Chagas Heart Disease Patients Research Articles

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.

Fenofibrate Increases the Population of Non-Classical Monocytes in Asymptomatic Chagas Disease Patients and Modulates Inflammatory Cytokines in PBMC.

Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 than cells from uninfected individuals (HI), irrespectively of the clinical stage, asymptomatic (Asy) or with Chagas heart disease (CHD). Fenofibrate reduces the levels of pro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higher percentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higher percentage of non-classical monocytes than CHD patients or HI. However, no difference in the intermediate monocyte subpopulation was found between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro with T. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes in the Asy group whereas the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD or HI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groups studied. Moreover, fenofibrate treatment of T. cruzi-stimulated cells, increased the frequency of the non-classical subpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in any groups. In conclusion, our results emphasize a potential role for fenofibrate as a modulator of monocyte subpopulations towards an anti-inflammatory and healing profile in different stages of chronic Chagas disease.

Recombinant antibody against Trypanosoma cruzi from patients with chronic Chagas heart disease recognizes mammalian nervous system.

BackgroundTo deeply understand the role of antibodies in the context of Trypanosoma cruzi infection, we decided to characterize A2R1, a parasite antibody selected from single-chain variable fragment (scFv) phage display libraries constructed from B cells of chronic Chagas heart disease patients.MethodsImmunoblot, ELISA, cytometry, immunofluorescence and immunohistochemical assays were used to characterize A2R1 reactivity. To identify the antibody target, we performed an immunoprecipitation and two-dimensional electrophoresis coupled to mass spectrometry and confirmed A2R1 specific interaction by producing the antigen in different expression systems. Based on these data, we carried out a comparative in silico analysis of the protein target´s orthologues, focusing mainly on post-translational modifications.FindingsA2R1 recognizes a parasite protein of ~50 kDa present in all life cycle stages of T. cruzi, as well as in other members of the kinetoplastid family, showing a defined immunofluorescence labeling pattern consistent with the cytoskeleton. A2R1 binds to tubulin, but this interaction relies on its post-translational modifications. Interestingly, this antibody also targets mammalian tubulin only present in brain, staining in and around cell bodies of the human peripheral and central nervous system.InterpretationOur findings demonstrate for the first time the existence of a human antibody against T. cruzi tubulin capable of cross-reacting with a human neural protein. This work re-emphasizes the role of molecular mimicry between host and parasitic antigens in the development of pathological manifestations of T. cruzi infection.

Association between circadian Holter ECG changes and sudden cardiac death in patients with Chagas heart disease

Objective: Chagas disease (ChD) is a parasitic illness, largely spread over South America. ChD usually causes progressive myocardium damage, either by direct parasite action or through autoimmune response. Sudden cardiac death (SCD) is prevalent in the early disease stages, being associated with a high variety of ectopic cardiac beats. This study aims at applying heart rate variability (HRV) and heart rate turbulence (HRT) techniques over Holter electrocardiogram (ECG) records to investigate the association with SCD in Chagas heart disease (ChHD). Approach: From a retrospective evaluation of a local database, the Holter records from 78 outpatients (34 female) were divided into groups: SCD deaths (20) and alive patients (56). To consider circadian autonomic changes, the analysis was performed in three periods: (a) entire 24 h record, (b) 12 h daylight period, and (c) the remaining 12 h including night rest. Eight variables were extracted using HRV and HRT approaches from each record and analysed together with the left ventricular ejection fraction (LVEF) estimated by echocardiography. Main results: The set of parameters was reduced by both the forward- and backward-stepwise approach and classification was performed using the k-nearest neighbours method and a leave-one-out cross-validation in a set of ten bootstrap trials, where SCD data were randomly taken and repositioned to balance the groups. The best 24 h model predicted SCD with 89.9% ± 0.9% accuracy using three HRV variables. The use of 12 h segments increased the accuracy up to 91.0% ± 1.2% in a model with the standard deviation parameter measured during the day (SDNNday) and night (SDNNnight). Although considered as playing a major role in SCD, LVEF did not show an association with SCD in this sample. Significance: The degree of HRV and its circadian changes are associated with SCD in ChHD patients.

Predictors of mortality and heart transplantation in patients with Chagas' cardiomyopathy and ventricular tachycardia treated with implantable cardioverter-defibrillators.

