Most therapeutic development is targeted at slowing disease progression, often long after the initiating events of disease incidence. Heart failure is a chronic, life-threatening disease and the most common reason for hospital admission in people over 65 years of age. Genetic factors that influence heart failure progression have not yet been identified. We performed an exome-wide association study in 8,089 patients with heart failure across two clinical trials, CHARM and CORONA, and one population-based cohort, the UK Biobank. We assessed the genetic determinants of the outcomes ‘time to cardiovascular death’ and ‘time to cardiovascular death and/or hospitalisation’, identifying seven independent exome-wide-significant associated genes, FAM221A , CUTC , IFIT5 , STIMATE , TAS2R20 , CALB2 and BLK . Leveraging public genomic data resources, transcriptomic and pathway analyses, as well as a machine-learning approach, we annotated and prioritised the identified genes for further target validation experiments. Together, these findings advance our understanding of the molecular underpinnings of heart failure progression and reveal putative new candidate therapeutic targets.

Halfdan ble født 3. mars 1943 og døde 11. februar i år.Han var en av pionerene som tok i bruk ultralyd for å avbilde hjertet, bankende på en skjerm.Resultatet ble et fantastisk gjennombrudd for hjertemedisin.Med ekkokardiografi viste han e er hvert hvordan man i detalj kan se hjertet i

This gene-based collapsing analysis assesses the contribution of rare variants to all-cause heart failure with and without reduced left ventricular ejection fraction. Question What is the contribution of rare genetic variants to all-cause heart failure with and without reduced left ventricular ejection fraction? Findings In this gene-based collapsing analysis of 5942 patients with heart failure and 13 156 controls using whole-exome sequencing, a significant enrichment of rare protein-truncating variants in the TTN gene and in general an increased burden of mendelian cardiomyopathy variants was demonstrated in patients with heart failure of mostly presumed ischemic etiology compared with controls. Meaning Mendelian genetic conditions may represent an important subset of complex late-onset diseases such as heart failure, irrespective of the clinical presentation. Importance Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated. Objective To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction. Design, Setting, and Participants This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020. Main Outcomes and Measures Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes. Results This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 x 10(-13); odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]). Conclusions and Relevance An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.

ISS Fro cu Fa Nu Kin Ins Pis Sa W D Ca Un BACKGROUND Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m (95% CI: 0.58 to 0.87; p 1⁄4 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction. (J Am Coll Cardiol 2019;74: 2893–904) © 2019 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). N 0735-1097 https://doi.org/10.1016/j.jacc.2019.09.059 m the Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, United Kingdom; Centre of Cardiovaslar Research and Education in Therapeutics, Monash University, Melbourne, Victoria, Australia; Norwich Medical School, culty of Medicine and Health Science, University of East Anglia, Norwich, United Kingdom; Centre for Statistics in Medicine, ffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United gdom; Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas; Cardiovascular and Cell Science titute, St. George’s University of London, London, United Kingdom; Department of Medical Sciences, IRCCS San Raffaele ana, Roma, Italy; Kardiologie, Angiologie und Internistische Intensivmedizin, Universitatsklinikum des Saarlandes, Homburg/ ar, Germany; Robertson Institute of Biostatistics and Clinical Trials Unit, University of Glasgow, Glasgow, United Kingdom; allenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; epartment of Cardiology, Charite Campus Virchow-Klinikum, Berlin, Germany; University of Groningen, Department of rdiology, University Medical Centre Groningen, RB Groningen, the Netherlands; Internal Medicine Department, Hospital iversitario Ramón y Cajal, Universidad de Alcalá (IRYCIS), Plaza de San Diego, Madrid, Spain; Department of Cardiology, Oslo SEE PAGE 2905 ABBR EV I A T I ON S

BACKGROUND Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES This study sought to investigate patient prognosis and the ef fi cacy of beta-blockers according to renal function using estimated glomerular fi ltration rate (eGFR). METHODS Analysis of 16,740 individual patients with left ventricular ejection fraction < 50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and strati fi ed by heart rhythm. RESULTS Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m 2 ; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m 2 , and 2,286 (13.7%) 30 to 44

The estimate of genotypic correlation coefficients in general higher than their corresponding phenotypic correlations indicating strong inherent association among the traits. Pod yield per plant had significant positive association with plant height, shelling per cent and sound mature kernel per cent, while its association with other characters viz., number of mature pods per plant and kernel yield per plant was found to be positive but non-significant. These characters can be considered as criteria for selection for higher yield, as these were mutually and directly associated with pod yield. The maximum positive direct positive effect on pod yield per plant was contributed by kernel yield per plant followed by number of well-filled and mature pods per plant, plant height and sound mature kernel per cent. The high direct effect of pods per plant appeared to be the main factor for its strong positive correlation with pod yield. Hence, a direct selection for this trait would be effective.

Aims:Recent guidelines recommend that patients with heart failure and left ventricular ejection fraction (LVEF) 40-49% should be managed similar to LVEF ≥ 50%. We investigated the effect of beta-blockers according to LVEF in double-blind, randomized, placebo-controlled trials. Methods and results:Individual patient data meta-analysis of 11 trials, stratified by baseline LVEF and heart rhythm (Clinicaltrials.gov: NCT0083244; PROSPERO: CRD42014010012). Primary outcomes were all-cause mortality and cardiovascular death over 1.3 years median follow-up, with an intention-to-treat analysis. For 14 262 patients in sinus rhythm, median LVEF was 27% (interquartile range 21-33%), including 575 patients with LVEF 40-49% and 244 ≥ 50%. Beta-blockers reduced all-cause and cardiovascular mortality compared to placebo in sinus rhythm, an effect that was consistent across LVEF strata, except for those in the small subgroup with LVEF ≥ 50%. For LVEF 40-49%, death occurred in 21/292 [7.2%] randomized to beta-blockers compared to 35/283 [12.4%] with placebo; adjusted hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.34-1.03]. Cardiovascular death occurred in 13/292 [4.5%] with beta-blockers and 26/283 [9.2%] with placebo; adjusted HR 0.48 (95% CI 0.24-0.97). Over a median of 1.0 years following randomization (n = 4601), LVEF increased with beta-blockers in all groups in sinus rhythm except LVEF ≥50%. For patients in atrial fibrillation at baseline (n = 3050), beta-blockers increased LVEF when < 50% at baseline, but did not improve prognosis. Conclusion:Beta-blockers improve LVEF and prognosis for patients with heart failure in sinus rhythm with a reduced LVEF. The data are most robust for LVEF < 40%, but similar benefit was observed in the subgroup of patients with LVEF 40-49%.

Objective: To assess the relationship between heart rate (HR), pulse pressure (PP), and their association with mortality in a population of high-risk patients following acute myocardial infarction (MI). Methods: We performed an analysis in 22,398 patients included in "The High-Risk Myocardial Infarction Database Initiative", a database of clinical trials evaluating pharmacologic interventions in patients with MI complicated by signs of heart failure (HF) or left ventricular dysfunction. We found an interaction between HR and PP. Based on median HR and median PP, patients were divided in four categories: (1) HR < 75 bpm and PP >= 50 mm Hg (reference), (2) HR < 75 bpm and PP < 50 mm Hg, (3) HR >= 75 bpm and PP >= 50 mm Hg, and (4) HR >= 75 bpm and PP < 50 mm Hg. The association between these categories and outcomes was studied using a Cox proportional hazard model. Results: After a median follow-up of 24 (18-33) months, 3561 (16%) patients died of all-causes and 3048 (14%) patients of cardiovascular (CV) causes. In multivariate analysis, patients from the fourth category had the highest risk of all-cause mortality (hazard ratio of 1.69; 95% CI: 1.53-1.86) and CV mortality (hazard ratio of 1.78; 95% CI: 1.60-1.97). Conclusions: There is an interaction between HR and PP in patients with HF following MI, with the highest risk being conferred by a clinical status with both an elevated HR and a lower PP. These findings identify a high-risk population likely to require an aggressive diagnostic and management strategy. (c) 2018 Published by Elsevier B.V.

The Steering Committee Lead (DK) and the Centre for Statistics in Medicine, Oxford, UK (DGA and JH), had full access to all the data and had joint responsibility for the decision to submit for publication after discussion with all the named authors. DK is funded by a National Institute for Health Research (NIHR) Career Development Fellowship (CDF-2015-08-074). The opinions expressed are those of the authors and do not represent the NIHR or the UK Department of Health. Abstract Background: The relationship between mortality and heart rate remains unclear for patients with heart failure and reduced ejection fraction (HFrEF) in either sinus rhythm or atrial fibrillation (AF). Objective: To investigate the prognostic importance of heart rate in HFrEF in randomized controlled trials (RCTs) comparing beta-blockers and placebo. Methods: The Beta-blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual-patient data from eleven double-blind RCTs. The primary outcome was all-cause mortality, analysed with Cox proportional hazard ratios (HR) modelling heart rate measured at baseline and approximately six-months post-randomization. Results: A higher heart rate at baseline was associated with greater all-cause mortality in patients with sinus rhythm (n=14,166; adjusted HR 1.11 per 10 beats/minute; 95% CI 1.07-1.15, p<0.0001), but not in AF (n=3,034; HR 1.03 per 10 beats/minute; 0.97-1.08, p=0.38). Beta-blockers reduced ventricular rate by 12 beats/minute in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomised to beta-blockers (HR 0.73 versus placebo, 95% CI 0.67-0.79; p<0.001), regardless of baseline heart rate (interaction p=0.35). Beta-blockers had no effect on mortality in patients with AF (HR 0.96, 95% CI 0.81-1.12; p=0.58) at any heart rate (interaction p=0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR 1.16 per 10 beats/minute increase, 95% CI 1.11-1.22; p<0.0001). Conclusions: Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with HFrEF in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm. Meta-analysis of individual-patient data from eleven double-blind randomized trials found that higher baseline heart rate was associated with greater all-cause mortality for those in sinus rhythm, but not for those in AF. Mortality was lower for patients in sinus rhythm assigned beta-blockers (HR 0.73, 95% CI 0.67-0.79; p<0.001), regardless of baseline heart rate. Beta-blockers had no effect on mortality in patients with AF (HR 0.96, 95% CI 0.81-1.12; p=0.58) at any heart rate. A lower achieved resting heart rate was associated with better prognosis only for patients in sinus rhythm (HR 1.16 per 10 beats/minute increase, 95% CI 1.11-1.22; p<0.0001).

BACKGROUND The relationship between mortality and heart rate remains unclear for patients with heart failure with reduced ejection fraction in either sinus rhythm or atrial fibrillation (AF).OBJECTIVES This analysis explored the prognostic importance of heart rate in patients with heart failure with reduced ejection fraction in randomized controlled trials comparing beta-blockers and placebo.METHODS The Beta-Blockers in Heart Failure Collaborative Group performed a meta-analysis of harmonized individual patient data from 11 double-blind randomized controlled trials. The primary outcome was all-cause mortality, analyzed with Cox proportional hazard ratios (HR) modeling heart rate measured at baseline and approximately 6 months post-randomization.RESULTS A higher heart rate at baseline was associated with greater all-cause mortality for patients in sinus rhythm (n = 14,166; adjusted HR: 1.11 per 10 beats/min; 95% confidence interval [CI]: 1.07 to 1.15; p < 0.0001) but not in AF (n = 3,034; HR: 1.03 per 10 beats/min; 95% CI: 0.97 to 1.08; p = 0.38). Beta-blockers reduced ventricular rate by 12 beats/min in both sinus rhythm and AF. Mortality was lower for patients in sinus rhythm randomized to beta-blockers (HR: 0.73 vs. placebo; 95% CI: 0.67 to 0.79; p < 0.001), regardless of baseline heart rate (interaction p = 0.35). Beta-blockers had no effect on mortality in patients with AF (HR: 0.96, 95% CI: 0.81 to 1.12; p = 0.58) at any heart rate (interaction p = 0.48). A lower achieved resting heart rate, irrespective of treatment, was associated with better prognosis only for patients in sinus rhythm (HR: 1.16 per 10 beats/min increase, 95% CI: 1.11 to 1.22; p < 0.0001).CONCLUSIONS Regardless of pre-treatment heart rate, beta-blockers reduce mortality in patients with heart failure with reduced ejection fraction in sinus rhythm. Achieving a lower heart rate is associated with better prognosis, but only for those in sinus rhythm. (C) 2017 by the American College of Cardiology Foundation.

