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.

Adherence to Treatment Guidelines in Ambulatory Heart Failure Patients with Reduced Ejection Fraction in a Latin-American Country: Observational Study of the Colombian Heart Failure Registry (RECOLFACA).

INTRODUCTION: Although several guidelines recommend that patients with heart failure with reduced ejection fraction (HFrEF) be treated with angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) or angiotensin receptor-neprilysin inhibitors (ARNIs), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 inhibitor (SGLT2i), there are still several gaps in their prescription and dosage in Colombia. This study aimed to describe the use patterns of HFrEF treatments in the Colombian Heart Failure Registry (RECOLFACA). METHODS: Patients with HFrEF enrolled in RECOLFACA during 2017-2019 were included. Heart failure (HF) medication prescription and daily dose were assessed using absolute numbers and proportions. Therapeutic schemes of patients treated by internal medicine specialists were compared with those treated by cardiologists. RESULTS: Out of 2,528 patients in the registry, 1,384 (54.7%) had HFrEF. Among those individuals, 88.9% were prescribed beta-blockers, 72.3% with ACEI/ARBs, 67.9% with MRAs, and 13.1% with ARNIs. Moreover, less than a third of the total patients reached the target doses recommended by the European HF guidelines. No significant differences in the therapeutic schemes or target doses were observed between patients treated by internal medicine specialists or cardiologists. CONCLUSION: Prescription rates and target dose achievement are suboptimal in Colombia. Nevertheless, RECOLFACA had one of the highest prescription rates of beta-blockers and MRAs compared to some of the most recent HF registries. However, ARNIs remain underprescribed. Continuous registry updates can improve the identification of patients suitable for ARNI and SGLT2i therapy to promote their use in clinical practice.

Clinical Characteristics and Outcomes of Patients with Heart Failure of Hypertensive Etiology: Analysis of Colombian Heart Failure Registry (RECOLFACA).

INTRODUCTION: Arterial hypertension represents one of the main comorbidities observed in patients with heart failure (HF) and one of the main risk factors for its development. Despite this, studies assessing this hypertensive etiology are scarce in Latin America. Our objective was to analyze the prevalence of HF of hypertensive etiology and evaluate its prognosis in patients enrolled in the Colombian Heart Failure Registry (RECOLFACA by its Spanish acronym). METHODS: RECOLFACA recruited adult patients diagnosed with HF in 60 centers in Colombia between 2017 and 2019. The primary outcome was all-cause mortality. A Cox proportional hazards regression model was used to assess factors associated with primary outcomes in patients with hypertensive HF. A p value <0.05 was considered significant. All statistical tests were two-tailed. RESULTS: Out of the total number of patients evaluated in RECOLFACA (n = 2,514), 804 had a diagnosis of HF with hypertensive etiology (31.9%). These patients were less frequently males and had a significantly older age and lower prevalence of comorbidities than those with HF of other etiologies. Additionally, patients with hypertensive HF had a higher prevalence of HF with preserved ejection fraction (HFpEF) (34.1% vs. 28.3%; p = 0.004). Finally, type 2 diabetes mellitus, chronic obstructive pulmonary disease diagnosis, and NYHA class IV were classified as independent mortality risk factors. CONCLUSIONS: Hypertensive HF represents about one-third of the total number of patients with HF in RECOLFACA. Compared with HF of other etiologies, it presents a differential clinical profile - older age and a higher prevalence of HFpEF. RECOLFACA has become a useful tool to characterize patients with HF in Colombia, with which it has been possible to carry out a more specific search and reach the diagnosis of this pathology in our population, and it has served as an example to stimulate registries of patients with HF in other countries in the region.

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.).

Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy.

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.

COVID-19 in Health-Care Workers: A Living Systematic Review and Meta-Analysis of Prevalence, Risk Factors, Clinical Characteristics, and Outcomes.