Data on long-term follow-up of patients with Chagas' heart disease (ChHD) receiving a secondary prevention implantable cardioverter-defibrillator (ICD) are limited and its benefit is controversial. The aim of this study was to evaluate the long-term outcomes of ChHD patients who received a secondary prevention ICD. We assessed the outcomes of consecutive ChHD patients referred to our Institution from 2006 to 2014 for a secondary prevention ICD [89 patients; 58 men; mean age 56 ± 11 years; left ventricular ejection fraction (LVEF), 42 ± 12%]. The primary outcome included a composite of death from any cause or heart transplantation. After a mean follow-up of 59 ± 27 months, the primary outcome occurred in 23 patients (5.3% per year). Multivariate analysis showed that LVEF < 35% [hazard ratio (HR) 4.64; P < 0.01] and age ≥ 65 years (HR 3.19; P < 0.01) were independent predictors of the primary outcome. Using these two risk factors, a risk score was developed, and lower- (no risk factors), intermediate- (one risk factor), and higher-risk (two risk factors) groups were recognized with an annual rate of primary outcome of 1.4%, 7.4%, and 20.4%, respectively. A high burden of appropriate ICD therapies (16% per year) and electrical storms were documented, however, ICD interventions did not impact on the primary outcome. Among ChHD patients receiving a secondary prevention ICD, older age (≥65 years) and left ventricular dysfunction (LVEF < 35%) portend a poor outcome and were associated with increased risk of death or heart transplantation. Most patients received appropriate ICD therapies, however, ICD interventions did not impact on the primary outcome.

The prognostic value of health-related quality of life in patients with Chagas heart disease

To verify the prognostic value of health-related quality of life (HRQoL) and the differences in HRQoL and clinical variables between groups of Chagas heart disease (CHD) patients with and without cardiovascular adverse events. Seventy-five CHD patients were evaluated by echocardiography, maximal exercise testing, and Short-form of Health Survey (SF-36) Questionnaire. Patients were followed during 6years. In the statistical analysis, uni- and multivariate Cox regression were performed to verify the accuracy of the HRQoL in predicting cardiovascular events. After the follow-up period (41 ± 12months), 20 patients (27%) had adverse events. Those with poor outcome had lower left ventricular ejection fraction (LVEF) (p = 0.002), higher left ventricular end-diastolic diameter (LVDd) (p = 0.019), and worse scores in general health perceptions (p = 0.047), social role functioning (p = 0.026), and mental component summary (p = 0.043) of SF-36. Patients with lower LVEF (p = 0.003), higher LVDd (p = 0.022), worse HRQoL in the general heath perceptions domain (p = 0.022), and mental component summary (p = 0.031) were associated with worse prognosis. In the multivariate Cox regression, LVEF (HR 0.94, 95% CI from 0.90 to 0.98, p = 0.007) and mental component summary (HR 0.98, 95% CI from 0.94 to 1.00, p = 0.047) remained as independent predictors of adverse events in CHD patients. The assessment of HRQoL, especially the mental component, should be taken into account to provide an accurate prognosis in addition to other well-established predictors of poor outcomes in CHD patients.

Reduced functional capacity in patients with Chagas disease: a systematic review with meta-analysis.

Reduced peak oxygen uptake (VO2peak) is a common clinical finding in progressive Chagas disease. However, the disease stage in which functional impairment is detectable remains uncertain. The present study compared functional capacity between healthy controls and patients with different clinical forms of Chagas disease. A systematic review and meta-analysis (PROSPERO database CRD42017058353) was conducted following a search of the MEDLINE, Web of Science, CINAHL, and LILACS databases from September to December 2017 for articles published in English, Spanish, or Portuguese, with no date restrictions. We included studies that compared the VO2peak between healthy and Chagas disease patients, stratified according to 3 clinical forms [no apparent cardiac disease, non-dilated Chagas heart disease (CHD), and dilated CHD]. Seven cross-sectional studies were included. Chagas disease patients without apparent cardiac disease (n=208) had VO2peak values [mean difference, -1.55ml/kg/min; 95% confidence interval (CI), -4.98ml/kg/min to 1.88ml/kg/min] similar to those of healthy controls (n=105; p=0.38, I2=52%). In non-dilated CHD (n=159), VO2peak was 8.71ml/kg/min lower (95% CI, -13.99 to -3.42ml/kg/min) than in healthy controls (n=59; p=0.001, I2=75%). VO2peak was also significantly lower (mean difference, -9.30ml/kg/min; 95% CI, -11.34 to -7.25ml/kg/min) in dilated CHD patients (n=131) than in healthy controls (n=53; p<0.001, I2=0%). Exercise capacity in Chagas disease patients without apparent cardiac disease is similar to that in healthy controls. Functional impairment in Chagas disease is detectable in the early stages of cardiac involvement, even in the absence of systolic dysfunction and signs of heart failure.

