Association of Anti-β 1 and Anti-M2 Antibodies with Autonomic Nervous System Modulation in Patients with Chronic Chagas Cardiomyopathy

Abstract Background: Different immune mechanisms of myocardial damage involved in the pathophysiology of Chagas disease coexist with high titers of autoantibodies induced by T. cruzi . There are few studies in the literature about the adaptive role of anti-β1 and anti-M2 antibodies in chronic Chagas cardiomyopathy (CCC). Objectives: To evaluate the association between anti-β1 and anti-M2 antibodies with heart rate variability (HRV) parameters on 24h Holter monitoring and the rate-pressure product (RPP) on cardiopulmonary exercise testing (CPET). Methods: Anti-β1 and anti-M2 antibody titers were measured by enzyme-linked immunosorbent assay (ELISA) in 64 patients affected by CCC. Analysis of HRV was performed through the time-domain indices NNs, mean NN, SDNN, SDANN, SDNN index, NNNs, RMSSD, and pNN50. Spearman's correlation coefficient was used to assess the association between antibody titers and numerical variables. The Mann-Whitney test was used for comparison between two groups. Multiple linear regression was used to identify independent variables capable of explaining anti-β1 and anti-M2 antibody titers at the 5% significance level. Results: On 24h Holter, during the period of greatest parasympathetic activation (2:00-6:00 a.m.), an inverse association was found between anti-β1 titers and SDNN (rs=-0.13, p =0.041, n=43), as well as a direct association between anti-M2 titers and SDANN ( r s=0.317, p =0.039, n=43). Regarding CPET variables, anti-β1 titers were directly associated with RPP (rs=0.371, p =0.005, n=56). The subgroup of patients with a normal chronotropic response showed higher anti-β1 titers than the subgroup with an impaired response (p=0.023). RPP was an independent explanatory variable for anti-β1 titers, although with a low coefficient of determination (R2=0.147). Conclusion: The findings of this study suggest that, in patients with CCC, anti-β1 and anti-M2 antibodies may affect HRV parameters. RPP was directly associated with higher anti-β1 titers.

Prediction of sudden cardiac death for chagasic patients / Predição de morte súbita cardíaca em pacientes chagásicos / Predicción de muerte súbita cardíaca en pacientes chagásicos federados

Objective: Identify the risk of patients with Chronic Chagas Cardiomyopathy (CCC) to prevent them from having Sudden Cardiac Death (SCD). Methods: We developed an SCD prediction system using a heterogeneous dataset of chagasic patients evaluated in 9 state-of-the-art machine learning algorithms to select the most critical clinical variables and predict SCD in chagasic patients even when the interval between the most recent exams and the SCD event is months or years. Results: 310 patients were analyzed, being 81 (14,7%) suffering from SCD. In the study, Balanced Random Forest showed the best performance, with AUC:80.03 and F1:75.12. Due to their high weights in the machine learning classifiers, we suggest Holter - Non-Sustained Ventricular Tachycardia, Total Ventricular Extrasystoles, Left Ventricular Systolic Diameter, Syncope, and Left Ventricular Diastolic Diameter as essential features to identify SCD. Conclusion: The high-risk pattern of SCD in patients with CCC can be identified and prevented based on clinical and laboratory variables.

Objetivo: Identificar o risco de pacientes com Cardiomiopatia Chagásica Crônica (CCC) para prevenir a Morte Súbita Cardíaca (MSC). Métodos: Desenvolvemos um sistema de MSC usando um conjunto de dados heterogêneo de pacientes chagásicos avaliados em 9 algoritmos de aprendizado de máquina de última geração para selecionar as variáveis clínicas mais críticas e prever MSC em pacientes chagásicos mesmo quando o intervalo mais recente entre os mais recentes exames e o evento MSC é meses ou anos. Resultados: Foram analisados 310 pacientes, sendo 81 (14,7%) portadores de CCC. No estudo, o algoritmo Balanced Random Forest apresentou o melhor desempenho, com AUC:80,03 e F1:75,12. Devido ao seu alto peso nos classificadores de aprendizado de máquina, sugerimos Holter - Taquicardia Ventricular Não Sustentada, Extrassístoles Ventriculares Totais, Diâmetro Sistólico do Ventrículo Esquerdo, Síncope e Diâmetro Diastólico do Ventrículo Esquerdo como características essenciais para identificar a CCC. Conclusão: O padrão de alto risco de MSC em pacientes com CCC pode ser identificado e prevenido com base em variáveis clínicas e laboratoriais.

Objetivo: Identificar el riesgo de los pacientes con Miocardiopatía Chagásica Crónica (MCC) para evitar que presenten Muerte Cardíaca Súbita (MCS). Métodos: Desarrollamos un sistema MCS utilizando un conjunto de datos heterogéneo de pacientes chagásicos evaluados en 9 algoritmos de aprendizaje automático de última generación para seleccionar las variables clínicas más críticas y predecir MCS en pacientes chagásicos incluso cuando el intervalo más reciente entre los más recientes exámenes y el evento MCS es meses o años. Resultados: Se analizaron 310 pacientes, siendo 81 (14,7%) con MSC. En el estudio, Balanced Random Forest mostró el mejor desempeño, con AUC:80.03 y F1:75.12. Debido a su alto peso en los clasificadores de aprendizaje automático, sugerimos Holter - Taquicardia ventricular no sostenida, Extrasístoles ventriculares totales, Diámetro sistólico del ventrículo izquierdo, Síncope y Diámetro diastólico del ventrículo izquierdo como características esenciales para identificar la MSC. Conclusión: El patrón de alto riesgo de MSC en pacientes con MCC se puede identificar y prevenir con base en variables clínicas y de laboratorio.

