Cardiomyopathy is a significant clinical problem. Better understanding of this entity is limited by lack of an appropriate animal model. We propose to further develop a new model of alcoholic """"""""cardiomyopathy"""""""" in the hamster. In pilot studies, hamsters were given 50% alcohol in their drinking water for periods of up to six months. The isolated, perfused, working hearts were characterized by depressed cardiac performance a low phosphorylation potential, and a depressed nucleotide pool, which corresponds to a decrease in the PCr/Pi, as evidence by 31p NMR. In one group, treated concurrently with verapamil, there was almost complete prevention of these deleterious effects. The hypothesis is that alcohol induced membrane abnormalities cause a myocardial calcium and energy imbalance, nucleotide depletion, and cellular damage, thus resulting in cardiac dysfunction. We propose to: 1) further establish and characterize this model of alcoholic cardiomyopathy, and 2) evaluate interventions which alter the cardiomyopathy in order to better understand its pathophysiology and potential treatment. Cardiac function of isolated, perfused hearts will be mesured by intraventicular pressure, left ventricular dP/dt, and two-dimensional echocardiography. Coronary flow will be measured directly and myocardial oxygen consumption calculated. Measurements will be made at rest and following stress (tachycardia, decreased coronary perfusion pressure, and volume loading) to test ventricular reserve. Myocardial metabolism will be characterized by 31P NMR (ATP, CP, Pi, pH) and by HPLC tissue analysis after freeze clamping (cAMP, adenine nucleotide pool). Free resting levels of intracellular calcium will be estimated using F NMR and a shift reagent F (BAPTA)-AM. Extracellular space will be determined with the chelating agent K (CoEDTA). Total (bound and free) calcium will be calculated from atomic absorption analysis of Co and Ca. Interventions which alter the cardiomyopathy will include drugs which affect calcium entry, or interventions which might preserve the nucleotide pool. Reversibility of function and metabolism will be determine at various times after beginning alcohol. Interventions will be tried for both prevention and treatment. Overall, this study will help define a new model of alcoholic """"""""cardiomyopathy"""""""" and provide important insights into its pathophysiology. This study may have important clinical implications for alcoholic cardiomyopathy in patients.
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