TNF-α inhibition attenuates adverse myocardial remodeling in a rat model of volume overload

Jobe LJ, Melendez GC, Levick SP, Du Y, Brower GL, Janicki JS. TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. Am J Physiol Heart Circ Physiol 297: H1462-H1468, 2009. First published August 7, 2009; doi: 10.1152/ajpheart.00442.2009.-Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-alpha are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-alpha with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-alpha inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-alpha antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-alpha has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.