Racial and Ethnic Differences in the Clinical Diagnosis of Aortic Stenosis.

Background Racial and ethnic minority groups are underrepresented among patients undergoing aortic valve replacement in the United States. We evaluated the impact of race and ethnicity on the diagnosis of aortic stenosis (AS). Methods and Results In patients with transthoracic echocardiography (TTE)-confirmed AS, we assessed rates of AS diagnosis as defined by assignment of an International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) code for AS within a large multicenter electronic health record. Multivariable Cox proportional hazard and competing risk regression models were used to evaluate the 1-year rate of AS diagnosis by race and ethnicity. Among 14 800 patients with AS, the 1-year diagnosis rate for AS following TTE was 37.4%. Increasing AS severity was associated with an increased likelihood of receiving an AS diagnosis (moderate: hazard ratio [HR], 3.05 [95% CI, 2.86-3.25]; P<0.0001; severe: HR, 4.82 [95% CI, 4.41-5.28]; P<0.0001). Compared with non-Hispanic White, non-Hispanic Black (HR, 0.65 [95% CI, 0.54-0.77]; P<0.0001) and non-Hispanic Asian individuals (HR, 0.72 [95% CI, 0.57-0.90], P=0.004) were less likely to receive a diagnosis of AS. Additional factors associated with a decreased likelihood of receiving an AS diagnosis included a noncardiology TTE ordering provider (HR, 0.92 [95% CI, 0.86-0.97]; P=0.005) and TTE performed in the inpatient setting (HR, 0.72 [95% CI, 0.66-0.78]; P<0.0001). Conclusions Rates of receiving an ICD diagnostic code for AS following a diagnostic TTE are low and vary significantly by race and ethnicity and disease severity. Further studies are needed to determine if efforts to maximize the clinical recognition of TTE-confirmed AS may help to mitigate disparities in treatment.

Caracterización clínica y tratamiento de pacientes con fibrilación auricular

Introducción: La fibrilación auricular o atrial fue considerada durante mucho tiempo como una alternativa al ritmo sinusal y es en la actualidad un serio problema de salud en muchos países del mundo, a la cual se le asocian muchos factores de riesgo como la insuficiencia cardiaca, la hipertensión arterial y la diabetes mellitus. Es la arritmia más prevalente en la práctica clínica. Objetivo: Caracterizar a la fibrilación auricular en cuanto a sus manifestaciones clínicas y tratamiento. Desarrollo: Se realizó una revisión bibliográfica de artículos publicados desde 2010 hasta 2020. Se consultaron las bases de datos SciELO, EBSCO, PubMed/Medline, Dialnet y revistas de acceso abierto, se emplearon los descriptores fibrilación auricular, arritmia supraventricular y mecanismos de reentrada, en idioma español e inglés. Se seleccionaron 25 referencias las cuales incluyen artículos científicos, anuario estadístico y guías de práctica clínica. En la literatura consultada se señaló que la fibrilación auricular es una arritmia supraventricular que se observa electrocardiográficamente como oscilaciones basales de baja amplitud con un ritmo ventricular irregular, que se produce por mecanismos de reentrada únicos o múltiples que generan una conducción eléctrica desordenada y generalmente se manifiesta por palpitaciones, fatiga y disnea, aunque pudiera ser asintomática. Conclusiones: Se constata que esta arritmia posee un cuadro clínico y electrocardiográfico reconocido y ampliamente estudiado. Se describen diversas clasificaciones y mecanismos fisiopatológicos, de acuerdo con sus etiologías. Los métodos diagnósticos y terapéuticos se encuentran en constante desarrollo y perfeccionamiento.

Introduction: Atrial fibrillation was considered for decades as an alternative for sinus rhythm and nowadays it is a severe health problem in many countries of the world associated with some risks factors as cardiac insufficiency, hypertension and diabetes mellitus. It is the most common type of arrhythmia in clinic marks. Objective: Characterize atrial fibrillation in terms of its clinical manifestations and treatment. Development: A bibliographical review was made on published articles from 2010 to 2020. Data Bases like SciELO, EBSCO, PubMed/Medline, Dialnet and open-access magazines were consulted, using the descriptive words atrial fibrillation, supraventricular arrhythmia and reentrance mechanisms for English and Spanish languages. A total of 28 references were selected. In the literature was checked that atrial fibrillation is a supraventricular arrhythmia that can be identified on electrocardiogram by low-amplitude basalts oscillations with an irregular ventricular rhythm. It is produced by unique or multiple reentrance mechanisms that generate a disordered electrical conduction and usually it is accompanied with palpitations, fatigue and dyspnea, but it could also be asymptomatic. Conclusions: Atrial fibrillation has studied clinical signs and treatment is oriented in four directions; frequency controlling, rhythm controlling, thromboembolism prevention and risks factors management.

