PLATELET-ACTIVATING-FACTOR ANTAGONISM - A NEW CONCEPT IN THE MANAGEMENT OF REGIONAL MYOCARDIAL ISCHEMIA-REPERFUSION INJURY

Reperfusion therapies for treatment of myocardial infarction successfu lly reduce patient mortality; however, regional myocardial ischemia-re perfusion (RMIR) causes its own expression of cardiovascular dysfuncti on, including myocardial depression, hemodynamic instability, and dysr hythmias, which have increased patient mortality within the first 24 h after starting reperfusion therapy. Current evidence suggests that th e release of oxygen-derived reactive substances and subsequent inflamm atory mediators during ischemia-reperfusion contribute toward this inj ury. Platelet-activating factor (PAF), a mediator released during RMIR , has been emphasized by many investigators as playing a central role in causing RMIR injury. Similar cardiovascular dysfunctions that occur during RMIR, including myocardial depression, hemodynamic instability , and dysrhythmias, occur after administration of PAF and are ameliora ted with PAF antagonists. Further, PAF antagonists have been shown to be cardioprotective and improve survival when administered before onse t of reperfusion. A variety of phospholipid analogues, naturally deriv ed compounds, and synthetic compounds have been developed that form th e different classes of PAF antagonists, each with unique antagonizing properties. Several of these compounds have successfully passed safety and efficacy testing in humans; however, to date, no clinical trials have investigated the protective effects of PAF antagonists against RM IR injury. A current theory in the pathogenesis of RMIR injury conside rs the ischemic and necrotic portion of the myocardium and regional dy sfunction due to tissue necrosis to be solely responsible for global c ardiac dysfunction leading to hemodynamic instability and death. Evide nce now suggests, however, that the global dysfunction is also due to the effect of inflammatory mediators such as PAF, thromboxanes, leukot rienes, and endothelins that are released during RMIR and are distribu ted throughout the heart on reperfusion. Antagonizing a central inflam matory mediator such as PAF, as adjunct treatment with currently used reperfusion therapies, improves cardiovascular function and survival i n animals and should be introduced into clinical trials to investigate if similar protective effects can be provided in humans.