Long-term follow-up of Chagas heart disease patients receiving an implantable cardioverter-defibrillator for secondary prevention.

Chagas heart disease (CHD) is a dilated cardiomyopathy characterized by malignant ventricular arrhythmias and increased risk of sudden cardiac death (SCD). Much controversy exists concerning the efficacy of implantable cardioverter-defibrillator (ICDs) in CHD because of mixed results observed. We report our long-term experience with ICDs for secondary prevention in CHD, with the specific aim of assessing the results in groups with preserved or depressed global left ventricular function. 111 patients (75 males; 60 ± 12 years) were followed for 1,948 ± 1,275 days after ICD. Time to death was the primary outcome; LVEF ≤ 45% the exposure; and age, gender, and ICD therapy delivery the potential confounders. We used time-to-event methods and Cox proportional models for analysis, censoring observations at time of death or at 5-year follow-up in survivors. Seventy-two percent of the patients presented at least one sustained ventricular arrhythmia requiring appropriate therapy, and only three patients received inappropriate therapy. Death occurred in 50 (45%) patients, with an annual mortality rate of 8.4%, mostly due to refractory heart failure or noncardiac causes. Unadjusted survival rates were significantly distinct between patients with left ventricular ejection fraction (LVEF)≤45% (26 deaths), 50.5% (95% confidence interval [CI]: 36.2%-63.2%) when compared to patients with LVEF>45% (10 deaths), 77.6% (95% CI: 62.3%-87.3%, P<0.01). After adjusting for confounders, low LVEF (hazard ratio [HR]: 5.2, 95% CI: 2.3-11.6), age (HR: 1.04, 95% CI: 1.01-1.07), and female gender (HR: 3.97, 95% CI: 1.85-8.54) were independently associated with the outcome. ICDs successfully aborted life-threatening arrhythmias in CHD patients. Impaired left ventricular function predicted higher mortality in CHD patients with an ICD for secondary prevention of SCD.

More effective prediction of mortality in Chagas heart disease patients? Importance of cardiopulmonary stress testing

More effective prediction of mortality in Chagas heart disease patients? Importance of cardiopulmonary stress testing

Inspiratory muscle weakness in patients with Chagas heart disease: Echocardiographic and functional predictors

BackgroundPatients with Chagas heart disease (CHD) usually present progressive fatigue and dyspnea. The inspiratory muscle weakness (IMW) may be a marker of exercise intolerance during disease progression. However, the factors related to IMW in CHD patients still remain unknown. MethodsForty-eight CHD patients aged 56.4 (53.3–59.5) years were selected and underwent respiratory muscle strength, echocardiography, Cardiopulmonary Exercise Testing and International Physical Activity Questionnaire (IPAQ). The sample was stratified according to the percentage (%) of maximum inspiratory pressure (MIP) achieved in preserved muscle strength (MIP>70%) or IMW (MIP≤70%). Chi-square and Poisson regression analysis was performed to verify the predictors of IMW. ResultsThe %MIP predicted correlated with left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVDd) and minute ventilation-carbon dioxide production slope (VE/VCO2 slope). Significant differences in the IPAQ scores (p=0.036), LVEF (p=0.020) and VE/VCO2 slope (p=0.008) were found between groups with preserved inspiratory muscle strength and with IMW. In multivariate analysis, sedentary patients and those with reduced LVEF and impaired VE/VCO2 slope had 6.3, 5.5 and 1.2-fold increased risk for IMW, respectively. ConclusionThe sedentary lifestyle, reduced LVEF and impaired VE/VCO2 slope showed to be independent predictors of IMW, probably by the association between these variables and the presence of inflammation in CHD patients. The detection of IMW may be helpful in identifying patients at high risk based on echocardiographic and functional aspects without much operating costs.

