CASPASE INHIBITION OF APOPTOSIS, INFANT CARDIAC SURGERY

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DESCRIPTION (Verbatim from Applicant's Abstract): A major limitation to successful outcome of the repair of congenital heart lesions is the development of ventricular dysfunction. While the etiology is undoubtedly multifactorial, evidence suggests that it in large part may be due to myocyte loss resulting from chronic cyanosis, prolonged exposure to abnormal hemodynamic loads, and one or more episodes of ischemia-reperfusion required for cardiac surgery. Death of myocytes can occur by either necrosis or apoptosis. In contrast to necrosis, apoptosis is the orderlv disassemblv of the cell by specific enzymatic pathways that are triggered by a wide variety of genetic, environmental and toxic stimuli. Recently, human and animal studies have shown that hypoxia, ischemia-reperfusion, abnormal mechanical loading, and inflammation can cause significant cardiomyocyte apoptosis. This occurs during myocardial ischemia, infarction, hypertrophy, and heart failure. The role of apoptosis in infants undergoing cardiac surgery is not known. Based upon this information and preliminary data from our laboratory, we believe that myocyte apoptosis is a significant problem in infants with normal and hypertrophied myocardium subjected to surgical ischemia-reperfusion. This loss of myocytes will be particularly injurious to the infant myocardium because of the loads imposed by future growth and residual hemodynamic abnormalities. Because the pathways triggering apoptosis in this setting are multiple, we have chosen to focus on the role of the caspase enzymes. Caspases are the focal point of propagation and execution of apoptosis, and are directly responsible for the proteolytic cleavage of specific proteins required for the process to occur. Experiments in Aim I will be the first to l)define which caspases are expressed, activated, and what key intracellular proteins are thereby cleaved in normal and hypertrophied myocardium exposed to surgical ischemia-repercusion, 2)quantify the amount of apoptosis that occurs in this setting, and 3)determine the effects of specific caspase inhibition on these events. Using a novel working heart transplant model with normal and hypertrophied infant hearts, Aim II will answer a question of critical importance, namely what is the effect of inhibition of caspases and apoptosis on long-term myocardial inflammation, fibrosis, and recovery of function? These experiments will be the first to study the beneficial versus harmful roles of apoptosis in myocardial ischemia-reperfusion injury. Overall, these studies will provide valuable new insights into therapeutic targets and strategies to preserve myocardial function in these patients. The results are also likely to be applicable to patients with ischemia, myocardial infarction, and heart failure.