PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from mendelian randomization, cohort studies and basic experiments

Abstract Background Current evidences suggest that Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) exhibit a protective influence on acute coronary syndrome (ACS). Nevertheless, further investigation is required to comprehend the impact and mechanisms of these pharmaceutical agents on inflammatory factors and arterial stiffness (AS) in patients with ACS. Consequently, the objective of this study is to ascertain the influence of PCSK9i on arterial stiffness in ACS patients and elucidate the underlying mechanisms behind their actions. Methods This study employed Mendelian randomization (MR) analysis to examine the association between genetic prediction of PCSK9 inhibition and arterial stiffness. A total of 71 patients with ACS were randomly allocated into either a PCSK9i group or a control group. Blood lipid levels, inflammatory markers and pulse wave velocity (PWV) data were collected before treatment and at 1 and 6 months after treatment for analysis. Additionally, cell experiments were conducted to investigate the impact of PCSK9i on osteogenesis of vascular smooth muscle cells (VSMCs), utilizing western blot (WB), enzyme-linked immunosorbent assay (ELISA), and calcification index measurements. Results The results of the MR analysis suggest that genetic prediction of PCSK9 inhibition has potential to reduce the pulse wave reflection index (PWV). Following treatment of statins combined with PCSK9 inhibitors for 1 and 6 months, the PCSK9i group exhibited significantly lower levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen (FIB) and procalcitonin (PCT) compared to the control group (p < 0.05). Additionally, PWV in the PCSK9i group demonstrated significant reduction after 6 months of treatment and was found to be associated with the circulating CRP level. In cell experiments, PCSK9i pretreatment ameliorated osteogenesis of VSMCs through reducing the deposition of calcium ions, alkaline phosphatase (ALP) activity, and expression of runt-related transcription factor 2(RUNX2). Conclusion PCSK9i have potential to enhance arterial stiffness at various aspects, including the genetic, clinical, and cellular domains. Specifically, at the clinical level, this impact may be attributed to alterations in circulating CRP levels. At the cellular level, it is associated with the signaling pathway linked to RUNX2.