Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy

Abstract: Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Predictors of death in chronic Chagas cardiomyopathy patients with pacemaker.

BACKGROUND: Chronic Chagas cardiomyopathy (CCC) is the most serious and frequent manifestation of Chagas disease. Conduction abnormalities and bradycardia requiring pacemaker are common. The aim of this study was to determine the rate and predictors of death in CCC patients with pacemaker. METHODS: In this single-center prospective cohort study we assessed the outcome of 396 CCC patients with pacemaker, followed-up for at least 24months. All patients underwent a clinical and device assessment, 12-lead electrocardiography and echocardiography. RESULTS: During the median follow-up of 1.9years (Interquartile range 1.6-2.4), there were 65 (16.4%) deaths, yielding an annual mortality rate of 8.6%. The major cause was sudden death (33.8%), followed by heart failure (HF), 32.3%. All the investigated variables were examined as potential predictors of death. The final multivariate logistic regression model included five independent variables: advanced HF functional class (OR [odds ratio] 6.71; 95% confidence interval [95% CI] 1.95-23.2; P=0.003), renal disease (OR 5.71; 95% CI 1.80-18.0; P=0.003), QRS ≥150ms (OR 2.80; 95% CI 1.08-7.27; P=0.034), left atrial enlargement (OR 2.75; 95% CI 1.09-6.95; P=0.032) and left ventricular ejection fraction ≤43% (OR 2.31; 95% CI 1.07-4.97; P=0.032). The model had good discrimination, confirmed by bootstrap validation (optimism-adjusted c-statistic of 0.78) and the calibration curve showed a proper calibration (slope=0.972). CONCLUSIONS: CCC patients with pacemaker have a high annual mortality rate despite that the pacemaker related variables were not predictors of death. The independent predictors of death can help us to identify the poor prognosis patients.

Predictors of Arrhythmic Events Detected by Implantable Loop Recorders in Renal Transplant Candidates / Preditores de Eventos Arrítmicos Detectados por Loop Recorders Implantáveis em Candidatos a Transplante Renal

AbstractBackground:The recording of arrhythmic events (AE) in renal transplant candidates (RTCs) undergoing dialysis is limited by conventional electrocardiography. However, continuous cardiac rhythm monitoring seems to be more appropriate due to automatic detection of arrhythmia, but this method has not been used.Objective:We aimed to investigate the incidence and predictors of AE in RTCs using an implantable loop recorder (ILR).Methods:A prospective observational study conducted from June 2009 to January 2011 included 100 consecutive ambulatory RTCs who underwent ILR and were followed-up for at least 1 year. Multivariate logistic regression was applied to define predictors of AE.Results:During a mean follow-up of 424 ± 127 days, AE could be detected in 98% of patients, and 92% had more than one type of arrhythmia, with most considered potentially not serious. Sustained atrial tachycardia and atrial fibrillation occurred in 7% and 13% of patients, respectively, and bradyarrhythmia and non-sustained or sustained ventricular tachycardia (VT) occurred in 25% and 57%, respectively. There were 18 deaths, of which 7 were sudden cardiac events: 3 bradyarrhythmias, 1 ventricular fibrillation, 1 myocardial infarction, and 2 undetermined. The presence of a long QTc (odds ratio [OR] = 7.28; 95% confidence interval [CI], 2.01–26.35; p = 0.002), and the duration of the PR interval (OR = 1.05; 95% CI, 1.02–1.08; p < 0.001) were independently associated with bradyarrhythmias. Left ventricular dilatation (LVD) was independently associated with non-sustained VT (OR = 2.83; 95% CI, 1.01–7.96; p = 0.041).Conclusions:In medium-term follow-up of RTCs, ILR helped detect a high incidence of AE, most of which did not have clinical relevance. The PR interval and presence of long QTc were predictive of bradyarrhythmias, whereas LVD was predictive of non-sustained VT.

