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Background: Chagas disease (CD) is a neglected tropical disease, endemic in Latin America, but due to migration and environmental changes it has become a global public health issue., Objectives: To assess the global prevalence and disability-adjusted life years due to CD using findings from the Global Burden of Disease Study 2019., Methods: The Global Burden of Disease data was obtained from the Global Burden of Disease Collaborative Network; results were provided by the Institute for Health Metrics and Evaluation. The prevalence and disability-adjusted life-years (DALYs) were described at a global, regional, and national level, including data from 1990 to 2019., Results: Globally, CD prevalence decreased by 11.3% during the study period, from 7,292,889 cases estimated in 1990 to 6,469,283 in 2019. Moreover, the global DALY rate of CD decreased by 23.7% during the evaluated period, from 360,872 in 1990 to 275,377 in 2019. In addition, significant differences in the burden by sex, being men the most affected, age, with the elderly having the highest burden of the disease, and sociodemographic index (SDI), with countries with the lowest SDI values having the highest prevalence of the disease, were observed. Finally, the prevalence trends have followed different patterns according to the region, with a sustained decrease in Latin America, compared to an increasing trend in North America and Europe until 2010., Conclusion: The global burden of CD has changed in recent decades, with a sustained decline in the number of cases. Although the majority of cases remain concentrated in Latin America, the increase observed in countries in North America and Europe highlights the importance of screening at-risk populations and raising awareness of this neglected tropical disease., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2022 The Author(s).)

Objective: To analyze the association of circulating dehydroepiandrosterone sulfate (DHEA-S) levels with cardiovascular outcomes in patients with chronic Chagas cardiomyopathy (CCM) diagnosis., Background: DHEA-S is among the main endogenous steroid hormones. Some studies have suggested a relevant role of this hormone in infections and the setting of CCM. Nevertheless, no study has evaluated the prognostic role of DHEA-S in CCM patients., Methods: Prospective cohort study. Patients with CCM and reduced ejection fraction were included. We explored the association of DHEA-S levels with NT-proBNP levels and echocardiographic variables using linear regression models. Next, by using Cox Proportional Hazard models, we examined whether levels of DHEA-S could predict a composite outcome (CO) including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD)., Results: Seventy-four patients were included (59% males, median age: 64 years). After adjustment for confounding factors, high DHEA-S levels were associated with better LVEF, lower left atrium volume, end-systolic volume of the left ventricle and lower NT-proBNP levels. 43% of patients experienced the CO during a median follow-up of 40 months. Increased levels of DHEA-S were associated with a lower risk of developing the CO (HR 0.43; 95%CI 0.21-0.86). Finally, adding DHEA-S to the multivariate model did not improve the prediction of the CO, but substituting NT-proBNP in the model with DHEA-S showed similar performance., Conclusions: In patients with CCM, higher DHEA-S levels were associated with lower mortality, heart transplantation, and LVAD implantation. Further larger studies are required to confirm our results and assess causality., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Currently, Chagas disease (CD) constitutes one of the main public health problems in Latin America. However, little is known about potential mechanisms of disease different from cardiac or digestive involvement, such as the coagulation disorders elicited by the parasite persistence in the tissues. The aim of this systematic review was to describe and characterize all the published literature that evaluated the pathophysiological aspects of coagulation disorders in CD., Methods: Searches in Medline, EMBASE, and LILACS databases (from inception to July 28th, 2020) were performed. Articles of any language reporting the levels of different coagulation factors/markers or the prevalence of abnormal levels of the mentioned molecules in patients with CD were included. Two reviewers independently selected the studies, extracted the data, and assessed the quality of evidence. Estimates were pooled using random-effects meta-analyses., Results: Seven studies evaluating a total of 676 participants fulfilled the criteria and were included, while only six were suitable for meta-analyzing (544 participants, 52% men, mean age: 49 ± 8 years). 57.16% of the patients in the meta-analysis had a serological confirmed diagnosis of CD, while 97% of these were in the indeterminate stage of the disease. Patients in the CD group had higher levels of F 1 + 2 (SMD 5.15. 95% CI 1.92, 8.38), PAI-1 (SMD 0.46. 95% CI 0.07; 0.89), and P-selectin (SMD 1.8; 95% CI 0.13-3.47) compared to healthy controls. Furthermore, benznidazole therapy was associated with a reduction in the levels of these biomarkers after treatment., Conclusion: The results of the present study suggest that patients with chronic T. cruzi infection are affected by a potential hypercoagulable state irrespective of the development of cardiac or digestive disease. Furthermore, the reduction in the levels of the coagulation markers after benznidazole therapy may suggest a significant role of the parasite load in the development of these coagulation disorders. There is a scarcity of research assessing the molecular and pathophysiological mechanisms of coagulation disorders in Chagas disease. Further research is needed to assess the benefit of benznidazole therapy on this hypercoagulable state in the long-term, along with its impact on the risk of thromboembolic events in CD patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Heart failure (HF) and type 2 Diabetes Mellitus (T2DM) represent two chronic interrelated conditions accounting for significant morbidity and mortality worldwide. Insulin resistance (IR) has been identified as a risk factor for HF; however, the risk of IR that HF confers has not been well elucidated. The present study aims to analyze the association between myocardial involvement in Chronic Chagas Cardiomyopathy (CCM) and IR, taking advantage of this non-metabolic model of the disease., Methods: Cross-sectional study performed during the period 2015-2016. Adults with a serological diagnosis of Chagas disease were included, being divided into two groups: CCM and non-CCM. IR was determined by HOMA-IR index. Bivariate analysis and multivariate logistic regression were performed to determine the association between IR as an outcome and CCM as primary exposure., Results: 200 patients were included in the study, with a mean age of 54.7 years and a female predominance (53.5%). Seventy-four (37.0%) patients were found to have IR, with a median HOMA-IR index of 3.9 (Q1 = 3.1; Q3 = 5.1). Multiple metabolic variables were significantly associated with IR. In a model analyzing only individuals with an altered HWI, an evident association between CCM and IR was observed (OR 4.08; 95% CI 1.55-10.73, p = 0.004)., Conclusion: CCM was significantly associated with IR in patients with an altered HWI. The presence of this association in a non-metabolic model of HF (in which the myocardial involvement is expected to be mediated mostly by the parasitic infection) may support the evidence of a direct unidirectional correlation between this last and IR., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2020 The Author(s).)

Introduction: Benznidazole (BZL) and Nifurtimox (NFX) are the pharmacological treatment for acute phase Chagas Disease (CD); however, therapy resistance and residual mortality development remain important unresolved issues. Posaconazole (POS) has shown a trypanocidal effect in vivo and in vitro. Thus, this study aimed at comparing the T. Cruzi parasitic load-reducing effect of the combination of BZL+POS against that of monotherapy with either, during acute phase CD, in an experimental murine model., Methods: Nineteen Wistar rats were randomly allocated to four groups and inoculated with the trypomastigotes of T. cruzi strain´s JChVcl1. The rats were administered anti-parasites from day 20-29 post-infection. The Pizzi and Brener method was used for parasitemia measurement. Longitudinal data analysis for the continuous outcome of repeated measures was performed using parasitemia as the outcome measured at days 20, 22, 24, 27, and 29 post-infection., Results: All four groups had similar parasitic loads (p=0.143) prior to therapy initiation. Among the three treatment groups, the BZL+POS (n=5) group showed the highest mean parasitic load reduction (p=0.000) compared with the control group. Likewise, the BZL+POS group rats showed an earlier therapeutic effect and were the only ones without parasites in their myocardial samples., Conclusions: Treatment of acute phase CD with BZL+POS was more efficacious at parasitemia and myocardial injury reduction, compared with monotherapy with either.

