{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T22:09:36Z","timestamp":1791670176609,"version":"4.3.4"},"reference-count":40,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T00:00:00Z","timestamp":1567728000000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100006775","name":"GE Healthcare","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006775","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008270","name":"Lantheus medical imaging","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008270","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006279","name":"St Jude Medical","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006279","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004374","name":"Medtronic","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004374","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008497","name":"Boston Scientific","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008497","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005035","name":"Biotronik","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005035","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006520","name":"Edwards Lifesciences","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006520","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>In mitral valve prolapse (MVP), leaflet thickening has recently been suggested to be due, in addition to a myxomatous degeneration, to the presence of a superimposed tissue (SIT), defined as an additional fibrous layer on top of the original leaflet. The mechanisms of SIT formation are currently unknown. We hypothesized that SIT formation would result from excessive leaflet stress and we used a unique ex vivo model to assess the correlation between leaflet remodelling and the type and location of mechanical stress and to elucidate the mechanisms underlying SIT formation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Human diseased mitral valves (MVs; n\u2009=\u200921) were histologically analysed for SIT formation and original leaflet thickening. The SIT comprised of various compositions of extracellular matrix and could reach more than 50% of total leaflet thickness. Original leaflet and SIT thickness did not show significant correlation (r\u2009=\u2009\u22120.27, P\u2009=\u20090.23), suggesting different regulatory mechanisms. To study the role of the mechanical environment on MV remodelling, mouse MV were cultured in their natural position in the heart and subjected to various haemodynamic conditions representing specific phases of the cardiac cycle and the MVP configuration. SIT formation was induced in the ex vivo model, mostly present on the atrial side, and clearly dependent on the duration, type, and extent of mechanical stress. Specific stainings and lineage tracing experiments showed that SIT comprises of macrophages and myofibroblasts and is associated with the activation of the transforming growth factor-beta and bone morphogenetic protein signalling pathways. Migration of valvular interstitial cells and macrophages through breakages of the endothelial cell lining contributed to SIT formation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Mechanical stresses induce specific cellular and molecular changes in the MV that result in SIT formation. These observations provide the first insights in the mechanism of SIT formation and represent an initial step to identify potential novel and early treatment for MVP.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvz204","type":"journal-article","created":{"date-parts":[[2019,9,4]],"date-time":"2019-09-04T15:27:19Z","timestamp":1567610839000},"source":"Crossref","is-referenced-by-count":11,"title":["Stress-induced remodelling of the mitral valve: a model for leaflet thickening and superimposed tissue formation in mitral valve disease"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9604-4563","authenticated-orcid":false,"given":"Boudewijn P T","family":"Kruithof","sequence":"first","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"},{"name":"Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands"},{"name":"Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7914-9582","authenticated-orcid":false,"given":"Laura","family":"Paardekooper","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine L","family":"Hiemstra","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9344-6746","authenticated-orcid":false,"given":"Marie-Jos\u00e9","family":"Goumans","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7213-5452","authenticated-orcid":false,"given":"Meindert","family":"Palmen","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Delgado","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J M","family":"Klautz","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Ajmone Marsan","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,9,8]]},"reference":[{"key":"2019092611214468700_cvz204-B1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1056\/NEJM199907013410101","article-title":"Prevalence and clinical outcome of mitral-valve prolapse","volume":"341","author":"Freed","year":"1999","journal-title":"N Engl J Med"},{"key":"2019092611214468700_cvz204-B2","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1161\/01.CIR.78.1.10","article-title":"Lifetime risk for patients with mitral valve prolapse of developing severe valve regurgitation requiring surgery","volume":"78","author":"Wilcken","year":"1988","journal-title":"Circulation"},{"key":"2019092611214468700_cvz204-B3","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/S1054-8807(98)00021-0","article-title":"Correlation between clinical and histologic patterns of degenerative mitral valve insufficiency: a histomorphometric study of 130 excised segments","volume":"8","author":"Fornes","year":"1999","journal-title":"Cardiovasc Pathol"},{"key":"2019092611214468700_cvz204-B4","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.carpath.2008.05.001","article-title":"Abundance and location of proteoglycans and hyaluronan within normal and myxomatous mitral valves","volume":"18","author":"Gupta","year":"2009","journal-title":"Cardiovasc Pathol"},{"key":"2019092611214468700_cvz204-B5","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1136\/hrt.44.6.674","article-title":"The floppy mitral valve. 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