Patogênese da miocardite chagásica crônica: o papel de fatores autoimunes e microvasculares

Rossi, Marcos A.; Mengel, José O.

doi:10.1590/S0036-46651992000600015

Resumos

A patogênese da miocardite chagásica crônica permanece incompletamente compreendida. Diferentes hipóteses têm sido propostas: (1) lesão direta do tecido pelo Trypanosoma cruzi;(2) teoria neurogênica; (3) reações imunológicas anti-miocárdio; e (4) doença microvascular. Apresentamos, no presente trabalho, uma hipótese alternativa. Acreditamos que o desenvolvimento da miocardite está relacionado à necrose celular focal progressiva e acumulativa, associada à fibrose intersticial reparativa e reativa e hipertrofia miocitária circunjacente. Esses processos seriam iniciados e perpetuados por fatores autoimunes e alterações na microcirculação do miocárdio. Esse mecanismo fisiopatogênico teria possíveis implicações em futuras estratégias terapêuticas no tratamento do paciente chagásico crônico visando otimizar o tratamento médico e auspiciosamente melhorar o prognóstico.

Miocardite chagásica crônica; Doença de Chagas; Trypanosoma cruzi; Cardiopatia chagásica; Miocardite

The pathogenesis of chronic chagasic myocarditis remains incompletely understood. Several hypotheses have been proposed: (1) direct tissue destruction by Trypanosoma cruzi; (2) neurogenic theory; (3) anti-heart immune reactions; and (4) microvascular disease. We present herein a dynamic alternative hypothesis. We believe that the development of myocarditis is related to progressive and additive focal cellular necrosis, and associated reactive and reparative myocardial fibrosis and surrounding myocytes hypertrophy. These processes may be initiated and perpetuated by autoimmune factors and alterations in the myocardial microcirculation. This could imply future therapeutic strategies in the management of chronic chagasic patients to optimize the medical treatment and hopefully improve the prognosis.

PONTO DE VISTA

Patogênese da miocardite chagásica crônica: o papel de fatores autoimunes e microvasculares

Chronic chagasic myocarditis pathogenesis: dependence on autoimmune and microvascular factors

Marcos A. Rossi^I; José O. Mengel^II

^IDepartamento de Patologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Pesquisador 1A do Conselho Nacional de Desenvolvimento Científico e Tecnológico (Proc. 301109/79-6)

^IIDepartamento de Parasitologia, Microbiologia e Imunologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo

^{Endereço para correspondência} Endereço para correspondência: Prof. Dr. Marcos A. Rossi Professor Titular de Patologia, Departamento de Patologia Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo 14049 - Ribeirão Preto, S.P., Brasil

RESUMO

A patogênese da miocardite chagásica crônica permanece incompletamente compreendida. Diferentes hipóteses têm sido propostas: (1) lesão direta do tecido pelo Trypanosoma cruzi;(2) teoria neurogênica; (3) reações imunológicas anti-miocárdio; e (4) doença microvascular. Apresentamos, no presente trabalho, uma hipótese alternativa. Acreditamos que o desenvolvimento da miocardite está relacionado à necrose celular focal progressiva e acumulativa, associada à fibrose intersticial reparativa e reativa e hipertrofia miocitária circunjacente. Esses processos seriam iniciados e perpetuados por fatores autoimunes e alterações na microcirculação do miocárdio. Esse mecanismo fisiopatogênico teria possíveis implicações em futuras estratégias terapêuticas no tratamento do paciente chagásico crônico visando otimizar o tratamento médico e auspiciosamente melhorar o prognóstico.

Unitermos: Miocardite chagásica crônica; Doença de Chagas; Trypanosoma cruzi; Cardiopatia chagásica; Miocardite.

