{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:10:12Z","timestamp":1790143812251,"version":"4.0.1"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014764","name":"China International Medical Foundation","doi-asserted-by":"publisher","award":["2022-N-01-5"],"award-info":[{"award-number":["2022-N-01-5"]}],"id":[{"id":"10.13039\/501100014764","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No. 82500329"],"award-info":[{"award-number":["No. 82500329"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["No. 2025M772027"],"award-info":[{"award-number":["No. 2025M772027"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2025QC1703"],"award-info":[{"award-number":["ZR2025QC1703"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Calcific aortic valve stenosis (CAVS) is the most prevalent valvular heart disease in the elderly, yet no pharmacological therapy can halt its progression, partly due to incomplete understanding of disease-associated metabolic alterations and the lack of circulating biomarkers for disease detection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>We aimed to characterize metabolic alterations associated with CAVS and evaluate a candidate circulating marker for CAVS detection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the discovery cohort, patients with severe CAVS and matched controls without aortic valve disease were enrolled. Untargeted serum metabolomics was performed to characterize metabolic profiles. Differential metabolites, pathway enrichment analysis, and machine-learning-based feature prioritization were conducted. Based on pathway-level metabolic annotation, biological evidence, and feasibility of targeted measurement, serotonin was selected as a biologically prioritized, hypothesis-generating candidate and evaluated by ELISA in an independent targeted assessment cohort including controls, non-severe CAVS, and severe CAVS. Associations between serum serotonin levels and CAVS were assessed using multivariable logistic regression, smooth curve analysis, subgroup analyses, and ROC analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The discovery cohort included 58 participants [29 with severe CAVS (69.7 \u00b1 7.5 years; 44.8% male) and 29 matched controls (66.8 \u00b1 5.1 years; 58.6% male)]. Untargeted metabolomics identified 70 differential metabolites. KEGG pathway enrichment analysis revealed serotonin-related metabolic annotations, while Random Forest analysis prioritized indoleacrylic acid as a discriminatory metabolite feature. Serotonin was not selected based on individual metabolite ranking but was evaluated based on pathway-level evidence, biological plausibility, and feasibility of targeted measurement. In the independent targeted assessment cohort of 303 individuals (101 controls, 101 non-severe CAVS, and 101 severe CAVS), serum serotonin levels were significantly lower in both non-severe and severe CAVS groups compared with controls, but did not differ between disease severity groups. Multivariable logistic regression adjusted for confounders confirmed its independent inverse association with CAVS. Incorporation of serum serotonin into the clinical model improved discrimination (AUC increased from 0.752 to 0.865), whereas serotonin alone showed moderate diagnostic performance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Reduced circulating serotonin is associated with the presence of CAVS and may represent a biologically plausible candidate adjunct biomarker for disease detection. Further multicenter prospective and mechanistic studies are required to determine its clinical utility and biological significance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1934998","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:49:15Z","timestamp":1790142555000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating serotonin is associated with calcific aortic valve stenosis: a two-phase metabolomics study"],"prefix":"10.3389","volume":"17","author":[{"given":"Wei","family":"Gao","sequence":"first","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenghu","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nizal","family":"Sarrafzadegan","sequence":"additional","affiliation":[{"name":"Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences","place":["Isfahan, Iran"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haowei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyuan","family":"Mei","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkang","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Gao","sequence":"additional","affiliation":[{"name":"The Sidney Kimmel Medical College at Thomas Jefferson University","place":["Philadelphia, PA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoyu","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"You","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyi","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Ni","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guipeng","family":"An","sequence":"additional","affiliation":[{"name":"State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1161\/CIRCULATIONAHA.122.063402","article-title":"Multiomics of tissue extracellular vesicles identifies unique modulators of atherosclerosis and calcific aortic valve stenosis","volume":"148","author":"Blaser","year":"2023","journal-title":"Circulation"},{"key":"B2","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1093\/eurheartj\/ehae829","article-title":"Calcific aortic stenosis: omics-based target discovery and therapy development","volume":"46","author":"Blaser","year":"2025","journal-title":"Eur. Heart J."