Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is an important cause of
cardiomyopathy. Microvascular
spasm and matrix dissolution, modulated by
endothelin-1 (ET-1), is implicated in the pathogenesis of chagasic
heart disease. To further elucidate the role of ET-1 in murine chagasic
heart disease, C57BL/6 x 129sv mice were infected with T. cruzi (10(3) trypomastigotes of the Brazil strain). These mice are resistant to death during the acute phase but progress to chronic
cardiomyopathy. Infected mice were compared with infected mice treated with
phosphoramidon, a non-specific
metalloprotease inhibitor that is also a potent inhibitor of
endothelin-converting enzyme, at a dose of 10 mg/kg. Mice were treated with
phosphoramidon for the initial 15 days post
infection (PI). All mice were evaluated 200 days PI. Examination of infected, untreated mice revealed marked
inflammation,
vasculitis and
fibrosis. The hearts of infected treated mice had significantly less pathology. Cardiac magnetic resonance imaging (MRI) revealed that right ventricular internal diameter (RVID) was significantly greater (P<0.05) in the infected untreated group (2.9+/-0.22 mm) as compared with the infected treated group (1.73+/-0.35 mm). In another experiment
phosphoramidon treatment was also tested in CD1 mice, which have a high mortality during the acute phase of
infection with 5 x 10(4) trypomastigotes of the Brazil strain. One group of CD1 mice was untreated while the other group received
phosphoramidon for the initial 15 days PI. The mortality rate in untreated mice was 70% by day 35 PI, while all treated infected mice lived. The
parasitemia in both groups was similar. The cardiac pathology was more severe in untreated mice. MRI revealed the RVID to be significantly greater in the untreated infected group as compared with the
phosphoramidon-treated infected mice (2.74+/-0.03 mm versus 1.64+/-0.4 mm P<0.05). Transthoracic echocardiography revealed that the percentage fractional shortening was reduced in infected CD1 mice but not in those infected mice treated with
phosphoramidon. There was no effect of
phosphoramidon in uninfected mice.
Phosphoramidon (100 microg/ml) had no effect on parasites in vitro. These data are consistent with the hypothesis that ET-1 contributes to the pathogenesis of murine chagasic
cardiomyopathy and suggests that interventions targeting ET-1 would improve the outcome in chagasic
heart disease.