Proteomic patterns according to ejection fraction: an EMPEROR-Program analysis
European Journal of Heart Failure, 2026
Ferreira J., Fioretti F., Sumin M., Anker S., Filippatos G., Monroy Kuhn M., Panova-Noeva M., Prochaska J., Saadati M., Stolze B., Zeller C., Zannad F., Butler J.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Background
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.
Aims
To study proteomic biomarker expression across LVEF using data from the EMPEROR-Program.
Methods
2254 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 NT-proBNP levels that varied by LVEF cutoffs 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), 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 hematopoiesis are overexpressed at mildly-reduced ejection fraction, but none of the proteins passed the 5%FDR cutoff, 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.