SUMMARY

The pathogenesis of chronic chagasic myocarditis remains incompletely understood. Several hypotheses have been proposed: (1) direct tissue destruction by Trypanosoma cruzi; (2) neurogenic theory; (3) anti-heart immune reactions; and (4) microvascular disease. We present herein a dynamic alternative hypothesis. We believe that the development of myocarditis is related to progressive and additive focal cellular necrosis, and associated reactive and reparative myocardial fibrosis and surrounding myocytes hypertrophy. These processes may be initiated and perpetuated by autoimmune factors and alterations in the myocardial microcirculation. This could imply future therapeutic strategies in the management of chronic chagasic patients to optimize the medical treatment and hopefully improve the prognosis.

Texto completo disponível apenas em PDF.

Full text available only in PDF format.

Recebido para publicação em 26/03/1992.

Aceito para publicação em 22/05/1992.

Financiado pelo Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

1. AMORIM, D.S.; GODOY, R.A.; MANÇO, J.C.; TANAKA, A. & GALLO Jr, L. - Effects of acute elevation in blood pressure and of atropine on heart rate in Chagas' disease. A preliminary report. Circulation, 38: 289-294, 1968.
2. ANDRADE, Z.A. - Mechanisms of myocardial damage in Trypanosoma cruzi infection. In: CIBA FOUNDATION SYMPOSIUM 99. Cytopathology of Parasitic Diseases, Ciba Foundation Symposium 99. London, Pitmann Books, 1983, p. 214-233.
3. ANDRADE, Z.A.; ANDRADE, S.G. & SADIGURSKY, M. - Enhancement of chronic Trypanosoma cruzi myocarditis in dogs treated with low doses of cyclosphosphamide. Amer. J. Path., 127: 467-473, 1987.
4. BEN YOUNES-CHENNOUFI, A.B.; SAID, G.; EISEN, H.; DURAND, A. & HONTEBEYRIE-JOSKOWICZ, M. - Cellular immunity to Trypanosoma cruzi is mediated by helper T cells (CD4+). Trans. roy. Soc. trop. Med. Hyg., 82: 84-89, 1989.
5. BONADONNA, G.; LECHI, C.; CORRADINI, P.; SINIGAGLIA, D.; TOGNI, P.D. & MIROSLAWA, G. - Verapamil inhibits platelet aggregation by a calcium independent mechanism. Thromb. Haemost., 56: 308-310, 1986.
6. BRITO, T. & VASCONCELOS, E. - Necrotizing arteritis in megaesophagus. Histopathology of ninety-one biopsies taken from the cardia. Rev. Inst. Med. trop. S. Paulo, 1: 195-206, 1959.
7. COBBOLD, S.P.; JAYASURIYA, A.; NASH, A.; PROSPERO, T.D. & WALDMANN, H. - Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature, 312: 548-551, 1984.
8. DAVILA, D.F.; ROSSELL, R.O. & DONIS, J.H. - Cardiac parasympathetic abnormalities: cause or consequence of Chagas' heart disease? Parasit. today, 5: 327-329, 1989.
9. FACTOR, S.M.; OKUN, E.M. & MINASE, T. - Capillary microaneurysms in the human diabetic heart. New Engl. J. Med., 302: 384-388, 1980.
