Original Article
Plasma Proprotein Convertase Subtilisin Kexin Type 9 as a Predictor of Carotid Atherosclerosis in Asymptomatic Adults

https://doi.org/10.1016/j.hlc.2015.10.017Get rights and content

Background

Atherosclerosis is a lipid-driven inflammatory disease of the arterial wall involving complex and multifactorial processes. Proprotein convertase subtilisin kexin type 9 (PCSK9) may play a role in the development of atherosclerosis.

Methods

We investigated the associations between serum PCSK9 and carotid intima-medial wall thickness (IMT), a measure of subclinical atherosclerosis that predicts cardiovascular events, in 295 asymptomatic subjects from community. Carotid IMT was determined by high-resolution B-mode carotid ultrasonography and serum PCSK9 was measured by immunoassay.

Results

In univariate analysis, serum PCSK9 concentration was positively (P<0.05 in all) associated with age (r=0.204), BMI (r=0.149), waist circumference (r=0.139), systolic blood pressures (r=0.116), glucose (r=0.211), insulin (r=0.178), HOMA score (r=0.195), plasma triglyceride (r=0.285), total cholesterol (r=0.241) and LDL-cholesterol concentrations (r=0.172). In multivariate regression including male gender, hypertension, smoking status, HOMA score, obesity, LDL-cholesterol, lipoprotein (a) or markers of inflammation, serum PCSK9 remained an independent predictor of mean carotid IMT (P<0.001).

Conclusions

These data suggest that serum levels of PCSK9 may contribute to increased risk of subclinical carotid atherosclerosis independent of conventional risk factors. Whether PCSK9 inhibition improves cardiovascular outcomes remains to be demonstrated in large, ongoing clinical trials.

Introduction

Atherosclerosis is a chronic, lipid-driven inflammatory disease of the arterial wall involving complex and multifactorial processes, such as endothelial dysfunction, influx and modification of low-density lipoprotein (LDL), leukocyte recruitment, foam cell formation and plaque development [1]. Individuals with subclinical atherosclerosis are at increased risk for future cardiovascular disease (CVD) [2], [3]. Although traditional plasma lipid and inflammatory factors are important for the development of atherosclerosis, they do not fully account for the variation in risk of CVD. Hence, identifying new plasma markers associated with subclinical atherosclerosis can have important application for clinical practice.

Proprotein convertase subtilisin kexin type 9 (PCSK9), a secretory protease produced by the liver and detectable in human plasma, has recently been suggested to play a role in the development of atherosclerosis [4]. Proprotein convertase subtilisin kexin type 9 is a key regulator of the LDL receptor and hence the metabolism of LDL [5]. In vitro and animal studies demonstrate that secreted PCSK9 binds to and redirects the LDL receptor to lysosomes for degradation; this inhibits the intracellular recycling of LDL receptors and the subsequent removal of LDL particles from plasma. Gain-of-function mutations of PCSK9 can express as familial hypercholesterolaemia (FH) with high risk of coronary artery disease, whereas PCSK9 deficiency results in low LDL-cholesterol and protection against coronary artery disease [6], [7]. More recently, experimental studies also indicate that PCSK9 could accelerate atherosclerosis by promoting vascular inflammation [8].

High-resolution B-mode carotid ultrasonography has been used for non-invasive detection of subclinical atherosclerosis in large community-based cohorts [9]. We and others have demonstrated that carotid intima-medial wall thickness (IMT), a measure of subclinical atherosclerosis that predicts incident coronary heart disease, is correlated with standard cardiovascular risk factors [10], [11], [12]. A report by Cohen et al. also found that genetic variations in PCSK9 were associated with changes in carotid IMT in a large population study [7]. In the present study, we investigated the association between serum PCSK9 concentration and carotid IMT in a cross sectional, community-based sample of asymptomatic subjects in Western Australia.

Section snippets

Study Population

The data presented here were derived from a sample of participants in the Perth Carotid Ultrasound Disease Assessment Study (CUDAS) [12], [13]. The selection criteria and study design of this community-based study have been detailed previously. The participants were randomly selected from the Perth Community population and assessed for cardiovascular risk factors and had carotid B-mode ultrasound performed. This present study sample was confined to the 295 asymptomatic subjects (151 men and 144

Results

The anthropometric, clinical and biochemical data of the 295 subjects are summarised in Table 1. The mean age was 53±13 yrs, with nearly equal number of men and women subjects. The prevalence of hypertension, smoking (current), diabetes, obesity and family history of CVD were 29%, 14%, 2.4%, 23% and 20%, respectively. About 6% of individuals (nine men and 10 women) were taking cholesterol-lowering (statin) medication. Compared with women, men were more likely to have higher BMI (27±4 kg/m2 vs

Discussion

Our major finding was that serum PCSK9 concentration was a significant predictor of carotid IMT in asymptomatic individuals from the community. This association was independent of traditional cardiovascular risk factors including gender, hypertension, smoking, obesity, LDL-cholesterol, triglycerides, Lp(a) and plasma markers of inflammation.

Few studies have examined the association between serum PCSK9 concentration and carotid IMT. Lee et al. reported, in 126 hypertensive Korean patients, that

Acknowledgements

This study was supported by research grants from the National Health and Medical Research Council (NHMRC) and Royal Perth Hospital Medical Research Foundation. DCC is a Career Development Fellow of the NHMRC. PHRB is a NHMRC Senior Research Fellow.

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    The controversial scenario emerging from prospective studies performed in different clinical settings underlies the debate on whether PCSK9 may exert a proatherogenic effect that is independent of lipid pathways and, more specifically, of plasma LDL-C [16]. In this regard, inconsistent data on the association between plasma PCSK9 concentrations and carotid intima-media thickness have been published [17,18]. At the coronary district, the association between plasma PCSK9 concentrations and either calcium score [19,20] or plaque necrotic core [21] was reported to be independent of several CV risk factors and LDL-C as well.

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1

Both authors contributed equally to this manuscript.

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