Linking Chronic Kidney Disease to Incident Heart Failure and Adverse Cardiac Remodeling Through the Plasma Proteome: The ARIC Study

Authors

• Leo F Buckley
• Pranav Dorbala
• Victoria Lamberson
• Brian L Claggett
• Yue Ren
• Morgan E Grams
• Josef Coresh
• Kunihiro Matsushita
• Ryan T Demmer
• Ruth F Dubin
• Rajat Deo
• Peter Ganz
• Christie M Ballantyne
• Ron C Hoogeveen
• Bing Yu
• Amil M Shah

Language

English

Publication Date

8-1-2025

Journal

JACC: Heart Failure

DOI

10.1016/j.jchf.2025.102512

PMID

40578264

Abstract

Background: Investigation of circulating plasma proteins may reveal insights into molecular pathways that contribute to the development of heart failure (HF) among people with chronic kidney disease.

Objectives: The authors aimed to identify circulating kidney function-related plasma proteins that are associated with the risk of incident HF.

Methods: The authors studied participants of the ongoing longitudinal ARIC (Atherosclerosis Risk In Communities) study. Relative plasma concentrations of 4,697 unique proteins were measured with the use of an aptamer assay (Somalogic). Each protein was tested for associations with estimated glomerular filtration rate (eGFR), log-transformed urine albumin-to-creatinine ratio (UACR), and incident HF by means of multivariable linear and Cox regression models. Protein-HF associations were validated externally in the CRIC (Chronic Renal Insufficiency Cohort) study. Two-sample mendelian randomization was used to test for potential causal associations.

Results: In fully adjusted models, 44 plasma proteins were associated with either eGFR or UACR and incident HF at 2 separate ARIC study visits, of which 29 were validated externally in CRIC. Most plasma proteins were associated with HF with preserved ejection fraction, but not reduced ejection fraction. A cluster within these 44 plasma proteins were associated with larger left ventricular end-diastolic volume index and left ventricular diastolic dysfunction. Mendelian randomization suggests that Golgi membrane protein 1 is causally associated with HF and eGFR.

Conclusions: This study identified 44 eGFR- and UACR-related plasma proteins that are associated with incident HF independently from demographics, risk factors, and kidney function. These results may inform future therapeutic and biomarker development for the prevention and treatment of incident HF.

Keywords

Female, Humans, Male, Middle Aged, Albuminuria, Biomarkers, Blood Proteins, Glomerular Filtration Rate, Heart Failure, Incidence, Longitudinal Studies, Mendelian Randomization Analysis, Proteome, Renal Insufficiency, Chronic, Risk Factors, Stroke Volume, United States, Ventricular Remodeling, chronic kidney disease, drug discovery, genomics, heart failure, proteomics

Published Open-Access

yes

Recommended Citation

Buckley, Leo F; Dorbala, Pranav; Lamberson, Victoria; et al., "Linking Chronic Kidney Disease to Incident Heart Failure and Adverse Cardiac Remodeling Through the Plasma Proteome: The ARIC Study" (2025). Faculty, Staff and Student Publications. 1586.
https://digitalcommons.library.tmc.edu/uthsph_docs/1586