10. FACTOR, S.M. & SONNENBLICK, E.H. - Hypothesis: is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (microvascular spasm)? Amer. J. Cardiol., 50: 1149-1152, 1982.
11. FACTOR, S.M.; MINASE, T.; CHO, S.; FEIN, F.; CAPASSO, J.M. & SONNENBLICK, E.H. - Coronary microvascular abnormalities in the hypertensive-diabetic rat: a primary cause of cardiomyopathy? Amer. J. Path., 116: 9-20, 1984.
12. FACTOR, S.M.; CHO, S.; WITTNER, M. & TANOWTTZ, H. - Abnormalities of the coronary micro-circulation in acute murine Chagas' disease. Amer. J. trop. Med. Hyg., 34: 246-253, 1985.
13. GAY, D.; MADDON, P.; SEKALY, R.; TALLE, M.A.; GODFREY, M.; LONG, E.; GOLDSTEIN, G.; CHESS, L.; AXEL, R.; KAPPLER, J. & MARRACK, P. - Functional interaction between human T cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature, 328: 626-629, 1987.
14. HAGAR, J.M.; TUBAU, J.F. & RAHIMTOOLA, S.H. - Chagas' heart disease in the USA: thallium abnormalities mimic coronary artery disease. Circulation, 84 (suppl. II): 631, 1991.
15. HONTEBEYRIE-JOSKOWICS, M.; SAID, G.; MILLON, G.; MARCHALL, G. & EISEN, H. - L3T4+ T cells able to mediate parasite-specific delayed type hypersensitivity play a role in the pathology of experimental Chagas' disease. Europ. J. Immunol., 17: 1027-1033, 1987.
16. JORG, M.E. - Tripanosomiasis cruzi; anarquia angiotopográfica por descapilarización mesenquimorreactiva, cofactor patogénico de la miocardiopatia crónica. Pren. med. argent., 61: 94-106, 1974.
17. KIERSZENBAUM, F. - Autoimmunity in Chagas' disease. J. Parasit., 72: 201-211, 1986.
18. KITAGAWA, S.; SATO, S.; HORI, S.; HAMAOKA, T. & FUJIWARA, H. - Induction of anti-allo-class I H-2 tolerance by inactivation of CD8+ helper T cells, and reversal of tolerance through introduction of third-party helper T cells. J. exp. Med., 172: 105-113, 1990.
19. KOBERLE, F. - Chagas' disease and Chagas syndromes: the pathology of American trypanosomiasis. Advanc. Parasit., 6: 63-116, 1968.
20. KOVACS, E.J. - Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol. today, 12: 17-23, 1991.
21. LOPES, E.R. & TAFURI, W.L. - Involvement of the autonomic nervous system in Chagas' heart disease. Rev. Soc. bras. Med. trop., 16: 206-212, 1983.
22. MARIN-NETO, J.A.; MARZULLO, P.; MASCASSA, C.; GALLO Jr, L.; MACIEL, B.C.; BELLINA, C.R. & L'ABBATE, A. - Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy. J. Amer. Coll. Cardiol., 15: 240A, 1990.
23. MINOPRIO, P.; EISEN, H.; JOSKOWICZ, M.; PEREIRA, P. & COUTTNHO A. - Suppression of polyclonal antibody production in Trypanosoma cruzi - infected mice by treatment with anti-L3T4 antibodies. J. Immunol., 139: 545-550, 1987.
24. MINOPRIO, P.; ITOHARA, S.; HEUSSER, C.; TONEGAWA, S. & COUTINHO, A. - Immunobiology of murine T. cruzi infection: the predominance of parasite-nonspecific responses and the activation of TCRI T cells. Immun. Rev., 112: 183-207, 1989.
