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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

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)

Scientific publications (5)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
VIRGILIO SILVA, LUIZ EDUARDO; FAZAN JR, RUBENS; MARIN-NETO, JOSE ANTONIO. PyBioS: A freeware computer software for analysis of cardiovascular signals. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE, v. 197, DEC 2020. Web of Science Citations: 0.
ROMANO, MINNA MOREIRA DIAS; MOREIRA, HENRIQUE TURIN; MARIN-NETO, JOSE ANTONIO; BACCELLI, PRISCILA ELIAS; ALENEZI, FAWAZ; KLEM, IGOR; MACIEL, BENEDITO CARLOS; KISSLO, JOSEPH; SCHMIDT, ANDRE; VELAZQUEZ, ERIC J. Early impairment of myocardial deformation assessed by regional speckle-tracking echocardiography in the indeterminate form of Chagas disease without fibrosis detected by cardiac magnetic resonance. PLoS Neglected Tropical Diseases, v. 14, n. 11 NOV 2020. Web of Science Citations: 0.
RIBEIRO CURY PAVAO, MARIA LICIA; ARFELLI, ELERSON; SCORZONI-FILHO, ADILSON; PAVAO, RAFAEL BROLIO; PAZIN-FILHO, ANTONIO; MARIN-NETO, JOSE ANTONIO; SCHMIDT, ANDRE. Electrical Storm in Chagas Cardiomyopathy Clinical Predictors, Outcome, and Arrhythmic Characteristics in a Prospective Registry. JACC-CLINICAL ELECTROPHYSIOLOGY, v. 6, n. 10, p. 1238-1245, OCT 2020. Web of Science Citations: 0.
TAVARES DE OLIVEIRA, MAYKON; SULLEIRO, ELENA; SILGADO GIMENEZ, AROA; DE LANA, MARTA; ZINGALES, BIANCA; SANTANA DA SILVA, JOAO; ANTONIO MARIN-NETO, J.; MOLINA, ISRAEL. Quantification of parasite burden of Trypanosoma cruzi and identification of Discrete Typing Units (DTUs) in blood samples of Latin American immigrants residing in Barcelona, Spain. PLoS Neglected Tropical Diseases, v. 14, n. 6 JUN 2020. Web of Science Citations: 0.
MARCUS VINICIUS SIMÕES; DENISE MAYUMI TANAKA; JOSÉ ANTONIO MARIN-NETO. Nuclear Medicine Methods for Assessment of Chronic Chagas Heart Disease. International Journal of Cardiovascular Sciences, v. 33, n. 6, p. 686-696, Dez. 2020.

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