The long-term objective of this application is to identify the pathophysiologic mechanisms implicated in the occurrence of post- infarction congestive dilated cardiomyopathy. The overall hypothesis to be tested is that the loss of a critical mass of myocardium in a segmental fashion leads to a sudden increase in workload on the surviving tissue, ventricular wall remodeling accompanied by side-to- side slippage of myocytes and ultimate development of severe myocardial dysfunction. Cellular hypertrophy may tend to compensate for the increase in both diastolic and systolic cell stresses, but an excessive enlargement of myocytes, accompanied by an inadequate growth of the coronary vasculature may evolve into further cell loss, collagen accumulation, greater chamber dilation, increased wall stress and oxygen consumption and irreversibly depressed cardiac and cellular performance. The time of onset, development and progression of the disease process will depend on original infarct size and other risk factors such as hypertension and aging. The left coronary artery will be occluded to produce infarcts of different sizes in order to correlate the time course of the alterations in ventricular hemodynamics with the number of cells lost and the nature and degree of reactive hypertrophy in the viable myocytes. These dynamic processes will be characterized quantitatively early after the acute event, and later during the recovery period up to six months following the initial ischemic insult. To assess the contribution of the coronary vasculature and microvasculature to the development of myocardial injury within the surviving myocardium with time, a morphometric analysis of the coronary circulation will be performed and cross-correlated with measurements of regional myocardial perfusion. Furthermore, the mechanical properties of papillary muscles, trabeculae carnae and isolated single myocytes will be determined to establish the influence of tissue and cellular hypertrophy exerts a detrimental role in the long-term outcome of myocardial infarction, experiments will be conducted in which therapeutic interventions will be employed in the attempt to reduce myocyte hypertrophy, maintain a more efficient proportion between the muscle mass and the coronary vasculature and preserve cardiac performance. In contrast, hypertension- and aging-induced cardiac hypertrophy prior to infarction are anticipated to lead to the precocious appearance of myocardial dysfunction not only because of greater infarct size but also as a result of excessive myocyte hypertrophy produced by the combination of these stresses on the heart.
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