Revisiting the History of Chagas Disease: "Live to tell"

Abstract In 1907, Carlos Chagas was designated to fight paludism in the Rio das Velhas region along the Central do Brasil railroad. During his field research, Chagas discovered a hematophagous insect ( Panstrongylus megitus ) carrying a new trypanosomatide, which he named Trypanosoma cruzi . On April 14th, 1909, he found the same parasite in the blood of a febrile child, submitting the announcement of his discoveries to the Brasil Médico scientific journal. Here, we discuss the early stages in the establishment of a new human morbid entity during the first decades after its discovery with a definite influence from its discoverer, Carlos Chagas, as well the first collaborators. Moreover, we cover the importance of the Center for the Study and Prophylaxis of Chagas Disease in Bambuí (MG), unraveling the most advanced developments in research within the disease's habitat and the widening perspectives for modern research that have emerged after the 1960s and continue to improve to this day. In this revisitation to the history of Chagas disease, we begin at Manguinhos (RJ ), making our way to Lassance (MG), where the discovery took place. Then, we travel back to Rio de Janeiro in the beginning of the twentieth century and Brazilian republic until the current day, revealing milestone publications that settled Chagas disease both as a source of pride for Brazilian medicine and as a challenge with important aspects that remain to be clarified. Any similarities to our country's politics and economy in the twentieth century are not mere coincidences.

Desnutrição e Caquexia na Insuficiência Cardíaca Descompensada e Cardiomiopatia Chagásica: Ocorrência e Associação com Desfechos Hospitalares / Undernutrition and Cachexia in Patients with Decompensated Heart Failure and Chagas Cardiomyopathy: Occurrence and Association with Hospital Outcomes

Resumo Fundamento Problemas nutricionais são comuns em pacientes com insuficiência cardíaca (IC) e estão associados a um prognóstico ruim. É relevante mencionar que algumas populações de pacientes, como os com Doença de Chagas, são normalmente excluídas da maioria das análises. Objetivo Buscamos analisar a ocorrência de desnutrição e caquexia em pacientes com Doença de Chagas durante episódios de IC descompensada (ICD) em comparação a outras etiologias, e investigar a influência desses achados em desfechos hospitalares. Método Realizamos um estudo de série de casos consecutivos com pacientes hospitalizados com ICD. Os pacientes foram submetidos à Avaliação Nutricional Subjetiva Global (ASG), além de medidas antropométricas e laboratoriais, e foram avaliados para a ocorrência de caquexia, baixa massa muscular e força. Estudamos a ocorrência de morte e transplante cardíaco de urgência durante a internação. Resultados Ao todo, 131 pacientes foram analisados e 42 (32,1%) tinham Doença de Chagas. Pacientes com Doença de Chagas apresentavam índice de massa corporal (IMC) menor (22,4 kg/m2 [19,9-25,3] vs. 23,6 kg/m2 [20,8-27,3], p=0,03), maior frequência de desnutrição (76,2% vs 55,1%, p=0,015) e mais ocorrências de morte ou transplante (83,3% vs. 41,6%, p<0,001). Observamos que, dentre os pacientes com etiologia da Doença de Chagas, a ocorrência de morte ou transplante cardíaco esteve associada com desnutrição (3 [42,9%] pacientes com alta hospitalar vs. 29 [82,9%] pacientes que morreram ou receberam transplante cardíaco, P=0,043). Conclusões Ao todo, nossos resultados indicam que pacientes com Doença de Chagas internados com ICD costumam apresentar problemas nutricionais, principalmente desnutrição. É importante mencionar que este achado esteve associado à ocorrência de morte e transplante cardíaco durante a internação.

Abstract Background Nutritional disorders are common among patients with heart failure (HF) and associated with poor prognosis. Importantly, some populations of patients, like the ones with Chagas disease, are frequently excluded from most analyses. Objective We sought to study the occurrence of undernutrition and cachexia in patients with Chagas disease during episodes of decompensated HF (DHF) as compared to other etiologies, and to investigate the influence of these findings on hospital outcomes. Methods We performed a consecutive case series study with patients hospitalized with DHF. Patients underwent the Subjective Global Assessment of nutritional status (SGA), besides anthropometric and laboratorial measures, and were evaluated for the occurrence of cachexia, low muscle mass and strength. We studied the occurrence of death or urgent heart transplantation during hospitalization. Results Altogether, 131 patients were analyzed and 42 (32.1%) had Chagas disease. Patients with Chagas disease had lower Body Mass Index (BMI) (22.4 kg/m2[19.9-25.3] vs. 23.6 kg/m2 [20.8-27.3], p=0.03), higher frequency of undernutrition (76.2% vs 55.1%, p=0.015) and higher occurrence of death or transplant (83.3% vs. 41.6%, p<0.001). We found that, in patients with Chagas etiology, the occurrence of death or cardiac transplantation were associated with undernutrition (3 [42.9%] patients with hospital discharge vs 29 [82.9%] patients with death or heart transplant, p=0.043). Conclusions Taken together, our results indicate that patients with Chagas disease hospitalized with DHF often present with nutritional disorders, especially undernutrition; importantly, this finding was associated with the occurrence of death and heart transplant during hospitalization.

