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

Chagas cardiomyopathy is the most frequent and most severe manifestation of chronic Chagas disease, and is one of the leading causes of morbidity and death in Latin America. Although the pathogenesis of Chagas cardiomyopathy is incompletely understood, it may involve several mechanisms, including parasite-dependent myocardial damage, immune-mediated myocardial injury (induced by the parasite itself and by self-antigens), and microvascular and neurogenic disturbances. In the past three decades, a consensus has emerged that parasite persistence is crucial to the development and progression of Chagas cardiomyopathy. In this context, antiparasitic treatment in the chronic phase of Chagas disease could prevent complications related to the disease. However, according to the results of the BENEFIT trial, benznidazole seems to have no benefit for arresting disease progression in patients with chronic Chagas cardiomyopathy. In this review, we give an update on the main pathogenic mechanisms of Chagas disease, and re-examine and discuss the results of the BENEFIT trial, together with its limitations and implications.

Chagas disease cardiomyopathy: current concepts of an old disease

Chagas disease continues to be a significant public health problem, as ca. 10 million people are still infected with T. cruzi in Latin America. Decades after primary infection, 30 percent of individuals can develop a form of chronic inflammatory cardiomyopathy known as Chagas disease cardiomyopathy (CCC). Data from both murine models and human studies support the view that an autoimmune response as well as a parasite-driven immune response involving inflammatory cytokines and chemokines may both play a role in generating the heart lesions leading to CCC. This review aims to summarize recent advances in the understanding of the immunopathogenesis of Chagas disease cardiomyopathy.

A doença de Chagas continua sendo importante problema de saúde pública uma vez que cerca de 10 milhões de indivíduos ainda estão infectados pelo T. cruzi. Décadas após a infecção primária, aproximadamente 30 por cento dos indivíduos podem desenvolver uma cardiomiopatia inflamatória crônica, a chamada Cardiomiopatia Chagásica Crônica (CCC). Dados de modelos murinos e de estudos em humanos apóiam a visão de que tanto respostas auto-imunes como as determinadas pelo parasita em conjunto com citocinas e quimiocinas inflamatórias participam da geração das lesões cardíacas típicas da CCC. A presente revisão tem como objetivo sumarizar os recentes avanços no entendimento da imunopatogênese da Cardiomiopatia Chagásica Crônica.

Case-control study of factors associated with chronic Chagas heart disease in patients over 50 years of age

A case-control study on chronic Chagas heart disease (CCHD) was carried out between 1997 and 2005. Ninety patients over 50 years of age were examined for factors related to (CCHD). Fourty-six patients (51.1 percent) with Chagas heart disease (anomalous ECG) were assigned to the case group and 44 (48.9 percent) were included in the control group as carriers of undetermined forms of chronic disease. Social, demographic (age, gender, skin color, area of origin), epidemiological (permanence within an endemic zone, family history of Chagas heart disease or sudden death, physical strain, alcoholism, and smoking), and clinical (systemic hypertension) variables were analyzed. The data set was assessed through single-variable and multivariate analysis. The two factors independently associated with heart disease were age - presence of heart disease being three times higher in patients over 60 years of age (odds ratio, OR: 2.89; confidence interval of 95 percent: 1.09-7.61) - and family history of Chagas heart disease (OR: 2.833, CI 95 percent: 1.11-7.23). Systemic hypertension and gender did not prove to hold any association with heart disease, as neither did skin color, but this variable showed low statistical power due to reduced sample size.

Chaga's disease: pathology of chronic lesions

The morphologic features of the indeterminate and the chronic cardiac forms of Chaga's disease, and their clinical correlations, are briefly reviewed. The significance of mild focal myocarditis as the main change of the indeterminate form, the myocardial inflammation and fibrosis of the chronic cardiac form, plus the involvement of the conducting system, are particulary considered.

