IN VIVO HEART PROTEIN METABOLISM IN DIABETES & ISCHEMIA

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The candidate is a clinically trained cardiologist interested in cardiac metabolism and its application to the study of cardiac disease. The goal of the projected research is to provide the candidate with the broad scientific training necessary to pursue this interest as an independent investigator and academic cardiologist. Physiologic measurement of protein turnover in vivo has not been accomplished previously in a non-destructive fashion. The specific aim of the proposed research involves the development of an isotope dilution technique to study in vivo cardiac amino acid utilization and protein metabolism. The technique will be validated and applied in a conscious dog model, in anticipation of its utilization in clinical investigation. Experimental methods to examine the physiologic regulation of protein metabolism in normal dogs will include the insulin clamp, substrate infusion, and insulin suppression with somatostatin. Alterations in metabolism in animals with diabetes and myocardial ischemia will be studied. Abnormalities in protein and amino acid metabolism may contribute to the abnormal cardiac reserve and cardiomyopathy observed in diabetic patients. Alterations in amino acid and protein metabolism in myocardial ischemia may be important to the rate and degree of recovery from ischemia. Further understanding of the pathophysiology of cardiac protein metabolism may impact directly on the treatment of patients wiht diabetes and those recovering from ischemic insult following reperfusion in acute myocardial infarction. Collaboration between the Divisions of Cardiology and Endocrinology and the Department of Molecular Biology and Biochemistry has established a strong interdisciplinary background at Yale in the area of cardiac and skeletal muscle metabolism. The methods to measure coronary blood flow, cardiac hemodynamics, and both global and regional cardiac performance are available in the Cardiology Division. Techniques to study the effects of insulin and metabolic substrates on protein turnover in the dog have been used in the Endocrine Division. Likewise, expertise in the measurement of high energy phosphate levels by NMR spectroscopy has been developed. This environment will provide the candidate with the solid background training to develop as an independent investigator in the area of cardiac metabolism.