TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. Am J Physiol Heart Circ Physiol 2009 Oct;297(4):H1462-8
Date
08/12/2009Pubmed ID
19666842Pubmed Central ID
PMC2770768DOI
10.1152/ajpheart.00442.2009Scopus ID
2-s2.0-70349611560 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
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.
Author List
Jobe LJ, Meléndez GC, Levick SP, Du Y, Brower GL, Janicki JSMESH terms used to index this publication - Major topics in bold
AnimalsAorta, Abdominal
Arteriovenous Fistula
Cardiovascular Agents
Cell Size
Collagen
Compliance
Disease Models, Animal
Disease Progression
Etanercept
Heart Failure
Hypertrophy, Left Ventricular
Immunoglobulin G
Injections, Subcutaneous
Male
Myocardial Contraction
Myocytes, Cardiac
Rats
Rats, Sprague-Dawley
Receptors, Tumor Necrosis Factor
Time Factors
Tumor Necrosis Factor-alpha
Venae Cavae
Ventricular Function, Left
Ventricular Pressure
Ventricular Remodeling