Cardiopatía crónica endémica rural chagásica o crónica común en chagásicos y no chagásicos / Rural endemic chronic cardiopathy or common cardiopathy among chagasic and non chagasic people

Se presentan evidencias de que la cardiopatía crónica rural en adultos no es diferente entre los chagásicos crónicos que entre los no chagásicos. Se conjuntaron los resultados epidemiológicos de LabMICE (una encuesta de prevalencia (1978-1983); un estudio de caso-control (1986-1988); y un estudio clínico de cohorte y de sobrevivencia (1978-1989) con las investigaciones clínicas de Diego Dávila y colaboradores (1988-2002). Ambos grupos pertenecen a la Universidad de Los Andes. Las inferencias de ambos contestan interrogantes que plantearon anatomopatólogos venezolanos entre 1937 y 1985. También están de acuerdo con publicaciones internacionales de 1970 a 2000. Los trabajos sugieren que existe una cardiopatía crónica endémica rural que es común entre seropositivos y seronegativos a T. cruzi en el medio rural. Parece claro que el Chagas crónico no es problema de salud pública, pero sí es prevalente una cardiopatía crónica que amerita nuevas investigaciones. Se invita a grupos de investigación interesados a usar el blanco comunitario de datos para deslindar el mito y la realidad en la cardiopatía rural crónica venezolana.

Farmacología molecular de la enfermedad de Chagas / Molecular pharmacology of the chagas disease

La enfermedad de Chagas es una parasitosis exclusiva del continente americano. Es endémica en 21 países, con 18-20 millones de personas infectadas y 100 millones en riesgo de infección. En Venezuela la enfermedad de Chagas es una enfermedad reemergente cuya frecuencia alcanza en algunas comunidades rurales el 22 por ciento. La prevención de la transmisión de la enfermedad de Chagas es un proceso sencillo, consiste en el control y eliminación del vector mediante rociamientos sistemáticos de las viviendas en las zonas endémicas y a través de políticas habitacionales, donde se sustituya los ranchos por viviendas higiénicas consolidadas. La enfermedad de Chagas no tiene tratamiento y los pacientes infectados con T. cruzi inexorablemente evolucionan hacia la miocardiopatía chagásica crónica cuya manifestación sindromática más frecuente es la insuficiencia cardíaca congestiva y/o las arritmias cardíacas, de difícil tratamiento y cuyo desenlace más frecuente es la muerte súbita. En los últimos años importantes avances han sido realizados en la fisiopatología de las miocardiopatías no chagásicas, cuyas bases moleculares parecen semejarse a la de las bases de la miocardiopatía chagásica crónica.En el presente trabajo se presenta una revisión de los eventos moleculares que parecen estar involucrados en la génesis y desarrollo de la miocardiopatía chagásica crónica, planteándose que la miocardiopatía chagásica crónica se inicia como un desbalance en los factores humorales y neurales que afectan el miocardio, el cual es causado por mediadores de la respuesta inmune, los cuales inician y mantienen una cascada de eventos, que afectan los elementos involucrados en las señales transmembranas, como por ejemplo; receptores para neurotransmisores (colinérgicos y adrenérgicos), sistemas transductores de la señal (proteína G) y efectores de la señal (canales iónicos o segundos mensajeros). Finalmente, se sugiere que el conocimiento de estos factores permitiría planear racionalmente estrategias terapéuticas no tripanomicidas

Avaliaçäo do tratamento especifíco para Trypanosoma cruzi em crianças, na evoluçäo da fase indeterminada / Specific treatment evaluation for Trypanosoma cruzi in children, in the evolution of the indeterminate phase

Doze pacientes com idades entre 7 a 12 anos, na forma indeterminada da doença de Chagas, com sorologia e xenodiagnóstico positivos, receberam tratamento específico. Dois pacientes tomaram 7mg/kg de nifurtimox durante 60 e 90 dias e 10 usaram 5-7mg/kg de benznidazol durante 60 dias. A evoluçäo clínica foi verificada através de exame clínico, eletrocardiograma, exame radiológico contrastado do esôfago. Após o tratamento somente uma (8,3 por cento) paciente apresentou todos os exames negativos. Oito deles foram avaliados após oito anos do tratamento e 4 acompanhados durante 20 anos. Sete (58,4 por cento) permaneceram na forma indeterminada e 4 (33,3 por cento) chagásicos progrediram clinicamente para cardiopatia grau II e/ou esofagopatia, apesar do tratamento precoce. Säo necessários estudos com maior número de crianças na fase indeterminada e acompanhamento a longo prazo para se estabelecer a influência do tratamento específico na evoluçäo da doença de Chagas

Interação clínica entre moléstia de Chagas e hipertensão arterial primária em um serviço de referência ambulatorial / Clinical relationship between Chagas' disease and primary arterial hypertension at an outpatient referral service

