MECHANISMS OF MYOCARDIAL DYSFUNCTION AND FAILURE

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

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

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