ABSTRACTTo explain the progression from infectious viral myocarditis to congestive cardiomyopathy an infection/immune hypothesis has been proposed stating that the primary viral process incites an excessive or disordered immunologic response against the myocardium. To test whether one form of immunosuppressive therapy might ameliorate this process, we used cyclosporine in a murine preparation of infectious myocarditis (encephalomyocarditis [EMC] virus), which has been shown to result in a congestive cardiomyopathy pathologically similar to that seen in man. Eight-week-old male DBA-2 mice were infected with EMC virus and randomized to a treatment or control group. Cyclosporine (25 mg/kg/day) was administered subcutaneously for 3 weeks, starting (1) at 1 week after infection during viral replication, and (2) at 3 weeks after infection, after the period of active viral replication. In mice treated during viral replication there was a significantly higher mortality rate compared with that of control mice (15/21 vs 9/29, p = .01). There was no evident reduction in myocardial pathology (inflammation, necrosis, or calcification) in the treated compared with the control groups. In mice treated after the period of viral replication, there was no improvement in mortality (8/22 vs 2/19, NS) compared with control. Treated mice showed no reduction in myocardial histopathologic lesions. Furthermore, treated mice had significantly greater heart weight/body weight ratios (1.3 ± 0.4% vs 1.0 ± 0.3%, p < .005), lung weight/body weight ratios (1. 1 ± 0.5% vs 0.8 ± 0.3%, p < .05), and liver weight/body weight ratios (6.0 ± 0.8% vs 5.4 ± 0.6%, p < .005) than control mice, suggesting more severe myocardial failure. Thus, the use of immunosuppressive therapy with cyclosporine in this murine preparation of acute viral myocarditis was associated with greater mortality when administered early in the illness, and greater myocardial failure when administered during the early recovery period, without evident reduction in pathologic indexes of myocardial injury to suggest possible longer term benefit. Clinical trials of cyclosporine therapy for inflammatory myocarditis secondary to an acute viral infection should be carried out with great caution and only in the setting of a carefully controlled clinical trial.