Patient- and Process-Related Contributors to the Underuse of Aortic Valve Replacement and Subsequent Mortality in Ambulatory Patients With Severe Aortic Stenosis.

Background Many patients with severe aortic stenosis (AS) and an indication for aortic valve replacement (AVR) do not undergo treatment. The reasons for this have not been well studied in the transcatheter AVR era. We sought to determine how patient- and process-specific factors affected AVR use in patients with severe AS. Methods and Results We identified ambulatory patients from 2016 to 2018 demonstrating severe AS, defined by aortic valve area [Formula: see text]1.0 cm2. Propensity scoring analysis with inverse probability of treatment weighting was used to evaluate associations between predictors and the odds of undergoing AVR at 365 days and subsequent mortality at 730 days. Of 324 patients with an indication for AVR (79.3±9.7 years, 57.4% men), 140 patients (43.2%) did not undergo AVR. The odds of AVR were reduced in patients aged >90 years (odds ratio [OR], 0.24 [95% CI, 0.08-0.69]; P=0.01), greater comorbid conditions (OR, 0.88 per 1-point increase in Combined Comorbidity Index [95% CI, 0.79-0.97]; P=0.01), low-flow, low-gradient AS with preserved left ventricular ejection fraction (OR, 0.11 [95% CI, 0.06-0.21]), and low-gradient AS with reduced left ventricular ejection fraction (OR, 0.18 [95% CI, 0.08-0.40]) and were increased if the transthoracic echocardiogram ordering provider was a cardiologist (OR, 2.46 [95% CI, 1.38-4.38]). Patients who underwent AVR gained an average of 85.8 days of life (95% CI, 40.9-130.6) at 730 days. Conclusions The proportion of ambulatory patients with severe AS and an indication for AVR who do not receive AVR remains significant. Efforts are needed to maximize the recognition of severe AS, especially low-gradient subtypes, and to encourage patient referral to multidisciplinary heart valve teams.

Comparison of Transvalvular Aortic Mean Gradients Obtained by Intraprocedural Echocardiography and Invasive Measurement in Balloon and Self-Expanding Transcatheter Valves.

Background Concerns about discordance between echocardiographic and invasive mean gradients after transcatheter aortic valve replacement (TAVR) with balloon-expandable valves (BEVs) versus self-expanding valves (SEVs) exist. Methods and Results In a multicenter study, direct-invasive and echocardiography-derived transvalvular mean gradients obtained before and after TAVR were compared as well as post-TAVR and discharge echocardiographic mean gradients in BEVs versus SEVs in 808 patients. Pre-TAVR, there was good correlation (R=0.614; P<0.0001) between direct-invasive and echocardiography-derived mean gradients and weak correlation (R=0.138; P<0.0001) post-TAVR. Compared with post-TAVR echocardiographic mean gradients, both valves exhibit lower invasive and higher discharge echocardiographic mean gradients. Despite similar invasive mean gradients, a small BEV exhibits higher post-TAVR and discharge echocardiographic mean gradients than a large BEV, whereas small and large SEVs exhibit similar post-TAVR and discharge mean gradients. An ejection fraction <50% (P=0.028) and higher Society of Thoracic Surgeons predicted risk of mortality score (P=0.007), but not invasive or echocardiographic mean gradient ≥10 mm Hg (P=0.378 and P=0.341, respectively), nor discharge echocardiographic mean gradient ≥20 mm Hg (P=0.393), were associated with increased 2-year mortality. Conclusions Invasively measured and echocardiography-derived transvalvular mean gradients correlate well in aortic stenosis but weakly post-TAVR. Post-TAVR, echocardiography overestimates transvalvular mean gradients compared with invasive measurements, and poor correlation suggests these modalities cannot be used interchangeably. Moreover, echocardiographic mean gradients are higher on discharge than post-TAVR in all valves. Despite similar invasive mean gradients, a small BEV exhibits higher post-TAVR and discharge echocardiographic mean gradients than a large BEV, whereas small and large SEVs exhibit similar post-TAVR and discharge mean gradients. Immediately post-TAVR, elevated echocardiographic-derived mean gradients should be assessed with caution and compared with direct-invasive mean gradients. A low ejection fraction and higher Society of Thoracic Surgeons score, but not elevated mean gradients, are associated with increased 2-year mortality.

