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.

Comparação entre classificação funcional e fração de ejeção em pacientes com insuficiência cardíaca na Doença de Chagas / Functional classification versus ejection fraction in patients with heart failure and Chagas Disease

Introdução: A doença de Chagas é uma infecção causada pelo protozoário Trypanosoma cruzi. É considerada um importante problema de saúde do mundo, tendo como manifestações a dilatação cardíaca, arritmias e morte. A insuficiência cardíaca é uma síndrome complexa e de elevada morbimortalidade, que evolui com complicações semelhantes. Para categorizar a gravidade da insuficiência cardíaca, utilizamos a classificação funcional da New York Heart Association, para estratificar risco e terapias para cardiopatias. Além disso, a reduzida fração de ejeção do ventrículo esquerdo, medida pelo ecocardiograma, tem relação direta com mau prognóstico. Objetivo: Comparar a relação entre a classificação funcional pela New York Heart Association e a medida da fração de ejeção do ventrículo esquerdo em pacientes ambulatoriais chagásicos e não chagásicos. Metódos: Estudo de corte transversal na coorte, composto de pacientes acompanhados em ambulatório de insuficiência cardíaca. Foram realizadas avaliação de prontuários, entrevista clínica e verificação da classificação funcional e da fração de ejeção do ventrículo esquerdo pelo ecocardiograma. Os dados foram arquivados em banco de dados e analisados pelo Statistical Package for the Social Sciences. Resultados: No período de agosto de 2018 a julho de 2019, foram selecionados 127 indivíduos com insuficiência cardíaca. Destes, 34 (26,8%) eram portadores da doença de Chagas e 93 (73,3%) eram não Chagas. Observou-se predominância do sexo masculino (53,5%) e de idade >60 anos (61,4%). Houve predomínio da classe funcional II nos grupos. Em relação à fração de ejeção dos pacientes chagásicos e não chagas, observou-se que, respectivamente, 71% contra 93% dos pacientes tinham fração de ejeção reduzida, 21% versus 6% tinham fração de ejeção intermediária e 8% versus 1% fração de ejeção preservada. Conclusão: Houve associação entre classe funcional avançada e reduzida fração de ejeção do ventrículo esquerdo principalmente em chagásicos, podendo ser usada para acompanhamento evolutivo ambulatorial. (AU)

Introduction: Chagas disease, an infection caused by the protozoan Trypanosoma cruzi, is an important health problem worldwide that causes cardiac dilation, arrhythmias, and death. Heart failure is a complex syndrome with high morbidity and mortality rates that progresses with similar complications. The New York Heart Association functional classification is used to categorize heart failure severity and stratify heart disease risks and therapies. A reduced left ventricular ejection fraction measured by echocardiography is directly related to a poor prognosis. Objective: To compare the relationship between New York Heart Association functional classification and left ventricular ejection fraction in Chagas versus no Chagas disease outpatients. Methods: Cross-sectional study in a cohort of patients followed at a heart failure clinic. Medical records, clinical interviews, functional classification, and left ventricular ejection fraction by echocardiography were analyzed. The data were filed in a database and analyzed using SPSS software. Results: A total of 127 patients with heart failure were selected from August 2018 to July 2019. Of them, 34 (26.8%) had Chagas disease and 93 (73.3%) had no Chagas disease. There was a predominance of men (53.5%) and patients aged > 60 years (61.4%). There was also a predominance of functional class II. Of the Chagas and no Chagas disease patients, 71% versus 93% had a reduced ejection fraction, 21% versus 6% had a mid-range ejection fraction, and 8% versus 1% had a preserved ejection fraction, respectively. Conclusion: There was an association between advanced functional class and reduced left ventricular ejection fraction, especially in Chagas patients, information that can be used for outpatient follow-up. (AU)

Deformação miocárdica (strain) e fibrose miocárdica na forma cardíaca leve da Doença de Chagas / Myocardial deformation (strain) and myocardial fibrosis in mild cardiac Chagas Disease

Fundamento: A identificação precoce do dano miocárdico parece ser importante na abordagem do paciente com doença de Chagas. A ecocardiografia com strain obtida por speckle tracking e a avaliação da fibrose miocárdica por meio da ressonância magnética cardíaca podem ser métodos diagnósticos promissores nesse sentido. Objetivo: Avaliar o acometimento miocárdico especificamente na forma crônica cardíaca leve da doença de Chagas por meio do strain por speckle tracking e da fibrose miocárdica pela ressonância magnética cardíaca, além de suas correlações. Método: Estudo de corte transversal que analisou portadores da forma cardíaca crônica leve da doença de Chagas (fração de ejeção preservada) submetidos à ecocardiografia com strain por speckle tracking e à ressonância magnética cardíaca. Resultados: Foram incluídos 21 participantes (mulheres: 62%; idade: 54 ± 5 anos). A prevalência de fibrose miocárdica por meio do realce tardio miocárdico foi de 50%. O strain longitudinal global encontrava-se diminuído em 17 pacientes (81%), com mediana de 14,1% (intervalo interquartil de 12,1 a 16,3). Os valores do mapa T1 encontravam-se, em média, elevados nos portadores de doença de Chagas (993 ± 163 ms). O mapa T1 foi significativamente correlacionado com o strain longitudinal global (r= 0,634; p = 0,015). Além disso, o índice de dispersão mecânica, obtido por strain, estava aumentado (> 55 ms) em 84%, com a maior área sob a curva Característica de Operação do Receptor (área sob a curva de 0,696; intervalo de confiança de 95% de 0,412-0,981) para discriminação de fibrose pelo realce tardio miocárdico. Conclusão: O strain miocárdico e o mapa T1 se comportam como marcadores precoces do dano miocárdico na cardiopatia chagásica crônica leve. O índice de dispersão mecânica estava elevado e foi o parâmetro que melhor se correlacionou com o realce tardio miocárdico. (AU)

