TNF-alpha is present early in a model of large myocardial infarction and is sustained into the later stage within the myocardium. Expression of this cytokine is not only confined strictly to the infarct or peri-infarct zone but is expressed by cardiac myocytes within the myocardium contralateral to the infarct. Therefore TNF-alpha production forms a part of an important intrinsic myocardial stress response system to injury.

Background-We investigated the potential contributions of tumor necrosis factor-␣ (TNF-␣) on the incidence of acute myocardial rupture and subsequent chronic cardiac dysfunction after myocardial infarction (MI) in TNF knockout (TNF Ϫ/Ϫ ) mice compared with C57/BL wild-type (WT) mice. Methods and Results-Animals were randomized to left anterior descending ligation or sham operation and killed on days 3, 7, 14, and 28. We monitored cardiac rupture rate, cardiac function, inflammatory response, collagen degradation, and net collagen formation. We found the following: (1) within 1 week after MI, 53.3% (nϭ120) of WT mice died of cardiac rupture, in contrast to 2.5% (nϭ80) of TNF Ϫ/Ϫ mice; (2) inflammatory cell infiltration and cytokine expression were significantly higher in the infarct zone in WT than TNF Ϫ/Ϫ mice on day 3; (3) matrix metalloproteinase-9 and -2 activity in the infarcted myocardium was significantly higher in WT than in TNF Ϫ/Ϫ mice on day 3; (4) on day 28 after MI compared with sham, there was a significant decrease in LV developed pressure (74%) and ϮdP/dt max (68.3%/65.3%) in WT mice but a less significant decrease in ϮdP/dt max (25.8%/28.8%) in TNF Ϫ/Ϫ mice; (5) cardiac collagen volume fraction was lower in WT than in TNF Ϫ/Ϫ mice on days 3 and 7 but higher on day 28 compared with TNF Ϫ/Ϫ mice; and (6) a reduction in myocyte apoptosis in TNF Ϫ/Ϫ mice occurred on day 28 compared with WT mice. Conclusions-Elevated local TNF-␣ in the infarcted myocardium contributes to acute myocardial rupture and chronic left ventricle dysfunction by inducing exuberant local inflammatory response, matrix and collagen degradation, increased matrix metalloproteinase activity, and apoptosis.