Abstract 4365619: Lipoprotein(a) particle characteristics and PCSK9 determine the monocyte subtype distribution in patients with increased Lp(a) levels

Abstract

Background: Monocytes, particularly the proinflammatory intermediate subsets (IM), drive atherosclerosis and predict cardiovascular events. The elevated levels of lipoprotein(a) (Lp(a)) further modulate the monocyte dynamics. However, the impact of lipid-lowering proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9i) on monocyte distribution in high-risk patients remains unknown. Purpose: We aimed to evaluate the effect of the individual lipoproteins and PCSK9i on monocyte subtypes’ distribution in patients with stable coronary disease and significantly elevated Lp(a) levels. Methods: We included 100 statin-treated patients in stable phase after myocardial infarction and elevated Lp(a) levels. The patients received placebo or PCSK9i every two weeks for 6 months. Biochemical, genetic and cell analysis at baseline and after 6 months were performed. Results: At baseline, the IM levels correlated with total cholesterol (TC) (ρ=-0.202, p =0.044), triglycerides (ρ=-0.324, p <0.001), apoA1 (ρ=0.241, p =0.016), and PCSK9 levels (ρ=-0.282, p =0.006), while PCSK9 levels were additionally associated with the CC-motif chemokine ligand 2 (CCL2) (ρ=0.298, p =0.005), a key monocyte recruitment chemokine. Adding PCSK9i to maximal statin therapy did not significantly alter the distribution of any monocyte subtypes. After treatment with PCSK9i, only an association between IM and Lp(a) levels (ρ=-0.258, p =0.041) remained significant. The number of KIV-2 repeats positively correlated with CCL2 levels (ρ=0.319, p =0.011). Changes in IM levels correlated with changes in TC (ρ=-0.315, p =0.011), low density lipoprotein cholesterol (ρ=-0.279, p =0.026), and apoB concentrations (ρ=-0.400, p =0.001), whereas other associations remained non-significant. Conclusion: In high-risk patients, PCSK9i modulate monocyte-lipoprotein interactions without altering the monocyte subtype distribution. Our data suggest that PCSK9 may express the proinflammatory effects through regulating CCL2, with the CCL2 expression more strongly related to Lp(a) composition than concentration.