Molecular Approaches to Heart Failure Therapy

363 Pages·2000·13.7 MB·English

by  G. Hasenfuss, E. Marbán (auth.), Prof. Dr. med. Gerd Hasenfuss, Eduardo Marbán M.D., Ph.D. (eds.)

G. HASENFUSS E. MARBÄN (Eds.)
Molecular Approaches to Heart Failure Therapy
Molecular Approaches tO
G. HASENFUSS
| herapy
E. MARBÄN
H E A RT F a i u re T
(EDS.)
With 114 Figures
in 174 Separate Illustrations
and 16 Tables
SPRINGER-VERLAG
BERLIN HEIDELBERG GMBH
Prof. Dr. med. GERD HASENFUSS
Georg-August-Universität Göttingen
Zentrum Innere Medizin, Abt. Kardiologie und Pneumologie
Robert-Koch-Straße 40
D-37075 Göttingen
EDUARDO MARBÄN, M.D., Ph.D.
Professor of Medicine and Physiology
Section of Molecular and Cellular Cardiology
844 Ross Building
The Johns Hopkins University
Baltimore MD 21205, USA
ISBN 978-3-642-63332-4 ISBN 978-3-642-57710-9 (eBook)
DOI 10.1007/978-3-642-57710-9
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Originally published by Steinkopff-Verlag Darmstadt in 2000
Softcover reprint of the hardcover 1st edition 2000
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Table of Contents
Introduction . .. .. .. .... . ... ... ........ ....... . . . .
G. HASENFUSS, E . MARBAN
Alterations in excitation-contraction coupling and potential gene
therapy targets in failing human hearts . . . . . . . . . . . . . . . . 5
B. PIESKE
2 Cardiac overexpression of If-adrenergic receptors 26
M. J. LOHSE, S. ENGELHARDT
3 Genetic approaches to elucidate the regulatory role
of phospholamban in the heart .... ... ... . ...... . . . . 39
A.G. SCHMIDT, E.G. KRANIAS
4 Manipulation of SERCA2a in the heart by gene transfer 53
F. DEL MONTE, S. E. HARDING, R. J. HAJJAR
5 Changing the cardiac calcium transient: SERCA2 overexpression
versus phospholamban inhibition ... . . . ... . . ..... .. .. 69
w.
H. DILLMANN
6 Adenovirus-mediated gene transfer of SERCA isoforms 76
G. INESI, M. CAVAGNA, J.M. O'DONNELL, C. SUMBILLA,
L. ZHONG, H. MA, M. G. KLEIN
7 Overexpression of FKBP12.6 to influence SR function 89
J. PRESTLE, P. M. L. JANSSEN, A. JANSSEN, G. HASENFUSS
8 Adenovirus-mediated myocardial gene therapy 100
J. K. DONAHUE
VI Table of Contents
9 Adenovirus-mediated transfection
of multicellular cardiac preparations 112
P. M. L. JANSSEN, S. E. LEHNART, J. K. DONAHUE,
J. PRESTLE, E. MAR BAN, G. HASENFUSS
10 Myocardial-specific gene delivery ........... . ........ 126
W.-M. FRANZ, O.J. MULLER, H.A. KATUS,
G. VON DEGENFELD, G. STEINBECK, P. BOEKSTEGERS
11 Transfection studies using a new cardiac 3D gel system ..... 144
T. ESCHENHAGEN, C. FINK, T. RAU, U. REMMERS,
J. WElL, W. H. ZIMMERMANN, S. AIGNER,
H. M. EpPENBERGER, T. WAKATSUKI, E. L. ELSON
12 Cellular mechanisms of cardiac arrhythmias -
do they playa role in heart failure? . ........ .. ....... 157
D. J. BEUCKELMANN, L. PRIEBE, U. C. HOPPE
13 Potassium channel overexpression . . . . . . . . . . . . . . . . ... . 180
U.C. HOPPE, H.B. Nuss, B. O'ROURKE, E. MARBAN,
D.C. JOHNS
14 Mechanisms and relevance of apoptosis . . . . . . . . . . ... . 1.9 .7
J. HOLTZ, M. TOSTLEBE, D. DARMER
15 Strategies to prevent apoptosis . . . . . . . . . . . . . . ... . .2 3. 2. .
A. HAUNSTETTER, S. IZUMO
16 Neurohumoral modulation of metalloproteinases
in cardiac failure: impact on remodeling ....... . ........ 247
D. A. KASS, H. SENZAKI, N. PAOLOCCI
17 Oxidative stress in heart failure 262
D. B. SAWYER, W. S. COLUCCI
18 Modulation of cardiac function by essential myosin light chains
in health and disease ....... . . . . . . . . . . . . . .. .. . 2.8 .5 .
1. MORANO
19 Myocardial infarction, infarct repair, and strategies
for muscle regeneration . . . . . . . . . . . . . . . . . . . .. .2 9.8 . . . .
