Human epididymis protein 4 (HE4), a fibrosis-associated biomarker expressed in activated myofibroblasts, has shown prognostic relevance in dilated cardiomyopathy, but its role in heart failure with reduced ejection fraction (HFrEF) remains unclear. A prospective cohort study published in Circulation Journal evaluated the prognostic significance of HE4 and its association with myocardial function in HFrEF.

Serum HE4 concentrations were measured in 140 patients with HFrEF, defined as left ventricular ejection fraction (LVEF) <40%, with follow-up of up to 3 years. The primary outcomes were cardiovascular (CV) death and heart failure hospitalization. Patients were stratified into high and low HE4 groups based on the median value. Kaplan-Meier analysis showed significantly higher CV event rates in the high HE4 group compared with the low HE4 group (log-rank P<0.001).

Multivariate Cox regression identified HE4 (ln[HE4]) as an independent predictor of adverse outcomes (hazard ratio [HR] 3.99; 95% confidence interval [CI] 2.05-7.75; P<0.001). Multivariate linear regression showed that HE4 was associated with age, serum creatinine, plasma B-type natriuretic peptide (BNP), E/e′, and global longitudinal strain (GLS) (β=−0.083; 95% CI −0.111 to −0.054; P<0.001). Combined assessment demonstrated that patients with high HE4 and low GLS had the highest CV event rates (log-rank P<0.001).

These findings support HE4 as an independent prognostic biomarker in HFrEF, with its association with GLS reflecting myocardial dysfunction and fibrotic remodeling observed in this population.