Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

The Effect of Omecamtiv Mecarbil in Hospitalized Patients as Compared With Outpatients With HFrEF: An Analysis of GALACTIC-HF.

BACKGROUND: In the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil, compared with placebo, reduced the risk of worsening heart failure (HF) events, or cardiovascular death in patients with HF and reduced ejection fraction. The primary aim of this prespecified analysis was to evaluate the safety and efficacy of omecamtiv mecarbil by randomization setting, that is, whether participants were enrolled as outpatients or inpatients. METHODS AND RESULTS: Patients were randomized either during a HF hospitalization or as an outpatient, within one year of a worsening HF event (hospitalization or emergency department visit). The primary outcome was a composite of worsening HF event (HF hospitalization or an urgent emergency department or clinic visit) or cardiovascular death. Of the 8232 patients analyzed, 2084 (25%) were hospitalized at randomization. Hospitalized patients had higher N-terminal prohormone of B-type natriuretic peptide concentrations, lower systolic blood pressure, reported more symptoms, and were less frequently treated with a renin-angiotensin system blocker or a beta-blocker than outpatients. The rate (per 100 person-years) of the primary outcome was higher in hospitalized patients (placebo group = 38.3/100 person-years) than in outpatients (23.1/100 person-years); adjusted hazard ratio 1.21 (95% confidence interval 1.12-1.31). The effect of omecamtiv mecarbil versus placebo on the primary outcome was similar in hospitalized patients (hazard ratio 0.89, 95% confidence interval 0.78-1.01) and outpatients (hazard ratio 0.94, 95% confidence interval 0.86-1.02) (interaction P = .51). CONCLUSIONS: Hospitalized patients with HF with reduced ejection fraction had a higher rate of the primary outcome than outpatients. Omecamtiv mecarbil decreased the risk of the primary outcome both when initiated in hospitalized patients and in outpatients.

Admixture mapping analysis reveals differential genetic ancestry associated with Chagas disease susceptibility in the Colombian population.

Chagas disease is an infection caused by the parasite Trypanosoma cruzi, endemic in Latino America. Leveraging the three-way admixture between Native American (AMR), European (EUR) and African (AFR) populations in Latin Americans, we aimed to better understand the genetic basis of Chagas disease by performing an admixture mapping study in a Colombian population. A two-stage study was conducted, and subjects were classified as seropositive and seronegative for T. cruzi. In stage 1, global and local ancestries were estimated using reference data from the 1000 Genomes Project (1KGP), and local ancestry associations were performed by logistic regression models. The AMR ancestry showed a protective association with Chagas disease within the major histocompatibility complex region [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.66-0.83, lowest P-value = 4.53 × 10-8]. The fine mapping assessment on imputed genotypes combining data from stage 1 and 2 from an independent Colombian cohort, revealed nominally associated variants in high linkage disequilibrium with the top signal (rs2032134, OR = 0.93, 95% CI = 0.90-0.97, P-value = 3.54 × 10-4) in the previously associated locus. To assess ancestry-specific adaptive signals, a selective sweep scan in an AMR reference population from 1KGP together with an in silico functional analysis highlighted the Tripartite Motif family and the human leukocyte antigen genes, with crucial role in the immune response against pathogens. Furthermore, these analyses emphasized the macrophages, neutrophils and eosinophils, as key players in the defense against T. cruzi. This first admixture mapping study in Chagas disease provided novel insights underlying the host immune response in the pathogenesis of this neglected disease.

Prevalence of Neutralizing Antibodies against Adeno-Associated Virus Serotypes 1, 2, and 9 in Non-Injected Latin American Patients with Heart Failure-ANVIAS Study.

