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, 49 (4), 1521-8

Treatment With Benznidazole During the Chronic Phase of Experimental Chagas' Disease Decreases Cardiac Alterations

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Treatment With Benznidazole During the Chronic Phase of Experimental Chagas' Disease Decreases Cardiac Alterations

Simone Garcia et al. Antimicrob Agents Chemother.

Abstract

Chagas' disease, caused by Trypanosoma cruzi infection, is one of the main causes of death due to heart failure in Latin American countries. Benznidazole, the chemotherapeutic agent most often used for the treatment of chagasic patients, is highly toxic and has limited efficacy, especially in the chronic phase of the disease. In the present study we used a mouse model of chronic Chagas' disease to investigate the effects of benznidazole treatment during the chronic phase on disease progression. The hearts of benznidazole-treated mice had decreased parasitism and myocarditis compared to the hearts of untreated chagasic mice. Both groups of Trypanosoma cruzi-infected mice had significant alterations in their electrocardiograms compared to those of the healthy mice. However, untreated mice had significantly higher cardiac conduction disturbances than benznidazole-treated mice, including intraventricular conduction disturbances, atrioventricular blocks, and extrasystoles. The levels of antibodies against T. cruzi antigens (epimastigote extract, P2beta, and trans-sialidase) as well as antibodies against peptides of the second extracellular loops of beta1-adrenergic and M2-muscarinic cardiac receptors were also lower in the sera from benznidazole-treated mice than in the sera from untreated mice. These results demonstrate that treatment with benznidazole in the chronic phase of infection prevents the development of severe chronic cardiomyopathy, despite the lack of complete parasite eradication. In addition, our data highlight the role of parasite persistence in the development of chronic Chagas' disease and reinforce the importance of T. cruzi elimination in order to decrease or prevent the development of severe chagasic cardiomyopathy.

Figures

FIG. 1.
FIG. 1.
Parasitemia during the acute phase of infection with the Colombian strain of T. cruzi in BALB/c mice. BALB/c mice were infected with 100 trypomastigotes of the Colombian strain of T. cruzi. Parasitemia was determined at different times after infection. Values represent the medians for five mice. The arrow indicates the beginning of benznidazole administration.
FIG. 2.
FIG. 2.
Parasitism and histopathological analyses of heart sections of T. cruzi-infected mice. Heart sections of untreated (A and C) or benznidazole-treated (B and D) T. cruzi-infected mice were analyzed for the presence of parasite foci by confocal microscopy (A and B; magnification, ×60) or inflammation by staining with hematoxylin-eosin (C and D; magnification, ×40).
FIG. 3.
FIG. 3.
Decreased parasitism and inflammation in the hearts of benznidazole-treated mice determined by quantification of parasite foci (A), inflammatory cells (B), and fibrosis (C) in heart sections of T. cruzi-infected BALB/c mice untreated (I) or treated with benznidazole (I + B). Values represent the means ± standard deviations for 5 mice per group (A) and 8 to 10 mice per group (B and C). *, P < 0.05 compared to the results for the untreated infected group by Student's t test.
FIG. 3.
FIG. 3.
Decreased parasitism and inflammation in the hearts of benznidazole-treated mice determined by quantification of parasite foci (A), inflammatory cells (B), and fibrosis (C) in heart sections of T. cruzi-infected BALB/c mice untreated (I) or treated with benznidazole (I + B). Values represent the means ± standard deviations for 5 mice per group (A) and 8 to 10 mice per group (B and C). *, P < 0.05 compared to the results for the untreated infected group by Student's t test.
FIG. 4.
FIG. 4.
ECG recordings from BALB/c mice. ECGs of untreated (A) and benznidazole-treated (B) T. cruzi-infected mice were recorded 10 months after infection. (C) ECG for a healthy BALB/c mouse. ▾, P wave; Δ, QRS complex; *, second-degree atrioventricular block.
FIG. 5.
FIG. 5.
Decreased levels of antibodies in sera from benznidazole-treated mice. Sera of untreated (I) or benznidazole-treated (I + B) T. cruzi-infected and health (N) BALB/c mice were tested by enzyme-linked immunosorbent assay in order to determine the levels of antibodies against T. cruzi antigen (A), TS (B), P2β (C), the second extracellular loop of the human M2-muscarinic cardiac receptor (D), and the second extracellular loop of the human β1-adrenergic cardiac receptor (E). The data represent the means ± standard deviations for 5 to 10 mice for each group. *, P < 0.05 compared to the results for the untreated infected group by one-way analysis of variance followed by Newman-Keuls multiple-comparison test. O.D., optical density.

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