scholarly journals Genetic Architecture of Heart Failure with Preserved versus Reduced Ejection Fraction

2021 ◽  
Author(s):  
Jacob Joseph ◽  
Qin Hui ◽  
Chang Liu ◽  
Krishna Aragam ◽  
Zeyuan Wang ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Clinical Trials ◽  
Ejection Fraction ◽  
Genetic Association ◽  
Genetic Architecture ◽  
Genome Wide Association ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Genome Wide

AbstractBackgroundPharmacologic clinical trials for heart failure (HF) with preserved ejection fraction (HFpEF) have been largely unsuccessful as compared to those for heart failure with reduced ejection fraction (HFrEF). Whether differences in the genetic underpinnings of these HF subtypes may provide insights into the disparate outcomes of these clinical trials remains unknown.ObjectivesWe pursued genetic association analyses to compare the genetic architecture of HFpEF with that of HFrEF.MethodsWe created a non-Hispanic White cohort including 19,495 HFrEF and 19,589 HFpEF cases among 43,344 unclassified HF cases, and 258,943 controls without HF in the Veterans Health Administration Million Veteran Program. We then conducted genome-wide association studies of unclassified HF, HFrEF and HFpEF, followed by genetic correlation analyses and Mendelian randomization analyses of established HF risk factors with HFrEF and HFpEF.ResultsWe found 13 loci associated with HFrEF at genome-wide significance, but only one associated with HFpEF. Among genome-wide significant loci for HFrEF, four loci were not associated with any HF risk factor. The single locus identified for HFpEF (FTO) is a known marker for obesity. Genetically determined associations were widely different between HFrEF and HFpEF for several risk factors including coronary artery disease, lipid levels, and pulse pressure.ConclusionsThe modest genetic discovery for HFpEF compared to HFrEF despite a robust sample size indicates that HFpEF, as currently defined, likely represents the amalgamation of several, distinct pathobiological entities. Development of consensus sub-phenotyping of HFpEF is paramount to better dissect the underlying genetic signals and contributors to HFpEF.Condensed AbstractWe utilized a large, uniformly phenotyped, single cohort of heart failure sub-classified into heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) based on current clinical definitions, to conduct detailed genetic analyses of the two HF sub-types. We found different genetic architectures and distinct genetic association profiles of HFrEF and HFpEF suggesting differences in underlying pathobiology. Furthermore, the low yield of HFpEF genome-wide association study (GWAS) compared to similarly powered HFrEF GWAS underscores the heterogeneity of HFpEF and the urgent need for developing consensus sub-phenotyping of HFpEF to improve the discovery in genetic mechanisms and therapeutic interventions.

scholarly journals Pharmacogenomic study of heart failure and candesartan response from the CHARM programme

2021 ◽  
Author(s):  
Marie-Pierre Dubé ◽  
Olympe Chazara ◽  
Audrey Lemaçon ◽  
Géraldine Asselin ◽  
Sylvie Provost ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Genetic Variant ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Genome Wide Association Studies ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Genome Wide ◽  
Cardiovascular Endpoint

Aims. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomised, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorised according to left ventricular ejection fraction and tolerability to an ACE inhibitor. We conducted a pharmacogenomic study of the CHARM studies to identify genetic predictors of heart failure progression and the efficacy and safety of treatment with candesartan. Methods. We performed genome-wide association studies (GWAS) with the composite endpoint of cardiovascular death or hospitalisation for heart failure in 2727 patients from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction. The safety endpoints were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure. We also conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint. Results. We found the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 to be associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study [hazard ratio (HR): 1.91, 95% confidence interval (CI): 1.55-2.35; P=1.7x10-9], but not in patients with reduced ejection fraction. None of the GWAS for candesartan safety or efficacy passed the significance threshold. Conclusions. We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication and we cannot exclude the possibility that the results may be chance findings.

