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Cytokines are being increasingly recognised as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. In our murine model of congestive heart failure resulting from encephalomyocarditis virus infection, survival and myocardial damage were markedly improved by treatment with vesnarinone. Vesnarinone inhibited the increase in natural killer cell activity and production of tumour necrosis factor-alpha (TNFalpha) in this animal model. Vesnarinone also inhibited the production of various cytokines by peripheral blood and by endothelial cells. These findings provide evidence that vesnarinone plays an important role in the regulation of cytokine production, and suggest that the reduction of cytokine release may contribute to the beneficial effects of the drug for the treatment of heart failure. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.