Soluble tumor necrosis factor receptor abrogates myocardial inflammation but not hypertrophy in cytokine-induced cardiomyopathy

Background - Transgenic mice with cardiac-specific overexpression of tumor necrosis factor (TNF)-α develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutralization of TNF-α on this model. Methods and Results - An adenovirus encoding the 55-kDa TNF receptor-IgG fusion protein (AdTNFRI) was injected intravenously into 6-week-old transgenic mice, which resulted in high levels of TNFRI in both plasma and myocardium. AdTNFRI did not reverse cardiomegaly but abrogated myocardial inflammation. Furthermore, AdTNFRI blocked the myocardial expression of intercellular adhesion molecule-1 and downstream cytokines, including interleukin-1β and monocyte chemotactic protein-1. Downregulation of α-myosin heavy chain was restored by the treatment, whereas upregulation of β-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic reticulum Ca²⁺-ATPase and phospholamban was normalized by AdTNFRI. Echocardiographic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this increase was reversed by the AdTNFRI treatment. However, left ventricular wall thickening was not reversed. Conclusions - These results suggest that anti-TNF therapy may hold promise in the treatment of end-stage heart failure.