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 Opportunities: Research Projects - Thematic Grants
• Start date: May 01, 2018
• End date: April 30, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: José Antonio Marin-Neto
• Grantee: José Antonio Marin-Neto
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Pesquisadores principais: André Schmidt ; Benedito Carlos Maciel ; Marcus Vinicius Simões
• Associated researchers: Edecio Cunha Neto ; Helio Cesar Salgado ; João Santana da Silva ; Maria de Lourdes Higuchi ; Minna Moreira Dias Romano ; Rubens Fazan Junior
• Associated research grant(s): 19/04864-6 - Multi-User Equipment approved in grant 2016/25403-9: echocardiography equipment, AP.EMU
• Associated scholarship(s): 19/21250-1 - Chronic Chagas Cardiomyopathy in experimental animal model: prospective study of anatomic and functional ventricular changes and the effect of therapeutic interventions, BP.PD; 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)

Scientific publications

(20)

(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)

SILVA, LUIZ E., V; MOREIRA, HENRIQUE T.; SCHMIDT, ANDRE; ROMANO, MINNA M. D.; SALGADO, HELIO C.; FAZAN, RUBENS, JR.; MARIN-NETO, J. ANTONIO; IEEE. The Relationship Between Nonlinear Heart Rate Variability and Echocardiographic Indices in Chagas Disease. 2020 11TH CONFERENCE OF THE EUROPEAN STUDY GROUP ON CARDIOVASCULAR OSCILLATIONS (ESGCO): COMPUTATION AND MODELLING IN PHYSIOLOGY NEW CHALLENGES AND OPPORTUNITIES, v. N/A, p. 2-pg., 2020-01-01. (18/21212-0, 16/25403-9)

TANAKA, DENISE MAYUMI; FABRICIO, CAMILA GODOY; MARIN-NETO, JOSE A.; DE BARROS FILHO, ANTONIO CARLOS LEITE; DE OLIVEIRA, LUCIANO FONSECA LEMOS; MEJIA, JORGE; ALMEIDA, RAFAEL RIBEIRO; VIEIRA, RAQUEL DE SOUZA; LOPES, CARLA DUQUE; BATAH, SABRINA SETEMBRE; et al. Pentoxifylline reduces inflammation and prevents myocardial perfusion derangements in experimental chronic Chagas' cardiomyopathy. JOURNAL OF NUCLEAR CARDIOLOGY, v. N/A, p. 11-pg., 2023-05-10. (17/16450-6, 16/25403-9, 19/21250-1)

TANAKA, D. M.; FABRICIO, C. G.; MARIN-NETO, J. A.; BARROS-FILHO, A. C. L.; DELARISSE, M. L.; LOPES, C. D.; OLIVEIRA, L. F. L.; RESENDE, A. R.; MOREIRA, H. T.; MEJIA, J.; et al. Prolonged use of pentoxifylline prevents progression of myocardial perfusion disturbance and reduces inflammation in the hamster experimental model of chronic Chagas cardiomyopathy. EUROPEAN JOURNAL OF HEART FAILURE, v. 22, p. 1-pg., 2020-09-01. (17/16450-6, 16/25403-9)

SILVA, LUIZ EDUARDO VIRGILIO; MOREIRA, HENRIQUE TURIN; DE OLIVEIRA, MARINA MADUREIRA; CINTRA, LORENA SAYORE SUZUMURA; SALGADO, HELIO CESAR; FAZAN, RUBENS, JR.; TINOS, RENATO; RASSI, ANIS, JR.; SCHMIDT, ANDRE; MARIN-NETO, J. ANTONIO. Heart rate variability as a biomarker in patients with Chronic Chagas Cardiomyopathy with or without concomitant digestive involvement and its relationship with the Rassi score. BIOMEDICAL ENGINEERING ONLINE, v. 21, n. 1, p. 19-pg., 2022-06-28. (16/25403-9, 18/21212-0)

RAFAEL BROLIO PAVÃO; HENRIQUE TURIN MOREIRA; ANTONIO OSWALDO PINTYA; JORGE LUIS HADDAD; ANDRÉ VANNUCHI BADRAN; MOYSÉS DE OLIVEIRA LIMA-FILHO; IGOR MATOS LAGO; JOÃO REYNALDO ABBUD CHIERICE; ANDRÉ SCHMIDT; J. ANTONIO MARIN-NETO. Aspirin plus verapamil relieves angina and perfusion abnormalities in patients with coronary microvascular dysfunction and Chagas disease: a pilot non-randomized study. Revista da Sociedade Brasileira de Medicina Tropical, v. 54, 2021-11-12. (16/25403-9)

DE OLIVEIRA, MAYKON TAVARES; FUZO, CARLOS ALESSANDRO; DA SILVA, MARIA CLAUDIA; DONADI, EDUARDO ANTONIO; DA SILVA, JOAO SANTANA; MOREIRA, HENRIQUE TURIN; SCHMIDT, ANDRE; MARIN-NETO, JOSE ANTONIO. Correlation of TcII discrete typing units with severe chronic Chagas cardiomyopathy in patients from various Brazilian geographic regions. PLoS Neglected Tropical Diseases, v. 16, n. 12, p. 13-pg., 2022-12-01. (16/25403-9, 18/22093-4)

