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.

Unraveling the role of miRNAs as biomarkers in Chagas cardiomyopathy: Insights into molecular pathophysiology

BACKGROUND: Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis. AIM: This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease. METHODS: The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions. RESULTS: The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM. CONCLUSION: In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.

Correlation of blood-based immune molecules with cardiac gene expression profiles reveals insights into Chagas cardiomyopathy pathogenesis.

Introduction: Understanding compartmentalized immune responses in target organs is crucial for elucidating the pathogenesis of various diseases. However, obtaining samples from affected vital organs often poses safety challenges. In this study, we aimed to investigate potential correlations between the levels of disease-associated immune molecules in the bloodstream with their gene expression profiles in the hearts of patients suffering from Chagas Cardiomyopathy (CCC). This debilitating and often fatal condition is caused by infection with the protozoan Trypanosoma cruzi. Methods: Blood samples were analyzed using the Bio-Plex platform. Gene Expression Omnibus (GEO) database was used to determine gene expression profile in heart tissue from CCC and non-Chagas controls (CTRL). Results: Elevated levels of inflammatory cytokines were detected in the plasma of CCC patients, and these levels correlated with clinical indicators of deteriorating cardiac function. Notably, 75% of the soluble factors assessed in the plasma exhibited a consistent relationship with their gene expression levels in the cardiac tissue of CCC patients. Analysis of interactions and signaling pathways related to these molecules revealed an overrepresentation of inflammatory pathways in both blood and heart compartments. Moreover, we identified that differentially expressed genes in CCC cardiac tissue were primarily associated with T-cell signaling pathways and correlated with the presence of CD8+ T cells in the myocardium. Discussion: Our findings establish a strong correlation between relevant immune molecules and their signaling pathways in both the blood and heart tissue in CCC. This validates the use of blood as a non-invasive medium for understanding immunopathology and identifying markers for cardiac dysfunction in Chagas disease.

Galectin-3 (Gal-3) and the tissue inhibitor of matrix metalloproteinase (TIMP-2) as potential biomarkers for the clinical evolution of chronic Chagas cardiomyopathy.

BACKGROUND: Chronic Chagas cardiomyopathy (CCC) is responsible for the highest morbidity and worst prognosis in Chagas disease patients. However, predicting factors that correlate with disease progression, morbidity, and mortality is challenging. It is necessary to have simple, quantitative, and economical risk biomarkers that add value to conventional methods and assist in the diagnosis and prognosis of patients with CCC or in evolution. OBJECTIVES: We evaluated molecules related to cardiac remodeling and fibrosis, such as MMP-2, MMP-9, TIMP-2, TIMP-1, PICP, CTXI, and Gal-3, and correlated these biomarkers with echocardiographic variables (LVDD, LVEF, and E/e' ratio). METHODS: Blood samples from Chagasic patients without apparent cardiopathy (WAC), CCC patients, and healthy individuals were used to perform plasma molecule dosages using Luminex or ELISA. RESULTS: MMP-2 and TIMP-2 presented higher levels in CCC; in these patients, the inhibitory role of TIMP-2 over MMP-2 was reinforced. The ratio of MMP-2/TIMP-2 in WAC patients showed a bias in favor of the gelatinase pathway. MMP-9 and TIMP-1 showed higher levels in Chagas patients compared to healthy subjects. PICP and CTXI are not associated with cardiac deterioration in Chagas disease. Increased levels of Gal-3 are associated with worse cardiac function in CCC. Receiver operating characteristic (ROC) curve analysis identified Gal-3 and TIMP-2 as putative biomarkers to discriminate WAC from cardiac patients. CONCLUSIONS: Among the molecules evaluated, Gal-3 and TIMP-2 have the potential to be used as biomarkers of cardiac remodeling and progressive myocardial fibrosis in Chagas disease.

Unraveling the role of miRNAs as biomarkers in Chagas cardiomyopathy: Insights into molecular pathophysiology.

BACKGROUND: Chagas cardiomyopathy (ChCM) is a severe form of Chagas disease and a major cause of cardiovascular morbidity and mortality. The dysregulation of the immune response leads to cardiac remodeling and functional disruptions, resulting in life-threatening complications. Conventional diagnostic methods have limitations, and therapeutic response evaluation is challenging. MicroRNAs (miRNAs), important regulators of gene expression, show potential as biomarkers for diagnosis and prognosis. AIM: This review aims to summarize experimental findings on miRNA expression in ChCM and explore the potential of these miRNAs as biomarkers of Chagas disease. METHODS: The search was conducted in the US National Library of Medicine MEDLINE/PubMed public database using the terms "Chagas cardiomyopathy" OR "Chagas disease" AND "microRNA" OR "miRNA" OR "miR." Additionally, bioinformatics analysis was performed to investigate miRNA-target interactions and explore enrichment pathways of gene ontology biological processes and molecular functions. RESULTS: The miR-21, miR-146b, miR-146a, and miR-155 consistently exhibited up-regulation, whereas miR-145 was down-regulated in ChCM. These specific miRNAs have been linked to fibrosis, immune response, and inflammatory processes in heart tissue. Moreover, the findings from various studies indicate that these miRNAs have the potential as biomarkers for the disease and could be targeted in therapeutic strategies for ChCM. CONCLUSION: In this review, we point out miR-21, miR-146b, miR-146a, miR-155, and miR-145-5p role in the complex mechanisms of ChCM. These miRNAs have been shown as potential biomarkers for precise diagnosis, reliable prognostic evaluation, and effective treatment strategies in the ChCM.

The Burden of Chagas Disease in the Contemporary World: The RAISE Study.

Chagas disease (ChD), a Neglected Tropical Disease, has witnessed a transformative epidemiological landscape characterized by a trend of reduction in prevalence, shifting modes of transmission, urbanization, and globalization. Historically a vector-borne disease in rural areas of Latin America, effective control measures have reduced the incidence in many countries, leading to a demographic shift where most affected individuals are now adults. However, challenges persist in regions like the Gran Chaco, and emerging oral transmission in the Amazon basin adds complexity. Urbanization and migration from rural to urban areas and to non-endemic countries, especially in Europe and the US, have redefined the disease's reach. These changing patterns contribute to uncertainties in estimating ChD prevalence, exacerbated by the lack of recent data, scarcity of surveys, and reliance on outdated models. Besides, ChD's lifelong natural history, marked by acute and chronic phases, introduces complexities in diagnosis, particularly in non-endemic regions where healthcare provider awareness is low. The temporal dissociation of infection and clinical manifestations, coupled with underreporting, has rendered ChD invisible in health statistics. Deaths attributed to ChD cardiomyopathy often go unrecognized, camouflaged under alternative causes. Understanding these challenges, the RAISE project aims to reassess the burden of ChD and ChD cardiomyopathy. The project is a collaborative effort of the World Heart Federation, Novartis Global Health, the University of Washington's Institute for Health Metrics and Evaluation, and a team of specialists coordinated by Brazil's Federal University of Minas Gerais. Employing a multidimensional strategy, the project seeks to refine estimates of ChD-related deaths, conduct systematic reviews on seroprevalence and prevalence of clinical forms, enhance existing modeling frameworks, and calculate the global economic burden, considering healthcare expenditures and service access. The RAISE project aspires to bridge knowledge gaps, raise awareness, and inform evidence-based health policies and research initiatives, positioning ChD prominently on the global health agenda.

Chagas cardiomyopathy in Boston, Massachusetts: Identifying disease and improving management after community and hospital-based screening.

BACKGROUND: Limited data exist regarding cardiac manifestations of Chagas disease in migrants living in non-endemic regions. METHODS: A retrospective cohort analysis of 109 patients with Chagas disease seen at Boston Medical Center (BMC) between January 2016 and January 2023 was performed. Patients were identified by screening and testing migrants from endemic regions at a community health center and BMC. Demographic, laboratory, and cardiac evaluation data were collected. RESULTS: Mean age of the 109 patients was 43 years (range 19-76); 61% were female. 79% (86/109) were diagnosed with Chagas disease via screening and 21% (23/109) were tested given symptoms or electrocardiogram abnormalities. Common symptoms included palpitations (25%, 27/109) and chest pain (17%, 18/109); 52% (57/109) were asymptomatic. Right bundle branch block (19%, 19/102), T-wave changes (18%, 18/102), and left anterior fascicular block (11%, 11/102) were the most common electrocardiogram abnormalities; 51% (52/102) had normal electrocardiograms. Cardiomyopathy stage was ascertained in 94 of 109 patients: 51% (48/94) were indeterminate stage A and 49% (46/94) had cardiac structural disease (stages B1-D). Clinical findings that required clinical intervention or change in management were found in 23% (25/109), and included cardiomyopathy, apical hypokinesis/aneurysm, stroke, atrial or ventricular arrhythmias, and apical thrombus. CONCLUSIONS: These data show high rates of cardiac complications in a cohort of migrants living with Chagas disease in a non-endemic setting. We demonstrate that Chagas disease diagnosis prompts cardiac evaluation which often identifies actionable cardiac disease and provides opportunities for prevention and treatment.