C. E. MURRY, M. ZHANG, H. REINECKE
Table of Contents VII
20 Cardiomyocytes can induce rhythmic contraction of skeletal
muscle cells. Potential use for infarct repair . ...... . ..... 316
H. REINECKE, G. H. MACDONALD, S. D. HAUSCHKA,
C.E. MURRY
21 Strategies to identify cardiomyocyte cell cycle regulatory genes 333
K. B. S. PASUMARTHI, L. J. FIELD
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 3. . . . . . . . .
List of Contributors
Prof. Dr. med. D. J. BEUCKELMANN Dr. med. W.-M. FRANZ
Klinik III fUr Innere Medizin Medizinische Universitat Lubeck
der Universitat zu Koln Medizinische Klinik II
Josef-Stelzmann-Str. 9 Ratzeburger Allee 160
D-50294 Koln D-23538 LUbeck
W. S. COLUCCI, MD R. J. HAJJAR, MD
Dept. of Cardiology Assistant Professor of Medicine
Boston Medical Center Massachusetts General Hospital
88 East Newton Street Cardiovascular Research Center
Boston, MA 02118, USA 149 13th Street, Room 4215
Charlestown, MA 02129-2060, USA
Prof. W. H. DILLMANN, MD
Division of Endocrinology/ A. HAUNSTETTER, MD
Metabolism Beth Israel Diaconess
University of California, San Diego Medical Center
9500 Gilman Drive, BSB/5063 330 Brookline Ave. SL-201
La Jolla, CA 92093-0618, USA Boston, MA 02215, USA
K. J. DONAHUE, MD Prof. Dr. med. J. HOLTZ
University of Cardiology Martin -Lu ther- Universi tat
Johns Hopkins University Halle-Wittenberg
School of Medicine Medizinische Fakultat
720 N. Rutland Ave. (844 Ross Bldg). Institut fur Pathophysiologie
Baltimore, MD 21205-2179, USA Magdeburger Str. 18
D-06097 Halle (Saale)
Prof. Dr. T. ESCHENHAGEN
Institut fur Experimentelle U. C. HOPPE, MD
und Klinische Pharmakologie Section of Molecular
Universitat Erlangen/Nurnberg and Cellular Cardiology
Fahrstr. 17 844 Ross Building
D-91054 Erlangen The Johns Hopkins University
School of Medicine
L.J. FIELD, MD 720 N. Rutland Ave.
Wells Center for Pediatric Research Baltimore, MD 2105, USA
James Withcomb Riley Hospital
for Children
702 Barnhill Drive, Room 2666
Indianapolis, IN 46202-5225, USA
x
List of Contributors
G. INESI, MD Prof. Dr. med. 1. MORANO
Dept. of Biochemistry Molecular Molekulare Medizin
Biology Max- Dellbriick- Zentrum
University of Maryland Robert-Roessle-Str. 10
School of Medicine D-13122 Berlin
108 N Green St.
Baltimore, MD 21201-1503, USA C. E. MURRY, MD, PhD
Dept. of Pathology
S. IZUMO, MD Box 357470, Room E-520 HSB
Beth Israel Deaconess Medical University of Washington
Center - Cardiovascular Division Seattle, WA 98195-7335, USA
330 Brookline Avenue SL-201
Boston MA 02215, USA K. B. S. PASUMARTHI, MD
Wells Center for Pediatric Research
Dr. med. P. M. L. JANSSEN James Withcomb Riley Hospital
Georg-August-Universitiit for Children
Zentrum Innere Medizin 702 Barnhill Drive, Room 2600
Abt. Kardiologie Indianapolis, JN 46202-5225, USA
und Pneumonologie
Robert-Koch-Str. 40 Priv.-Doz. Dr. med. B. PIESKE
D-37075 Gottingen Georg-August- Universitiit
Zentrum Innere Medizin
D. A. KASS, MD Abt. Kardiologie
Profressor of Medicine and und Pneumonologie
Biomedical Engineering Robert-Koch-Str. 40
Cardiology Division D-37075 Gottingen
johns-Hopkins Hospital
Halsted 500 Dr. med. J. PRESTLE
600 N. Wolfe Street Georg-August- Universitiit
Baltimore, MD 21287, USA Zentrum Innere Medizin
Abt. Kardiologie
Prof. Dr. med. M. J. LOHSE und Pneumologie
Universitiit Wiirzburg Robert-Koch-Str. 40
Abteilung Pharmakologie D-37075 Gottingen
Versbacher Str. 9
D-97078 Wiirzburg H. REINECKE, PhD
Dept. of Pathology
E. MAR BAN, MD, PhD Box 357470, E-520 HSB
Professor of Medicine University of Washington
and Physiology Seattle, WA 98195-7335, USA
Section of Molecular
and Cellular Cardiology D. B. SAWYER, MD, PhD
844 Ross Building Dept. of Cardiology
The Johns-Hopkins University Boston Medical Center
Baltimore, MD 21205, USA 88 East Newton Street
Boston, MA 02118, USA
F. DEL MONTE, MD
Massachusetts General Hospital A.G. SCHMIDT, MD
Cardiovascular Research Center Department of Pharmacology
149 13th Street and Cell Biophysis
Boston, MA 02129-2060, USA University of Cincinnati
College of Medicine
Cincinnati, OH 45267-0575, USA
Introduction
G. HASENFUSS, E. MARBAN
Heart failure embodies the central irony of modern medicine. As we have
become increasingly adept at treating the major proximate causes of death
in Western society, we have effectively converted acute illness into chronic
malady. The last twenty years have witnessed a revolution in the treatment
of acute coronary syndromes, myocardial infarction in particular. Patients
who reach the hospital now have every expectation of leaving alive, but not
necessarily well. Our ability to blunt the edge of ischemic insults has en
gendered new problems: a new cohort of patients whose hearts function
well enough to enable short-term survival, but at the cost of decreased ex
ercise tolerance, dyspnea and increased long-term mortality. The irony is
compounded by our increasingly sophisticated pharmacopeia for the treat
ment of heart failure, which, by slowing the progression of ventricular dys
function, has created a chronic illness. The fact of its chronicity makes
heart failure no less deadly. In symptomatic patients, mortality exceeds
5-10% per year even with the best contemporary therapy. Not all heart
failure is ischemic, of course, but the final common phenotype is eerily
concordant regardless of the proximate cause. No wonder, then, that heart
failure is the leading cause of hospitalization in America and in Western
Europe and that the prevalence of the disease continues to rise.