PURPOSE: To evaluate the clinical relationship between Chagas' disease and primary arterial hypertension. METHODS: The study involved 878 chronic chagasic outpatients followed by the Chagas' Disease Study Group of the University Hospital (Unicamp), over a 15-year period. Initially, the age, gender, race, clinical form of Chagas' disease and the presence of hypertension were noted for each patient. Subsequently, the data for matched hypertensive and normotensive chagasic patients were compared. RESULTS: Of the chagasic patients 37were hypertensive, of those, 65had some form of heart disease compared to 49in the normotensive group. Of those patients with Chagas' disease and arterial hypertension, 41were blacks and 35were caucasians. Fifty percent of the hypertensive chagasic patients were over 45 years old compared to only 29of the non-hypertensive patients. CONCLUSION: Most of the hypertensive chagasic patients were 45 or more years old and showed some degree of heart failure compared to the normotensive group.

Estudio del sistema nervioso autónomo cardiovascular en la enfermedad de Chagas en etapa crónica indeterminada / Study of cardiovascular autonomous system in the chronic undetermined chronic stage of Chagas disease

La enfermedad de Chagas tiene una alta prevalencia en el continente americano. Pasa por una etapa aguda y una crónica. En la etapa crónica sintomática es frecuente el compromiso del sistema nervioso autónomo (SNA). Nuestro objetivo fue pesquisar la presencia de afectación autonómica cardiovascular en la etapa crónica indeterminada o asintomática. Estudiamos 94 chagásicos en etapa indeterminada y 69 controles sanos menores de 50 años. Comparamos en ambos grupos la variabilidad espontánea de la frecuencia cardíaca basal (FCB); su variación con la respiración profunda (Relación inspiración/espiración); la prueba del ortostatismo y la presencia de hipotensión ortostática (HO). En 27 chagásicos dosificamos catecolaminas (CA) urinarias. Encontramos diferencias estadísticamente significativas entre ambos grupos en las pruebas que valoran la frecuencia cardíaca, no hallamos HO ni alteración en las CA urinarias en los chagásicos. Interpretamos estos resultados como confirmación de la afectación autonómica parasimpática cardiovascular en los chagásicos en etapa indeterminada

Pathogenesis of chronic Chagas's myocarditis

The pathogenesis of chronic Chagas' myocarditis is still not completely understood. Several theories have been advanced. l)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 myocyte hypertrophy. These processes may be initiated and perpetuated by anti immune factors and alterations in the myocardial microcirculation. The destruction of the ganglion cells of the heart may be involved in the patho-clinical evolution of chronic Chagas' cardiopathy. This could imply future therapeutic strategies in the management of chronic Chagas' patients to enhance medical treatment and, hopefully, improve prognosis.

Ethiological treatment of acute and chronic Chagas' heart disease

The uncertainties in the ethiological treatment of Chagas' Disease are consequence of the lack of entire knowledge of its pathogeny and the non existence of a healing criterium. There is a consensus that antiparasite drugs should be used in the acute phase of the infection, regardless of the infection route, in new crisis, in patients under immunossuppression and in organs transplantation. There is still controversy regarding subacute, chronic or undetermined phase or cases with mild cardiac/digestive forms, not included in the situations listed above neither in a research protocol. The treatment includes oral benzonidazol 5 mg/kg/day, bid or tid for 60 days. In 71 patients monitored in this fashion, the authors have found 60 percent of negative xenodiagnostic at the end of treatment. It is still necessary, however, to continue to investigate and accomplishing more randomized trials to confirm the efficacy of such method, and also to try to obtain effective and less toxic agents. It is also fundamental to standardize a more reliable healing criterium.

Miocardiopatía chagásica crónica: estudio serológico y anatomopatológico / Chronic chagasic myocardiopathy: serological and anatomopathological study

Se presenta un estudio serológico y anatomopatológico postmortem para enfermedad de Chagas en 40 individuos autopsiados entre noviembre de 1987 y agosto de 1999 en el Servicio de Anatomía Patológica del Hospital Regional de Antofagasta y en la sección Medicina Legal del Ministerio de Justicia en Antofagasta. Se comprobó serología chagásica postmortem positiva en líquido pericárdico por inmunofluorescencia indirecta en 3 casos, entre los cuales el estudio histopatológico de músculo cardíaco demostró elementos de daño tipo trypanosoma cruzi. El estudio morfológico macroscópico no demostró hallazgos relevantes. Los resultados revelan la necesidad de implementar sistemas de estudios anatomopatológicos de rutina que contribuyan a dimensionar la etiología chagásica como causa de muerte entre la población del área de endemia chilena