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

Background

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.

Conclusion

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

References

1. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U. S. A. 100 (2003) 928-933
2. Urban D, Poss J, Bohm M, et al. Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62 (2013) 1401-1408
3. Tang Z, Jiang L, Peng J, et al. PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-kappaB activation in THP-1-derived macrophages. Int J Mol Med 30 (2012) 931-938
4. Poirier S, Maye Gr, Benjannet S, et al. The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2. J Biol Chem 283 (2008) 2363-2372
5. Wu CY, Tang ZH, Jiang L, et al. PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. Mol Cell Biochem 359 (2012) 347-358
6. Nair A, Margolis MP, Kuban BD, et al. Automated coronary plaque characterisation with intravascular ultrasound backscatter: ex vivo validation. Eurointervention 3 (2007) 113-120
7. Cheng JM, Garcia-Garcia HM, de Boer SP, et al. In vivo detection of high-risk coronary plaques by radiofrequency intravascular ultrasound and cardiovascular outcome: results of the ATHEROREMO-IVUS study. Eur Heart J 35 (2014) 639-647
8. Stone GW, Maehara A, Lansky AJ, et al. A prospective natural-history study of coronary atherosclerosis. New Engl J Med 364 (2011) 226-235
9. Calvert PA, Obaid DR, O'Sullivan M, et al. Association between IVUS findings and adverse outcomes in patients with coronary artery disease: the VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study. JACC Cardiovasc Imaging 4 (2011) 894-901
10. Libby P. Inflammation in atherosclerosis. Nature 420 (2002) 868-874