Therapeutic Strategies to Reduce TNF- Mediated Cardiac Contractile Depression Following Ischemia and Reperfusion

Recent evidence has implicated proinflammatory mediators such as TNF- alpha in the pathophysiology of ischemia-reperfusion (I/R) injury. Clinically, serum levels of TNF-alpha are increased after myocardial infarction and after cardiopulmonary bypass. Each of these represent clinically relevant instances of cardiac I/R injury. We and others have recently reported that TNF-alpha is produced by the heart following experimental I/R in animals and that TNF-alpha directly decreases animal and human myocardial contractility in a dose dependent fashion. Thus, strategies to reduce or neutralize myocardial TNF- alpha production should conceptually decrease myocardial contractile dysfunction following I/R. The purposes of this manuscript are: 1) to explore the clinical and experimental instances of I/R injury in which TNF-alpha is elevated, 2) to review the molecular mechanisms of TNF- alpha induced contractile dysfunction, 3) to examine both experimental and clinical strategies of reducing myocardial TNF-alpha production, and 4) to determine the influence of reducing post-I/R TNF-alpha on cardiac contractile function in both animals and man.