Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-α Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats

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Abstract
Background—Although patients with heart failure express elevated circulating levels of tumor necrosis factor-α (TNF-α) in their peripheral circulation, the structural and functional effects of circulating levels of pathophysiologically relevant concentrations of TNF-α on the heart are not known. Methods and Results—Osmotic infusion pumps containing either diluent or TNF-α were implanted into the peritoneal cavity of rats. The rate of TNF-α infusion was titrated to obtain systemic levels of biologically active TNF-α comparable to those reported in patients with heart failure (≈80 to 100 U/mL), and the animals were examined serially for 15 days. Two-dimensional echocardiography was used to assess changes in left ventricular (LV) structure (remodeling) and LV function. Video edge detection was used to assess isolated cell mechanics, and standard histological techniques were used to assess changes in the volume composition of LV cardiac myocytes and the extracellular matrix. The reversibility of cytokine-induced effects was determined either by removal of the osmotic infusion pumps on day 15 or by treatment of the animals with a soluble TNF-α antagonist (TNFR:Fc). The results of this study show that a continuous infusion of TNF-α led to a time-dependent depression in LV function, cardiac myocyte shortening, and LV dilation that were at least partially reversible by removal of the osmotic infusion pumps or treatment of the animals with TNFR:Fc. Conclusions—These studies suggest that pathophysiologically relevant concentrations of TNF-α are sufficient to mimic certain aspects of the phenotype observed in experimental and clinical models of heart failure.