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. 2024 Jul 1;9(7):649-658.
doi: 10.1001/jamacardio.2024.1178.

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

Diego Ramonfaur  1   2 , Leo F Buckley  2 , Victoria Arthur  1 , Yimin Yang  2 , Brian L Claggett  2 , Chiadi E Ndumele  3   4 , Keenan A Walker  5 , Thomas Austin  6 , Michelle C Odden  7 , James S Floyd  6 , Sandra Sanders-van Wijk  8 , Joyce Njoroge  9 , Jorge R Kizer  10 , Dalane Kitzman  11 , Suma H Konety  12 , Jennifer Schrack  3 , Fangyu Liu  3 , B Gwen Windham  13 , Priya Palta  14 , Josef Coresh  15 , Bing Yu  16 , Amil M Shah  1
Affiliations

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

Diego Ramonfaur et al. JAMA Cardiol. .

Abstract

Importance: Heart 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.

Objective: To identify shared pathways between incident HF and frailty in late life using large-scale proteomics.

Design, setting, and participants: In 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.

Exposures: Protein aptamers, measured at study V3 and V5.

Main outcomes and measures: Outcomes 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.

Results: A 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 < 1.0 × 10-5), 83 of which were also associated with incident after V5 (336 events; P < 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 < 6.0 × 10-4), 18 of which were also associated with incident frailty at V6 (152 cases; P < 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 relevance: In 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Austin reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and outside the submitted work. Dr Sanders-van Wijk reported receiving grants and personal fees from Roche Diagnostics, AstraZeneca, Boehringer Ingelheim, and Pfizer and receiving personal fees from Novartis outside the submitted work. Dr Kizer reported owning stock in Abbott, AbbVie, Bristol-Myers Squibb, Johnson & Johnson, Eli Lilly and Co, Medtronic, Merck, and Pfizer outside the submitted work. Dr Kitzman reported receiving honoraria as a consultant for Corvia Medical, Boehringer Ingelheim, Rivus, NovoNordisk, AstraZeneca, and Pfizer; receiving grant funding from Novartis, Bayer, NovoNordisk, Rivus, Pfizer, and AstraZeneca; and owning stock in Gilead Sciences outside the submitted work. Dr Schrack reported receiving grants from the National Institute on Aging (NIA) during the conduct of the study and serving as a consultant for Edwards Lifesciences outside the submitted work. Dr Windham reported receiving grants from the NIH National Institute of Neurological Disorders and Stroke and NIA during the conduct of the study. Dr Palta reported receiving grants from NIH during the conduct of the study. Dr Coresh reported receiving grants from NIH during the conduct of the study and receiving personal fees from Soma Logic for serving on the scientific advisory board from 2022 to 2023 outside the submitted work. Dr Shah reported receiving research support through Brigham and Women’s Hospital from Novartis and receiving personal fees from Philips Ultrasound and Janssen Pharmaceuticals for serving on their advisory boards outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations of Candidate Proteins With Heart Failure (HF) and Frailty in the Atherosclerosis in Communities (ARIC) Study and Cardiovascular Health Study (CHS)
Figure 2.
Figure 2.. Cross-Sectional Association of Candidate Proteins With Phenotypes and Subtypes of Heart Failure and Components of Frailty
e′ Average indicates average measurement between lateral and medial e′; Eep average, E/e′ average between lateral and medial E/e′; GLS, global longitudinal strain, HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LAVI, left atrium volume index; LVEDVI, left ventricular end diastolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; LVESVI, left ventricular end systolic volume index; MWT, mean wall thickness, PASP, pulmonary artery systolic pressure.
Figure 3.
Figure 3.. Combined Manhattan-Type Plot Showing Single and Multimarker Cis–Protein Quantitative Trait Loci (pQTLs) for Frailty, Heart Failure (HF), and Cardiac Magnetic Resonance Imaging Measures of Left Ventricle Size and Function
A, Effect estimates for significant pQTLs among the Age/Gene-Environment Susceptibility (AGES) study; Atherosclerosis Risk in Communities (ARIC) Study; Interval, and Fenland study cohorts. Dotted line indicates nominal significance threshold, solid line indicates Bonferroni significance threshold. LVEDV indicates left ventricular end diastolic volume; LVEF, left ventricular ejection fraction, LVESV, left ventricular end systolic volume; MR, mendelian randomization.
See this image and copyright information in PMC

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