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

Background-Transgenic mice with cardiac-specific overexpression of tumor ne crosis factor (TNF)-alpha develop dilated cardiomyopathy. The present study was designed to evaluate therapeutic effects of adenovirus-mediated neutra lization of TNF-alpha on this model. Methods and Results-An adenovirus encoding the 55-kDa TNF receptor-Iga fusi on 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 a dhesion molecule-1 and downstream cytokines, including interleukin-1 beta a nd monocyte chemotactic protein-1. Downregulation of alpha-myosin heavy cha in was restored by the treatment, whereas upregulation of beta-myosin heavy chain was not reversed. In contrast, the downregulation of sarcoplasmic re ticulum Ca2+-ATPase and phospholamban was normalized by AdTNFRI. Echocardio graphic measurements showed that left ventricular end-systolic diameter was significantly larger in transgenic mice than in control mice, and this inc rease 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.