A "Hibernating-Like" Viable State Induced by Lentiviral Vector-Mediated Pigment Epithelium-Derived Factor Overexpression in Rat Acute Ischemic Myocardium

The failure to maintain the viability of ischemic myocardium is one of the mechanisms that causes ischemic heart dysfunction after revascularization. Hibernating myocardium is considered to be able to maintain long-term viability during chronic hypoperfusion. Pigment epithelium-derived factor (PEDF) decreases the contractility of hypoxic cardiomyocytes and protects cardiomyocytes against ischemic injury, which is strikingly similar to the pathophysiologic characteristics of hibernating myocardium. It was therefore postulated that PEDF may induce acute ischemic myocardium into a "hibernating-like" state to maintain its viability. Adult Sprague-Dawley rat models of acute myocardial infarction were surgically established. Lentiviral vectors carrying the PEDF gene (PEDF-LVs) were delivered into myocardium with infarction to overexpress PEDF locally. It was found that PEDF local overexpression significantly reduced myocardial infarct size and cardiomyocytes necrosis but did not improve cardiac function at rest. The contractile reserve assessed by low-dose dobutamine stress echocardiography and "perfusion-metabolism mismatch" assessed by positron emission tomography, which are the characteristics of viable myocardium in hibernation, were observed in the PEDF overexpressed ischemic heart. Ultrastructural changes observed by electron microscopy and glycogen deposition explored by Periodic acid-Schiff staining were similar to the histological characteristics of hibernating myocardium. Moreover, PEDF overexpression protected the cardiomyocytes against anoxic injury and retained their functional recovery potential after reoxygenation in vitro. PEDF local overexpression may induce acute ischemic myocardium into a "hibernating-like" state and maintain its viability. This novel effect of PEDF presents an important clinical approach to enhance functional recovery after revascularization therapy in acute myocardial infarction.