Data collected recently suggest that the underlying structural mechanism by which the heart dilates and fails is different that what is generally believed to occur. Difficulties inherent in human experiments (e.g. fibrosis, multiple disease processes, obtaining adequate controls, availability of fresh tissue), however, led to this proposal which will examine ventricular remodeling under more carefully controlled conditions in an experimental animal model of heart failure without fibrosis. The major hypothesis to be tested is that ventricular dilation due to congestive heart failure is due to remodeling of myocyte shape, rather than myocyte slippage. Since it appears that an important specific defect in heart failure is due to inadequate transverse myocyte growth, most work will focus on this problem. Consequently, it is proposed that adaptive changes in myocyte shape during heart failure are due to changes in the genetic expression of (a) specific cytoskeletal protein(s) or the disruption of intermyocyte collagen struts. Additionally, the effects of ACE inhibition on ventricular remodeling in heart failure will be examined. A final goal is to determine if hemodynamic overload in adults stimulates atrial myocyte hyperplasia in addition to karyokinesis. Alterations in myocyte shape (length, cross-sectional area, volume from isolated myocytes) will be correlated with functional and anatomic data obtained from cardiac catheterization and echocardiography from guinea pigs with cardiac hypertrophy and failure due to construction of the descending thoracic aorta. Specific changes in cytoskeletal proteins associated with altered myocyte shape will also be evaluated using protein gels and immunofluorescent microscopy. Tissue will also be perfusion-fixed for examination of myocyte and interstitial compartments (e.g., collagen struts) by light and electron microscopy (TEM and SEM). Nuclear number and DNA content will be examined using isolated myocytes. There is a high probability that this work will lead to a breakthrough in understanding the mechanism of cardiac dilation associated with congestive heart failure.
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