{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T14:49:49Z","timestamp":1767970189247,"version":"3.49.0"},"reference-count":94,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2021,3,13]],"date-time":"2021-03-13T00:00:00Z","timestamp":1615593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004281","name":"Narodowe Centrum Nauki","doi-asserted-by":"publisher","award":["UMO\u20102015\/19\/B\/NZ5\/00647"],"award-info":[{"award-number":["UMO\u20102015\/19\/B\/NZ5\/00647"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Eur J Clin Investigation"],"published-print":{"date-parts":[[2021,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Aortic stenosis (AS) prevalence is estimated to reach 4.5 million cases worldwide by the year 2030. AS is a progressive disease without a pharmacological treatment. In the current review, we aimed to investigate novel therapeutic approaches for non\u2010surgical AS treatment, at least in patients with mild\u2010to\u2010moderate AS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>The most recent and relevant papers concerned with novel molecular pathways that have potential as therapeutic targets in AS were selected from searches of PubMed and Web of Science up to February 2021.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Growing evidence indicates that therapies using proprotein convertase subtilisin\/kexin type 9 (PCSK9) inhibitors, simvastatin\/ezetimibe combination, cholesteryl ester transfer protein inhibitors or antisense oligonucleotides targeting apolipoprotein(a) reduce the risk of AS progression. It has been shown that enhanced valvular lipid oxidation may drive AS development by leading to the activation of valvular interstitial cells (VICs), the most abundant valvular cells having a major contribution to valve calcification. Since VICs are able to release pro\u2010inflammatory cytokines, clotting factors and proteins involved in calcification, strategies targeting these cell activations seem promising as therapeutic interventions. Recently, non\u2010vitamin K antagonist oral anticoagulants (NOACs) have been shown to inhibit activation of VICs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Several novel molecular pathways of AS development have been identified over the past few years. Therapies using PCSK9 inhibitors, simvastatin\/ezetimibe combination, lipoprotein(a)\u2010lowering therapy are highly promising candidates as therapeutics in the prevention of mild AS progression, while preclinical studies show that NOACs may inhibit valvular inflammation and coagulation activation and slower the rate of AS progression.<\/jats:p><\/jats:sec>","DOI":"10.1111\/eci.13527","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T20:56:08Z","timestamp":1614113768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Aortic valvular stenosis: Novel therapeutic strategies"],"prefix":"10.1111","volume":"51","author":[{"given":"Joanna","family":"Natorska","sequence":"first","affiliation":[{"name":"John Paul II Hospital Krak\u00f3w Poland"},{"name":"Institute of Cardiology Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Kopytek","sequence":"additional","affiliation":[{"name":"John Paul II Hospital Krak\u00f3w Poland"},{"name":"Institute of Cardiology Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3716-1724","authenticated-orcid":false,"given":"Anetta","family":"Undas","sequence":"additional","affiliation":[{"name":"John Paul II Hospital Krak\u00f3w Poland"},{"name":"Institute of Cardiology Jagiellonian University Medical College Krak\u00f3w Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,3,13]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.015"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.302523"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.900027"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0804602"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa043876"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1910555"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.33963\/KP.15522"},{"key":"e_1_2_7_9_1","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1093\/oxfordjournals.eurheartj.a060602","article-title":"Factors associated with calcific aortic valve degeneration in the elderly","volume":"15","author":"Lindroos M","year":"1994","journal-title":"EurHeart J"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(96)00563-3"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(87)91144-1"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(00)02572-1"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1586\/erc.12.171"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.104.486738"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1080\/00313029700169315"},{"issue":"3","key":"e_1_2_7_16_1","first-page":"231","article-title":"Cell biology of valvular interstitial cells","volume":"12","author":"Mulholland DL","year":"1996","journal-title":"Can J Cardiol"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.234138"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.90.2.844"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-012-9565-z"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2019.03.047"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.11.1522"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.070251"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2009.03.108"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.107.154989"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00137.2007"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvq076"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0003-4975(02)04312-6"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.110.177915"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2014.02.014"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2020.106679"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0000000000000300"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2017.03.015"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/875363"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.19.5.1218"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH14-10-0861"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065810"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13239-014-0197-3"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.05.105"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvq052"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2017.02.004"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.016757"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1109034"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2018.3798"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-013-0310-3"},{"issue":"1","key":"e_1_2_7_45_1","first-page":"28","article-title":"Alirocumab (praluent): first in the new class of PCSK9 inhibitors","volume":"41","author":"Manniello M","year":"2016","journal-title":"P T"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0903849106"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1105803"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI29383"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.33963\/KP.15529"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1177\/0300060516648030"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2020.05.004"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1206"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamacardio.2020.0728"},{"issue":"9","key":"e_1_2_7_54_1","first-page":"27","article-title":"PCSK9 inhibitor causes a decrease in the level of oxidatively modified low\u2010density lipoproteins in patients with coronary artery diseases","volume":"90","author":"Lankin VZ","year":"2018","journal-title":"Ter Arkh"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1706444"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacl.2015.11.014"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)60158-1"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)61252-1"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31009-1"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-019-01243-5"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2019.08.037"},{"issue":"10","key":"e_1_2_7_62_1","doi-asserted-by":"crossref","first-page":"636","DOI":"10.20452\/pamw.791","article-title":"Evidence for tissue factor expression in aortic valves in patients with aortic stenosis","volume":"119","author":"Natorska J","year":"2009","journal-title":"Pol Arch Med Wewn"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH10-09-0612"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2010.07.047"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1160\/TH12-07-0455"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1011670"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvt343"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2015.03.023"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10557-012-6411-3"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.194837"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/432080"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32458-3"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehr226"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.12.008"},{"issue":"7","key":"e_1_2_7_75_1","first-page":"460","article-title":"Assessment of patients with coronary artery disease who may benefit from the use of rivaroxaban in the real world: implementation of the COMPASS trial criteria in the TERCET registry population","volume":"129","author":"Desperak P","year":"2019","journal-title":"Pol Arch Intern Med"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2018.11.119"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9150(03)00284-3"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00220-6"},{"key":"e_1_2_7_79_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2559.2011.03977.x"},{"key":"e_1_2_7_80_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314143"},{"key":"e_1_2_7_81_1","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2019.1654797"},{"key":"e_1_2_7_82_1","doi-asserted-by":"publisher","DOI":"10.4330\/wjc.v7.i12.829"},{"key":"e_1_2_7_83_1","article-title":"Extracellular Histones Inhibit Fibrinolysis through Noncovalent and Covalent Interactions with Fibrin","author":"Locke M","year":"2020","journal-title":"Thromb Haemost"},{"key":"e_1_2_7_84_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-011-9384-7"},{"key":"e_1_2_7_85_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198805193182007"},{"key":"e_1_2_7_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mvr.2009.12.005"},{"key":"e_1_2_7_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharma.2014.05.002"},{"key":"e_1_2_7_88_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2001.280.5.E685"},{"key":"e_1_2_7_89_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.667576"},{"key":"e_1_2_7_90_1","doi-asserted-by":"publisher","DOI":"10.1002\/jor.23083"},{"key":"e_1_2_7_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabet.2015.01.006"},{"key":"e_1_2_7_92_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-012-0306-0"},{"key":"e_1_2_7_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.exger.2014.05.001"},{"key":"e_1_2_7_94_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-020-01068-7"},{"key":"e_1_2_7_95_1","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9570616"}],"container-title":["European Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.13527","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/eci.13527","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/eci.13527","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T19:00:24Z","timestamp":1724526024000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/eci.13527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,13]]},"references-count":94,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2021,7]]}},"alternative-id":["10.1111\/eci.13527"],"URL":"https:\/\/doi.org\/10.1111\/eci.13527","archive":["Portico"],"relation":{},"ISSN":["0014-2972","1365-2362"],"issn-type":[{"value":"0014-2972","type":"print"},{"value":"1365-2362","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,13]]},"assertion":[{"value":"2020-12-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-02-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-03-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e13527"}}