scholarly journals Interleukin 6 and Development of Heart Failure With Preserved Ejection Fraction in the General Population

2021 ◽  
Vol 10 (11) ◽  
Author(s):  
Yook Chin Chia ◽  
Lyanne M. Kieneker ◽  
Gaston van Hassel ◽  
S. Heleen Binnenmars ◽  
Ilja M. Nolte ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Left Ventricular ◽  
Community Dwelling ◽  
Left Ventricular Ejection ◽  
Preserved Ejection Fraction ◽  
Ventricular Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
New Onset

Background The cause of heart failure with preserved ejection fraction (HFpEF) is poorly understood, and specific therapies are lacking. Previous studies suggested that inflammation plays a role in the development of HFpEF. Herein, we aimed to investigate in community‐dwelling individuals whether a higher plasma interleukin 6 (IL‐6) level is associated with an increased risk of developing new‐onset heart failure (HF) over time, and specifically HFpEF. Methods and Results We performed a case‐cohort study based on the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) study, a prospective general population‐based cohort study. We included 961 participants, comprising 200 participants who developed HF and a random group of 761 controls. HF with reduced ejection fraction or HFpEF was defined on the basis of the left ventricular ejection fraction of ≤40% or >40%, respectively. In Cox proportional hazard regression analyses, IL‐6 levels were statistically significantly associated with the development of HF (hazard ratio [HR], 1.28; 95% CI, 1.02–1.61; P =0.03) after adjustment for key risk factors. Specifically, IL‐6 levels were significantly associated with the development of HFpEF (HR, 1.59; 95% CI, 1.16–2.19; P =0.004), whereas the association with HF with reduced ejection fraction was nonsignificant (HR, 1.05; 95% CI, 0.75–1.47; P =0.77). In sensitivity analyses, defining HFpEF as left ventricular ejection fraction ≥50%, IL‐6 levels were also significantly associated with the development of HFpEF (HR, 1.47; 95% CI, 1.04–2.06; P =0.03) after adjustment for key risk factors. Conclusions IL‐6 is associated with new‐onset HFpEF in community‐dwelling individuals, independent of potential confounders. Our findings warrant further research to investigate whether IL‐6 might be a novel treatment target to prevent HFpEF.

Risk factors for rehospitalization in heart failure with preserved ejection fraction compared with reduced ejection fraction

2014 ◽  
Vol 30 (5) ◽  
pp. 595-603 ◽  
Author(s):  
Masahiko Setoguchi ◽  
Yuji Hashimoto ◽  
Taro Sasaoka ◽  
Takashi Ashikaga ◽  
Mitsuaki Isobe
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Ejection Fraction ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction

Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies

2021 ◽  
Vol 73 (1) ◽  
Author(s):  
Kazunori Omote ◽  
Frederik H. Verbrugge ◽  
Barry A. Borlaug
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Treatment Strategies ◽  
Annual Review ◽  
Publication Date ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
Prevalence Of Obesity

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

223-OR: Heart Failure with Reduced, Midrange and Preserved Ejection Fraction in Chinese with Type 2 Diabetes: Risk Factors and Prognosis

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 223-OR
Author(s):  
ANDREA LUK ◽  
XINGE ZHANG ◽  
ERIK FUNG ◽  
HONGJIANG WU ◽  
ERIC S. LAU ◽  
...  
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Type 2 Diabetes ◽  
Ejection Fraction ◽  
Diabetes Risk ◽  
Preserved Ejection Fraction ◽  
Diabetes Risk Factors

Abstract 12849: Changes in N-terminal Pro Brain Natriuretic Peptide Levels Predicts Mortality and Heart Failure Hospitalization in Patients With Heart Failure and Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Gianluigi Savarese ◽  
Camilla Hage ◽  
Ulf Dahlström ◽  
Pasquale Perrone-Filardi ◽  
Lars H Lund
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Total Mortality ◽  
Preserved Ejection Fraction ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure ◽  
The Impact