ResumoFundamento:A documentação de eventos arrítmicos (EA) em candidatos a transplante renal (CTR) submetidos à diálise é limitada pelo registro de eletrocardiograma convencional. Um monitoramento contínuo do ritmo cardíaco parece ser o procedimento mais adequado para a detecção automática de arritmia, contudo esse método não foi explorado anteriormente.Objetivo:O objetivo deste estudo foi investigar a incidência e os preditores de EA em CTR usando um gravador de eventos implantável, do inglês, “loop recorder implantável” (ILR).Métodos:Um estudo prospectivo observacional foi conduzido entre Junho/2009 a Janeiro/2011. Cem CTR ambulatoriais consecutivos foram submetidos ao ILR e acompanhados pelo menos por um ano. Uma regressão logística multivariada foi aplicada para definir os preditores de EA.Resultados:Durante o tempo médio de acompanhamento de 424 ± 127 dias, EA foram detectados em 98% dos pacientes, sendo que 92% deles tinham mais de um tipo de arritmia, a maioria não considerada potencialmente séria. Taquicardia atrial sustentada e fibrilação atrial ocorreram respectivamente em 7% e 13% dos pacientes; bradiarritmia em 25% e taquicardia ventricular (TV) não-sustentada ou sustentada em 57%. Ocorreram 18 óbitos, 7 por morte cardíaca súbita, 3 por bradiarritmias, 1 por fibrilação ventricular, 1 por infarto do miocárdio e 2 óbitos devido à causas desconhecidas. A presença de QTc longo (Razão de Probabilidade [RP] = 7,28; intervalo de confiança de 95% [IC] 2,01-26,35; p = 0,002) e duração do intervalo PR (RP = 1,05; IC 95%: 1,02-1,08; p < 0,001) foram associados independentemente a bradiarritmias. A dilatação ventricular esquerda (DVE) foi independentemente associada à TV não-sustentada (RP = 2,83; IC 95%: 1,01-7,96; p = 0,041).Conclusões:Em acompanhamento de médio prazo de CTR, o ILR detectou uma alta incidência de EA, a maioria sem relevância clínica. O intervalo PR e a presença de QTc longo foram preditivos de bradiarritmias e DVE de TV não‑sustentada.

Predictors of Arrhythmic Events Detected by Implantable Loop Recorders in Renal Transplant Candidates.

BACKGROUND: The recording of arrhythmic events (AE) in renal transplant candidates (RTCs) undergoing dialysis is limited by conventional electrocardiography. However, continuous cardiac rhythm monitoring seems to be more appropriate due to automatic detection of arrhythmia, but this method has not been used. OBJECTIVE: We aimed to investigate the incidence and predictors of AE in RTCs using an implantable loop recorder (ILR). METHODS: A prospective observational study conducted from June 2009 to January 2011 included 100 consecutive ambulatory RTCs who underwent ILR and were followed-up for at least 1 year. Multivariate logistic regression was applied to define predictors of AE. RESULTS: During a mean follow-up of 424 ± 127 days, AE could be detected in 98% of patients, and 92% had more than one type of arrhythmia, with most considered potentially not serious. Sustained atrial tachycardia and atrial fibrillation occurred in 7% and 13% of patients, respectively, and bradyarrhythmia and non-sustained or sustained ventricular tachycardia (VT) occurred in 25% and 57%, respectively. There were 18 deaths, of which 7 were sudden cardiac events: 3 bradyarrhythmias, 1 ventricular fibrillation, 1 myocardial infarction, and 2 undetermined. The presence of a long QTc (odds ratio [OR] = 7.28; 95% confidence interval [CI], 2.01-26.35; p = 0.002), and the duration of the PR interval (OR = 1.05; 95% CI, 1.02-1.08; p < 0.001) were independently associated with bradyarrhythmias. Left ventricular dilatation (LVD) was independently associated with non-sustained VT (OR = 2.83; 95% CI, 1.01-7.96; p = 0.041). CONCLUSIONS: In medium-term follow-up of RTCs, ILR helped detect a high incidence of AE, most of which did not have clinical relevance. The PR interval and presence of long QTc were predictive of bradyarrhythmias, whereas LVD was predictive of non-sustained VT.

