Effect of an exercise-based cardiac rehabilitation program on quality of life of patients with chronic Chagas cardiomyopathy: results from the PEACH randomized clinical trial.

To investigate the effect of an exercise-based cardiac rehabilitation program on the quality of life (QoL) of patients with chronic Chagas cardiomyopathy (CCC). PEACH study was a single-center, superiority randomized clinical trial of exercise training versus no exercise (control). The sample comprised Chagas disease patients with CCC, left ventricular ejection fraction < 45%, without or with HF symptoms (CCC stages B2 or C, respectively). QoL was assessed at baseline, after three months, and at the end of six months of follow-up using the SF-36 questionnaire. Patients randomized for the exercise group (n = 15) performed exercise training (aerobic, strength and stretching exercises) for 60 min, three times a week, during six months. Patients in the control group (n = 15) were not provided with a formal exercise prescription. Both groups received identical nutritional and pharmaceutical counseling during the study. Longitudinal analysis of the effects of exercise training on QoL, considering the interaction term (group × time) to estimate the rate of changes between groups in the outcomes (represented as beta coefficient), was performed using linear mixed models. Models were fitted adjusting for each respective baseline QoL value. There were significant improvements in physical functioning (ß = + 10.7; p = 0.02), role limitations due to physical problems (ß = + 25.0; p = 0.01), and social functioning (ß = + 19.2; p < 0.01) scales during the first three months in the exercise compared to the control group. No significant differences were observed between groups after six months. Exercise-based cardiac rehabilitation provided short-term improvements in the physical and mental aspects of QoL of patients with CCC.Trial registration: ClinicalTrials.gov Identifier: NCT02517632; August 7, 2015.

Stroke in Chagas disease: from pathophysiology to clinical practice.

Despite substantial progress toward its control, Chagas disease continues to be a major public health problem in Latin America and has become a global health concern. The disease affects approximately 6 million people, of whom 20-40% will develop cardiomyopathy over the years after the initial Trypanosoma cruzi infection. Chagas cardiomyopathy is the most serious and frequent manifestation of Chagas disease. Clinical manifestations vary widely according to the severity of myocardial dysfunction, ranging from asymptomatic to severe forms, including dilated cardiomyopathy with heart failure, arrhythmias, thromboembolism events, and sudden death. Chagas disease is a risk factor for stroke regardless of the severity of cardiomyopathy, which is a leading cause of chronic disability. Classically, stroke etiology in patients with Chagas disease is thought to be cardioembolic and related to apical aneurysm, mural thrombus, and atrial arrhythmias. Although most strokes are thromboembolic, other etiologies have been observed. Small vessel disease, atherosclerosis, and cryptogenic diseases have been reported in patients with Chagas disease and stroke. The potential mechanisms involved in non-embolic strokes include the presence of associated risk factors, pro-inflammatory and prothrombotic disease states, and endothelial dysfunction. However, the contribution of each mechanism to stroke in Chagas disease remains unclear. The review aims to provide an overview of stroke in Chagas disease, highlighting the main pathophysiological mechanisms, clinical presentation, approaches for prevention, and unanswered questions regarding treatment strategies.

Acute and subacute hemodynamic responses and perception of effort in subjects with chronic Chagas cardiomyopathy submitted to different protocols of inspiratory muscle training: a cross-over trial.

