Recently, the intriguing possibility has been raised that heart failure may be mediated by the biological effects of cytokines. Indeed, we found elevation of plasma concentrations of various cytokines in patients with myocardial disease. We also detected positive tumor necrosis factor (TNF-alpha) immunoreactivity in right atrial tissues obtained during surgery from patients with severe heart failure. Therefore, we postulated that some aspects of heart failure may be related to non-lethal down-modulation of cardiac function by immune cells and their cytokines. Testing this hypothesis in an experimental model of murine myocarditis, we found that injection of recombinant human TNF-alpha increased mortality of the animals infected with myocarditis virus. The anti-TNF-alpha monoclonal antibody improved survival and attenuated the myocardial lesions. Whereas, administration of recombinant human IL-2 in the acute viremic stage increased survival rate, and resulted in less intense pathological changes in the myocardium while in the subacute aviremic stage, the same amount of IL-2 reduced survival rate and exacerbated severity of the disease. Therefore, cytokine release may initiate a beneficial inflammatory and immune response in the acute phase of the disease process, but the continued induction of cytokines and the enhanced natural killer (NK) cell activity in the later stage are no longer protective. Vesnarinone, a recently synthesized inotropic agent which has proved to benefit patients with congestive heart failure by improving prognosis, also increased the survival of individual subjects in the above-mentioned murine model of heart failure. Cytotoxicity of NK cells obtained from the virus infected animals was substantially reduced when treated with vesnarinone. Vesnarinone also inhibited production of TNF-alpha and other cytokines from stimulated human lymphocytes and cultured murine splenocytes. We conclude, therefore, that inhibition of NK cell activity and suppression of cytokine production appear to be important immunological defense mechanisms which could contribute to the observed salutary effects of vesnarinone in the treatment of chronic heart failure. More broadly, immunomodulation could pave the way for a new frontier in the management of heart failure.