Dual effects of tumor necrosis factor alpha on myocardial injury following prolonged hypoperfusion of the heart

Objective: To examine the dose response of TNF alpha in an ex vivo rat model of myocardial ischemia reperfusion. Methods and Results: Seventy-two rat hearts were mounted on Langendorff apparatus and perfused with oxygenated Krebs-Henseleit solutions. Ischemia was induced by reducing the perfusate flow rate. During reperfusion, incremental doses of recombinant TNF alpha were infused as a part of perfusate. TNF alpha was blocked with monoclonal TNF alpha antibody. Myocardial function was measured by dP/dT and relaxation time (IVRT). Cellular injury was assessed by released myoglobin and tissue concentration of malondialdehyde activity of the heart homogenates. Baseline +dP/dT was 1645 +/- 125 mmHg/sec, -dP/dT was 945 +/- 73 mmHg/sec and IVRT was 65 +/- 5 msec. At the conclusion of reperfusion period, lower doses of TNF alpha increased +dP/dT and lowered IVRT. In contrast, the higher doses of TNF alpha decreased +dP/dT and prolonged IVRT. Pretreating the hearts with monoclonal TNF alpha antibody completely abolished the effects of TNF alpha on myocardial contractility and relaxation comparable to ischemia controls. Conclusion: Low dose TNF alpha improved myocardial function and decreased resultant cellular injury while high dose TNF alpha decreased myocardial function and increased myocardial injury following ischemia and reperfusion.