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Grant number: 17/16450-6
Support Opportunities:Regular Research Grants
Duration: April 01, 2018 - September 30, 2020
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marcus Vinicius Simões
Grantee:Marcus Vinicius Simões
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated researchers:Edecio Cunha Neto ; Helio Cesar Salgado ; Paulo Louzada Junior


Rational foundation: Several physiopathogenetic aspects of the Chronic Chagas Cardiomyopathy (CCC) are still unclear, mainly the mechanisms leading to the late development of the myocardial tissue damage, arising 2 to 3 decades after the acute phase. Beyond the 2 main mechanisms, i.e. persistent parasitism and exacerbated inflammatory aggression, myocardial ischemia due to microvascular dysfunction may also be involved in producing myocardial lesion. The next peace of evidence to be produced in order to test the correlation between inflammation and microvascular ischemia in CCC is the demonstration that pharmacologic interventions aiming at the inflammation reduction could also be associated to the reduction of the perfusion disturbance and attenuate the progression of the left ventricular dysfunction. In this scenario, the use of in vivo high-resolution images in an experimental model of CCC in hamsters has the potential to provide valuable information regarding these physiopatogenetic mechanisms. General objectives: The general objective of this study is to test, both in clinical and experimental grounds, the effect of prolonged administration of pentoxifylline over the myocardial inflammation and over the myocardial perfusion derangements, and the repercussion of these changes over the development of global and segmental myocardial dysfunction in CCC. Methods - Experimental study: We will employ female hamsters (Mesocricetus auratus) assigned to 4 experimental groups: 1. Infected animals (n=15), 6-months after inoculation of 3,5 x 105 Y-strain Y-strain T cruzi trypomastigots infecting forms), treated with pentoxifylline (20 mg/Kg/dia, intraperitoneal, during 60 days); 2. Infected animals (n-15) treated with i.p placebo during 60 days; 3. control non-infected animals treated with pentoxifylline (n=15) in the same way as infected groups; 4. control non-infect animals treated with placebo (n=15). At baseline condition, before the pentoxifylline/placebo administration, all animals will be submitted to: 2D-Echo-Doppler Echocardiogram, High-resolution myocardial perfusion SPECT, 18F-FDG PET imaging for myocardial viability and inflammation detection. After the treatment period, the same images methods will be repeated. After that, animals will be euthanized, and myocardial tissue collected for histological analyses, expression of cytokines-RNA and T cruzi-DNA in myocardial tissue,. In addition, blood samples will be collected for cytokines (TNF-alfa, IL-6, INF-gama e IL-1) and anti-T cuzi antibody quantifications. Clinical study: This is a prospective double-blinded, randomized, placebo controlled clinical study testing a therapeutic intervention with pentoxifyllline. The study will include CCC patients, with typical Echocardiogram abnormalities and 2 positive serologic tests, with LVEF e 35%. Patients will be randomly assigned to 2 investigations groups: 1. Pentoxifylline group (G-PTX) (n=23), that will received pentoxifylline (400 mg p.o. 3 times/day, during 6 months); 2. Control Group (G-CTRL) (n=23) that will receive placebo in the same doses schedule during 6 months. The patients and investigators will be blinded regarding the treatment group for each patient. At the baseline and after treatment period, the patients will be submitted to: clinical examination, 12-lead-EKG, 2D-Doppler-Echocardiogram, 24-hour-Holter monitoring, Stress-Rest Myocardial Perfusion Scintigraphy-SPECT-Sestamibi, plasma levels of inflammatory cytokines TNF-alfa, IL-6, INF-gama e IL-1. (AU)

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Scientific publications (4)
(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)
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., . (17/16450-6, 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., . (17/16450-6, 16/25403-9, 19/21250-1)
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, . (17/16450-6, 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., . (17/16450-6, 16/25403-9, 19/21250-1)

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