Assessment of health-related quality of life in patients with Chagas cardiomyopathy using Minnesota living with heart failure questionnaire: A validation study.

OBJECTIVE: Chagas cardiomyopathy (ChC) is the most severe clinical form of Chagas disease and, in association with psychosocial factors, can compromise the health-related quality of life (HRQoL) of affected patients. To date, there is no specific instrument to assess the HRQoL of these patients, and the Minnesota Living with Heart Failure Questionnaire (MLwHFQ), specific for heart failure, is being used both in research and current clinical practice. Therefore, we aimed to verify the validity of the MLwHFQ in the assessment of HRQoL of patients with ChC. METHODS: Fifty patients with ChC (50.6 ± 10.1 years, NYHA I-III) were evaluated. The MLwHFQ, Short-Form of Health Survey (SF-36), Beck Depression Inventory (BDI), and Human Activity Profile (HAP) were applied. All patients underwent echocardiography and Cardiopulmonary Exercise Testing (CPET). RESULTS: The MLwHFQ score correlated with almost all SF-36 domains (with r-value ranging from -0.38 to -0.69), except pain (p = 0.118). The MLwHFQ score also correlated with the BDI score (r = 0.748; p < 0.001), HAP score (r = -0.558; p = 0.001), peak oxygen uptake (r = -0.352; p = 0.01), and left ventricular ejection fraction (r = -0.329; p = 0.021). There was no significant difference in the score found on the MLwHFQ among NYHA classes (p = 0.101), as well as between patients with systolic dysfunction (n = 30) and preserved cardiac function (n = 20) (p = 0.058). Similarly, there was no significant difference in the score found on the physical (p = 0.423) and mental (p = 0.858) components of SF-36 between patients with systolic dysfunction and preserved cardiac function (p = 0.271 and p = 0.609, respectively). There was also no difference in the mental component of SF-36 among NYHA classes (p = 0.673). However, the HRQoL using the physical component of SF-36 was worse in advanced NYHA classes (p = 0.014). CONCLUSION: MLwHF correlated with most SF-36 HRQoL domains, depressive symptoms, physical activity, and systolic function and seems to be valid in assessing the HRQoL of ChC patients.

Chagas disease stroke and associated risk factors: A case-control study.

INTRODUCTION: The intricate relationship between Chagas disease and ischemic stroke remains unclear. Limited evidence exists concerning secondary prophylaxis, etiological diagnosis, and stroke-related determinants. This study aims to discern factors linked to stroke in Chagas disease by contrasting patients with and without a history of ischemic stroke. METHODS: Retrospective data from all outpatient Chagas disease patients from two Brazilian hospitals - one Chagas center and one stroke clinic - were examined. Descriptive analyses were conducted to identify stroke-associated factors. Variables were compared between patients with and without ischemic stroke history. RESULTS: Among 678 subjects, 72 had experienced stroke. Univariate associations with stroke included male gender, heart failure, prior or ongoing alcoholism, electrocardiographic features (non-sinus rhythm, left bundle branch, right bundle branch block, left anterosuperior fascicular block, atrial fibrillation), as well as echocardiographic findings indicative of reduced left ventricular ejection fraction and segmental abnormalities. After logistic regression (multivariate analysis), congestive heart failure, right bundle branch block, left anterosuperior divisional block, and atrial fibrillation retained independent associations. CONCLUSION: In this study, cardiac involvement emerged as the predominant factor correlated with stroke in Chagas disease. While atherosclerosis-related risk factors were prevalent, their influence on ischemic stroke in Chagas disease appeared limited.

Risk stratifier for sudden cardiac death beyond the left ventricular ejection fraction in Chagas cardiomyopathy.