Chronic Chagas cardiomyopathy: characterization of cases and possibilities of action in primary healthcare / Cardiomiopatia chagásica crônica: caracterização de casos e possibilidades para ação na atenção primária à saúde / Miocardiopatía chagásica crónica: caracterización de los casos y posibilidades de actuación de la atención primaria de salud

Despite the drastic decrease in the incidence of Chagas disease in Brazil, past cases still greatly impact health services in the country. Thus, this study aimed to characterize Chagas disease cases regarding their cardiac staging and death prognosis and, based on that, to propose primary healthcare (PHC) case follow-ups. This is a cross-sectional study based on secondary data from the medical records of patients with chronic Chagas cardiomyopathy (CCC). A logistic regression was applied to estimate crude and adjusted odds ratios (OR). A total of 433 medical records were evaluated. More severe CCC cases were associated with a greater number of hospitalizations (OR = 3.41; 95%CI: 1.59-7.30) and longer hospitalization (OR = 3.15; 95%CI: 1.79-5.53). Cases with a higher risk of death were associated with a higher number of hospitalizations (OR = 1.92; 95%CI: 1.09-3.37), longer hospital stays (OR = 2.04; 95%CI: 1.30-3.18), and visits to the outpatient clinic (OR = 2.18; 95%CI: 1.39-3.41) and the emergency department of the assessed hospital (OR = 3.12; 95%CI: 1.27-7.66). Analyzing the medical records at two moments, 72.9% of the cases remained in the stages in which they were initially evaluated. Overall, 44.4% of cases were classified as mild to moderate risk of death and 68.3% as low ones. The cases classified in the most severe stages of CCC and with high or intermediate risk of death were associated with greater hospital dependence. However, most cases were classified as milder forms of the disease, with a low risk of death and clinical stability. These findings aim to promote the role of PHC as a protagonist in the longitudinal follow-up of CCC cases in Brazil.

Apesar da diminuição importante na incidência da doença de Chagas no Brasil, as infecções ocorridas no passado ainda têm um impacto grande sobre os serviços de saúde no país. Portanto, o estudo buscou caracterizar os casos de doença de Chagas quanto ao estadiamento cardíaco e prognóstico de morte, e com base nisso, propor o seguimento dos casos na atenção primária à saúde (APS). O estudo transversal usou dados secundários dos prontuários de pacientes com cardiomiopatia chagásica crônica (CCC). Foi aplicada a regressão logística para estimar os odds ratios (OR) brutos e ajustados. Foram avaliados 433 prontuários médicos. Casos mais graves de CCC estavam associados com número maior de hospitalizações (OR = 3,41; IC95%: 1,59-7,30) e tempo de internação (OR = 3,15; IC95%: 1,79-5,53). Os casos com risco maior de morte estavam associados com número maior de hospitalizações (OR = 1,92; IC95%: 1,09-3,37), tempo de internação (OR = 2,04; IC95%: 1,30-3,18) e visitas aos ambulatórios (OR = 2,18; IC95%: 1,39-3,41) e serviços de emergência (OR = 3,12; IC95%: 1,27-7,66). Ao analisar os prontuários em dois momentos, 72,9% dos casos permaneceram nos estágios inicialmente avaliados. No total, 44,4% dos casos foram classificados como formas leves a moderadas e 68,3% como risco baixo de morte. Os casos classificados nos estágios mais graves de CCC e com risco de morte alto ou intermediário estavam associados com maior dependência hospitalar. Entretanto, a maioria dos casos foram classificados como formas mais leves da doença, clinicamente estáveis e com baixo risco de morte. Os achados apoiam a promoção do papel da APS como protagonista no seguimento longitudinal dos casos de CCC no Brasil.

A pesar de la drástica disminución de la incidencia de la enfermedad de Chagas en Brasil, los casos infectados en el pasado siguen teniendo un gran impacto en los servicios de salud del país. Por lo tanto, este estudio tuvo como objetivo caracterizar los casos de enfermedad de Chagas en lo que se refiere al estadio cardíaco y al pronóstico de muerte y, con base en eso, proponer el seguimiento de los casos por parte de la atención primaria de salud (APS). Se trata de un estudio transversal basado en datos secundarios de las historias clínicas de los pacientes con miocardiopatía chagásica crónica (MCC). Se aplicó la regresión logística para estimar las odds ratio (OR) crudas y ajustadas. Se evaluaron 433 historias clínicas. Los casos de MCC más graves se asociaron a un mayor número de hospitalizaciones (OR = 3,41; IC95%: 1,59-7,30) y días de hospitalización (OR = 3,15; IC95%: 1,79-5,53). Los casos con mayor riesgo de muerte se asociaron a un mayor número de hospitalizaciones (OR = 1,92; IC95%: 1,09-3,37), días de hospitalización (OR = 2,04; IC95%: 1,30-3,18), y las visitas a los ambulatorios (OR = 2,18; IC95%: 1,39-3,41) y al servicio de urgencias (OR = 3,12; IC95%: 1,27-7,66). Analizando las historias clínicas en dos momentos, el 72,9% de los casos permanecieron en los estadios en los que fueron evaluados inicialmente. En general, el 44,4% de los casos fueron clasificados como formas leves o moderadas y el 68,3% como de bajo riesgo de muerte. Los casos clasificados en los estadios más graves de la MCC y con riesgo de muerte alto o intermedio se asociaron a una mayor dependencia hospitalaria. Sin embargo, la mayoría de los casos fueron clasificados como formas más leves de la enfermedad, con bajo riesgo de muerte y clínicamente estables. Estos resultados pretenden promover el papel de la APS como protagonista en el seguimiento longitudinal de los casos de MCC en Brasil.

