Free Radicals in Ischemic and Reperfusion Myocardial Injury: Is this the Time for Clinical Trials?

Abstract

An increasing number of studies in cell cultures, isolated perfused hearts, and intact animal preparations purport to show the significance of free radical production in the pathophysiology of myocardial injury and necrosis of ischemic and reoxygenated or reperfused tissue. Additionally an impressive array of therapeutic approaches has been developed to interfere with the generation of free radicals and to thereby salvage jeopardized myocardium. Based on these data clinical trials are now being conducted or planned. However, a critical examination of the experimental data raises questions that undermine total acceptance of the conclusions of the investigators and the enthusiastic extrapolations to the clinical arena. Issues such as endotoxin contamination of infused free radical scavenger enzymes, incorrect dosing, possibly improper selection of control conditions, species specificity, inadequate consideration of the dependence of infarct size on coronary collateral blood flow, and the possibly transient nature of any benefits of anti-free radical interventions cast doubt on some of the accumulated data and their general applicability to humans. These issues must be satisfactorily addressed before this experimental approach can be fully embraced by the clinical cardiologist. Additionally, uniformity in the experimental model and conditions might eliminate some of the confusion and make it easier to compare the results of different studies. Free radical mechanisms may be important in the heart, but more data are needed to rigorously document an unequivocal effect of therapeutic interventions in experimental models before clinical trials are appropriate.