[ Scientific Activities - Actividades Científicas ]Microvascular disturbances in Chagas heart disease
Dr. Marcus V. Simões
A considerable amount of clinical and experimental data
gives support to the concept that transitory ischemic events caused by functional
disturbances of coronary blood flow regulation is a relevant pathogenetic mechanism in
chronic Chagas cardiomyopathy1,2, 3 . In fact, atypical precordial chest pain,
usually prolonged and recurrent, but with no clear provocative factors, is a frequent and
disabling complaint by chagasic patients4 . Sometimes the symptom assumes an acute coronary syndrome presentation,
masquerading as acute myocardial infarction or unstable angina, but with normal coronary
arteries at angiographic studies 5,6,7 .
Its worth to note that investigations of esophagus, an organ often involved in
Chagas disease digestive tract manifestation, as a possible alternative source of
these angina-like symptoms has produced no conclusive results
8,9. Thus, considering the association between chest pain and
laboratory documentation of myocardial ischemia with normal coronary arteries ,
its conceivable to suppose the participation of functional alterations of the
arterial coronary bed in the genesis of that clinical set.
This hypothesis is primarily based on reports of hystopathological studies showing small coronary artery lesions 10,11,12,13,14,15 , and has been recently reinforced by experimental model observations and some scarce clinical reports 16,17,18,19,20,21.
Chronic Chagas myocarditis is characterized, fundamentally, by focal mononuclear inflammatory infiltrates associated to reactive interstitial fibrosis and myocitolytic necrosis.
Myocytolysis is a particular form of cell degeneration
apparently related to hypoxia secondary to low intensity repetitive ischemic episodes as
it has been observed in ischemia and reperfusion experimental models22. Moreover, the occurrence of flow disturbances at the microcirculatory level is
quite conceivable as the tissue lesion is focal, encompassing discrete cellular groups,
and the associated reparative interstitial fibrosis seems to be characteristic of chronic
hypoxic damage. These hystopathological aspects give support to the participation of
myocardial ischemia, depending on microvascular abnormalities, in the pathogenesis of
chronic Chagas myocardiopathy23.
Early pathological observations have already documented inflammatory lesions of small coronary vessels in humans, both in heart and digestive tract, and similar findings were also reported in murine experimental models. The topographic distribution of myocardial capillar chagasic vessels, in comparison to normal individuals, has shown areas of reduced vascularization. This named "mesenquimal-reactive decapillarization" seems to be secondary to extra-luminal compression, being responsible for the myocytolysis found in these hearts.
The course of the murine model of acute and chronic Chagas myocarditis reproduces quite closely the main pathological features seen in human disease. Platelet aggregation generating occlusive thrombi has been reported in small epicardial and intra-mural coronary vessels. Further studies in murine model, employing hystochemical methods has shown evidence of myocardial hypoxic alterations related to foci of myocitolitic necrosis . Furthermore, morphological studies of the microcirculation in mice with acute T. cruzi infection have demonstrated areas of focal vascular constriction, microaneurysm formation, dilatation, and proliferation of microvessels24. In addition, the use of verapamil, a calcium channel blocker (with vasodilatory action in small vessels and anti-platelet activity), achieved significant reduction in mortality and ameliorated myocardial tissue lesions in mice infected with T. cruzi.
The usage of the scintigraphic method for myocardial
blood flow distribution assessment in humans has also yielded results consonant with this
hypothesis. Rest Thallium-201 studies has shown marked heterogeneity in radiotracer
distribution in the majority of patients, that was significantly improved after prolonged
treatment with dypiridamole25. These findings were confirmed by myocardial perfusion studies in Chagas
heart disease patients employing rubdium-86 that showed reduced myocardial blood flow at
rest and poor increment during stress26. More recently, these observations were extended to
patients with chronic Chagas cardiomyopathy presenting precordial chest pain and
angiographically normal coronary arteries27 by Thallium201 myocardial perfusion studies at stress and rest. A high
frequency of perfusion defects in areas with normal left ventricular wall motion was
detected. All patients in that report had at least one segment of left ventricular wall
showing perfusion defects. Transient perfusion defects, ischemic or paradoxical (both
potentially related to abnormalities in regional blood flow) were predominantly found. The
evaluation of myocardial perfusion using scintigraphic images after intracoronary
injection of 99mTc-labeled-microespheres in chagasic patients with chest pain also yielded
positive results of prominent perfusion disturbances with normal coronary arteries.