Respiratory and functional tests in the assessment and prognosis of patients with chagas disease

Chagas disease causes an important impact on cardiorespiratory system, functional and working capacity of the patient. Performing a functional assessment on these individuals becomes essential, since the impact of physical limitation is an important factor that is related with other life domains, such as risk of cardiovascular events in a brief period and risk of death. The goal of this work was to perform a literature review to present the evaluative and prognostic value of main valid respiratory and functional tests in patients with Chagas disease, as well as their applicability and reproducibility. A literature search was performed from 1981 to 2020 in Scielo, Pubmed/Medline, Science Direct, Scopus and Web of Science databases. Only complete studies published in English, Portuguese or Spanish were analyzed which specifically discussed the respiratory and functional tests used in patients with Chagas disease. In total, 544 articles were retrieved of which 35 were eligible. The main functional tests approached were Cardiopulmonary Exercise Testing, Incremental Exercise Testing and Six-Minute Walk Test. Several studies show themselves as useful markers for predicting quality of life, mortality and functional impairment, in addition to other patients' characteristics. Several tests can be used to assess the respiratory and functional impact to patients' health, as well as its relationship with important domains of their lives

Acometimento miocárdico na Doença de Chagas: uma perspectiva a partir da avaliação pela ressonância magnética cardiovascular / Myocardial involvement in Chagas Disease: from the perspective of cardiovascular magnetic ressonance assessment

A doença de Chagas representa um importante problema de saúde pública, sobretudo nos países endêmicos da América Latina. Dentre suas apresentações clínicas, a cardiomiopatia crônica é a mais frequente. De patogênese multifatorial, o acometimento miocárdico pode levar à insuficiência cardíaca, a eventos tromboembólicos, a arritmias e à morte súbita. Nesse contexto, a ressonância magnética cardiovascular é um excelente método não invasivo para a investigação do dano miocárdico e a compreensão dos mecanismos e consequências relacionados às essas lesões. Com elevada resolução espacial e capacidade de caracterização tecidual, a ressonância magnética cardiovascular proporciona análise morfofuncional altamente confiável e possibilita a identificação de marcadores de risco de eventos adversos em pacientes com doença de Chagas, sendo de grande utilidade para o diagnóstico e o acompanhamento desses indivíduos na rotina clínica. (AU)

Chagas disease represents an important public health problem, especially in endemic countries in Latin America. Chronic cardiomyopathy is its most frequent clinical presentation. Myocardial involvement has a multifactorial pathogenesis and can lead to heart failure, thromboembolic events, arrhythmias, and sudden death. In this context, cardiovascular magnetic resonance imaging (CMR) is an excellent noninvasive method for investigating myocardial damage and understanding the mechanisms and consequences of these injuries. CMR has high spatial resolution and tissue characterization capacity, enabling a highly reliable morphofunctional analysis and the identification of risk markers for adverse events in patients with Chagas disease. This exam is very useful for the diagnosis and follow-up of these patients in the routine clinical setting. (AU)

Enfermedad de Chagas en niño residente en zona urbana a 2850 metros sobre el nivel del mar, reporte de caso / Chagas disease in a child living in an urban area at 2850 meters above sea level, case report

Introducción: La enfermedad de Chagas es una afección parasitaria, transmitida por vectores con características eco epidemiológicas causada por el protozoario Trypanosoma cruzi, del 2013 al 2019 el Ecuador reportó 108 casos agudos de los cuales 7 estuvieron en la provincia de Pichincha. Presentamos el caso por sus características eco-epidemiológicas. Caso clínico: un caso agudo de paciente masculino de 14 años, residente en zona no endémica que inició con signo de Romaña, fiebre de tres semanas de evolución con esplenomegalia leve e hipertrofia concéntrica del ventrículo izquierdo. Evolución: el paciente fue tratado con benznidazol 7mg/kg/día vía oral cada 8 horas por dos meses, medidas de soporte y seguimiento multidisciplinario. Conclusión: La zona de detección fue el noreste del distrito metropolitano de Quito, la cual es parte del distrito de salud 17D01, sin reportes previos hasta el año 2016, cuya aparición se podría relacionar con cambios en el ecosistema local y el impacto en la transmisión de enfermedades vectoriales.

