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

Figure 1
Figure 1
Tukey plot of serum proprotein convertase subtilisin-kexin type 9 (PCSK9) in healthy controls (CTR; n=27) and patients with non-ST-elevation myocardial infarction (NSTEMI; n=117) on admission. P values are adjusted for age and body mass index (BMI).
Figure 2
Figure 2
Serum PCSK9 in patients with non-ST-elevation myocardial infarction (NSTEMI) receiving placebo (n=59) or tocilizumab (n=58) during hospitalisation and at 3 and 6 months of follow-up. Circles represent geometric back-transformed estimated marginal means and 95% CIs, respectively. *P

Figure 3

Serum PCSK9 during hospitalisation in…

Figure 3

Serum PCSK9 during hospitalisation in non-ST-elevation myocardial infarction (NSTEMI) stratified by hypercholesterolaemia. (A)…

Figure 3
Serum PCSK9 during hospitalisation in non-ST-elevation myocardial infarction (NSTEMI) stratified by hypercholesterolaemia. (A) Comparison of AUC during hospitalisation for PCSK9 in groups stratified by treatment and presence of hypercholesterolaemia (HC). Boxes represent median and 25th and 75th percentiles. (B) Serum PCSK9 during hospitalisation stratified by treatment and hypercholesterolaemia. The p values in (B) represent the group effects from the repeated measures analysis of variance (ANOVA). Circles represent geometric back-transformed estimated marginal means 95% CIs. AFN, afternoon; AUC, area under the curve; BL, baseline; EVE, evening; MO, morning; PCSK9, proprotein convertase subtilisin-kexin type 9.

Figure 4

Correlation between AUC during hospitalisation…

Figure 4

Correlation between AUC during hospitalisation for neutrophils and PCSK9 stratified by absence (top…

Figure 4
Correlation between AUC during hospitalisation for neutrophils and PCSK9 stratified by absence (top panel) or presence (bottom panel) of hypercholesterolaemia and treatment (clear circles, placebo; filled circles, tocilizumab). Correlation coefficients within each stratification group are given and p value when significant. The small graph in each panel shows the average white cell count within each stratification group according to treatment during hospitalisation. AUC, area under the curve; BL, baseline; PCSK9, proprotein convertase subtilisin-kexin type 9.
Figure 3
Figure 3
Serum PCSK9 during hospitalisation in non-ST-elevation myocardial infarction (NSTEMI) stratified by hypercholesterolaemia. (A) Comparison of AUC during hospitalisation for PCSK9 in groups stratified by treatment and presence of hypercholesterolaemia (HC). Boxes represent median and 25th and 75th percentiles. (B) Serum PCSK9 during hospitalisation stratified by treatment and hypercholesterolaemia. The p values in (B) represent the group effects from the repeated measures analysis of variance (ANOVA). Circles represent geometric back-transformed estimated marginal means 95% CIs. AFN, afternoon; AUC, area under the curve; BL, baseline; EVE, evening; MO, morning; PCSK9, proprotein convertase subtilisin-kexin type 9.
Figure 4
Figure 4
Correlation between AUC during hospitalisation for neutrophils and PCSK9 stratified by absence (top panel) or presence (bottom panel) of hypercholesterolaemia and treatment (clear circles, placebo; filled circles, tocilizumab). Correlation coefficients within each stratification group are given and p value when significant. The small graph in each panel shows the average white cell count within each stratification group according to treatment during hospitalisation. AUC, area under the curve; BL, baseline; PCSK9, proprotein convertase subtilisin-kexin type 9.

References

    1. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563–75. 10.1038/nrcardio.2014.84
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. 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
    1. Gabay C. Interleukin-6 and chronic inflammation. Arthritis Res Ther 2006;8 Suppl 2(Suppl 2):S3 10.1186/ar1917
    1. Ikeda U, Ito T, Shimada K. Interleukin-6 and acute coronary syndrome. Clin Cardiol 2001;24:701–4. 10.1002/clc.4960241103
    1. 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
    1. Norheim OF, Gjelsvik B, Kjeldsen SE, et al. , 2009. National guidelines for individual primary prevention of cardiovascular disease: Norwegian Directorate of Health
    1. 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
    1. 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
    1. 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
    1. 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
    1. Armendariz AD, Krauss RM. Hepatic nuclear factor 1-alpha: inflammation, genetics, and atherosclerosis. Curr Opin Lipidol 2009;20:106–11. 10.1097/MOL.0b013e3283295ee9
    1. Tall AR, Cholesterol Y-CL. inflammation and innate immunity. Nature reviews Immunology 2015;15:104–16.
    1. 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
    1. 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
    1. 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

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit