Physicians' Academy for Cardiovascular Education

PCSK9 levels linearly associated with atherosclerotic inflammatory markers

Cheng JM et al., Atherosclerosis 2016


PCSK9 in relation to coronary plaque inflammation: Results of the ATHEROREMO-IVUS study

Cheng JM, Oemrawsingh RM, Garcia-Garcia HM, et al.
Atherosclerosis 2016;248:117-122


The PCSK9 protein induces an increase in LDL-C level by promoting the degradation of LDL receptors [1,2]. Experimental data exist that show that PCSK9 may also directly stimulate inflammation, apoptotic cell death and endothelial dysfunction in atherosclerosis, independently of its influence on the LDL receptors [3-5].
Intravascular ultrasound virtual histology (IVUS-VH) imaging allows for accurate measurement of the extent of coronary atherosclerosis and of the type of plaque tissue. This includes necrotic core tissue, which is considered to be a result of continuous inflammation [6-10]. The amount of necrotic core tissue has been shown to be predictive of CV outcomes [7-9].
In this ATHEROREMO-IVUS study, the association between serum PCSK9 levels and the fraction and amount of necrotic core tissue in non-culprit coronary atherosclerotic plaque was evaluated, using IVUS-VH imaging in 581 patients who underwent coronary angiography for ACS or stable angina.

Main results:

After adjustment for established cardiac risk factors, statin use and serum LDL-c, serum PCSK9 levels were linearly associated with:
  • the fraction of plaque consisting of necrotic core tissue: β= 1.24% increase per 100 mg/L increase in PCSK9; 95%CI: 0.55-1.94; P = 0.001
  • the absolute volume of necrotic core tissue: β = 0.09; 95%CI: 0.01-0.18; P = 0.033
No significant association was noted between serum PCSK9 levels and:
  • plaque burden (P = 0.11)
  • plaque volume (P = 0.22)
  • the presence of IVUS-VH-derived thincap fibroatheroma lesions (P = 1.0)
PCSK9 levels were:  
  • inversely associated with fractions of fibrous tissue (β = -1.45; 95% CI: -2.43 to -0.47; P = 0.004) and fibro-fatty tissue (β = -0.83; 95% CI: -1.36  to -0.30; P = 0.002)
  • positively associated with dense calcium fraction (β = 0.97; 95%CI: 0.32 - 1.62; P = 0.004)
Subgroup analysis showed that the positive association between serum PCSK9 levels and necrotic core fraction was present in all patient subgroups, including statin users and non-statin users, as well as patients with low and high LDL cholesterol.
Although this study was not primarily designed to investigate the association between serum PCSK9 levels and CV outcomes, and the number of clinical endpoints was relatively small, it is worth noting that in multivariable analysis, higher serum PCSK9 levels were significantly associated with a higher rate of death and ACS after 1 year follow-up: HR: 1.42 per 100 mg/L increase in serum PCSK9 level; 95% CI 1.02-1.99; P = 0.040.


In patients with established CAD, serum PCSK9 levels were linearly associated with the fraction and amount of IVUS-VH-derived necrotic core tissue in coronary atherosclerosis, independently of serum LDL-c levels and statin use. These results support the hypothesis that PCSK9 is directly involved in promoting inflammatory processes contributing to atherosclerosis by mechanisms independent of LDL-c levels.
Find this article online at Atherosclerosis


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