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Published on: June 7, 2011
Cardioprotective effects of phosphoramidon on myocardial structure and function in murine Chagas' disease
Linda A Jelicks1, Madhulika Chandra, Jamshid Shirani
1Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
Insights
Chagas
Area of Science:
- Cardiovascular Research
- Infectious Diseases
- Pharmacology
Background:
- Chagas' disease, caused by Trypanosoma cruzi, is a significant cause of cardiomyopathy.
- Endothelin-1, a vasoactive peptide, is implicated in the pathogenesis of chagasic cardiomyopathy.
Purpose of the Study:
- To investigate the role of endothelin-1 in chagasic cardiomyopathy.
- To evaluate the therapeutic potential of phosphoramidon, an endothelin-converting enzyme inhibitor, in a murine model of Chagas' disease.
Main Methods:
- C57BL/6 x 129sv and CD1 mice were infected with Trypanosoma cruzi.
- Mice were treated with phosphoramidon (10mg/kg for 15 days post-infection) or left untreated.
- Cardiac pathology, magnetic resonance imaging, and echocardiography were used to assess myocardial damage and function.
Main Results:
- Phosphoramidon treatment significantly reduced myocardial inflammation and fibrosis in infected mice.
- Cardiac imaging revealed attenuated right and left ventricular dilation and improved cardiac function in treated mice.
- Phosphoramidon treatment improved survival rates in CD1 mice during acute infection.
Conclusions:
- Endothelin-1 contributes to the pathogenesis of Chagas' disease cardiomyopathy.
- Inhibiting endothelin-1 synthesis with phosphoramidon demonstrates a protective effect on myocardial structure and function in murine Chagas' disease.
Abstract:
Chagas' disease is an important cause of cardiomyopathy. Endothelin-1, a vasoactive peptide has been implicated in the pathogenesis of chagasic cardiomyopathy. C57BL/6 x 129sv and CD1 mice were thus, infected with trypomastigotes of Trypanosoma cruzi (Brazil strain) and these infected mice were compared with infected mice treated with phosphoramidon. This compound inhibits endothelin-converting enzyme and neutral endopeptidases and does not affect the growth of the parasite in culture. Phosphoramidon was given in a dose of 10mg/kg for the initial 15 days post-infection None of the C57Bl/6 x 129sv mice died as a result of infection. However, there was marked myocardial inflammation and fibrosis in infected, untreated mice. The hearts of the infected, phosphoramidon-treated mice showed significantly less pathology. Cardiac magnetic resonance imaging of infected mice revealed right ventricular dilation that was less severe in those treated with phosphoramidon. Phosphoramidon-treated CD1 mice survived the acute infection. Transthoracic echocardiography demonstrated left ventricular dilation and reduced percent fractional shortening and relative wall thickness. These alterations were also attenuated as a result of phosphoramidon treatment. These data suggest that endothelin-1 contributes to the pathogenesis of chagasic cardiomyopathy and interventions that inhibit the synthesis of endothelin-1 and/or neutral endopeptidase might have a protective effect on myocardial structure and function in murine Chagas' disease.
