Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

Nicolas Perrot; Vincenza Valerio; Donato Moschetta; S. Matthijs Boekholdt; Christian Dina; Hao Yu Chen; Erik Abner; Andreas Martinsson; Hasanga D. Manikpurage; Sidwell Rigade; Romain Capoulade; Elvira Mass; Marie Annick Clavel; Thierry Le Tourneau; David Messika-Zeitoun; Nicholas J. Wareham; James C. Engert; Gianluca Polvani; Philippe Pibarot; Tõnu Esko; J. Gustav Smith; Patrick Mathieu; George Thanassoulis; Jean Jacques Schott; Yohan Bossé; Marina Camera; Sébastien Thériault; Paolo Poggio; Benoit J. Arsenault

doi:10.1016/j.jacbts.2020.05.004

Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

Nicolas Perrot, Vincenza Valerio, Donato Moschetta, S. Matthijs Boekholdt, Christian Dina, Hao Yu Chen, Erik Abner, Andreas Martinsson, Hasanga D. Manikpurage, Sidwell Rigade, Romain Capoulade, Elvira Mass, Marie Annick Clavel, Thierry Le Tourneau, David Messika-Zeitoun, Nicholas J. Wareham, James C. Engert, Gianluca Polvani, Philippe Pibarot, Tõnu EskoJ. Gustav Smith, Patrick Mathieu, George Thanassoulis, Jean Jacques Schott, Yohan Bossé, Marina Camera, Sébastien Thériault, Paolo Poggio, Benoit J. Arsenault

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Pages (from-to)	649-661
Number of pages	13
Journal	JACC: Basic to Translational Science
Volume	5
Issue number	7
DOIs	https://doi.org/10.1016/j.jacbts.2020.05.004
Publication status	Published - Jul 2020

Keywords

aortic valve interstitial cell
apolipoprotein B
calcific aortic valve stenosis
LDL cholesterol
lipoprotein(a)
proprotein convertase subtilisin/kexin type 9

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacbts.2020.05.004

Cite this

Perrot, N., Valerio, V., Moschetta, D., Boekholdt, S. M., Dina, C., Chen, H. Y., Abner, E., Martinsson, A., Manikpurage, H. D., Rigade, S., Capoulade, R., Mass, E., Clavel, M. A., Le Tourneau, T., Messika-Zeitoun, D., Wareham, N. J., Engert, J. C., Polvani, G., Pibarot, P., ... Arsenault, B. J. (2020). Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. JACC: Basic to Translational Science, 5(7), 649-661. https://doi.org/10.1016/j.jacbts.2020.05.004

Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. / Perrot, Nicolas; Valerio, Vincenza ; Moschetta, Donato; Boekholdt, S. Matthijs; Dina, Christian; Chen, Hao Yu; Abner, Erik; Martinsson, Andreas; Manikpurage, Hasanga D.; Rigade, Sidwell; Capoulade, Romain; Mass, Elvira; Clavel, Marie Annick; Le Tourneau, Thierry; Messika-Zeitoun, David; Wareham, Nicholas J.; Engert, James C.; Polvani, Gianluca; Pibarot, Philippe; Esko, Tõnu; Smith, J. Gustav; Mathieu, Patrick; Thanassoulis, George; Schott, Jean Jacques; Bossé, Yohan; Camera, Marina; Thériault, Sébastien; Poggio, Paolo; Arsenault, Benoit J.

In: JACC: Basic to Translational Science, Vol. 5, No. 7, 07.2020, p. 649-661.

Research output: Contribution to journal › Article › peer-review

Perrot, N, Valerio, V , Moschetta, D, Boekholdt, SM, Dina, C, Chen, HY, Abner, E, Martinsson, A, Manikpurage, HD, Rigade, S, Capoulade, R, Mass, E, Clavel, MA, Le Tourneau, T, Messika-Zeitoun, D, Wareham, NJ, Engert, JC, Polvani, G, Pibarot, P, Esko, T, Smith, JG, Mathieu, P, Thanassoulis, G, Schott, JJ, Bossé, Y, Camera, M, Thériault, S, Poggio, P & Arsenault, BJ 2020, 'Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis', JACC: Basic to Translational Science, vol. 5, no. 7, pp. 649-661. https://doi.org/10.1016/j.jacbts.2020.05.004

Perrot, Nicolas ; Valerio, Vincenza ; Moschetta, Donato ; Boekholdt, S. Matthijs ; Dina, Christian ; Chen, Hao Yu ; Abner, Erik ; Martinsson, Andreas ; Manikpurage, Hasanga D. ; Rigade, Sidwell ; Capoulade, Romain ; Mass, Elvira ; Clavel, Marie Annick ; Le Tourneau, Thierry ; Messika-Zeitoun, David ; Wareham, Nicholas J. ; Engert, James C. ; Polvani, Gianluca ; Pibarot, Philippe ; Esko, Tõnu ; Smith, J. Gustav ; Mathieu, Patrick ; Thanassoulis, George ; Schott, Jean Jacques ; Bossé, Yohan ; Camera, Marina ; Thériault, Sébastien ; Poggio, Paolo ; Arsenault, Benoit J. / Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis. In: JACC: Basic to Translational Science. 2020 ; Vol. 5, No. 7. pp. 649-661.

