Oral Administration of GW788388, an Inhibitor of Transforming Growth Factor Beta Signaling, Prevents Heart Fibrosis in Chagas Disease

Cardiac damage and dysfunction are prominent features in patients with chronic Chagas disease, which is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi) and affects 10–12 million individuals in South and Central America. Our group previously reported that transforming growth factor beta (TGFß) is implicated in several regulatory aspects of T. cruzi invasion and growth and in host tissue fibrosis. In the present work, we evaluated the therapeutic action of an oral inhibitor of TGFß signaling (GW788388) administered during the acute phase of experimental Chagas disease. GW788388 treatment significantly reduced mortality and decreased parasitemia. Electrocardiography showed that GW788388 treatment was effective in protecting the cardiac conduction system, preserving gap junction plaque distribution and avoiding the development of cardiac fibrosis. Inhibition of TGFß signaling in vivo appears to potently decrease T. cruzi infection and to prevent heart damage in a preclinical mouse model. This suggests that this class of molecules may represent a new therapeutic tool for acute and chronic Chagas disease that warrants further pre-clinical exploration. Administration of TGFß inhibitors during chronic infection in mouse models should be further evaluated, and future clinical trials should be envisaged

Usefulness of PCR-based assays to assess drug efficacy in Chagas disease chemotherapy: value and limitations

One major goal of research on Chagas disease is the development of effective chemotherapy to eliminate the infection from individuals who have not yet developed cardiac and/or digestive disease manifestations. Cure evaluation is the more complex aspect of its treatment, often leading to diverse and controversial results. The absence of reliable methods or a diagnostic gold standard to assess etiologic treatment efficacy still constitutes a major challenge. In an effort to develop more sensitive tools, polymerase chain reaction (PCR)-based assays were introduced to detect low amounts of Trypanosoma cruzi DNA in blood samples from chagasic patients, thus improving the diagnosis and follow-up evaluation after chemotherapy. In this article, I review the main problems concerning drug efficacy and criteria used for cure estimation in treated chagasic patients, and the work conducted by different groups on developing PCR methodologies to monitor treatment outcome of congenital infections as well as recent and late chronic T. cruzi infections

Sintomas do trato digestivo superior e distúrbios motores do esôfago em pacientes portadores da forma indeterminada da doença de Chagas crônica Upper gastrointestinal symptoms and esophageal motility disorders in indeterminate Chagas’ disease patients

O estudo descreve os sintomas referidos por portadores da forma indeterminada da doença de Chagas crônica e avalia sua associação com alterações da motilidade esofágica. Manometria do esôfago foi realizada em 50 pacientes, medindo-se a extensão e a pressão do esfíncter inferior do esôfago, o peristaltismo e a amplitude de contração do corpo esofágico. Oito (16%) pacientes apresentaram relaxamento parcial do esfíncter inferior, 13 (26%) apresentaram aperistalse parcial e 20 (40%) apresentaram hipocontratilidade no esôfago distal. Sintomas digestivos altos foram referidos por 24 (48%) pacientes, sendo mais freqüentes a pirose, a regurgitação e o desconforto intermitente à deglutição. Esses sintomas foram referidos por 17 (51,5%) de 33 pacientes com alterações motoras do esôfago e por 7 (41,2%) de 17 pacientes com manometria normal, diferença essa não estatisticamente significante (p=0,69). Esses achados sugerem que portadores da FCI apresentam sintomas inespecíficos do trato digestivo superior que podem dificultar a sua classificação com base apenas no exame clínico e radiológico, e que é alta a freqüência de portadores desta forma que apresentam distúrbios motores do esôfago.<br>This study describes the symptoms reported by patients with the indeterminate form of chronic Chagas’ disease and evaluates associations between these symptoms and alterations in esophageal motility. Esophageal manometry was performed on 50 patients, with measurements of the length and pressure of the lower esophageal sphincter, peristaltism and the amplitude of contractions of the esophageal body. Eight (16%) patients presented partial relaxation of the lower sphincter, 13 (26%) presented partial lack of peristalsis and 20 (40%) presented hypocontractility of the distal esophagus. Upper digestive symptoms were reported by 24 (48%) patients, and the most frequent of these were heartburn, regurgitation and intermittent discomfort when swallowing. Such symptoms were reported by 17 (51.5%) of the 33 patients with esophageal motor disorders and by 7 (41.2%) of the 17 patients with normal manometry, which was not a statistically significant difference (p=0.69). These findings suggest that patients with the indeterminate form of Chagas’ disease present nonspecific symptoms in the upper digestive tract that may make it difficult to classify the disease solely on the basis of radiological and clinical examination. Furthermore, a high proportion of patients with this form present esophageal motor disorders