Neutralizing antibody (NAb) activity against the viral capsid of adeno-associated viral (AAV) vectors decreases transduction efficiency, thus limiting transgene expression. Several reports have mentioned a variation in NAb prevalence according to age, AAV serotype, and, most importantly, geographic location. There are currently no reports specifically describing the anti-AAV NAb prevalence in Latin America. Here, we describe the prevalence of NAb against different serotypes of AAV vectors (AAV1, AAV2, and AAV9) in Colombian patients with heart failure (HF) (referred to as cases) and healthy individuals (referred to as controls). The levels of NAb were evaluated in serum samples of 60 subjects from each group using an in vitro inhibitory assay. The neutralizing titer was reported as the first dilution inhibiting ≥50% of the transgene signal, and the samples with neutralizing titers at ≥1:50 dilution were considered positive. The prevalence of NAb in the case and control groups were similar (AAV2: 43% and 45%, respectively; AAV1 33.3% in each group; AAV9: 20% and 23.2%, respectively). The presence of NAb for two or more of the serotypes analyzed was observed in 25% of the studied samples, with the largest amount in the positive samples for AAV1 (55-75%) and AAV9 (93%), suggesting serial exposures, cross-reactivity, or coinfection. Moreover, patients in the HF group exhibited more common combined seropositivity for NAb against AAV1 d AAV9 than those in the control group (91.6% vs. 35.7%, respectively; p = 0.003). Finally, exposure to toxins was significantly associated with the presence of NAb in all regression models. These results constitute the first report of the prevalence of NAb against AAV in Latin America, being the first step to implementing therapeutic strategies based on AAV vectors in this population in our region.

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

Survival after heart transplantation for Chagas cardiomyopathy using a conventional protocol: A 10-year experience in a single center.

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.

Circulating Trypanosoma cruzi load and major cardiovascular outcomes in patients with chronic Chagas cardiomyopathy: a prospective cohort study.

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.

OBJECTIFS: Analyser l'effet de la charge parasitaire évaluée par PCR quantitative de transcription inverse (RT-qPCR) dans le sérum sur le pronostic des patients atteints de cardiomyopathie chronique de Chagas (CCM) après un suivi de deux ans. MÉTHODES: Etude de cohorte prospective menée entre 2015 et 2017. Une centaine de patients atteints de CCM ont été inclus. Les niveaux de parasitémie basale de Trypanosoma cruzi (T. cruzi) ont été mesurés en utilisant un test de réaction en chaîne de la polymérase quantitative (qPCR). Le principal résultat composite (RC) était la mortalité toutes causes, la transplantation cardiaque et l'implantation d'un dispositif d'assistance ventriculaire gauche. Les critères secondaires étaient les niveaux de base des biomarqueurs sériques et des variables échocardiographiques. RÉSULTATS: Après 2 ans de suivi, le taux de RC primaire était de 16%. Une qPCR positive n'était pas associée à un risque plus élevé de RC. Cependant, lorsque la parasitémie était évaluée en comparant les tertiles (tertile 1: parasitémie indétectable, tertile 2: parasitémie faible et tertile 3: parasitémie élevée), un risque plus élevé de RC (HR: 3,66; IC95%: 1,11-12,21) a été mis en évidence dans le tertile 2. De plus, les patients du tertile 2 avaient des niveaux significativement plus élevés de troponine T et de cystatine-C à haute sensibilité et présentaient plus fréquemment une fraction d'éjection <50%. CONCLUSION: Une faible parasitémie était associée à des marqueurs de sévérité des lésions myocardiques et à un risque plus élevé de résultat composite par rapport à une parasitémie indétectable. Cette découverte pourrait être hypothétiquement expliquée par une réponse immunitaire plus vigoureuse chez les patients présentant une faible parasitémie qui pourrait diminuer la charge de T. cruzi plus efficacement mais être associée à une augmentation des lésions myocardiques. Des études supplémentaires avec un plus grand nombre de patients et une mesure des cytokines sont nécessaires pour étayer cette hypothèse.

Echocardiographic parameters, speckle tracking, and brain natriuretic peptide levels as indicators of progression of indeterminate stage to Chagas cardiomyopathy.

