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Linking Chronic Kidney Disease to Incident Heart Failure and Adverse Cardiac Remodeling Through the Plasma Proteome:
Leo F Buckley1, Pranav Dorbala1, Victoria Lamberson1
1Brigham and Women's Hospital, Boston, Massachusetts, USA.
Insights
Researchers identified 44 plasma proteins linked to kidney function and heart failure (HF) risk. These proteins may offer new targets for preventing HF in chronic kidney disease patients.
Area of Science:
- Cardiovascular Medicine
- Nephrology
- Proteomics
Background:
- Circulating plasma proteins may illuminate molecular pathways in heart failure (HF) development among individuals with chronic kidney disease (CKD).
- Understanding these pathways is crucial for developing targeted interventions.
Purpose of the Study:
- To pinpoint circulating plasma proteins related to kidney function that are associated with the risk of new-onset HF.
- To explore potential biomarkers and therapeutic targets for HF prevention in CKD.
Main Methods:
- Utilized aptamer-based assays to measure 4,697 plasma proteins in the Atherosclerosis Risk In Communities (ARIC) study.
- Assessed associations between protein levels, estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and incident HF using regression models.
- Validated findings in the Chronic Renal Insufficiency Cohort (CRIC) study and employed Mendelian randomization for causal inference.
Main Results:
- Identified 44 plasma proteins associated with eGFR or UACR and incident HF in the ARIC study, with 29 validated in the CRIC study.
- Most identified proteins correlated with HF with preserved ejection fraction, not reduced ejection fraction.
- Mendelian randomization suggested a causal link between Golgi membrane protein 1, HF, and eGFR.
Conclusions:
- This study identified 44 plasma proteins linked to kidney function markers (eGFR, UACR) and incident HF, independent of traditional risk factors.
- These proteins represent potential novel biomarkers and therapeutic targets for preventing HF in individuals with CKD.
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.
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