Circulating PCSK9 and cardiovascular events in FH patients with standard lipid-lowering therapy

Ye-Xuan Cao,Rui-Xia Xu,Hui-Hui Liu,Cheng-Gang Zhu,Jian-Jun Li,Jing-Lu Jin,Di Sun,Jing Sun,Qian Dong,Yuan-Lin Guo,Na-Qiong Wu

doi:10.1186/s12967-019-2123-9

Abstract

BackgroundProprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Familial hypercholesterolemia (FH) is characterized by high prevalence of CAD and major cardiovascular events (MACEs). However, no data is available on the association between PCSK9 levels and MACEs in FH patients with standard lipid lowering therapy.MethodsA total of 338 consecutive heterozygous FH (Dutch Lipid Clinic Network score ≥ 6) was enrolled and followed up for the occurrence of MACEs. Multidetector CT and coronary angiography were performed to determine coronary artery calcification score (CACS) and Gensini score (GS). Multivariable Cox regression analyses were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Plasma PCSK9 concentrations were determined by enzyme immunoassay.ResultsPCSK9 was independently and positively associated CACS and GS at baseline. During a mean follow-up of 3 years, 33 (9.8%) events occurred. Patients with MACEs had higher median PCSK9 compared with those without (332.47 vs. 311.89 ng/mL, p = 0.038). Kaplan–Meier analysis revealed that patients with higher PCSK9 presented lower event-free survival (p = 0.0017). PCSK9 was statistically correlated with MACEs after adjusting for confounding factors, with the HR per SD being 1.86 (1.31–2.65) and 3.70 (1.16–11.82) for the highest tertile compared with the lowest tertile. Adding PCSK9 to Cox prediction model led to a statistical improvement in net reclassification and integrated discrimination.ConclusionElevated levels of PCSK9 were positively associated with the development of CAD and future cardiovascular events, suggesting that measurement of PCSK9 concentration might be useful for cardiovascular risk stratification. Further studies are needed to confirm our results.

Highlights

Proprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD)
In patients with DM, the association was not statistically significant (p for interaction = 0.031). In this prospective cohort of patients with Familial hypercholesterolemia (FH), we investigated the association of plasma PCSK9 levels with the calcification and stenosis in coronary atherosclerosis and future cardiovascular events under the condition of the era of optimal lipid-lowering therapy
We found that elevated PCSK9 was associated with a worse prognosis in patients with FH and the association was persisted after adjustment for multiple established CAD risk factors and baseline statin use

Summary

Introduction

Proprotein convertase subtilisin/kexin 9 (PCSK9) has been proposed as a novel target for coronary artery disease (CAD). Most studies investigated the effects of PCSK9 on LDL-C metabolism, an increasing number of experimental and clinical studies have demonstrated that PCSK9 contributed directly to the progression of atherosclerosis by enhancing the expression of pro-inflammatory genes, promoting apoptotic cell death and leading to endothelial dysfunction independent of its effect on the LDLR [7, 8]. In this situation, the plasma concentration of PCSK9 has attracted scientific interest as a novel marker for major adverse cardiovascular events (MACEs). It is noticeable that the association between plasma concentration of PCSK9 and future MACEs has not been investigated in the setting of FH

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