Abstract 313: Elucidation Of The Fibrotic Transcription Factors Gene Network Leading To Chagas Heart Disease

Background: Trypanosoma cruzi the causative agent of Chagas heart disease (CHD) remains incurable. The major pathology induced by the parasite is cardiac fibrosis leading to heart failure followed by death. The mechanisms of T. cruzi induced cardio-pathology remains largely unknown. We hypothesize that T. cruzi infection regulates the expression of profibrotic genes in human cardiac myocytes (HCM), tilting the heart towards a profibrotic phenotype seen in CHD patients. Methods and Results: To elucidate the molecular mechanisms of T. cruzi induced cardiac fibrosis, we challenged primary HCM with T. cruzi for two hours and purified total RNA for microarray. We investigated changes at the whole transcriptome level on an affymetrix platform. The arrays were done in triplicates at different time points; changes in gene expression greater than 2-fold and having a Benjamini and Hochburg false discovery rate corrected p-value &lt;0.05 were considered significant. The microarray data was validated using real-time PCR followed by PCR array and immunoblotting, to evaluate changes in the protein expression levels of fibrotic transcription factors. Protein expression levels were evaluated in triplicate and analyzed by ANOVA. The fibrotic interactome induced by T. cruzi in HCM was elucidated using Cytoscape. Our results indicate that exposure of HCM to T. cruzi upregulates the transcript levels of two transcription factors associated with fibrosis, SNAI1 (more than 2 fold up-regulated) and Early Growth Response protein 1, EGR1, (about four fold up-regulated). SNAI1 and EGR1 were increased at the protein level. Furthermore, we identified the first interactome regulating fibrosis in primary HCM induced by T. cruzi . Conclusions: This is the first report showing that T. cruzi upregulates the expression of profibrotic transcription factors in HCM early during the process of cellular infection and the operational fibrotic interactome. Thus, abnormal sustained expression of SNAI1 and EGR1 upregulate the expression of genes essential for conversion of HCM towards a profibrotic phenotype in CHD. Elucidation of the molecular mechanisms by which T. cruzi induces cardiac fibrosis will lead to the identification of new therapeutic targets for CHD.

Implantable cardioverter-defibrillators for treatment of sustained ventricular arrhythmias in patients with Chagas' heart disease: comparison with a control group treated with amiodarone alone

Evidence is inconclusive concerning the benefit of implantable cardioverter-defibrillators (ICDs) for secondary prevention of mortality in patients with Chagas' heart disease (ChHD). The aim of this study was to compare the outcomes of ChHD patients with life-threatening ventricular arrhythmias (VAs), who were treated either with ICD implantation plus amiodarone or with amiodarone alone. The ICD group [76 patients; 48 men; age, 57 ± 11 years; left ventricular ejection fraction (LVEF), 39 ± 12%] and the historical control group treated with amiodarone alone (28 patients; 18 men; age, 54 ± 10 years; LVEF, 41 ± 10%) had comparable baseline characteristics, except for a higher use of beta-blockers in the ICD group (P < 0.0001). Amiodarone was also used in 90% of the ICD group. Therapy with ICD plus amiodarone resulted in a 72% reduced risk of all-cause mortality (P = 0.007) and a 95% reduced risk of sudden death (P = 0.006) compared with amiodarone-only therapy. The survival benefit of ICD was greatest in patients with LVEF < 40% (P = 0.01) and was not significant in those with LVEF ≥ 40% (P = 0.15). Appropriate ICD therapies occurred in 72% of patients and the rates of interventions were similar across patients with LVEF < 40% and ≥40%. Compared with amiodarone-only therapy, ICD implantation plus amiodarone reduced the risk of all-cause mortality and sudden death in ChHD patients with life-threatening VAs. Patients with LVEF < 40% derived significantly more survival benefit from ICD therapy. The majority of ICD-treated patients received appropriate therapies regardless of the LV systolic function.

Is autonomic function associated with left ventricular systolic function in Chagas heart disease patients undergoing treatment for heart failure?

The association between cardiac autonomic and left ventricular (LV) dysfunction in Chagas disease (ChD) is controversial. A standardized protocol that includes the Valsalva maneuver, a respiratory sinus arrhythmia (RSA) test, and an echocardiographic examination was used. Spearman correlation coefficients (rho) were used to investigate associations. The study population consisted of 118 ChD patients undergoing current medical treatment, with an average LV ejection fraction of 51.4±2.6%. The LV ejection fraction and diastolic dimension were correlated with the Valsalva index (rho=0.358, p<0.001 and rho=-0.266, p=0.004, respectively) and the RSA (rho=0.391, p<0.001 and rho=-0.311, p<0.001, respectively). The impairment of LV function is directly associated with a reduction of cardiac autonomic modulation in ChD.

