Predictors of Trypanosoma cruzi PCR positivity in patients with chronic Chagas disease.

BACKGROUND: A positive Trypanosoma cruzi polymerase chain reaction (PCR) is associated with a worse prognosis in patients with chronic Chagas disease (CD). OBJECTIVES: To study the association of clinical, electrocardiographic, and echocardiographic characteristics and biomarker blood levels with positive T. cruzi PCR in chronic CD. METHODS: This is a single-centre observational cross-sectional study. Positive T. cruzi PCR association with clinical, electrocardiographic, and echocardiographic characteristics, and biomarker blood levels were studied by logistic regression analysis. p values < 0.05 were considered significant. FINDINGS: Among 333 patients with chronic CD (56.4% men; 62 ± 10 years), T. cruzi PCR was positive in 41.1%. Stepwise multivariate logistic regression showed an independent association between positive T. cruzi PCR and diabetes mellitus {odds ratio (OR) 0.53 [95% confidence interval (CI) 0.30-0.93]; p = 0.03}, right bundle branch block [OR 1.78 (95% CI 1.09-2.89); p = 0.02], and history of trypanocidal treatment [OR 0.13 (95% CI 0.04-0.38); p = 0.0002]. Among patients with a history of trypanocidal treatment (n = 39), only four (10%) patients had a positive T. cruzi PCR. MAIN CONCLUSIONS: Among several studied parameters, only diabetes mellitus, right bundle branch block, and history of trypanocidal treatment showed an independent association with positive T. cruzi PCR. History of trypanocidal treatment was a strong protective factor against a positive T. cruzi PCR.

Quality of life and associated factors in patients with chronic Chagas disease.

OBJECTIVES: To evaluate the quality of life (QoL) of patients with Chagas disease (CD) and the association between QoL domains and several clinical, socioeconomic and lifestyle characteristics of this population. METHODS: Cross-sectional observational study conducted from March 2014 to March 2017 including a total of 361 outpatients followed at Evandro Chagas National Institute of Infectious Disease, Brazil. QoL was assessed using the Portuguese shorter version of the original WHO Quality of Life questionnaire (WHOQOL-BREF). Information about clinical CD presentation, presence of comorbidities, functional class, previous benznidazole treatment, socioeconomic profile and lifestyle was also obtained. RESULTS: Environment and physical domains presented the worst QoL scores, while the social relationship domain presented the highest score. Multivariate regression analysis demonstrated that variables independently associated with QoL were functional class, sex, clinical presentation of CD, sleep duration, schooling, physical activity level, smoking, income per capita and residents by domicile. CONCLUSIONS: The low socioeconomic status and the physical limitations imposed by the disease presented an important impact on the QoL reduction among CD patients, especially on environment and physical domains. Strategies to improve QoL among CD patients should be tailored and consider many different variables to maximise improvements not only of patients' physical but also of their mental health.

Correlation of transforming growth factor-ß1 and tumour necrosis factor levels with left ventricular function in Chagas disease.

BACKGROUND: Transforming growth factor ß1 (TGF-ß1) and tumour necrosis factor (TNF) have been implicated in Chagas disease pathophysiology and may correlate with left ventricular (LV) function. OBJECTIVES: We determined whether TGF-ß1 and TNF serum levels correlate with LV systolic and diastolic functions and brain natriuretic peptide (BNP) serum levels in chronic Chagas disease. METHODS: This cross-sectional study included 152 patients with Chagas disease (43% men; 57 ± 12 years old), classified as 53 patients with indeterminate form and 99 patients with cardiac form (stage A: 24, stage B: 25, stage C: 44, stage D: 6). TGF-ß1, TNF, and BNP were determined by enzyme-linked immunosorbent assay ELISA. Echocardiogram was used to determine left atrial and LV diameters, as well as LV ejection fraction and diastolic function. FINDINGS: TGF-b1 serum levels were lower in stages B, C, and D, while TNF serum levels were higher in stages C and D of the cardiac form. TGF-ß1 presented a weak correlation with LV diastolic function and LV ejection fraction. TNF presented a weak correlation with left atrial and LV diameters and LV ejection fraction. CONCLUSIONS: TNF is increased, while TGF-ß1 is decreased in the cardiac form of chronic Chagas disease. TNF and TGF-ß1 serum levels present a weak correlation with LV systolic and diastolic function in Chagas disease patients.

