What is the clinical evidence from this study?

Study design: Observational. Population: Heart failure with reduced ejection fraction (HFrEF) (n=140). Intervention: High serum human epididymis protein 4 (HE4) vs. Low serum HE4. Primary outcome: Composite of cardiovascular death or hospitalization for heart failure (HR 3.99, 95% CI 2.05-7.75, p=<0.001).

What question did this study set out to answer?

The aim is to evaluate the significance of HE4 levels as a prognostic marker in patients with heart failure and reduced ejection fraction.

April 1, 2026Open Access

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

Q: What are the key findings of this study?

Elevated serum human epididymis protein 4 (HE4) levels independently predicted a nearly four-fold increased risk of cardiovascular death or heart failure hospitalization in patients with HFrEF (HR 3.99).

Q: What question did this study set out to answer?

The aim is to evaluate the significance of HE4 levels as a prognostic marker in patients with heart failure and reduced ejection fraction.

Key Result

Elevated serum human epididymis protein 4 (HE4) levels independently predicted a nearly four-fold increased risk of cardiovascular death or heart failure hospitalization in patients with HFrEF (HR 3.99).

Key Points

The aim is to evaluate the significance of HE4 levels as a prognostic marker in patients with heart failure and reduced ejection fraction.
Measured serum HE4 concentrations in 140 patients with heart failure and reduced ejection fraction over 3 years.
Utilized Kaplan-Meier analysis to assess cardiovascular event rates based on HE4 levels.
Conducted multivariate Cox regression analysis to determine HE4's predictive value for adverse outcomes.
Patients in the high HE4 group had significantly higher cardiovascular event rates (log-rank P<0.001).
HE4 identified as an independent predictor of adverse outcomes with a hazard ratio of 3.99 (95% CI 2.05-7.75; P<0.001).
High HE4 combined with low global longitudinal strain indicated the highest cardiovascular event rate (log-rank P<0.001).

Study Design

Type

Observational (n=140)

Multicenter

Structured PICO

Does high serum HE4 concentration predict cardiovascular death or heart failure hospitalization in patients with HFrEF?

Population

140 patients with HFrEF (LVEF <40%), mean age 65, 75% male, admitted to Kumamoto University Hospital (Japan). Key exclusions: eGFR <30 mL/min/1.73 m2, active malignancy, fibrotic diseases, absence of cardiac catheterization, acute coronary syndrome, and HF requiring mechanical circulatory support.

Intervention

High serum Human Epididymis Protein 4 (HE4) concentrations (above the median of 67.7 pmol/L)

Comparator

Low serum Human Epididymis Protein 4 (HE4) concentrations (below the median of 67.7 pmol/L)

Outcome

Composite of cardiovascular death or hospitalization for heart failure events within 3 yearscomposite

Elevated serum HE4 levels are an independent prognostic biomarker for cardiovascular death and heart failure hospitalization in patients with HFrEF, providing incremental prognostic value over established risk factors.

Main Result

Effect estimate: HR 3.99 (95% CI 2.05-7.75)

p-value: p=<0.001

Limitations

Single-center retrospective observational study with a small sample size
Limited number of primary events restricted model complexity, preventing uniform inclusion of renal indices in all multivariable models
Inclusion of various etiologies makes it unclear if HE4 is reliable for each specific etiology
Serial measurements of HE4 were not available to assess temporal changes

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 (lnHE4) 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.

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