Role of cardiac myocyte-derived endothelin-1 in chagasic cardiomyopathy: Molecular genetic evidence

Trypanosoma cruzi is the aetiological agent of Chagas' disease, an important cause of chronic cardiomyopathy. We previously demonstrated a role for endothelin-1 (ET-1) in the pathogenesis of chagasic heart disease. In order to explore further the significance of ET-1 in chagasic heart disease, we infected ET-1 (flox/flox); α-MHC-Cre(+) (ET-IKO) mice, in which the ET-1 gene has been deleted from cardiac myocytes, with 10⁴ T. cruzi (Brazil strain) trypomastigotes. As controls, we used ET-1 (flox/flox);Cre(-) (FLOX) and C57BL/6 × 129sv (WT) mice. All mice survived and were evaluated 150-160 days post-infection. Cardiac magnetic resonance imaging revealed a significant increase in right ventricular internal diameter in all infected animals except ET-IKO mice (control WT, 1.6±0.10 mm; infected WT, 2.8±0.15 mm; control FLOX, 2.04±0.02 mm; infected FLOX, 2.76±0.28 mm). There was no significant difference in right ventricular internal diameter between infected and uninfected ET-IKO mice (control ET-IKO, 1.83±0.11 mm; infected ET-IKO, 2.14±0.20 mm). In another series of experiments, transthoracic echocardiography was performed on uninfected as well as infected ET-IKO mice, and uninfected and infected FLOX mice. Both infected groups had an increased left ventricular end-diastolic diameter and reduced fractional shortening. In addition, relative wall thickness was also decreased in infected animals. However, the magnitude of these changes was less in infected ET-IKO mice. These data provide further support for a role for ET-1 in the pathogenesis of chronic chagasic heart disease, and indicate that cardiac myocytes are an important source of ET-1 in this disease.