Correlation of 6-min walk test with left ventricular function and quality of life in heart failure due to Chagas disease.

OBJECTIVES: To evaluate the correlation of the total distance walked during the six-minute walk test (6MWT) with left ventricular function and quality of life in patients with Chagas Disease (ChD) complicated by heart failure. METHODS: This is a cross-sectional study of adult patients with ChD and heart failure diagnosed based on Framingham criteria. 6MWT was performed following international guidelines. New York Heart Association functional class, brain natriuretic peptide (BNP) serum levels, echocardiographic parameters and quality of life (SF-36 and MLHFQ questionnaires) were determined and their correlation with the distance covered at the 6MWT was tested. RESULTS: Forty adult patients (19 male; 60 ± 12 years old) with ChD and heart failure were included in this study. The mean left ventricular ejection fraction was 35 ± 12%. Only two patients (5%) ceased walking before 6 min had elapsed. There were no cardiac events during the test. The average distance covered was 337 ± 105 metres. The distance covered presented a negative correlation with BNP (r = -0.37; P = 0.02), MLHFQ quality-of-life score (r = -0.54; P = 0.002), pulmonary artery systolic pressure (r = -0.42; P = 0.02) and the degree of diastolic dysfunction (r = -0.36; P = 0.03) and mitral regurgitation (r = -0.53; P = 0.0006) and positive correlation with several domains of the SF-36 questionnaire. CONCLUSIONS: The distance walked during the 6MWT correlates with BNP, quality of life and parameters of left ventricular diastolic function in ChD patients with heart failure. We propose this test to be adopted in endemic areas with limited resources to aid in the identification of patients who need referral for tertiary centres for further evaluation and treatment.

EFFICACY OF CARPENTIER-EDWARDS PERICARDIAL PROSTHESES: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVES: The Carpentier-Edwards pericardial (CEP) prostheses are the type of bioprostheses most used worldwide. Although they were designed to minimize the rate of valve deterioration and reoperation, their clinical superiority over other prostheses models still lacks confirmation. The objective of this study was to evaluate its effectiveness. METHODS: We performed a systematic review and meta-analysis in the PubMed, Embase, Cochrane, and Lilacs databases. Operative mortality, overall mortality and reoperation rates after heart valve surgery were compared between the use of CEP and other cardiac prostheses. Two independent reviewers screened studies for inclusion and extracted the data. Disagreements were resolved by consensus. The GRADE criterion was used to assess the evidence quality. RESULTS: A total of twenty-eight studies were selected, including 19,615 individuals. The studies presented a high heterogeneity and low quality of evidence what limited the reliability of the results. The pooled data from the selected studies did not demonstrate significant differences between CEP and porcine, pericardial or stentless prostheses regarding operative mortality, overall mortality and reoperation rates. However, the pooled data from 3 observational trials pointed out a higher risk for reoperation after valve replacement using CEP prostheses against mechanical prostheses (OR 4.92 [95 percent confidence interval 2.43-9.96]). CONCLUSIONS: The current data present in the literature still does not support a clinical advantage for the use of CEP prostheses over other bioprostheses. The quality of the studies in the literature is limited and further studies are needed to address if CEP prostheses will have a clinical advantage over other prostheses.

Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function.

Although protein S-nitrosylation is increasingly recognized as mediating nitric oxide (NO) signaling, roles for protein denitrosylation in physiology remain unknown. Here, we show that S-nitrosoglutathione reductase (GSNOR), an enzyme that governs levels of S-nitrosylation by promoting protein denitrosylation, regulates both peripheral vascular tone and ß-adrenergic agonist-stimulated cardiac contractility, previously ascribed exclusively to NO/cGMP. GSNOR-deficient mice exhibited reduced peripheral vascular tone and depressed ß-adrenergic inotropic responses that were associated with impaired ß-agonist-induced denitrosylation of cardiac ryanodine receptor 2 (RyR2), resulting in calcium leak. These results indicate that systemic hemodynamic responses (vascular tone and cardiac contractility), both under basal conditions and after adrenergic activation, are regulated through concerted actions of NO synthase/GSNOR and that aberrant denitrosylation impairs cardiovascular function. Our findings support the notion that dynamic S-nitrosylation/denitrosylation reactions are essential in cardiovascular regulation.

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.

Biomarkers and Echocardiographic Predictors of Cardiovascular Outcome in Patients With Chronic Chagas Disease.

