Sudden cardiac death multiparametric classification system for Chagas heart disease's patients based on clinical data and 24-hours ECG monitoring.

About 6.5 million people are infected with Chagas disease (CD) globally, and WHO estimates that $ > million people worldwide suffer from ChHD. Sudden cardiac death (SCD) represents one of the leading causes of death worldwide and affects approximately 65% of ChHD patients at a rate of 24 per 1000 patient-years, much greater than the SCD rate in the general population. Its occurrence in the specific context of ChHD needs to be better exploited. This paper provides the first evidence supporting the use of machine learning (ML) methods within non-invasive tests: patients' clinical data and cardiac restitution metrics (CRM) features extracted from ECG-Holter recordings as an adjunct in the SCD risk assessment in ChHD. The feature selection (FS) flows evaluated 5 different groups of attributes formed from patients' clinical and physiological data to identify relevant attributes among 57 features reported by 315 patients at HUCFF-UFRJ. The FS flow with FS techniques (variance, ANOVA, and recursive feature elimination) and Naive Bayes (NB) model achieved the best classification performance with 90.63% recall (sensitivity) and 80.55% AUC. The initial feature set is reduced to a subset of 13 features (4 Classification; 1 Treatment; 1 CRM; and 7 Heart Tests). The proposed method represents an intelligent diagnostic support system that predicts the high risk of SCD in ChHD patients and highlights the clinical and CRM data that most strongly impact the final outcome.

Socio-epidemiological factors and comorbidities associated with Chagas disease manifestations in two urban reference health care centres in Rio de Janeiro, Brazil.

BACKGROUND: Chagas disease (CD) is still an important public health issue in Latin America. This study aims to analyse the association between socio-epidemiological factors and comorbidities with clinical manifestations of CD. METHODS: We performed a cross-sectional study of 985 adult patients (65±11 y; 59.5% women) with CD. Data collection was based on questionnaires and medical records review. CD clinical forms (indeterminate, digestive, cardiac and cardiodigestive) and the stages of the cardiac form were classified according to the II Brazilian Consensus on CD. Statistical analyses were based on univariate and multivariate logistic regression. RESULTS: Older age and Brazilian birth state (Minas Gerais and Bahia) were associated with a greater likelihood of the cardiac form of CD. A greater likelihood of the digestive form was seen in men and those of older age. Patients with arterial hypertension and diabetes were less likely to have the digestive form. Men had a greater likelihood of having a more severe cardiac presentation. Those from Minas Gerais and Bahia states had a greater likelihood of having stage B1 or B2. CONCLUSIONS: The results reinforce the aging of the CD population living in urban areas in Brazil, the high prevalence of comorbidities and that epidemiology, sex and the presence of comorbidities may be related to the clinical form of CD.

Circulating Plasma MicroRNA-208a as Potential Biomarker of Chronic Indeterminate Phase of Chagas Disease.

Chagas cardiomyopathy is the most severe clinical manifestation of chronic Chagas disease. The disease affects most of the Latin American countries, being considered one of the leading causes of morbidity and death in the continent. The pathogenesis of Chagas cardiomyopathy is very complex, with mechanisms involving parasite-dependent cytopathy, immune-mediated myocardial damage and neurogenic disturbances. These pathological changes eventually result in cardiac myocyte hypertrophy, arrhythmias, congestive heart failure and stroke during chronic infection phase. Herein, we show that miR-208a, a microRNA that is a key factor in promoting cardiovascular dysfunction during cardiac hypertrophy processes of heart failure, has its circulating levels increased during chronic indeterminate phase when compared to cardiac (CARD) clinical forms in patients with Chagas disease. In contrast, we have not found altered serum levels of miR-34a, a microRNA known to promote pro-apoptotic role in myocardial infarction during degenerative process of cardiac injuries thus indicating intrinsic differences in the nature of the mechanisms underlying the heart failure triggered by Trypanosoma cruzi infection. Our findings support that the chronic indeterminate phase is a progressive phase involved in the genesis of chagasic cardiopathy and point out the use of plasma levels of miR-208a as candidate biomarker in risk-prediction score for the clinical prognosis of Chagas disease.

Ventricular arrhythmias are related to the presence of autoantibodies with adrenergic activity in chronic chagasic patients with preserved left ventricular function.

