The myocardial injury that is manifest when the arrested heart is reperfused may be due to pre-arrest ischemia or ischemia imposed by aortic cross-clamping or the reperfusion process itself i.e. the reperfusion injury (RI). We, and others, have shown that despite meticulous adherence to presently known principles of hypothermic cardioplegic arrest, RI continues to occur and contributes to the operative mortality that occurs subsequent to cardiac operations that have been performed in a technically acceptable manner. Recovery from ischemic arrest involves: (1) the resumption of normal oxidative metabolism with the restoration of myocardial energy reserves and (2) the reversal of ischemic induced change such as cell swelling, ion redistribution, membrane dysfunction and destabilized metabolic pathways. We propose to focus on specific areas that have a high probability of success in ameliorating the RI. Specifically, we plan to focus on alternative biologic markers that are manifest as RI such as: (1) Deranged myocardial energetics as evidenced by myocardial oxygen consumption at peak work loads. Using sonomicrometry techniques, mechanical energy expenditure will be equated to oxygen utilization in order to measure myocardial energy efficiency and to develop exact equations to define this change; (2) Accumulation of intracellular calcium and sodium ion that is an effect of membrane and ion pump derangement; (3) Changes in membrane phospholipid composition and RI-induced changes in phospholipase activity as an activator of calcium release and intracellular calcium accumulation as well as studying the ameliorative effects of calmodulin antagonists. (4) Variations in coronary vascular resistance as related to our earlier demonstration of platelet obstruction of the coronary microciculation. Such changes in vascular resistance are subsequent to the effects of vasoactive end-products of platelet activation as shown in a recently developed perfused, quiescent, heart model; and (5) Investigate the RI in the immature heart compared to the adult heart by utilizing the biologic markers listed above as well as intermediary metabolite levels in order to develop new myocardial protection strategies specific for infant cardiac surgery. As a consequence of these studies, we hope to contribute to the resolution of the chaos of conflicting reports in the field of myocardial protection by developing precise biologic markers and agreed upon end-point criteria to measure the effects of the reperfusion injury.
Showing the most recent 10 out of 90 publications