BACKGROUND: Chronic Chagas cardiomyopathy (CCM) is characterized by a unique type of cardiac involvement. Few studies have characterized echocardiographic (Echo) transitions from the indeterminate Chagas disease (ChD) form to CCM. The objective of this study was to identify the best cutoffs in multiple Echo parameters, speckle tracking, and N-terminal pro B-type natriuretic peptide (NT-proBNP) to distinguish patients without CCM (stage A) vs patients with myocardial involvement (stages B, C, or D). METHODS: Cross-sectional study conducted in 273 consecutive patients with different CCM stages. Echo parameters, NT-proBNP, and other clinical variables were measured. Logistic regression models (dichotomized in stage A versus B, C, and D) adjusted for age, sex, body mass index, and NT-proBNP were performed. RESULTS: Left ventricular global longitudinal strain (LV-GLS), mitral flow E velocity, LV mass index, and NT-proBNP identified early changes that differentiated stages A vs B, C, and D. The LV-GLS with a cutoff -20.5% showed the highest performance (AUC 92.99%; accuracy 84.56% and negative predictive value (NPV) 88.82%), which improved when it was additionally adjusted by NT-proBNP with a cutoff -20.0% (AUC 94.30%; accuracy 88.42% and NPV 93.55%). CONCLUSIONS: Our findings suggest that Echo parameters and NT-proBNP may be used as diagnostic variables in detecting the onset of myocardial alterations in patients with the indeterminate stage of ChD. LV-GLS was the more accurate measurement regarding stage A differentiation from the stages B, C, and D. Prospective longitudinal studies are needed to validate these findings.

Chagas Cardiomyopathy: An Update of Current Clinical Knowledge and Management: A Scientific Statement From the American Heart Association.

BACKGROUND: Chagas disease, resulting from the protozoan Trypanosoma cruzi, is an important cause of heart failure, stroke, arrhythmia, and sudden death. Traditionally regarded as a tropical disease found only in Central America and South America, Chagas disease now affects at least 300 000 residents of the United States and is growing in prevalence in other traditionally nonendemic areas. Healthcare providers and health systems outside of Latin America need to be equipped to recognize, diagnose, and treat Chagas disease and to prevent further disease transmission. METHODS AND RESULTS: The American Heart Association and the Inter-American Society of Cardiology commissioned this statement to increase global awareness among providers who may encounter patients with Chagas disease outside of traditionally endemic environments. In this document, we summarize the most updated information on diagnosis, screening, and treatment of T cruzi infection, focusing primarily on its cardiovascular aspects. This document also provides quick reference tables, highlighting salient considerations for a patient with suspected or confirmed Chagas disease. CONCLUSIONS: This statement provides a broad summary of current knowledge and practice in the diagnosis and management of Chagas cardiomyopathy. It is our intent that this document will serve to increase the recognition of Chagas cardiomyopathy in low-prevalence areas and to improve care for patients with Chagas heart disease around the world.

A systematic review and meta-analysis of mortality in chronic Chagas cardiomyopathy versus other cardiomyopathies: higher risk or fiction?

INTRODUCTION AND OBJECTIVES: Although multiple studies suggest that chronic Chagas cardiomyopathy (CCC) has higher mortality than other cardiomyopathies, the absence of meta-analyses supporting this perspective limits the possibility of generating robust conclusions. The aim of this study was to systematically evaluate the current evidence on mortality risk in CCC compared with that of other cardiomyopathies. METHODS: PubMed/Medline and EMBASE were searched for studies comparing mortality risk between patients with CCC and those with other cardiomyopathies, including in the latter nonischemic cardiomyopathy (NICM), ischemic cardiomyopathy, and non-Chagas cardiomyopathy (nonCC). A random-effects meta-analysis was performed to combine the effects of the evaluated studies. RESULTS: A total of 37 studies evaluating 17 949 patients were included. Patients with CCC had a significantly higher mortality risk compared with patients with NICM (HR, 2.04; 95%CI, 1.60-2.60; I2, 47%; 8 studies) and non-CC (HR, 2.26; 95%CI, 1.65-3.10; I2, 71%; 11 studies), while no significant association was observed compared with patients with ischemic cardiomyopathy (HR, 1.72; 95%CI, 0.80-3.66; I2, 69%; 4 studies) in the adjusted-measures meta-analysis. CONCLUSIONS: Patients with CCC have an almost 2-fold increased mortality risk compared with individuals with heart failure secondary to other etiologies. This finding highlights the need for effective public policies and targeted research initiatives to optimally address the challenges of CCC.

