The development of ischemic injury and myocardial failure is known to be more rapid in the hypertrophied and hemodynamic factors in the conversion of the hypertrophied functionally stable heart to myocardial failure is not clear. The hypothesis being tested is that during development of cardiac hypertrophy, vascular alterations restrict blood flow reserves causing intermittent ischemia and myocardial metabolic adaptation. The increased rate of glycolytic metabolism, though protective when low continues flow occurs, increases injury during total ischemia, possibly due to more rapid accumulation of glycolytic byproducts. Further, we propose that the intermittent ischemia leads to myocardial fibrosis and congestive failure. We will use a model of severe cardiac hypertrophy (>100%) and congestive failure we have developed in the rat with banding of the ascending aorta at 23 days of age. We will use whole animal models, isolated perfused hearts, and isolated myocytes in culture to describe morphologic, biochemical and functional aspects of cardiac hypertrophy and failure. Specific aims are to 1) temporally characterize development of hypertrophy and failure in the rat model, 2) determine the effects of altering chronic work load on the development of myocardial failure, 3) explore that role of humoral factors in the renal-angiotensin-adrenal system on the separate effects of hypertension and hypertrophy on development of injury in the hypertrophied myocardium, and 4) evaluate the capacity of hypertrophied myocytes in culture to respond to specific stresses. Morphologic and biochemical measurements of whole hearts will be used to test the effect of several humoral and hemodynamic interventions on the pathogenesis of hypertrophy and failure, and the isolated perfused heart will be used to assay function. Isolated myocytes in culture will be used to evaluate response of hypertrophied cells to specific stresses or biochemical agents. These studies are designed to investigate mechanisms which control the development of hypertrophy, the adaptation to chronic work load by conversion to glycolytic metabolism, the increased susceptibility of hypertrophied myocardium to ischemic injury, and the development of myocardial failure. The role of intramyocardial vessel wall thickening in the pathogenesis of myocardial failure will be explored. It is anticipated that these studies will provide a better understanding of factors responsible for the conversion of cardiac hypertrophy to myocardial failure.