Association Between HNP1 ‐3 and Atherosclerotic Plaque Burden in Subclinical Atherosclerosis and the Mediating Effect of PCSK9

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Abstract
Subclinical atherosclerosis is a key predictor of cardiovascular events. While inflammation plays a crucial role in atherosclerosis, the involvement of Human Neutrophil Peptides 1–3 (HNP1‐3) in its progression remains unclear. The study investigates the association of HNP1‐3 and PCSK9 with coronary atherosclerotic burden and explores the potential mediatory role of PCSK9 in HNP1‐3's effect on atherogenesis. Patients who underwent coronary computed tomographic angiography (CCTA) and had subclinical atherosclerosis (luminal stenosis < 50%) or normal coronary arteries were included in this cross‐sectional study. HNP1‐3 and PCSK9 levels were measured using ELISA, and coronary plaque burden was quantified using the modified Gensini score. Patients with subclinical atherosclerosis had significantly higher levels of HNP1‐3 ( p < 0.001), PCSK9 ( p < 0.001), and lipoprotein(a) [Lp(a)] ( p < 0.001) compared to controls. HNP1‐3 was an independent predictor of subclinical atherosclerosis ( p < 0.001), and its levels positively correlated with the modified Gensini score ( p < 0.001). In multinomial logistic regression, higher levels of HNP1‐3, PCSK9, and Lp(a) were independently associated with higher modified Gensini score tertiles. Mediation analysis revealed that PCSK9 mediated 48.7% of the effect of HNP1‐3 on the modified Gensini score. After adjusting for hsCRP and cardiovascular risk factors, the direct effect of HNP1‐3 became statistically insignificant, while the indirect effect via PCSK9 remained significant, suggesting that PCSK9 fully mediates the pro‐atherogenic effects of HNP1‐3. In conclusion, HNP1‐3 is a novel independent predictor of subclinical atherosclerosis and coronary plaque burden, with its effects being mediated through PCSK9. These findings suggest that targeting PCSK9 could mitigate the inflammatory actions of HNP1‐3, offering potential therapeutic insights for atherosclerosis prevention.

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