HE4 as a Prognostic Biomarker of Major Adverse Cardiovascular Events in Patients with Abdominal Aortic Aneurysm: A Canadian Prospective Observational Study.

Background

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease characterized by the proteolytic breakdown of the extracellular matrix. A clinical biomarker is needed for risk stratification and prognosis.

Methods

In this single-center, 5-year observational study, 452 patients were enrolled: 343 with AAA (≥3 cm), and 109 controls (<3 cm). Plasma levels of six inflammatory proteins (human epididymis protein 4 (HE4), matrix metalloproteinase (MMP) 1 and 3, cathepsin S, chitinase 3 like-1, cathepsin S, and B-cell activating factor (BAFF)) were quantified at baseline. Patients were followed for a total of 5 years (60 months), and major adverse cardiovascular events (MACEs, defined as the composite of myocardial infarction, cerebrovascular attack, and cardiovascular-related death) were recorded. A Cox proportional hazard model was created using biomarker levels, age, sex, hypertension, hypercholesterolemia, diabetes mellitus, smoking status, and coronary artery disease to determine whether the baseline levels of these proteins were associated with MACEs over 5 years.

Results

HE4, MMP-3, BAFF, and cathepsin S levels were significantly elevated in AAA patients compared to controls (all p < 0.05). HE4/WFDC2, MMP-3, and Chitinase 3-like 1 were significantly linearly associated with AAA diameter at baseline. With every normalized unit increase in HE4/WFDC2, MMP-3, and Chitinase 3-like 1, there was an increase in abdominal aortic diameter by 0.154 (95% CI: 0.032-0.276, p = 0.013), 0.186 (95% CI: 0.064-0.309, p = 0.003), and 0.231 (0.110-0.353, p < 0.001) centimeters, respectively. Among patients with AAA, elevated HE4 was associated with higher risk of MACEs (adjusted HR 1.249; 95% CI: 1.057-1.476; p = 0.009). Patients with high baseline HE4 (≥9.338 ng/mL) had significantly lower freedom from MACEs at 5 years (76.7% vs. 84.8%, p = 0.022).

Conclusions

HE4 may be a potential prognostic biomarker that can be used to risk stratify patients with AAA to better personalize treatment strategies to reduce adverse events.