Background: The early identification of myocardial damage seems important in the management of patients with Chagas disease. However, it is unknown whether speckle tracking echocardiography strain and cardiac magnetic resonance imaging are promising methods for assessing myocardial involvement and fibrosis, respectively. Objective: To evaluate myocardial involvement in the mild chronic cardiac form of Chagas disease using speckle tracking strain and myocardial fibrosis by cardiac magnetic resonance and assess their correlations. Method: This cross-sectional study analyzed patients with the mild chronic cardiac form of Chagas disease (preserved ejection fraction) using speckle tracking echocardiography and cardiac magnetic resonance. Results: The study included 21 participants (women: 62%; age: 54 ± 5 years). The prevalence of myocardial fibrosis was 50% on delayed myocardial enhancement. The median global longitudinal strain was decreased (14.1%; interquartile range, 12.1­16.3%) in 17 patients (81%). The mean T1 mapping value was high in patients with Chagas disease (993 ± 163 ms). The T1 map was significantly correlated with the global longitudinal strain (r = 0.634; p = 0.015). In addition, the mechanical dispersion index obtained by strain was increased (>55 ms) by 84%, with the largest area under the receiver operating characteristic curve (area under the curve, 0.696; 95% confidence interval, 0.412­0.981) for fibrosis discrimination by delayed myocardial enhancement. Conclusion: Myocardial strain and T1 mapping are early markers of myocardial damage in mild chronic Chagas heart disease. The mechanical dispersion index was high and the most closely correlated with delayed myocardial enhancement. (AU)

Nuclear Medicine Methods for Assessment of Chronic Chagas Heart Disease

Abstract Several different imaging methods can be used to evaluate patients with Chagas heart disease (CHD) for diagnostic and prognostic purposes, including plain chest radiography; echocardiography; myocardial perfusion scintigraphy, for detection of ischemia and fibrosis; radionuclide gated-angiography, for evaluation of biventricular function; 123I-MIBG labeling of sympathetic myocardial innervation; MRI, for detection and quantitation of myocardial fibrosis; and coronary angiography. This study aims to review the contributions of these nuclear medicine methods to understanding of the pathophysiology of chronic Chagas cardiomyopathy (CCC). Careful analysis and integration of findings provided by these imaging methods in patients with CCC at different stages has contributed significantly to improving understanding of several peculiarities of the disease. Clinical and experimental studies in animal models show that perfusion abnormalities detected in association with dysfunctional but viable myocardium are a common finding in CCC patients and correspond to areas of cardiac sympathetic denervation, as assessed by 123I-MIBG imaging. Furthermore, recent reports have demonstrated a close relationship between coronary microvascular disturbances and myocardial inflammation. Thus, ongoing research, mainly focused on refinements of 18F-FDF -PET techniques and further exploration of nuclear methods, such as SPECT, have the potential to contribute to detection and monitoring of early subclinical myocardial damage thereby enabling evaluation of therapeutic strategies targeting inflammation and microvascular ischemia that could result in better prognostic stratification of patients with CHD.

Exercise tests in Chagas cardiomyopathy: an overview of functional evaluation, prognostic significance, and current challenges

Abstract Patients with Chagas cardiomyopathy (ChC) usually progress with fatigue and dyspnea. Exercise tests are valuable for the functional evaluation of these patients. However, information about the applicability of the exercise tests is scattered, and no studies have systematically reviewed the results. Thus, the present review explored the general aspects and prognostic value of exercise tests in patients with ChC. A literature search of the MEDLINE, Web of Science, CINAHL, Scopus, and LILACS databases was performed to identify relevant studies. There were no data restrictions, and articles that met the objective of the study were selected. Articles written in English, Portuguese, and Spanish were considered, and 25 articles were finally included. The peak oxygen uptake (VO2peak) was correlated with demographic and echocardiographic variables. Echocardiographic features of the left ventricular diastolic function and right ventricular systolic function appeared to be determinants of functional capacity, in addition to age and sex. VO2peak was associated with higher mortality, especially in patients with dilated ChC. The minute ventilation/carbon dioxide production slope (VE/VCO2 slope) was a strong predictor of survival; however, more studies are needed to verify this observation. Field tests showed moderate to strong correlation with VO2peak and thus may be inexpensive tools for the functional evaluation of patients with ChC. However, few studies have verified their prognostic significance. While exercise tests are useful tools for functional assessment, information is scarce regarding further considerations, and many of the criteria are based on guidelines for other heart diseases.

Analysis of Iron Metabolism in Chronic Chagasic Cardiomyopathy / Análise do Metabolismo do Ferro na Cardiomiopatia Chagásica Crônica

Abstract Changes in iron metabolism in heart failure (HF) have been described as an important prognostic marker. To check if the markers of iron kinetics are related to the morbidity and etiology of chagasic cardiomyopathy. Patients with Chronic Chagasic Cardiomyopathy (CCC, n = 40), with indeterminate form (IND, n = 40), besides non-chagasic cardiomyopathy (NCh, n = 40). The mean age was 50.98 ± 5.88 in CCC, 50% were male, 49.68 ± 5.28 in IND, 52.2% were male, and 49.20 ± 10.09 in NCh, 12.5% were male. Lower levels of iron (FeSe) were observed in the CCC groups (93.15 ± 36.53), when compared to IND (125.30 ± 22.79) and NCh (114.77 ± 18.90) (p = 0.0004), lower IST transferrin saturation index in CCC (29.48 ± 6.59), when compared to IND (30.95 ± 7.06) and in the NCh group (39.70 ± 7.54) p = 0.0001), total binding capacity of the lower CTLF iron in the CCC group (297.30 ± 36.46), when compared to the IND group (196.52 ± 56.95) and the NCh group (275.18 ± 33, 48) (p = 0.0001), lower ferritin in the CCC group (134.55, 1.56-42.36), when compared to the IND group (156,25, 1,72-42,20) and the NCh group (112.95, 2.88-42.66) (p = 0.0004). It was also observed that FeSe (95% CI 1.00-1.04, p = 0.0014), IST (95% CI 1.02-1.22) (p = 0.0012) and gender (95% CI 1.07-14.43 p = 0.0038) were independently associated with the degree of ventricular dysfunction in chagasic cardiomyopathy. CCC patients showed greater change in iron metabolism regarding the indeterminate form and other forms of cariomyopathies.

Resumo A alteração do metabolismo do ferro na insuficiência cardíaca (IC) tem sido descrita como um importante marcador prognóstico. Verificar se os marcadores da cinética do ferro guardam relação com a morbidade e a etiologia da cardiomiopatia chagásica. Pacientes com cardiomiopatia chagásica crônica (CCC, n = 40), com a forma indeterminada (IND, n = 40), além de cardiomiopatia não chagásica (NCh, n = 40). A idade média foi de 50,98 ± 5,88 no CCC, 50% eram do sexo masculino, 49,68 ± 5,28 no IND, 52,2% eram do sexo masculino e 49,20 ±10,09 no NCh, 12,5% eram do sexo masculino. Observaram-se níveis de ferro (FeSe) menores no grupos CCC (93,15 ± 36,53), quando comparados ao IND (125,30 ± 22,79) e NCh (114,77 ± 18,90) (p = 0,0004), índice de saturação de transferrina (IST) menor no CCC (29,48 ± 6,59), quando comparado ao IND (30,95 ± 7,06) e no grupo NCh (39,70 ± 7,54) (p= 0,0001), capacidade total de ligação do ferro CTLF menor no grupo CCC (297,30 ± 36,46), quando comparado ao grupo IND (196,52 ± 56,95) e ao grupo NCh (275,18 ± 33,48) (p = 0,0001), ferritina menor no grupo CCC (134,55, 1,56-42,36), quando comparada ao grupo IND (156,25, 1,72 - 42,20) e ao grupo NCh (112,95, 2,88-42,66) (p = 0.0004). Verificou-se também que o FeSe (IC% 95% 1,00-1,04; p = 0,0014), o IST (IC 95% 1,02-1,22) (p = 0,0012) e o sexo (IC 95% 1,07-14,43 p = 0,0038) associaram-se independentemente ao grau de disfunção ventricular na cardiomiopatia chagásica. Os pacientes com CCC demonstraram maior alteração no metabolismo do ferro em relação a forma indeterminada e outras formas de miocardiopatias.

Echocardiographic Study of the Coronary Sinus in the Indeterminate Form of Chagas Disease

Abstract INTRODUCTION: We investigated the occurrence of coronary sinus abnormalities in the indeterminate form of Chagas disease (CD). METHODS: Differences between the maximum and minimum diameters of the coronary sinus (∆%) on echocardiography were evaluated in individuals with the indeterminate form of CD (n=14) and those without (n=16) CD. The association of the difference with abnormalities detected by echocardiography and myocardial scintigraphy was assessed. RESULTS: The mean Δ% values did not differ significantly between the groups. There was no correlation of the measurements with echocardiographic and myocardial scintigraphy findings. CONCLUSIONS: The coronary sinus evaluation revealed no differences between the groups.

Obstructive Sleep Apnea is Common and Associated with Heart Remodeling in Patients with Chagas Disease / Apneia Obstrutiva do Sono é Comum e está Associada à Remodelação Cardíaca em Pacientes com Doença de Chagas

Abstract Background: Chagas Disease (CD) is an important cause of morbimortality due to heart failure and malignant arrhythmias worldwide, especially in Latin America. Objective: To investigate the association of obstructive sleep apnea (OSA) with heart remodeling and cardiac arrhythmias in patients CD. Methods: Consecutive patients with CD, aged between 30 to 65 years old were enrolled. Participants underwent clinical evaluation, sleep study, 24-hour Holter monitoring, echocardiogram and ambulatory blood pressure monitoring. Results: We evaluated 135 patients [age: 56 (45-62) years; 30% men; BMI: 26 ± 4 kg/m2, Chagas cardiomyopathy: 70%]. Moderate to severe OSA (apnea-hypopnea index, AHI, ≥ 15 events/h) was present in 21% of the patients. OSA was not associated with arrhythmias in this population. As compared to patients with mild or no OSA, patients with moderate to severe OSA had higher frequency of hypertension (79% vs. 72% vs. 44%, p < 0.01) higher nocturnal systolic blood pressure: 119 ± 17 vs. 113 ± 13 vs. 110 ± 11 mmHg, p = 0.01; larger left atrial diameter [37 (33-42) vs. 35 (33-39) vs. 33 (30-36) mm, p < 0.01]; and a greater proportion of left ventricular dysfunction [LVEF < 50% (39% vs. 28% vs. 11%), p < 0.01], respectively. Predictor of left atrial dimension was Log10 (AHI) (b = 3.86, 95% CI: 1.91 to 5.81; p < 0.01). Predictors of ventricular dysfunction were AHI > 15 events/h (OR = 3.61, 95% CI: 1.31 - 9.98; p = 0.01), systolic blood pressure (OR = 1.06, 95% CI: 1.02 - 1.10; p < 0.01) and male gender (OR = 3.24, 95% CI: 1.31 - 8.01; p = 0.01). Conclusions: OSA is independently associated with atrial and ventricular remodeling in patients with CD.

Resumo Fundamento: A doença de Chagas (DC) é uma causa importante de morbimortalidade por insuficiência cardíaca e arritmias malignas em todo o mundo, especialmente na América Latina. Objetivo: Investigar a associação entre apneia obstrutiva do sono (AOS) com remodelação cardíaca e arritmias cardíacas em pacientes com DC. Métodos: Foram incluídos pacientes consecutivos com DC, com idade entre 30 e 65 anos. Os participantes foram submetidos à avaliação clínica, estudo do sono, Holter de 24 horas, ecocardiograma e monitorização ambulatorial da pressão arterial. Resultados: Foram avaliados 135 pacientes [idade: 56 (45-62) anos; 30% homens; IMC: 26 ± 4 kg/m2, cardiomiopatia chagásica: 70%]. AOS moderada a grave (índice de apneia-hipopneia, IAH, ≥ 15 eventos/h) estava presente em 21% dos pacientes. AOS não estava associada a arritmias nessa população. Em comparação com pacientes com AOS leve ou ausente, pacientes com AOS moderada a grave apresentaram maior frequência de hipertensão (79% vs. 72% vs. 44%, p < 0,01) e pressão arterial sistólica noturna mais alta: 119 ± 17 vs. 113 ± 13 vs. 110 ± 11 mmHg, p = 0,01; diâmetro do átrio esquerdo maior [37 (33‑42) vs. 35 (33-39) vs. 33 (30-36) mm, p < 0,01]; e maior proporção de disfunção ventricular esquerda [FEVE < 50% (39% vs. 28% vs. 11%), p < 0,01], respectivamente. O preditor de dimensão do átrio esquerdo foi Log10 (IAH) (β = 3,86, IC 95%: 1,91 a 5,81; p < 0,01). Os preditores de disfunção ventricular foram IAH >15 eventos/h (OR = 3,61, IC 95%: 1,31 - 9,98; p = 0,01), pressão arterial sistólica (OR = 1,06, IC95%: 1,02 - 1,10; p < 0,01) e sexo masculino (OR = 3,24, IC 95%: 1,31 - 8,01; p = 0,01). Conclusões: A AOS está independentemente associada à remodelação atrial e ventricular em pacientes com DC.