Impact of an online course on enhancing the diagnosis of Chagas disease in Latin America.

Objective: Chagas disease poses a public health problem in Latin America, and the electrocardiogram is a crucial tool in the diagnosis and monitoring of this pathology. In this context, the aim of this study was to quantify the change in the ability to detect electrocardiographic patterns among healthcare professionals after completing a virtual course. Materials and Methods: An asynchronous virtual course with seven pre-recorded classes was conducted. Participants answered the same questionnaire at the beginning and end of the training. Based on these responses, pre and post-test results for each participant were compared. Results: The study included 1656 participants from 21 countries; 87.9% were physicians, 5.2% nurses, 4.1% technicians, and 2.8% medical students. Initially, 3.1% answered at least 50% of the pre-test questions correctly, a proportion that increased to 50.4% after the course (p=0.001). Regardless of their baseline characteristics, 82.1% of course attendees improved their answers after completing the course. Conclusions: The implementation of an asynchronous online course on electrocardiography in Chagas disease enhanced the skills of both medical and non-medical personnel to recognize this condition.

Global, Regional, and National Trends of Chagas Disease from 1990 to 2019: Comprehensive Analysis of the Global Burden of Disease Study.

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.

Longitudinal Speckle Tracking Strain Abnormalities in Chagas Disease: A Systematic Review and Meta-Analysis.

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.

Circulating DHEA-S levels and major cardiovascular outcomes in chronic Chagas cardiomyopathy: A prospective cohort study.

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.

Circulating MicroRNAs and myocardial involvement severity in chronic Chagas cardiomyopathy.

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.

Sacubitril/Valsartan and Frailty in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Frailty is an increasingly common problem, and frail patients are less likely to receive new pharmacologic therapies because the risk-benefit profile is perceived to be less favorable than in nonfrail patients. OBJECTIVES: This study investigated the efficacy of sacubitril/valsartan according to frailty status in 4,796 patients with heart failure with preserved ejection fraction randomized in the PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. METHODS: Frailty was measured by using the Rockwood cumulative deficit approach. The primary endpoint was total heart failure hospitalizations or cardiovascular death. RESULTS: A frailty index (FI) was calculable in 4,795 patients. In total, 45.2% had class 1 frailty (FI ≤0.210, not frail), 43.5% had class 2 frailty (FI 0.211-0.310, more frail), and 11.4% had class 3 frailty (FI ≥0.311, most frail). There was a graded relationship between FI class and the primary endpoint, with a significantly higher risk associated with greater frailty (class 1: reference; class 2 rate ratio: 2.19 [95% CI: 1.85-2.60]; class 3 rate ratio: 3.29 [95% CI: 2.65-4.09]). The effect of sacubitril/valsartan vs valsartan on the primary endpoint from lowest to highest FI class (as a rate ratio) was: 0.98 [95% CI: 0.76-1.27], 0.92 [95% CI: 0.76-1.12], and 0.69 [95% CI: 0.51-0.95]), respectively (Pinteraction = 0.23). When FI was examined as a continuous variable, the interaction with treatment was significant for the primary outcome (Pinteraction = 0.002) and total heart failure hospitalizations (Pinteraction < 0.001), with those most frail deriving greater benefit. CONCLUSIONS: Frailty was common in heart failure with preserved ejection fraction and associated with worse outcomes. Compared with valsartan, sacubitril/valsartan seemed to show a greater reduction in the primary endpoint with increasing frailty, although this was not significant when FI was examined as a categorical variable. (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Coagulation disorders in Chagas disease: A pathophysiological systematic review and meta-analysis.