Association Between Angiotensin Receptor-Neprilysin Inhibition, Cardiovascular Biomarkers, and Cardiac Remodeling in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain. METHODS: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index. RESULTS: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m2, respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged -27.9% (95% CI, -35.1% to -20.7%; P<0.001) for NT-proBNP; -6.7% (95% CI, -8.8% to -4.7%; P<0.001) for hs-cTnT; and -1.6% (95% CI, -2.9% to -0.4%; P<0.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in left ventricular ejection fraction and left atrial volume index. There was no association between changes in sST2 and changes in other measures. CONCLUSIONS: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Perception channels and cognitive styles: opponents, followers or learning allies?

This article presents the findings in the process of evaluating the relationship between perception channels and cognitive styles, from the analysis of conceptions over time and their involvement. Establishing through an experiment, and applying two didactic strategies, the associations with learning. Channels are characterized with VAK, Styles with CHAEA, and Performance with a pre-test/post-test design. It was shown that channels and styles are allies that independently encourage the teaching-learning process. Outcome shows that people with multiple channels and styles develop more skills, achieving better results. Games as ludic activities stimulate all channels, and favor the construction of knowledge, thus improving performance with positive differences in p-values between 0.014 and 0.022.

Plasma Soluble Suppression of Tumorigenicity-2 Associates with Ventilator Liberation in Acute Hypoxemic Respiratory Failure.

Rationale: Standard physiologic assessments of extubation readiness in patients with acute hypoxemic respiratory failure (AHRF) may not reflect lung injury resolution and could adversely affect clinical decision-making and patient outcomes. Objectives: We hypothesized that elevations in inflammatory plasma biomarkers sST2 (soluble suppression of tumorigenicity-2) and IL-6 indicate ongoing lung injury in AHRF and better inform patient outcomes compared with standard clinical assessments. Methods: We measured daily plasma biomarkers and physiologic variables in 200 patients with AHRF for up to 9 days after intubation. We tested the associations of baseline values with the primary outcome of unassisted breathing at Day 29. We analyzed the ability of serial biomarker measurements to inform successful ventilator liberation. Measurements and Main Results: Baseline sST2 concentrations were higher in patients dead or mechanically ventilated versus breathing unassisted at Day 29 (491.7 ng/ml [interquartile range (IQR), 294.5-670.1 ng/ml] vs. 314.4 ng/ml [IQR, 127.5-550.1 ng/ml]; P = 0.0003). Higher sST2 concentrations over time were associated with a decreased probability of ventilator liberation (hazard ratio, 0.80 per log-unit increase; 95% confidence interval [CI], 0.75-0.83; P = 0.03). Patients with higher sST2 concentrations on the day of liberation were more likely to fail liberation compared with patients who remained successfully liberated (320.9 ng/ml [IQR, 181.1- 495.6 ng/ml] vs. 161.6 ng/ml [IQR, 95.8-292.5 ng/ml]; P = 0.002). Elevated sST2 concentrations on the day of liberation decreased the odds of successful liberation when adjusted for standard physiologic parameters (odds ratio, 0.325; 95% CI, 0.119-0.885; P = 0.03). IL-6 concentrations did not associate with outcomes. Conclusions: Using sST2 concentrations to guide ventilator management may more accurately reflect underlying lung injury and outperform traditional measures of readiness for ventilator liberation.

Reverse Cardiac Remodeling Following Initiation of Sacubitril/Valsartan in Patients With Heart Failure With and Without Diabetes.

