Mechanisms and Therapy of Myocardial Reperfusion Injury

Forman, Mervyn B. MD, PhD
Virmani, Renu MD
Puett, David W. MD

Department of Medicine, Division of Cardiology, Vanderbilt University Medical Center, Nashville, Tennessee, and the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC.

Address for correspondence: Mervyn B. Forman, MD, PhD, Division of Cardiology, Vanderbilt University Medical Center, CC-2218 Medical Center North, Nashville, TN 37232.

Supported in part by National Institutes of Health grants R29 HC-38294 and 1 RO1 HL-40892–01 and by Alpha Therapeutic Corporation, Los Angeles, California. M.B.F. is a recipient of a First Award from the National Institutes of Health.

Circulation 81(3):p IV-78, March 1990.

Recent advances in thrombolytic therapy and balloon angioplasty have resulted in reperfusion therapy as a logical maneuver in the treatment of evolving myocardial infarction. The introduction of electrolytes, oxygen, and cellular elements, especially neutrophils, however, into the previously ischemic bed may initiate cellular and biochemical changes that limit the amount of potentially salvageable myocardium (reperfusion injury). Experimental studies have demonstrated that microvascular damage may play an important role in the pathogenesis of this phenomenon. Reperfusion enhances the infiltration of activated neutrophils into the ischemic bed, and neutrophil plugging of capillary lumens in association with extensive disruption of endothelial cells results in a progressive decrease in blood flow (the “no-reflow” phenomenon). Activated neutrophils may potentiate the inflammatory response, produce cellular damage, and reduce capillary blood flow by producing chemoattractants, proteolytic enzymes and reactive oxygen species, and arachidonate products, respectively. Therapeutic strategies that modify the interaction between neutrophils and endothelium have shown promising results in experimental preparations for reperfusion. The administration of both perfluorochemical (Fluosol, Alpha Therapeutic Corp., Los Angeles, California) and adenosine after reperfusion has resulted in enhanced myocardial salvage after 90 minutes of ischemia in the canine model. Histological studies have shown reduced neutrophil infiltration and relative preservation of endothelial cells without neutrophil plugging with both agents. Both adenosine and perfluorochemical have been shown to reduce neutrophil adherence and cytotoxicity to endothelial cell cultures. These findings suggest that suppression of neutrophil activation, especially chemotaxis, might be an ideal step to reduce this component from the inflammatory response in the ischemic myocardium after reperfusion. Clinical trials seem warranted to determine the role of reperfusion injury in limiting myocardial salvage in patients undergoing reperfusion within the first few hours of a thrombotic event.