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Circulating Human Epididymis Protein 4 Predicts 10-Year Mortality and Major Adverse Cardiovascular Events in Patients
Axel Muendlein1, Christine Heinzle1,2, Kathrin Geiger1,2
1Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Feldkirch, Austria.
Insights
High levels of Human Epididymis protein 4 (HE4) predict long-term mortality and major adverse cardiovascular events (MACE) in peripheral artery disease (PAD) patients. HE4 improves risk reclassification for mortality, offering valuable prognostic insight.
Area of Science:
- Cardiovascular Medicine
- Biomarker Research
- Clinical Prognostics
Background:
- Human Epididymis protein 4 (HE4) is linked to fibrosis and cardiovascular disease.
- Prognostic relevance of HE4 in peripheral artery disease (PAD) is not well-established.
Purpose of the Study:
- To investigate the association between circulating HE4 levels and long-term outcomes in symptomatic PAD patients.
Main Methods:
- Prospective cohort study of 291 PAD patients followed for 10 years.
- Serum HE4 measured by ELISA at baseline.
- Primary endpoints: all-cause mortality and major adverse cardiovascular events (MACE).
Main Results:
- Higher HE4 levels independently predicted all-cause mortality (HR 1.35) and MACE (HR 1.24) per doubling.
- HE4 was associated with both cardiovascular and non-cardiovascular mortality.
- HE4 significantly improved risk discrimination and reclassification for all-cause mortality when added to risk factors.
Conclusions:
- Circulating HE4 is a robust, independent predictor of long-term mortality and MACE in PAD.
- HE4 offers incremental prognostic value for mortality, particularly in risk reclassification.
Background:
Human epididymis protein 4 (HE4) has emerged as a biomarker linked to fibrosis and cardiovascular disease. However, its prognostic relevance in peripheral artery disease (PAD) remains unclear. We therefore investigated the association of circulating HE4 with long-term outcomes in patients with PAD.
Methods:
In this prospective cohort study, 291 patients with symptomatic PAD were enrolled and followed for 10 years. Serum HE4 concentrations were measured by ELISA at baseline. Primary endpoints were all-cause mortality and major adverse cardiovascular events (MACE); secondary endpoints were cardiovascular and non-cardiovascular mortality.
Results:
During follow-up, 44.7% of patients died and 41.2% experienced MACE. In univariable models, higher HE4 levels were associated with all-cause mortality and MACE. These associations remained significant after adjustment for established cardiovascular risk factors and renal function: HR 1.35 (95% CI 1.14-1.58; p < 0.001) for all-cause mortality and HR 1.24 (95% CI 1.05-1.46; p = 0.010) for MACE per doubling of HE4. In secondary analyses, HE4 was independently associated with both cardiovascular and non-cardiovascular mortality. Addition of HE4 to established risk factors significantly improved risk discrimination and reclassification for all-cause mortality (NRI = 0.412, p < 0.001; IDI = 0.028, p = 0.004), whereas incremental prognostic value for MACE was not statistically significant.
Conclusion:
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.
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