TIME-COURSE OF CORONARY ENDOTHELIAL HEALING AFTER INJURY DUE TO ISCHEMIA AND REPERFUSION

Background Although it has been demonstrated in shortterm preparations that ischemia with early reperfusion results in coronary vascular injury manifested by abnormal endothelium-dependent relaxation and increased permeability to plasma proteins, it has not been clear whether these abnormalities are permanent or reversible. Methods and Results In a canine model, regional coronary ischemia was accomplished by 1 hour of left anterior descending coronary artery ligation, and follow-up studies were performed after reperfusion for 1 hour, 48 hours, 2 weeks, or 9 weeks. Vasorelaxation was measured in vitro with preconstricted epicardial coronary artery rings subjected to increasing concentrations of the endothelium-dependent vasodilator ADP and the endothelium-independent vasodilator nitroprusside. At 1 and 48 hours of reperfusion, relaxation of rings from the ischemic reperfused artery to ADP was blunted, but relaxation to nitroprusside was normal. At 2 weeks there was a nonsignificant trend toward a blunted response to ADP in the ischemic/reperfused rings, and at 9 weeks a completely normal response to ADP was observed. Coronary microvascular permeability was assessed by measurement of protein leak index (PLI), by using a double-isotope technique with autologous radiolabeled transferrin and erythrocytes. At 1 and 48 hours of reperfusion there were substantial increases in PLI in the previously ischemic regions, indicative of increased extravascular transferrin. There was a small increase in PLI at 2 weeks but a completely normal measurement at 9 weeks. Electron microscopy of ischemic/reperfused vessels demonstrated endothelial cell swelling and other abnormalities in epicardial arteries and the microcirculation at 48 hours of reperfusion but normal endothelium at 2 weeks of reperfusion. Conclusions After 1 hour of regional coronary ischemia, coronary endothelial injury occurs early in reperfusion with abnormalities in epicardial coronary artery endothelium-dependent relaxation, coronary microvascular permeability, and both epicardial coronary artery and microvascular histology. This pattern of injury persists for at least 48 hours, but there is partial functional and complete histological recovery within 2 weeks and complete functional recovery within 9 weeks.