Background Chagas disease (CD) presents an ominous prognosis. The predictive value of biomarkers and new echocardiogram parameters in adjusted models have not been well studied. Methods and Results There were 361 patients with chronic CD (57.6% men, 61±11 years of age, clinical forms: indeterminate 27.1%, cardiac 56.6%, digestive 3.6%, cardiodigestive 12.7%) included in this single-center, observational, prospective longitudinal study. Echocardiographic evaluation included strain analyses of left atrial, left ventricular (LV), and right ventricular and 3-dimensional analyses of left atrial and LV volumes. Biomarkers included cardiac troponin I, brain natriuretic peptide, transforming growth factor ß1, tumor necrosis factor, matrix metalloproteinases, and Trypanosoma cruzi polymerase chain reaction. The studied end point was a composite of CD-related mortality, heart transplant, hospital admission due to worsening heart failure, or new cardiac device insertion. Event-free survival was analyzed by multivariable regression analyses adjusted for competing risks. P values <0.05 were considered significant. The composite event occurred in 79 patients after 4.9±2.0 years follow-up. LV end-diastolic volume (hazard ratio [HR], 1.01 [95% CI, 1.00-1.02]; P=0.02), peak negative global atrial strain (HR, 1.08 [95% CI, 1.00-1.17]; P=0.04), LV global circumferential strain (HR, 1.12 [95% CI, 1.04-1.21]; P=0.003), LV torsion (HR, 0.55 [95% CI, 0.35-0.81]; P=0.003), brain natriuretic peptide (HR, 2.03 [95% CI, 1.23-3.34]; P=0.005), and positive T cruzi polymerase chain reaction (HR, 1.80 [95% CI, 1.12-2.91]; P=0.01) were end point predictors independent from age, sex, 2-dimensional echocardiographic indexes, hypertension, previous cardiac device, and CD cardiac form. Conclusions Two-dimensional strain- and 3-dimensional-derived parameters, brain natriuretic peptide, and positive T cruzi polymerase chain reaction can be useful for prediction of CD cardiovascular events.

Corrigendum: Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): a study protocol for a randomized clinical trial.

[This corrects the article DOI: 10.3389/fmed.2022.1087188.].

Two-dimensional strain derived parameters provide independent predictors of progression to Chagas cardiomyopathy and mortality in patients with Chagas disease.

BACKGROUND: Patients with chronic Chagas disease (CD) cardiomyopathy have a high mortality. We evaluated if two-dimensional (2D) strain (ε) parameters provide independent predictors of progression to CD cardiomyopathy and all-cause mortality. METHODS: A total of 408 patients with chronic CD (58.6% women; 53 ± 11 years; clinical forms: indeterminate 34.1%, cardiac 57.6%, digestive 1.2%, cardiodigestive 7.1%) were consecutively included in this single-center prospective longitudinal study. Echocardiographic evaluation included left atrial and left ventricular (LV) function on ε analyses. Primary end-point was a composite of all-cause mortality or heart transplant. Secondary end-point was CD progression defined as the occurrence of changes typical of CD in electrocardiogram, sustained ventricular tachycardia, wall motion abnormalities, or heart failure among patients with the indeterminate form at baseline. Multivariable Cox-proportional-hazards regression analyses were performed to test if 2D ε parameters were associated with the studied end-points. P values < 0.05 were considered significant. RESULTS: The primary end-point occurred in 91 patients after a follow-up of 6.5 ± 2.7 years. CD progression occurred in 26 out of 144 patients without cardiac form at baseline (2.88 cases/100 patient-years). Peak LV circumferential (HR 1.09, 95% CI 1.01-1.18, P = .02) and radial (HR 0.97, 95% CI 0.95-0.99, P = .007) ε, and LV torsion (HR 0.51, 95% CI 0.35-0.74, P = .0004) were independent predictors of the primary end-point. Peak LV radial ε (HR 0.96, 95% CI 0.93-0.99, P = .03) was an independent predictor of CD progression. CONCLUSIONS: Therefore, 2D ε derived parameters can be useful for CD progression and mortality prediction.

Selenium, TGF-Beta and Infectious Endemic Cardiopathy: Lessons from Benchwork to Clinical Application in Chagas Disease.