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Background: Chronic Chagas Cardiomyopathy (CCM) is characterized by a unique pathophysiology in which inflammatory, microvascular and neuroendocrine processes coalesce in the development of one of the most severe cardiomyopathies affecting humans. Despite significant advances in understanding the molecular mechanisms involved in this disease, scarce information is available regarding microRNAs and clinical parameters of disease severity. We aimed to evaluate the association between circulating levels of six microRNAs with markers of myocardial injury and prognosis in this population. Methods: Patients with CCM and reduced ejection fraction were included in a prospective exploratory cohort study. We assessed the association of natural log-transformed values of six circulating microRNAs (miR-34a-5p, miR-208a-5p, miR-185-5p, miR-223-5p, let-7d-5p, and miR-454-5p) with NT-proBNP levels and echocardiographic variables using linear regression models adjusted for potential confounders. By using Cox Proportional Hazard models, we examined whether levels of microRNAs could predict a composite outcome (CO), including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). Finally, for mRNAs showing significant associations, we predicted the target genes and performed pathway analyses using Targetscan and Reactome Pathway Browser. Results: Seventy-four patients were included (59% males, median age: 64 years). After adjustment for age, sex, body mass index, and heart failure medications, only increasing miR-223-5p relative expression levels were significantly associated with better myocardial function markers, including left atrium area (Coef. -10.2; 95% CI -16.35; -4.09), end-systolic (Coef. -45.3; 95% CI -74.06; -16.61) and end-diastolic volumes (Coef. -46.1; 95% CI -81.99; -10.26) of the left ventricle. Moreover, we observed that higher miR-223-5p levels were associated with better left-ventricle ejection fraction and lower NT-proBNP levels. No associations were observed between the six microRNAs and the composite outcome. A total of 123 target genes for miR-223-5p were obtained. From these, several target pathways mainly related to signaling by receptor tyrosine kinases were identified. Conclusions: The present study found an association between miR-223-5p and clinical parameters of CCM, with signaling pathways related to receptor tyrosine kinases as a potential mechanism linking low levels of miR-223-5p with CCM worsening. [ABSTRACT FROM AUTHOR]

Background: Chronic Chagas Cardiomyopathy (CCM) is characterized by a unique pathophysiology in which inflammatory, microvascular and neuroendocrine processes coalesce in the development of one of the most severe cardiomyopathies affecting humans. Despite significant advances in understanding the molecular mechanisms involved in this disease, scarce information is available regarding microRNAs and clinical parameters of disease severity. We aimed to evaluate the association between circulating levels of six microRNAs with markers of myocardial injury and prognosis in this population. Methods: Patients with CCM and reduced ejection fraction were included in a prospective exploratory cohort study. We assessed the association of natural log-transformed values of six circulating microRNAs (miR-34a-5p, miR-208a-5p, miR-185-5p, miR-223-5p, let-7d-5p, and miR-454-5p) with NT-proBNP levels and echocardiographic variables using linear regression models adjusted for potential confounders. By using Cox Proportional Hazard models, we examined whether levels of microRNAs could predict a composite outcome (CO), including all-cause mortality, cardiac transplantation, and implantation of a left ventricular assist device (LVAD). Finally, for mRNAs showing significant associations, we predicted the target genes and performed pathway analyses using Targetscan and Reactome Pathway Browser. Results: Seventy-four patients were included (59% males, median age: 64 years). After adjustment for age, sex, body mass index, and heart failure medications, only increasing miR-223-5p relative expression levels were significantly associated with better myocardial function markers, including left atrium area (Coef. -10.2; 95% CI -16.35; -4.09), end-systolic (Coef. -45.3; 95% CI -74.06; -16.61) and end-diastolic volumes (Coef. -46.1; 95% CI -81.99; -10.26) of the left ventricle. Moreover, we observed that higher miR-223-5p levels were associated with better left-ventricle ejection fraction and lower NTproBNP levels. No associations were observed between the six microRNAs and the composite outcome. A total of 123 target genes for miR-223-5p were obtained. From these, several target pathways mainly related to signaling by receptor tyrosine kinases were identified. Conclusions: The present study found an association between miR-223-5p and clinical parameters of CCM, with signaling pathways related to receptor tyrosine kinases as a potential mechanism linking low levels of miR-223-5p with CCM worsening. [ABSTRACT FROM AUTHOR]

