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      Serum PCSK9 is modified by interleukin-6 receptor antagonism in patients with hypercholesterolaemia following non-ST-elevation myocardial infarction

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          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.

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          Most cited references16

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          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.

          Ola Kleveland, Gabor Kunszt, Marte Bratlie … (2016)
          Interleukin-6 (IL-6) contributes to atherosclerotic plaque destabilization and is involved in myocardial injury during ischaemia-reperfusion. Interleukin-6 is therefore a potential therapeutic target in myocardial infarction (MI). We hypothesized that the IL-6 receptor antagonist tocilizumab would attenuate inflammation, and secondarily reduce troponin T (TnT) release in non-ST-elevation MI (NSTEMI).
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            High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol.

            Greg Welder, Robert Konrad, Guoqing Cao … (2010)
            Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of serum LDL-cholesterol (LDL-C) levels. PCSK9 is secreted by the liver into the plasma and binds the hepatic LDL receptor (LDLR), causing its subsequent degradation. We first demonstrated that a moderate dose of atorvastatin (40 mg) increases PCSK9 serum levels, suggesting why increasing statin doses may have diminished efficacy with regard to further LDL-C lowering. Since that initial observation, at least two other groups have reported statin-induced PCSK9 increases. To date, no analysis of the effect of high-dose atorvastatin (80 mg) on PCSK9 over time has been conducted. Therefore, we studied the time course of atorvastatin (80 mg) in human subjects. We measured PCSK9 and lipid levels during a 2-week lead-in baseline period and every 4 weeks thereafter for 16 weeks. We observed that atorvastatin (80 mg) caused a rapid 47% increase in serum PCSK9 at 4 weeks that was sustained throughout 16 weeks of dosing. Importantly, while PCSK9 levels were highly correlated with total cholesterol (TC), LDL-C, and triglyceride (TG) levels at baseline, atorvastatin (80 mg) completely abolished all of these correlations. Together, these results further suggest an explanation for why increasing doses of statins fail to achieve proportional LDL-C lowering.
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              Prognostic value of PCSK9 levels in patients with acute coronary syndromes.

              Baris Gencer, Fabrizio Montecucco, David Nanchen … (2016)
              Proprotein convertase subtilisin kexin 9 (PCSK9) is an emerging target for the treatment of hypercholesterolaemia, but the clinical utility of PCSK9 levels to guide treatment is unknown. We aimed to prospectively assess the prognostic value of plasma PCSK9 levels in patients with acute coronary syndromes (ACS).
              Article 0 comments Cited 61 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Open Heart
                Journal ID (iso-abbrev): Open Heart
                Journal ID (hwp): openhrt
                Journal ID (publisher-id): openheart
                Title: Open Heart
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Electronic): 2053-3624
                Publication date Collection: 2018
                Publication date (Electronic): 18 September 2018
                Volume: 5
                Issue: 2
                Electronic Location Identifier: e000765
                Affiliations
                [1 ] departmentResearch Institute of Internal Medicine , Oslo University Hospital Rikshospitalet , Oslo, Norway
                [2 ] departmentInstitute of Clinical Medicine , University of Oslo , Oslo, Norway
                [3 ] departmentKG Jebsen TREC , University of Tromsø , Tromsø, Norway
                [4 ] departmentDepartment of Clinic of Cardiology , St Olavs Hospital , Trondheim, Norway
                [5 ] departmentDepartment of Circulation and Medical Imaging , Norwegian University of Science and Technology (NTNU) , Trondheim, Norway
                [6 ] departmentCentre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine , Norwegian University of Science and Technology (NTNU) , Trondheim, Norway
                [7 ] departmentSection of Clinical Immunology and Infectious Diseases , Oslo University Hospital Rikshospitalet , Oslo, Norway
                [8 ] departmentDepartment of Cardiology , Oslo University Hospital Rikshospitalet , Oslo, Norway
                [9 ] departmentCenter for Heart Failure Research , University of Oslo , Oslo, Norway
                Author notes
                [Correspondence to ] Dr Thor Ueland; thor.ueland@ 123456medisin.uio.no
                Article
                Publisher ID: openhrt-2017-000765
                DOI: 10.1136/openhrt-2017-000765
                PMC ID: 6150185
                PubMed ID: 30258647
                SO-VID: 77dc317b-e89d-47d6-be87-4270f295a051
                Copyright © © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

                History
                Date received : 18 December 2017
                Date revision received : 06 April 2018
                Date accepted : 15 May 2018
                Categories
                Subject: Coronary Artery Disease
                Subject: 1506
                Series title: Original research article
                Custom metadata
                special-feature unlocked

                Keywords: pcsk9,acute coronary syndrome,anti-il6 therapy,inflammation
                Data availability:
                Keywords: pcsk9, acute coronary syndrome, anti-il6 therapy, inflammation

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