BACKGROUND: The presence of G-type immunoglobulins with functional activity was previously demonstrated in chronic chagasic patients (CChP) with heart failure. Here we evaluated the profile and the arrhythmogenic effects of sera from CChP with preserved ventricular function. METHODS: Electrocardiography (ECG), Holter monitoring, exercise testing, and left ventricular ejection fraction of 40 CChP were measured. Serum from each patient was characterized in isolated rabbit hearts where ECG parameters were analyzed. RESULTS: From the total sera of the 40 CChP tested in rabbit hearts, 42.5% activated ß-adrenergic receptors (Ab-ß), 5% activated muscarinic receptors (Ab-M), and 30% activated both muscarinic and ß-receptors (Ab-Mß). In addition, 22.5% of the sera were not reactive (Ab-NR). Ab-ß patients presented more cases of arrhythmias in exercise testing (P < .001). In Holter, ventricular arrhythmias appeared more than twice as often in the Ab-ß group than in the Ab-NR group and in numbers similar to the Ab-Mß group (Ab-NR: 2; Ab-ß: 5; Ab-Mß: 3). Arrhythmias were induced by Ab-Mß in isolated rabbit hearts. Sera from patients with Ab-Mß, who had longer PR intervals, were able to reversibly prolong PR when perfused in isolated rabbit heart (r² = 0.74; P = .02). CONCLUSIONS: High prevalence of Ab-ß in CChP with preserved left ventricular function led to a greater incidence of ventricular arrhythmias in the patients.

Iodine-123 metaiodobenzylguanidine cardiac imaging as a method to detect early sympathetic neuronal dysfunction in chagasic patients with normal or borderline electrocardiogram and preserved ventricular function.

PURPOSE: The indeterminate form of Chagas disease represents the most common chronic presentation. The aim of this study was to assess cardiovascular autonomic system function with I-123 metaiodobenzylguanidine (MIBG) scintigraphy in chagasic patients with normal or "borderline" electrocardiographic alterations and preserved left ventricular function evaluated by echocardiography. MATERIALS AND METHODS: A total of 40 chagasic patients and 19 control subjects were included in this study. Patients had normal echocardiogram and chest radiography; no arrhythmias or myocardial ischemia; and normal exercise performance for age, gender, and body mass index. I-123 MIBG scintigraphy was performed and the heart-to-mediastinum (H/M) uptake was used as the primary predictor in the present analysis. The data analysis was performed by using Nonparametric Regression Trees and the Survival Agreement Plot. We included only patients with preserved right and left ventricular function assessed by echocardiographic methods. RESULTS: Variables analyzed in the regression tree were age, sex, 20 minutes and 3 hours H/M uptake after injection of I-123 MIBG, washout rate, and single photon emission computed tomography imaging. The 3 hours H/M ratio was the only significant variable (P<0.001) and for 95% of chagasic patients, this value was less than 2.19. CONCLUSIONS: This study presents evidence that cardiac autonomic sympathetic modulation may be affected in chagasic subjects with preserved ventricular function evaluated by echocardiography, especially in those with "borderline" electrocardiogram.

Biodistribution of bone marrow mononuclear cells in chronic chagasic cardiomyopathy after intracoronary injection.

BACKGROUND: Animal and human clinical studies have indicated that bone marrow (BM) mononuclear cell (MNC) therapy for Chagasic Cardiomyopathy (ChC) is feasible, safe and potentially efficacious. Nevertheless, little is known about the retention of these cells after intracoronary (IC) infusion. METHODS: Our study investigated the homing of technetium-99m ((99m)Tc) labeled BM MNCs and compared it to thallium-201 ((201)Tl) myocardial perfusion images using the standard 17-segment model. Six patients with congestive heart failure of chagasic etiology were included. RESULTS: Scintigraphic images revealed an uptake of 5.4%±1.7, 4.3%±1.5 and 2.3%±0.6 of the total infused radioactivity in the heart after 1, 3 and 24h, respectively. The remaining activity was distributed mainly to the liver and spleen. Of 102 segments analyzed, homing took place in 36%. Segments with perfusion had greater homing (58.6%) than those with decreased or no perfusion (6.8%), p<0.0001. There was no correlation between the number of injected cells and the number of segments with homing for each patient (r=-0.172, p=0.774). CONCLUSIONS: These results indicate that (99m)Tc-BM MNCs delivered by IC injection homed to the chagasic myocardium. However, cell biodistribution was heterogeneous and limited, being strongly associated with the myocardial perfusion pattern at rest. These initial data suggest that the IC route may present limitations in chagasic patients and that alternative routes of cell administration may be necessary.

Abnormal cardiac repolarization in anabolic androgenic steroid users carrying out submaximal exercise testing.

1. The aim of the present study was to investigate the cardiovascular effects of anabolic androgenic steroid (AAS) abuse by comparing the electrocardiographic parameters before and after submaximal exercise between AAS users and non-AAS users. 2. A total of 22 men who regularly engaged in both resistance and aerobic exercise at fitness academies volunteered for the study (control group: n = 11, age 25 ± 4 years; AAS group: n = 11, age 27 ± 5 years). All subjects were submitted to submaximal exercise testing using an Astrand-Rhyming protocol. Heart rate and electrocardiography parameters were measured at rest and at the third minute of the post-exercise recovery time. 3. AAS users presented higher QTc and QTd at rest (10% and 55%, respectively) and at the post-exercise period (17% and 43%, respectively), compared with control subjects. The maximal and minimum QTc interval of the AAS group was significantly prolonged at the post-exercise period (12% and 15%, respectively). The haemodynamic parameters were similar in both groups (P > 0.05). The AAS group showed a lower heart rate recovery at the first minute after the test (P = 0.0001), and a higher exertion score (P < 0.0001) at a lower workload, compared with the control group. 4. Our results show that the QTc interval and dispersion are increased in individuals who abuse AAS, suggesting the presence of ventricular repolarization abnormalities that could potentially increase the risk of cardiac arrhythmias and sudden cardiac death.

The presence of antiautonomic membrane receptor antibodies do not correlate with brain lesions in Chagas' disease.

UNLABELLED: We previously demonstrated correlation between parasympathetic dysfunction and brain white matter lesions in chronic chagasic patients. OBJECTIVE: To correlate serum functional circulating antibodies with beta adrenergic (Ab-beta), muscarinic (Ab-M) or muscarinic and beta adrenergic (Ab-Mbeta) activity, the autonomic system function and brain lesions in chronic chagasic patients. METHOD: In fifteen consecutive chagasic patients, the autonomic nervous system was evaluated and brain magnetic resonance imaging (MRI) was performed. The sera of all patients were tested to the presence of circulating functional antibodies. RESULTS: Sera from 11 of 15 chronic chagasic patients had some activity (Ab-beta: 7; Ab-M: 1; Ab-Mbeta: 3); however, there was no significant correlation between the presence of antibodies and the autonomic system function or the presence of hyperintensities in MRI. CONCLUSION: The mechanism involved in the genesis of hyperintense lesions seen in brain MRI of chronic chagasic patients is still unresolved, although apparently related to parasympathetic dysfunction.

The presence of antiautonomic membrane receptor antibodies do not correlate with brain lesions in Chagas' disease / A presença de anticorpos anti-autonômicos não se correlaciona a lesões cerebrais na doença de Chagas

We previously demonstrated correlation between parasympathetic dysfunction and brain white matter lesions in chronic chagasic patients. OBJECTIVE: To correlate serum functional circulating antibodies with beta adrenergic (Ab-β), muscarinic (Ab-M) or muscarinic and beta adrenergic (Ab-Mβ) activity, the autonomic system function and brain lesions in chronic chagasic patients. METHOD: In fifteen consecutive chagasic patients, the autonomic nervous system was evaluated and brain magnetic resonance imaging (MRI) was performed. The sera of all patients were tested to the presence of circulating functional antibodies. RESULTS: Sera from 11 of 15 chronic chagasic patients had some activity (Ab-β: 7; Ab-M: 1; Ab-Mβ: 3); however, there was no significant correlation between the presence of antibodies and the autonomic system function or the presence of hyperintensities in MRI. CONCLUSION: The mechanism involved in the genesis of hyperintense lesions seen in brain MRI of chronic chagasic patients is still unresolved, although apparently related to parasympathetic dysfunction.