OBJECTIVE: This study sought to determine whether patients with heart failure and reduced ejection fraction (HFrEF) with type 2 diabetes mellitus (T2DM) have similar reverse cardiac remodeling with sacubitril/valsartan as patients without T2DM. BACKGROUND: Sacubitril/valsartan promotes reverse cardiac remodeling and improves outcomes in patients with HFrEF. Patients with HFrEF with T2DM have worse prognosis than those without T2DM. METHODS: In this post hoc analysis of PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure), we examined changes in N-terminal pro-b-type natriuretic peptide (NT-proBNP), measures of cardiac remodeling, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) scores from baseline to 12 months following initiation of sacubitril/valsartan between patients with HFrEF with and without T2DM. Using latent growth curve modeling, we evaluated the longitudinal association between changes in NT-proBNP, left ventricular ejection fraction, and KCCQ-OS. RESULTS: Among 794 patients enrolled, 361 (45.5%) had T2DM. NT-proBNP concentrations were modestly higher at baseline among patients with T2DM but were reduced after initiation of sacubitril/valsartan. Cross-sectional improvement was observed in left ventricular ejection fraction (T2DM: 28.3% at baseline and 37% at 12 months vs. non-T2DM: 28.1% at baseline and 38.3% at 12 months) and KCCQ-OS (T2DM: 71 at baseline and 83 at 12 months vs. non-T2DM: 76 at baseline and 88 at 12 months). Similar changes were also observed for other echocardiographic measures. In longitudinal analyses, the average NT-proBNP change was similar in patients with T2DM (-5.6% vs. -7.1% per 90-day interval; p = 0.64), whereas improvements in KCCQ-OS scores were slightly smaller (2.1 vs. 3.46 per 90-day interval; p = 0.07). CONCLUSIONS: Sacubitril/valsartan favorably affects natriuretic peptide levels, reverse cardiac remodeling, and health status in patients with HFrEF with and without T2DM. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Improvement of Health Status Following Initiation of Sacubitril/Valsartan in Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Treatment of heart failure with reduced ejection fraction (EF) may improve patient-reported health outcomes. OBJECTIVES: The purpose of this study was to determine timing and magnitude of change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores following initiation of sacubitril/valsartan and interaction with change in amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations. METHODS: From a single-arm, open-label study of patients initiated on sacubitril/valsartan, KCCQ-23 scores and NT-proBNP were obtained at baseline and follow-up through 12 months. Cross-sectional and longitudinal analyses evaluated magnitude and rate of change in KCCQ-23 scores and associations with NT-proBNP. Patient-level data from the randomized EVALUATE-HF study were used as historic controls. RESULTS: The analysis cohort (n = 678, age 64.7 years, 71.5% men, EF 28.9%) had a baseline KCCQ-23 overall score (OS) of 65.6. Following sacubitril/valsartan initiation, the majority (n = 412; 60.8%) of participants experienced a rise in KCCQ-23 OS ≥10 points; 26.0% increased by ≥20 points. Comparable improvement in KCCQ-23 scores was seen in various subgroups. Change in KCCQ-23 OS was inversely associated with change in circulating NT-proBNP concentrations. Among a control group of patients in EVALUATE-HF, linear rate of change in KCCQ-12 OS/14-day interval in the enalapril arm was 0.37 points (p = 0.06), whereas in the sacubitril/valsartan arm, scores increased at a rate of 1.19 points (p < 0.001), nearly identical to this dataset (1.08 points; p < 0.001). CONCLUSIONS: Treatment of heart failure with reduced EF with sacubitril/valsartan is associated with rapid and significant improvement in KCCQ-23 scores which was significantly related to change in NT-proBNP. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction.

OBJECTIVES: This study sought to assess associations between longitudinal change in atrial natriuretic peptide (ANP) and reverse cardiac remodeling following initiation of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Neprilysin inhibition results in an increase of several vasoactive peptides that may mediate the beneficial effects of sacubitril/valsartan, including ANP. METHODS: In a prospective study of initiation and titration of sacubitril/valsartan in patients with HFrEF, blood was collected at scheduled time points into tubes containing protease inhibitors. This pre-specified exploratory analysis included patients in whom ANP was measured at baseline and serially through 12 months of treatment. RESULTS: Among 144 participants (mean age: 64.5 years; left ventricular ejection fraction: 30.8%), following initiation of sacubitril/valsartan, there was an early and significant increase in ANP, with the majority of rise from 99 pg/ml at baseline to 156 pg/ml at day 14 (p < 0.001). There was a further trend toward a second increase from day 30 to day 45 (p = 0.07). At maximal rise, ANP had doubled. In longitudinal analyses, early rise in ANP was followed by a subsequent increase in urinary cycle guanosine monophosphate. Larger early increase in ANP was associated with larger later improvements in left ventricular ejection fraction and left atrial volume index (p < 0.001 for both). CONCLUSIONS: Concentrations of ANP doubled after initiation of sacubitril/valsartan in patients with HFrEF. Larger early increases in ANP were associated with a greater magnitude of subsequent reverse cardiac remodeling. (Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes [PROVE-HF]; NCT02887183).

