Immunomodulating agents for the management of heart failure with myocarditis and cardiomyopathy--lessons from animal experiments.

We have developed murine models of viral myocarditis induced by the encephalomyocarditis (EMC) virus in which there is a high incidence of severe myocarditis, congestive heart failure and dilated cardiomyopathy. From these models, we have learned of their natural history and pathogenesis and assessed new diagnostic methods and therapeutic and preventive interventions. Our recent studies showed that increased circulating cytokines have been detected in patients with acute myocarditis and cardiomyopathy and suggest that cytokines may play some role in the pathogenesis of myocardial injury in these diseases. In our animal model of EMC virus myocarditis, plasma tumour necrosis factor-(TNF)-alpha was elevated in the acute stage and exogenously administered anti-TNF-alpha antibody improved survival and reduced the myocardial lesion, suggesting the importance of TNF-alpha in the pathogenesis. A recently developed positive inotropic agent, vesnarinone, was effective in the treatment of EMC virus myocarditis by its immunomodulating effects such as inhibition of production of TNF-alpha The plasma angiotensin II level was increased in EMC virus myocarditis, and a new angiotensin II type I antagonist, TCV-116, prevented development of myocarditis.