Human epididymis protein 4 is a predictor of long-term mortality and major adverse cardiovascular events in patients with coronary artery disease

Human epididymis protein 4 (HE4; WFDC2) has emerged as a profibrotic biomarker associated with adverse outcomes across multiple diseases. However, its prognostic value in patients with established coronary artery disease (CAD) remains insufficiently characterized and was addressed in the present study. We prospectively studied 395 patients with angiographically confirmed CAD. Circulating HE4 levels were measured at baseline and analyzed both as log2-transformed values and by using a data-derived cut-off of 8.0 ng/mL, derived from Youden’s index. The primary endpoints were major adverse cardiovascular events (MACE) and all-cause mortality during a 10-year follow-up. Multivariable Cox regression models were adjusted for traditional risk factors, including age, body mass index, hypertension, type 2 diabetes mellitus, LDL cholesterol, HDL cholesterol, and the presence of significant coronary artery disease (Model 1), and additionally for renal function, C-reactive protein, fibrinogen, and N-terminal pro–B-type natriuretic peptide (Model 2). Higher HE4 levels, analyzed as a log2-transformed continuous variable, indicated a significantly increased risk of MACE and all-cause mortality across all adjustment models, with HRs of 1.2–1.4 per doubling of HE4. Also, the categorical HE4 cut-off was significantly associated with all endpoints across all adjustment levels, and the addition of HE4 to the fully adjusted baseline model improved overall risk reclassification across all endpoints. In conclusion, HE4 is significantly associated with long-term cardiovascular outcomes and all-cause mortality in patients with established CAD and may provide prognostic information beyond inflammatory and cardiorenal markers.