25. MORRIS, S.A.; WEISS, L.M.; FACTOR, S.; BILEZIKIAN, J.P.; TANOWITZ, H.B. & WITTNER, M. - Verapamil ameliorates clinical, pathological and biochemical manifestations of experimental chagasic cardiomyopathy in mice. J. Amer. Coll. Cardiol., 14: 782-789, 1989.
26. MORRIS, S.A.; TANOWITZ H.B.; WITTNER, M. & BILEZIKIAN, J.P. - Pathophysiological insights into the cardiomyopathy of Chagas' disease. Circulation, 82: 1900-1909, 1990.
27. MOSMANN, T.R.; CHERWINSKI, H.; BOND, M.W.; GIEDLIN, M.A. & COFFMAN, R.L. - Two types of murine helper T cell clone. 1. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol., 136: 2348-2355, 1986.
28. OKUMURA, M.; BRITO, T.; PEREIRA da SILVA, L.H.; CARVALHO-da-SILVA, A. & CORREA-NETO, A. - The pathology of experimental Chagas' disease in mice. I. Digestive tract changes with special reference to necrotizing arteritis. Rev. Inst. Med. trop. S. Paulo, 2: 17-18, 1960.
29. OLIVEIRA, J.S.M. - A natural model of intrinsic heart nervous system denervation: Chagas' cardiopathy. Amer. Heart J., 110: 1092-1098, 1985.
30. RIBEIRO dos SANTOS, R. & HUDSON, L. - Trypanosoma cruzi: immunological consequences of parasite modification of host cells. Clin. exp. Immunol., 30: 36-41, 1980.
31. RIBEIRO dos SANTOS, R. & ROSSI, M.A. - Imunopatologia. In: CANÇADO, J.R. & CHUSTER, M. ed. Cardiopatia Chagásica. Belo Horizonte, Fundaçăo Carlos Chagas, 1985. p. 10-22.
32. RIBEIRO dos SANTOS, R.; ROSSI, M.A.; LAUS, J.L.; SANTANA SILVA, J.; SAVINO, W. & MENGEL, J. - Anti-CD4 abrogates rejection and reestablishes long-term tolerance to syngeneic newbom hearts grafted in mice chronically infected with Trypanosoma cruzi. J. exp. Med., 175: 29-39, 1992.
33. RIZZO, L.V.; CUNHA-NETO, E. & TEIXEIRA, A.R.L. - Autoimmunity in Chagas' disease: specific inhibition of reactivity of CD4+ T cells against myosin in mice chronically infected with Trypanosoma cruzi. Infect. Immun., 57: 2640-2644, 1989.
34. ROSSI, M.A.; GONÇALVES, S. & RIBEIRO dos SANTOS, R. - Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice. The potential role of intravascular platelet aggregation in its genesis. Amer. J. Path., 114: 209-216, 1984.
35. ROSSI, M.A. & CAROBREZ, S.G. - Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice: histochemical evidence of hypoxic changes in the myocardium. Brit. J. exp. Path., 66: 155-160, 1985.
36. ROSSI, M.A. - Microvascular changes as a cause of chronic cardiomyopathy in Chagas' disease. Amer. Heart J., 120: 233-236, 1990.
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38. RUSSO, M.; STAROBINAS, N.; MINOPRIO, P.; COUTINHO, A. & HONTEBEYRIE-JOSKOWICZ, M. - Parasitic load increases and myocardial inflammation decreases in Trypanosoma cruzi infected mice after inactivation of helper T cells. Ann. Inst. Pasteur Immunol. (Paris), 139: 225-236, 1988.
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Endereço para correspondência:

