The effects of cyclophosphamide on experimental viral myocarditis

Jeon, Eun Seok; Kwak, Byeng Su; Park, Ki Nam; Choi, Yong Seok; Kang, Seung Sik; Kim, Baek Su; Park, Chong Hun; Seo, Jung Don; Lee, Young Woo

Abstract

BACKGROUND
Viral myocarditis is considered as a cause of dilated cardiomyopathy. At present, two pathogenic mechanisms may be involved in the pathogenesis of viral myocarditis and subsequent cardiomyopathy. First, the virus infection of myocyte may directly lead to either cell death or persistent metabolic dysfunction. Second, virus-induced immune or autoimmune mechanism may play a role. METHODS: To test the therapeutic efficacy of immunosuppression with cyclophophamide(CYP) on coxsackievirus B3(CB3) myocarditis, 10-14 week-old Balb/c mice were inoculated with 4000 plaque-forming units of CB3. In experiment 1, CYP (100mg/kg/day subcutaneous injection, s.c) was administrated daily on days 1-7(group 2, n=16). In experiment 2, CYP 30mg/kg/day s.c(group 3, n=32) or CYP 100mg/kg/day s.c(group 4, n=32) were administrated on days 8-14. The animals of infected controls(group 1, n=26) and group 2, 3, 4 were dissected at days 4, 7, 15, 22 and spleen, heart, thymus and body weights were measured. RESULTS: In experiment 1. survival rate in group 2 on day 7, 15 were low compared with group 1(85%, 0% vs 100%, p<0.05). and myocardial virus titers in group 2 on day 4 was 50 times, and on day 7, 1000 times higher compared with group 1, Histologically, on day 7, focal cellular infiltrations were prominent findings in group 1, but diffuse myocardial necrosis without cellular infiltration were observed in group 2. In experiment 2, survival rate, cardiac histopathology myocardial virus titer and serum neutralizing antibody titers did not differ among groups 1, 3 and 4. In experiment 1 and 2, the spleen-to-body-weight and thymus-to-body-weight ratios were significantly lower in CYP treated groups than those in controls and marked cellular depletions in spleens and thymus were observed in CYP treated groups. CONCLUSIONS: As the results of above, it can be concluded that the immunosuppression during viremic phase of murine viral myocarditis aggravated the myocardial necrosis, and during aviremic phase, the administration of CYP didnot affect the process of viral myocarditis. Thus, direct viral mechanisms in the production of cardiomyocyte injury in CB3-infected mice appear to bo more important than cell mediated immune mechanism. To understand relevant pathogenic mechanisms of clinical myocarditis and dilated cardiomyopathy resulting from viral infection, the experimental study expanding into nonmurine animals and into various models using other infectious agents may be required.