Coronary occlusion and reperfusion produces a predictable pattern of morphologic injury and contractile dysfunction. Recent studies suggest that the ultimate extent of myocardial damage resulting from reversible coronary occlusion is the sum of ischemic injury and reperfusion injury. Therapy directed specifically at the reperfusion injury component should reduce infarct size and improve contractile function. However, the hydrodynamic (coronary pressure-flow) conditions of reflow is not recognized as a determinant of postischemic injury. The studies in this proposal will test the overall hypothesis that appropriate control exercised over the hydrodynamic conditions during the early moments of reperfusion will reduce the extent of morphologic injury and contractile dysfunction in the area at risk compared to the abruptly reperfused counterpart. Furthermore, we will test the hypotheses that the mechanisms underlying this myocardial salvage by controlled reperfusion hydrodynamics are 1) preservation of endothelial integrity and elaboration of endothelium-derived relaxing factors (EDRF, nitric oxide), or 2) prolonged washout of endogenous adenosine or hydrogen ions from the reperfused area at risk. In acute models of left anterior descending (LAD) coronary artery occlusion, LAD blood flow will be restored either ABRUPTLY (simulating angioplasty and immediate thrombosis) or gradually in a CONTROLLED manner over the early moments of reperfusion. Coronary blood flow will be adjusted using an extracorporeal perfusion system. Parameters of myocardial salvage include segmental contractile function (sonomicrometry), regional myocardial blood flow (radioactive microspheres), infarct size, ultrastructure, and endothelial-dependent and independent responses related to EDRF.
SPECIFIC AIM 1 will determine the appropriate management of controlled (gradual) reperfusion and characterize its efficacy and longevity over clinically relevant ranges of ischemia.
SPECIFIC AIM 2 will determine the potential mechanisms of myocardial salvage, including 1) preservation of endothelial integrity and the role of endothelial-derived factors, 2) prolonged washout of adenosine from the reperfused segment allowing greater exertion of its myoprotective effects, and 3) gradual rather than abrupt washout of acidosis. The process of controlled reperfusion is clinically feasible and the myocardial salvage attained clinically relevant. The data from these experiments will provide a fundamental understanding of reperfusion injury, and will develop a rationale for clinical avoidance of reperfusion injury, resulting in greater myocardial salvage, and decreased patient morbidity and mortality.
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