Teste ergométrico e o Holter de 24 horas na detecção de arritmias ventriculares complexas em diferentes estádios da cardiopatia chagásica crônica Exercise testing and 24 hours Holter monitoring in the detection of complex ventricular arrhythmias in different stages of chronic Chagas' heart disease

Comparou-se o teste ergométrico com Holter de 24 horas na detecção de arritmias ventriculares complexas em diferentes estádios da cardiopatia chagásica crônica. Avaliados 71 pacientes sem outras doenças associadas, idade=51±10,3, metade mulheres. Divididos em quatro grupos conforme o grau de acometimento cardíaco. A estatística esta discriminada no corpo do trabalho. Ao Holter, no grupo IA as arritmias ventriculares complexas foram detectadas em 4,3%, IB em 25%, II em 55% e no grupo III em 90%. Nos grupos II e III não houve diferença entre os exames na detecção de arritmias ventriculares complexas (p=NS). Nos grupos IA e IB, houve uma concordância de 100% no teste ergométrico na não detecção de arritmias ventriculares complexas entre dois observadores. No grupo II, a concordância foi de 70% (kappa=0,368, p=0,003) e de 90% (kappa=0,78, p=0,002) no grupo III. Foi observado diferenças na presença de arritmias ventriculares complexas entre os pacientes dos grupos em fase inicial e avançada da cardiopatia chagásica crônica. Nos pacientes dos grupos II e III não houve diferença entre os dois exames na detecção das arritmias ventriculares complexas. Pacientes dos grupos IA e IB é razoável indicar Holter e/ou o teste ergométrico na ocorrência de progressão da doença.<br>To detect complex ventricular arrhythmias in different stages of chronic chagasic cardiopathy, the results of exercise testing to 24 hours Holter monitoring have been compared. We evaluated a group of 71 patients, half women, aged 51±10.3, with no others associated diseases. These patients were separated in 4 groups according to degree of cardiac involvement. Statistical data can be found elsewhere in the study. In group IA, Holter monitoring detected 4.3% of complex ventricular arrhythmias, group IB 25%, group II 55% and group III 90%. We found no difference between Holter and exercise testing in the detection of complex ventricular arrhythmias in groups II and III (p = ns). In groups IA and IB we found 100% concordance, concerning the no detection of complex ventricular arrhythmias by exercise testing seen by two independent examiners. In group II there was a 70% concordance (kappa=0.368, p=0.003) and 90% in group III (kappa=0.78, p=0.002). Different results were found, concerning the presence of complex ventricular arrhythmias, among patients in the initial and advanced stages of chronic chagasic cardiopathy. In groups II and III we found no difference between the two methods in the detection of complex ventricular arrhythmias. It seems reasonable to recommend either Holter on exercise testing in groups IA and IB if progression of disease is noticed

Inflammation enhances the risks of stroke and death in chronic chagas disease patients.

Ischemic strokes have been implicated as a cause of death in Chagas disease patients. Inflammation has been recognized as a key component in all ischemic processes, including the intravascular events triggered by vessel interruption, brain damage and repair. In this study, we evaluated the association between inflammatory markers and the death risk (DR) and stroke risk (SR) of patients with different clinical forms of chronic Chagas disease. The mRNA expression levels of cytokines, transcription factors expressed in the adaptive immune response (Th1, Th2, Th9, Th17, Th22 and regulatory T cell), and iNOS were analyzed by realtime PCR in peripheral blood mononuclear cells of chagasic patients who exhibited the indeterminate, cardiac, digestive and cardiodigestive clinical forms of the disease, and the levels of these transcripts were correlated with the DR and SR. Cardiac patients exhibited lowermRNA nexpression levels of GATA-3, FoxP3, AHR, IL-4, IL-9, IL-10 and IL 22 but exhibited higher expression of IFN-γ and TNF-α compared with indeterminate patients. Digestive patients showed similar levels of GATA-3, IL-4 and IL-10 than indeterminate patients. Cardiodigestive patients exhibited higher levels of TNF-α compared with indeterminate and digestive patients. Furthermore, we demonstrated that patients with high DR and SR exhibited lower GATA-3, FoxP3, and IL-10 expression and higher IFN-γ, TNF-α and iNOS mRNA expression than patients with low DR and SR. A negative correlation was observed between Foxp3 and IL-10 mRNA expression and the DR and SR. Moreover, TNF-α and iNOS expression was positively correlated with DR and SR. Our data suggest that an inflammatory imbalance in chronic Chagas disease patients is associated with a high DR and SR. This study provides a better understanding of the stroke pathobiology in the general population and might aid the development of therapeutic strategies for controlling the morbidity and mortality of Chagas disease