Introduction: Changes in N-terminal pro brain natriuretic peptide (NT-proBNP) have been demonstrated to correlate with outcomes in patients with heart failure (HF) and reduced ejection fraction (EF). However the prognostic value of a change in NT-proBNP in patients with heart failure and preserved ejection fraction (HFPEF) is unknown. Hypothesis: To assess the impact of changes in NT-proBNP on all-cause mortality, HF hospitalization and their composite in an unselected population of patients with HFPEF. Methods: 643 outpatients (age 72+12 years; 41% females) with HFPEF (ejection fraction ≥40%) enrolled in the Swedish Heart Failure Registry between 2005 and 2012 and reporting NT-proBNP levels assessment at initial registration and at follow-up were prospectively studied. Patients were divided into 2 groups according the median value of NT-proBNP absolute change that was 0 pg/ml. Median follow-up from first measurement was 2.25 years (IQR: 1.43 to 3.81). Adjusted Cox’s regression models were performed using total mortality, HF hospitalization (with censoring at death) and their composite as outcomes. Results: After adjustments for 19 baseline variables including baseline NT-proBNP, as compared with an increase in NT-proBNP levels at 6 months (NT-proBNP change>0 pg/ml), a reduction in NT-proBNP levels (NT-proBNP change<0 pg/ml) was associated with a 45.2% reduction in risk of all-cause death (HR: 0.548; 95% CI: 0.378 to 0.796; p:0.002), a 50.1% reduction in risk of HF hospitalization (HR: 0.49; 95% CI: 0.362 to 0.689; p<0.001) and a 42.6% reduction in risk of the composite outcome (HR: 0.574; 95% CI: 0.435 to 0.758; p<0.001)(Figure). Conclusions: Reductions in NT-proBNP levels over time are independently associated with an improved prognosis in HFPEF patients. Changes in NT-proBNP could represent a surrogate outcome in phase 2 HFPEF trials.

scholarly journals Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Andreas B. Gevaert ◽  
Katrien Lemmens ◽  
Christiaan J. Vrints ◽  
Emeline M. Van Craenenbroeck
Keyword(s):  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Exercise Training ◽  
Ejection Fraction ◽  
Current Knowledge ◽  
Beta Blockers ◽  
Preserved Ejection Fraction ◽  
Cellular Mechanisms ◽  
Converting Enzyme Inhibitors ◽  
Reduced Ejection Fraction

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF.

scholarly journals Treatment of Atrial Fibrillation in Patients with Co-existing Heart Failure and Reduced Ejection Fraction: Time to Revisit the Management Guidelines?

2018 ◽  
Vol 7 (2) ◽  
pp. 91 ◽  
Author(s):  
Alex Baher ◽  
Nassir F Marrouche ◽  
◽  
◽  
◽  
...  
Keyword(s):  
Heart Failure ◽  
Clinical Trials ◽  
Catheter Ablation ◽  
Ejection Fraction ◽  
Rhythm Control ◽  
Pharmacological Interventions ◽  
Reduced Ejection Fraction ◽  
Increased Risk ◽  
Patients With Heart Failure ◽  
Heart Failure Hospitalisation

AF in patients with heart failure and reduced ejection fraction (HFrEF) is common and is associated with an increased risk of stroke, heart failure hospitalisation and all-cause mortality. Rhythm control of AF in this population has been traditionally limited to the use of antiarrhythmic drugs. Clinical trials assessing superiority of pharmacological rhythm control over rate control have been largely disappointing. Catheter ablation has emerged as a viable alternative to pharmacological rhythm control in symptomatic AF and has enjoyed significant technological advancements over the past decade. Recent clinical trials have suggested that catheter ablation is superior to pharmacological interventions in patients with co-existing AF and HFrEF. In this article, we will review the therapeutic options for AF in patients with HFrEF in the context of the latest clinical trials beyond the current established guidelines.

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