Sympathetic Dysautonomia in Heart Failure by 123I-MIBG: comparison between Chagasic, non-Chagasic and heart transplant patients / Disautonomia Simpática na Insuficiência Cardíaca pela 123I-MIBG: Comparação entre Pacientes Chagásicos, não-Chagásicos e Transplantados Cardíacos

Abstract Background: Heart failure (HF) is a severe public health problem because of its high morbidity and mortality and elevated costs, thus requiring better understanding of its course. In its complex and multifactorial pathogenesis, sympathetic hyperactivity plays a relevant role. Considering that sympathetic dysfunction is already present in the initial phases of chronic Chagas cardiomyopathy (CCC) and frequently associated with a worse prognosis, we assumed it could be more severe in CCC than in cardiomyopathies of other etiologies (non-CCC). Objectives: To assess the cardiac sympathetic dysfunction 123I-MIBG) of HF, comparing individuals with CCC to those with non-CCC, using heart transplant (HT) patients as denervated heart parameters. Methods: We assessed 76 patients with functional class II-VI HF, being 25 CCC (17 men), 25 non-CCC (14 men) and 26 HT (20 men), by use of cardiac 123I-metaiodobenzylguanidine 123I-MIBG) scintigraphy, estimating the early and late heart-to-mediastinum ratio (HMR) of 123I-MIBG uptake and cardiac washout (WO%). The 5% significance level was adopted in the statistical analysis. Results: The early and late HMR values were 1.73 ± 0.24 and 1.58 ± 0.27, respectively, in CCC, and 1.62 ± 0.21 and 1.44 ± 0.16 in non-CCC (p = NS), being, however, higher in HT patients (p < 0.001). The WO% values were 41.65 ± 21.4 (CCC), 47.37 ± 14.19% (non-CCC) and 43.29 ± 23.02 (HT), p = 0.057. The late HMR values showed a positive weak correlation with left ventricular ejection fraction (LVEF) in CCC and non-CCC (r = 0.42 and p = 0.045; and r = 0.49 and p = 0.015, respectively). Conclusion: Sympathetic hyperactivity 123I-MIBG) was evidenced in patients with class II-IV HF, LVEF < 45%, independently of the HF etiology, as compared to HT patients.

Resumo Fundamentos: A insuficiência cardíaca (IC) representa um grave problema de saúde pública pela alta morbimortalidade e custos envolvidos, exigindo uma melhor compreensão de sua evolução. Em sua patogênese, complexa e multifatorial, a hiperatividade simpática ocupa relevante papel. Considerando que a disfunção simpática está presente já nas fases iniciais da cardiopatia chagásica crônica (CCC), frequentemente associando-se a um pior prognóstico, supomos que pudesse ser mais grave na CCC que nas demais etiologias (não-CCC). Objetivos: Avaliar a disfunção simpática cardíaca (123I-MIBG) da IC, comparando-se os portadores de CCC aos não-CCC, utilizando os pacientes transplantados cardíacos (TC) como parâmetro de coração desnervado. Métodos: Estudamos 76 pacientes com IC classe funcional II-VI, sendo 25 CCC (17 homens), 25 não-CCC (14 homens) e 26 TC (20 homens), pela cintilografia cardíaca (123I-MIBG), estimando-se a captação (HMR) precoce e tardia e o washout cardíaco (Wc%). Nas análises estatísticas, o nível de significância foi de 5%. Resultados: Os valores da HMR precoce e da tardia foram 1,73 ± 0,24 e 1,58 ± 0,27, respectivamente, na CCC, e 1,62 ± 0,21 e 1,44 ± 0,16 na não-CCC (p = NS), sendo, porém, mais elevados nos TC (p < 0,001). Os valores de Wc% foram 41,65 ± 21,4 (CCC), 47,37 ± 14,19% (não-CCC) e 43,29 ± 23,02 (TC), p = 0,057. Os valores de HMR tardia apresentaram correlação positiva fraca com a fração de ejeção de ventrículo esquerdo (FEVE) na CCC e na não-CCC (r = 0,42 e p = 0,045; e r = 0,49 e p = 0,015, respectivamente). Conclusão: Evidenciou-se a presença de hiperatividade simpática (123I-MIBG) em pacientes com IC classe II-IV, FEVE < 45%, independentemente da etiologia da IC, quando comparados aos pacientes TC.

Terapia de Resgate com Nifurtimox e Dipiridamol na Miocardite Chagásica Aguda Grave com Insuficiência Cardíaca em Camundongos NMRI / Rescue Therapy with Nifurtimox and Dipyridamole for Severe Acute Chagas Myocarditis with Congestive Heart Failure in NMRI Albino Mice