PURPOSE: This study aimed to evaluate acute and subacute hemodynamic responses and perception of effort in individuals with CCC submitted to different IMT protocols. MATERIALS AND METHODS: This was a randomized cross-over trial conducted on CCC subjects with systolic left ventricular dysfunction (<45% left ventricular ejection fraction) without or with heart failure (stages B2 and C, respectively). Twenty-one participants performed two IMT protocols, one targeting 60% maximal inspiratory pressure with 3 × 10 repetitions (MIP60) and the other targeting 30% maximal inspiratory pressure (MIP30) with 3 × 20 repetitions with a 2 min recovery between sets for both. MIP60 and MIP30 were performed on the same day with a 2 h washout period. Measurements were taken at baseline, during and 60 min after IMT. RESULTS: No differences in hemodynamic variables were observed across protocols. The perception of effort increased in both protocols, with higher scores for the MIP30 protocol (ß = +1.6, p = 0.01; ß = +1.1, p = 0.02; ß = +0.9, p = 0.08 for the 1st, 2nd and 3rd sets, respectively). CONCLUSIONS: There were no differences in hemodynamic responses comparing MIP60 and MIP30 protocols in subjects with CCC. Despite the higher perception of effort during endurance protocol, both protocols can be considered a safe therapeutic strategy.IMPLICATIONS FOR REHABILITATIONDespite inspiratory muscle training may result in functional capacity improvements, no previous study evaluated the hemodynamic acute and subacute responses to inspiratory muscle training in chronic Chagas cardiomyopathy.The two inspiratory muscle training protocols (30% and 60% of maximal inspiratory pressure) did not cause significant hemodynamic repercussions in subjects with chronic Chagas cardiomyopathy.Inspiratory muscle training seems to be an effective strategy to improve functional capacity and can be implemented in the rehabilitation programs for patients with Chagas cardiomyopathy.Since no significant adverse responses were observed in any of the hemodynamic parameters during the inspiratory muscle training sessions, these two protocols of inspiratory muscle training (30% and 60% of maximal inspiratory pressure) seems to be safe in subjects with Chagas cardiomyopathy.

Does left ventricular reverse remodeling influence long-term outcomes in patients with Chagas cardiomyopathy?

BACKGROUND: The impact of left ventricular reverse remodeling (LVRR) on the prognosis of Chagas cardiomyopathy is unknown. The aim of this study was to determine whether the presence of LVRR can predict mortality in these patients. METHODS: From January 2000 to December 2010, the medical charts of 159 patients were reviewed. LVRR was defined as an increase of left ventricular ejection fraction (LVEF) and a decrease of left ventricular end-diastolic diameter (LVDD) by two-dimensional echocardiography. No patient underwent cardiac resynchronization therapy or required mechanical ventricular assistance. RESULTS: At baseline, median (25th-75th) LVDD was 64 mm (59-70), and median LVEF was 33.2% (26.4-40.1). LVRR was detected in 24.5% of patients in a 40-month (26-64) median follow-up. In the LVRR group, LVDD decreased from 64 mm (59-68) to 60 mm (56-65; p < 0.001), and LVEF increased from 31.3% (24.1-39.0) to 42.5% (32.2-47.7; p < 0.001). However, LVRR was not associated with heart failure hospitalization, cardiogenic shock, heart transplantation, or mortality (p > 0.05 for all comparisons). The Cox proportional hazard model analysis identified only cardiogenic shock (hazard ratio [HR]: 2.41; 95% confidence interval [CI]: 1.51-3.85; p < 0.001) and serum sodium level (HR: 0.91; 95% CI: 0.86-0.96; p < 0.001) as independent predictors of all-cause mortality. CONCLUSIONS: Left ventricular reverse remodeling occurs in one quarter of patients with Chagas cardiomyopathy and have no impact on the outcomes of patients with this condition.

Immunomodulation for the Treatment of Chronic Chagas Disease Cardiomyopathy: A New Approach to an Old Enemy.

Chagas disease is a parasitic infection caused by the intracellular protozoan Trypanosoma cruzi. Chronic Chagas cardiomyopathy (CCC) is the most severe manifestation of the disease, developed by approximately 20-40% of patients and characterized by occurrence of arrhythmias, heart failure and death. Despite having more than 100 years of discovery, Chagas disease remains without an effective treatment, especially for patients with CCC. Since the pathogenesis of CCC depends on a parasite-driven systemic inflammatory profile that leads to cardiac tissue damage, the use of immunomodulators has become a rational alternative for the treatment of CCC. In this context, different classes of drugs, cell therapies with dendritic cells or stem cells and gene therapy have shown potential to modulate systemic inflammation and myocarditis in CCC models. Based on that, the present review provides an overview of current reports regarding the use of immunomodulatory agents in treatment of CCC, bringing the challenges and future directions in this field.

Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease.

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFß1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.

Advanced Therapies for Ventricular Arrhythmias in Patients With Chagasic Cardiomyopathy: JACC State-of-the-Art Review.

