Abstract
Background
Myocardial perfusion defects (MPD) due to coronary microvascular dysfunction is frequent in chronic Chagas cardiomyopathy (CCC) and may be involved with development of myocardial damage. We investigated whether MPD precedes left ventricular systolic dysfunction and tested the hypothesis that prolonged use of dipyridamole (DIPY) could reduce MPD in an experimental model of CCC in hamsters.
Methods and results
We investigated female hamsters 6-months after T. cruzi infection (baseline condition) and control animals, divided into T. cruzi-infected animals treated with DIPY (CH + DIPY) or placebo (CH + PLB); and uninfected animals treated with DIPY (CO + DIPY) or placebo (CO + PLB). The animals were submitted to echocardiogram and rest SPECT-Sestamibi-Tc99m myocardial perfusion scintigraphy. Next, the animals were treated with DIPY (4 mg/kg bid, intraperitoneal) or saline for 30 days, and reevaluated with the same imaging methods. At baseline, the CH + PLB and CH + DIPY groups showed larger areas of perfusion defect (13.2 ± 13.2% and 17.3 ± 13.2%, respectively) compared with CO + PLB and CO + DIPY (3.8 ± 2.2% e 3.5 ± 2.7%, respectively), P < .05. After treatment, we observed: reduction of perfusion defects only in the CH + DIPY group (17.3 ± 13.2% to 6.8 ± 7.6%, P = .001) and reduction of LVEF in CH + DIPY and CH + PLB groups (from 65.3 ± 9.0% to 53.6 ± 6.9% and from 69.3 ± 5.0% to 54.4 ± 8.6%, respectively, P < .001). Quantitative histology revealed greater extents of inflammation and interstitial fibrosis in both Chagas groups, compared with control group (P < .001), but no difference between Chagas groups (P > .05).
Conclusions
The prolonged use of DIPY in this experimental model of CCC has reduced the rest myocardial perfusion defects, supporting the notion that those areas correspond to viable hypoperfused myocardium.
Similar content being viewed by others
Abbreviations
- CCC:
-
Chronic Chagas cardiomyopathy
- MPD:
-
Myocardial perfusion defects
- DIPY:
-
Dipyridamole
- PLB:
-
Placebo
- LV:
-
Left ventricle
- LVEDD:
-
Left ventricle end diastolic dimension
- LVESD:
-
Left ventricle end systolic dimension
- LVEF:
-
Left ventricular ejection function
- PD:
-
Perfusion defects
- SPECT:
-
Single photon emission computerized tomography
References
Organización Panamericana de la Salud. Organización Panamericana de la Salud. Estimación cuantitativa de la enfermedad de Chagas en las Américas. Washington, DC; 2006.
Nunes MC, Dones W, Morillo CA, Encina JJ, Ribeiro AL. Council on Chagas Disease of the Interamerican Society of C. Chagas disease: An overview of clinical and epidemiological aspects. J Am Coll Cardiol 2013;62:767-76.
Gascon J, Bern C, Pinazo MJ. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop 2010;115:22-7.
Marin-Neto JA, Cunha-Neto E, Maciel BC, Simoes MV. Pathogenesis of chronic Chagas heart disease. Circulation 2007;115:1109-23.
Benvenuti LA, Roggerio A, Freitas HF, Mansur AJ, Fiorelli A, Higuchi ML. Chronic American trypanosomiasis: Parasite persistence in endomyocardial biopsies is associated with high-grade myocarditis. Ann Trop Med Parasitol 2008;102:481-7.
Borges DC, Araujo NM, Cardoso CR, Lazo Chica JE. Different parasite inocula determine the modulation of the immune response and outcome of experimental Trypanosoma cruzi infection. Immunology 2013;138:145-56.
Hagar JM, Rahimtoola SH. Chagas’ heart disease in the United States. N Engl J Med 1991;325:763-8.
Marin-Neto JA, Marzullo P, Marcassa C, Gallo Junior L, Maciel BC, Bellina CR, et al. Myocardial perfusion abnormalities in chronic Chagas’ disease as detected by thallium-201 scintigraphy. Am J Cardiol 1992;69:780-4.