For over 60 years, selenium (Se) has been known as an essential microelement to many biological functions, including cardiovascular homeostasis. This review presents a compilation of studies conducted in the past 20 years related to chronic Chagas disease cardiomyopathy (CCC), caused by Trypanosoma cruzi infection, a neglected disease that represents a global burden, especially in Latin America. Experimental and clinical data indicate that Se may be used as a complementary therapy to prevent heart failure and improve heart function. Starting from the main questions "Is Se deficiency related to heart inflammation and arrhythmogenesis in CCC?" and "Could Se be recommended as a therapeutic strategy for CCC?", we show evidence implicating the complex and multidetermined CCC physiopathology, discussing its possible interplays with the multifunctional cytokine TGF-ß as regulators of immune response and fibrosis. We present two new proposals to face this global public health challenge in vulnerable populations affected by this parasitic disease: fibrosis modulation mediated by TGF-ß pathways and the possible use of selenoproteins as antioxidants regulating the increased reactive oxygen stress present in CCC inflammatory environments. We assess the opportunity to consider the beneficial effects of Se in preventing heart failure as a concept to be applied for CCC patients.

The association of exercise test variables with long-term mortality in patients with chronic Chagas disease.

Background: The identification of variables obtained in the exercise test (ET) associated with increased risk of death is clinically relevant and would provide additional information for the management of Chagas disease (CD). The objective of the present study was to evaluate the association of ET variables with mortality in patients with chronic CD. Methods: This retrospective longitudinal observational study included 232 patients (median age 46.0 years; 50% women) with CD that were followed at the Evandro Chagas National Institute of Infectious Diseases (Rio de Janeiro, Brazil) and performed an ET between 1989 and 2000. The outcome of interest was all-cause mortality. Results: There were 103 deaths (44.4%) during a median follow-up of 21.5 years (IQR 25-75% 8.0-27.8), resulting in 24.5 per 1,000 patients/year incidence rate. The ET variables associated with mortality after adjustments for potential confounders were increased maximal (HR 1.02; 95% CI 1.00-1.03 per mmHg) and change (HR 1.03; 95% CI 1.01-1.06 per mmHg) of diastolic blood pressure (DBP) during ET, ventricular tachycardia at rest (HR 3.95; 95% CI 1.14-13.74), during exercise (HR 2.73; 95% CI 1.44-5.20), and recovery (HR 2.60; 95% CI 1.14-5.91), and premature ventricular complexes during recovery (HR 2.06; 1.33-3.21). Conclusion: Our findings suggest that ET provides important prognostic value for mortality risk assessment in patients with CD, with hemodynamic (increased DBP during exercise) and electrocardiographic (presence of ventricular arrhythmias) variables independently associated with an increased mortality risk in patients with CD. The identification of individuals at higher mortality risk can facilitate the development of intervention strategies (e.g., close follow-up) that may potentially have an impact on the longevity of patients with CD.

Home-based exercise program in the indeterminate form of Chagas disease (PEDI-CHAGAS study): A study protocol for a randomized clinical trial.

Background: Chagas disease (CD) is a neglected endemic disease with worldwide impact due to migration. Approximately 50-70% of individuals in the chronic phase of CD present the indeterminate form, characterized by parasitological and/or serological evidence of Trypanosoma cruzi infection, but without clinical signs and symptoms. Subclinical abnormalities have been reported in indeterminate form of CD, including pro-inflammatory states and alterations in cardiac function, biomarkers and autonomic modulation. Moreover, individuals with CD are usually impacted on their personal and professional life, making social insertion difficult and impacting their mental health and quality of life (QoL). Physical exercise has been acknowledged as an important strategy to prevent and control numerous chronic-degenerative diseases, but unexplored in individuals with the indeterminate form of CD. The PEDI-CHAGAS study (which stands for "Home-Based Exercise Program in the Indeterminate Form of Chagas Disease" in Portuguese) aims to evaluate the effects of a home-based exercise program on physical and mental health outcomes in individuals with indeterminate form of CD. Methods and design: The PEDI-CHAGAS is a two-arm (exercise and control) phase 3 superiority randomized clinical trial including patients with indeterminate form of CD. The exclusion criteria are <18 years old, evidence of non-Chagasic cardiomyopathy, musculoskeletal or cognitive limitations that preclude the realization of exercise protocol, clinical contraindication for regular exercise, and regular physical exercise (≥1 × per week). Participants will be assessed at baseline, and after three and 6 months of follow-up. The primary outcome will be QoL. Secondary outcomes will include blood pressure, physical fitness components, nutritional status, fatigability, autonomic modulation, cardiac morphology and function, low back pain, depression and anxiety, stress, sleep quality, medication use and adherence, and biochemical, inflammatory and cardiac biomarkers. Participants in the intervention group will undergo a home-based exercise program whilst those in the control group will receive only general information regarding the benefits of physical activity. Both groups will receive the same general nutritional counseling consisting of general orientations about healthy diets. Conclusion: The findings from the present study may support public health intervention strategies to improve physical and mental health parameters to be implemented more effectively in this population. Clinical trial registration: [https://ensaiosclinicos.gov.br/rg/RBR-10yxgcr9/], identifier [U1111-1263-0153].