Prof. Dr. Marcos A. Rossi

Professor Titular de Patologia, Departamento de Patologia

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo

14049 - Ribeirão Preto, S.P., Brasil

Datas de Publicação

Publicação nesta coleção
11 Set 2006
Data do Fascículo
Dez 1992

Histórico

Aceito
22 Maio 1992
Recebido
26 Mar 1992

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1. AMORIM, D.S.; GODOY, R.A.; MANÇO, J.C.; TANAKA, A. & GALLO Jr, L. - Effects of acute elevation in blood pressure and of atropine on heart rate in Chagas' disease. A preliminary report. Circulation, 38: 289-294, 1968.

[2] 2. ANDRADE, Z.A. - Mechanisms of myocardial damage in Trypanosoma cruzi infection. In: CIBA FOUNDATION SYMPOSIUM 99. Cytopathology of Parasitic Diseases, Ciba Foundation Symposium 99. London, Pitmann Books, 1983, p. 214-233.

[3] 3. ANDRADE, Z.A.; ANDRADE, S.G. & SADIGURSKY, M. - Enhancement of chronic Trypanosoma cruzi myocarditis in dogs treated with low doses of cyclosphosphamide. Amer. J. Path., 127: 467-473, 1987.

[4] 4. BEN YOUNES-CHENNOUFI, A.B.; SAID, G.; EISEN, H.; DURAND, A. & HONTEBEYRIE-JOSKOWICZ, M. - Cellular immunity to Trypanosoma cruzi is mediated by helper T cells (CD4+). Trans. roy. Soc. trop. Med. Hyg., 82: 84-89, 1989.

[5] 5. BONADONNA, G.; LECHI, C.; CORRADINI, P.; SINIGAGLIA, D.; TOGNI, P.D. & MIROSLAWA, G. - Verapamil inhibits platelet aggregation by a calcium independent mechanism. Thromb. Haemost., 56: 308-310, 1986.

[6] 6. BRITO, T. & VASCONCELOS, E. - Necrotizing arteritis in megaesophagus. Histopathology of ninety-one biopsies taken from the cardia. Rev. Inst. Med. trop. S. Paulo, 1: 195-206, 1959.

[7] 7. COBBOLD, S.P.; JAYASURIYA, A.; NASH, A.; PROSPERO, T.D. & WALDMANN, H. - Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature, 312: 548-551, 1984.

[8] 8. DAVILA, D.F.; ROSSELL, R.O. & DONIS, J.H. - Cardiac parasympathetic abnormalities: cause or consequence of Chagas' heart disease? Parasit. today, 5: 327-329, 1989.

[9] 9. FACTOR, S.M.; OKUN, E.M. & MINASE, T. - Capillary microaneurysms in the human diabetic heart. New Engl. J. Med., 302: 384-388, 1980.

[10] 10. FACTOR, S.M. & SONNENBLICK, E.H. - Hypothesis: is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (microvascular spasm)? Amer. J. Cardiol., 50: 1149-1152, 1982.

[11] 11. FACTOR, S.M.; MINASE, T.; CHO, S.; FEIN, F.; CAPASSO, J.M. & SONNENBLICK, E.H. - Coronary microvascular abnormalities in the hypertensive-diabetic rat: a primary cause of cardiomyopathy? Amer. J. Path., 116: 9-20, 1984.

[12] 12. FACTOR, S.M.; CHO, S.; WITTNER, M. & TANOWTTZ, H. - Abnormalities of the coronary micro-circulation in acute murine Chagas' disease. Amer. J. trop. Med. Hyg., 34: 246-253, 1985.

[13] 13. GAY, D.; MADDON, P.; SEKALY, R.; TALLE, M.A.; GODFREY, M.; LONG, E.; GOLDSTEIN, G.; CHESS, L.; AXEL, R.; KAPPLER, J. & MARRACK, P. - Functional interaction between human T cell protein CD4 and the major histocompatibility complex HLA-DR antigen. Nature, 328: 626-629, 1987.

[14] 14. HAGAR, J.M.; TUBAU, J.F. & RAHIMTOOLA, S.H. - Chagas' heart disease in the USA: thallium abnormalities mimic coronary artery disease. Circulation, 84 (suppl. II): 631, 1991.

[15] 15. HONTEBEYRIE-JOSKOWICS, M.; SAID, G.; MILLON, G.; MARCHALL, G. & EISEN, H. - L3T4+ T cells able to mediate parasite-specific delayed type hypersensitivity play a role in the pathology of experimental Chagas' disease. Europ. J. Immunol., 17: 1027-1033, 1987.

[16] 16. JORG, M.E. - Tripanosomiasis cruzi; anarquia angiotopográfica por descapilarización mesenquimorreactiva, cofactor patogénico de la miocardiopatia crónica. Pren. med. argent., 61: 94-106, 1974.

[17] 17. KIERSZENBAUM, F. - Autoimmunity in Chagas' disease. J. Parasit., 72: 201-211, 1986.

[18] 18. KITAGAWA, S.; SATO, S.; HORI, S.; HAMAOKA, T. & FUJIWARA, H. - Induction of anti-allo-class I H-2 tolerance by inactivation of CD8+ helper T cells, and reversal of tolerance through introduction of third-party helper T cells. J. exp. Med., 172: 105-113, 1990.

