{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T11:28:10Z","timestamp":1790681290818,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2021,7,27]],"date-time":"2021-07-27T00:00:00Z","timestamp":1627344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Agence Nationale de la Recherche (Paris, France) Program Grant CHOPIN","award":["ANR-16-RHUS-0007"],"award-info":[{"award-number":["ANR-16-RHUS-0007"]}]},{"name":"European Union (European Regional Development Fund INTERREG V) and the R\u00e9gion R\u00e9union"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charit\u00e9 Hospital (Berlin) between 2015 and 2020. They were hypercholesterolaemic at very high cardiovascular disease risk with low-density lipoprotein (LDL)-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150\u2009mg) or Evolocumab (140\u2009mg) every 2\u2009weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by western blot. PCSK9i sharply reduced LDL-cholesterol (\u221257%), apoB100 (\u221247%), and Lp(a) (\u221236%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r\u2009=\u20090.363, P\u2009=\u20090.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r\u2009=\u20090.350, P\u2009=\u20090.0001) and larger (r\u2009=\u20090.324, P\u2009=\u20090.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (P\u2009&amp;lt;\u20090.0001).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The size of apo(a) is an independent determinant of the response to PCSK9i. Each additional kringle domain is associated with a 3% additional reduction in Lp(a). This explains in part the variable efficacy of PCSK9i and allows to identify patients who will benefit most from these therapies in terms of Lp(a) lowering.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvab247","type":"journal-article","created":{"date-parts":[[2021,7,24]],"date-time":"2021-07-24T15:09:47Z","timestamp":1627139387000},"page":"2103-2111","source":"Crossref","is-referenced-by-count":29,"title":["The size of apolipoprotein (a) is an independent determinant of the reduction in lipoprotein (a) induced by PCSK9 inhibitors"],"prefix":"10.1093","volume":"118","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9970-0530","authenticated-orcid":false,"given":"Valentin","family":"Blanchard","sequence":"first","affiliation":[{"name":"Universit\u00e9 de La R\u00e9union, INSERM UMR 1188 D\u00e9TROI , Plateforme CYROI, 2 Rue Maxime Rivi\u00e8re, 97490 Sainte-Clotilde , France"},{"name":"Departments of Medicine, Centre for Heart Lung Innovation, Providence Healthcare Research Institute, St. Paul's Hospital, University of British Columbia , Vancouver BC , Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e9vin","family":"Chemello","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de La R\u00e9union, INSERM UMR 1188 D\u00e9TROI , Plateforme CYROI, 2 Rue Maxime Rivi\u00e8re, 97490 Sainte-Clotilde , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Hollstein","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Campus Virchow-Klinikum, Charit\u00e9 Universit\u00e4tsmedizin , Berlin , Germany"},{"name":"Division of Endocrinology, Diabetology and Clinical Nutrition, Department of Internal Medicine 1, University of Kiel , Kiel , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9ment Chong","family":"Hong-Fong","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de La R\u00e9union, INSERM UMR 1188 D\u00e9TROI , Plateforme CYROI, 2 Rue Maxime Rivi\u00e8re, 97490 Sainte-Clotilde , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Schumann","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Campus Virchow-Klinikum, Charit\u00e9 Universit\u00e4tsmedizin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Grenkowitz","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Campus Virchow-Klinikum, Charit\u00e9 Universit\u00e4tsmedizin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3719-7903","authenticated-orcid":false,"given":"Brice","family":"Nativel","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de La R\u00e9union, INSERM UMR 1188 D\u00e9TROI , Plateforme CYROI, 2 Rue Maxime Rivi\u00e8re, 97490 Sainte-Clotilde , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-8979","authenticated-orcid":false,"given":"Stefan","family":"Coassin","sequence":"additional","affiliation":[{"name":"Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbr\u00fcck , Innsbr\u00fcck , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5449-5817","authenticated-orcid":false,"given":"Mika\u00ebl","family":"Croyal","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Nantes, CNRS, INSERM, l'institut du thorax , Nantes , France"},{"name":"Universit\u00e9 de Nantes , CHU Nantes, Inserm, CNRS, SFR Sant\u00e9, Nantes , France"},{"name":"CRNH-Ouest Mass Spectrometry Core Facility , Nantes , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Kassner","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Campus Virchow-Klinikum, Charit\u00e9 Universit\u00e4tsmedizin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-5806","authenticated-orcid":false,"given":"Claudia","family":"Lamina","sequence":"additional","affiliation":[{"name":"Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbr\u00fcck , Innsbr\u00fcck , Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Steinhagen-Thiessen","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Campus Virchow-Klinikum, Charit\u00e9 Universit\u00e4tsmedizin , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5632-0685","authenticated-orcid":false,"given":"Gilles","family":"Lambert","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de La R\u00e9union, INSERM UMR 1188 D\u00e9TROI , Plateforme CYROI, 2 Rue Maxime Rivi\u00e8re, 97490 Sainte-Clotilde , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,27]]},"reference":[{"key":"2022072219591618900_cvab247-B1","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1111\/j.1365-2796.2012.02592.x","article-title":"Lipoprotein(a): resurrected by genetics","volume":"273","author":"Kronenberg","year":"2013","journal-title":"J Intern Med"},{"key":"2022072219591618900_cvab247-B2","doi-asserted-by":"crossref","first-page":"2682","DOI":"10.1016\/j.jacc.2020.03.065","article-title":"Ascertainment bias in the association between elevated lipoprotein(a) and familial hypercholesterolemia","volume":"75","author":"Trinder","year":"2020","journal-title":"J Am Coll Cardiol"},{"key":"2022072219591618900_cvab247-B3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jacc.2017.11.014","article-title":"NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis","volume":"71","author":"Tsimikas","year":"2018","journal-title":"J Am Coll Cardiol"},{"key":"2022072219591618900_cvab247-B4","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s41569-018-0153-2","article-title":"Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease","volume":"16","author":"Boffa","year":"2019","journal-title":"Nat Rev Cardiol"},{"key":"2022072219591618900_cvab247-B5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/CS20160403","article-title":"The complexity of lipoprotein (a) lowering by PCSK9 monoclonal antibodies","volume":"131","author":"Lambert","year":"2017","journal-title":"Clin Sci (Lond)"},{"key":"2022072219591618900_cvab247-B6","doi-asserted-by":"crossref","first-page":"e0180869","DOI":"10.1371\/journal.pone.0180869","article-title":"Roles of the low density lipoprotein receptor and related receptors in inhibition of lipoprotein(a) internalization by proprotein convertase subtilisin\/kexin type 9","volume":"12","author":"Romagnuolo","year":"2017","journal-title":"PLoS One"},{"key":"2022072219591618900_cvab247-B7","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jacbts.2016.06.006","article-title":"PCSK9 modulates the secretion but not the cellular uptake of lipoprotein(a) ex vivo: an effect blunted by alirocumab","volume":"1","author":"Villard","year":"2016","journal-title":"JACC Basic Transl Sci"},{"key":"2022072219591618900_cvab247-B8","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.1194\/jlr.M076232","article-title":"A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms","volume":"58","author":"Mack","year":"2017","journal-title":"J Lipid Res"},{"key":"2022072219591618900_cvab247-B9","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s40256-020-00411-3","article-title":"PCSK9 inhibitors in a german single-center clinical practice: real-world treatment of patients at high cardiovascular risk over 68 weeks","volume":"21","author":"Hollstein","year":"2021","journal-title":"Am J Cardiovasc Drugs"},{"key":"2022072219591618900_cvab247-B10","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1093\/eurheartj\/ehw106","article-title":"2016 European Guidelines on cardiovascular disease prevention in clinical