Introduction: Chagas disease is a parasitic disease transmitted by vectors with echo-epidemiological characteristics caused by the protozoan Trypanosoma cruzi. From 2013 to 2019, Ecuador reported 108 acute cases, of which 7 were in the province of Pichincha. We present the case due to its ecoepidemiological characteristics. Clinical case: An acute case of a 14-year-old male resident in a nonendemic area that began with Romaña's sign, fever of three weeks of evolution with mild splenomegaly and concentric hypertrophy of the left ventricle. Evolution: The patient was treated with benznidazole 7 mg/kg/day orally every 8 hours for two months, support measures and multidisciplinary follow-up. Conclusion: The detection zone was the northeast of the metropolitan district of Quito, which is part of health district 17D01, without previous reports until 2016, whose appearance could be related to changes in the local ecosystem and the impact on the transmission of vector diseases.

Determinantes da capacidade funcional em pacientes com doença de chagas / Determinants of functional capacity in patients with chagas disease

Resumo Fundamento: A doença de Chagas leva à redução da capacidade funcional. Entretanto, o estágio em que o comprometimento funcional é detectável permanece obscuro. Objetivos: O presente estudo teve como objetivo comparar a capacidade funcional de pacientes em diferentes estágios da doença de Chagas e de indivíduos saudáveis e verificar os determinantes do consumo de oxigênio de pico (VO2pico). Métodos: Em um estudo transversal, foram selecionados 160 indivíduos, 35 saudáveis e 125 com doença de Chagas. No grupo chagásico, 61 (49%) estavam na forma indeterminada da doença, 45 (36%) com cardiomiopatia chagásica (CC) e função cardíaca preservada e 19 (15%) com disfunção cardíaca e CC dilatada. Os dados foram analisados por meio de análise de regressão univariada e multivariada. A significância estatística foi fixada em 5%. Resultados: Pacientes na forma indeterminada da doença apresentaram capacidade funcional semelhante a indivíduos saudáveis (p> 0,05). Pacientes com ChC e função cardíaca preservada apresentaram VO2pico menor que os pacientes na forma indeterminada (p <0,05), mas apresentaram valores de VO2pico semelhantes ao ChC dilatado (p = 0,46). A idade, sexo masculino, classe funcional da NYHA, pressão arterial diastólica, razão entre a velocidade do fluxo transmitral diastólico precoce e a velocidade anular mitral diastólica precoce, a fração de ejeção do ventrículo esquerdo (FEVE) e o diâmetro diastólico final do ventrículo esquerdo foram associados à capacidade funcional. Porém, apenas idade, sexo masculino, FEVE e classe funcional da NYHA permaneceram associados ao VO2pico no modelo final (R2 ajustado = 0,60). Conclusão: Pacientes com CC apresentam menor capacidade funcional do que pacientes na forma indeterminada. FEVE, idade, sexo masculino e classe funcional da NYHA foram determinantes do VO2pico em pacientes com doença de Chagas.

Abstract Background: Chagas disease leads to reduced functional capacity. However, the stage at which functional impairment is detectable remains unclear. Objectives: The present study was addressed to compare the functional capacity of patients at different stages of Chagas disease and healthy individuals and to verify the determinants of peak oxygen uptake (VO2peak). Methods: In a cross-sectional study, 160 individuals were selected, 35 healthy and 125 with Chagas disease. In the Chagasic group, 61 (49%) were in the indeterminate form of the disease, 45 (36%) with Chagas cardiomyopathy (ChC) and preserved cardiac function and 19 (15%) with cardiac dysfunction and dilated ChC. The data were analyzed using univariate and multivariate regression analysis. Statistical significance was set at 5%. Results: Patients in the indeterminate form of disease showed similar functional capacity to healthy individuals (p>0.05). Patients with ChC and preserved cardiac function had lower VO2peak than patients in the indeterminate form (p<0.05), but showed similar VO2peak values than dilated ChC (p=0.46). The age, male sex, NYHA functional class, diastolic blood pressure, ratio of the early diastolic transmitral flow velocity to early diastolic mitral annular velocity, left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter were associated with functional capacity. However, only age, male sex, LVEF and NYHA functional class, remained associated with VO2peak in the final model (adjusted R2=0.60). Conclusion: Patients with ChC had lower functional capacity than patients in the indeterminate form. LVEF, age, male sex and NYHA functional class were determinants with VO2peak in patients with Chagas disease.

Treinamento com Exercício Físico e Doença de Chagas: Função Potencial dos MicroRNAs / Physical Exercise Training and Chagas Disease: Potential Role of MicroRNAs

Resumo A doença de Chagas (DC) é causada pelo Trypanosoma Cruzi. Esse parasita pode infectar vários órgãos do corpo humano, especialmente o coração, causando inflamação, fibrose, arritmias e remodelação cardíaca, e promovendo a cardiomiopatia chagásica crônica (CCC) no longo prazo. Entretanto, poucas evidências científicas elucidaram os mecanismos moleculares que regulam os processos fisiopatológicos nessa doença. Os microRNAs (miRNAs) são reguladores de expressão gênica pós-transcricional que modulam a sinalização celular, participando de mecanismos fisiopatológicos da DC, mas o entendimento dos miRNAs nessa doença é limitado. Por outro lado, há muitas evidências científicas demonstrando que o treinamento com exercício físico (TEF) modula a expressão de miRNAs, modificando a sinalização celular em indivíduos saudáveis. Alguns estudos também demonstram que o TEF traz benefícios para indivíduos com DC, porém esses não avaliaram as expressões de miRNA. Dessa forma, não há evidências demonstrando o papel do TEF na expressão dos miRNAs na DC. Portanto, essa revisão teve o objetivo de identificar os miRNAs expressos na DC que poderiam ser modificados pelo TEF.