Fundamento: A doença de Chagas é um problema de saúde global, sendo necessário o desenvolvimento de novos protocolos terapêuticos. Nosso grupo demonstrou recentemente que o nifurtimox associado ao dipiridamol tem efeitos curativos em camundongos com doença de Chagas aguda. Neste estudo, avaliamos o efeito deste protocolo terapêutico em camundongos chagásicos com insuficiência cardíaca. Objetivo: Avaliar se o nifurtimox e o dipiridamol são úteis no tratamento de resgate em camundongos com miocardite chagásica aguda com insuficiência cardíaca. Métodos: Foram divididos em três grupos 42 camundongos com miocardite chagásica aguda e insuficiência cardíaca congestiva: Controle Chagas (n = 11); Nif-Dip, tratados com nifurtimox e dipiridamol (n = 14); e Nif-Dip-Insuficiência Cardíaca, tratados com nifurtimox e dipiridamol, associados com digoxina, furosemida e captopril (n = 17). As doses de nifurtimox e dipiridamol foram de 40 e 30mg/kg/dia, respectivamente, durante 6 semanas. Os camundongos foram submetidos a avaliações clínicas, eletrocardiográficas, hemoparasitológicas e histopatológicas. Resultados: Observou-se menor mortalidade no Grupo Nif-Dip (n = 4; 28,57%) em relação ao Controle Chagas (n = 6; 54,54%) e ao Nif-Dip-Insuficiência Cardíaca (n = 9; 52,9%). Clinicamente, os camundongos tratados com nifurtimox e dipiridamol aumentaram o peso corporal e melhoraram a insuficiência cardíaca, sem mostrar esplenomegalia. Nestes grupos, foram erradicadas as parasitemias e os parasitas teciduais; a fibrose, a miocitólise, o infiltrado de células inflamatórias e os mastócitos diminuíram. Os distúrbios de repolarização, os intervalos QRS e o QT prolongados, o aumento da amplitude da onda S e a dissociação atrioventricular foram revertidos pelo tratamento. Conclusão: O tratamento com nifurtimox e dipiridamol pode ser usado no resgate em camundongos com doença chagásica aguda grave, já que o nifurtimox teve atividade tripanocida, e o dipiridamole potenciou seu efeito. O dipiridamol seria útil na insuficiência cardíaca chagásica

Background: Chagas disease is a global health problem; therefore, the development of new therapeutic protocols is necessary. Our group recently demonstrated that nifurtimox associated with dipyridamole has curative effects in mice with acute Chagas disease. In this study, we assess the effect of this therapeutic protocol in chagasic mice with heart failure. Objective: To evaluate whether nifurtimox and dipyridamole are useful to rescue mice with severe acute chagasic myocarditis with heart failure. Methods: 42 mice with acute chagasic myocarditis and congestive heart failure were divided into three groups: control chagas (n = 11), Nif-Dip treated with nifurtimox and dipyridamole (n = 14) and Nif-Dip-heart failure treated with nifurtimox and dipyridamole associated with digoxin, furosemide, and captopril (n = 17). Nifurtimox and dipyridamole doses were 40 and 30 mg/kg/day, respectively, for 6 weeks. Mice underwent clinical, electrocardiographic, hemoparasitological and histopathological assessments. Results: Lower mortality in Nif-Dip (28.57%; n = 4) compared to control chagas (54.54%; n = 6) and Nif-Dip-heart failure (52.9%; n = 9) was observed. Clinically, nifurtimox and dipyridamole-treated mice increased body weight and improved heart failure without splenomegaly. In these groups, parasitemia and tissue parasites were eradicated; fibrosis, myocytolysis, inflammatory cell infiltrate and mast cells decreased. Repolarization disorders, prolonged QRS and QT intervals, increase of S wave amplitude and atrioventricular dissociation were reversed by the treatment. Conclusion: Nifurtimox with dipyridamole can rescue NMRI mice from severe acute chagas disease, as nifurtimox showed trypanocidal activity and dipyridamole potentiated its effect. Dipyridamole would be useful in chagasic heart failure

Prognostic Factors in Severe Chagasic Heart Failure / Fatores Prognósticos na Insuficiência Cardíaca Grave de Etiologia Chagásica

Abstract Background: Prognostic factors are extensively studied in heart failure; however, their role in severe Chagasic heart failure have not been established. Objectives: To identify the association of clinical and laboratory factors with the prognosis of severe Chagasic heart failure, as well as the association of these factors with mortality and survival in a 7.5-year follow-up. Methods: 60 patients with severe Chagasic heart failure were evaluated regarding the following variables: age, blood pressure, ejection fraction, serum sodium, creatinine, 6-minute walk test, non-sustained ventricular tachycardia, QRS width, indexed left atrial volume, and functional class. Results: 53 (88.3%) patients died during follow-up, and 7 (11.7%) remained alive. Cumulative overall survival probability was approximately 11%. Non-sustained ventricular tachycardia (HR = 2.11; 95% CI: 1.04 - 4.31; p<0.05) and indexed left atrial volume ≥ 72 mL/m2 (HR = 3.51; 95% CI: 1.63 - 7.52; p<0.05) were the only variables that remained as independent predictors of mortality. Conclusions: The presence of non-sustained ventricular tachycardia on Holter and indexed left atrial volume > 72 mL/m2 are independent predictors of mortality in severe Chagasic heart failure, with cumulative survival probability of only 11% in 7.5 years.

Resumo Fundamento: Fatores prognósticos são bastante estudados na insuficiência cardíaca (IC), mas ainda não possuem um papel estabelecido na IC grave de etiologia chagásica. Objetivo: Identificar a associação de fatores clínicos e laboratoriais com o prognóstico da IC grave de etiologia chagásica, bem como a associação desses fatores com a taxa de mortalidade e a sobrevida em um seguimento de 7,5 anos. Métodos: 60 pacientes portadores de IC grave de etiologia chagásica foram avaliados com relação às seguintes variáveis: idade, pressão arterial, fração de ejeção, sódio plasmático, creatinina, teste de caminhada de 6 minutos, taquicardia ventricular não sustentada, largura do QRS, volume do átrio esquerdo indexado e classe funcional. Resultados: 53 (88,3%) pacientes foram a óbito durante o período de seguimento e 7 (11,7%) permaneceram vivos. A probabilidade de sobrevida geral acumulada foi de aproximadamente 11%. Taquicardia ventricular não sustentada (HR = 2,11; IC 95%: 1,04 - 4,31; p<0,05) e volume do átrio esquerdo indexado ≥ 72 ml/m2 (HR = 3,51; IC 95%: 1,63 - 7,52; p<0,05) foram as únicas variáveis que permaneceram como preditores independentes de mortalidade. Conclusão: A presença de taquicardia ventricular não sustentada ao Holter e o volume do átrio esquerdo indexado > 72 ml/m2 são preditores independentes de mortalidade na IC chagásica grave, com probabilidade de sobrevida acumulada de apenas 11% em 7,5 anos.