Racial and Ethnic Differences in Biomarkers, Health Status, and Cardiac Remodeling in Patients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan.

BACKGROUND: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking. METHODS: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling. RESULTS: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (g=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (g<0.10). Following S/V initiation, NT-proBNP decreased in all 3 groups (P<0.0001) associated with improvements in LV ejection fraction, LV end-diastolic volume index, and LV end-systolic volume index. Although total improvement in LV measures was similar between groups, Black patients averaged larger gains in the first half of the trial while White patients averaged larger gains in the second half. Improvements in Kansas City Cardiomyopathy Questionnaire-23 Total Symptom scores were seen in all 3 groups. Treatment with S/V was well-tolerated. CONCLUSIONS: Among Black, Hispanic, and White patients with heart failure and reduced ejection fraction, treatment with S/V was associated with similar reduction in NT-proBNP, improvement in health status, and reverse remodeling. More data regarding racial and ethnic responses to heart failure and reduced ejection fraction treatment are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Sex-based differences in biomarkers, health status, and reverse cardiac remodelling in patients with heart failure with reduced ejection fraction treated with sacubitril/valsartan.

AIMS: We sought to determine sex-based differences in biomarkers, self-reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). METHODS AND RESULTS: This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE-HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P < 0.001) and faster pace of KCCQ change (P < 0.001) over the course of the trial. Women and men demonstrated similar degrees of reverse left ventricular remodelling following S/V initiation; however, women did so earlier than men with more consistent changes. These results remained unchanged with adjustment for relevant covariates. Reduction in NT-proBNP was associated with reverse cardiac remodelling in both women and men. Treatment with S/V was well tolerated in all. CONCLUSIONS: In women with HFrEF, treatment with S/V was associated with significant NT-proBNP reduction, health status improvement and reverse cardiac remodelling.

Proteomic Signatures During Treatment in Different Stages of Heart Failure.

BACKGROUND: Proteomics have already provided novel insights into the pathophysiology of heart failure (HF) with reduced ejection fraction. Previous studies have evaluated cross-sectional protein signatures of HF, but few have characterized proteomic changes following HF with reduced ejection fraction treatment with ARNI (angiotensin receptor/neprilysin inhibitor) therapy or left ventricular assist devices. METHODS: In this retrospective omics study, we performed targeted proteomics (N=625) of whole blood sera from patients with American College of Cardiology/American Heart Association stage D (N=29) and stage C (N=12) HF using proximity extension assays. Samples were obtained before and after (median=82 days) left ventricular assist device implantation (stage D; primary analysis) and ARNI therapy initiation (stage C; matched reference). Oblique principal component analysis and point biserial correlations were used for feature extraction and selection; standardized mean differences were used to assess within and between-group differences; and enrichment analysis was used to generate and cluster Gene Ontology terms. RESULTS: Core sets of proteins were identified for stage C (N=9 proteins) and stage D (N=18) HF; additionally, a core set of 5 shared HF proteins (NT-proBNP [N-terminal pro-B type natriuretic peptide], ESM [endothelial cell-specific molecule]-1, cathepsin L1, osteopontin, and MCSF-1) was also identified. For patients with stage D HF, moderate (δ, 0.40-0.60) and moderate-to-large (δ, 0.60-0.80) sized differences were observed in 8 of their 18 core proteins after left ventricular assist devices implantation. Additionally, specific protein groups reached concentration levels equivalent (g<0.10) to stage C HF after initiation on ARNI therapy. CONCLUSIONS: HF with reduced ejection fraction severity associates with distinct proteomic signatures that reflect underlying disease attributes; these core signatures may be useful for monitoring changes in cardiac function following initiation on ARNI or left ventricular assist device implantation.

