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This article was published at www.annals.org on 22 March 2016.
From Heinrich Heine University, Düsseldorf, Germany; Systematic Investigation and Research on Interventions and Outcomes MEDICINE and Inova Heart and Vascular Institute, Fairfax, Virginia; Collegium Medicum in Bydgoszcz, University of Nicolaus Copernicus, Toruń, Poland; and Christ Hospital Heart and Vascular Center/Lindner Research Center, Cincinnati, Ohio.
Acknowledgment: This project is a contribution of Systematic Investigation and Research on Interventions and Outcomes MEDICINE (www.siriomedicine.com).
Disclosures: Dr. Navarese reports personal fees from Sanofi–Regeneron outside the submitted work. Dr. Kereiakes reports personal fees from Sanofi and grants from Amgen and Pfizer during the conduct of the study. Dr. Gurbel reports personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Janssen Pharmaceuticals, New Haven Pharmaceuticals, Bayer, and Haemonetics; grants from Haemonetics, Merck, Duke Clinical Research Institute, Harvard Clinical Research Institute, National Institutes of Health, New Haven Pharmaceuticals, Coramed Technologies, and Sinnowa; a patent for platelet function testing; and stock options in Merck outside the submitted work. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-2994.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Requests for Single Reprints: Eliano P. Navarese, MD, PhD, Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Universitatsstrasse 1, 40225 Düsseldorf, Germany; e-mail, email@example.com.
Current Author Addresses: Drs. Navarese and Kołodziejczak: Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich Heine University, Universitatsstrasse 1, 40225 Düsseldorf, Germany.
Dr. Kereiakes: Christ Hospital Heart and Vascular Center/Lindner Research Center, 2123 Auburn Avenue, Cincinnati, OH 45219.
Drs. Tantry, Gurbel, and O'Connor: Inova Heart and Vascular Institute, 3600 Gallows Road, Fairfax, VA 22042.
Author Contributions: Conception and design: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes.
Analysis and interpretation of the data: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes.
Drafting of the article: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes, U.S. Tantry, C. O'Connor, P.A. Gurbel.
Critical revision of the article for important intellectual content: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes, U.S. Tantry, C. O'Connor, P.A. Gurbel.
Final approval of the article: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes, U.S. Tantry, C. O'Connor, P.A. Gurbel.
Collection and assembly of data: E.P. Navarese, M. Kołodziejczak, D.J. Kereiakes.
Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) are an emerging therapy for dyslipidemia. Acute coronary events induce a dynamic increase of PCSK9 levels that may play a role in plaque vulnerability of both culprit and nonculprit coronary vessels. Growing evidence highlights a potential key role of PCSK9 antibodies in managing acute coronary syndrome. This review describes the influence of PCSK9 antibodies on plaque composition and instability, as well as the pharmacokinetic profile and the potential anti-inflammatory and antithrombotic mechanisms associated with PCSK9 inhibition that may confer benefits during the early phase of acute coronary syndrome. The authors posit a rationale for the use of PCSK9 antibodies in patients with acute coronary syndrome and highlight the need for further investigation in this area.
Several adverse mechanisms on coronary plaque by PCSK9.
ACS = acute coronary syndrome; LDL = low-density lipoprotein; MMP = matrix metalloproteinase; NF-κB = nuclear factor-κB; PCSK9 = proprotein convertase subtilisin/kexin type 9.
Time pattern of change of PCSK9 levels from experimental studies.
AMI = acute myocardial infarction; GAPDH = glyceraldehyde-3-phosphate dehydrogenase; PCSK9 = proprotein convertase subtilisin/kexin type 9.
* Evidence from animal studies.
Potential antiplatelet effects of PCSK9 antibodies.
Native LDL binds to the ApoER2 and activates cPLA2 through the p38MAPK pathway. cPLA2 releases AA from membrane phospholipids that is converted to prostaglandin H2 by the COX-1 enzyme and subsequently to TxA2 by Tx synthase. TxA2 acts synergistically with downstream signaling generated by the binding of platelet agonists (ADP, collagen, and thrombin) to respective receptors to activate GPIIb/IIIa receptors. Activated GPIIb/IIIa receptors from adjacent platelets bind to fibrinogen, which causes platelet aggregation and thrombosis at the site of plaque rupture. Similarly, oxLDL binds to scavenger receptors (CD36 and SRA) and activates p38MAPK. PCSK9 antibodies prevent LDL receptor degradation and thereby enhance LDL cholesterol clearance from the circulation. The latter effect decreases the platelet activation and aggregation induced by native LDL and oxLDL. AA = arachidonic acid; ACS = acute coronary syndrome; ADP = adenosine diphosphate; ApoER2 = apolipoprotein E receptor-2; COX-1 = cyclooxygenase-1; cPLA2 = cytosolic phospholipase A2; GPIIb/IIIa = glycoprotein IIb/IIIa; LDL = low-density lipoprotein; mLPA = membrane phospholipids; oxLDL = oxidized low-density lipoprotein; p38MAPK = p38mitogen-activated protein kinase; PCSK9 = proprotein convertase subtilisin/kexin type 9; SRA = scavenger receptor A; Tx = thromboxane; TxA2 = thromboxane A2.
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