Role of oxygen radicals in myocardial reperfusion injury: Experimental and clinical evidence

Timely reperfusion with intravenous thrombolytic agents has been shown to reduce mortality in patients with acute myocardial infarction. However, the magnitude of improvement in left ventricular function has always been less than expected. Reperfusion in fact causes a specific form of tissue injury, termed reperfusion injury, which would substract from the benefit obtained by terminating ischemia. Oxygen free radical generation has been proposed to be a major mechanism in the pathogenesis of reperfusion injury. Using an isolated perfused rabbit heart model we have demonstrated that administration of oxygen free radical scavengers, such as recombinant human superoxide dismutase (h-SOD) and iron chelators, such as deferoxamine, beginning at the time of reperfusion, reduce the severity of reperfusion injury, as judged by recovery of ventricular function and high energy phosphate metabolism, assessed quantitatively using 31-phosphorus nuclear magnetic resonance spectroscopy. Using electron paramagnetic resonance spectroscopy we have documented a burst of oxygen free radical generation during the early minutes of reperfusion and that this burst can be eliminated by superoxide radical scavengers, such as h-SOD, hydroxyl radical scavengers, such as mannitol, as well as agents that inhibit generation of oxygen free radicals, such as the iron chelator, deferoxamine. Taken together these results strongly support the role of oxygen free radicals in the pathogenesis of reperfusion injury. We have recently completed the first randomized placebo controlled clinical trial of a free radical scavenger (h-SOD) in patients with acute myocardial infarction, undergoing urgent angioplasty of their occluded coronary artery with preservation of left ventricular function as the major study endpoint. While the results of this initial trial were largely negative, issues related to the dose and duration of therapy have been raised. Furthermore, new methods of assessment of regional left ventricular function were developed with improved sensitivity.