Hiss FC, Lascala TF, Maciel BC, Marin-Neto JA, Simoes MV. Changes in myocardial perfusion correlate with deterioration of left ventricular systolic function in chronic Chagas’ cardiomyopathy. JACC Cardiovasc Imaging 2009;2:164-72.
Torres CM. Arteriosclerosis of the fine arterial branches of the myocardium (Chagas’ coronaritis) & focal myocytolysis in chronic Chagas’ heart disease. Hospital (Rio J) 1958;54:597-610.
Higuchi ML. Endomyocardial biopsy in Chagas’ heart disease: pathogenetic contributions. Sao Paulo Med J 1995;113:821-5.
Oliveira LFL, Carvalho EEV, Romano MMD, Mejia J, Tanaka DM, Abdalla DR et al. Regional myocardial perfusion disturbance in experimental model of chronic Chagas cardiomyopathy. In: European Heart Journal European Society of Cardiology Congress. Barcelona, Spain; 2017. p. 5413.
Bilate AM, Salemi VM, Ramires FJ, de Brito T, Silva AM, Umezawa ES, et al. The Syrian hamster as a model for the dilated cardiomyopathy of Chagas’ disease: a quantitative echocardiographical and histopathological analysis. Microbes Infect 2003;5:1116-24.
Mall G, Schikora I, Mattfeldt T, Bodle R. Dipyridamole-induced neoformation of capillaries in the rat heart. Quantitative stereological study on papillary muscles. Lab Investig 1987;57:86-93.
Mattfeldt T, Mall G. Dipyridamole-induced capillary endothelial cell proliferation in the rat heart–a morphometric investigation. Cardiovasc Res 1983;17:229-37.
Umezawa ES, Nascimento MS, Kesper N Jr, Coura JR, Borges-Pereira J, Junqueira AC, et al. Immunoblot assay using excreted-secreted antigens of Trypanosoma cruzi in serodiagnosis of congenital, acute, and chronic Chagas’ disease. J Clin Microbiol 1996;34:2143-7.
Mejia J, Galvis-Alonso OY, Castro AA, Braga J, Leite JP, Simoes MV. A clinical gamma camera-based pinhole collimated system for high resolution small animal SPECT imaging. Braz J Med Biol Res 2010;43:1160-6.
Oliveira LF, Mejia J, Carvalho EE, Lataro RM, Frassetto SN, Fazan R Jr, et al. Myocardial infarction area quantification using high-resolution SPECT images in rats. Arq Bras Cardiol 2013;101:59-67.
Oliveira LFL, Romano MMD, Carvalho EEV, Mejia J, Salgado HC, Fazan R Jr, et al. Histopathological correlates of global and segmental left ventricular systolic dysfunction in experimental chronic chagas cardiomyopathy. J Am Heart Assoc 2016;5:e002786.
Simoes MV, Pintya AO, Bromberg-Marin G, Sarabanda AV, Antloga CM, Pazin-Filho A, et al. Relation of regional sympathetic denervation and myocardial perfusion disturbance to wall motion impairment in Chagas’ cardiomyopathy. Am J Cardiol 2000;86:975-81.
Schuster JP, Schaub GA. Experimental Chagas disease: the influence of sex and psychoneuroimmunological factors. Parasitol Res 2001;87:994-1000.
Assuncao AN Jr, Jerosch-Herold M, Melo RL, Mauricio AV, Rocha L, Torreao JA, et al. Chagas’ heart disease: gender differences in myocardial damage assessed by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2016;18:88.
Hayashi D, Ohshima S, Isobe S, Cheng XW, Unno K, Funahashi H, et al. Increased (99 m)Tc-Sestamibi washout reflects impaired myocardial contractile and relaxation reserve during dobutamine stress due to mitochondrial dysfunction in dilated cardiomyopathy patients. J Am Coll Cardiol 2013;61:2007-17.
Tatsumi T, Matoba S, Kawahara A, Keira N, Shiraishi J, Akashi K, et al. Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes. J Am Coll Cardiol 2000;35:1338-46.
Ferreira LR, Frade AF, Baron MA, Navarro IC, Kalil J, Chevillard C, et al. Interferon-gamma and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy. World J Cardiol 2014;6:782-90.
Zabalgoitia M, Ventura J, Lozano JL, Anderson L, Carey KD, Hubbard GB, et al. Myocardial contrast echocardiography in assessing microcirculation in baboons with chagas disease. Microcirculation 2004;11:271-8.