AimsTo examine the impact of diabetes mellitus on long-term clinical outcomes in patients with myocardial infarction (MI) complicated by clinical signs of heart failure (HF) or left ventricular dysfunction (LVD).Methods and resultsThe High-Risk MI Database consists of individual data from 28 771 patients and was created by merging four large recent randomized clinical trials (VALIANT, EPHESUS, OPTIMAAL, and CAPRICORN) that each examined the impact of pharmacological interventions following MI in patients with evidence of HF or LVD. The mean age of patients was 65 years, 70% were male, and almost 94% Caucasian. Overall, 7368 (26%) had a history of diabetes. All the major outcomes were adjudicated by independent end-point committees. Strong and highly significant associations were found with all major clinical outcomes. Diabetes was associated with an increased risk for all-cause death [adjusted hazard ratio (HR) 1.37; confidence interval (CI) 1.28-1.46; P < 0.001]. The higher risk for all-cause death was largely mediated by higher risk for cardiovascular death (adjusted HR 1.38; CI 1.27-1.48; P < 0.001) predominantly due to a substantially increased risk for fatal re-infarction (adjusted HR 1.78; CI 1.42-2.23; P < 0.001). Additionally, diabetes was associated with an increased risk for hospitalizations, particularly HF hospitalization (adjusted HR 1.50; CI 1.39-1.63; P < 0.001). There were also elevated risks for composite outcomes, particularly death or hospitalization due to HF (adjusted HR 1.48; CI 1.38-1.59; P < 0.001).ConclusionThe risk for adverse outcomes associated with diabetes remains elevated even after debut of coronary artery disease in patients with MI complicated by clinical signs of HF or LVD. This association is particularly strong for HF-related outcomes.

Introduction: Up to a third of patients with type-2 diabetes mellitus (T2DM) and heart failure (HF) are treated with insulin. Hypothesis: As insulin causes sodium retention and hypoglycemia, its us...

OBJECTIVES:This study sought to evaluate whether a panel of biomarkers improved prognostication in patients with heart failure (HF) and reduced ejection fraction of ischemic origin using a systematized approach according to suggested requirements for validation of new biomarkers. BACKGROUND:Modeling combinations of multiple circulating markers could potentially identify patients with HF at particularly high risk and aid in the selection of individualized therapy. METHODS:From a panel of 20 inflammatory and extracellular matrix biomarkers, 2 different biomarker panels were created and added to the Seattle HF score and the prognostic model from the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study (n = 1,497), which included conventional clinical characteristics and C-reactive protein and N-terminal pro-B-type natriuretic peptide. Interactions with statin treatment were also assessed. RESULTS:The two models-model 1 (endostatin, interleukin 8, soluble ST2, troponin T, galectin 3, and chemokine [C-C motif] ligand 21) and model 2 (troponin T, soluble ST2, galectin 3, pentraxin 3, and soluble tumor necrosis factor receptor 2)-significantly improved the CORONA and Seattle HF models but added only modestly to their Harrell's C statistic and net reclassification index. In addition, rosuvastatin had no effect on the levels of a wide range of inflammatory and extracellular matrix markers, but there was a tendency for patients with a lower level of biomarkers in the 2 panels to have a positive effect from statin treatment. CONCLUSIONS:In the specific HF patient population studied, a multimarker approach using the particular panel of biomarkers measured was of limited clinical value for identifying future risk of adverse outcomes.

BACKGROUND:The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail.METHODS:We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization.RESULTS:Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis.CONCLUSIONS:Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death. (Funded by the China Scholarship Council and the University of Glasgow.).