Health-care workers (HCWs) are at the frontline of response to coronavirus disease 2019 (COVID-19), being at a higher risk of acquiring the disease and, subsequently, exposing patients and others. Searches of 8 bibliographic databases were performed to systematically review the evidence on the prevalence, risk factors, clinical characteristics, and prognosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among HCWs. A total of 97 studies (all published in 2020) met the inclusion criteria. The estimated prevalence of SARS-CoV-2 infection from HCWs' samples, using reverse transcription-polymerase chain reaction and the presence of antibodies, was 11% (95% confidence interval (CI): 7, 15) and 7% (95% CI: 4, 11), respectively. The most frequently affected personnel were nurses (48%, 95% CI: 41, 56), whereas most of the COVID-19-positive medical personnel were working in hospital nonemergency wards during screening (43%, 95% CI: 28, 59). Anosmia, fever, and myalgia were the only symptoms associated with HCW SARS-CoV-2 positivity. Among HCWs positive for COVID-19 by reverse transcription-polymerase chain reaction, 40% (95% CI: 17, 65) were asymptomatic at time of diagnosis. Finally, severe clinical complications developed in 5% (95% CI: 3, 8) of the COVID-19-positive HCWs, and 0.5% (95% CI: 0.02, 1.3) died. Health-care workers suffer a significant burden from COVID-19, with those working in hospital nonemergency wards and nurses being the most commonly infected personnel.

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.

Evaluation of a pre-co-seasonal and a perennial schedule of a single multiallergen depigmented-polymerized subcutaneous immunotherapy in paediatric patients.

AIM: Compare a pre-co-seasonal with a perennial schedule using an undiluted mixture of a depigmented-polymerized grass/Olea europaea immunotherapy (2,000 DPP/mL) in pediatric patients with rhinitis/rhinoconjunctivitis with or without controlled asthma. MATERIAL AND METHODS: Primary objective was to determine the non-superiority of a perennial compared to a pre-co-seasonal schedule by means of Paediatric/Adolescent Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ/AdolRQLQ). Secondary objectives were Paediatric Asthma/Caregiver´s Quality of Life Questionnaire (PAQLQ/PACQLQ) Asthma Control Test (ACT), Visual Analogue Scale global assessment of allergic disease (VAS), use of resources and immunological response. All variables were compared during the pollen season (April-June) without (2015) and with (2016) immunotherapy. RESULTS: Forty patients were included in the study of which 29 patients were assigned to the perennial and 11 to the pre-co-seasonal schedule. During 2016 pollen season a significant improvement in the PRQLQ/AdolRQLQ, PAQLQ/AdolAQLQ, ACT and VAS score were observed both in perennial and pre-co-seasonal schedule group. No significant differences were seen between treatment schedules for PRQLQ/AdolRQLQ, PAQLQ/AdolAQLQ and ACT scores comparing both pollen seasons. A significant increase in sIgG4 and reduction in the number of rescue medications used and number of patients who needed visit to any specialist was observed in both treatment schedules during 2016 pollen season. No relevant differences were found in the safety profile of any treatment schedule. DISCUSSION: Treatment with undiluted mixture of a depigmented-polymerized Grass/Olea europaea allergen immunotherapy has proven to be effective both using a perennial and a pre-co-seasonal schedule and therefore suitable for polyallergic patients.

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.

Egg OIT in clinical practice (SEICAP II): Maintenance patterns and desensitization state after normalizing the diet.

BACKGROUND: It is unknown which are the most suitable maintenance pattern and egg consumption to maintain the desensitization state after ending the oral immunotherapy (OIT). This multicenter, randomized, controlled trial compared two OIT maintenance patterns with pasteurized egg white (PEW), evaluating the egg consumption effect on the desensitization state after ending the OIT. METHODS: One hundred and one children with confirmed egg allergy were randomized: 25 to an egg-free diet (CG) and 76 to an OIT year with PEW and two maintenance patterns, 38 patients to daily 3.3 g proteins (AG) and 38 to every two days (BG). PEW challenge (DBPCFC), adverse reactions, and immune markers were assessed at baseline, at the end of the OIT, and at 6 and 12 months later on ad libitum egg consumption (T0, T12, T18, and T24). A questionnaire evaluated the egg consumption at T18. RESULTS: At T12, 64 of 76 (84.21%) OIT patients had reached total desensitization (32 AG and 32 BG) vs 4 of 25 (16.00%) CG who passed the PEW DBPCFC. Thirty (93.75%) AG vs 25 (78.12%) BG patients completed an OIT year. At T18, 27 of 29 (93.1%) AG vs 20 of 24 (83.3%) BG passed the PEW DBPCFC, 96% consuming at least two egg servings/week. At T24, 97.43% OIT patients passed the challenge. Most patients had adverse reactions, more frequent in the BG patients; frequency and severity of reactions decreased through the study. PEW skin prick test wheal and sIgE antibody serum levels similarly decreased in AG or BG, but AG patients had greater increase in PEW sIgG4 (P < 0.05). CONCLUSIONS: Daily OIT maintenance achieves better adherence, effectiveness, and safety. Two egg servings/week ensure maintained desensitization after the end of an OIT year.