A correlação entre disfunção parassimpática e lesões de substância branca cerebral em pacientes chagásicos já foi previamente demonstrada. OBJETIVO: Correlacionar a presença de anticorpos circulantes funcionais com atividade beta-adrenérgica (Ab-β), muscarínica (Ab-M) ou muscarínica e beta adrenérgica (Ab-Mβ), a presença de disautonomia e lesões de substância branca cerebral em pacientes chagásicos crônicos. MÉTODO: Em quinze pacientes chagásicos consecutivos, foram realizados a avaliação do sistema nervoso autônomo e ressonância magnética (RM) do crânio. O soro dos pacientes foi testado para a presença de anticorpos funcionais circulantes. RESULTADOS: O soro de 11 dos 15 pacientes chagásicos apresentou alguma atividade (Ab-β: 7; Ab-M: 1; Ab-Mβ: 3); porém não houve correlação significativa entre a presença de anticorpos circulantes e disautonomia ou de hiperintensidades à RM. CONCLUSÃO: O mecanismo envolvido na gênese das lesões hiperintensas à RM do crânio dos pacientes chagásicos crônicos não está esclarecida ainda, apesar de aparentemente relacionada à disfunção parassimpática.

Antibodies with beta-adrenergic activity from chronic chagasic patients modulate the QT interval and M cell action potential duration.

AIMS: The aim of this study was to investigate whether the sera from chronic chagasic patients (CChPs) with beta-1 adrenergic activity (Ab-beta) can modulate ventricular repolarization. Beta-adrenergic activity has been described in CChP. It increases the L-type calcium current and heart rate in isolated hearts, but its effects on ventricular repolarization has not been described. METHODS AND RESULTS: In isolated rabbit hearts, under pacing condition, QT interval was measured under Ab-beta perfusion. Beta-adrenergic activity was also tested in guinea pig ventricular M cells. Furthermore, the immunoglobulin fraction (IgG-beta) of the Ab-beta was tested on Ito, ICa, and Iks currents in rat, rabbit, and guinea pig myocytes, respectively. Beta-adrenergic activity shortened the QT interval. This effect was abolished in the presence of propranolol. In addition, sera from CChP without beta-adrenergic activity (Ab-beta) did not modulate QT interval. The M cell action potential duration (APD) was reversibly shortened by Ab-beta. Atenolol inhibited this effect of Ab-beta, and Ab- did not modulate the AP of M cells. Ito was not modulated by isoproterenol nor by IgG-beta. However, IgG-beta increased ICa and IKs. CONCLUSION: The shortening of the QT interval and APD in M cells and the increase of IKs and ICa induced by IgG-beta contribute to repolarization changes that may trigger malignant ventricular arrhythmias observed in patients with chronic chagasic or idiopathic cardiomyopathy.

Human antibodies with muscarinic activity modulate ventricular repolarization: basis for electrical disturbance.

INTRODUCTION: In chronic chagasic patients sudden death has been reported when QT interval dispersion is increased and antibodies with muscarinic-like activity have been demonstrated to trigger arrhythmias. The aims were to investigate, in vivo and in vitro, relation between these antibodies and heterogeneity of ventricular repolarization and to identify predictors of cardiac death in chronic chagasic patients. METHODS AND RESULTS: Clinical, electrocardiograph and echocardiograph variables from 32 chronic chagasic patients with moderate to severe left ventricular dysfunction, followed-up for 10 years were analyzed. Sera from chronic chagasic patients with or without muscarinic activity were tested in isolated rabbit hearts to study ventricular repolarization. Stepwise multivariate logistic analysis was applied to identify independent predictors of cardiac death. QT interval dispersion of patients with muscarinic activity (75.9+/-5.5 ms) was larger than that of patients without muscarinic activity (51.3+/-4.0 ms, p<0.001). Maximum uncorrected and corrected QT intervals were not significantly different between groups of patients. Sera from patients with muscarinic activity significantly and reversibly increased QT interval in isolated rabbit hearts (p=0.002). This effect was abolished in the presence of the muscarinic antagonist atropine. Multivariate analysis identified maximum corrected QT intervals and left ventricular end diastolic index as independent predictors of cardiac death (p=0.03 and p=0.02, respectively). CONCLUSIONS: Sera with muscarinic activity from chagasic patients have a strong contribution to evoke ventricular repolarization rhythm disorder. In these patients, ventricular repolarization heterogeneity is increased significantly. In vitro, muscarinic sera reversibly increased repolarization duration. Maximum corrected QT intervals and left ventricular end diastolic index are independent predictors of cardiac death.

Norepinephrine and heart rate variability: a marker of dysautonomia in chronic Chagas cardiopathy.

