Retirada del tratamiento betabloqueante en pacientes con insuficiencia cardíaca con función sistólica preservada e incompetencia cronotrópica. Efecto sobre la capacidad funcional

La insuficiencia cardiaca con fracción de eyección preservada presenta una fisiopatología compleja y multifactorial. Entre los potenciales mecanismos, la incompetencia cronotrópica podría contribuir a la limitación de la capacidad funcional. Cabe reseñar que un gran porcentaje de pacientes con insuficiencia cardiaca con fracción de eyección preservada reciben tratamiento con betabloqueantes a pesar de la falta de evidencia en este perfil de pacientes. Con estas premisas, la hipótesis fue que la retirada del tratamiento betabloqueante en pacientes con insuficiencia cardiaca con fracción de eyección preservada, con criterios de estabilidad clínica, en tratamiento crónico y estable con betabloqueantes y que presentaban incompetencia cronotrópica (determinada a través de la realización de una prueba de esfuerzo cardiopulmonar máxima), se asociaba a una mejoría de la capacidad funcional y de otros parámetros relacionados con la gravedad de la enfermedad. El objetivo primario fue evaluar el cambio desde el valor inicial en el consumo pico de oxígeno y en el porcentaje del consumo pico de oxígeno predicho. Al analizar los resultados, el cambio del valor pico de consumo de oxígeno y del valor pico predicho de oxígeno respecto del valor inicial aumentó significativamente en los pacientes sin betabloqueante en comparación con los que mantuvieron el betabloqueante (1,84 frente a -0,21 ml/kg/min; p<0,001 y 8,86% frente a -2,82%; p<0,001, respectivamente). Así pues, la conclusión que obtenemos es que en pacientes con insuficiencia cardiaca con fracción de eyección preservada e incompetencia cronotrópica, la retirada del tratamiento betabloqueante reflejó una mejoría de la capacidad funcional a corto plazo. Se deben señalar algunas limitaciones del estudio: los resultados obtenidos solo se deben aplicar en pacientes con insuficiencia cardiaca con fracción de eyección preservada en fase de estabilidad clínica, con incompetencia cronotrópica, y predominantemente en ritmo sinusal y también que el estudio no evaluó a medio-largo plazo el efecto sobre la capacidad funcional de la retirada del tratamiento betabloqueante

Effect of β-Blocker Withdrawal on Functional Capacity in Heart Failure and Preserved Ejection Fraction

BACKGROUND Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet b-blockers are commonly used in HFpEF despite the lack of robust evidence. OBJECTIVES This study aimed to evaluate the effect of b-blocker withdrawal on peak oxygen consumption (peak VO2) in patients with HFpEF and chronotropic incompetence. METHODS This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with b-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n ¼ 26) versus continuing (arm B: n ¼ 26) b-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak VO2 and percentage of predicted peak VO2 (peak VO2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. RESULTS The mean age was 72.6 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVO2 and peak VO2% were 12.4 2.9 mL/kg/min, and 72.4 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak VO2 and peak VO2% increased significantly after b-blocker withdrawal (14.3 vs 12.2 mL/kg/min [D þ2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [D þ11.7%]; P < 0.001, respectively). CONCLUSIONS b-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. b-blocker use in HFpEF deserves profound re-evaluation. (b-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39) (J Am Coll Cardiol 2021;78:2042–2056) © 2021 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction—a substudy of the DAPA-VO2 study

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%–p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8–72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5–37.8), 67.4 ml/min/1.73 m2 (50.7–82.8), 1,285 pg/ml (898–2,305), 623.4 pg/ml (533.5–736.6), and 72.6 RU/ml (62.6–96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9–37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ−4.6, (−1.7 to −5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Índice cronotrópico y eventos adversos a largo plazo en insuficiencia cardiaca con fracción de eyección conservada

Introduction and objectives: Little is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. Methods: This single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. Results: The mean age of the sample was 73.2 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P = .319, and WHF events, P = .573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction = .002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. Conclusions: In patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation.Introducción y objetivos Poco se sabe sobre la utilidad de la respuesta de la frecuencia cardiaca (FC) al ejercicio para la estratificación del riesgo en la insuficiencia cardiaca con fracción de eyección conservada (ICFEp). El objetivo de este estudio fue evaluar la asociación entre la respuesta de la FC al ejercicio y el riesgo de episodios de descompensación por insuficiencia cardiaca (DIC) en pacientes sintomáticos estables con ICFEp. Métodos Se trata de un estudio unicéntrico que incluyó a un total de 133 pacientes con ICFEp (NYHA II-III) tras la realización de una prueba de esfuerzo cardiopulmonar máxima. La respuesta de la FC al ejercicio se evaluó mediante la fórmula del índice cronotrópico (IxC). Para el análisis se utilizó un método de regresión binomial negativa. Resultados La edad media fue de 73,2 ± 10,5 años, el 56,4% eran mujeres y el 51,1% estaban en fibrilación auricular. La mediana de IxC fue de 0,4 (0,3-0,55). Tras una mediana de seguimiento de 2,4 (1,6-5,3) años, se registraron un total de 146 DIC en 58 pacientes y 41 (30,8%) muertes. El IxC no se asoció con eventos adversos (muerte, p = 0,319, y DIC, p = 0,573) cuando se analizó de forma conjunta toda la muestra. Sin embargo, se encontró un efecto diferencial en función del ritmo electrocardiográfico para DIC (p para interacción = 0,002). El IxC se asoció inversa y linealmente con el riesgo de DIC en aquellos pacientes con ritmo sinusal y de forma lineal y positiva con aquellos en fibrilación auricular. Conclusiones En pacientes con ICFEp, el IxC se asoció diferencialmente con el riesgo de DIC en función del ritmo electrocardiográfico. Un Ixc más bajo surgió como un factor de riesgo para predecir un mayor riesgo de DIC en pacientes en ritmo sinusal. Por el contrario, un IxC más alto identificó un mayor riesgo en aquellos pacientes en fibrilación auricular