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Published on: February 20, 2019
PCSK9 inhibitors ameliorate arterial stiffness in ACS patients: evidences from Mendelian randomization, a
Linghao Xu1, Liang Wang1, Yuanqi Wang1
1Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
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. Data of 71 patients with ACS were retrospectively collected, including PCSK9i group (n = 36, PCSK9 inhibitors combined with statins) and control group (n = 35, statins only). 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 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 in ACS patients. 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.
Insights
Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) may improve arterial stiffness in acute coronary syndrome (ACS) patients by reducing inflammatory markers like C-reactive protein (CRP). This study explored PCSK9i
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- Proprotein Convertase Subtilisin/kexin Type 9 inhibitors (PCSK9i) show promise in managing acute coronary syndrome (ACS).
- The precise impact of PCSK9i on inflammatory factors and arterial stiffness (AS) in ACS patients requires further elucidation.
Purpose of the Study:
- To investigate the effect of PCSK9 inhibitors on arterial stiffness in patients with acute coronary syndrome.
- To explore the underlying mechanisms, including inflammatory markers and cellular pathways, influenced by PCSK9 inhibitors.
Main Methods:
- Mendelian randomization (MR) analysis was performed to assess the genetic association between PCSK9 inhibition and arterial stiffness.
- Retrospective analysis of 71 ACS patients comparing a PCSK9 inhibitor plus statin group with a statin-only control group.
- Measurements included lipid profiles, inflammatory markers, and pulse wave velocity (PWV) at baseline and follow-up points (1 and 6 months). Cell experiments (Western blot, ELISA, calcification assays) investigated PCSK9i effects on vascular smooth muscle cell osteogenesis.
Main Results:
- MR analysis suggested PCSK9 inhibition may reduce PWV.
- The PCSK9i group showed significantly reduced total cholesterol, LDL-C, CRP, IL-6, fibrinogen, and procalcitonin compared to controls (p < 0.05).
- Significant PWV reduction was observed in the PCSK9i group after 6 months, correlated with CRP levels. Cell studies indicated PCSK9i ameliorated VSMC osteogenesis by reducing calcium deposition, ALP activity, and RUNX2 expression.
Conclusions:
- PCSK9 inhibitors demonstrate potential to improve arterial stiffness in ACS patients, possibly mediated by reduced CRP levels.
- Cellular mechanisms involve the regulation of vascular smooth muscle cell osteogenesis via the RUNX2 signaling pathway.
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