QT longo congênito em portador de marcapasso definitivo e nefropatiaespoliadora de magnésio / Congenital long QT syndrome in a pacemaker user and renal magnesium wasting syndrome

A síndrome do QT longo congênito representa importante distúrbio genético, e está associada asíncope, parada cardíaca e morte súbita. O diagnóstico é baseado principalmente na medida do intervalo QT corrigido associada a critérios clínicos e história familiar. A estratificação de risco auxilia na decisão terapêutica. Relatamos o caso de uma paciente com síndrome do QT longo congênito, portadora de marcapasso definitivo e nefropatia espoliadora de magnésio, que evoluiu com necessidade de upgrade para cardiodesfibrilador implantávelna ocasião da troca do gerador do dispositivo.

The congenital long QT syndrome represents an important genetic disorder related to syncope, cardiac arrest and sudden death. The diagnosis is mainly based on corrected QT interval measurement associated with clinical criteria and family history. The risk stratification of patients with long QT syndrome has implications in the prognosis and treatment. We report a case of a patient with congenital long QT syndrome, with cardiac pacemaker who required an upgrade to implantable cardioverter defibrillator at the time of the generator replacement.

Effects of cardiac resynchronization therapy on muscle sympathetic nerve activity.

INTRODUCTION: Muscle sympathetic nerve activity (MSNA) is an independent prognostic marker in patients with heart failure (HF). Therefore, its relevance to the treatment of HF patients is unquestionable. OBJECTIVES: In this study, we investigated the effects of cardiac resynchronization therapy (CRT) on MSNA response at rest and during exercise in patients with advanced HF. METHODS: We assessed 11 HF patients (51 ± 3.4 years; New York Heart Association class III-IV; left ventricular ejection fraction 27.8 ± 2.2%; optimal medical therapy) submitted to CRT. Evaluations were made prior to and 3 months after CRT. MSNA was performed at rest and during moderate static exercise (handgrip). Peak oxygen consumption (VO2 ) was evaluated by means of cardiopulmonary exercise test. HF patients with advanced NYHA class without CRT and healthy individuals were also studied. RESULTS: CRT reduced MSNA at rest (48.9 ± 11.1 bursts/min vs 33.7 ± 15.3 bursts/min, P < 0.05) and during handgrip exercise (MSNA 62.3 ± 13.1 bursts/min vs 46.9 ± 14.3 bursts/min, P < 0.05). Among HF patients submitted to CRT, the peak VO2 increased (12.9 ± 2.8 mL/kg/min vs 16.5 ± 3.9 mL/kg/min, P < 0.05) and an inverse correlation between peak VO2 and resting MSNA (r = -0.74, P = 0.01) was observed. CONCLUSIONS: In patients with advanced HF and severe systolic dysfunction: (1) a significant reduction of MSNA (at rest and during handgrip) occurred after CRT, and this behavior was significantly superior to HF patients receiving only medical therapy; (2) MSNA reduction after CRT had an inverse correlation with O2 consumption outcomes.

Terapia de ressincronização cardíaca na cardiomiopatia chagásicacrônica: boa resposta clínica e pior prognóstico / Cardiac resynchronization therapy in chronic chagasic cardiomyopathy: a good clinical response and the worst prognosis

Os efeitos da terapia de ressincronização cardíaca (TRC) em pacientes com cardiomiopatiaisquêmica (CMI) e dilatada (CMD) são bem conhecidos. Entretanto, faltam evidências científicas da TRC nacardiomiopatia chagásica crônica (CCC). Objetivo: avaliar o comportamento clínico de pacientes submetidos àTRC, considerando a importância da CCC. Método: no período de janeiro de 2005 a dezembro de 2007 foramincluídos 343 pacientes em seguimento clínico na Unidade de Estimulação Cardíaca do Instituto do Coração,submetidos a intervenção cirúrgica relacionada à TRC. A análise estatística de previsores de mortalidade foirealizada por regressão logística com seleção stepwise, incluindo variáveis com p<0,1 na análise univariada. Asvariáveis estudadas foram: idade, gênero, classe funcional (CF) da New York Heart Association, cardiopatia, tipode bloqueio de ramo, parâmetros ecocardiográficos, medicações em uso e óbito. Resultados: foram selecionados343 pacientes, 65% do sexo masculino, com idade média de 59,7 ± 12,3 anos e seguimento médio de 4,2 ± 2,7anos após a TRC. A CF pré-implante foi II em 18,3%, III em 64,5% e IV em 17,3%. A fração de ejeção média doventrículo esquerdo foi de 27,66 ± 8,99. A cardiopatia de base distribuiu-se em: CMD em 35%; CMI em 29,4%;CCC em 22,4% e outras etiologias em 13,1%. A taxa de melhora da classe funcional após a TRC foi semelhante,independente da cardiopatia, mas a CCC mostrou pior prognóstico (odds ratio=3,03; IC 95%, 1,15-7,97, p<0,001).Conclusão: pacientes com CCC submetidos à TRC apresentam melhora sintomática, porém o risco de óbito é trêsvezes maior em comparação com as outras cardiopatias.

