Serum PCSK9 is modified by interleukin-6 receptor antagonism in patients with hypercholesterolaemia following non-ST-elevation myocardial infarction
Thor Ueland, Ola Kleveland, Annika E Michelsen, Rune Wiseth, Jan Kristian Damås, Pål Aukrust, Lars Gullestad, Bente Halvorsen, Arne Yndestad, Thor Ueland, Ola Kleveland, Annika E Michelsen, Rune Wiseth, Jan Kristian Damås, Pål Aukrust, Lars Gullestad, Bente Halvorsen, Arne Yndestad
Abstract
Objective: It is unclear if activation of inflammatory pathways regulates proprotein convertase subtilisin-kexin type 9 (PCSK9) levels.
Approach: We evaluated (1) the temporal course of serum PCSK9 during hospitalisation following acute coronary syndrome and associations with markers of inflammation (leucocyte counts, interleukin (IL)-6, C-reactive protein) and lipid levels and (2) the effect of inhibition of IL-6 signalling with the IL-6 receptor antibody tocilizumab on PCSK9 levels in a randomised, double-blind, placebo-controlled trial release in patients with non-ST-elevation myocardial infarction.
Results: Serum PCSK9 increased during the acute phase and this response was modestly associated with neutrophil counts (r=0.24, p=0.009) and presence of hypercholesterolaemia (r=0.019, p=0.045), but was not modified by tocilizumab. However, a modifying effect of tocilizumab on PCSK9 levels was observed in patients with hypercholesterolaemia (p=0.024, repeated measures analysis of variance) and this effect was strongly correlated with the decrease in neutrophils (r=0.66, p=0.004).
Conclusions: Our study suggests that patients with a more atherogenic profile may benefit from anti-IL-6 therapy with regard to PCSK9.
Trial registration number: NCT01491074.
Keywords: PCSK9; acute coronary syndrome; anti-IL6 therapy; inflammation.
Conflict of interest statement
Competing interests: None declared.
Figures
References
- Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563–75. 10.1038/nrcardio.2014.84
- Abifadel M, Rabès JP, Devillers M, et al. . Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mutat 2009;30:520–9. 10.1002/humu.20882
- Robinson JG, Farnier M, Krempf M, et al. . Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–99. 10.1056/NEJMoa1501031
- Sabatine MS, Giugliano RP, Keech AC, et al. . Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017;376:1713–22. 10.1056/NEJMoa1615664
- Ferri N, Corsini A, Macchi C, et al. . Proprotein convertase subtilisin kexin type 9 and high-density lipoprotein metabolism: experimental animal models and clinical evidence. Transl Res 2016;173:19–29. 10.1016/j.trsl.2015.10.004
- Laugsand LE, Åsvold BO, Vatten LJ, et al. . Circulating PCSK9 and Risk of Myocardial Infarction. JACC Basic Transl Sci 2016;1:568–75. 10.1016/j.jacbts.2016.06.007
- Burchardt P, Rzeźniczak J, Dudziak J, et al. . Evaluation of plasma PCSK9 concentrations, transcript of LDL receptor, as well as the total number of monocyte LDL receptors in acute coronary syndrome patients. Cardiol J 2016;23:604–9. 10.5603/CJ.a2016.0068
- Gencer B, Montecucco F, Nanchen D, et al. . Prognostic value of PCSK9 levels in patients with acute coronary syndromes. Eur Heart J 2016;37:546–53. 10.1093/eurheartj/ehv637
- Navarese EP, Kolodziejczak M, Winter MP, et al. . Association of PCSK9 with platelet reactivity in patients with acute coronary syndrome treated with prasugrel or ticagrelor: The PCSK9-REACT study. Int J Cardiol 2017;227:644–9. 10.1016/j.ijcard.2016.10.084
- Cariou B, Guérin P, Le May C, et al. . Circulating PCSK9 levels in acute coronary syndrome: Results from the PC-SCA-9 prospective study. Diabetes Metab 2017;43:529–35. 10.1016/j.diabet.2017.07.009
- Tang Z, Jiang L, Peng J, et al. . PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages. Int J Mol Med 2012;30:931–8. 10.3892/ijmm.2012.1072
- 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 2012;359(1-2):347–58. 10.1007/s11010-011-1028-6
- Ferri N, Tibolla G, Pirillo A, et al. . Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis 2012;220:381–6. 10.1016/j.atherosclerosis.2011.11.026
- Cheng JM, Oemrawsingh RM, Garcia-Garcia HM, et al. . PCSK9 in relation to coronary plaque inflammation: Results of the ATHEROREMO-IVUS study. Atherosclerosis 2016;248:117–22. 10.1016/j.atherosclerosis.2016.03.010
- Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006;8 Suppl 2(Suppl 2):S3 10.1186/ar1917
- Ikeda U, Ito T, Shimada K. Interleukin-6 and acute coronary syndrome. Clin Cardiol 2001;24:701–4. 10.1002/clc.4960241103
- Kleveland O, Kunszt G, Bratlie M, et al. . Effect of a single dose of the interleukin-6 receptor antagonist tocilizumab on inflammation and troponin T release in patients with non-ST-elevation myocardial infarction: a double-blind, randomized, placebo-controlled phase 2 trial. Eur Heart J 2016;37:2406–13. 10.1093/eurheartj/ehw171
- Norheim OF, Gjelsvik B, Kjeldsen SE, et al. , 2009. National guidelines for individual primary prevention of cardiovascular disease: Norwegian Directorate of Health
- Almontashiri NA, Vilmundarson RO, Ghasemzadeh N, et al. . Plasma PCSK9 levels are elevated with acute myocardial infarction in two independent retrospective angiographic studies. PLoS One 2014;9:e106294 10.1371/journal.pone.0106294
- Feingold KR, Moser AH, Shigenaga JK, et al. . Inflammation stimulates the expression of PCSK9. Biochem Biophys Res Commun 2008;374:341–4. 10.1016/j.bbrc.2008.07.023
- Le Bras M, Roquilly A, Deckert V, et al. . Plasma PCSK9 is a late biomarker of severity in patients with severe trauma injury. J Clin Endocrinol Metab 2013;98:E732–E736. 10.1210/jc.2012-4236
- Zhang Y, Liu J, Li S, et al. . Proprotein convertase subtilisin/kexin type 9 expression is transiently up-regulated in the acute period of myocardial infarction in rat. BMC Cardiovasc Disord 2014;14:192 10.1186/1471-2261-14-192
- Armendariz AD, Krauss RM. Hepatic nuclear factor 1-alpha: inflammation, genetics, and atherosclerosis. Curr Opin Lipidol 2009;20:106–11. 10.1097/MOL.0b013e3283295ee9
- Tall AR, Cholesterol Y-CL. inflammation and innate immunity. Nature reviews Immunology 2015;15:104–16.
- Wright HL, Cross AL, Edwards SW, et al. . Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology 2014;53:1321–31. 10.1093/rheumatology/keu035
- Soehnlein O, Drechsler M, Hristov M, et al. . Functional alterations of myeloid cell subsets in hyperlipidaemia: relevance for atherosclerosis. J Cell Mol Med 2009;13(11-12):4293–303. 10.1111/j.1582-4934.2009.00965.x
- Welder G, Zineh I, Pacanowski MA, et al. . High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res 2010;51:2714–21. 10.1194/jlr.M008144
Source: PubMed