Egg oral immunotherapy in children (SEICAP I): Daily or weekly desensitization pattern.

BACKGROUND: Studies are required before incorporating egg oral immunotherapy (OIT) into clinical practice. The Spanish Society of Pediatric Allergy, Asthma and Clinical Immunology (SEICAP) conducted a multicenter, randomized controlled study assessing the effectiveness and safety of the OIT using pasteurized egg white (PEW) in egg-allergic children. METHODS: One hundred and one egg-allergic children (6-9 years) were randomized for 1 year: 25 to an egg-free-diet (CG) and 76 to OIT (target dose 3.3 g PEW proteins), PI (30% weekly plus 5% daily increments) or PII (only 30% weekly increments) buildup patterns. Egg skin prick test, sIgE and sIgG4 serum levels, PEW double-blind placebo-controlled food challenge (DBPCFC), and dosing adverse reactions (DARs) were evaluated in all patients from inclusion (T0) until completing 1 year of follow-up (T12). At T12, egg-allergic control patients could start OIT. The effectiveness and safety of OIT and the effect of the buildup pattern were analyzed. RESULTS: At T12, 4/25 (16.0%) CG patients passed the PEW DBPCFC vs 64/76 (84.2%) OIT that reached total desensitization (P = 0.000); 12 egg-allergic control patients started OIT. Finally, 72/88 (81.81%) patients reached total desensitization, 96.15% PI vs 75.80% on PII (P = 0.01). Induction period (121.12 ± 91.43, median 98.00 days) was longer in patients on PII buildup pattern, and those with allergic asthma, minor threshold dose, or higher egg sIgE (P < 0.05). Most patients (89.06%) developed DARs: 74.53% were mild; 21.90% moderate; and 3.5% requiring adrenaline-treatment. Moderate reactions and those requiring adrenaline were more frequent in patients with allergic asthma, PII pattern, or higher egg sIgE serum antibody levels (P < 0.05). CONCLUSIONS: PEW OIT is an effective treatment for children with persistent egg allergy. A 30% weekly plus 5% daily increment pattern could be more effective and safer than one with only 30% weekly increments.

CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis.

OBJECTIVE: Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). METHODS: Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. RESULTS: Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C1917 (P = 0.35). In children who received a PPI dose between ≥1.54 and ≤2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C1917 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C1917 OR [95% CI] = 8.19[1.42, 50.57], P = 0.023). CONCLUSIONS: Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.

Long-term Treatment With Proton Pump Inhibitors Is Effective in Children With Eosinophilic Esophagitis.

OBJECTIVES: Proton pump inhibitor (PPI)-responsive eosinophilic esophagitis (EoE) is frequently observed in children, but data on long-term treatment are scarce. The objective of this study is to evaluate the long-term efficacy and safety of PPIs in children with EoE. METHODS: This prospective study enrolled children with EoE and histological remission to an 8-week esomeprazole trial (1 mg/kg/dose, twice daily). Esomeprazole was maintained at 1 mg/kg/day for 1 year. Symptom recurrence and adverse events were monitored and a follow-up endoscopy was performed at 12 months. Complete histological remission was defined as ≤5 eosinophils/high-power field (eos/hpf), and partial histological remission as >5 and <15 eos/hpf. Patients had no concomitant dietary restrictions or topical steroid. RESULTS: Fifty-seven children were included. Histological remission on maintenance PPI therapy was present in 40 children (70.1%; 95% CI 56.5-81.5). Long-term remission rate was higher in children with initial complete histological remission than in those with partial remission (81% vs 50%, P = 0.014). Forty-nine children (86%) remained asymptomatic. Pretreatment clinical and histological findings and median PPI dose/kg/day were similar between relapsers and nonrelapsers. Eleven out of 12 children (91.6%) receiving esomeprazole 0.5 mg ·â€Škg ·â€Š day for 12 additional months remained in remission. Mild and transient side effects without requiring PPI avoidance were observed in 5 children. CONCLUSIONS: Up to 70% of children with PPI-responsive EoE remain in histological and clinical remission on a low-dose maintenance treatment at 1-year follow-up, with adequate safety profile. Complete histological remission to an 8-week PPI trial was associated with higher probability of histological remission on maintenance therapy.