Resumen
A más de 110 años del descubrimiento de la enfermedad de Chagas, aún se desconocen aspectos sobre los mecanismos implicados en la fisiopatología del daño cardiaco. Anteriormente se consideraba al Trypanosoma cruzi como el único causante de la lesión en el miocardio. Ahora se conocen otros mecanismos implicados en la fisiopatología, como la respuesta inmunitaria-inflamatoria, la autoinmunidad, las anomalías microvasculares y el daño nervioso, los cuales se encuentran interrelacionados para contribuir en el daño cardiaco. En la actualidad se reconoce al parásito como el principal causante del daño durante la etapa aguda y el que inicia la compleja red fisiopatológica que desencadena los otros mecanismos mencionados. El resultado de todos estos mecanismos fisiopatológicos es el deterioro progresivo de la función cardiaca, lo cual termina por establecer la cardiomiopatía chagásica crónica. El propósito de esta revisión es describir y discutir los principales mecanismos fisiopatológicos que se postulan con respecto al daño cardiaco en la infección por T. cruzi.
Abstract
More than 110 years after Chagas disease discovery, some aspects of the mechanisms involved in the physiopathology of heart damage are still unknown. Previously, Trypanosoma cruzi was considered to be the only cause of myocardial injury. Currently, there are other known mechanisms involved in the physiopathology of Chagas heart disease, including the immune-inflammatory response, autoimmunity, microvascular abnormalities and nerve damage, which are interrelated and contribute to cardiac damage. Nowadays, the parasite is the main cause of cardiac damage during the acute stage of Chagas disease and the one that initiates the complex physiopathological network that triggers the other mentioned mechanisms. The consequence of these pathophysiological mechanisms is progressive deterioration of cardiac function that ultimately establishes Chronic Chagasic cardiomyopathy. The aim of this review is to describe and discuss the main physiopathological mechanisms that are currently being postulated with respect to cardiac damage in T. cruzi infection.
Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2018;391:82-94. doi:10.1016/S0140-6736(17)31612-4
Arnal A, Waleckx E, Dumonteil E. Estimating the current burden of Chagas disease in Mexico:a systematic review and meta-analysis of epidemiological surveys from 2006-2017. PLoS Negl Trop Dis. 2019;13(4):e0006859. doi:10.1371/journal.pntd.0006859
Bern C, Kjos S, Yabsley MJ, Montgomery SP. Trypanosoma cruzi and Chagas'disease in the United States. Clin Microbiol Rev. 2011;24(4):655-81. doi:10.1128/CMR.00005-11
Salazar-Schettino PM, Bucio-Torres MI, Cabrera-Bravo M, Alba-Alvarado MC, Castillo-Saldaña DR, Zenteno-Galindo EA, et al. Enfermedad de Chagas en México. Rev Fac Med (Mex). 2016;59(3):6-16.
Newton-Sánchez OA, Espinoza-Gómez F, Melnikov V, Delgado-Enciso I, Rojas-Larios F, Dumonteil E, et al. Seroprevalencia y factores de riesgo a T. cruzi en Colima, México. Gac Med Mex. 2017;153(2):179-84.
Martin DL, Lowe KR, McNeill T, Thiele EA, Roellig DM, Zajdowicz J, et al. Potential sexual transmission of Trypanosoma cruzi in mice. Acta Trop. 2015;149:15-8. doi:10.1016/j.actatropica.2015.05.002
Blanco-Arreola FG, Nájera-Ortiz JC, Ruiz-Balbuena F. Frecuencia de serorreactividad a Chagas en un hospital de Chiapas, México. Rev Salud Publica Nutr. 2018;17(1):1-6.
Villanueva-Lizama L, Teh-Poot C, Majeau A, Herrera C, Dumonteil E. Molecular genotyping of Trypanosoma cruzi by next-generation sequencing of the mini-exon gene reveals infections with multiple parasite discrete typing units in chagasic patients from Yucatan, Mexico. J Infect Dis. 2019;219(12):1980-8. doi:10.1093/infdis/jiz047
Molina I, Salvador F, Sánchez-MontalváA. Actualización en enfermedad de Chagas. Enferm Infecc Microbiol Clin. 2016;34(2):132-8. doi:10.1016/j.eimc.2015.12.008
Rojo-Medina J, Ruiz-Matus C, Salazar-Schettino PM, González-Roldán JF. Enfermedad de Chagas en México. Gac Med Mex. 2018;154:605-12. doi:10.24875/GMM.18004515
Bern C. Chagas'disease. N Engl J Med. 2015;373(5):456-66. doi:10.1056/NEJMra1410150
Bonney KM, Luthringer DJ, Kim SA, Garg NJ, Engman DM. Pathology and pathogenesis of Chagas heart disease. Annu Rev Pathol. 2019;14:421-47. doi:10.1146/annurev-pathol-020117-043711
Hoffman KA, Reynolds C, Bottazzi ME, Hotez P, Jones K. Improved biomarker and imaging analysis for characterizing progressive cardiac fibrosis in a mouse model of chronic chagasic cardiomyopathy. J Am Heart Assoc. 2019;8(22):e013365. doi:10.1161/JAHA.119.013365
Simões VS, Dias-Romano MM, Schmidt A, Macedo-Martins KS, Marin-Neto JA. Chagas disease cardiomyopathy. Int J Cardiovasc Sci. 2018;31(2):173-89. doi:10.5935/2359-4802.20180011
