MECHANISMS OF MYOCARDIAL DYSFUNCTION AND FAILURE

  • Factor, Stephen M. (PI)
  • Gulati, Jagdish (PI)
  • Krueger, John (PI)
  • Fishman, Glenn (PI)
  • Aronson, Ronald (PI)
  • Scheuer, James (PI)
  • Leinwand, Leslie (PI)
  • Calvin, Eng (PI)
  • Yellin, Edward (PI)
  • Wells, James (PI)
  • Liew, C. (PI)
  • Fein, Frederick (PI)
  • Sonnenblick, Edmund (PI)
  • Liew, C. (PI)

Project: Research project

Project Details

Description

The major goal of this proposal is to use a multidisciplinary
approach to identify the factors that may convert the initial
adaptive phase of cardiac hypertrophy to the terminal phase of
myocardial failure and death. A second and related goal is to
investigate the pathophysiologic basis for the mechanical,
structural, and electrical dysfunction associated with cardiac
hypertrophy itself. To achieve these goals the Program is
comprised of nine research projects designed to investigate various
aspects of a pathophysiologic sequence of events we have formulated
on the basis of previous experimental work in models of myocardial
disease: (1) Hypertrophy induced by pressure overload; (2)
Reactive hypertrophy after myocardial infarction; (3) Acquired
cardiomyopathy induced by combined pressure overload hypertrophy
and diabetes; (4) Genetic cardiomyopathy. Tissue from failing
human hearts removed prior to transplantation also will be studied.
A variety of experimental techniques will be used: voltage clamp
studies in isolated single cardiac cells; assessment of myocardial
mechanics and sarcomere dynamics by light diffraction in isolated
cells and intact muscles; characterization of intrinsic connective
tissue by special staining techniques, immuno-localization, and
scanning electron microscopy; biochemical analysis of myosin
isoenzymes, protease activity and sarcolemmal composition;
investigation of vascular architecture and distribution;
morphometric analysis of infarct size; use of recombinant DNA
techniques to isolate and characterize the genes associated with
myosin heavy chains and other contractile proteins; measurements
of transmittal flow and hemodynamic parameters in the intact heart.
The importance of elucidating the mechanisms responsible for
causing the evolution of adaptive hypertrophy to cardiac failure
is emphasized by the fact that despite palliation of symptoms, no
presently available therapeutic interventions have been shown to
improve the survival of patients with congestive cardiomyopathy and
heart failure. Furthermore, many patients with cardiac failure
die suddenly without evidence of hemodynamic deterioration; sudden
death in those patients is believed to be due to arrhythmias. We
believe that the results of the proposed studies will provide a
better understanding of the pathophysiologic processes that
ultimately lead to cardiac failure, lethal arrhythmias, and death
in patients with heart disease. We anticipate that elucidation of
such pathophysiologic processes should improve our ability to
prevent the often fatal outcome of patients with cardiac failure.
StatusFinished
Effective start/end date9/30/889/29/94

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)

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