Abstract Chagas disease (CD) is caused by Trypanosoma Cruzi. This parasite can infect several organs of the human body, mainly the heart, causing inflammation, fibrosis, arrhythmias, and cardiac remodeling, promoting long-term Chronic Chagas Cardiomyopathy (CCC). However, little scientific evidence has elucidated the molecular mechanisms that govern the pathophysiological processes in this disease. MicroRNAs (miRNAs) are regulators of post-transcriptional gene expression that modulate signaling pathways, participating in pathophysiological mechanisms in CD, but the understanding of miRNAs in this disease is limited. On the other hand, a wide range of scientific evidence shows that physical exercise training (PET) modulates the expression of miRNAs by modifying different signaling pathways in healthy individuals. Some studies also show that PET is beneficial for individuals with CD; however, these did not evaluate the miRNA expressions. Thus, there is no evidence showing the role of PET in the expression of miRNAs in CD. Therefore, this review aimed to identify miRNAs expressed in CD that could potentially be modified by PET.

Prevalence of Chagas heart disease in dilated cardiomyopathy / Prevalencia de cardiopatía chagásica en la miocardiopatía dilatada

Abstract Objectives: The main objective is to determine the prevalence of American trypanosomiasis in patients with dilated cardiomyopathy in a tertiary hospital in western Mexico. Methods: From January 1991 to February 2016, 387 consecutive patients with a confirmed diagnosis of dilated cardiomyopathy were included in the study. Cases with ventricular dilatation secondary to ischemic heart disease, valvular heart disease, hypertension, lung disease, pericardial disease, or congenital heart disease were excluded from the study. Diagnosis was made detecting antibodies against Trypanosoma cruzi with two different methods or parasite in blood. Results: Were included 387 patients with dilated cardiomyopathy, Chagas cardiomyopathy was confirmed in 6.9%, two patients in the acute phase (in one, suspected transfusion transmission was detected). Most patients were born in rural areas. About 96.2% showed congestive heart failure, only one patient with apical left ventricular aneurysm manifested palpitations. About 66% with right bundle branch block, left anterior fascicular block, or the association of both, in 14.8%, non-sustained ventricular tachycardia was found. Conclusions: Chagas cardiomyopathy is common in México, mainly in people who were born or lived during childhood in rural areas. It is a common cause of heart failure. Chagas’ heart disease should be suspected in patients receiving a blood transfusion, even without another epidemiological history.

Resumen Objetivo: El objetivo principal del estudio es conocer la prevalencia de tripanosomiasis americana en pacientes con cardiomiopatía dilatada, en un hospital de concentración en el occidente de México. Métodos: Desde enero de 1991 a febrero de 2016 se incluyeron 387 pacientes consecutivos con diagnóstico de cardiomiopatía dilatada, se excluyeron los casos con dilatación ventricular secundaria a cardiopatía isquémica, valvulopatías, hipertensión arterial sistémica, enfermedad pulmonar, enfermedad pericárdica o cardiopatías congénitas. El diagnóstico se realizó mediante la detección de anticuerpos anti-tripanosoma cruzi con 2 métodos positivos diferentes o con la detección del parásito en sangre. Resultados: Se incluyeron 387 paciente con cardiomiopatía dilatada, en el 6.9% se confirmó cardiopatía chagásica; dos pacientes en fase aguda (uno con sospecha de transmisión transfusional). La mayoría de los pacientes provenían de zonas rurales. El 96.2% de los casos presentó insuficiencia cardiaca congestiva, un paciente con aneurisma apical del ventrículo izquierdo solo manifestó palpitaciones. El 66% presentó bloqueo de la rama derecha del haz de His, hemibloqueo anterior izquierdo o la asociación de ambos, en el 14.8% se encontró taquicardia ventricular no sostenida. Conclusiones: La cardiopatía chagásica es frecuente en nuestro medio, principalmente en personas que nacieron o vivieron durante la infancia en áreas rurales. Es causa común de insuficiencia cardiaca. La cardiomiopatía chagásica debe sospecharse en pacientes que reciben transfusión sanguínea, incluso sin otros antecedentes epidemiológicos

Os Efeitos da Doxorrubicina na Biossíntese e no Metabolismo do Heme em Cardiomiócitos / Effects of Doxorubicin on Heme Biosynthesis and Metabolism in Cardiomyocyte

