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Investigations on the pathogenesis, pathophysiology and therapy in humans and in an experimental model with the chronic cardiomyopathy of Chagas Disease

Grant number: 16/25403-9
Support type:Research Projects - Thematic Grants
Duration: May 01, 2018 - April 30, 2023
Field of knowledge:Health Sciences - Medicine
Principal Investigator:José Antonio Marin-Neto
Grantee:José Antonio Marin-Neto
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Co-Principal Investigators:André Schmidt ; Benedito Carlos Maciel ; Marcus Vinicius Simões
Assoc. researchers:Edecio Cunha Neto ; Helio Cesar Salgado ; João Santana da Silva ; Maria de Lourdes Higuchi ; Minna Moreira Dias Romano ; Rubens Fazan Junior
Associated grant(s):19/04864-6 - Multi-User Equipment approved in grant 2016/25403-9: echocardiography equipment, AP.EMU
Associated scholarship(s):18/22909-4 - Chronic chagas cardiomyopathy in experimental animal model: prospective study of anatomic and functional ventricular changes and the effect of therapeutic interventions, BP.PD
18/22093-4 - "genotyping of Trypanosoma Cruzi in samples from patients with chronic chagas' heart disease'', BP.PD
18/21212-0 - Prediction of the evolution of Chagas' Disease through heart rate variability, BP.PD

Abstract

This thematic proposal encompasses 13 investigations to be carried out by a group of 26 clinical, basic research scientists and post-graduate students, from 8 academic institutions, on the pathogenesis, pathophysiology and therapeutic aspects related to the chronic Chagas cardiomyopathy (CCC). The investigations will be performed in humans and in Syrian hamsters experimentally infected with the T. cruzi. The parasite persistence hypothesis of the pathogenesis of CCC will be challenged with the etiologic treatment offered to individuals with the indeterminate form and to patients with early phases of the CCC. We will seek to standardize and validate the application of both classical methods and of the novel echocardiographic approaches assessing myocardial deformation with speckle tracking to evaluate biventricular function and other anatomic and functional parameters in patients with CCC. Several studies will focus on the pathophysiological hypothesis that microvascular disturbances cause myocardial ischemia and cell damage in Chagas disease. In special, the hypothesis that a mechanism similar to the myocardial hybernation described in patients with coronary artery disease may exist in patients with myocardial segmental dysfunction caused by microvascular ischemia will be directly tested. Coronary resistance and flow reserve will be directly measured in patients with angiographycally normal coronary arteries during cardiac catheterization. Three therapeutic interventions will be implemented aiming at the reduction of microvascular perfusion disturbances by promoting vasodilation and blocking platelet activation in humans with Chagas disease and in the Syrian hamster model of T. cruzi chronic infection. Studies in this model will obviate the obstacle of the long natural history period that exists in the transition from the indeterminate to the CCC form of Chagas disease. Cardiac magnetic resonance will provide the gold standard for the validation of the echocardiographic methods and to test whether trypanocidal treatment is able to minimize the appearance of myocardial fibrosis. The method will also be used to study the presence and extent of fibrosis in patients with malignant arrythmia whose follow-up after empirically receiving an ICD is frequently neglected in CCC. Finally, in the sample population of 284 Brazilian patients with CCC included in the BENEFIT study, the T. cruzi genotype of the parasite found before treatment with benznidazole or placebo will be correlated with the clinical manifestations and evolution of the patients. (AU)

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