Diagnosing heart failure with preserved ejection fraction (HFpEF) remains difficult because symptoms are often nonspecific and conventional biomarkers may have limited diagnostic accuracy. A diagnostic case-control study published in Frontiers in Cardiovascular Medicine evaluated whether combining multiple circulating biomarkers could better identify HFpEF than single biomarkers alone.

Serum samples from 58 patients with HFpEF and 30 healthy controls were analyzed using a multiplex proteomic assay platform. Diagnostic models were compared with receiver operating characteristic curve analysis. The analysis assessed both individual biomarkers and several combined biomarker panels.

Serum levels of Delta-like 1 homolog (DLK-1), pulmonary surfactant protein D (PSP-D), and proprotein convertase subtilisin/kexin type 9 (PCSK-9) were higher in patients with HFpEF than in controls. Regression analysis showed that N-terminal pro-B-type natriuretic peptide (NT-proBNP), uric acid (UA), and PCSK-9 were associated with HFpEF, with coefficients of 0.009, 0.006, and 1.061, respectively.

The combination of NT-proBNP, DLK-1, PSP-D, and PCSK-9 had the highest area under the curve (AUC) at 0.794. This was numerically higher than NT-proBNP plus PCSK-9 (0.788), the three-marker model of DLK-1, PSP-D, and PCSK-9 (0.622), and each biomarker alone, including NT-proBNP (0.778), PCSK-9 (0.628), DLK-1 (0.578), and PSP-D (0.523).

These findings suggest that integrating multiple biomarkers may improve diagnostic separation compared with single-marker approaches in this dataset and may merit validation in larger HFpEF populations.