Decompensated chagasic heart failure versus non-chagasic heart failure at a tertiary care hospital: Clinical characteristics and outcomes / Insuficiência cardíaca descompensada chagásica versus não chagásica em um hospital de atenção terciária: características e desfechos clínicos

Summary Objective: To evaluate clinical and epidemiological characteristics and clinical outcomes in patients hospitalized with decompensated heart failure (DHF), with a comparison between Chagas and non-Chagas disease. Method: This is a retrospective cohort study involving 136 patients consecutively admitted with DHF between January 1 and December 31, 2011, with the following outcomes: acute renal failure, cardiogenic shock, rehospitalization, and hospital death. Individuals aged ≥ 18 years with DHF were included while those with more than 10% of missing data regarding outcomes were excluded. Statistical analysis was performed using SPSS version 17.0. Chi-squared test was used to compare proportions. Student's T test was used to compare means. Kaplan-Meier and log-rank tests were used to compare rehospitalization rates between the two groups over time. Results: Chagasic and non-chagasic patients were compared. The first had lower mean systolic blood pressure (111.8±18.4 versus 128.8±24.4, p<0.01), lower mean diastolic blood pressure (74.5±13.6 versus 82.0±15.2, p<0.01) and lower left ventricular ejection fraction (26.5±6.2 versus 41.5±18.9, p<0.01). In all, 20 patients with Chagas (50.1%) were rehospitalized, compared to 35 patients in the non-Chagas group (35.4%, p=0.04). Log rank test = 4.5 (p<0.01) showed that rehospitalization rates between the two groups over time (Kaplan-Meier curves) differed. Conclusion: Chagas disease was associated with lower systolic and diastolic blood pressure and lower left ventricular ejection fraction. The rehospitalization rate was higher in Chagas disease.

Resumo Objetivo: Avaliar características clínico-epidemiológicas e desfechos clínicos em pacientes internados por insuficiência cardíaca descompensada (ICD), estabelecendo uma comparação entre pacientes chagásicos e não chagásicos. Método: Trata-se de um estudo de coorte retrospectivo abrangendo 136 pacientes internados consecutivamente com ICD entre 1 de janeiro e 31 de dezembro de 2011, tendo como desfechos: lesão renal aguda, choque cardiogênico, reinternamento e óbito hospitalar. Foram incluídos indivíduos com idade ≥ 18 anos com ICD e excluídos aqueles com mais de 10% de dados faltantes em relação aos desfechos. Para a análise estatística, foi utilizado o SPSS® versão 17.0. Para a comparação entre proporções, foi utilizado o teste Qui-quadrado. O teste T de Student foi utilizado para comparar médias. Utilizamos as curvas de Kaplan-Meier e o teste do log rank para comparar as taxas de reinternações entre os dois grupos ao longo do tempo. Resultados: Na comparação entre chagásicos e não chagásicos, os primeiros apresentaram menor média de pressão arterial sistêmica (111,8±18,4 versus 128,8±24,4; p<0,01), menor média de pressão arterial diastólica (74,5±13,6 versus 82,0±15,2; p<0,01) e menor fração de ejeção do ventrículo esquerdo (26,5±6,2 versus 41,5±18,9; p<0,01). Um total de 20 chagásicos (50,1%) reinternaram contra 35 não chagásicos (35,4%; p=0,04). O teste do log rank = 4,5 (p<0,01) mostrou que as taxas de reinternações entre os dois grupos ao longo do tempo (curvas de Kaplan-Meier) diferiram. Conclusão: A doença de Chagas associou-se a menores valores de pressão arterial sistólica e diastólica, além de menor fração de ejeção do ventrículo esquerdo. A taxa de reinternamento foi maior em chagásicos.

The potential influence of atherogenic dyslipidemia on the severity of chronic Chagas heart disease / Influencia de la dislipidemia aterogénica en la gravedad de la miocardiopatía chagásica crónica

SUMMARY Introduction: chronic Chagas heart disease (CCHD) is the most common manifestation of American Trypanosomiasis, causing about 50,000 deaths annually. Several factors bear correlation with the severity of CCHD. However, to our knowledge, the assessment on the contribution of major cardiovascular risk factors (CRF), such as hypertension and atherogenic dyslipidemia (AD) to CCHD severity is scarce, despite their well-established role in coronary artery disease, heart failure and stroke. Objective: to explore the potential relationship of blood pressure and AD with the clinical profile of patients with CCHD. Methods: we performed a cross-sectional study in T. cruziseropositive patients categorized according to a standard CCHD classification. All individuals were subjected to complete clinical examination. Autoantibodies induced by T. cruzi were assessed by ELISA. Results: we observed that Atherogenic index (AI) levels rose significantly in relation to the severity of the CCHD stage, with CCHD III cases showing the highest values of AI. Furthermore, those patients with globally dilated cardiomyopathy with reduced ejection fraction showed higher levels of AI. In regard to autoantibodies, anti-B13 also showed relation with the severity of the disease. Conclusion: we observed that AI correlated with CCHD stages and contributed, in association with anti-B13 antibodies and age, to the prediction of systolic heart failure.

RESUMO Introducción: la miocardiopatía chagásica (MCC) es la manifestación más común de la tripanosomiasis americana, causando cerca de 50.000 muertes al año. Varios factores se asocian con la gravedad de MCC. Sin embargo, la evaluación de la contribución de los principales factores de riesgo cardiovascular (FRC), como la hipertensión y la dislipidemia aterogénica (DA), a la gravedad de la MCC es escasa, a pesar de su papel bien establecido en la enfermedad arterial coronaria, insuficiencia cardíaca y accidente cerebrovascular. Objetivo: explorar la posible relación de la presión arterial y la DA con el perfil clínico de los pacientes con MCC. Método: estudio transversal en pacientes con serología positiva para T. cruzi categorizados de acuerdo a la clasificación estándar de MCC. Se realizó en todos los pacientes un examen clínico-cardiológico completo. Los autoanticuerpos inducidos por T. cruzi se evaluaron mediante ELISA. Resultados: se observó que los niveles de índice aterogénico (IA) aumentaron significativamente en relación con la gravedad de la etapa de la MCC, siendo que los pacientes pertenecientes al grupo MCC III mostraron los más altos valores de IA. Por otra parte, los pacientes con miocardiopatía dilatada global con fracción de eyección reducida mostraron mayores niveles de IA. En lo que respecta a autoanticuerpos, anti-B13 también mostró relación con la gravedad de la enfermedad. Conclusión: observamos que el IA se correlacionó con las etapas de MCC y contribuyó, en asociación con anticuerpos anti-B13, a la predicción de insuficiencia cardíaca sistólica.