The effects of cardiac resynchronization therapy (CRT) in patients with ischemic (ICM) and dilated(DCM) cardiomyopathy are known. In chronic chagasic cardiomyopathy (CCC), scientific evidence is lacking.Objective: To evaluate the clinical response of patients undergoing CRT, considering the importance of theCCC. Methods: From January 2005 to December 2007, we included 343 patients in clinical follow-up in CardiacPacing Unit of Heart Institute, who underwent surgery related to CRT. Statistical analysis of mortality predictorswas performed using logistic regression with stepwise selection, including variables with P<0.1 in the univariateanalysis. The variables studied were age, gender, functional class of New York Heart Association, etiology of heartdisease, type of bundle branch block, echocardiographic parameters, medications and death. Results: The studyenrolled 343 patients, 65% male, mean age 59.7 ± 12.3 years, with a mean follow-up after CRT of 4.2 ± 2.7 years. The functional class before implant was II, III and IV in 18.3%, 64.5% and 17.3%, respectively. The mean ejectionfraction of the left ventricle was 27.66 ± 8.99. The underlying heart disease was DMC, ICM, CCC and othercauses in 35%, 29.4%, 22.4% and 13.1%, respectively. The rate of improvement in functional class after CRT wassimilar, independent of heart disease etiology, but the CCC showed the worst prognosis (Odds ratio=3.03; 95%CI 1.15-7.97, P<0.001). Conclusion: Patients with CCC undergoing CRT show symptomatic improvement, butthe risk of death is three times higher, compared with other heart diseases.

Los efectos de la terapia de resincronización cardiaca (TRC) en pacientes con miocardiopatía isquémica(MCI) y dilatada (MCD) son conocidos. En la miocardiopatía chagásica crónica (MCC), sin embargo, faltanevidencias científicas. Objetivo: Evaluar el comportamiento clínico de pacientes sometidos a la TRC, considerándosela importancia de la MCC. Métodos: En el período de enero de 2005 a diciembre de 2007, fueron incluidos 343pacientes en seguimiento clínico en la Unidad de Estimulación Cardiaca del Instituto del Corazón, sometidos ala intervención quirúrgica relacionada a la TRC. El análisis estadístico de predictores de mortalidad fue llevado acabo por regresión logística con selección stepwise, incluyéndose variables con p<0,1 en el análisis univariado. Lasvariables estudiadas fueron: edad, género, clase funcional (CF) de la New York Heart Association, cardiopatía, tipode bloqueo de rama, parámetros ecocardiográficos, fármacos en uso y defunción. Resultados: Fueron seleccionados343 pacientes, el 65% del sexo masculino, edad media de 59,7 ± 12,3 años, con seguimiento medio tras la TRC de4,2 ± 2,7 años. La CF pre implante fue II en el 18,3%, III en el 64,5% y IV en el 17,3%. La fracción de eyección deventrículo izquierdo media fue de 27,66 ± 8,99. La cardiopatía de base se distribuyó en: MCD en el 35%; MCI enel 29,4%; MCC en el 22,4% y otras etiologías en el 13,1%. El índice de mejora de clase funcional tras la TRC fuesemejante, independientemente de la cardiopatía, pero la MCC mostró peor pronóstico (Odds Ratio=3,03 IC95%1,15-7,97, p<0,001). Conclusión: Pacientes con MCC sometidos a la TRC presentan mejora sintomática, sin embargo,riesgo de fallecimiento tres veces mayor, en comparación con las otras cardiopatías.