The current understanding of myocardial ischemia emphasizes that the degree of damage is related to the duration and severity of coronary occlusion. Consequently, therapeutic management has been directed toward limiting ischemic damage by reducing the duration and severity of oxygen supply and demand disparity. We hypothesize that the total damage following coronary occlusion is caused by alterations set up during ischemia but then further extended during reperfusion. This hypothesis suggests that reperfusion injury can be avoided by modifying the reperfusion phase. Surgical revascularization of acute evolving myocardial infarction using cardioplegia allows control of the composition of the initial reperfusate as well as the conditions of its delivery. When delivered into the ischemic segment, cardioplegia is the first reperfusate to which that segment is exposed. Control of reperfusion can avoid this reperfusion injury to a large extent. Such control of reperfusion is not possible with nonsurgical revascularization using thrombolysis and/or angioplasty. Although well tested in global models, the role of surgical revascularization of acute evolving myocardial infarction remains unclear. The studies outlined in the following application will demonstrate that the fate of the ischemic myocardium is related not only to the ischemic phase, but is in large part determined by events occurring during reperfusion. In a canine model of 1, 3 and 6 hour left anterior descending coronary artery occlusions, we will a) determine the functional, metabolic , and morphological characteristics of ischemic and reperfusion injury, b) determine the pathophysiological mechanisms underlying """"""""stunned"""""""" myocardium and describe stunning as as manifestation of reperfusion injury, c) provide insight on the failure of nonsurgical revascularization to restore postischemic function, d) show that reperfusion injury can be avoided by modifying the conditions and composition of reperfusion with surgical revascularization using cardioplegia, resulting in immediate restoration of postischemic function and metabolism, e) determine the optimal cardioplegia for the setting of evolving infarction, f) determine the long-tem benefits of surgical versus nonsurgical revascularization in chronic studies, g) and examine the benefits of retrograde coronary sinus cardioplegia over antegrade delivery.
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