Drugs have indeed revolutionized heart failure therapy, ACE inhibitors
and beta-adrenergic blockers having the most outstanding records to date.
The utility of these and other blockers of humoral stress pathways illumi
nates a central truism - that the disease may be dominated by the body's
own limited repertoire of innate responses to circulatory insufficiency.
What is good in the short run becomes maladaptive in the long run. No
one would argue that catecholamines are bad in acute cardiogenic shock,
for example; however, if the body's response to stress continues unchecked,
beta receptors become downregulated and desensitized, perpetuating a
downward spiral. Hence the paradoxical benefit of beta blockers in heart
failure: the vicious cycle is broken. However, antagonists of various auto
coids have their own limitations. Most notably, such drugs will not suffice
to negate the initial insult and its impact on circulatory function. We now
know that the heart failure syndrome cannot be completely attributed to
the body's maladaptive efforts to defend central circulation. Our clinical
experience with patients who have been supported by left ventricular assist
2 G. Hasenfuss, E. Marban
devices (LVADs) is particularly instructive. While on such external sup
port, autocoid reactions subside, and the programs of gene expression that
underlie the heart failure phenotype revert to those characteristic of nor
mal healthy hearts. One might then have reason to hope that, having
"rested" the heart with an LVAD and broken the vicious cycle, heart failure
might not recur once the machine is removed. Not so. These patients gen
erally re-develop heart failure once removed from the LVAD. This experi
ence means that we will have to pay attention not only to blocking the
reactions to heart failure but also to reversing the initial injury.
To reverse the injury will require new approaches, in which we are cur
rently limited by a conceptual gap. While palliative therapy is ever-improv
ing, we simply do not know enough to be able to reverse the disease. The
way we now approach end-stage heart failure serves to illustrate the cur
rent sad state of affairs. Until patients become bedridden, we push auto
coid-blocking therapy to the limits of tolerance. At that point, in despera
tion, we begin subjecting patients to infusions of catecholamines and phos
phodiesterase inhibitors. We know these therapies actually decrease sur
vival in heart failure patients. Nevertheless, the obvious short-term hemo
dynamic benefits provide bridges to the most extreme of heart failure
treatments, cardiac transplantation. While transplantation may become
practical after we overcome immunological and infectious obstacles to
xenotransplants, the enormous expense and limited success of the proce
dure as it now stands relegates it to a therapy of last recourse.
The present book grew out of a conference which was held in order to
confront the conceptual gap and to explore ways of potentially overcoming
the impass we now face. The various chapters address molecular
approaches to the therapy of heart failure based on careful analysis of the
pathophysiological alterations occurring in failing heart. This includes
alterations of the myocyte phenotype as well as of the extracellular matrix.
Furthermore, the current status of myocardial gene transfer techniques is
addressed.
Based on the finding that altered excitation-contraction coupling is of
significant relevance for the pathophysiology of human heart failure, ino
tropic stimulation by targeting various components of the calcium cycling
system seems promising. This includes overexpression of the fJ-adrenocep
tor system, stimulation of sarcoplasmic reticulum calcium accumulation by
overexpressing the calcium pump or targeting its inhibitory protein, phos
pholamban, or by manipulating the sarcoplamic reticulum calcium release
channel. One caution in inotropic therapy is the possibility that it may
paradoxicall decrease survival, as seen with milrinone and with beta
adrenergic agonists.
The harmful effects of oxidative stress in myocardial ischemia have been
extensively investigated. Only recently, however, has oxidative stress been
considered to be a major player contributing to the transition from com
pensated to decompensated heart failure. Likewise, although its relevance
in heart failure is not completely understood, apoptosis may be relevant