Natriuretic Peptides as Inclusion Criteria in Clinical Trials: A JACC: Heart Failure Position Paper.

This study investigated the use of natriuretic peptides as inclusion criteria and to develop recommendations regarding their use. B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are commonly used as inclusion criteria for heart failure (HF) clinical trials, but no consensus exists regarding their optimal use for this purpose. A comprehensive search of the Aggregate Analysis of ClincalTrials.gov database identified 3,446 HF trials. Of these, 365 recently completed or ongoing HF clinical trials (10.6%) used either BNP or NT-proBNP as inclusion criteria. A panel of experts discussed current practices and a path forward for the use of natriuretic peptides as inclusion criteria for HF trials. Significant variations existed across trials regarding which natriuretic peptide and which cutoff value were used. Overall, 43% used both natriuretic peptides, 33% used only NT-proBNP, and 24% used only BNP in determining eligibility. Studies using BNP and NT-proBNP concentrations as inclusion criteria had higher cardiovascular event rates and higher concentrations for study entry and were generally associated with higher event rates. Areas of uncertainty included use in certain patient populations in which natriuretic peptides are historically lower (e.g., black patients, obese patients, patients with HF with preserved ejection fraction) or higher (older patients, patients with atrial fibrillation). This paper discusses best practices regarding use of BNP or NT-proBNP in clinical trials and identification of gaps in medical literature, including importance of documentation in ClinicalTrials.gov studies to inform future research efforts.

Primeros dos años de notificación de las enfermedades huérfanas-raras en Cali e identificación de algunas variables asociadas con la mortalidad / First 2 years of municipal registry of orphan-rare diseases in Cali and identification of some sociodemographic and clinical variables associated with mortality

RESUMEN Introducción: en los últimos años Colombia reconoció las enfermedades huérfanas-raras como problema de interés en salud pública y ordenó su notificación obligatoria. Objetivo: describir la información sobre las enfermedades huérfanas-raras obtenida en Cali a través del SIVIGILA en los primeros 2 años de registro. Materiales y métodos: estudio observacional transversal analítico. Se calcularon frecuencias absolutas y relativas. Se realizó un análisis de normalidad con el Test Shapiro-Wilk. Se calcularon prevalencias. Se evaluó la relación de diferentes variables sociodemográficas y clínicas y el riesgo de mortalidad usando modelos lineales generalizados, la familia de distribución de Poisson con función de enlace logarítmica y modelos de varianza. Resultados: fueron notificados 635 casos: 78 en el 2016 (prevalencia 3,25/100.0009) y 557 en el 2017 (prevalencia 23,01/100.000). La mayoría de los casos pertenecen al régimen contributivo. Las comunas con mayor número de casos y mayor prevalencia fueron la 17 y la 22. Entre las primeras enfermedades huérfanas-raras más comunes está la drepanocitosis, fue la más notificada en Cali con 25 casos para el 2016 (prevalencia 1,04/100.000) y 77 casos para el 2017 (prevalencia 3,1/100.000). La tasa cruda de mortalidad estimada para el periodo de estudio fue 0,83/100.000, las enfermedades con mayor mortalidad fueron la drepanocitosis en mujeres (0,12/100.000) y la polineuropatía en hombres (0,13/100.000). Discusión: es necesario realizar y publicar en el futuro análisis más profundos a través de la revisión detallada de historias clínicas y la incorporación de otras fuentes disponibles, como el Registro Individual de la Prestación de Servicios (RIPS) y el Registro Único de Afiliados (RUAF), con el fin de disminuir el subregistro y suministrar a toda la comunidad información más precisa y detallada.