Resumo Fundamento A doxorrubicina está associada à cardiotoxicidade e à morbidade cardíaca tardia. O heme está relacionado ao stress oxidativo celular. Entretanto, sua regulação específica em cardiomiócitos sob os efeitos de doxorrubicina ainda não foi documentada. Objetivo Nosso objetivo é avaliar as alterações de enzimas limitantes de velocidade no caminho metabólico do heme sob o efeito de doxorrubicina. Métodos Cardiomiócitos H9c2 com doxorrubicina em concentrações diferentes (1, 2, 5, 10μM respectivamente). Os testes de PCR em tempo real e Western Blot foram usados para determinar a expressão de proteína e mRNA para quatro enzimas cruciais (ALAS1, ALAS2, HOX-1, e HOX-2) que regulam o metabolismo do heme celular, e os níveis de heme foram detectados por ELISA. Um p<0,01 foi considerado significativo. Resultados Observamos um padrão com alteração dependendo da dose nos níveis de heme nas células H9c2 com o nível mais alto na concentração de 5μM de doxorrubicina, o que ocorreu sincronicamente com o nível mais alto de regulação para cima de ALAS1, bem como as enzimas degenerativas HOX-1 e HOX-2 na expressão de proteína e mRNA. Em contraste, observamos que a ALAS2 foi regulada para baixo gradualmente, inversamente proporcional às concentrações de doxorrubicina. Conclusão O aumento da expressão de ALAS1 pode ter um papel na elevação do nível do heme quando o cardiomiócito H9c2 for exposto à doxorrubicina, e pode ser um alvo terapêutico para a toxicidade miocárdica induzida por doxorrubicina. (Arq Bras Cardiol. 2021; 116(2):315-322)

Abstract Background Doxorubicin is associated with cardiotoxicity and late cardiac morbidity. Heme is related to cellular oxidative stress. However, its specific regulation in cardiomyocytes under doxorubicin effects has not yet been documented. Objective This study seeks to evaluate the changing profiles of rate-limiting enzymes in the heme metabolism pathway under the effect of doxorubicin. Methods H9c2 cardiomyocytes were incubated with doxorubicin at different concentrations (1,2,5,10μM respectively). The real-time PCR and Western Blot were used to determine the mRNA and protein expression for four pivotal enzymes (ALAS1, ALAS2, HOX-1, and HOX-2) regulating cellular heme metabolism, as well as the levels of heme were detected by ELISA. p<0.01 was considered significant. Results This study observed a dose-dependent changing pattern in heme levels in H9c2 cells with the highest level at the 5μM concentration for doxorubicin, which occurred synchronously with the highest upregulation level of ALAS1, as well as the degradative enzymes, HOX-1, and HOX-2 in mRNA and protein expression. By contrast, ALAS2, contrary to the increasing concentrations of doxorubicin, was found to be progressively down-regulated. Conclusion The increase in ALAS1 expression may play a potential role in the heme level elevation when H9c2 cardiomyocyte was exposed to doxorubicin and may be a potential therapeutic target for doxorubicin-induced myocardial toxicity. (Arq Bras Cardiol. 2021; 116(2):315-322)

Galectina-3 Associada a Formas Graves e Mortalidade em Longo Prazo em Pacientes com Doença de Chagas / Galectin-3 Associated with Severe Forms and Long-term Mortality in Patients with Chagas Disease

Resumo Fundamento As características histopatológicas da doença de Chagas (DCC) são: presença de miocardite, destruição das fibras cardíacas e fibrose miocárdica. A Galectina-3 (Gal-3) é um biomarcador envolvido no mecanismo de fibrose e inflamação que pode ser útil para a estratificação de indivíduos com DCC por risco. Objetivos Nosso objetivo foi avaliar se níveis elevados de Gal-3 estão associados a formas graves de cardiomiopatia chagásica (CC) e são preditivos de mortalidade. Métodos Estudamos doadores de sangue (DS) positivos para anti-T. cruzi: não-CC-DS (187 DS sem CC com eletrocardiograma [ECG] e fração de ejeção do ventrículo esquerdo [FEVE] normais); CC-Não-Dis-DS (46 DS com CC e apresentando ECG anormal, mas FEVE normal); e 153 controles negativos correspondentes. Esta amostra foi composta por 97 pacientes com CC grave (CC-Dis). Usamos as correlações de Kruskall-Wallis e Spearman para testar a hipótese de associações, assumindo um p bicaudal <0,05 como significativo. Resultados O nível de Gal-3 foi de 12,3 ng/mL para não-CC-DS, 12,0 ng/mL para CC-Não-Dis-DS, 13,8 ng/mL para controles e 15,4 ng/mL para CC-Dis. FEVE <50 foi associada a níveis mais elevados de Gal-3 (p=0,0001). Em nosso modelo de regressão linear ajustado, encontramos associação entre os níveis de Gal-3 e os parâmetros do ecocardiograma em indivíduos positivos para T. cruzi. Nos pacientes CC-Dis, encontramos uma associação significativa de níveis mais elevados de Gal-3 (≥15,3 ng/mL) e morte ou transplante cardíaco em acompanhamento de cinco anos (Hazard ratio - HR 3,11; IC95% 1,21- 8,04; p=0,019). Conclusões Em pacientes com CC, níveis mais elevados de Gal-3 estiveram significativamente associados a formas graves da doença e maior taxa de mortalidade em longo prazo, o que significa que pode ser um meio efetivo para identificar pacientes de alto risco. (Arq Bras Cardiol. 2021; 116(2):248-256)

