fields are likely to provide complementary information during the progression
toward an effective therapy.

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Cell Therapy in Heart Failure

Otmar Pfister, Mohit Jain, and Ronglih Liao

303

Current heart failure treatments fail to address the cellular basis of ventricular dysfunction, namely the loss of functional cardiomyocytes and vascular cells. Recent advances in
stem cell research, notably the discovery of stem cell populations with myogenic and
angiogenic potential, have prompted attempts to regenerate lost myocardium and vasculature by cell-based therapies. Initial cell transplantation studies have provided
encouraging results regarding the use of cell therapy modalities in the treatment of
ischemic heart disease and heart failure. This review discusses advantages and limitations of specific cell types and gives an overview of the first clinical trials using cardiac
cell therapy in patients who have heart failure.

Index

313

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