Alleviation of Reperfusion-Mediated Cardiac Dysfunction

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DESCRIPTION (provided by applicant): One child in 150 births suffers from congenital heart disease, which remains a leading cause of infant mortality. As diagnoses and support systems improve, more children are undergoing cardiac surgery to palliate complex congenital defects earlier in life. The increased susceptibility of the immature myocardium to ischemia and the prolonged cardiopulmonary bypass (CPB) period required for repair of congenital defects often result in myocardial dysfunction after pediatric cardiac surgery. Myocardial protective strategies for infants and children are lacking and often are only extrapolations of adult therapies. Reperfusion of ischemic heart stimulates the activity of cysteine proteases called calpains and their endogenous inhibitor, calpastatin, in cardiomyocytes. Calpain activity is associated with interruption of calcium-regulated myocyte contraction, degradation of myocardial contractile proteins, and enhanced cell death. The long-term goal of this application is to define mechanisms contributing to myocardial dysfunction after ischemia and reperfusion in children. The immediate goal is to identify pathways in myocardium that can facilitate development of interventions to reduce postoperative reperfusion injury. The hypothesis is that calpain and calpastatin pathways are critical mediators of reperfusion injury in immature myocardium. The specific aims of this project are: 1) determine the degree to which augmentation of calpastatin expression can reduce myocardial dysfunction associated with ischemia and reperfusion in an immature animal model, 2) define the role of calpastatin in mediating cardiac apoptosis associated with reperfusion injury, and 3) establish mechanisms by which calpain and calpastatin regulate changes in contractile proteins after reperfusion of ischemic myocardium. Adenoviral-mediated gene transfer of calpastatin domains with two distinct functions for mediating calcium influx and inhibiting calpain activity examines the roles of calpain and calpastatin in a clinically relevant piglet model of reperfusion injury. Determining calpain and calpastatin regulation of the cell death cascade and degradation of myocardial contractile proteins, such as troponin I, identifies new therapeutic targets for intervention to reduce postoperative myocardial dysfunction in pediatric patients.