Exercise-Induced Decrease in Myocardial High-Energy Phosphate Metabolites in Patients With Chagas Heart Disease

BackgroundThe influence of exercise on cardiac metabolic response in patients with Chagas disease is incompletely understood. Methods and ResultsChanges in cardiac energetic metabolism were investigated in Chagas disease patients before and during isometric handgrip exercise with 31P magnetic resonance spectroscopy (MRS). Twenty-eight patients (10 with systolic dysfunction: group I; 10 with normal systolic function and electrocardiogram (ECG) abnormalities: group II; and 8 asymptomatic without ECG abnormalities: group III) and 8 healthy control subjects (group C) were evaluated by electrocardiogram, echocardiogram, functional tests for coronary artery disease, and image-selected localized cardiac 31P-MRS. The myocardial phosphocreatine to [β-phosphate]adenosine triphosphate ratio (PCr/β-ATP) was measured at rest and during isometric handgrip exercise. Exercise testing or 99mTc–sestamibi scintigraphy were negative for myocardial ischemia in all individuals. At rest, cardiac PCr/β-ATP was decreased in all Chagas groups (1.23 ± 0.37) versus group C (1.88 ± 0.08; P < .001) and was lower in group I (0.89 ± 0.24) versus groups II (1.44 ± 0.23) and III (1.40 ± 0.37; P < .001). There was no stress-induced change in cardiac PCr/β-ATP (1.88 ± 0.08 at rest vs 1.89 ± 0.08 during exercise; P = NS) in group C. Mean cardiac PCr/β-ATP was 0.89 ± 0.24 and 0.56 ± 0.21 at rest and during exercise, respectively, in group I (37% decrease; P < .001). In group II, PCr/β-ATP was 1.44 ± 0.23 at rest and 0.97 ± 0.37 during exercise (33% decrease; P < .001). In group III, PCr/β-ATP was 1.40 ± 0.37 at rest and 0.60 ± 0.19 during exercise (57% decrease; P < .001). ConclusionsMyocardial high-energy phosphates are reduced at rest in Chagas heart disease patients, and the reduction is greater in patients with left ventricular dysfunction. Regardless of left ventricular function, Chagas patients exhibit an exercise-induced decline in cardiac high-energy phosphates consistent with myocardial ischemia, suggesting the possibility that this metabolic approach may offer a tool to probe new interventions in Chagas disease patients.

Morbidity and prognostic factors in chronic chagasic cardiopathy

Chagas disease is a pleomorphic clinical entity that has several unique features. The aim of this study is to summarise some of the recent contributions from our research group to knowledge of the morbidity and prognostic factors in Chagas heart disease. A retrospective study suggested that ischaemic stroke associated with left ventricular (LV) apical thrombi is the first clinical manifestation of Chagas disease observed in a large proportion of patients. LV function and left atrial volume (LAV) are independent risk factors for ischaemic cerebrovascular events during follow-up of Chagas heart disease patients. Pulmonary congestion in Chagas-related dilated cardiomyopathy is common but usually mild. Although early right ventricular (RV) involvement has been described, we have shown by Doppler echocardiography that RV dysfunction is evident almost exclusively when it is associated with left ventricle dilatation and functional impairment. In addition, RV dysfunction is a powerful predictor of survival in patients with heart failure secondary to Chagas disease. We have also demonstrated that LAV provides incremental prognostic information independent of clinical data and conventional echocardiographic parameters that predict survival.

Molecular Diagnosis, Follow-up and Identification of Natural Trypanosome cruzi Populations in Chagas Heart Disease Patients Undergoing Clinical Reactivation after Heart Transplantation

Molecular Diagnosis, Follow-up and Identification of Natural Trypanosome cruzi Populations in Chagas Heart Disease Patients Undergoing Clinical Reactivation after Heart Transplantation

Follow-up of the chagas heart disease patients with left ventricle disfunction and rate responsive pacing regulated by ventricle contractility

Follow-up of the chagas heart disease patients with left ventricle disfunction and rate responsive pacing regulated by ventricle contractility