Rassi A Jr, Marin JA, Rassi A. Chronic Chagas cardiomyopathy:a review of the main pathogenic mechanisms and the efficacy of aetiological treatment following the benznidazole evaluation for interrupting trypanosomiasis (BENEFIT) trial. Mem Inst Oswaldo Cruz. 2017;112(3):224-35. doi:10.1590/0074-02760160334
Lewis MD, Kelly JM. Putting infection dynamics at the heart of Chagas disease. Trends Parasitol. 2016;32(11):899-911. doi:10.1016/j.pt.2016.08.009
Nunes MCP, Beaton A, Acquatella H, Bern C, Bolger AF, Echeverría LE, et al. Chagas cardiomyopathy:an update of current clinical knowledge and management:a scientific statement from the American Heart Association. Circulation. 2018;138(12):e169-209. doi:10.1161/CIR.0000000000000599
Marin-Neto JA, Cunha-Neto E, Maciel BC, Simões MV. Pathogenesis of chronic Chagas heart disease. Circulation. 2007;115(9):1109-23. doi:10.1161/CIRCULATIONAHA.106.624296
Booney KM, Engman DM. Autoimmune pathogenesis of Chagas heart disease:looking back, looking ahead. Am J Pathol. 2015;185(6):1537-47. doi:10.1016/j.ajpath.2014.12.023
Ribeiro AL, Nunes MP, Teixeira MM, Rocha MO. Diagnosis and management of Chagas disease and cardiomyopathy. Nat Rev Cardiol. 2012;9(10):57-689. doi:10.1038/nrcardio.2012.109
De Bona E, Lidani KCF, Bavia L, Omidian Z, Gremski LH, Sandriet TL, et al. Autoimmunity in chronic Chagas disease:a road of multiple pathways to cardiomyopathy?Front Immunol. 2018;9:1842. doi:10.3389/fimmu.2018.01842
Teixeira AR, Hecht MM, Guimaro MC, Sousa AO, Nitz N. Pathogenesis of Chagas'disease:parasite persistence and autoimmunity. Clin Microbiol Rev. 2011;24(3):592-630. doi:10.1128/CMR.00063-10
Nogueira LG, Santos RH, Fiorelli AI, Mairena EC, Benvenuti LA, Bocchi EA, et al. Myocardial gene expression of T-bet, GATA-3, Ror-gt, FoxP3, and hallmark cytokines in chronic Chagas disease cardiomyopathy:an essentially unopposed TH1-type response. Mediators Inflamm. 2014;2014:914326. doi:10.1155/2014/914326
Guedes PM, Gutierrez FR, Silva GK, Dellalibera-Joviliano R, Rodrigues GJ, Bendhack LM, et al. Deficient regulatory T cell activity and low frequency of IL-17-producing T cells correlate with the extent of cardiomyopathy in human Chagas'disease. PLoS Negl Trop Dis. 2012;6(4):e1630. doi:10.1371/journal.pntd.0001630
Ferreira LR, Frade AF, Baron MA, Navarro IC, Kalil J, Chevillard C, et al. Interferon-g and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy. World J Cardiol. 2014;6(8):782-90. doi:10.4330/wjc.v6.i8.782
Machado F, Dutra W, Esper L, Gollob K, Teixeira M, Factor S, et al. Current understanding of immunity to Trypanosoma cruzi infection and pathogenesis of Chagas disease. Semin Immunopathol. 2012;34(6):753-70. doi:10.1007/s00281-012-0351-7
Bonney K, Engman D. Autoimmune pathogenesis of Chagas heart disease. Am J Pathol. 2015;185(6):1537-47. doi:10.1016/j.ajpath.2014.12.023
Chaves AT, Menezes CAS, Costa HS, Nunes MCP, Rocha MOC. Myocardial fibrosis in Chagas disease and molecules related to fibrosis. Parasite Immunol. 2019;41(10):e12663.
Gutierrez FR, Guedes PM, Gazzinelli RT, Silva JS. The role of parasite persistence in pathogenesis of Chagas heart disease. Parasite Immunol. 2009;31(11):673-85. doi:10.1111/j.1365-3024.2009.01108.x
Lescure FX, Le Loup G, Freilij H, Develoux M, Paris L, Brutus L, et al. Chagas disease:changes in knowledge and management. Lancet Infect Dis. 2010;10(8):556-70. doi:10.1016/S1473-3099(10)70098-0
Rossi MA, Tanowitz HB, Malvestio LM, Celes MR, Campos EC, Blefari V, et al. Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms. PLoS Negl Trop Dis. 2010;4(8):e674. doi:10.1371/journal.pntd.0000674
Scharfstein J, Andrade D. Infection-associated vasculopathy in experimental Chagas disease pathogenic roles of endothelin and kinin pathways. Adv Parasitol. 2011;76:101-27. doi:10.1016/B978-0-12-385895-5.00005-0
RoffêE, Souza ALS, Machado PP, Barcelos LS, Romanha AJ, Mariano FS, et al. Endothelin-1 receptors play a minor role in the protection against acute Trypanosoma cruzi infection in mice. Braz J Med Biol Res. 2007;40(3):391-9. doi:10.1590/s0100-879x2007000300015
González FB, Villar SR, Pacini MF, Bottasso OA, Pérez AR. Immune-neuroendocrine and metabolic disorders in human and experimental T. cruzi infection:new clues for understanding Chagas disease pathology. Biochim Biophys Acta Mol Basis Dis. 2020;1866(3):165642. doi:10.1016/j.bbadis.2019.165642
Nascimento BR, Araújo CG, Rocha MO, Domingues JD, Rodrigues AB, Barros MV, et al. The prognostic significance of electrocardiographic changes in Chagas disease. J Electrocardiol. 2012;45(1):43-8. doi:10.1016/j.jelectrocard.2011.04.011