Reperfusion injury in acute myocardial infarction

Abstract

Since the early 1970s, infarct size has been identified as a major predictor of prognosis after myocardial infarction: infarct size parallels with arrhythmia, heart failure, and mortality [1]. Apart from this finding, infarct size is not only determined by the area at risk; that is, the myocardium perfused by the infarct-related artery. In a seminal work, Reimer and coworkers could show that irreversible myocardial injury, as determined by cardiac myocyte necrosis, progresses as a wavefront from the subendocardium towards the subepicardium [2]. This observation led to the concept that early reperfusion therapy can salvage myocardium at risk from injury. Early reperfusion therapy within the first 3 to 6 hours after the onset of ischemia was, in consequence, rapidly introduced into clinical routine and is now standard treatment of patients with acute myocardial infarction. In parallel, it was recognized that reperfusion of temporarily nonperfused myocardium itself has effects on cellular integrity [2]. Reperfusion saves viable myocytes. However, it accelerates the disruption of irreversibly injured myocytes, and thereby permits the process of inflammation, phagocytosis, and infarct repair to begin quickly. It leads to interstitial hemorrhage from vessels that are injured by ischemia but are reperfusable at the time of reflow; that is, in the border zone of the infarction. The hemorrhage itself increases the interstitial pressure, which in consequence worsens the tissue perfusion again. Moreover, reperfusion induces severe morphologic alterations of the myocardium such as cardiac myocytes swelling, mitochondrial damage, hypercontracture, and loss of myofibrillar organization [3]. The observation that reperfusion itself influences infarct size has led to the concept of lethal reperfusion injury [2,3]. It became quickly clear that reperfusion injury is not only determined by mechanical factors such as hemorrhage or interstitial pressure. Reperfusion leads to the activation of many signaling pathways that contribute independently to both apoptotic and necrotic tissue injury and thus decrease the amount of viable myocardium (reviewed in [4,5]). The concept of additional myocardial damage is induced by lethal reperfusion injury has been supported by the observation that interventions started before reperfusion can reduce infarct size, as discussed below [4,5]. Studies in animals suggest that lethal reperfusion injury accounts to up to 50% of the final size of a myocardial infarction. Clinically, reperfusion injury may be seen in four different types of cardiac dysfunction: myocardial stunning - that is persistent mechanical dysfunction despite restored blood flow which is usually reversible within weeks; the no-reflow phenomenon after opening of an infarcted coronary artery; reperfusion arrhythmia; and lethal, irreversible injury of the myocardium. In the recent years, rapid revascularization was instituted to prevent reperfusion injury. From a clinical view, currently there seems to be no potential to further reduce infarct size by faster restoration of blood flow. Therefore other than mechanical strategies to reduce reperfusion injury and in consequence infarct size are highly welcome to improve the outcome of the patients. To further understand potential strategies, the molecular mechanisms contributing to reperfusion injury are of importance.