Student views of research training programmes in medical schools.

CONTEXT: Research activity is not a mandatory component of medical education in many developing countries, including Brazil, although such experiences can have a positive impact on the quality of medical education. The interest and involvement of medical students in research and the barriers they face in accessing research training in developing countries have not been adequately addressed. OBJECTIVES: We sought to assess the availability of scientific training programmes in Brazilian medical schools, the degree of involvement of medical students in these programmes, the main barriers to student involvement in research and possible reasons for the lack of scientific training programmes. METHODS: This study examined 13 medical programmes conducted in six Brazilian states. A total of 1004 medical students were interviewed. We evaluated the availability of scientific training in the institutions attended by these students, the participation of the students in such activities and students' reasons for not joining such programmes based on student answers to our questionnaire. RESULTS: Although only 7% of the medical students expressed no interest in research, only 60% of them were involved in research training. Students regarded a lack of institutional incentive as the most significant barrier to their participation in research activities. Other significant barriers included defective infrastructure and insufficient time available for professors to mentor undergraduate students. According to the feedback from the students, eight of the 13 schools investigated featured structured programmes for scientific training. However, a mean of only 47% of students participated in scientific training programmes on their campuses and 13% of students were compelled to pursue such activities off-campus. CONCLUSIONS: Although scientific training during medical education in Brazil is still less frequent than expected, most of the students were interested in research activities. The barriers to undergraduate scientific training described in this paper may help the Brazilian government improve research training in medical schools. These issues might also be explored in other developing countries.

The Search for Biomarkers and Treatments in Chagas Disease: Insights From TGF-Beta Studies and Immunogenetics.

The anti-inflammatory cytokine transforming growth factor beta (TGF-ß) plays an important role in Chagas disease (CD), a potentially life-threatening illness caused by Trypanosoma cruzi. In this review we revisited clinical studies in CD patients combined with in vitro and in vivo experiments, presenting three main sections: an overview of epidemiological, economic, and clinical aspects of CD and the need for new biomarkers and treatment; a brief panorama of TGF-ß roles and its intracellular signaling pathways, and an update of what is known about TGF-ß and Chagas disease. In in vitro assays, TGF-ß increases during T. cruzi infection and modulates heart cells invasion by the parasite fostering its intracellular parasite cycle. TGF-ß modulates host immune response and inflammation, increases heart fibrosis, stimulates remodeling, and slows heart conduction via gap junction modulation. TGF-ß signaling inhibitors reverts these effects opening a promising therapeutic approach in pre-clinical studies. CD patients with higher TGF-ß1 serum level show a worse clinical outcome, implicating a predictive value of serum TGF-ß as a surrogate biomarker of clinical relevance. Moreover, pre-clinical studies in chronic T. cruzi infected mice proved that inhibition of TGF-ß pathway improved several cardiac electric parameters, reversed the loss of connexin-43 enriched intercellular plaques, reduced fibrosis of the cardiac tissue, restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Finally, TGF-ß polymorphisms indicate that CD immunogenetics is at the base of this phenomenon. We searched in a Brazilian population five single-nucleotide polymorphisms (-800 G>A rs1800468, -509 C>T rs1800469, +10 T>C rs1800470, +25 G>C rs1800471, and +263 C>T rs1800472), showing that CD patients frequently express the TGF-ß1 gene genotypes CT and TT at position -509, as compared to noninfected persons; similar results were observed with genotypes TC and CC at codon +10 of the TGF-ß1 gene, leading to the conclusion that 509 C>T and +10 T>C TGF-ß1 polymorphisms are associated with Chagas disease susceptibility. Studies in genetically different populations susceptible to CD will help to gather new insights and encourage the use of TGF-ß as a CD biomarker.

Chagas heart disease: An overview of diagnosis, manifestations, treatment, and care.