The involvement of the autonomic nervous system (ANS) in Chagas' disease has been the subject of many studies, which have become more numerous since Köberle's pioneering work in the 1950s, showing the partial or total destruction of cardiac neurons. In order to investigate ANS involvement in the pathogenesis of chronic Chagas cardiopathy, seventy-five patients with the condition were examined and divided into four groups, according to the Los Andes classification: I-A, I-B, II and III. Groups I-A and I-B included patients at an early stage of cardiac involvement; group II, patients at an advanced stage without heart failure (HF); and group III, patients at an advanced stage with HF. Norepinephrine (NE) levels were measured in 24 h urine collected from fifty-two chronic Chagas patients (69%); twelve cardiopathic patients of other etiologies, in functional class IV of the New York Heart Association (NYHA), selected as the control group; and ten normal individuals. 24-hour Holter monitoring was performed in fifty-six patients (74.6%) to assess heart rate variability (HRV). HRV parameters were analyzed and distributed according to the Los Andes classification. Norepinephrine levels were significantly higher (p = 0.0001) in the controls (non-Chagas cardiopathic patients, NYHA IV) than in group III (chronic Chagas cardiopathic patients) according to the Los Andes classification. Reduction of HRV was observed in Chagas patients, but unrelated to functional class, and the indices reflecting parasympathetic activity (pNN50 and rMSSD) were increased in our Chagas patients. Our study concluded that the NE levels in Chagas patients in an advanced stage of cardiac involvement (group III) did not rise as in cardiopathic patients of other etiologies with a similar degree of cardiac involvement, which might be interpreted as an impairment of the sympathetic nervous system in the cases studied, but the increased levels of NE in groups I-A and I-B of the Chagas patients can be interpreted as an early impairment of the autonomic nervous system (sympathetic). HRV was reduced in our patients, but the indices reflecting parasympathetic activity (pNN50 and rMSSD) were preserved in almost all Chagas patients. However, the pNN50 index was reduced in group I-A, suggesting that parasympathetic dysautonomia may be an early phenomenon and may precede left ventricular systolic dysfunction.

Reposta proliferativa das células T contra a cruzipaina na cardiopatia chagásica crônica / T cells proliferative responses to cruzipaina in chronic chagasic cardiopathy

In this paper, we sought to determine if chronic chagasic patients with cardiopathy could be distinguished from those displaying non-chagasic cardiopathy on the basis of T cell proliferative responses to cruzipain (GP57/51), a major antigen of T. cruzi. Assays were performed with peripheral blood mononuclear cells from 24 individuals classified as follows: normal donors (n = 8), patients with non-chagasic cardiopathy (n = 8), patients with chronic chagasic cardiopathy without morbid associations (n = 8). The analysis of variance indicated that the proliferative responses stimulated by cruzipain were significantly higher in the group of chagasic patients (p = 0.0001). Turkey's multiple comparison test showed that the proliferative index medium from normal and non-chagasic cardiopathy was not significantly different from each other. We conclude that the T cell responses against T. cruzipain, as measured by proliferative indices of cells found in peripheral blood, are exclusively associated with Chagas, disease. In view of the abundance of cruzipain antigen in amastigotes it is possible that these T cell specificities contribute to the heart tissue damage observed in chronic Chagas, disease patients.

Estudo longitudinal do eletrocardiograma na doença de Chagas desde a fase aguda / A longitudinal electrocardiogram study of Chagas' disease from the acute phase

Vários trabalhos com eletrocardiograma na doença de Chagas têm sido feitos. Alguns referindo-se a grupos selecionados de casos, outros a estudos longitudinais, relatam as características da mortalidade nas diversas fases da doença. Com o objetivo de avaliar o valor do eletrocardiograma como índice de avaliaçäo terapêutica e de seu comportamento na doença de Chagas desde a fase aguda, no presente trabalho, analisou-se evolutivamente o eletrocardiograma de 42 pacientes (18 mulheres e 24 homens) procedentes da zona rural do Norte de Minas Gerais; predomínio etário foi nas duas primeiras décadas; todos com comprometimento cardíaco; todos receberam tratamento específico. O acompanhamento dos 42 pacientes foi de 9 anos dos quais 3 pacientes tiveram seguimento de 20 anos. Foram analisados 270 eletrocardiogramas. Nós utilizamos os seguiente critérios para a análise do ECG: código de Minnesota modificado para doença de Chagas; WHO/I.S.F.C.TASK FORCE para conduçäo intraventricular e critérios de Pieretti para área eletricamente inativa. Concluímos que as alteraçöes eletrocardiográficas agravam com a evoluçäo da doença e que o eletrocardiograma näo serve de índice de avaliaçäo terapêutica