BACKGROUND: Sudden cardiac death (SCD) risk markers are needed in Chagas cardiomyopathy (CC). Action potential duration restitution (APDR) dynamics is capable of extracting information on cardiac regional heterogeneity. This study intends to develop a patient-specific variables-based algorithm to predict SCD in the low-intermediate subgroups of the Rassi risk score. METHODS: Cross-sectional study of patients who underwent 24-h Holter for research purposes between January 1992 and February 2017. From 4-h ECG segment, RR series were generated and APDR dynamics metrics were calculated. Classification tree and sensitivity analysis were applied. As outcomes, SCD, SCD-free and non-cardiovascular death and 34 variables were included. RESULTS: Two hundred twenty-one (129 in the group SCD-free, 80 in the SCD group and 12 non-cardiovascular death group) were analyzed. In the groups with and without SCD (209 patients), the median age was 66 years, 52% were female, the cardiac involvement was mild to moderate in 72% with a Rassi point median of 8 (IQ: 3 to 11). The SCD group had more ventricular remodeling and more ventricular electrical instability. The occurrence of a %beats QTend/TendQ ratio > 1 (AUC, 0.96 (95% CI 0.89-0.98) present in more than 56.7% of the 4-h ECG segments was sufficient to identify patients of the SCD subgroup. Variables representing different stages of CC were also relevant in the model. CONCLUSION: It is possible to use APDR dynamics as an adjuvant in the SCD risk assessment in a subgroup of patients with a high risk of SCD and a very low risk of non-CV death with high power of discrimination.

Mapa de evidências Doença de Chagas: Diagnóstico, Tratamento e Análise de risco

O mapa apresenta uma visão geral das evidências sobre as formas de diagnóstico, de tratamento e de aspectos relacionados ao risco de transmissão da doença de Chagas, bem como do desenvolvimento da cardiopatia chagásica. A partir de uma ampla busca bibliográfica foram incluídos no mapa 43 estudos que foram avaliados, caracterizados e categorizados no mapa. No mapa estão representadas graficamente 82 associações entre 29 intervenções e 29 desfechos para doença de Chagas, com indicação do efeito reportado nos estudos.

Inspiratory Muscle Strength in Chagas Cardiomyopathy: A Systematic Scoping Review.

The increase in inflammatory markers associated with persistent chronic fibrosing myocarditis, a characteristic of chronic Chagas disease, can result in a reduction in inspiratory muscle strength (IMS) in Chagas cardiomyopathy (CC). However, literature in this field is still scarce. This review aimed to map and summarize the evidence regarding IMS in patients with CC. The inclusion criteria included reports with adult participants with a CC diagnosis, with or without heart failure (HF). The core concept examined was the maximum inspiratory pressure evaluated in the untrained and trained groups in the pre-training period. The context was open, including but not limited to hospitals and health centers. Two authors independently identified eligible studies and extracted the data. Descriptive synthesis was used as the primary strategy for analyzing the results. Nine studies (five clinical trials, three cross-sectional, and one cohort) were included. The CC classification differed among the studies, with no mention of HF in five and no CC staging specification in six. IMS was assessed using a manovacuometer, and only six studies analyzed and interpreted the data concerning the predicted values. The CC population with HF appeared to have impaired IMS. All studies involved only Brazilian volunteers. In conclusion, randomized clinical trials evaluating IMS and the effects of inspiratory muscle training need to be conducted to better understand the prevalence and risk of inspiratory muscle weakness in the CC population, as well as the effects of training. Such studies should be conducted at different stages of CC in different populations and countries.

Chronic Chagas Cardiomyopathy in the Brazilian Amazon region: clinical characteristics and regional distinctiveness.

Objectives: This study aims to provide a comprehensive analysis of clinical and epidemiological data related to Chronic Chagas Cardiomyopathy (CCC) in the Amazon region of Brazil. Methods: A review of observational, retrospective, and cross-sectional studies related to Chagas Disease in the Amazon region of Brazil was conducted, and a case series addressing CCC in patients treated at the FMT-HVD outpatient clinic, a reference center for Chagas disease in Brazil, was carried out. Results: Clinical characteristics of 55 patients from the Amazon region with CCC were described. The most common electrocardiographic alteration observed was abnormal ventricular repolarization (AVR), present in 40% of cases. The most common echocardiographic finding was left ventricular systolic dysfunction (49%), followed by akinesia or hypokinesia of the inferior and/or inferolateral walls (38.1%) and the presence of an apical aneurysm (32.7%). Conclusions: Overall, this study demonstrates that CCC in the Amazon region presents clinical characteristics and severity that are similar to those observed in other regions. However, certain peculiarities, such as the frequency of right bundle branch block (RBBB) and anterior and septal involvement during the acute phase, require additional investigation to better comprehend the disease in the region. Overall, the study provides crucial clinical insights for the diagnosis and treatment of CCC in the Amazon region.

Exploring the Historical Background and Clinical Implications of Electrocardiogram in the Context of Chagas Disease Research.

