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. 2025 Apr;18(4):e011208.
doi: 10.1161/CIRCHEARTFAILURE.123.011208. Epub 2025 Mar 7.

Harnessing the Plasma Proteome to Predict Mortality in Heart Failure Subpopulations

Jessica Chadwick  1 , Michael A Hinterberg  2 , Folkert W Asselbergs  3   4 , Hannah Biegel  2 , Eric Boersma  5 , Thomas P Cappola  6 , Julio A Chirinos  7 , Joseph Coresh  8 , Peter Ganz  9 , David A Gordon  10 , Natasha Kureshi  2 , Kelsey M Loupey  1 , Alena Orlenko  11 , Rachel Ostroff  1 , Laura Sampson  2 , Sama Shrestha  2 , Nancy K Sweitzer  12 , Stephen A Williams  1 , Lei Zhao  10 , Isabella Kardys  5 , David E Lanfear  13
Affiliations

Harnessing the Plasma Proteome to Predict Mortality in Heart Failure Subpopulations

Jessica Chadwick et al. Circ Heart Fail. 2025 Apr.

Abstract

Background: We derived and validated proteomic risk scores (PRSs) for heart failure (HF) prognosis that provide absolute risk estimates for all-cause mortality within 1 year.

Methods: Plasma samples from individuals with HF with reduced ejection fraction (HFrEF; ejection fraction <40%; training/validation n=1247/762) and preserved ejection fraction (HFpEF; ejection fraction ≥50%; training/validation n=725/785) from 3 independent studies were run on the SomaScan Assay measuring ≈5000 proteins. Machine learning techniques resulted in unique 17- and 14-protein models for HFrEF and HFpEF that predict 1-year mortality. Discrimination was assessed via C-index and 1-year area under the curve (AUC), and survival curves were visualized. PRSs were also compared with Meta-Analysis Global Group in Chronic HF (MAGGIC) score and NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurements and further assessed for sensitivity to disease progression in longitudinal samples (HFrEF: n=396; 1107 samples; HFpEF: n=175; 350 samples).

Results: In validation, the HFpEF PRS performed significantly better (P≤0.1) for mortality prediction (C-index, 0.79; AUC, 0.82) than MAGGIC (C-index, 0.71; AUC, 0.74) and NT-proBNP (PRS C-index, 0.76 and AUC, 0.81 versus NT-proBNP C-index, 0.72 and AUC, 0.76). The HFrEF PRS performed comparably to MAGGIC (PRS C-index, 0.76 and AUC, 0.83 versus MAGGIC C-index, 0.75 and AUC, 0.84) but had a significantly better C-Index (P=0.026) than NT-proBNP (PRS C-index, 0.75 and AUC, 0.78 versus NT-proBNP C-index, 0.73 and AUC, 0.77). PRS included known HF pathophysiology biomarkers (93%) and novel proteins (7%). Longitudinal assessment revealed that HFrEF and HFpEF PRSs were higher and increased more over time in individuals who experienced a fatal event during follow-up.

Conclusions: PRSs can provide valid, accurate, and dynamic prognostic estimates for patients with HF. This approach has the potential to improve longitudinal monitoring of patients and facilitate personalized care.

Keywords: cardiovascular diseases; heart failure; natriuretic peptide, brain; prognosis; proteomics.

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Conflict of interest statement

SomaLogic Inc funded the costs of the proteomic assays, and Drs Chadwick, Loupey, Hinterberg, Sampson, and Ostroff and N. Kureshi are employees of the company. Dr Ganz is a member of SomaLogic’s Medical Advisory Board for which he accepts no financial remuneration of any kind. Dr Kardys received travel reimbursement from SomaLogic and Olink.

Figures

Figure 1.
Figure 1.
Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) proteomic risk score overview. Schematic overview of the HFrEF (A) and HFpEF (B) model training and validation program. Full demographic details of participants in each study are shown in Table 1. Study fractions outlined in red represent independent validation data sets, which were analyzed independently and merged and analyzed as a single data set. ARIC indicates Atherosclerosis Risk in Communities; Bio-SHiFT, The Role of Biomarkers and Echocardiography in Predication of Prognosis of Chronic Heart Failure Patients; HFGR, Henry Ford Heart Failure Genomic Registry; PHFS, Penn Heart Failure Study; and TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial.
Figure 2.
Figure 2.
Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) proteomic risk score Kaplan-Meier. Observed survival probability and average time to event (death) in the combined HFrEF (A) and HFpEF (B) validation data set when stratified by relative risk bins. The Kaplan-Meier point estimate of observed events up to 12 months, stratified by risk bin: low risk, bottom quartile (absolute risk score 0≥x≤0.057 for HFrEF and 0≥x≤0.017 for HFpEF); medium risk, middle 2 quartiles (absolute risk score 0.057>x≤0.187 for HFrEF and 0.017>x≤0.081 for HFpEF); and high risk, top quartile (absolute risk score 0.187>x≤1.00 for HFrEF and 0.081>x≤1.00 for HFpEF).
Figure 3.
Figure 3.
Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) proteomic risk score change in risk. A, Plot of estimated marginal means of predicted HFrEF (1-year) risk in participants who have a fatal event after timepoint 3 (event group) vs participants with no fatal event during follow-up (no event group). B, Plot of mean predicted HFpEF (1-year) risk in event group vs no event group. The error bars represent the 95% CI for each timepoint. The dashed horizontal lines represent the baseline risk prediction for each group. Bio-SHiFT indicates The Role of Biomarkers and Echocardiography in Predication of Prognosis of Chronic Heart Failure Patients; and TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial.
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