Myocardial reperfusion injury: Role of oxygen radicals and potential therapy with antioxidants

Experimental studies have demonstrated that reperfusion is associated with a host of distinctive pathophysiologic derangements, the most important of which are reperfusion arrhythmias, transient mechanical dysfunction or "myocardial stunning," and cell death. Reperfusion arrhythmias and myocardial stunning occur in experimental animals after transient ischemia followed by reperfusion, and there is considerable evidence that these derangements also develop in humans, although the existence of malignant reperfusion arrhythmias in humans remains uncertain. Reperfusion arrhythmias and myocardial stunning can be considered manifestations of sublethal, reversible cellular injury. The pathogenesis of reperfusion arrhythmias and stunning has not been conclusively established; however, there is considerable evidence that generation of oxygen radicals and perturbations of calcium homeostasis play an important role. Antioxidants and calcium antagonists have been shown to mitigate these manifestations of reperfusion injury. In contrast, the likelihood of lethal reperfusion-induced injury remains highly controversial. Although many studies have reported reduction of infarct size with antioxidants, numerous others have failed to reproduce these results. Consequently, intense controversy persists regarding whether oxygen radicals contribute to extending cell death following reperfusion and whether reperfusion itself causes cell death. Neither the resolution of this controversy nor the availability of clinical therapies to reduce reperfusion-induced cell death is likely in the near future.