Cardiac contractile dysfunction has been richly described phenomenologically. Myocardium subjected to low-flow ischemia exhibits a reversible decrease in the force of contraction known as """"""""hibernation"""""""". In contrast, """"""""stunning"""""""" prevails during reperfusion after brief periods of ischemia: force development remains impaired for days despite the maintenance of histologic integrity. """"""""Cardiomyopathy"""""""" refers to a hereditary or required disease of heart muscle characterized by depressed contractile strength. The overall goal of the present proposal is to formulate a new, investigation of the various steps in excitation- contraction (E-C) coupling. The E-C coupling pathway in perfused ferret and hamster hearts will be broken down into its individual components: action potentials; Ca2+ transients; myofilament Ca2+ sensitivity; and maximal Ca2+-activated pressure. Each component will be investigated in well-defined perfused heart models of contractile dysfunction, beginning with hypoxia. We will test the hypothesis that pump failure in mild to moderate hypoxia is due primarily to altered myofilament responsiveness to Ca2+. The findings will be compared with those during the early contractile failure of severe (total) ischemia. We will address the following question: is the prompt contractile failure of ischemia attributable to a loss of excitability, to a decrease in Ca2+ transients, or to altered myofilament Ca2+ responsiveness? For """"""""hibernating"""""""" myocardium, we will investigate the mechanisms of the contractile changes that accompany graded decreases in coronary pressure. Phosphorus metabolites and la tate efflux will be measured for metabolic evidence of ischemia. In """"""""stunned"""""""" myocardium, a decrease in force in reperfused myocardium. We will determine whether a decrease in Ca2+ transients also contributes to the contractile dysfunction, or if myofilament Ca2+ sensitivity is altered. Finally, Ca2+ transients and maximal Ca2+-activated pressure will be measured in failing hearts from cardiomyopathic Syrian hamsters to characterize their abnormal E-C coupling. This line of investigation promises to provide major new insights into the basic mechanisms of ischemic, post-ischemic, and cardiomyopathic contractile dysfunction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Pulmonary Research A Study Section (CVA)
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Johns Hopkins University
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