@article{496120e1a84546edab5105c410654ddf,

title = "Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis",

abstract = "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.",

keywords = "aortic valve interstitial cell, apolipoprotein B, calcific aortic valve stenosis, LDL cholesterol, lipoprotein(a), proprotein convertase subtilisin/kexin type 9",

author = "Nicolas Perrot and Vincenza Valerio and Donato Moschetta and Boekholdt, {S. Matthijs} and Christian Dina and Chen, {Hao Yu} and Erik Abner and Andreas Martinsson and Manikpurage, {Hasanga D.} and Sidwell Rigade and Romain Capoulade and Elvira Mass and Clavel, {Marie Annick} and {Le Tourneau}, Thierry and David Messika-Zeitoun and Wareham, {Nicholas J.} and Engert, {James C.} and Gianluca Polvani and Philippe Pibarot and T{\~o}nu Esko and Smith, {J. Gustav} and Patrick Mathieu and George Thanassoulis and Schott, {Jean Jacques} and Yohan Boss{\'e} and Marina Camera and S{\'e}bastien Th{\'e}riault and Paolo Poggio and Arsenault, {Benoit J.}",

note = "Funding Information: The authors thank all study participants as well as Anna Guarino and Barbara Micheli for the collection and processing of the control specimens (Cardiovascular Tissue Bank, Milan, Italy). 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-H?pitaux de Paris (PHRC National 2005 and 2010, and PHRC r?gional 2007) (Dr. Messika-Zeitoun). Dr. Capoulade is supported by a ?Connect Talent? research chair from R?gion Pays de la Loire and Nantes M?tropole. Dr. Mass is supported by the German Research Foundation (Excellence Cluster ImmunoSensation), the Fritz Thyssen Foundation and Daimler and Benz Foundation. Drs. Clavel, Th?riault, and Arsenault hold junior scholar awards from the Fonds de Recherche du Qu?bec: Sant? (FRQS). Ms. Chen was funded by a studentship from the McGill University Health Centre Foundation. Dr. Le Tourneau is supported by the F?d?ration Fran?aise 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, Sk?ne 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. Boss? 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. Publisher Copyright: {\textcopyright} 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = jul,

doi = "10.1016/j.jacbts.2020.05.004",

language = "English",

volume = "5",

pages = "649--661",

journal = "JACC: Basic to Translational Science",

issn = "2452-302X",

publisher = "Elsevier Inc.",

number = "7",

}

TY - JOUR

T1 - Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

AU - Perrot, Nicolas

AU - Valerio, Vincenza

AU - Moschetta, Donato

AU - Boekholdt, S. Matthijs

AU - Dina, Christian

AU - Chen, Hao Yu

AU - Abner, Erik

AU - Martinsson, Andreas

AU - Manikpurage, Hasanga D.

AU - Rigade, Sidwell

AU - Capoulade, Romain

AU - Mass, Elvira

AU - Clavel, Marie Annick

AU - Le Tourneau, Thierry

AU - Messika-Zeitoun, David

AU - Wareham, Nicholas J.

AU - Engert, James C.

AU - Polvani, Gianluca

AU - Pibarot, Philippe

AU - Esko, Tõnu

AU - Smith, J. Gustav

AU - Mathieu, Patrick

AU - Thanassoulis, George

AU - Schott, Jean Jacques

AU - Bossé, Yohan

AU - Camera, Marina

AU - Thériault, Sébastien

AU - Poggio, Paolo

AU - Arsenault, Benoit J.

N1 - Funding Information: The authors thank all study participants as well as Anna Guarino and Barbara Micheli for the collection and processing of the control specimens (Cardiovascular Tissue Bank, Milan, Italy). 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-H?pitaux de Paris (PHRC National 2005 and 2010, and PHRC r?gional 2007) (Dr. Messika-Zeitoun). Dr. Capoulade is supported by a ?Connect Talent? research chair from R?gion Pays de la Loire and Nantes M?tropole. Dr. Mass is supported by the German Research Foundation (Excellence Cluster ImmunoSensation), the Fritz Thyssen Foundation and Daimler and Benz Foundation. Drs. Clavel, Th?riault, and Arsenault hold junior scholar awards from the Fonds de Recherche du Qu?bec: Sant? (FRQS). Ms. Chen was funded by a studentship from the McGill University Health Centre Foundation. Dr. Le Tourneau is supported by the F?d?ration Fran?aise 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, Sk?ne 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. Boss? 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. Publisher Copyright: © 2020 The Authors Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/7

Y1 - 2020/7

N2 - 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.

AB - 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.

KW - aortic valve interstitial cell

KW - apolipoprotein B

KW - calcific aortic valve stenosis

KW - LDL cholesterol

KW - lipoprotein(a)

KW - proprotein convertase subtilisin/kexin type 9

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M3 - Article

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JO - JACC: Basic to Translational Science

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ER -

Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

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