Author + information
- Received March 4, 2020
- Revision received May 8, 2020
- Accepted May 8, 2020
- Published online July 27, 2020.
- Nicolas Perrot, MSca,b,∗,
- Vincenza Valerio, MScc,d,∗,
- Donato Moschetta, MScc,e,
- S. Matthijs Boekholdt, MD, PhDf,
- Christian Dina, PhDg,
- Hao Yu Chen, MSch,
- Erik Abner, PhDi,
- Andreas Martinsson, MD, PhDj,k,
- Hasanga D. Manikpurage, MSca,l,
- Sidwell Rigade, MScg,
- Romain Capoulade, PhDg,
- Elvira Mass, PhDm,
- Marie-Annick Clavel, DVM, PhDa,b,
- Thierry Le Tourneau, MDg,
- David Messika-Zeitoun, MD, PhDn,o,
- Nicholas J. Wareham, MBBS, PhDp,
- James C. Engert, PhDh,
- Gianluca Polvani, MDc,q,
- Philippe Pibarot, DVM, PhDa,b,
- Tõnu Esko, PhDi,
- J. Gustav Smith, MD, PhDj,k,
- Patrick Mathieu, MD, MSca,r,
- George Thanassoulis, MDh,
- Jean-Jacques Schott, PhDg,
- Yohan Bossé, PhDa,s,
- Marina Camera, PhDc,e,
- Sébastien Thériault, MD, MSca,l,
- Paolo Poggio, PhDc,∗∗ ( and )
- Benoit J. Arsenault, PhDa,b,∗ (, )@ArsenaultBenoit
- aCentre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada
- bDepartment of Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada
- cCentro Cardiologico Monzino IRCCS, Milan, Italy
- dUniversità degli Studi di Napoli Federico II, Dipartimento di Medicina Clinica e Chirurgia, Naples, Italy
- eDepartment of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy
- fDepartment of Cardiology, Academic Medical Center, Amsterdam, the Netherlands
- gl'Institut du thorax, INSERM, CNRS, UNIV Nantes, CHU Nantes, Nantes, France
- hMcGill University Health Center Research Institute, Montreal, Québec, Canada
- iEstonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
- jDepartment of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
- kWallenberg Center for Molecular Medicine and Lund University Diabetes Center, Lund University, Lund, Sweden
- lDepartment of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec, Québec, Canada
- mUniversity of Bonn, Developmental Biology of the Innate Immune System, Life & Medical Sciences Institute (LIMES), Bonn, Germany
- nDepartment of Cardiology, Assistance Publique – Hôpitaux de Paris, Bichat Hospital, Paris, France
- oUniversity of Ottawa Heart Institute, Ottawa, Ontario, Canada
- pDepartment of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- qDepartment of Cardiovascular Sciences and Community Health, University of Milan, Milan, Italy
- rDepartment of Surgery, Faculty of Medicine, Université Laval, Québec, Québec, Canada
- sDepartment of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Québec, Canada
- ↵∗Address for correspondence:
Dr. Benoit J. Arsenault, Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval Y-3106, Pavillon Marguerite D'Youville, 2725 Chemin Ste-Foy, Québec G1V 4G5, Canada.
- ↵∗∗Dr. Paolo Poggio, Centro Cardiologico Monzino IRCCS, Unit for the Study of Aortic, Valvular, and Coronary Pathologies, Via Parea 4, 20138 Milan, Italy.
• Aortic stenosis was less prevalent in carriers of the PCSK9 R46L variant.
• Variation at the PCSK9 locus influences LDL-C levels, but not Lp(a).
• PCSK9 is produced and secreted by aortic valves.
• In vitro, PCSK9 inhibition might lower calcification in aortic valve cells.
• PCSK9 inhibition could represent a therapeutic strategy for aortic stenosis.
The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.
- aortic valve interstitial cell
- apolipoprotein B
- calcific aortic valve stenosis
- LDL cholesterol
- proprotein convertase subtilisin/kexin type 9
↵∗ Mr. Perrot and Ms. Valerio contributed equally to this work and are joint first authors.
