Reperfusion of the acutely ischemic and infarcted human myocardium by Streptokinase/thrombolysis, by PTCA, by acute coronary artery surgery or a combination of all these methods has become increasingly utilized. Therefore, intraoperative myocardial protection of the ischemic myocardium to reduce the magnitude of the myocardial injury after coronary occlusion and reperfusion continues to be of the highest priority. Based on our work beginning in 1981, and continuing through the RO1 grant period, we have established more sophisticated techniques to evaluate local and global myocardial function after acute coronary occlusion and have begun to evaluate agents to either increase delivery of oxygen to ischemic myocardium or to interfere with the pathophysiologic effects of ischemia and reperfusion. In this grant period we will continue to pursue the concept of preparation of the ischemic area prior to reperfusion as well as treatment of the pathophysiologic effects of acute myocardial ischemia concurrently. We will evaluate 1) free oxygen radicals in both the acute and chronic ischemia models as well as the ex vivo preserved heart to define more precisely the mechanisms of their action, 2) thromboxane synthetase inhibitors in both the acute and chronic model, 3) calcium channel blockers and 4) agents that increase oxygen delivery to the ischemic myocardium, oxygenated crystalloid cardioplegia, blood cardioplegia and fluocarbons. In addition we intend to explore the use of other protective agents, particularly the oxygenated cardioplegic compounds applied distal to the site of coronary artery occlusion in our closed chest model simulating PTCA treatment of coronary occlusion. These studies will impact positively on the pre- hospital, invasive and operative treatment of acute MI, the leading cause of death in America. By reducing the total amount of infarcted muscle and improving regional myocardial function by these experimental approaches, the early and late mortality after myocardial infarction should be improved.
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