[19] 19. KOBERLE, F. - Chagas' disease and Chagas syndromes: the pathology of American trypanosomiasis. Advanc. Parasit., 6: 63-116, 1968.

[20] 20. KOVACS, E.J. - Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol. today, 12: 17-23, 1991.

[21] 21. LOPES, E.R. & TAFURI, W.L. - Involvement of the autonomic nervous system in Chagas' heart disease. Rev. Soc. bras. Med. trop., 16: 206-212, 1983.

[22] 22. MARIN-NETO, J.A.; MARZULLO, P.; MASCASSA, C.; GALLO Jr, L.; MACIEL, B.C.; BELLINA, C.R. & L'ABBATE, A. - Myocardial perfusion abnormalities in chronic Chagas' disease as detected by thallium-201 scintigraphy. J. Amer. Coll. Cardiol., 15: 240A, 1990.

[23] 23. MINOPRIO, P.; EISEN, H.; JOSKOWICZ, M.; PEREIRA, P. & COUTTNHO A. - Suppression of polyclonal antibody production in Trypanosoma cruzi - infected mice by treatment with anti-L3T4 antibodies. J. Immunol., 139: 545-550, 1987.

[24] 24. MINOPRIO, P.; ITOHARA, S.; HEUSSER, C.; TONEGAWA, S. & COUTINHO, A. - Immunobiology of murine T. cruzi infection: the predominance of parasite-nonspecific responses and the activation of TCRI T cells. Immun. Rev., 112: 183-207, 1989.

[25] 25. MORRIS, S.A.; WEISS, L.M.; FACTOR, S.; BILEZIKIAN, J.P.; TANOWITZ, H.B. & WITTNER, M. - Verapamil ameliorates clinical, pathological and biochemical manifestations of experimental chagasic cardiomyopathy in mice. J. Amer. Coll. Cardiol., 14: 782-789, 1989.

[26] 26. MORRIS, S.A.; TANOWITZ H.B.; WITTNER, M. & BILEZIKIAN, J.P. - Pathophysiological insights into the cardiomyopathy of Chagas' disease. Circulation, 82: 1900-1909, 1990.

[27] 27. MOSMANN, T.R.; CHERWINSKI, H.; BOND, M.W.; GIEDLIN, M.A. & COFFMAN, R.L. - Two types of murine helper T cell clone. 1. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol., 136: 2348-2355, 1986.

[28] 28. OKUMURA, M.; BRITO, T.; PEREIRA da SILVA, L.H.; CARVALHO-da-SILVA, A. & CORREA-NETO, A. - The pathology of experimental Chagas' disease in mice. I. Digestive tract changes with special reference to necrotizing arteritis. Rev. Inst. Med. trop. S. Paulo, 2: 17-18, 1960.

[29] 29. OLIVEIRA, J.S.M. - A natural model of intrinsic heart nervous system denervation: Chagas' cardiopathy. Amer. Heart J., 110: 1092-1098, 1985.

[30] 30. RIBEIRO dos SANTOS, R. & HUDSON, L. - Trypanosoma cruzi: immunological consequences of parasite modification of host cells. Clin. exp. Immunol., 30: 36-41, 1980.

[31] 31. RIBEIRO dos SANTOS, R. & ROSSI, M.A. - Imunopatologia. In: CANÇADO, J.R. & CHUSTER, M. ed. Cardiopatia Chagásica. Belo Horizonte, Fundaçăo Carlos Chagas, 1985. p. 10-22.

[32] 32. RIBEIRO dos SANTOS, R.; ROSSI, M.A.; LAUS, J.L.; SANTANA SILVA, J.; SAVINO, W. & MENGEL, J. - Anti-CD4 abrogates rejection and reestablishes long-term tolerance to syngeneic newbom hearts grafted in mice chronically infected with Trypanosoma cruzi. J. exp. Med., 175: 29-39, 1992.

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