High Human Epididymis Protein 4 Levels Are Associated With Lower Systolic Function and Poor Prognosis in Heart Failure With Reduced Ejection Fraction

Clinical Snapshot

Key Findings

• P Value: P<0.001

• Effect Size: Hazard ratio 3.99 for ln(HE4) as continuous variable

• Primary Outcome: Composite of cardiovascular death and heart failure hospitalization

• Nnt Or Sensitivity: Significantly higher event rates in high HE4 group versus low HE4 group (log-rank P<0.001)

• Confidence Interval: 95% CI 2.05-7.75

Clinical Application

Requires laboratory capability for HE4 measurement, which may not be routinely available in all centres Would need TGA approval for diagnostic use; could complement existing HF biomarkers like NT-proBNP covered under PBS. Relevant to RACGP chronic disease management and specialist cardiology referral pathways Patients with established HFrEF (LVEF <40%) in cardiology or heart failure clinic settings

Abstract

BACKGROUND: Human epididymis protein 4 (HE4) is a novel fibrosis marker expressed in activated myofibroblasts. Although we previously demonstrated its prognostic value in dilated cardiomyopathy, its significance in general heart failure with reduced ejection fraction (HFrEF) remains unclear. METHODS AND RESULTS: Serum HE4 concentrations were measured in 140 patients with HFrEF (left ventricular ejection fraction <40%) and followed for up to 3 years to assess cardiovascular (CV) death and heart failure hospitalization. Kaplan-Meier analysis revealed significantly higher CV event rates in the high HE4 group (above the median) than in the low HE4 group (log-rank P<0.001). Multivariate Cox regression analysis identified HE4 (ln[HE4]) as an independent predictor of adverse outcomes (hazard ratio 3.99; 95% confidence interval [CI] 2.05-7.75; P<0.001). In multivariate linear regression, HE4 was significantly associated with age, serum creatinine, plasma B-type natriuretic peptide, E/e', and global longitudinal strain (GLS; β=-0.083; 95% CI -0.111, -0.054; P<0.001). Combining HE4 and GLS demonstrated that patients with high HE4 and low GLS had the highest CV event rate (log-rank P<0.001). CONCLUSIONS: HE4 is an independent prognostic biomarker in HFrEF, and its association with GLS may reflect underlying myocardial dysfunction and fibrotic remodeling leading to adverse outcomes.

References

1. 1.Okuno, Y., Hanatani, S., Ogata, F., Yamaguchi, S., Yamamoto, M., Kuyama, N., Ishii, M., Usuku, H., Yamamoto, E., Oda, S., Izumiya, Y., Soejima, H., Kawano, H., Hirai, T., & Tsujita, K. (2026). High Human Epididymis Protein 4 Levels Are Associated With Lower Systolic Function and Poor Prognosis in Heart Failure With Reduced Ejection Fraction. Circulation Journal. https://doi.org/10.1253/circj.CJ-25-0942