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.

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.

Cardiovascular Biomarkers and Diastolic Dysfunction in Patients With Chronic Chagas Cardiomyopathy.

Background: Chronic Chagas Cardiomyopathy is a unique form of cardiomyopathy, with a significantly higher mortality risk than other heart failure etiologies. Diastolic dysfunction (DD) plays an important role in the prognosis of CCM; however, the value of serum biomarkers in identifying and stratifying DD has been poorly studied in this context. We aimed to analyze the correlation of six biochemical markers with diastolic function echocardiographic markers and DD diagnosis in patients with CCM. Methods: Cross-sectional study of 100 adults with different stages of CCM. Serum concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), high-sensitivity troponin T (hs-cTnT), soluble (sST2), and cystatin-C (Cys-c) were measured. Tissue Doppler imaging was used to measure echocardiographic parameters indicating DD. Multivariate logistic regression models adjusted by age, sex, BMI, and NYHA classification were used to evaluate the association between the biomarkers and DD. Results: From the total patients included (55% male with a median age of 62 years), 38% had a preserved LVEF, but only 14% had a normal global longitudinal strain. Moreover, 64% had a diagnosis of diastolic dysfunction, with most of the patients showing a restrictive pattern (n = 28). The median levels of all biomarkers (except for sST2) were significantly higher in the group of patients with DD. Higher levels of natural log-transformed NTproBNP (per 1-unit increase, OR = 3.41, p < 0.001), Hs-cTnT (per 1-unit increase, OR = 3.24, p = 0.001), NGAL (per 1-unit increase, OR = 5.24, p =0.003), and Cys-C (per 1-unit increase, OR = 22.26, p = 0.008) were associated with increased odds of having diastolic dysfunction in the multivariate analyses. Finally, NT-proBNP had the highest AUC value (88.54) for discriminating DD presence. Conclusion: Cardiovascular biomarkers represent valuable tools for diastolic dysfunction assessment in the context of CCM. Additional studies focusing mainly on patients with HFpEF are required to validate the performance of these cardiovascular biomarkers in CCM, allowing for an optimal assessment of this unique population.

Cardiovascular biomarkers as predictors of adverse outcomes in chronic Chagas cardiomyopathy.

BACKGROUND: Chronic Chagas Cardiomyopathy (CCM) is a unique form of cardiomyopathy compared to other etiologies of heart failure. In CCM, risk prediction based on biomarkers has not been well-studied. We assessed the prognostic value of a biomarker panel to predict a composite outcome (CO), including the need for heart transplantation, use of left ventricular assist devices, and mortality. METHODS: Prospective cohort study of 100 adults with different stages of CCM. Serum concentrations of amino-terminal pro-B type natriuretic peptide (NT-proBNP), galectin-3 (Gal-3), neutrophil gelatinase-associated lipocalin (NGAL), high sensitivity troponin T (hs-cTnT), soluble (sST2), and cystatin-C (Cys-c) were measured. Survival analyses were performed using Cox proportional hazard models. RESULTS: During a median follow-up of 52 months, the mortality rate was 20%, while the CO was observed in 25% of the patients. Four biomarkers (NT-proBNP, hs-cTnT, sST2, and Cys-C) were associated with the CO; concentrations of NT-proBNP and hs-cTnT were associated with the highest AUC (85.1 and 85.8, respectively). Combining these two biomarkers above their selected cut-off values significantly increased risk for the CO (HR 3.18; 95%CI 1.31-7.79). No events were reported in the patients in whom the two biomarkers were under the cut-off values, and when both levels were above cut-off values, the CO was observed in 60.71%. CONCLUSION: The combination of NT-proBNP and hs-TnT above their selected cut-off values is associated with a 3-fold increase in the risk of the composite outcome among CCM patients. The use of cardiac biomarkers may improve prognostic evaluation of patients with CCM.