Chagas disease is caused by infection from the protozoan parasite Trypanosoma cruzi. Although it is endemic to Latin America, global migration has led to an increased incidence of Chagas in Europe, Asia, Australia, and North America. Following acute infection, up to 30% of patients will develop chronic Chagas disease, with most patients developing Chagasic cardiomyopathy. Chronic Chagas cardiomyopathy is highly arrhythmogenic, with estimated annual rates of appropriate implantable cardioverter-defibrillator therapies and electrical storm of 25% and 9.1%, respectively. Managing arrhythmias in patients with Chagasic cardiomyopathy is a major challenge for the clinical electrophysiologist, requiring intimate knowledge of cardiac anatomy, advanced training, and expertise. Endocardial-epicardial mapping and ablation strategy is needed to treat arrhythmias in this patient population, owing to the suboptimal long-term success rate of endocardial mapping and ablation alone. We also describe innovative approaches to improve acute and long-term clinical outcomes in patients with refractory ventricular arrhythmias following catheter ablation, such as bilateral cervicothoracic sympathectomy and bilateral renal denervation, among others.

Chagas Disease: Chronic Chagas Cardiomyopathy.

Chagas disease (CD) is a tropical vector-borne infection caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), also known as American Trypanosomiasis. It is considered endemic in all South and Central America and in this past decades its becoming a burden particularly in the United States and Europe due to human migration. The vast majority of patients during the acute phase are asymptomatic, while chronic symptomatic phase appears years later, with around 30% progressing toward detectable organ damage affecting mainly the cardiovascular and digestive systems. Chagas cardiomyopathy is the leading cause of nonischemic cardiomyopathy (NICM) in Latin America and affects around 30% of infected patients. The foremost characteristics are a diffuse myocarditis with focal fibrosis, mainly located in the apex and basal segments of the posterior and inferior wall, leading to a highly arrhythmogenic disease. Treatment can be etiologic during the parasitic infection, without and established efficacy during the advanced chronic symptomatic phase. Chronic Chagas cardiomyopathy treatment consists in guided medical therapy for non-ischemic cardiomyopathy, but more studies are imperative to improve clinical outcomes, some of them already in progress, and hopefully soon refine treatment and recommendations.

Chagas' cardiomyopathy and Lyme carditis: Lessons learned from two infectious diseases affecting the heart.

Chagas' disease and Lyme disease are two endemic, vector-borne zoonotic infectious diseases that impact multiple organ systems, including the heart. Chagas' cardiomyopathy is a progressive process that can evolve into a dilated cardiomyopathy and heart failure several decades after the acute infection; in contrast, although early-disseminated Lyme carditis has been relatively well characterized, the sequelae of Lyme disease on the heart are less well-defined. A century of research on Chagas' cardiomyopathy has generated compelling data for pathophysiological models, evaluated the efficacy of therapy in large randomized controlled trials, and explored the social determinants of health impacting preventative measures. Recognizing the commonalities between Chagas' disease and Lyme disease, we speculate on whether some of the lessons learned from Chagas' cardiomyopathy may be applicable to Lyme carditis.

Effect of exercise training on cardiovascular autonomic and muscular function in subclinical Chagas cardiomyopathy: a randomized controlled trial.