Background: Heart transplant (HT) remains the most frequently indicated therapy for patients with end‐stage heart failure that improves prognosis in Chagas cardiomyopathy (CCM). However, the lack of benznidazole therapy and availability of RT‐PCR follow‐up in many centers is a major limitation to perform this life‐saving intervention, as there are concerns related with the risk of reactivation. We aimed to describe the outcomes of a cohort of patients with CCM who underwent HT using a conventional protocol with mycophenolate mofetil, without benznidazole prophylaxis or RT‐PCR follow‐up. Methods: Retrospective cohort study. Between 2008 and 2018, 43 patients with CCM underwent HT. A descriptive analysis to characterize outcomes as rejection, infectious and neoplastic complications and a survival analysis was carried out. Results: Median of follow‐up was 4.3 (IR 4.28) years. Survival at 1 month, 1 year, and 5 years was 95%, 85%, and 75%, respectively, infections being the main cause of death (60%). Reactivations occurred in only three patients (7.34%) and were not related to mortality. Conclusion: This cohort showed a favorable survival and a low reactivation rate without an impact on mortality. Our results suggest that performing HT in patients with CCM following conventional guidelines and recommendations for other etiologies is a safe approach. [ABSTRACT FROM AUTHOR]

Objectives: To analyse the effect of parasite load assessed by quantitative reverse transcription PCR (RT‐qPCR) in serum on the prognosis of patients with chronic Chagas cardiomyopathy (CCM) after a 2‐year follow‐up. Methods: Prospective cohort study conducted between 2015 and 2017. One hundred patients with CCM were included. Basal parasitaemia levels of Trypanosoma cruzi (T. cruzi) were measured using a quantitative polymerase chain reaction (qPCR) test. The primary composite outcome (CO) was all‐cause mortality, cardiac transplantation and implantation of a left ventricular assist device. Secondary outcomes were the baseline levels of serum biomarkers and echocardiographic variables. Results: After a 2 years of follow‐up, the primary CO rate was 16%. A positive qPCR was not associated with a higher risk of the CO. However, when parasitaemia was evaluated by comparing tertiles (tertile 1: undetectable parasitaemia, tertile 2: low parasitaemia and tertile 3: high parasitaemia), a higher risk of the CO (HR 3.66; 95% CI 1.11–12.21) was evidenced in tertile 2. Moreover, patients in tertile 2 had significantly higher levels of high‐sensitivity troponin T and cystatin C and more frequently exhibited an ejection fraction <50%. Conclusion: Low parasitaemia was associated with severity markers of myocardial injury and a higher risk of the composite outcome when compared with undetectable parasitaemia. This finding could be hypothetically explained by a more vigorous immune response in patients with low parasitaemia that could decrease T. cruzi load more efficiently, but be associated with increased myocardial damage. Additional studies with a larger number of patients and cytokine measurement are required to support this hypothesis. [ABSTRACT FROM AUTHOR]

Background: Chagas disease (CD) is a major public health concern in Latin America and a potentially serious emerging threat in non-endemic countries. Although the association between CD and cardiac abnormalities is widely reported, study design diversity, sample size and quality challenge the information, calling for its update and synthesis, which would be very useful and relevant for physicians in non-endemic countries where health care implications of CD are real and neglected. We performed to systematically review and meta-analyze population-based studies that compared prevalence of overall and specific ECG abnormalities between CD and non-CD participants in the general population. Methods: Six databases (EMBASE, Ovid Medline, Web of Science, Cochrane Central, Google Scholar and Lilacs) were searched systematically. Observational studies were included. Odds ratios (OR) were computed using random-effects model. Results: Forty-nine studies were selected, including 34,023(12,276 CD and 21,747 non-CD). Prevalence of overall ECG abnormalities was higher in participants with CD (40.1%; 95%CIs=39.2-41.0) compared to non-CD (24.1%; 95%CIs=23.5-24.7) (OR=2.78; 95%CIs=2.37-3.26). Among specific ECG abnormalities, prevalence of complete right bundle branch block (RBBB) (OR=4.60; 95%CIs=2.97-7.11), left anterior fascicular block (LAFB) (OR=1.60; 95%CIs=1.21-2.13), combination of complete RBBB/LAFB (OR=3.34; 95%CIs=1.76-6.35), first-degree atrioventricular block (A-V B) (OR=1.71; 95%CIs=1.25-2.33), atrial fibrillation (AF) or flutter (OR=2.11; 95%CIs=1.40-3.19) and ventricular extrasystoles (VE) (OR=1.62; 95%CIs=1.14-2.30) was higher in CD compared to non-CD participants. Conclusions: This systematic review and meta-analysis provides an update and synthesis in this field. This research of observational studies indicates a significant excess in prevalence of ECG abnormalities (40.1%) related to T. cruzi infection in the general population from Chagas endemic regions, being the most common ventricular (RBBB and LAFB), and A-V B (first-degree) node conduction abnormalities as well as arrhythmias (AF or flutter and VE). Also, prevalence of ECG alterations in children was similar to that in adults and suggests earlier onset of cardiac disease. [ABSTRACT FROM AUTHOR]