Chagas heart disease (CHD) affects approximately 30% of patients chronically infected with the protozoa Trypanosoma cruzi. CHD is classified into four stages of increasing severity according to electrocardiographic, echocardiographic, and clinical criteria. CHD presents with a myriad of clinical manifestations, but its main complications are sudden cardiac death, heart failure, and stroke. Importantly, CHD has a higher incidence of sudden cardiac death and stroke than most other cardiopathies, and patients with CHD complicated by heart failure have a higher mortality than patients with heart failure caused by other etiologies. Among patients with CHD, approximately 90% of deaths can be attributed to complications of Chagas disease. Sudden cardiac death is the most common cause of death (55%-60%), followed by heart failure (25%-30%) and stroke (10%-15%). The high morbimortality and the unique characteristics of CHD demand an individualized approach according to the stage of the disease and associated complications the patient presents with. Therefore, the management of CHD is challenging, and in this review, we present the most updated available data to help clinicians and cardiologists in the care of these patients. We describe the clinical manifestations, diagnosis and classification criteria, risk stratification, and approach to the different clinical aspects of CHD using diagnostic tools and pharmacological and non-pharmacological treatments.

Benznidazole decreases the risk of chronic Chagas disease progression and cardiovascular events: A long-term follow up study.

BACKGROUND: Chagas disease (CD) remains an important endemic disease in Latin America. However, CD became globalized in recent decades. The majority of the chronically infected individuals did not receive etiologic treatment for several reasons, among them the most conspicuous is the lack of access to diagnosis. The impact of trypanocidal treatment on CD chronic phase, without cardiac involvement (indeterminate form ICF), is yet to be determined. We aimed to evaluate the effect of trypanocidal treatment with benznidazole (BZN) on the rate of progression to Chagas heart disease in patients with ICF. METHODS: This is a retrospective cohort observational study including patients with ICF treated with BZN and compared to a group of non-treated patients matched for age, sex, region of origin, and the year of cohort entry. We reviewed the medical charts of all patients followed from May 1987 to June 2020 at the outpatient center of the Evandro Chagas National Institute of Infectious Diseases (INI) of the Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil. Patients' follow-up included at least one annual medical visit and one annual electrocardiogram (ECG). Echocardiographic exams were performed at baseline and during the follow-up. Disease progression from ICF to cardiac form was defined by changes in baseline ECG. Cumulative incidence and the incidence rate were described in the incidence analysis. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association between BZN and CD progression, cardiovascular events or death. FINDINGS: One hundred and fourteen treated patients met the study inclusion criteria. A comparison group of 114 non-treated patients matched for age, sex, region of origin, and the year of cohort entry was also included, totalizing 228 patients. Most patients included in the study were male (70.2%), and their mean age was 31.3 (+7.4) years. Over a median follow-up of 15.1 years (ranging from 1.0 to 32.4), the cumulative CD progression incidence in treated patients was 7.9% vs. 21.1% in the non-treated group (p = 0.04) and the CD progression rate was 0.49 per 1.000 patients/year in treated patients vs. 1.10 per 1.000 patients/year for non-treated patients (p = 0.02). BZN treatment was associated with a decreased risk of CD progression in both unadjusted (HR 0.46; 95%CI 0.21 to 0.98) and adjusted (HR 0.43; 95%CI 0.19 to 0.96) models and with a decreased risk of occurrence of the composite of cardiovascular events only in the adjusted (HR 0.15; 95%CI 0.03 to 0.80) model. No association was observed between BZN treatment and mortality. INTERPRETATION: In a long-term follow-up, BZN treatment was associated with a decreased incidence of CD progression from ICF to the cardiac form and also with a decreased risk of cardiovascular events. Therefore, our results indicate that BZN treatment for CD patients with ICF should be implemented into clinical practice.

Effects of Selenium treatment on cardiac function in Chagas heart disease: Results from the STCC randomized Trial.