practice","volume":"37","author":"Piepoli","year":"2016","journal-title":"Eur Heart J"},{"key":"2022072219591618900_cvab247-B11","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.vph.2019.03.002","article-title":"Treatment with PCSK9 inhibitors reduces atherogenic VLDL remnants in a real-world study","volume":"116","author":"Hollstein","year":"2019","journal-title":"Vasc Pharmacol"},{"key":"2022072219591618900_cvab247-B12","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1161\/ATVBAHA.116.308704","article-title":"Lipoprotein(a) mass levels increase significantly according to APOE genotype","volume":"37","author":"Moriarty Patrick","year":"2017","journal-title":"ATVB"},{"key":"2022072219591618900_cvab247-B13","doi-asserted-by":"crossref","first-page":"3390","DOI":"10.1210\/jc.2017-01049","article-title":"Effect of APOE \u03b5 genotype on lipoprotein(a) and the associated risk of myocardial infarction and aortic valve stenosis","volume":"102","author":"Kritharides","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"2022072219591618900_cvab247-B14","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.jacbts.2019.03.002","article-title":"Reduced lipoprotein(a) associated with the apolipoprotein E2 genotype confers cardiovascular protection in familial hypercholesterolemia","volume":"4","author":"Blanchard","year":"2019","journal-title":"JACC Basic Transl Sci"},{"key":"2022072219591618900_cvab247-B15","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","article-title":"Evolocumab and clinical outcomes in patients with cardiovascular disease","volume":"376","author":"Sabatine","year":"2017","journal-title":"N Engl J Med"},{"key":"2022072219591618900_cvab247-B16","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1056\/NEJMoa1801174","article-title":"Alirocumab and cardiovascular outcomes after acute coronary syndrome","volume":"379","author":"Schwartz","year":"2018","journal-title":"N Engl J Med"},{"key":"2022072219591618900_cvab247-B17","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1161\/CIRCULATIONAHA.118.037184","article-title":"Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk","volume":"139","author":"O\u2019Donoghue","year":"2019","journal-title":"Circulation"},{"key":"2022072219591618900_cvab247-B18","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1194\/jlr.P065334","article-title":"PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor\u2019s role","volume":"57","author":"Raal","year":"2016","journal-title":"J Lipid Res"},{"key":"2022072219591618900_cvab247-B19","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1177\/2047487320915803","article-title":"Discordant responses of plasma low-density lipoprotein cholesterol and lipoprotein(a) to alirocumab: a pooled analysis from 10 ODYSSEY Phase 3 studies","volume":"28","author":"Mahmood","year":"2021","journal-title":"Eur J Prev Cardiol"},{"key":"2022072219591618900_cvab247-B20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.amjcard.2016.09.010","article-title":"Effect of alirocumab on lipoprotein(a) over \u22651.5 years (from the Phase 3 ODYSSEY Program)","volume":"119","author":"Gaudet","year":"2017","journal-title":"Am J Cardiol"},{"key":"2022072219591618900_cvab247-B21","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.jacl.2017.03.001","article-title":"Discordant response of low-density lipoprotein cholesterol and lipoprotein(a) levels to monoclonal antibodies targeting proprotein convertase subtilisin\/kexin type 9","volume":"11","author":"Edmiston","year":"2017","journal-title":"J Clin Lipidol"},{"key":"2022072219591618900_cvab247-B22","doi-asserted-by":"crossref","first-page":"e010932","DOI":"10.1161\/JAHA.118.010932","article-title":"Relationship between low-density lipoprotein cholesterol and lipoprotein(a) lowering in response to PCSK9 inhibition with evolocumab","volume":"8","author":"Shapiro","year":"2019","journal-title":"J Am Heart Assoc"},{"key":"2022072219591618900_cvab247-B23","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1194\/jlr.P119000173","article-title":"PCSK9 loss-of-function variants and Lp(a) phenotypes among black US adults","volume":"60","author":"Mefford","year":"2019","journal-title":"J Lipid Res"},{"key":"2022072219591618900_cvab247-B24","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1210\/jc.2016-1206","article-title":"PCSK9 R46L loss-of-function mutation reduces lipoprotein(a), LDL cholesterol, and