Ischemia, reperfusion, and the determinants of tissue injury

Much of the damage arising during ischemia and reperfusion can be attributed to the consequences of flow deprivation. However, while reperfusion is a prerequisite for the survival of tissue, it may have an injurious component, which, if counteracted, might enhance postischemic recovery. The complex and dynamic changes that occur during ischemia in the diseased human heart are difficult to model in experimental preparations. As a consequence, much remains to be learned about the identity and manipulability of cellular changes leading to irreversible injury. Although the subject of most studies, injury to the myocyte may not be the primary determinant of tissue injury and changes in the endothelium or vascular smooth muscle may play an important role. Once critical ischemia-induced cellular changes have been identified, interventions can be developed to delay their progression such that at the time of reperfusion more cells are potentially salvable. Suboptimal reperfusion may limit the recovery of the tissue through the induction of "reperfusion injury." Much controversy surrounds the importance and even the existence of this phenomenon. It is proposed that reperfusion injury may express itself in four distinct forms: a) reperfusion-induced arrhythmias, which are potentially lethal (but preventable or reversible) events occurring in otherwise viable tissue; b) myocardial stunning, which is expressed as prolonged (but eventually fully reversible) contractile and metabolic dysfunction; c) the induction of lethal injury in tissue that was potentially viable in the moments before reperfusion; d) accelerated necrosis in tissue that is already irreversibly injured (the "oxygen paradox"). All but the third of these categories has been shown to exist experimentally and clinically, and can be advantageously manipulated. Although it is likely that lethal reperfusion injury also exists, there is as yet no definitive proof. Clarification of this issue is of considerable importance to those undergoing angioplasty or thrombolytic procedures.