Most recently, additional evidence for abnormal coronary blood flow regulation was obtained by assessment of flow responses to pharmacologic stimuli employing intra-coronary doppler studies. Paradoxical responses of flow reduction to acetilcholine, and attenuated vasodilation to adenosine were documented. These results indicate endothelial dysfunction as responsible for abnormal coronary vasodilation capacity.. Furthermore, abnormal vasoconstrictor behavior of epicardial coronary artery vessels was observed in chagasic patients with precordial chest pain submitted to the hyperventilation stimulus.
The time course relationship between myocardial ischemia and development of regional myocardial contraction disturbances has been recently addressed28. In this study three groups of patients with progressive severity of Chagas disease myocardial damage were studied with stress-rest Thallium-201 myocardial scintigraphy. A high incidence of perfusion defects was documented even in patients asymptomatic with normal EKG, and global and segmental normal LV function. About 40% of perfusion defects in each group were ischemic and occurred with normal coronary arteries (Figure A shows an example of one patient of this series with reversible perfusion defect in the inferior and lower septal regions. In each projection, the top, middle and lower panels represent respectively the stress, redistribution and rest reinjection of the tracer). More extensive perfusion defects were found in groups with more severe heart disease and global LV dysfunction. A significant positive correlation was found between the total area of abnormal myocardial perfusion and decrease in LV ejection fraction. Furthermore, a very significant topographic relationship was found between ischemic defects and abnormal segmental contraction. These findings strongly suggest that myocardial ischemia depending on functional coronary blood flow regulation participates in the genesis of myocardial damage in CHD.
However, the actual interpretation of these findings should consider the disease main pathogenic process, namely the inflammatory process. In this sense, most probably the functional disturbances in flow regulation may happen secondarily to action of vasoactive substances produced by the inflammatory infiltrate, like cytokines, and Thromboxan-A2 delivered by platelets aggregation. Ultra-structural studies have suggested that the aggression to small vessels wall is also related to immune effector cell aggression29. So, even though the myocardial ischemia constitutes conspicuous phenomena, it likely plays an ancillary role in the pathogenetic complex of chronic Chagas myocarditis and most probably acts as an amplification factor in producing myocardial damage.
1. Morris SA, Tanowitz HB, Wittner M, Bilezikian
JP. Pathophysiological insights into the cardimyopathy of Chagas disease. Circulation
1990; 82: 1900-1909.
2. Rossi MA. Microvascular changes as a cause of chronic cardiomyopathy in Chagas' disease. Am Heart J 1990; 120:233-6.
3. Mengel JO, Rossi MA. Chronic chagasic myocarditis pathogenesis: dependence on autoimmune and microvascular factors. Am Heart J 1992; 124: 1052-57.
4. Marin-Neto JA, Simões MV, Maciel BC. Specific diseases: Cardiomyopathies and pericardial diseases. Other Cardiomyopathies, In: Evidence Based Cardiology. Yusuf S, Cairns J, Camn J, Falen E, Gersh BJ, Eds. BMJ Books, Brit Medical Association, London GB, pp. 744-761, 1998.
5. Feit A, El-Sherif N, Korostoff S. Chagas disease masqerading as coronary artery disease. Arch Intern Med 1983; 143: 144-5.
6. Simões MV, Ayres EM, Santos JLA, Schmidt A, Pintya AO, Maciel BC, Marin-Neto JÁ. Detection of myocardial ischemia in Chagas disease patients with angina-like symptoms by effort test and holter monitoring. Arq Bras Cardiol 1993; 60: 315-319.
7. Hagar JM, Rahimtoola SH. Chagas' heart disease in the United States. N Engl J Med 1991; 325: 763-8.
8. Simões MV, Dantas RO, Ejima FH, Meneghelli UG, Maciel BC, Marin-Neto JÁ. Origem esofágica da dor precordial em pacientes chagásicos com artérias coronárias normais. Arq Bras Cardiol 1995; 64: 103-7.
9. Ejima FH, Dantas RO, Simões MV, Marin-Neto JA, Meneghelli UG. Intraesophageal balloon distension test in Chagas disease patients with noncardiac chest pain. Dig Dis Sci 1998; 43: 2567-71.
10. Torres CM. Miocitólise e fibrose do miocárdio na doença de Chagas. Mem Inst Osw Cruz 1960; 58(2): 161-182.
11. Torres CM. Arterioloesclerose das finas ramificações arteriais do miocárdio (coronarite chagásica) e miocitólise focal do miocárdio na cardiopatia chagásica crônica. O Hospital 1958; 54(5): 19-34.