risk of aortic valve stenosis","volume":"101","author":"Langsted","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"2022072219591618900_cvab247-B25","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1194\/jlr.M078212","article-title":"The roles of apo(a) size, phenotype, and dominance pattern in PCSK9-inhibition-induced reduction in Lp(a) with alirocumab","volume":"58","author":"Enkhmaa","year":"2017","journal-title":"J Lipid Res"},{"key":"2022072219591618900_cvab247-B26","doi-asserted-by":"crossref","first-page":"e001696","DOI":"10.1161\/CIRCGEN.117.001696","article-title":"Impact of apolipoprotein(a) isoform size on lipoprotein(a) lowering in the HPS2-THRIVE study","volume":"11","author":"Parish","year":"2018","journal-title":"Circ Cardiovasc Genet"},{"key":"2022072219591618900_cvab247-B27","doi-asserted-by":"crossref","first-page":"5048","DOI":"10.1074\/jbc.272.8.5048","article-title":"Influence of allelic variation on apolipoprotein(a) folding in the endoplasmic reticulum","volume":"272","author":"White","year":"1997","journal-title":"J Biol Chem"},{"key":"2022072219591618900_cvab247-B28","doi-asserted-by":"crossref","first-page":"5417","DOI":"10.1021\/bi972761t","article-title":"Intracellular metabolism of human apolipoprotein(a) in stably transfected Hep G2 cells","volume":"37","author":"Lobentanz","year":"1998","journal-title":"Biochemistry"},{"key":"2022072219591618900_cvab247-B29","doi-asserted-by":"crossref","first-page":"32403","DOI":"10.1074\/jbc.271.50.32403","article-title":"The number of identical kringle IV repeats in apolipoprotein(a) affects its processing and secretion by HepG2 cells","volume":"271","author":"Brunner","year":"1996","journal-title":"J Biol Chem"},{"key":"2022072219591618900_cvab247-B30","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1042\/CS20180040","article-title":"PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate","volume":"132","author":"Croyal","year":"2018","journal-title":"Clin Sci (Lond)"},{"key":"2022072219591618900_cvab247-B31","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/j.jacbts.2020.03.008","article-title":"Lipoprotein(a) cellular uptake ex vivo and hepatic capture in vivo is insensitive to PCSK9 inhibition with alirocumab","volume":"5","author":"Chemello","year":"2020","journal-title":"JACC Basic Transl Sci"},{"key":"2022072219591618900_cvab247-B32","doi-asserted-by":"crossref","first-page":"9978","DOI":"10.1021\/bi049536d","article-title":"Identification of sequences in apolipoprotein(a) that maintain its closed conformation: a novel role for apo(a) isoform size in determining the efficiency of covalent Lp(a) formation","volume":"43","author":"Becker","year":"2004","journal-title":"Biochemistry"},{"key":"2022072219591618900_cvab247-B33","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1001\/jamacardio.2019.1041","article-title":"Estimation of the required lipoprotein(a)-lowering therapeutic effect size for reduction in coronary heart disease outcomes: a Mendelian Randomization Analysis","volume":"4","author":"Lamina","year":"2019","journal-title":"JAMA Cardiol"},{"key":"2022072219591618900_cvab247-B34","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1016\/S0140-6736(19)31950-6","article-title":"Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options","volume":"394","author":"Ray","year":"2019","journal-title":"Lancet"}],"container-title":["Cardiovascular Research"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/cardiovascres\/advance-article-pdf\/doi\/10.1093\/cvr\/cvab247\/39590928\/cvab247.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/118\/9\/2103\/45049642\/cvab247.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article-pdf\/118\/9\/2103\/45049642\/cvab247.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T16:01:07Z","timestamp":1658505667000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cardiovascres\/article\/118\/9\/2103\/6329261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,27]]},"references-count":34,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,7,27]]},"published-print":{"date-parts":[[2022,7,20]]}},"URL":"https:\/\/doi.org\/10.1093\/cvr\/cvab247","relation":{},"ISSN":["0008-6363","1755-3245"],"issn-type":[{"value":"0008-6363","type":"print"},{"value":"1755-3245","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,6,1]]},"published":{"date-parts":[[2021,7,27]]}}}