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Updated: May 4, 2026
Author Spotlight: Advancing the Analysis of Plasma Extracellular Vesicle Proteome for Cardiovascular Biomarker Studies
Published on: January 31, 2025
Proteomic patterns according to ejection fraction: an EMPEROR-programme analysis
João Pedro Ferreira1,2, Francesco Fioretti3,4, Mikhail Sumin5
1RISE-Health, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, Porto 4200-319, Portugal.
Insights
Proteomic biomarkers show trends across left ventricular ejection fraction (LVEF) categories in heart failure patients. However, circulating proteins weakly correlate with LVEF and do not reliably discriminate ejection fraction levels.
Area of Science:
- Cardiology
- Proteomics
- Biomarker Discovery
Background:
- Left ventricular ejection fraction (LVEF) is a key criterion in heart failure (HF) trials.
- Patient characteristics, risk, and treatment response differ across LVEF.
- Understanding biological processes related to LVEF is crucial.
Purpose of the Study:
- To investigate proteomic biomarker expression across different LVEF categories.
- Utilize data from the EMPEROR-Programme to analyze protein expression patterns.
- Identify potential protein biomarkers associated with LVEF variations.
Main Methods:
- Analysis of proteomic data from 2254 patients using Olink® platforms.
- Focus on the EMPEROR-Preserved dataset for main analyses.
- Ordinal logistic regression used to compare protein concentrations across LVEF categories (41%-49%, 50%-59%, ≥60%), adjusted for covariates and FDR correction.
Main Results:
- 297 proteins showed expression trends across LVEF categories in EMPEROR-Preserved.
- Top proteins included NT-pro BNP, Wnt inhibitory factor-1, and natriuretic peptides B.
- Correlation between these proteins and LVEF was generally weak (Rho ≤0.2).
Conclusions:
- Differentially expressed proteins suggest involvement of natriuretic peptide, cell-adhesion, and clonal hematopoiesis pathways.
- No proteins met the 5% FDR threshold, and correlations with LVEF were weak.
- Circulating proteins may not be effective discriminators of ejection fraction in HF.
Aims:
Left ventricular ejection fraction (LVEF) has been incorporated as an inclusion criterion in HF trials. Patient's characteristics, event risk, and treatment response vary according to LVEF. A better understanding of the biological processes across LVEF is warranted. To study proteomic biomarker expression across LVEF using data from the EMPEROR-Programme.
Methods:
Two thousand two hundred and fifty-four patients who had proteomic measurements available using 1134 proteins overlapping between the Explore 1536 and 3072 Olink® platforms were included. Main analyses were performed within the EMPEROR-Preserved dataset due to differences in entry criteria between EMPEROR-Preserved and EMPEROR-Reduced with higher entry N-terminal pro B-type natriuretic peptide (NT-proBNP) levels that varied by LVEF cut-offs in the latter. Protein concentrations were compared using ordinal logistic regression across LVEF categories: 41%-49%, 50%-59%, and ≥60%. The resulting β-coefficient indicates the change in the log-odds for the outcome of being in a lower LVEF category for every NPX unit in log2 scale. Analyses were adjusted for covariates and a false-discovery-rate (FDR) correction was applied.
Results:
A total of 297 proteins exhibited a trend of expression across LVEF categories in EMPEROR-Preserved after adjustment for potential confounders and correction for test multiplicity. Of these, the top 10 proteins were: NT-pro BNP (β = 0.18, 95% CI 0.09-0.27), Wnt inhibitory factor-1 (β = 0.40, 95% CI 0.19-0.61), sialomucin core protein 24 (β = 0.48, 95% CI 0.22-0.74), phospholipid transfer protein (β = 0.38, 95% CI 0.17-0.59), natriuretic peptides B (β = 0.13, 95% CI 0.06-0.20), intercellular adhesion molecule 5 (β = 0.31, 95% CI 0.14-0.49), neural cell adhesion molecule 2 (β = 0.45, 95% CI 0.19-0.70), neural cell adhesion molecule L1-like protein (β = 0.45, 95% CI 0.19-0.71), interactor protein for cytohesin exchange factors 1 (β = 0.12, 95% CI 0.05-0.19), and 3-ketoacyl-CoA thiolase, peroxisomal (β = 0.17, 95% CI 0.07-0.26). The correlation between these proteins and LVEF was generally weak (Rho ≤0.2).
Conclusions:
Within EMPEROR-Preserved, the top differentially expressed circulating proteins suggest that pathways related to natriuretic peptides, cell-adhesion, and clonal haematopoiesis are overexpressed at mildly-reduced ejection fraction, but none of the proteins passed the 5%FDR cut-off, and the correlation between circulating proteins and LVEF was weak. These findings suggest that circulating proteins may not be a good discriminant of ejection fraction.
