New insights into the pathological role of TNF-α in early cardiac dysfunction and subsequent heart failure after infarction in rats

Abstract

A marked increase in plasma TNF-alpha has been described in patients with chronic heart failure (CHF). Nevertheless, little is known about the direct role of this cytokine early after myocardial infarction (MI) and its possible effects on the subsequent development of CHF. Wistar rats were subjected to permanent in vivo coronary artery ligation. At 5, 7, and 9 days after MI, cardiac function, passive compliance of the left ventricle (LV), and cardiac geometry were evaluated. The same model was used to perform pharmacological studies 7 days and 10 wk after MI in rats treated with monomeric recombinant human soluble TNF-alpha receptor type II (sTNF-RII, 40 microg/kg iv) or a placebo on day 3. Maximal alterations of cardiac function and geometry occurred 7 days after MI, which correlated chronologically with a peak of cardiac and serum TNF-alpha, as shown by immunohistochemistry and ELISA, respectively. sTNF-RII improved LV end-diastolic pressure under basal conditions and after volume overload 7 days and 10 wk after MI. Moreover, a significant leftward shift of the pressure-volume curve in the sTNF-RII-treated group 7 days after MI indicated a preservation of LV volume. Infarct expansion index was also significantly improved by sTNF-RII 7 days after MI (P < 0.01). Nevertheless, 10 wk after MI, geometric indexes and passive pressure-volume curves were not significantly improved by the treatment. In conclusion, TNF-alpha plays a major role in cardiac alterations 7 days after MI in rats and contributes to hemodynamic derangement, but not to cardiac remodeling, in subsequent CHF.

Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction

“…However, the roles of TNF-␣ in MI remain controversial. Blockade of TNF-␣ has been reported to be both beneficial (1,15,24,26,27) and deleterious (2,18,22). In the present study, we evaluated the pathophysiological roles of two distinct cell surface receptors (TNFR1 and TNFR2) in the process of infarct healing and cardiac remodeling after MI.…”

The immune system and cardiac repair

“…Inhibition studies have produced contradictory findings regarding the effects of TNF-α neutralization on the infarcted heart. Several studies demonstrated injurious effects of TNF-α signaling in mediating infarct expansion [153], and cardiac dysfunction [154]. On the other hand, other investigations indicated protective effects of TNF-α signaling in the infarcted myocardium.…”

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling

“…Irwin et al (10) have extended these data by showing that TNF-␣ mRNA and protein are persistently expressed by myocytes in the noninfarcted regions of the myocardium from 1 day to 5 wk after coronary artery ligation. Finally, we have demonstrated that the TNF-␣ protein is transiently overexpressed 7 days after infarction in rats and that the inhibition of this cytokine reduces cardiac alterations and improves the long-term prognosis of MI (2). Nevertheless, these observations were made on an extreme experimental model in which infarction was obtained by permanent ligation of the left coronary artery, inducing massive and transmural necrosis of the LV free wall.…”