Several pathophysiological aspects of chronic chagasic cardiomyopathy (CCC) still need more elucidation, especially the mechanisms that determine the appearance of chronic myocardial injury in the late phase, 2 to 3 decades after the acute phase. In addition to the persistence of the parasite in cardiac tissue and the exacerbated inflammatory response associated with aspects of autoimmunity, experimental and clinical evidences suggest the participation of autonomic denervation and microvascular ischemia contributing in the process of cardiomyopathy progression. However, a longitudinal clinical study that allows the evaluation of these aspects, exhibits virtual impediment considering the long term of observation. In this scenario, the use of the experimental model in hamster that reproduces the chronic phase of CCC after 6 months of infection could provide valuable observations about these pathophysiological mechanisms and the effects of drug therapy on the progression of the disease. This study tests the hypothesis that wall motion abnormalities may have important prognostic implications and succeed therapies to prevent reverse remodeling in HF may prevent the CCC progression. In addition, we will test the hypothesis that hypoperfused myocardial regions exhibiting wall motion abnormalities correspond to a phenomenon similar to the myocardium hibernation seen in atherosclerotic ischemic heart disease and are amenable to functional recovery through a therapeutic intervention aimed to reduce the degree of myocardial hypoperfusion at rest. Thus, the present study, divided into two subprojects, has the following objectives: 1- To investigate longitudinally the biventricular functional and geometric changes, as well as to evaluate the effects of the beta-adrenergic blockade and/or renin-angiotensin system, established early in the natural history of CD; 2- Evaluate the effects of phosphodiesterase-5 inhibitor on myocardial perfusion changes and the evolution of myocardial dysfunction in CCC model in Syrian hamsters. Initially the project will be divided into two stages. In the first stage the animals infected with T. cruzi will be divided into 4 groups and will receive saline, enalapril, carvedilol and the association between enalapril + carvedilol, respectively. The animals will be compared with respective control animals receiving saline. Drug therapy will be started after 30 days of infection. The animals will be submitted to high resolution Doppler echocardiography (DE) for the evaluation of the geometric parameters of the LV as well as their global and segmental systolic function (including speckle tracking) in the basal condition, acute phase of the infection and in the temporal windows of 2, 4, 6, 8 and 10 months after infection. In the second stage the animals will be divided into groups (2 controls and 2 infected) who will receive saline or tadalafil for 4 weeks from 6 months after infection. Evaluations of myocardial function by Echo, assessments of myocardial perfusion by using mini-SPECT and myocardial viability with MicroPET will be performed. At the end of the study, myocardial tissue will be processed for histological analysis of myocardial fibrosis and inflammation and for quantification of INF-gamma, TNF-alpha, IL-10 and CCL3.
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