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      Serum Levels of PCSK9 Are Associated with Coronary Angiographic Severity in Patients with Acute Coronary Syndrome

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          Abstract

          Background

          Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a circulating protein that promotes degradation of the low density lipoprotein receptor. PCSK9 has emerged as a target for lipid-lowering therapy, but the predictive value of the serum level of PCSK9 for the severity of coronary disease is largely unknown.

          Methods

          From December 2009 to July 2012, 121 individuals who underwent coronary angiography (CAG) because of clinically suspected acute coronary syndrome were enrolled in this study. Serum levels of PCSK9 and metabolic parameters were measured. SYNTAX (SYNergy between percutaneous coronary intervention with [paclitaxel-eluting] TAXUS stent and cardiac surgery) and GRACE (Global Registry of Acute Coronary Events) scores were calculated.

          Results

          Individuals with CAG lesions ( n=100) had significantly higher levels of PCSK9 than those without lesions ( n=21). The study population was stratified into three groups according to serum levels of PCSK9. The odds radio for occurrence of one or more CAG lesions was significantly higher in the group with the highest level of PCSK9 (odds ratio, 7.468; P=0.011) than in the group with the lowest level of PCSK9. Serum PCSK9 was positively associated with the number of involved coronary arteries. Multivariable linear regression indicated that levels of PCSK9 were positively correlated with GRACE risk scores and SYNTAX scores.

          Conclusion

          Serum PCSK9 concentrations are higher in patients with coronary artery lesions, and are associated with SYNTAX and GRACE scores, suggesting that PCSK9 is a potential biomarker of the severity of coronary artery disease.

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          Most cited references10

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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.

          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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            Cross-talk between LOX-1 and PCSK9 in vascular tissues.

            Lectin-like ox-LDL receptor-1 (LOX-1) plays an important role in inflammatory diseases, such as atherosclerosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulates LDL receptor degradation and influences serum LDL levels. The present study was designed to investigate the possible interaction between PCSK9 and LOX-1.
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              Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors.

              The secreted protein proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising new target for lowering plasma low-density lipoprotein cholesterol and preventing cardiovascular disease (CVD). The relationship between circulating PCSK9 and incident CVD in the general population is unknown. We investigated whether serum PCSK9 concentration is associated with incident CVD in a prospective cohort study of 4232 men and women 60 years of age at the time of recruitment.
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                Author and article information

                Journal
                Diabetes Metab J
                Diabetes Metab J
                DMJ
                Diabetes & Metabolism Journal
                Korean Diabetes Association
                2233-6079
                2233-6087
                June 2018
                02 May 2018
                : 42
                : 3
                : 207-214
                Affiliations
                [1 ]Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.
                [2 ]Department of Internal Medicine, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine, Daegu, Korea.
                [3 ]Biostatistics Center, School of Medicine, Kyungpook National University, Daegu, Korea.
                [4 ]New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Korea.
                Author notes
                Corresponding authors: Keun-Gyu Park. Department of Internal Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea. kpark@ 123456knu.ac.kr
                Corresponding authors: Jang Hoon Lee. Department of Internal Medicine, School of Medicine, Kyungpook National University, 680 Gukchaebosang-ro, Jung-gu, Daegu 41944, Korea. ljhmh75@ 123456knu.ac.kr

                *Kwi-Hyun Bae and Sung Woo Kim contributed equally to this study as first authors.

                Author information
                https://orcid.org/0000-0002-7101-0236
                https://orcid.org/0000-0002-8403-1298
                Article
                10.4093/dmj.2017.0081
                6015969
                29885102
                40904b9b-41c0-4867-9487-9a5b12f934bf
                Copyright © 2018 Korean Diabetes Association

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 November 2017
                : 05 January 2018
                Funding
                Funded by: National Research Foundation of Korea, CrossRef http://dx.doi.org/10.13039/501100003725;
                Award ID: NRF-2017M3A9G7073086
                Award ID: NRF-2015R1A2A1A10052745
                Funded by: Ministry of Health and Welfare, CrossRef http://dx.doi.org/10.13039/501100003625;
                Award ID: HI16C1501
                Award ID: HI15C0001
                Categories
                Original Article
                Complications

                Endocrinology & Diabetes
                cardiovascular diseases,coronary angiography,proprotein convertase 9

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