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      Plasma PCSK9 Levels Are Elevated with Acute Myocardial Infarction in Two Independent Retrospective Angiographic Studies

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          Abstract

          Objective

          Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein (LDL) receptor. Mutations that block PCSK9 secretion reduce LDL-cholesterol and the incidence of myocardial infarction (MI). However, it remains unclear whether elevated plasma PCSK9 associates with coronary atherosclerosis (CAD) or more directly with rupture of the plaque causing MI.

          Methods and Results

          Plasma PCSK9 was measured by ELISA in 645 angiographically defined controls (<30% coronary stenosis) and 3,273 cases of CAD (>50% stenosis in a major coronary artery) from the Ottawa Heart Genomics Study. Because lipid lowering medications elevated plasma PCSK9, confounding association with disease, only individuals not taking a lipid lowering medication were considered (279 controls and 492 with CAD). Replication was sought in 357 controls and 465 with CAD from the Emory Cardiology Biobank study. PCSK9 levels were not associated with CAD in Ottawa, but were elevated with CAD in Emory. Plasma PCSK9 levels were elevated in 45 cases with acute MI (363.5±140.0 ng/ml) compared to 398 CAD cases without MI (302.0±91.3 ng/ml, p = 0.004) in Ottawa. This finding was replicated in the Emory study in 74 cases of acute MI (445.0±171.7 ng/ml) compared to 273 CAD cases without MI (369.9±139.1 ng/ml, p = 3.7×10 −4). Since PCSK9 levels were similar in CAD patients with or without a prior (non-acute) MI, our finding suggests that plasma PCSK9 is elevated either immediately prior to or at the time of MI.

          Conclusion

          Plasma PCSK9 levels are increased with acute MI.

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          Most cited references25

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          Genetic and metabolic determinants of plasma PCSK9 levels.

          Aileen C. Cohen, Helen H. Hobbs, Thomas Lagace … (2009)
          PCSK9 is a secreted protein that influences plasma levels of low-density lipoprotein cholesterol (LDL-C) and susceptibility to coronary heart disease. PCSK9 is present in human plasma, but the factors that contribute to differences in plasma concentrations of PCSK9 and how they impact on the levels of lipoproteins have not been well-characterized. The aim of the study was to measure PCSK9 levels in a large, ethnically diverse population (n = 3138) utilizing a sensitive and specific sandwich ELISA. We conducted an observational study in the Dallas Heart Study, a multiethnic, probability-based sample of Dallas County. Plasma levels of PCSK9 varied over approximately 100-fold range (33-2988 ng/ml; median, 487 ng/ml). Levels were significantly higher in women (517 ng/ml) than in men (450 ng/ml), and in postmenopausal women compared to premenopausal women (P < 0.0001), irrespective of estrogen status. Plasma levels of PCSK9 correlated with plasma levels of LDL-C (r = 0.24) but explained less than 8% of the variation in LDL-C levels (r(2) = 0.073). Other factors that correlated with PCSK9 levels included plasma levels of triglycerides, insulin, and glucose. Individuals with loss-of-function mutations in PCSK9 and reduced plasma levels of LDL-C also had significantly lower plasma levels of PCSK9 after adjusting for age, gender, and LDL-C levels (P < 0.0001). Multiple metabolic and genetic factors contribute to variation in plasma levels of PCSK9 in the general population. Although levels of PCSK9 correlate with plasma levels of LDL-C, they account for only a small proportion of the variation in the levels of this lipoprotein.
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            Dental disease and risk of coronary heart disease and mortality.

            R Anda, Jeff D. Williamson, Kathryn M W Russell … (1993)
            To investigate a reported association between dental disease and risk of coronary heart disease. National sample of American adults who participated in a health examination survey in the early 1970s. Prospective cohort study in which participants underwent a standard dental examination at baseline and were followed up to 1987. Proportional hazards analysis was used to estimate relative risks adjusted for several covariates. Incidence of mortality or admission to hospital because of coronary heart disease; total mortality. Among all 9760 subjects included in the analysis those with periodontitis had a 25% increased risk of coronary heart disease relative to those with minimal periodontal disease. Poor oral hygiene, determined by the extent of dental debris and calculus, was also associated with an increased incidence of coronary heart disease. In men younger than 50 years at baseline periodontal disease was a stronger risk factor for coronary heart disease; men with periodontitis had a relative risk of 1.72. Both periodontal disease and poor oral hygiene showed stronger associations with total mortality than with coronary heart disease. Dental disease is associated with an increased risk of coronary heart disease, particularly in young men. Whether this is a causal association is unclear. Dental health may be a more general indicator of personal hygiene and possibly health care practices.
            Article 0 comments Cited 123 times – based on 0 reviews     Review now
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              Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.

              James M. McKenney, Michael Koren, Dean Kereiakes … (2012)
              The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l). Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9. This double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C ≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for ≥6 weeks to: subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W), alternating with placebo for a total treatment period of 12 weeks. SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72% with 50, 100, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis. When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40% to 72%. These additional reductions are both dose- and dosing frequency-dependent. (Efficacy and Safety Evaluation of SAR236553 [REGN727] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy; NCT01288443). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Michael Lipinski: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 2 September 2014
                Volume: 9
                Issue: 9
                Electronic Location Identifier: e106294
                Affiliations
                [1 ]Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
                [2 ]Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
                [3 ]Center for Genetics and Inherited Diseases, Taibah University, Almadina, Saudi Arabia
                [4 ]Department of Medicine, Emory University, Atlanta, Georgia, United States of America
                [5 ]Department of Medicine, McGill University, Montreal, Canada
                [6 ]Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
                [7 ]Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
                Washington Hospital Center, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: NAMA AFRS. Performed the experiments: NAMA. Analyzed the data: NAMA ROV HHC NG. Contributed reagents/materials/analysis tools: RR AQ SD AFRS. Contributed to the writing of the manuscript: NAMA HHC NG RR AQ AFRS.

                Article
                Publisher ID: PONE-D-14-15937
                DOI: 10.1371/journal.pone.0106294
                PMC ID: 4152257
                PubMed ID: 25180781
                SO-VID: 9d7cc57c-3460-47b6-afc7-24bc62143bc4
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 9 April 2014
                Date accepted : 28 July 2014
                Page count
                Pages: 9
                Funding
                This work was supported by grants from the Canadian Institutes of Health Research, CIHR #MOP82810 (RR), CIHR #MOP77682 (AFRS), CIHR #MOP179197 (HHC), the Canada Foundation for Innovation, CFI #11966 (RR), a student scholarship from Taibah University, Saudi Arabia, and a University of Ottawa Endowed Graduate Award at the Heart Institute (NAMA). The Emory Cardiovascular Biobank was supported by National Institutes of Health (NIH) Grant R01 HL89650-01, Robert W. Woodruff Health Sciences Center Fund, Emory Heart and Vascular Center Funds, and supported in part by NIH Grant UL1 RR025008 from the Clinical and Translational Science Award Program. These funding agencies played no part in the study's design, conduct, and reporting.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Anatomy
                Subject: Body Fluids
                Subject: Blood
                Subject: Physiology
                Subject: Cardiovascular Physiology
                Subject: Blood Circulation
                Custom metadata
                Data Availability The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. The data cannot be made available in the manuscript in its raw unanalyzed form because it contains patient information that could be traced back to individuals. Individuals wishing to consult our data can send a request to Alexandre Stewart at email: astewart@ 123456ottawaheart.ca .

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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