This study was funded by the European Research Area Network on Cardiovascular Disease (ERA-CVD) Joint Transnational Call 2018 (PICASSO JTC2018-042), which is a European Research Area Network (ERA-Net) comprising 24 partners from 19 countries/regions that has been granted for funding through the current EU Framework Programme for Research and Innovation ‘Horizon 2020,’ (Drs. Poggio, Arsenault, Capoulade, and Mass) by the Italian Ministry of Health (GR-2018-12366423) (Dr. Poggio), by the Fondation de l’IUCPQ (Dr. Arsenault), by the Fondazione Gigi & Pupa Ferrari ONLUS (FPF-14) Dr. Poggio, Merck (Dr. Arsenault), and Pfizer (Dr. Arsenault). The EPIC-Norfolk Study is funded by Cancer Research UK grant number 14136 and the Medical Research Council grant number G1000143 (Dr. Wareham). The COFRASA (Aortic Stenosis in Elderly: Determinant of Progression; NCT00338676) and GENERAC (Genetic of Aortic Valve Stenosis-Clinical and Therapeutic Implications; NCT00647088) studies are supported by grants from the Assistance Publique-Hôpitaux de Paris (PHRC National 2005 and 2010, and PHRC régional 2007) (Dr. Messika-Zeitoun). Dr. Capoulade is supported by a “Connect Talent” research chair from Région Pays de la Loire and Nantes Métropole. Dr. Mass is supported by the German Research Foundation (Excellence Cluster ImmunoSensation), the Fritz Thyssen Foundation and Daimler and Benz Foundation. Drs. Clavel, Thériault, and Arsenault hold junior scholar awards from the Fonds de Recherche du Québec: Santé (FRQS). Ms. Chen was funded by a studentship from the McGill University Health Centre Foundation. Dr. Le Tourneau is supported by the Fédération Française de Cardiologie, a Fondation Coeur et Recherche and an Inserm Translational Research grant. Dr. Pibarot holds the Canada Research Chair in Valvular Heart Disease and his research program is supported by a Foundation Scheme Grant from the Canadian Institutes of Health Research (CIHR). Dr. Smith was supported by grants from the Swedish Heart-Lung Foundation (2016-0134 and 2016-0315), the Swedish Research Council (2017-02554), the European Research Council (ERC-STG-2015-679242), the Crafoord Foundation, Skåne University Hospital, the Scania county, governmental funding of clinical research within the Swedish National Health Service, a generous donation from the Knut and Alice Wallenberg foundation to the Wallenberg Center for Molecular Medicine in Lund, and funding from the Swedish Research Council (Linnaeus grant Dnr 349-2006-237, Strategic Research Area Exodiab Dnr 2009-1039) and Swedish Foundation for Strategic Research (Dnr IRC15-0067) to the Lund University Diabetes Center. Dr. Mathieu holds a FRQS Research Chair on the Pathobiology of Calcific Aortic Valve Disease. Prof. Bossé holds a Canada Research Chair in Genomics of Heart and Lung Diseases. Dr. Thanassoulis is supported by R01 HL128550 from the National Institutes of Health/National Heart, Lung, and Blood Institute; and has received research research funding from Servier and Ionis Pharmaceuticals; has been a consultant for Amgen, Sanofi/Regerenon, Boehringer Ingelheim, and Ionis Pharmaceuticals, Novartis and HLS Therapeutics. Dr. Clavel has received funding from Medtronic; and her institution has a core laboratory contract with Edwards Lifesciences for which she is not directly compensated. Dr. Le Tourneau has received funding from Abbott/St. Jude. Dr. Messika-Zeitoun has received funding from Edwards Lifesciences. Dr. Pibarot has received funding from Edwards Lifesciences and Medtronic. Dr. Mathieu has been a consultant for Casebia Therapeutics. Dr. Arsenault has received research funding from Pfizer, Merck, and Ionis Pharmaceuticals; and has been a consultant for Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received March 4, 2020.
- Revision received May 8, 2020.
- Accepted May 8, 2020.
- 2020 The Authors