12. Brito T, Vasconcelos E. Necrotizing arteritis in megaesophagus. Histopathology of ninety one biopsies taken from the cardia. Rev Inst Med Trop São Paulo 1959; 1(3): 195-206.
13. Okamura M, Brito T, Pereira-da-Silva LH, Carvalho-da-Silva A, Correa-Netto A. The pathology of experimental Chagas disease in mice: digestive tract changes, with reference to necrotizing arterites. Rev Inst Med Trop São Paulo 1960; 2(1): 17-28.
14. Jörg ME. Tripanosomiasis cruzi; anarquia angiotopográfica por descapilarizacion mesenquimoreactiva, cofactor patogénico de la miocardiopatia crónica. Pren Med Argent 1974; 61:94-106.
15. Ferrans VJ, Milei J, Tomita Y, Storino RA. Basement membrane thickening in cardiac myocites and capillaries in chronic Chagas disease. Am J Cardiol 1988; 61:1137-1140.
16. Rossi MA, Gonçalves S, Ribeiro-dos-Santos R. Experimental Trypanosoma cruzi cadiomyopathy in BALB/c mice: the potential role of intravascular platelet aggregation in its genesis. Am J Pathol 1984; 114:209-16.
17. Rossi MA, Carobrez SG. Experimental Trypanosoma cruzi cardiomyopathy in BALB/c mice: histochemical evidence of hypoxic changes in the myocardium. Br J Exp Pathol 1985; 66:155-60.
18. Morris SA, Weiss LM, Factor S, Bilezikian JP, Tanowitz HB, Wittner M. Verapamil amiliorates clinical, pathological and biochemical manifestations of experimental chagasic cardiomyopathy in mice. J Am Coll Cardiol 1989; 14:782-789.
19. Marin-Neto JA, Marzullo P, Marcassa et al. Myocardial perfusion abnormalities in chronic Chagas disease as detected by Thallium-201 scintigraphy. Am J Cardiol 1992; 69:780-4.
20. Torres FW, Acquatella H, Condado J, Dinsmore R, Palacios I. Coronary vascular reactivity is abnormal in patients with Chagas' heart disease. Am Heart J 1995; 129: 995-1001.
21. Simões MV, Ayres-Neto EM, Attab-Santos JL, Maciel BC, Marin-Neto JA. Chagas' heart patients without cardiac enlargement have impaired epicardial coronary vasodilation but no vasotonic angina. J Am Coll Cardiol 1996; 27: 394-395A.
22. Baroldi G. Different types of myocardial necrosis in coronary heart disease: a pathophysiologic review of their functional significance. Am Heart J 1975; 89: 742-52.
23. Rossi MA, Ramos SG. Alterações microvasculares coronarianas na doença de Chagas. Arq Bras Cardiol 1996; 66: 169-72.
24. 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(2): 246-53.
25. Rotondaro D, Castelleti LJ, Rios V, Nivayuolo J, Di Nunzio H, Smith A, Gallardo EA. Cambios en las imagenes de perfusion miocardica com Talio 201 en pacientes com miocardiopatía Chagásica crónica, despues del tratamiento com dipiridamol. Rev Arg Cardiol 1979; 47: 129-136.
26. Kuschnir E, Epelman M, Kutich F, Santamarina N, Podio RB. Valoración del flujo miocárdico com Rb 86, en pacientes com cardiopatia chagásica, com insuficiencia coronaria y en controles normales. Arq Bras Cardiol 1974; 27: 721-732.
27. Marin-Neto JA, Marzullo P, Ayres-Neto EM, Maciel BC, Attab-Santos JL, Simões MV, LAbbate A. Myocardial perfusion disturbances detected by 99mTc-microspheres in chagas patients with angiographicaly normal coronary arteries. Circulation 1995; 92(8):I47.
28. MV Simões, AO Pintya, AV Sarabanda, A Pazin-Filho, Antloga CM, BC Maciel, JA Marin-Neto. Regional sympathetic denervation and myocardial ischemia precede wall motion abnormalities in chagas' cardiomyopathy. J Nucl Cardiol 1999; in press.
29. Andrade ZA, Andrade SG, Correa R, Sadigursky M, Ferrans VJ. Myocardial changes in acute Trypanosoma cruzi infection: Ultrastructural evidence of immune damage and the role of microangiopathy. Am J Pathol 1994; 144: 1403-1411.
These companies contributed to the Congress