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Study of the effect of a vasodilating agent of the coronary microcirculation on myocardial perfusion disorders and left ventricular dysfunction in a hamster model of chronic chagasic cardiomyopathy

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Denise Mayumi Tanaka
Total Authors: 1
Document type: Master's Dissertation
Press: Ribeirão Preto.
Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
Defense date:
Examining board members:
Marcus Vinícius Simões; Edecio Cunha Neto; Jose Antonio Marin Neto
Advisor: Marcus Vinícius Simões

Chagas disease continues to be an important public health problem in endemic regions of Latin America, where 8 to 10 million infected people are estimated to live. Microvascular ischemia is frequent in chronic chagasic cardiomyopathy (CCC) and may be involved in the physiopathogenic processes that lead to left ventricular systolic dysfunction (LVSD). The hypothesis is raised that reduction of microvascular ischemia may attenuate the progression of LVSD in CCC. Thus, our objective was to assess the effects of prolonged use of dipyridamole (DIPY), a coronary microvascular dilator agent, on myocardial perfusion and on left ventricular systolic function using imaging methods in vivo. A total of 60 adult female hamsters were divided into the following groups: T. cruzi-infected animals treated with DIPY (Chagas + DIPY, n=15); infected animals treated with placebo (Chagas + Placebo, n=15); uninfected animals treated with DIPY (Control + DIPY, n=15) and treated with placebo (Control + placebo, n=15). After 6 months of infection (baseline condition), the animals were submitted to an echocardiogram and to rest myocardial perfusion scintigraphy by SPECT with SestamibiTc99m. Next, the animals were treated with intraperitoneal injections of DIPY (4 mg/kg) twice a day or with an equal volume of saline for 30 days. After treatment, the animals were reevaluated by the same imaging methods and euthanized. Cardiac tissue was prepared for quantitative histological analysis of the extent of fibrosis (picrosirius red staining) and of the inflammatory infiltrate (hematoxylin-eosin staining). At baseline, the group Chagas + placebo and Chagas + DIPY showed a larger area of perfusion defect (19.2 ± 5.4% and 20.9 ± 4.2%, respectively) compared to control + placebo and control + DIPY (3.8 ± 0.7% e 3.6 ± 0.9%, respectively), p<0.05, but similar left ventricular ejection fraction (LVEF), p=0.3, and left ventricular diastolic diameter (LVdD), p=0.2. After treatment, a significant reduction of perfusion defects was observed only in the Chagas + DIPY group (p=0.02). When the values after treatment were compared to baseline values, Chagas + DIPY and Chagas + placebo animals showed a reduction of LVEF (from 65.3 ± 2.5% to 53.6 ± 1.9% and from 69.3 ± 1.4% to 54.4 ± 2.%5, respectively), p<0.001, and an increase of LVdD from 0.68 ± 0,15 cm to 0.76 ± 0.17 cm and from 0.64 ± 0.01 cm to 0.70 ± 0,02 cm, respectively, p<0.002. Quantitative histological analysis revealed a larger number of nuclei of mononuclear inflammatory cells in the Chagas + DIPY (998.1 ± 116.0 cel/mm²) and Chagas + Placebo (1191.4 ± 133.2 cells/mm²) groups compared to the Control + DIPY (396.5 ± 28.3 cells/mm²) and Control + Placebo (257.1 ± 21.6 cells/mm²) groups, p=0.05. The percentage of fibrosis was higher in the Chagas + DIPY (4.7 ± 0.4%) and Chagas + Placebo (5.4 ± 0.2%) groups compared to the Control + Placebo group (3.2 ± 0.3%). There was no difference between the Chagas + DIPY and Chagas + Placebo groups regarding the two histological variables. Conclusions: The prolonged use of DIPY in animals with CCC was associated with a significant reduction of myocardial perfusion defects assessed in vivo. However, the resolution of microvascular ischemia with the use of DIPY did not prevent the progression of left ventricular dysfunction. These results suggest that microvascular ischemia may not be a central myocardial injury mechanism in the physiopathogenic complex of this CCC model. It is plausible to assume that microvascular ischemia may be a marker of the presence of an underlying injury process probably of an inflammatory nature. (AU)

FAPESP's process: 14/07722-4 - Study of the effects of a coronary microcirculation vasodilator drug on the myocardial perfusion and left ventricular dysfunction in a model of chronic chagas cardiomyopathy in hamsters
Grantee:Denise Mayumi Tanaka
Support Opportunities: Scholarships in Brazil - Master