Interaction between serum endotoxemia and proprotein convertase subtilisin/kexin 9 (PCSK9) in patients with atrial fibrillation: A post-hoc analysis from the ATHERO-AF cohort

Background and aims: Lipopolysaccharides (LPS) is emerging as a novel risk factor for cardiovascular events (CVEs). Furthermore, in vitro evidence suggested that LPS may elicit proprotein convertase subtilisin/kexin 9 (PCSK9) expression, but their relationship in vivo has not been investigated. Methods: We conducted a post-hoc analysis of a prospective, single centre cohort study of 907 patients with nonvalvular atrial fibrillation (AF). At baseline, PCSK9, LPS and NADPH oxidase (sNox2-dp) were measured. PCSK9 and LPS were correlated with the incidence of CVEs. Results: Median PCSK9 and LPS were 1200 [900-1970] and 49.9 [15.0-108.2] pg/ml, respectively. LPS and PCSK9 were significantly correlated (rS 0.378, p < 0.001). Logistic regression analysis showed that LPS was associated with PCSK9 above the median (odds ratio [OR] 1.727 95% confidence interval [CI] 1.147-2.600 p=0.009). Other factors associated with PCSK9 above the median were sNox2-dp (OR 1.759 C.I. 95% 1.167-2.650, p=0.007), use of antiplatelet drugs (OR 0.437 95%CI 0.219-0.871 p=0.017) and high adherence to Mediterranean diet (OR 0.737 95%CI 0.643-0.845 p=0.001). Olive oil (OR 0.376 95%CI 0.185-0.763, p=0.001) and wine (OR 0.460 95%CI 0.289-0.733 p=0.007) were negatively associated with PCSK9. Patients with concomitant high PCSK9 and LPS (LPS=88 pg/ml and PCSK9=1570 pg/ml) had an increased risk of CVEs compared to those with low levels (LPS< 24.3 pg/ml and PCSK9< 1000 pg/ml, Log-Rank test, p = 0.022). Conclusions: This study demonstrated, for the first time in vivo, that circulating levels of PCSK9 and LPS are associated with a mechanism possibly involving NADPH oxidase activation. Patients with concomitant increase of PCSK9 and LPS showed a higher risk of CVEs.