| Abstract |
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Previous studies have shown that chronic regional left ventricular dysfunction in patients with coronary artery disease does not always arise from irreversible tissue necrosis and, to some extent, can be reversed by restoration of blood flow. This condition, which is often referred to as ''myocardial hibernation'', has been proposed to result from the adaptation of the ischemic myocardium to a state of chronic hypoperfusion. Until now, elucidation of the exact mechanisms leading to hibernation 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 coronary revascularization, in whom we assessed how parameters of regional. myocardial perfusion, metabolism and ultrastructure correlated with the reversibility of their dysfunction. We initially studied anginal patients without a previous infarction who had a chronic occlusion of a major coronary artery, and measured regional myocardial blood flow and metabolism with positron emission tomography. In these patients, despite coronary occlusion, myocardial perfusion and oxygen consumption in the dysfunctional segments were found to be normal. Yet, collateral flow reserve was markedly depressed, suggesting that repetitive episodes of ischemia with a persistent stunning effect was the most likely cause of dysfunction. As a second step, in the same patients, as well as in additional patients with a previous myocardial infarction, transmural 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 dysfunction, including less tissue fibrosis and more cardiomyocytes showing cellular swelling, loss of myofibrillar content and accumulation of glycogen. Also, samples from dysfunctional myocardium exhibited aspects of cellular dedifferentiation including fetal distribution of intracellular titin, absence of cardiotin and re-expression of the alpha-smooth muscle cell actin. In a third study, we examined the timecourse of functional recovery of the dysfunctional segments after revascularization. The recovery of function was slowly progressive overtime, with as much as 30% of the total improvement taking place between the 2nd and the 6th month after revascularization. The rate of functional recovery was inversely related to the severity of ultrastructural abnormalities. Taken together, these clinical studies on the flow? metabolic and ultrastructural correlates of hibernating myocardium have provided new 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 reminiscent of cell dedifferentiation. Further work should focus on designing appropriate animal models and on elucidating the molecular and genetic bases of this phenomenon. |
