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Effects of prolonged use of PENTOXIFILINE over myocardial perfusion changes, arrythmia events and left ventricular dysfunction in the chronic chagas cardiomyopathy

Grant number: 17/16450-6
Support type:Regular Research Grants
Duration: April 01, 2018 - March 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Marcus Vinicius Simões
Grantee:Marcus Vinicius Simões
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Assoc. researchers:Edecio Cunha Neto ; Helio Cesar Salgado ; Paulo Louzada Junior

Abstract

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)