Growth Differentiation Factor‐15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy

Binder, Michael; Yanek, Lisa R.; Butcher, Barbara; Norgard, Sanaz; Marine, Joseph E.; Kolandaivelu, Aravindan; Chrispin, Jonathan; Fedarko, Neal S.; Calkins, Hugh; O’Rourke, Brian; Wu, Kathérine C.; Tomaselli, Gordon F.; Barth, Andreas S.

doi:10.1161/jaha.122.026003

Cited by 5 publications

(3 citation statements)

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“…For example, when GDF‐15 was considered as a continuous variable (per doubling in concentration), the risk of cardiovascular death or hospitalization for heart failure increased by 1.4‐fold, the risk of sustained kidney function deterioration increased by 2‐fold, and the risk of death increased by 1.7‐fold, after correction for other prognostic variables, including the level of natriuretic peptides and cardiac troponin. Our findings are remarkably similar to those in previous studies 6,30–32 . Prior reports in patients with heart failure have also proposed potential relationships of GDF‐15 with characteristics reflecting disease severity (e.g.…”

Section: Discussionsupporting

confidence: 92%

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Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

Ferreira,

Packer,

Butler

et al. 2023

European J of Heart Fail

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BackgroundGrowth differentiation factor 15 (GDF‐15) is upregulated in part in response to cardiomyocyte stretch and stress, and it exerts a protective role that is mediated by its action to suppress signaling through insulin‐like growth factor (IGF) and enhance signaling through adenosine monophosphate‐activated protein kinase (AMPK). Sodium glucose co‐transporter 2 (SGLT2) inhibitors improve outcomes in heart failure, which has been experimentally linked to AMPK.AimsTo study the associations of GDF‐15 with baseline characteristics, the prognostic significance of GDF‐15, and the effect of empagliflozin on GDF‐15 in patients with heart failure with a reduced and preserved ejection fraction.MethodsGDF‐15 was determined in serum samples from the EMPEROR‐Reduced and EMPEROR‐Preserved trials. Cox regression and mixed models for repeated measures were used to study the association with outcomes and the effect of empagliflozin on GDF‐15, respectively.ResultsWe studied 1124 patients (560 placebo and 564 empagliflozin) with median GDF‐15 levels at baseline of 2442 (IQR 1603‐3780) pg/mL. Patients with higher GDF‐15 levels were typically older men with more severe symptoms, higher NT‐proBNP levels, worse kidney function and who were prescribed metformin. Baseline levels of GDF‐15 were well correlated with levels of insulin‐like binding protein 7 (IGFBP‐7; rho=0.64). Higher levels of GDF‐15 were independently associated with an increased risk of cardiovascular death, heart failure hospitalizations, and worse kidney outcomes. When considered as a continuous variable, for each doubling in GDF‐15, the adjusted hazard ratio for cardiovascular death or HF hospitalization was 1.40 (95%CI 1.15,1.71; P<0.001). The relative effect of empagliflozin on cardiovascular death and hospitalization for heart failure was most pronounced in patients with higher baseline levels of GDF‐15 (interaction P‐trend=0.031). At week 52, when compared with placebo, empagliflozin increased GDF‐15 by an additional 8% (P=0.020), an effect that was primarily seen in patients not receiving metformin, a known AMPK activator.ConclusionsGDF‐15 is a marker of worse heart failure severity, is an independent predictor of major heart failure outcomes and may be associated with more pronounced benefits of empagliflozin. GDF‐15 is increased among metformin users, and empagliflozin was associated with an increase in GDF‐15 levels, primarily in patients not receiving metformin.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 92%

“…Our findings are remarkably similar to those in previous studies. 6,[30][31][32] Prior reports in patients with heart failure have also proposed potential relationships of GDF-15 with characteristics reflecting disease severity (e.g. congestion, inflammation, or iron deficiency), without influence of ejection fraction on GDF-15 levels.…”

Section: Discussionmentioning

confidence: 99%

Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

Ferreira,

Packer,

Butler

et al. 2023

European J of Heart Fail

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“…However, associations of WFDC1 with frailty have not been previously described. Finally, GDF15, a ligand of transforming growth factor-β, involved in inflammatory pathways and cellular growth and repair, has been extensively studied as a marker of outcomes in cardiomyopathy and in frailty …”