PURPOSE: Patients with chronic chagasic cardiomyopathy with preserved ventricular function present with autonomic imbalance. This study evaluated the effects of exercise training (ET) in restoring peripheral and cardiac autonomic control and skeletal muscle phenotype in patients with subclinical chronic chagasic cardiomyopathy. METHODS: This controlled trial (NCT02295215) included 24 chronic chagasic cardiomyopathy patients who were randomized www.random.org/lists/ into two groups: those who underwent exercise training (n = 12) and those who continued their usual activities (n = 12). Eight patients completed the exercise training protocol, and 10 patients were clinically followed up for 4 months. Muscular sympathetic nerve activity was measured by microneurography and muscle blood flow (MBF) using venous occlusion plethysmography. The low-frequency component of heart rate variability in normalized units (LFnuHR) reflects sympathetic activity in the heart, and the low-frequency component of systolic blood pressure variability in normalized units reflects sympathetic activity in the vessels. The infusion of vasoactive drugs (phenylephrine and sodium nitroprusside) was used to evaluate cardiac baroreflex sensitivity, and a vastus lateralis muscle biopsy was performed to evaluate atrogin-1 and MuRF-1 gene expression. RESULTS: The baroreflex sensitivity for increases (p = 0.002) and decreases (p = 0.02) in systolic blood pressure increased in the ET group. Muscle blood flow also increased only in the ET group (p = 0.004). Only the ET group had reduced resting muscular sympathetic nerve activity levels (p = 0.008) and sympathetic activity in the heart (LFnu; p = 0.004) and vessels (p = 0.04) after 4 months. Regarding skeletal muscle, after 4 months, participants in the exercise training group presented with lower atrogin-1 gene expression than participants who continued their activities as usual (p = 0.001). The reduction in muscular sympathetic nerve activity was positively associated with reduced atrogin-1 (r = 0.86; p = 0.02) and MuRF-1 gene expression (r = 0.64; p = 0.06); it was negatively associated with improved baroreflex sensitivity both for increases (r = -0.72; p = 0.020) and decreases (r = -0.82; p = 0.001) in blood pressure. CONCLUSIONS: ET improved cardiac and peripheral autonomic function in patients with subclinical chagasic cardiomyopathy. ET reduced MSNA and sympathetic activity in the heart and vessels and increased cardiac parasympathetic tone and baroreflex sensitivity. Regarding peripheral muscle, after 4 months, patients who underwent exercise training had an increased cross-sectional area of type I fibers and oxidative metabolism of muscle fibers, and decreased atrogin-1 gene expression, compared to participants who continued their activities as usual. In addition, the reduction in MSNA was associated with improved cardiac baroreflex sensitivity, reduced sympathetic cardiovascular tone, and reduced atrogin-1 and MuRF-1 gene expression. TRIAL REGISTRATION: ID: NCT02295215. Registered in June 2013.

Tolerogenic Dendritic Cells Reduce Cardiac Inflammation and Fibrosis in Chronic Chagas Disease.

Chronic Chagas disease cardiomyopathy (CCC) is the most frequent and severe form of this parasitic disease. CCC is caused by a progressive inflammation in the heart, resulting in alterations that can culminate in heart failure and death. The use of dendritic cells (DCs) appears as an option for the development of treatments due to their important role in regulating immune responses. Here, we investigated whether tolerogenic cells (tDCs) could interfere with the progression of CCC in an experimental model of Chagas disease. The tDCs were generated and characterized as CD11b+ CD11c+ cells, low expression of MHC-II, CD86, CD80, and CD40, and increased expression of PD-L. These cells produced low levels of IL-6 and IL-12p70 and higher levels of IL-10, compared to mature DCs (mDCs). Interestingly, tDCs inhibited lymphoproliferation and markedly increased the population of FoxP3+ Treg cells in vitro, compared to mature DCs. In a mouse model of CCC, treatment with tDCs reduced heart inflammation and fibrosis. Furthermore, tDCs treatment reduced the gene expression of pro-inflammatory cytokines (Ifng and Il12) and of genes related to cardiac remodeling (Col1a2 and Lgals3), while increasing the gene expression of IL-10. Finally, administration of tDCs, increased the percentage of Treg cells in the hearts and spleens of chagasic mice. Ours results show that tolerogenic dendritic cells have therapeutic potential on CCC, inhibiting disease progression.

Risk Score for Predicting 2-Year Mortality in Patients With Chagas Cardiomyopathy From Endemic Areas: SaMi-Trop Cohort Study.