SUMMARY Introduction: In recent years, Colombia recognized orphan diseases as a problem of public health interest and ordered its mandatory notification. Objective: Describe the information on orphan-rare diseases obtained in Cali through SIVIGILA in the first 2 years of registration. Materials and methods: Analytical cross-sectional observational study. Absolute and relative frequencies were calculated. Normality analysis of Shapiro Wilk was performed. Prevalence was calculated. The relationship of different sociodemographic and clinical variables and mortality risk was evaluated, using Generalized Linear Models, the Poisson distribution family, Logarithmic link function and robust variance models. Results: 635 cases were notified, 78 in 2016 for a prevalence of 3,25 / 100.000 and 557 in 2017 for a pre-valence of 23,01 / 100.000. Most cases belong to the tax system. The communes with the highest number of cases and the highest prevalence were 17 and 22. Among the first most common orphan-rare diseases, sickle cell disease was the most reported in Cali with 25 cases in 2016 (prevalence 1,04/100.000) and 77 cases in 2017 (prevalence 3,1/100.000). The estimated crude mortality rate for the study period was 0,83 / 100.000, and the diseases with the highest mortality were sickle cell disease in women (0,12 / 100.000) and polyneuropathy in men (0,13 / 100.000). Discussion: It is necessary to carry out and publish in the future, deeper analyzes through the detailed review of medical records and the incorporation of other available sources such as the Individual Registry of Provision of Services (RIPS) and the Unique Registry of Affiliates (RUAF), with in order to reduce the sub-registry and provide the whole community with more precise and detailed information.

Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction.

IMPORTANCE: In patients with heart failure and reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan reduces N-terminal pro-b-type natriuretic peptide (NT-proBNP) concentrations. The effect of sacubitril-valsartan on cardiac remodeling is uncertain. OBJECTIVE: To determine whether NT-proBNP changes in patients with HFrEF treated with sacubitril-valsartan correlate with changes in measures of cardiac volume and function. DESIGN, SETTING, AND PARTICIPANTS: Prospective, 12-month, single-group, open-label study of patients with HFrEF enrolled in 78 outpatient sites in the United States. Sacubitril-valsartan was initiated and the dose adjusted. Enrollment commenced on October 25, 2016, and follow-up was completed on October 22, 2018. EXPOSURES: NT-proBNP concentrations among patients treated with sacubitril-valsartan. MAIN OUTCOMES AND MEASURES: The primary outcome was the correlation between changes in log2-NT-proBNP concentrations and left ventricular (LV) EF, LV end-diastolic volume index (LVEDVI), LV end-systolic volume index (LVESVI), left atrial volume index (LAVI), and ratio of early transmitral Doppler velocity/early diastolic annular velocity (E/e') at 12 months. RESULTS: Among 794 patients (mean age, 65.1 years; 226 women [28.5%]; mean LVEF = 28.2%), 654 (82.4%) completed the study. The median NT-proBNP concentration at baseline was 816 pg/mL (interquartile range [IQR], 332-1822) and 455 pg/mL (IQR, 153-1090) at 12 months (difference, P < .001). At 12 months, the change in log2-NT-proBNP concentration was correlated with changes in LVEF (r = -0.381 [IQR, -0.448 to -0.310]; P < .001), LVEDVI (r = 0.320 [IQR, 0.246 to 0.391]; P < .001), LVESVI (r = 0.405 [IQR, 0.335 to 0.470]; P < .001), LAVI (r = 0.263 [IQR, 0.186 to 0.338]; P < .001), and E/e' (r = 0.269 [IQR, 0.182 to 0.353]; P < .001). At 12 months, LVEF increased from 28.2% to 37.8% (difference, 9.4% [95% CI, 8.8% to 9.9%]; P < .001), while LVEDVI decreased from 86.93 to 74.15 mL/m2 (difference, -12.25 mL/m2 [IQR, -12.92 to -11.58]; P < .001) and LVESVI decreased from 61.68 to 45.46 mL/m2 (difference, -15.29 mL/m2 [95% CI, -16.03 to -14.55]; P < .001). LAVI and E/e' ratio also decreased significantly. The most frequent adverse events were hypotension (17.6%), dizziness (16.8%), hyperkalemia (13.2%), and worsening kidney function (12.3%). CONCLUSIONS AND RELEVANCE: In this exploratory study of patients with HFrEF treated with sacubitril-valsartan, reduction in NT-proBNP concentration was weakly yet significantly correlated with improvements in markers of cardiac volume and function at 12 months. The observed reverse cardiac remodeling may provide a mechanistic explanation for the effects of sacubitril-valsartan in patients with HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02887183.

1,3-Bis(ethoxy-meth-yl)-1H-benzimidazole-2(3H)-thione.

In the structure of the title compound, C(13)H(18)N(2)O(2)S, mol-ecules are linked together by inter-molecular C-H⋯S inter-actions into one-dimensional extended chains along the a axis. The crystal packing is further influenced by weak C-H⋯O inter-actions.