Abstract Background The histopathological characteristics of Chagas disease (ChD) are: presence of myocarditis, destruction of heart fibers, and myocardial fibrosis. Galectin-3 (Gal-3) is a biomarker involved in the mechanism of fibrosis and inflammation that may be useful for risk stratification of individuals with ChD. Objectives We sought to evaluate whether high Gal-3 levels are associated with severe forms of Chagas cardiomyopathy (CC) and whether they are predictive of mortality. Methods We studied anti-T. cruzi positive blood donors (BD): Non-CC-BD (187 BD without CC with normal electrocardiogram [ECG] and left ventricular ejection fraction [LVEF]); CC-Non-Dys-BD (46 BD with CC with abnormal ECG but normal LVEF); and 153 matched serum-negative controls. This cohort was composed of 97 patients with severe CC (CC-Dys). We used Kruskall-Wallis and Spearman's correlation to test hypothesis of associations, assuming a two-tailed p<0.05 as significant. Results The Gal-3 level was 12.3 ng/mL for Non-CC-BD, 12.0 ng/mL for CC-Non-Dys-BD, 13.8 ng/mL for controls, and 15.4 ng/mL for CC-Dys. LVEF<50 was associated with higher Gal-3 levels (p=0.0001). In our linear regression adjusted model, we found association between Gal-3 levels and echocardiogram parameters in T. cruzi-seropositive subjects. In CC-Dys patients, we found a significant association of higher Gal-3 levels (≥15.3 ng/mL) and subsequent death or heart transplantation in a 5-year follow-up (Hazard ratio - HR 3.11; 95%CI 1.21-8.04; p=0.019). Conclusions In ChD patients, higher Gal-3 levels were significantly associated with severe forms of the disease and more long-term mortality, which means it may be a useful means to identify high-risk patients. (Arq Bras Cardiol. 2021; 116(2):248-256)

Estilo de vida e nível de atividade física de indivíduos portadores de miocardiopatia chagásica / Lifestyle and level of physical activity in individuals with chagasic myocardiopathy

INTRODUÇÃO: A doença de Chagas (DC) constitui uma infecção parasitária causada pelo protozoário flagelado Tripanosoma cruzi. Estimativas apontam a existência de, aproximadamente, cinco milhões de indivíduos infectados, principalmente na América Latina, com o Brasil datando entre 1,9 a 4,6 milhões de indivíduos sob o mesmo aspecto infeccioso. O desfecho cardíaco configura um dos aspectos mais importantes, com manifestações condizentes à disfunção ventricular sistólica ou diastólica, disfunção autonômica cardíaca e morte súbita. OBJETIVO: correlacionar o estilo de vida e o nível de atividade física de indivíduos portadores de miocardiopatia chagásica (MC). MATERIAL E MÉTODOS: Realizou-se um estudo analítico, de corte transversal, em ambulatório de referência para Miocardiopatias, com abrangência estadual. Utilizou-se formulário próprio construído pelas autoras, o qual contemplava além das variáveis clínicas e demográficas, variáveis relativas à análise do estilo de vida e atividade física dos participantes, sendo esse aplicado em sala de espera, enquanto os sujeitos aguardavam atendimento médico. RESULTADOS: Foram selecionados 74 indivíduos portadores de MC. A média de idade da amostra foi de 61,2 ± 8,5 anos, sendo que 50 (68,0%) indivíduos eram do sexo feminino. Em relação ao nível de atividade física, houve predomínio da categoria "não ativo", correspondendo a 60 indivíduos (71,0%). O estilo de vida foi classificado como "muito bom" para 41 (55,0%) participantes e "bom" para 22 (30,0%) participantes, não havendo indivíduos alocados na categoria "necessita melhorar" do questionário. CONCLUSÃO: Os resultados obtidos permitem concluir que, de modo geral, o estilo de vida e o nível de atividade física de indivíduos portadores de MC caracterizaram-se como "bom" / "muito bom" e não ativos, respectivamente.

INTRODUCTION: Chagas disease (CD) is a parasitic infection caused by the flagellated protozoan Trypanosoma cruzi. Estimates point to the existence of approximately five million infected individuals, mainly in Latin America, with Brazil dating between 1.9 and 4.6 million individuals under the same infectious aspect. The cardiac outcome is one of the most important aspects with manifestations consistent with systolic or diastolic ventricular dysfunction, cardiac autonomic dysfunction, and sudden death. OBJECTIVE: To correlate the lifestyle and physical activity level of individuals with Chagas cardiomyopathy (CM). MATERIAL AND METHODS: A cross-sectional analytical study was carried out in a reference outpatient clinic for cardiomyopathies, with state coverage. A form was created by the authors, which included, in addition to the clinical variables and demographic, variables related to the analysis of the participants' lifestyle and physical activity, this being applied in the waiting room, while the subjects waited for medical care. RESULTS: Seventy-four individuals with CM were selected. The mean age of the sample was 61.2 ± 8.5 years, with 50 (68.0%) individuals being female. Regarding the level of physical activity, the "not active" category was predominant, corresponding to 60 individuals (71.0%). The lifestyle was classified as "very good" for 41 (55.0%) participants and "good" for 22 (30.0%) participants, with no individuals allocated to the "need to improve" category of the questionnaire. CONCLUSION: The results obtained allow us to conclude that, in general, the lifestyle and the level of physical activity of individuals with CM were characterized as "good" / "very good" and not active, respectively.