DE OLIVEIRA, MAYKON TAVARES; SULLEIRO, ELENA; DA SILVA, MARIA CLAUDIA; SILGADO, AROA; DE LANA, MARTA; DA SILVA, JOAO SANTANA; MOLINA, ISRAEL; ANTONIO MARIN-NETO, J.. Intra-Discrete Typing Unit TcV Genetic Variability of Trypanosoma cruzi in Chronic Chagas' Disease Bolivian Immigrant Patients in Barcelona, Spain. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 8, MAY 20 2021. (16/25403-9, 18/22093-4, 19/11943-0)

VIRGILIO SILVA, LUIZ EDUARDO; MOREIRA, HENRIQUE TURIN; MADISSON BERNARDO, MARIANI MENDES; SCHMIDT, ANDRE; DIAS ROMANO, MINNA MOREIRA; SALGADO, HELIO CESAR; FAZAN JR, RUBENS; TINOS, RENATO; MARIN-NETO, J. ANTONIO. Prediction of echocardiographic parameters in Chagas disease using heart rate variability and machine learning. Biomedical Signal Processing and Control, v. 67, p. 12-pg., 2021-03-01. (18/21212-0, 16/25403-9)

DE OLIVEIRA, MAYKON TAVARES; SCHMIDT, ANDRE; DA SILVA, MARIA CLAUDIA; DONADI, EDUARDO ANTONIO; DA SILVA, JOAO SANTANA; MARIN-NETO, JOSE ANTONIO. Parasitic Load Correlates With Left Ventricular Dysfunction in Patients With Chronic Chagas Cardiomyopathy. FRONTIERS IN CARDIOVASCULAR MEDICINE, v. 8, SEP 16 2021. (18/22093-4, 16/25403-9)

VARGAS, ARTHUR LAUAND; DIAS, BEATRIZ DE PAULA; MOREIRA, HENRIQUE TURIN; DE OLIVEIRA-FILHO, EDGARD CAMILO; TANAKA, DENISE MAYUMI; SIMOES, MARCUS VINICIUS; MACIEL, BENEDITO CARLOS; SCHMIDT, ANDRE; MARIN-NETO, JOSE ANTONIO; DIAS ROMANO, MINNA MOREIRA. Prospective study of ventricular function and myocardial deformation related to survival in acute Chagas disease: an experimental animal model. Revista do Instituto de Medicina Tropical de São Paulo, v. 63, 2021. (16/25403-9)

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. (16/25403-9)

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. (18/21212-0, 16/25403-9)

BARROS FILHO, ANTONIO C. L.; MOREIRA, HENRIQUE T.; DIAS, BEATRIZ P.; RIBEIRO, FERNANDO F. F.; TANAKA, DENISE M.; SCHMIDT, ANDRE; MACIEL, BENEDITO C.; SIMOES, MARCUS V.; MARIN-NETO, JOSE A.; ROMANO, MINNA M. D.. Feasibility and reference intervals assessed by conventional and speckle-tracking echocardiography in normal hamsters. PHYSIOLOGICAL REPORTS, v. 9, n. 5, MAR 2021. (16/25403-9)

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, 2020-11-25. (17/16450-6, 16/25403-9)

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. (16/25403-9)

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. (16/25403-9, 19/11943-0)

BRAGGION-SANTOS, MARIA FERNANDA; MOREIRA, HENRIQUE T.; VOLPE, GUSTAVO J.; KOENIGKAM-SANTOS, MARCEL; MARIN-NETO, JOSE ANTONIO; SCHMIDT, ANDRE. Electrocardiogram abnormalities in chronic Chagas cardiomyopathy correlate with scar mass and left ventricular dysfunction as assessed by cardiac magnetic resonance imaging. JOURNAL OF ELECTROCARDIOLOGY, v. 72, p. 6-pg., 2022-03-25. (16/25403-9)

RIBEIRO, FERNANDO FONSECA FRANCA; MOREIRA, HENRIQUE TURIN; DE BARROS-FILHO, ANTONIO CARLOS LEITE; TANAKA, DENISE M.; FABRICIO, CAMILA G.; OLIVEIRA, LUCIANO F. L.; PRADO, CIBELE M.; SIMOES, MARCUS V.; SCHMIDT, ANDRE; MACIEL, BENEDITO C.; et al. rospective analysis of myocardial strain through the evolution of Chagas disease in the hamster animal mode. INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING, v. 38, n. 1, SEP 2021. (16/25403-9)

MOREIRA, HENRIQUE TURIN; VOLPE, GUSTAVO JARDIM; MESQUITA, GUSTAVO MARQUES; BRAGGION-SANTOS, MARIA FERNANDA; PAZIN-FILHO, ANTONIO; MARIN-NETO, JOSE ANTONIO; SCHMIDT, ANDRE. Association of left ventricular abnormalities with incident cerebrovascular events and sources of thromboembolism in patients with chronic Chagas cardiomyopathy. JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE, v. 24, n. 1, p. 11-pg., 2022-11-03. (16/25403-9)

TANAKA, DENISE MAYUMI; SIMOES, MARCUS VINICIUS; MARIN-NETO, JOSE ANTONIO. Coronary microvascular dysfunction due to Chagas disease: where are we now ?. EXPERT REVIEW OF CARDIOVASCULAR THERAPY, v. 21, n. 6, p. 9-pg., 2023-05-25. (17/16450-6, 16/25403-9, 19/21250-1)