BACKGROUND: Chagas disease (caused by Trypanosoma cruzi infection) evolves to chronic chagasic cardiomyopathy (CCC) affecting 1.8 million people worldwide. This is the first randomized, placebo-controlled, double-blinded, clinical trial designed to estimate efficacy and safety of selenium (Se) treatment in CCC. METHODS: 66 patients with CCC stages B1 (left ventricular ejection fraction [LVEF] > 45% and no heart failure; n = 54) or B2 (LVEF < 45% and no heart failure; n = 12) were randomly assigned to receive 100 mcg/day sodium selenite (Se, n = 32) or placebo (Pla, n = 34) for one year (study period: May 2014-September 2018). LVEF changes over time and adverse effects were investigated. Trial registration number: NCT00875173 (clinicaltrials.gov). FINDINGS: No significant differences between the two groups were observed for the primary outcome: mean LVEF after 6 (ß= +1.1 p = 0.51 for Se vs Pla) and 12 months (ß= +2.1; p = 0.23). In a subgroup analysis, statistically significant longitudinal changes were observed for mean LVEF in the stage B2 subgroup (ß= +10.1; p = 0.02 for Se [n = 4] vs Pla [n = 8]). Se treatment was safe for CCC patients, and the few adverse effects observed were similarly distributed across the two groups. INTERPRETATION: Se treatment did not improve cardiac function (evaluated from LVEF) in CCC. However, in the subgroup of patients at B2 stage, a potential beneficial influence of Se was observed. Complementary studies are necessary to explore diverse Se dose and/or associations in different CCC stages (B2 and C), as well as in A and B1 stages with longer follow-up. FUNDING: Brazilian Ministry of Health, Fiocruz, CNPq, FAPERJ.

Mitral annular remodeling to treat functional mitral regurgitation: a pilot acute study in a canine model.

BACKGROUND: The aim of this study was to evaluate the feasibility and efficacy of the injection of a nonabsorbable substance into the base of the left ventricle (LV) to treat functional mitral regurgitation (MR). METHODS: Tyramine-based hyaluronan hydrogel was injected into the base of the LV of the beating heart in a canine model of rapid ventricular pacing-induced functional MR (n = 4). The severity of MR was evaluated by epicardial echocardiography before and after hydrogel injection. RESULTS: The injection improved MR grade from 3.4 +/- 0.8 to 1.3 +/- 0.5 (P = .006) without inducing hemodynamic instability or any evidence of myocardial ischemia. We noted significant decreases in the septal-lateral dimension at the mitral annulus (3.4 +/- 0.4 cm to 2.9 +/- 0.3 cm; P = .039) and MR volume (20.6 +/- 7.3 mm3 to 5.2 +/- 2.2 mm3; P = .044). CONCLUSIONS: A novel treatment consisting of hydrogel injection into the base of the LV between the 2 papillary muscles was found to be feasible and effective for reducing functional MR in a canine model.

Left Atrial Structure and Function Predictors of New-Onset Atrial Fibrillation in Patients with Chagas Disease.

BACKGROUND: Atrial fibrillation (AF) carries ominous consequences in patients with Chagas disease. The aim of this study was to determine whether left atrial (LA) volume and function assessed using three-dimensional echocardiographic (3DE) imaging and two-dimensional speckle-tracking echocardiographic deformation analysis of strain (ε) could predict new-onset AF in patients with Chagas disease. METHODS: A total of 392 adult patients with chronic Chagas disease (59% women; mean age, 53 ± 11 years) who underwent echocardiography were consecutively enrolled in this prospective longitudinal study. Echocardiographic evaluation included two-dimensional (2D) Doppler echocardiography, with evaluation of left ventricular systolic and diastolic function, LA size, and LA and left ventricular function on 3DE and ε analyses. Multivariate Cox proportional-hazards regression analysis models adjusting for age, sex, hypertension, presence of a pacemaker, and 2D Doppler echocardiographic parameters were used to test if the variables of interest had independent prognostic value for AF prediction. RESULTS: Patients with Chagas disease were followed for 5.6 ± 2.7 years. Among these, 139 (35.5%) had the indeterminate form, 224 (57.1%) had the cardiac form, five (1.3%) had the digestive form, and 24 (6.1%) had the cardiodigestive form. The study end point of AF occurred in 45 patients. Total LA emptying fraction (hazard ratio, 0.93; 95% CI, 0.89-0.98; P = .002), passive LA emptying fraction (HR, 0.95; 95% CI, 0.91-0.99; P = .02), and peak negative global LA ε (HR, 1.22; 95% CI, 1.05-1.41; P = .01) were predictors of new-onset AF independent of clinical and 2D Doppler echocardiographic parameters. CONCLUSIONS: LA function assessed on 3DE and ε analyses predicts new-onset AF in patients with Chagas disease independent of clinical and 2D Doppler echocardiographic indexes.