Excessive tumor necrosis factor activation post-infarction contributes to myocardial rupture and heart failure

Cytokines such as tumor necrosis factor alpha (TNF-a) are activated locally during both acute and late phases following myocardial infarction (MI), and contribute to ventricular remodeling. Cardiac rupture and heart failure are serious adverse complications of MI acutely and chronically, and we investigated the potential contributions of TNF-a to the rupture and subsequent heart failure post MI. We evaluated the role of TNF-a in tissue repair and remodeling after MI in an infarct model in TNF homozygous knockout (TNF−/−) mice and age-matched C57/BL wild-type (WT) controls. The animals of either genotype were randomized to LAD ligation or sham operation, and we compared rupture rate, ventricular morphology, inflammatory response, local collagen formation and the left ventricular function. Of the WT mice, 53.3% died acutely of cardiac rupture, vs. 2.5% of the KO mice died of the same cause within 1 week of MI. Pathology revealed that at early stage post-MI, there were extensive inflammatory cell infiltrate, significantly increased MMP 2 and 9 activations, less collagen formation and prominent peri-infarct as well as normal remote zone apoptosis in the WT mice, associated with very high levels of local TNF production. Knockout TNF−/− littermates in contrast had more attenuated inflammatory infiltrate, significantly lower MMP activations and much more limited apoptosis. The ventricular morphology shows ventricular dilatation from the infarct as well as contralateral zone in WT mice and no dilatation showing in TNF−/− at 28 day follow-up. Accompanying the adverse remodeling, Langendorff preparation also revealed poor ventricular function in that the WT mice had a decrease of 68.3/65.3% in +/− dp/dt compared to sham operated hearts; while, TNF−/− mice showed only 23/20% decrease in +/− dp/dt. We conclude that elevated local production of TNF post infarction in the susceptible host myocardium predisposes the host to infarct rupture and heart failure. The ability to decrease excessive TNF production leads to significant reductions in mortality, decreased incidence of myocardial rupture, and improve late stage heart function.