Characterization of cardiopulmonary function and cardiac muscarinic and adrenergic receptor density adaptation in C57BL/6 mice with chronic Trypanosoma cruzi infection

Abstract

Circulating antibodies in chagasic patients interact with myocardial beta adrenergic and muscarinic cholinergic receptors, triggering intracellular signals that alter cardiac function along the course of the disease. However, until now, experimental data in models of chronically infected chagasic mice linking the effects on myocardial beta adrenergic and muscarinic receptors to cardiopulmonary dysfunction is lacking. Thus, we studied C57BL/6 mice 8 months after intraperitoneal injection of 100 trypomastigote forms of the Colombian strain of T. cruzi. Uninfected mice, matched in age, were used as controls. Histopathological analyses (inflammation and fibrosis) and radio-ligand binding assays for estimation of muscarinic and adrenergic receptor density were performed in myocardium tissue samples. When compared to controls, infected mice had electrical conduction disturbances, diastolic dysfunction, lower O2 consumption and anaerobic threshold. In addition, hearts of chronic chagasic mice had intense inflammation and fibrosis, and decreased beta adrenergic and increased muscarinic receptor densities than normal controls. Our data suggest that chronic T. cruzi infection causes alterations in cardiac receptor density and fibrosis deposition which can be associated with cardiac conduction abnormalities, diastolic dysfunction and lower exercise capacity, associating for the first time all these functional and histopathological alterations in chagasic mice.

Mitochondrial Complex III Defects Contribute to Inefficient Respiration and ATP Synthesis in the Myocardium ofTrypanosoma cruzi–Infected Mice

“…Data (mean AE SD) are representative of three independent experiments (n ¼ 9 mice per group). associated with electrical conduction disturbances, diastolic dysfunction, lower O 2 consumption, and anaerobic threshold (26). We and others have shown that myocardial energetics and ATP content were compromised in infected rodents (38,42).…”

“…Tissue damage and fibrosis associated with diffused inflammation become prominent during the chronic phase (13). Symptomatic defects include cardiomegaly, diffused myocarditis, self-perpetuating myofibril destruction, and a decline in LV ejection fraction (9,26,36), a picture reminiscent of the chronic form of Chagas disease observed in humans (24,25). Moderate-to-severe electrocardiographic and echocardiographic alterations evident in rodent hearts (3,7) are FIG.…”

Chagas disease: Present status of pathogenic mechanisms and chemotherapy

“…In addition, they could cause quantitative alterations in adrenergic and cholinergic receptors and, consequently, potential myocardial damage due to the cardiac autonomic dysfunctions known to occur in Chagasic cardiomyopathy (Hernandez et al, 2008;Ribeiro et al, 2009a;Rocha et al, 2006a;Rocha et al, 2006b). The clinical consequence of parasympathetic denervation is the absence of mechanisms, mediated by the vagus nerve, that trigger bradycardia or tachycardia in response to transient changes in blood pressure or venous return (Miziara et al, 2006;Ribeiro et al, 2009a;Rocha et al, 2009;Rocha et al, 2006b). However, the relative importance of the parasympathetic autonomic dysfunction has been recently questioned, raising the possibility that neurohormonal activation is the main underlying mechanism of disease progression (Davila et al, 2008).…”

Trypanosoma cruzi infection induces up-regulation of cardiac muscarinic acetylcholine receptors in vivo and in vitro

“…The result of either insult should promote the development of functional supersensitivity and/or up-regulation of postsynaptic mAChR in the cardiac muscle, due to a denervation phenomenon. Rocha et al (28) observed that C57BL/ 6 mice that have been inoculated intraperitoneally with T. cruzi trypomastigotes have an increased cardiac muscarinic receptor density 8 months after infection. In our in vivo chagasic rat model, the up-regulation of mAChR was restricted to the right ventricle from chronic chagasic adult rat heart, which suggests a selective denervation of the right ventricle vagal fibers.…”