Uso de membrana de oxigenação extracorpórea venoarterial em um caso de miocardite chagásica fulminante como ponte para transplante cardíaco / Use of venoarterial extracorporeal membrane oxygenation in fulminant chagasic myocarditis as a bridge to heart transplant

RESUMO Jovem com 17 anos de idade atendido com dispneia progressiva há 15 dias e piora nas últimas 24 horas. Foi admitido em estado de insuficiência respiratória e choque cardiogênico com disfunção de múltiplos órgãos. O ecocardiograma mostrou fração de ejeção ventricular esquerda de 11%, grave hipocinesia difusa e pressão sistólica da artéria pulmonar de 50mmHg. Houve necessidade de suporte hemodinâmico com uso de dobutamina (20mcg/kg/minuto) e noradrenalina (1,7mcg/kg/minuto). Após 48 horas, o paciente não apresentou melhora hemodinâmica nem clínica, optando-se, então, pela implantação de membrana de oxigenação extracorpórea. Ocorreu melhora do ponto de vista hemodinâmico, da perfusão sistêmica, da função renal e hepática, porém, após 72 horas, não houve recuperação da função cardíaca. Optou-se, assim, pela transferência para outro hospital. O paciente foi transferido por transporte aéreo de Salvador (BA) para Recife (PE). Foi realizado transplante cardíaco com rápida recuperação da função hepática e renal, e boa função do enxerto. A histopatologia do coração explantado demonstrou miocardite crônica ativa e amastigotas de Trypanosoma cruzi. A prevalência global estimada de infecção por T. cruzi caiu de 18 milhões em 1991, quando a primeira iniciativa regional de controle teve início, para 5,7 milhões em 2010. A miocardite é uma doença inflamatória causada por condições infecciosas ou não infecciosas. As manifestações clínicas variam desde um quadro subclínico até insuficiência cardíaca e choque cardiogênico. Diversos relatos sugerem que o uso de membrana de oxigenação extracorpórea em pacientes com quadro grave e refratário de miocardite é uma opção como terapia ponte até transplante cardíaco, nos casos sem recuperação espontânea da função ventricular. Em uma consulta ambulatorial de acompanhamento realizada 6 meses após o transplante, o paciente encontrava-se bem e assintomático.

ABSTRACT A 17-year-old Brazilian male presented with progressive dyspnea for 15 days, worsening in the last 24 hours, and was admitted in respiratory failure and cardiogenic shock, with multiple organ dysfunctions. Echocardiography showed a left ventricle ejection fraction of 11%, severe diffuse hypokinesia, and a systolic pulmonary artery pressure of 50mmHg, resulting in the need for hemodynamic support with dobutamine (20mcg/kg/min) and noradrenaline (1.7mcg/kg/min). After 48 hours with no clinical or hemodynamic improvement, an extracorporeal membrane oxygenation was implanted. The patient presented with hemodynamic, systemic perfusion and renal and liver function improvements; however, his cardiac function did not recover after 72 hours, and he was transfer to another hospital. Air transport was conducted from Salvador to Recife in Brazil. A heart transplant was performed with rapid recovery of both liver and kidney functions, as well as good graft function. Histopathology of the explanted heart showed chronic active myocarditis and amastigotes of Trypanosoma cruzi. The estimated global prevalence of T. cruzi infections declined from 18 million in 1991, when the first regional control initiative began, to 5.7 million in 2010. Myocarditis is an inflammatory disease due to infectious or non-infectious conditions. Clinical manifestation is variable, ranging from subclinical presentation to refractory heart failure and cardiogenic shock. Several reports suggest that the use of extracorporeal membrane oxygenation in patients presenting with severe refractory myocarditis is a potential bridging therapy to heart transplant when there is no spontaneous recovery of ventricular function. In a 6-month follow-up outpatient consult, the patient presented well and was asymptomatic.

Left Atrial Function in Patients with Chronic Chagasic Cardiomyopathy / Função Atrial Esquerda em Pacientes com Miocardiopatia Chagásica Crônica

Chagas disease is a cause of dilated cardiomyopathy, and information about left atrial (LA) function in this disease still lacks.

A doença de Chagas é uma causa de miocardiopatia dilatada, sendo ainda pouco conhecida a função do átrio esquerdo (AE) nessa doença.

Predictive factrrs for the progression of chronc chagas cardiomyopathy in patiients without left ventricular dysfunction / Preditores da evolução da cardiopatia chagásica crônica em pacientes sem disfunção ventricular esquerda

The identification of predictors for the progression of chronic Chagas cardiomyopathy (CCC) is essential to ensure adequate patient management. This study looked into a non-concurrent cohort of 165 CCC patients between 1985 and 2010 for independent predictors for CCC progression. The outcomes were worsening of the CCC scores and the onset of left ventricular dysfunction assessed by means of echo-Doppler cardiography. Patients were analyzed for social, demographic, epidemiologic, clinical and workup-related variables. A descriptive analysis was conducted, followed by survival curves based on univariate (Kaplan-Meier and Cox’s univariate model) and multivariate (Cox regression model) analysis. Patients were followed from two to 20 years (mean: 8.2). Their mean age was 44.8 years (20-77). Comparing both iterations of the study, in the second there was a statistically significant increase in the PR interval and in the QRS duration, despite a reduction in heart rates (Wilcoxon < 0.01). The predictors for CCC progression in the final regression model were male gender (HR = 2.81), Holter monitoring showing pauses equal to or greater than two seconds (HR = 3.02) increased cardiothoracic ratio (HR = 7.87) and time of use of digitalis (HR = 1.41). Patients with multiple predictive factors require stricter follow-up and treatment.