Background Risk stratification of Chagas disease patients in the limited-resource setting would be helpful in crafting management strategies. We developed a score to predict 2-year mortality in patients with Chagas cardiomyopathy from remote endemic areas. Methods and Results This study enrolled 1551 patients with Chagas cardiomyopathy from Minas Gerais State, Brazil, from the SaMi-Trop cohort (The São Paulo-Minas Gerais Tropical Medicine Research Center). Clinical evaluation, ECG, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) were performed. A Cox proportional hazards model was used to develop a prediction model based on the key predictors. The end point was all-cause mortality. The patients were classified into 3 risk categories at baseline (low, <2%; intermediate, ≥2% to 10%; high, ≥10%). External validation was performed by applying the score to an independent population with Chagas disease. After 2 years of follow-up, 110 patients died, with an overall mortality rate of 3.505 deaths per 100 person-years. Based on the nomogram, the independent predictors of mortality were assigned points: age (10 points per decade), New York Heart Association functional class higher than I (15 points), heart rate ≥80 beats/min (20 points), QRS duration ≥150 ms (15 points), and abnormal NT-proBNP adjusted by age (55 points). The observed mortality rates in the low-, intermediate-, and high-risk groups were 0%, 3.6%, and 32.7%, respectively, in the derivation cohort and 3.2%, 8.7%, and 19.1%, respectively, in the validation cohort. The discrimination of the score was good in the development cohort (C statistic: 0.82), and validation cohort (C statistic: 0.71). Conclusions In a large population of patients with Chagas cardiomyopathy, a combination of risk factors accurately predicted early mortality. This helpful simple score could be used in remote areas with limited technological resources.

Effect of Physical Exercise Training in Patients With Chagas Heart Disease (from the PEACH STUDY).

Chagas heart disease (HD) is a chronic fibrosing myocarditis with high mortality. The PEACH study aimed to evaluate if exercise training can improve the functional capacity of Chagas HD patients with left ventricular dysfunction and/or heart failure. The PEACH study was a single center, parallel-group, clinical trial that randomized 30 clinical stable Chagas HD patients with left ventricular ejection fraction <45% or heart failure symptoms to either supervised exercise training 3 times/week for 6 months or a control group. Both groups had the same monthly pharmaceutical and nutritional counseling and usual care. Primary end point was functional capacity assessed by peak exercise oxygen consumption (peak VO2) obtained by cardiopulmonary exercise test. Secondary end points included other cardiopulmonary exercise test variables, cardiac function by echocardiography, body composition, muscle respiratory strength, and metabolic biomarkers. Peak VO2 increased among patients in exercise group from 17.60 ± 4.65 mlO2 kg-1 min-1 to 19.40 ± 5.51 mlO2 kg-1 min-1 while decreased in controls from 15.40 ± 6.30 mlO2 kg-1 min-1 to 12.96 ± 4.50 mlO2 kg-1 min-1, resulting in significant difference in change in peak VO2 between groups after 6 months (ß = +4.6, p = 0.004). There were significant differences between groups in changes in anaerobic threshold (ß = 3.7, p = 0.05), peak oxygen pulse (ß = +2.7, p = 0.032) and maximum minute ventilation (ß = +13.9, p < 0.0001) after 6 months of intervention. In conclusion, exercise training improved functional capacity of chronic Chagas HD patients with left ventricular dysfunction and/or heart failure.

Chagas disease is associated with a poor outcome at 1-year follow-up after cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) is a therapeutic modality for patients with heart failure (HF). The effectiveness of this treatment for event reduction is based on clinical trials where the population of patients with Chagas' disease (DC) is underrepresented. OBJECTIVE: To evaluate the prognosis after CRT of a population in which CD is an endemic cause of HF. METHODS: A retrospective cohort conducted between January 2015 and December 2016 that included patients with HF and left ventricular ejection fraction (LVEF) of less than 35% and undergoing CRT. Clinical and demographic data were collected to search for predictors for the combined outcome of death or hospitalization for HF at one year after CRT implantation. RESULTS: Fifty-four patients were evaluated, and 13 (24.1%) presented CD as the etiology of HF. The mean LVEF was 26.2± 6.1%, and 36 (66.7%) patients presented functional class III or IV HF. After the mean follow-up of 15 (±6,9) months, 17 (32.1%) patients presented the combined outcome. In the univariate analysis, CD was associated with the combined event when compared to other etiologies of HF, 8 (47%) vs. 9 (13,5%), RR: 3,91 CI: 1,46-10,45, p=0,007, as well as lower values of LVEF. In the multivariate analysis, CD and LVEF remained independent risk factors for the combined outcome. CONCLUSION: In a population of HF patients undergoing CRT, CD was independently associated with mortality and hospitalization for HF.