Background/objectives Up 30 to 40% of Chagas patients exhibit cardiomyopathy with different degrees of cardiac involvement. Biomarkers may help in differentiation of the severity of Chagas cardiomyopathy (CCM). This study sought to examine the diagnostic value of a panel of biomarkers to distinguish the severity of (CCM). Methods 100 patients with CCM were included in this cross-sectional study. Based on electrocardiogram and echocardiogram, CCM patients were classified in three stages according to disease's severity. Levels of high-sensitivity cardiac troponin T (Hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), soluble ST2 (sST2) and cystatin-c (Cys-c) were measured. Logistic regression models were used to assess the association between levels of natural log-transformed values of biomarkers and stages C/D versus B. We also calculated the area under curve (AUC) for each of the models. Results In models adjusted for age, sex, body mass index, kidney function and medication use, increased levels of NT-proBNP (per 1 unit natural log-transformed values, odds ratio (OR) = 5.55; 95CI%:1.65–18.72) and Hs-cTnT (per 1 unit natural log-transformed values, OR = 7.11; 95CI%:1.41–35.90) showed significant association with the severity of CCM per 1 unit increase of biomarkers. The accuracy of NT-proBNP and Hs-cTnT for diagnosis of the severity of CCM was high: AUC of 0.968 and 0.956 respectively. No significant difference was found in the AUC between NT-proBNP and Hs-cTnT. No association was found between Gal-3, NGAL, sST2 and Cys-C and severity of CCM. Conclusions NT-proBNP and Hs-cTnT have both same diagnostic value in distinguishing severity of CCM. [ABSTRACT FROM AUTHOR]

Background: Chronic Chagas cardiomyopathy (CCM) is ranked among heart failure etiologies with the highest mortality rates. CCM is characterized by alterations in left ventricular function with a typical and unique pattern of myocardial involvement. Left ventricle longitudinal speckle tracking strain is emerging as an important additive method for evaluating left ventricular function and risk of future cardiovascular events. This systematic review aimed to characterize the left ventricle (LV) longitudinal strain by speckle tracking patterns in the different stages of Chagas disease, compared to healthy controls. Methods: Searches in Medline, EMBASE, and LILACS databases (from inception to 20 May 2021) were performed. Articles written in any language that assessed patients with Chagas disease and reported any measures derived from the left ventricular strain by speckle tracking were included. Two reviewers independently selected the studies, extracted the data, and assessed the quality of evidence. Standardized mean differences (SMD) were pooled using random-effects meta-analyses. Results: Of 1044 references, ten studies, including a total of 1222 participants (CCM: 477; indeterminate form: 444; healthy controls: 301), fulfilled the selection criteria and were included in the final analysis. Patients with CCM had a significantly higher mean global longitudinal strain (GLS) value than indeterminate form (IF) patients (SMD 1.253; 95% CI 0.53, 1.98. I2 = 94%), while no significant difference was observed between IF patients and healthy controls (SMD 0.197; 95% CI −0.19, 0.59. I2 = 80%). Segmental strain analyses revealed that patients with the IF form of CD had significantly worse strain values in the basal-inferoseptal (SMD 0.49; 95% CI 0.24, 0.74. I2: 24%), and mid-inferoseptal (SMD 0.28; 95% CI 0.05, 0.50. I2: 10%) segments compared to healthy controls. Conclusions: Our results suggest different levels of functional derangements in myocardial function across different stages of Chagas disease. Further research is needed to assess the prognostic role of LV longitudinal strain and other measures derived from speckle tracking in CD patients regarding progression to cardiomyopathy and clinical outcomes prediction. [ABSTRACT FROM AUTHOR]