Chagas disease (CD) remains one of the most significant endemic diseases in Latin America. Approximately 30% of individuals with CD develop the cardiac form, the main determinant of morbidity and mortality, which is characterized by typical electrocardiogram (ECG) changes caused by chronic chagasic cardiopathy (CCC). This review accentuates to how crucial it is for research teams and reference centers that treat patients with CD to standardize ECG in CCC. This was a non-systematic review of the literature. ECG is the most widely used examination in the diagnosis and evaluation of CCC, and it is also employed in epidemiological surveys, risk stratification for cardiovascular events and death, and monitoring the clinical progression of the disease. Carlos Chagas and Eurico Villela published the first work addressing CCC in 1922. Other works followed, including the study by Evandro Chagas' which was the first to perform ECG in CD, culminating in Francisco Laranja's seminal work in 1956. Since the 1980s, standardizations and ECG reading codes for CD have been established. This standardization aimed to code complex arrhythmias and characteristic ventricular conduction disorders and standardize ECG readings for clinical and epidemiological studies in CD. Nearly all existing electrocardiographic abnormalities can be found in CD, with a predominance of abnormalities in the formation and conduction of cardiac stimuli. The complex and heterogeneous substrate of CD with varied electrocardiographic manifestations poses a significant challenge when comparing studies involving patients with CCC, emphasizing the need for ECG standardization in CD.

Assessment of biomarkers and clinical parameters as predictors of survival in patients with chagasic heart failure.

BACKGROUND: Chagas disease, endemic in Latin America and spreading globally due to emigration, has a significant health burden, particularly in relation to chagasic heart failure (HF). Chagasic cardiomyopathy (CCM) is characterized by chronic inflammatory myocardial disease. This study aimed to identify inflammatory parameters and biomarkers that could aid in the management of patients with chagasic HF. METHODS AND FINDINGS: A cohort study was conducted at a tertiary cardiology single-center over a mean follow-up period of 2.4 years. The study included patients with HF secondary to CCM enrolled between October 2013 and July 2017. Various clinical parameters, echocardiography findings, parasitemia status, brain natriuretic peptide (BNP) and troponin T (TnT) levels, and inflammatory biomarkers (IL-6, IL-10, IL-12p70, IL-17A, adiponectin, and IFN-γ) were assessed. The study encompassed a cohort of 103 patients, with a median age of 53 years and 70% being male. The left ventricular ejection fraction (LVEF) was 28%, with 40% of patients classified as NYHA II functional class. The median BNP level was 291 pg/ml. The observed mortality rate during the study period was 38.8%. Predictors of lower survival were identified as elevated levels of BNP, TnT, reduced LVEF, and increased adiponectin (thresholds: BNP > 309 pg/ml, TnT > 27.5 ng/ml, LVEF < 25.5%, adiponectin > 38 µg/mL). Notably, there was no evidence indicating a relationship between parasitemia and the inflammatory parameters with lower survival in these patients, including INF-γ, IL-6, IL-10, IL12-(p70), and IL17a. CONCLUSION: Despite the presence of a chronic inflammatory process, the evaluated inflammatory biomarkers in this cohort were not predictive of survival in patients with chagasic HF with reduced ejection fraction (HFrEF). However, reduced LVEF, elevated BNP, adiponectin levels, and troponin T were identified as predictors of lower survival in these patients.

Cytokine profile levels and their relationship with parasitemia and cardiomyopathy in people with Chagas disease in Spain. A prospective observational study.

Immunoregulatory networks may have a role in controlling parasitemia in the chronic phase of human Chagas disease. The aim was to describe the serum cytokine profile of Trypanosoma cruzi in chronically infected patients and to evaluate its relationship with parasitemia and Chagas cardiomyopathy.This prospective observational study included adult patients with chronic Chagas disease. Demographic and clinical data were collected, and peripheral blood samples were used to perform T. cruzi real-time polymerase chain reaction (RT-PCR) and determine the serum cytokine profile.Fifty-eight patients were included; 17 (29.3%) had positive RT-PCR results. This group had a higher median concentration of TNF-α (p = 0.003), IL-6 (p = 0.021), IL-4 (p = 0.031), IL-1ß (p = 0.036), and IL-17A (p = 0.043) than those with a negative RT-PCR. Patients with cardiac involvement had a higher median concentration of IL-5 (p = 0.016) than those without.These results reinforce the key role that cytokines play in Chagas disease patients with parasitemia and cardiac involvement.