{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T20:45:26Z","timestamp":1786308326771,"version":"build-2736575974"},"reference-count":92,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Functional valve regurgitation (FVR) progression has traditionally been attributed to external anatomic alterations, without consideration of leaflet-intrinsic pathology. Emerging evidence now implicates valvular leaflets as active contributors rather than passive bystanders in FVR pathogenesis. Systematic investigations into leaflet-specific pathomechanisms remain absent for major FVR subtypes, particularly functional mitral regurgitation (FMR) and functional tricuspid regurgitation (FTR).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>The association of FVR with clinical parameters was analyzed in a heart transplantation cohort. Comprehensive microscopic pathology evaluated fibrotic remodeling in mild, moderate, and severe FMR\/FTR leaflets, validated in an independent bulk RNA sequencing cohort (FMR\/FTR: n=41 each). Single-cell RNA sequencing was performed on 19 FVR leaflets (FMR: 3 mild\/2 moderate\/3 severe; FTR: 5 mild\/3 moderate\/3 severe). Subsequent analyses (cluster annotation, cellular proportions, trajectory inference, and cell-cell communication) explored cellular mechanisms of fibrotic remodeling in FVR, focusing on unique and shared changes between FMR and FTR. Histopathology and bulk transcriptomics validated single-cell RNA sequencing findings. Primary valvular endothelial cells and valvular interstitial cells from FVR patients underwent pharmacological intervention. A monocrotaline-induced rat pulmonary hypertension model established FTR, followed by pharmacological treatment to assess leaflet-directed therapy efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>Fibrotic leaflet remodeling scores independently predicted FMR\/FTR severity with high precision and significantly improved prediction beyond anatomic anomalies. Fibrotic remodeling showed divergent mechanisms between FMR and FTR. In FMR, suppressed retinoic acid metabolism drove antifibrotic-to-neutral valvular interstitial cell transition. In FTR, impaired IFN (interferon) signaling promoted antifibrotic-to-profibrotic valvular interstitial cell transdifferentiation, worsened by endothelial-to-mesenchymal transition\u2013derived profibrotic valvular endothelial cells. Targeted PDK4 (pyruvate dehydrogenase kinase 4) upregulation or IFN signaling activation reduced FTR severity in vitro and in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Leaflet-specific organic fibrotic remodeling actively involves FVR beyond functional adaptation, with distinct fibrotic mechanisms in FMR versus FTR. PDK4 and IFN modulation demonstrate therapeutic potential for FTR.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/atvbaha.125.324134","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T10:00:30Z","timestamp":1772100030000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Valvular Leaflets Are Not Innocent Bystanders: Divergent Fibrotic Remodeling Accompanies Functional Mitral and Tricuspid Regurgitation"],"prefix":"10.1161","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3035-7812","authenticated-orcid":true,"given":"Hongjie","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"Wuhan Clinical Center for Minimally Invasive Treatment of Structural Heart Disease, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan, China (H.S., Xing Chen, H.H., K.H., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8659-197X","authenticated-orcid":true,"given":"Songren","family":"Shu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease (S. Shu, Xiao Chen, Xiaohu Wang, W.W., Xianqiang Wang, S. Song, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."},{"name":"The Cardiomyopathy Research Group (S. Shu, Xiao Chen, Xiaohu Wang, W.W., S. Song, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."},{"name":"Department of Cardiovascular Surgery (S. Shu, Xianqiang Wang, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."},{"name":"Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, Affiliated Cardiovascular Hospital of Kunming Medical University (S. Shu)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8994-0298","authenticated-orcid":true,"given":"Xing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery, Wuhan, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"Wuhan Clinical Center for Minimally Invasive Treatment of Structural Heart Disease, China (H.S., Xing Chen, H.H., K.H., J.L.)."},{"name":"State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan, China (H.S., Xing Chen, H.H., K.H., J.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease (S. Shu, Xiao Chen, Xiaohu Wang, W.W., Xianqiang Wang, S. Song, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."},{"name":"The Cardiomyopathy Research Group (S. Shu, Xiao Chen, Xiaohu Wang, W.W., S. Song, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7088-8602","authenticated-orcid":true,"given":"Xiaohu","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease (S. Shu, Xiao Chen, Xiaohu Wang, W.W., Xianqiang Wang, S. Song, J.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing."},{"name":"The Cardiomyopathy Research Group (S. 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