Circulating HE4 is a robust and independent predictor of long-term mortality and MACE in patients with PAD, with incremental prognostic value for mortality, primarily in terms of risk reclassification.
Key Findings
Results
Higher serum HE4 levels were independently associated with all-cause mortality in PAD patients after adjustment for established cardiovascular risk factors and renal function.
Cohort consisted of 291 patients with symptomatic PAD followed prospectively for 10 years
HR 1.35 (95% CI 1.14–1.58; p < 0.001) per doubling of HE4 for all-cause mortality in multivariable models
44.7% of patients died during the 10-year follow-up period
Serum HE4 concentrations were measured by ELISA at baseline
Results
Higher serum HE4 levels were independently associated with major adverse cardiovascular events (MACE) after multivariable adjustment.
HR 1.24 (95% CI 1.05–1.46; p = 0.010) per doubling of HE4 for MACE in adjusted models
41.2% of patients experienced MACE during the 10-year follow-up
Association remained significant after adjustment for established cardiovascular risk factors and renal function
Results
HE4 was independently associated with both cardiovascular and non-cardiovascular mortality in secondary analyses.
Secondary endpoints included cardiovascular and non-cardiovascular mortality analyzed separately
Associations with both subcategories of mortality remained statistically significant in adjusted models
This suggests HE4's prognostic relevance extends beyond purely cardiovascular pathways
Results
Addition of HE4 to established risk factors significantly improved risk discrimination and reclassification for all-cause mortality.
Net Reclassification Improvement (NRI) = 0.412, p < 0.001 for all-cause mortality
Integrated Discrimination Improvement (IDI) = 0.028, p = 0.004 for all-cause mortality
Incremental prognostic value for MACE was not statistically significant when HE4 was added to established risk factors
Results
In univariable models, higher HE4 levels were associated with both all-cause mortality and MACE before any covariate adjustment.
Univariable associations were observed for both primary endpoints: all-cause mortality and MACE
These associations were subsequently confirmed in multivariable models adjusting for established cardiovascular risk factors and renal function
Study design was a prospective cohort study with 10-year follow-up
What This Means
This research examined whether a blood protein called Human Epididymis Protein 4 (HE4), previously linked to fibrosis and heart disease, could predict long-term outcomes in people with peripheral artery disease (PAD) — a condition where narrowed arteries reduce blood flow to the limbs. The study followed 291 PAD patients for 10 years, measuring HE4 levels in their blood at the start. During that decade, nearly 45% of patients died and about 41% had major adverse cardiovascular events such as heart attacks or strokes.
The study found that patients with higher HE4 levels in their blood were significantly more likely to die or experience serious cardiovascular events over the following 10 years, even after accounting for other known risk factors like kidney function and traditional cardiovascular risks. Each doubling of the HE4 level was associated with a 35% increased risk of death and a 24% increased risk of major cardiovascular events. Notably, adding HE4 measurements to standard risk assessment tools meaningfully improved the ability to correctly classify patients' mortality risk, though its added value for predicting cardiovascular events specifically was less clear.
This research suggests that measuring HE4 in the blood of PAD patients could provide doctors with additional prognostic information beyond what current risk assessment tools offer, particularly for predicting who is at higher risk of dying over the long term. Since HE4 predicted both cardiovascular and non-cardiovascular death, it may reflect broader biological processes such as organ fibrosis or systemic disease burden that go beyond heart and vascular disease alone.
Muendlein A, Heinzle C, Geiger K, Brandtner E, Schnetzer L, Dopheide J, et al.. (2026). Circulating Human Epididymis Protein 4 Predicts 10-Year Mortality and Major Adverse Cardiovascular Events in Patients With Peripheral Artery Disease.. European journal of clinical investigation. https://doi.org/10.1111/eci.70236