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HE4 as a Prognostic Biomarker of Major Adverse Cardiovascular Events in Patients with Abdominal Aortic Aneurysm: A
Hamzah Khan1,2, Abdelrahman Zamzam1,2, Farah Shaikh1,2
1Division of Vascular Surgery, St. Michael's Hospital, Toronto, ON M5B 1W8, Canada.
Insights
Human epididymis protein 4 (HE4) shows promise as a biomarker for abdominal aortic aneurysm (AAA). Elevated HE4 levels in AAA patients correlate with larger aneurysm size and increased risk of major adverse cardiovascular events (MACEs).
Area of Science:
- Cardiovascular Research
- Inflammatory Disease Biomarkers
- Vascular Biology
Background:
- Abdominal aortic aneurysm (AAA) is a chronic inflammatory condition involving extracellular matrix degradation.
- Current risk stratification and prognostic tools for AAA are insufficient, highlighting the need for a clinical biomarker.
Purpose of the Study:
- To investigate the association between plasma levels of inflammatory proteins and the risk of major adverse cardiovascular events (MACEs) in patients with abdominal aortic aneurysm (AAA).
- To evaluate the potential of these proteins, particularly human epididymis protein 4 (HE4), as prognostic biomarkers for AAA.
Main Methods:
- A 5-year observational study involving 452 participants (343 with AAA, 109 controls).
- Quantification of plasma levels of six inflammatory proteins (HE4, MMP-1, MMP-3, cathepsin S, chitinase 3 like-1, BAFF) at baseline.
- Analysis using Cox proportional hazard models, incorporating clinical factors, to assess the association between protein levels and MACEs.
Main Results:
- Elevated levels of HE4, MMP-3, BAFF, and cathepsin S were observed in AAA patients compared to controls.
- HE4, MMP-3, and Chitinase 3-like 1 levels showed a significant linear association with AAA diameter.
- Elevated baseline HE4 levels in AAA patients were significantly associated with an increased risk of MACEs over 5 years.
Conclusions:
- Human epididymis protein 4 (HE4) demonstrates potential as a prognostic biomarker for abdominal aortic aneurysm (AAA).
- HE4 can aid in risk stratification of AAA patients, potentially enabling personalized treatment strategies to mitigate adverse cardiovascular events.
Abstract:
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.
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