A identificação de preditores da progressão da cardiopatia chagásica crônica (CCC) é essencial ao manejo adequado do paciente. Estudo coorte não concorrente de 165 pacientes portadores de CCC entre 1985-2010 quanto a preditores independentes da evolução da CCC. Os desfechos foram piora da classificação da CCC e surgimento de disfunção ventricular esquerda ao ecoDopplercardiograma. Variáveis sócio-demográficas, epidemiológicas, clínicas e propedêuticas foram estudadas e realizadas análise descritiva, análise de sobrevida com análise univariada (Kaplan-Meier e modelo univariado de Cox) e multivariada (modelo de regressão de Cox). O seguimento foi de dois a 20 anos, com média de 8,2 anos. A média de idade dos pacientes foi de 44,8 anos (20- 77 anos). Comparando ambos os tempos do estudo, no tempo 2 houve significância estatística do aumento do intervalo PR e da duração do QRS, além da redução da frequência cardíaca (Wilcoxon < 0,01). Os preditores da evolução da CCC no modelo final de regressão foram sexo masculino (HR = 2,81), pausas iguais ou maiores que dois segundos ao Holter (HR = 3,02), aumento do índice cardiotorácico (HR = 7,87) e tempo de uso de digital (HR = 1,41), destacando-se necessidade de seguimento e tratamento mais rigoroso para os chagásicos que cumulam estes fatores.

Severity of chronic experimental Chagas' heart disease parallels tumour necrosis factor and nitric oxide levels in the serum: models of mild and severe disease

Heart tissue inflammation, progressive fibrosis and electrocardiographic alterations occur in approximately 30% of patients infected by Trypanosoma cruzi, 10-30 years after infection. Further, plasma levels of tumour necrosis factor (TNF) and nitric oxide (NO) are associated with the degree of heart dysfunction in chronic chagasic cardiomyopathy (CCC). Thus, our aim was to establish experimental models that mimic a range of parasitological, pathological and cardiac alterations described in patients with chronic Chagas’ heart disease and evaluate whether heart disease severity was associated with increased TNF and NO levels in the serum. Our results show that C3H/He mice chronically infected with the Colombian T. cruzi strain have more severe cardiac parasitism and inflammation than C57BL/6 mice. In addition, connexin 43 disorganisation and fibronectin deposition in the heart tissue, increased levels of creatine kinase cardiac MB isoenzyme activity in the serum and more severe electrical abnormalities were observed in T. cruzi-infected C3H/He mice compared to C57BL/6 mice. Therefore, T. cruzi-infected C3H/He and C57BL/6 mice represent severe and mild models of CCC, respectively. Moreover, the CCC severity paralleled the TNF and NO levels in the serum. Therefore, these models are appropriate for studying the pathophysiology and biomarkers of CCC progression, as well as for testing therapeutic agents for patients with Chagas’ heart disease.

Clinical and echocardiographic predictors of mortality in chagasic cardiomyopathy - systematic review / Preditores clínicos e ecocardiográficos de mortalidade na cardiopatia chagásica - revisão sistemática

Diagnosis, prognosis and evaluation of death risk in Chagas cardiomyopathy still constitute a challenge due to the diversity of manifestations, which determine the importance of using echocardiography, tissue Doppler and biomarkers. To evaluate, within a systematic review, clinical and echocardiographic profiles of patients with chronic chagasic cardiomyopathy, which may be related to worse prognosis and major mortality risk. To perform the systematic review, we used Medline (via PubMed), LILACS and SciELO databases to identify 82 articles published from 1991 to 2012, with the following descriptors: echocardiography, mortality and Chagas disease. We selected 31 original articles, involving diagnostic and prognostic methods. The importance of Chagas disease has increased due to its emergence in Europe and United States, but most evidence came from Brazil. Among the predictors of worse prognosis and higher mortality risk are morphological and functional alterations in the left and right ventricles, evaluated by conventional echocardiography and tissue Doppler, as well as the increase in brain natriuretic peptide and troponin I concentrations. Recently, the evaluations of dyssynchrony, dysautonomia, as well as strain, strain rate and myocardial twisting were added to the diagnostic arsenal for the early differentiation of Chagas cardiomyopathy. Developments in imaging and biochemical diagnostic procedures have enabled more detailed cardiac evaluations, which demonstrate the early involvement of both ventricles, allowing a more accurate assessment of the mortality risk in Chagas disease.

O diagnóstico, o prognóstico e a avaliação do risco de morte por miocardiopatia chagásica crônica ainda são desafiadores pela diversidade de manifestações, do que deriva a importância da ecocardiografia, do Doppler tissular e dos biomarcadores. Avaliar de forma sistemática os perfis clínico e ecocardiográfico de pacientes com miocardiopatia chagásica crônica, que possam estar relacionados com pior prognóstico e mortalidade. Para revisão sistemática, empregaram-se as bases de dados MedLine (via PubMed), LILACS e SciELO, e localizaram-se 82 artigos publicados entre 1991 e 2012, empregando os descritores echocardiography, mortality e Chagas disease. Foram selecionados 31 artigos originais, envolvendo métodos diagnósticos ou prognósticos de miocardiopatia chagásica. Constatou-se que a importância da doença de Chagas tem aumentado devido a seu aparecimento na Europa e nos Estados Unidos, entretanto a maior parte das evidências originou-se do Brasil. Dentre os preditores de pior prognóstico e maior mortalidade, estiveram alterações morfofuncionais dos ventrículos esquerdo e direito, avaliadas por ecocardiografia convencional e Doppler tissular, bem como o aumento da concentração do peptídeo natriurético cerebral e da troponina I. Recentemente, integraram o arsenal diagnóstico as avaliações de dissincronia, disautonomia, além de strain, strain rate e twisting miocárdico para diferenciação precoce da miocardiopatia chagásica. A evolução dos meios diagnósticos de imagem e bioquímicos possibilitou avaliações cardíacas mais minuciosas, que dão conta do comprometimento precoce de ambos os ventrículos, permitindo determinar com maior precisão o risco de mortalidade na doença de Chagas.