Abdelmoneim SS, Basu A, Bernier M, Dhoble A, Abdel-Kader SS, Pellikka PA, et al. Detection of myocardial microvascular disease using contrast echocardiography during adenosine stress in type 2 diabetes mellitus: prospective comparison with single-photon emission computed tomography. Diab Vasc Dis Res 2011;8:254-61.
Bult H, Fret HR, Jordaens FH, Herman AG. Dipyridamole potentiates the anti-aggregating and vasodilator activity of nitric oxide. Eur J Pharmacol 1991;199:1-8.
Chakrabarti S, Freedman JE. Dipyridamole, cerebrovascular disease, and the vasculature. Vascul Pharmacol 2008;48:143-9.
Houslay MD, Sullivan M, Bolger GB. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol 1998;44:225-342.
Nyby MD, Hori MT, Ormsby B, Gabrielian A, Tuck ML. Eicosapentaenoic acid inhibits Ca2+ mobilization and PKC activity in vascular smooth muscle cells. Am J Hypertens 2003;16:708-14.
Sakuma I, Akaishi Y, Fukao M, Makita Y, Makita MA, Kobayashi T, et al. Dipyridamole potentiates the anti-aggregating effect of endothelium-derived relaxing factor. Thromb Res Suppl 1990;12:87-90.
Kukreja RC, Salloum FN, Das A, Koka S, Ockaili RA, Xi L. Emerging new uses of phosphodiesterase-5 inhibitors in cardiovascular diseases. Exp Clin Cardiol 2011;16:e30-5.
Venkatesh PK, Pattillo CB, Branch B, Hood J, Thoma S, Illum S, et al. Dipyridamole enhances ischaemia-induced arteriogenesis through an endocrine nitrite/nitric oxide-dependent pathway. Cardiovasc Res 2010;85:661-70.
Petkova SB, Huang H, Factor SM, Pestell RG, Bouzahzah B, Jelicks LA, et al. The role of endothelin in the pathogenesis of Chagas’ disease. Int J Parasitol 2001;31:499-511.
Rossi MA, Goncalves S, Ribeiro-dos-Santos R. Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice. The potential role of intravascular platelet aggregation in its genesis. Am J Pathol 1984;114:209-16.
Factor SM, Cho S, Wittner M, Tanowitz H. Abnormalities of the coronary microcirculation in acute murine Chagas’ disease. Am J Trop Med Hyg 1985;34:246-53.
Schwartz RG, Wexler O. Early identification and monitoring progression of Chagas’ cardiomyopathy with SPECT myocardial perfusion imaging. JACC Cardiovasc Imaging 2009;2:173-5.
Disclosures
Denise Mayumi Tanaka, Luciano Fonseca Lemos de Oliveira, José Antônio Marin-Neto, Minna Moreira Dias Romano, Eduardo Elias Vieira de Carvalho, Antonio Carlos Leite de Barros Filho, Fernando Fonseca França Ribeiro, Jorge Mejia Cabeza, Carla Duque Lopes, Camila Godoy Fabricio, Norival Kesper, Henrique Turin Moreira, Lauro Wichert-Ana, André Schmidt, Maria de Lourdes Higuchi, Edécio Cunha-Neto, and Marcus Vinícius Simões declare that they have no conflict of interest.
Funding
This study was supported by a research grant from Fundação de Apoio à Pesquisa do Estado de São Paulo (FAPESP—Process: 2014/07722-4) and Fundação de Apoio ao Ensino Pesquisa e Assistência do Hospital das Clínicas (FAEPA).
Author information
Authors and Affiliations
Corresponding author
Additional information
All editorial decisions for this article, including selection of reviewers and the final decision, were made by guest editor Alberto Cuocolo, MD.
Rights and permissions
About this article
Cite this article
Tanaka, D.M., de Oliveira, L.F.L., Marin-Neto, J.A. et al. Prolonged dipyridamole administration reduces myocardial perfusion defects in experimental chronic Chagas cardiomyopathy. J. Nucl. Cardiol. 26, 1569–1579 (2019). https://doi.org/10.1007/s12350-018-1198-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12350-018-1198-7