Section: Discussionmentioning

confidence: 99%

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life

Ramonfaur,

Buckley,

Arthur

et al. 2024

JAMA Cardiol

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ImportanceHeart failure (HF) and frailty frequently coexist and may share a common pathobiology, although the underlying mechanisms remain unclear. Understanding these mechanisms may provide guidance for preventing and treating both conditions.ObjectiveTo identify shared pathways between incident HF and frailty in late life using large-scale proteomics.Design, Setting, and ParticipantsIn this cohort study, 4877 aptamers (Somascan v4) were measured among participants in the community-based longitudinal Atherosclerosis Risk In Communities (ARIC) cohort study at visit 3 (V3; 1993-1995; n = 10 638) and at visit 5 (V5; 2011-2013; n = 3908). Analyses were externally replicated among 3189 participants in the Cardiovascular Health Study (CHS). Data analysis was conducted from February 2022 to June 2023.ExposuresProtein aptamers, measured at study V3 and V5.Main Outcomes and MeasuresOutcomes assessed included incident HF hospitalization after V3 and after V5, prevalent frailty at V5, and incident frailty between V5 and visit 6 (V6; 2016-2017; n = 4131). Frailty was assessed using the Fried criteria. Analyses were adjusted for age, gender, race, field center, hypertension, diabetes, smoking status, body mass index, estimated glomerular filtration rate, prevalent coronary heart disease, prevalent atrial fibrillation, and history of myocardial infarction. Mendelian randomization (MR) analysis was performed to assess potential causal effects of candidate proteins on HF and frailty.ResultsA total of 4877 protein aptamers were measured among 10 638 participants at V3 (mean [SD] age, 60 [6] years; 4886 [46%] men). Overall, 286 proteins were associated with incident HF after V3 (822 events; P &lt; 1.0 × 10−5), 83 of which were also associated with incident after V5 (336 events; P &lt; 1.7 × 10−4). Among HF-free participants at V5 (n = 3908; mean [SD] age, 75 [5] years; 1861 [42%] men), 48 of 83 HF-associated proteins were associated with prevalent frailty (223 cases; P &lt; 6.0 × 10−4), 18 of which were also associated with incident frailty at V6 (152 cases; P &lt; 1.0 × 10−3). These proteins enriched fibrosis and inflammation pathways and demonstrated stronger associations with incident HF with preserved ejection fraction (HFpEF) than HF with reduced ejection fraction. All 18 proteins were associated with both prevalent frailty and incident HF in CHS. MR identified potential causal effects of several proteins on frailty and HF.Conclusions and RelevanceIn this study, the proteins associated with risk of HF and frailty enrich for pathways related to inflammation and fibrosis as well as risk of HFpEF. Several of these proteins could potentially contribute to the shared pathophysiology of frailty and HF.

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Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

Luo,

Shen

2024

Aging Clin Exp Res

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Background Growth differentiation factor 15 (GDF15) is a crucial biomarker in various physiological and pathological processes. While elevated GDF15 levels are linked to increased mortality risk, the role of DNA methylation (DNAm)-predicted GDF15 in predicting mortality has not been extensively studied. The purpose of the study is to investigate the association between DNAm-predicted GDF15 levels and all-cause and cardiovascular disease (CVD) mortality in a nationally representative cohort. Methods Data from NHANES 1999–2002 were analyzed. DNAm-predicted GDF15 levels were estimated using a regression model. Weighted multivariate Cox regressions were employed to assess the relationship between DNAm-predicted GDF15 and mortality outcomes. Restricted cubic splines were used to explore dose-response relationships, and subgroup analyses were conducted to enhance result reliability. Results Higher DNAm-predicted GDF15 levels were significantly associated with increased all-cause mortality risk (HR = 1.08, 95% CI: 1.02–1.15). Participants in the highest DNAm-predicted GDF15 tertile showed significantly higher all-cause mortality risk (HR = 1.56, 95% CI: 1.16–2.10) and a 2.52-fold increased risk of cardiovascular mortality (HR = 2.52, 95% CI: 1.22–5.19). Kaplan-Meier curves revealed decreasing survival probability with higher DNAm-predicted GDF15 tertiles. Restricted cubic spline analysis demonstrated a non-linear dose-response relationship between DNAm-predicted GDF15 levels and cardiovascular mortality. The positive correlation between DNAm-predicted GDF15 and mortality remained robust in most of subgroups. Conclusions DNAm-predicted GDF15 independently predicts all-cause and cardiovascular mortality. This association persists across multiple models and stratified subgroups, supporting GDF15’s value as a biomarker for mortality risk stratification. Future research should elucidate underlying biological mechanisms and evaluate GDF15’s clinical utility in guiding mortality risk reduction interventions.

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Growth Differentiation Factor‐15 Predicts Mortality and Heart Failure Exacerbation But Not Ventricular Arrhythmias in Patients With Cardiomyopathy

Cited by 5 publications

References 30 publications

Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

Growth differentiation factor‐15 and the effect of empagliflozin in heart failure: Findings from the EMPEROR program

High Throughput Plasma Proteomics and Risk of Heart Failure and Frailty in Late Life

Association between DNA methylation predicted growth differentiation factor 15 and mortality: results from NHANES 1999–2002

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