CHRONIC LEFT-VENTRICULAR ISCHEMIC DYSFUNC TION IN CORONARY PATIENTS -INSIGHTS INTO PATHOPHYSIOLOGICAL MECHANISMS

Previous studies have shown that chronic regional left ventricular dys function in patients with coronary artery disease does not always aris e from irreversible tissue necrosis and, to some extent, can be revers ed by restoration of blood flow. This condition, which is often referr ed to as ''myocardial hibernation'', has been proposed to result from the adaptation of the ischemic myocardium to a state of chronic hypope rfusion. Until now, elucidation of the exact mechanisms leading to hib ernation has remained difficult, owing mainly to the lack of relevant animal models. Therefore, we performed the present studies in patients with chronic left ventricular ischemic dysfunction undergoing coronar y revascularization, in whom we assessed how parameters of regional. m yocardial perfusion, metabolism and ultrastructure correlated with the reversibility of their dysfunction. We initially studied anginal pati ents without a previous infarction who had a chronic occlusion of a ma jor coronary artery, and measured regional myocardial blood flow and m etabolism with positron emission tomography. In these patients, despit e coronary occlusion, myocardial perfusion and oxygen consumption in t he dysfunctional segments were found to be normal. Yet, collateral flo w reserve was markedly depressed, suggesting that repetitive episodes of ischemia with a persistent stunning effect was the most likely caus e of dysfunction. As a second step, in the same patients, as well as i n additional patients with a previous myocardial infarction, transmura l myocardial biopsies were obtained from the dysfunctional area at the time of bypass surgery. Analysis of these tissue samples demonstrated distinct morphological alterations in segments with improved function after revascularization, as compared to segments with persistent dysf unction, including less tissue fibrosis and more cardiomyocytes showin g cellular swelling, loss of myofibrillar content and accumulation of glycogen. Also, samples from dysfunctional myocardium exhibited aspect s of cellular dedifferentiation including fetal distribution of intrac ellular titin, absence of cardiotin and re-expression of the alpha-smo oth muscle cell actin. In a third study, we examined the timecourse of functional recovery of the dysfunctional segments after revasculariza tion. The recovery of function was slowly progressive overtime, with a s much as 30% of the total improvement taking place between the 2nd an d the 6th month after revascularization. The rate of functional recove ry was inversely related to the severity of ultrastructural abnormalit ies. Taken together, these clinical studies on the flow? metabolic and ultrastructural correlates of hibernating myocardium have provided ne w insights into the pathophysiology of reversible ischemic dysfunction . Repetitive ischemia and stunning appear to be the most likely cause of dysfunction, which is associated with structural abnormalities remi niscent of cell dedifferentiation. Further work should focus on design ing appropriate animal models and on elucidating the molecular and gen etic bases of this phenomenon.