efficacy and safety of mineralocorticoid receptor antagonist therapy in heart failure with reduced ejection fraction

CoNCluSIoNS: The present review highlights the benefit of MRAs across the spectrum of HFrEF despite a higher incidence of hyperkalemia. Therefore, MRA therapy should not be withheld from appropriately selected patients with HFrEF because the risk of adverse events does not appear to exceed the overall benefit in mortality reduction

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Pharmacist- or Nurse Practitioner–Led Assessment and Titration of Sacubitril/Valsartan in a Heart Failure Clinic: A Cohort Study

ABSTRACTBackground: Sacubitril/valsartan is a first-in-class angiotensin receptor–neprilysin inhibitor indicated in the management of heart failure with reduced ejection fraction, based on the results of the PARADIGM-HF trial. Practice-based studies are needed to validate its effect in real-world settings. Clinical pharmacists are ideally situated to assess and titrate sacubitril/valsartan.Objective: To evaluate the utilization, safety, and tolerability of sacubitril/ valsartan in a multidisciplinary heart failure clinic, with assessment and titration by a clinical pharmacist or a nurse practitioner.Methods: A retrospective cohort study was conducted at a heart failure clinic in Abbotsford, Canada. Included were adult patients with heart failure who were currently or formerly taking sacubitril/valsartan. Data collected for the period October 2015 to February 2019 included patient characteristics, New York Heart Association (NYHA) classification, concurrent medications, sacubitril/valsartan dose, adverse effects, and discontinuation rate.Results: In total, 128 patients were included. Mean age was 70.1 years, 98 (77%) of the patients were men, and 79 (62%) had NYHA class 2 heart failure. The clinical pharmacist managed care for 78 (61%) of the patients, and the nurse practitioner managed care for 50 (39%). Forty-one (32%) of the patients met modified PARADIGM-HF inclusion criteria. Eighty-five (66%) of the patients achieved the target dose of sacubitril/valsartan, with similar proportions for the clinical pharmacist and nurse practitioner groups, over a mean of 2.2 clinic visits. Patients who achieved the sacubitril/valsartan target dose, relative to those who did not, were significantly younger and had higher mean systolic blood pressure at baseline. Twenty-nine percent of patients (35/119) had an improvement in NYHA classification from before initiation of sacubitril/valsartan to achievement of target or maximally tolerated dose. Eighty-five (66%) of the patients experienced an adverse effect, primarily hypotension, and 12 (9%) required a dose reduction. Only 9 (7%) patients discontinued therapy.Conclusions: This study demonstrates the real-world safety and tolerability of sacubitril/valsartan in the treatment of heart failure, and reinforces that clinical pharmacists can effectively assess and titrate medications in a multidisciplinary heart failure clinic.RÉSUMÉContexte : Le sacubitril-valsartan est un inhibiteur novateur des récepteurs de l’angiotensine-néprilysine, indiqué dans la gestion de l’insuffisance cardiaque accompagnée d’une baisse de la fraction d’éjection, selon les résultats de l’essai PARADIGM-HF. Des études fondées sur la pratique sont nécessaires pour valider ses effets en contexte réel. Les pharmaciens cliniciens sont bien placés pour évaluer et titrer le sacubitril-valsartan.Objectif : Évaluer l’utilisation, l’innocuité et le seuil de tolérance du sacubitril-valsartan en clinique multidisciplinaire d’insuffisance cardiaque, l’évaluation et le titrage étant effectués par un pharmacien clinicien ou une infirmière praticienne.Méthodes : Une étude de cohorte rétrospective a été menée au sein d’une clinique d’insuffisance cardiaque à Abbotsford, au Canada. Les patients adultes inclus dans l’étude souffraient d’insuffisance cardiaque, ils prenaient ou avaient pris du sacubitril-valsartan. Les données recueillies entre octobre 2015 et février 2019 comprenaient les caractéristiques des patients, la classification de la New York Heart Association (NYHA), les médicaments pris de façon concomitante, la dose de sacubitril-valsartan, les effets secondaires et le taux d’abandon.Résultats : Au total, 128 patients ont participé à l’étude. L’âge moyen des patients était de 70,1 ans, 98 d’entre eux (77 %) étaient des hommes et 79 (62 %) souffraient d’une insuffisance cardiaque de classe 2 selon la classification de la NYHA. Le pharmacien clinicien gérait les soins de 78 patients (61 %) et la pharmacienne praticienne gérait ceux de 50 patients (39 %). Quarante-et-un patients (32 %) répondaient aux critères d’inclusion modifiés de PARADIGM-HF. Quatre-vingt-cinq (66 %) patients atteignaient le dosage ciblé de sacubitril-valsartan dans des proportions similaires entre le groupe du pharmacien clinicien et celui de l’infirmière praticienne, à raison d’une moyenne de 2,2 visites en clinique. Les patients ayant atteint le dosage ciblé de sacubitril-valsartan, par rapport à ceux ne l’ayant pas atteint, étaient considérablement plus jeunes et leur tension artérielle systolique moyenne de base était plus élevée. Une amélioration de la classification NYHA a été observée chez 29 % des patients (35/119) entre le début de la prise de sacubitril-valsartan et l’atteinte du dosage ciblé ou de la dose maximale tolérée. Des effets secondaires ont été observés chez 85 patients (66 %), principalement une hypotension, et 12 d’entre eux (9 %) ont dû réduire la dose. Seuls 9 patients (7 %) ont dû abandonner la thérapie.Conclusions : Cette étude démontre l’innocuité et le seuil de tolerance en contexte réel du sacubitril-valsartan pour le traitement de l’insuffisance cardiaque. Elle renforce le fait que les pharmaciens cliniciens peuvent efficacement évaluer et titrer des médicaments au sein d’une Clinique d’insuffisance cardiaque multidisciplinaire