Abstract 313: Interleukin-6 Mediates Concentric Hypertrophy, Diastolic Dysfunction and Myocardial Fibrosis in Rats

Abstract

Induction of inflammatory cytokines has been implicated in the progression of myocardial remodeling and heart failure (HF). Increased levels of circulating TNF-α and interleukin-6 (IL-6) in patients with HF, suggest that these cytokines may be involved in the pathogenesis of heart disease. In previous studies we have shown that TNF-α is an important contributor to the adverse myocardial remodeling. TNF-α is known to mediate collagen degradation as well as in-series sarcomeric addition contributing to ventricular dilatation. However, the effects of IL-6 on cardiac remodeling in vivo have not been investigated. Accordingly, in this study we explore the hypothesis that up-regulation of IL-6 mediates adverse myocardial remodeling. To this end, a group of adult male Sprague Dawley rats was infused with IL-6 (2.5 μg/kg/hr, IP) for 7 days via osmotic minipump and compared to aged-matched shams. LV pressure, size, and function were measured using a blood-perfused isolated heart preparation. At the end of the experiment, hearts were weighed and analyzed for collagen volume fraction (CVF) and isolated cardiomyocyte size. The EDP-EDV (End Diastolic Pressure and Volume) relationship provided that IL-6 infusion produced LV stiffness and a clear tendency for a shift of the EDP-EDV curve to the left due to ventricular hypertrophy and diastolic dysfunction. LV weight differences demonstrate concentric hypertrophy (749 mg versus 660 mg in control hearts; p< 0.05) and a marked increase in interstitial collagen in the IL-6 infused hearts relative to that in control hearts (CVF of 6.2% vs. 1.7%, respectively; p< 0.001). The cardiomyocyte hypertrophy at the cellular level also reflected a concentric phenotype, with cells being significantly longer and thicker (18% and 32%, respectively; p< 0.01). These novel observations demonstrate a direct effect of IL-6 on cardiac remodeling in vivo, which in contrast to TNF-α, induces a dramatic myocardial fibrosis together with concentric cardiac hypertrophy. This suggests that IL-6 may contribute to the development of diastolic dysfunction, and as such could drive the transition to heart failure.