In viral myocarditis, inflammation and destruction of cardiac myocytes leads to fibrosis, causing progressive impairment in cardiac function. Here we show the etiologic importance of serine elastase activity in the pathophysiology of acute viral myocarditis and the therapeutic efficacy of an elastase inhibitor. In DBA/2 mice inoculated with the encephalomyocarditis virus, a more than 150% increase in myocardial serine elastase activity is observed. This is suppressed by a selective serine elastase inhibitor, ZD0892, which is biologically effective after oral administration. Mice treated with this compound had little evidence of microvascular constriction and obstruction associated with myocarditis-induced ischemia reperfusion injury, much less inflammation and necrosis, only mild fibrosis and myocardial collagen deposition, and normal ventricular function, compared with the infected nontreated group.
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We thank J. Jowlabar and S. Taylor for secretarial assistance and C. Coulber, S. Ciura, E. Sitarz and K. Aitken for technical assistance. We also thank the staff of the Animal Care Facility at The Toronto Hospital General Division for their support with animal care, and members of the Department of Pathology at The Hospital for Sick Children for preparing the specimens for microscopy. This work was supported by a grants #74026 and T-2373 from the Heart and Stroke Foundation of Ontario and from the Medical Research Council of Canada.
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