Association of plasma PCSK9 levels and atherosclerosis progression beyond LDL-C

Xie W,  Liu J, Wang W, et al.
Int J Cardiol 2016; published online ahead of print

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the LDL receptor (LDLR) and is therefore crucial for LDL-C metabolism [1]. Recent randomised trials showed that the addition of PCSK9 inhibitors to maximal statin therapy significantly reduced LDL-C levels by 60% and consequently reduced cardiovascular events by 50% [2,3].
Recent studies indicate that PCSK9 may have roles beyond LDL-C regulation in the progression of atherosclerosis [4-10]. Poirier et al showed that PCKS9 activity also affects the very low-density lipoprotein cholesterol (VLDL-C) metabolism as it contributes to the degradation of its receptor (VLDLR) [11]. Additionally, it was reported that the association of plasma PCSK9 levels with cardiovascular events in coronary heart patients was lost after correction for triglycerides in an observational study [12], and clinical trials found that inhibition of PCSK9 also reduces VLDL-C levels dose-dependently [13,14].
To verify an LDL-independent association of plasma PCSK9 levels with progression of atherosclerosis, carotid plaque formation and total plaque area (TPA) were measured in a Chinese multi-provincial patient cohort (CMCS). In this cohort, 643 participants without carotid plaque and free of CV disease or lipid-lowering medication use completed 10 years of follow-up. Furthermore, the association of PCSK9 with other lipoprotein pathways in the progression of atherosclerosis was examined.

Main results

• PCSK9 levels were significantly positively associated with LDL-P, VLDL-C and triglyceride levels in men and women.
• 61.3% of participants had new carotid plaque formation during follow-up. Relative risk of plaque formation was 1.09 (95%CI: 1.03-1.15, P=0.003) per quartile increase in PCSK9 level.
• TPA enlarged by increasing baseline LDL-C (P<0.001) and PCSK9 (P=0.008) levels.
• TPA linearly increased with baseline VLDL-C levels but only when LDL-C levels were low (lowest tertile P-trend: =0.036, second tertile t not-significant P-trend=0.268).
• A linear relationship was observed between PCSK9 and VLDL-C levels regardless of LDL-C levels.
• The association of TPA with PCSK9 levels in those in the lowest or second LDL-C level tertile (<3.59 mmol/L) disappeared after adjustment for VLDL-C levels (p=0.072).
• The association of TPA with PCSK9 levels was modified by smoking (TPA increase of 15.66 mm² per 100 ng/mL increase in PCSK9 for smokers, 2.39 mm² for non-smokers, P-interaction=0.008).

Conclusion

This is the first prospective study that shows the association between baseline plasma PCSK9 levels and the 10-year progression of carotid atherosclerosis measured by new plaque formation and TPA in the general population. Smoking may affect the association of PCSK9 levels with TPA. This study suggests an LDL-independent association of PCSK9 levels with atherosclerosis progression, possibly via regulation by PCSK9 of VLDL-C levels.  

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