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.1093\/eurheartj\/ehy696","article-title":"Activated platelets promote an osteogenic programme and the progression of calcific aortic valve stenosis","volume":"40","author":"Bouchareb","year":"2019","journal-title":"Eur. Heart J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"e037991","DOI":"10.1161\/JAHA.124.037991","article-title":"Global, Regional, and National Burden of Valvular Heart Disease, 1990 to 2021","volume":"13","author":"Chen","year":"2024","journal-title":"J. Am. Heart Assoc."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jcin.2018.09.041","article-title":"Blood disorders in patients undergoing transcatheter aortic valve replacement: a review","volume":"12","author":"De Larochelli\u00e8re","year":"2019","journal-title":"JACC Cardiovasc Interv."},{"key":"B6","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/j.jacc.2025.06.049","article-title":"The pathophysiologic basis and management of Calcific aortic valve stenosis: JACC state-of-the-art review","volume":"86","author":"Desai","year":"2025","journal-title":"JACC"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1016\/j.jacc.2012.02.093","article-title":"Calcific aortic stenosis: a disease of the valve and the myocardium","volume":"60","author":"Dweck","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1002\/jcb.29847","article-title":"Serotonin receptor type 2B activation augments TNF-\u03b1-induced matrix mineralization in murine valvular interstitial cells","volume":"122","author":"Fong","year":"2021","journal-title":"J. Cell Biochem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"10813","DOI":"10.3390\/ijms262210813","article-title":"Molecular network analysis of circulating microRNAs highlights miR-17-5p and miR-29a-3p as potential biomarkers of aortic valve calcification","volume":"26","author":"Galeone","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1093\/cvr\/cvab142","article-title":"Role of oxidative stress in calcific aortic valve disease and its therapeutic implications","volume":"118","author":"Greenberg","year":"2022","journal-title":"Cardiovasc Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3390\/nu18030507","article-title":"Serotonin, Kynurenine, and indole pathways of Tryptophan metabolism in humans in health and disease","volume":"18","author":"Hole\u010dek","year":"2026","journal-title":"Nutrients"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2018","DOI":"10.1093\/cvr\/cvab243","article-title":"Trimethylamine N-oxide induces osteogenic responses in human aortic valve interstitial cells in vitro and aggravates aortic valve lesions in mice","volume":"118","author":"Li","year":"2022","journal-title":"Cardiovasc Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1161\/ATVBAHA.125.322959","article-title":"Metabolic rewiring in calcific aortic valve disease: it goes beyond immunometabolism","volume":"45","author":"Lupieri","year":"2025","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1161\/CIRCULATIONAHA.105.554667","article-title":"Deficiency of the 5-hydroxytryptamine transporter gene leads to cardiac fibrosis and valvulopathy in mice","volume":"113","author":"Mekontso-Dessap","year":"2006","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e72","DOI":"10.1161\/CIR.0000000000000923","article-title":"2020 ACC\/AHA Guideline for the management of patients with valvular heart disease: a report of the American college of Cardiology\/American heart Association Joint Committee on clinical practice Guidelines","volume":"143","author":"Otto","year":"2021","journal-title":"Circulation"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1001\/jama.2024.16477","article-title":"Calcific aortic stenosis: a review","volume":"332","author":"Otto","year":"2024","journal-title":"JAMA"},{"key":"B17","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.jacc.2023.11.021","article-title":"Large-Scale proteomics identifies novel biomarkers and circulating risk factors for aortic stenosis","volume":"83","author":"Shelbaya","year":"2024","journal-title":"J. Am. Coll. Cardiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1161\/ATVBAHA.116.308615","article-title":"Biomarkers of Calcific aortic valve disease","volume":"37","author":"Small","year":"2017","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"e109","DOI":"10.1161\/CIR.0000000000001254","article-title":"Unraveling the mechanisms of valvular heart disease to identify medical therapy targets: a scientific statement from the American heart Association","volume":"150","author":"Small","year":"2024","journal-title":"Circulation"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1764","DOI":"10.1001\/jama.2014.13959","article-title":"Association of low-density lipoprotein cholesterol-related genetic variants with aortic valve calcium and incident aortic stenosis","volume":"312","author":"Smith","year":"2014","journal-title":"JAMA"},{"key":"B21","doi-asserted-by":"publisher","first-page":"560","DOI":"10.1007\/s12265-019-09903-3","article-title":"Oxidized HDL, as a novel biomarker for Calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells","volume":"12","author":"Sun","year":"2019","journal-title":"J. Cardiovasc Transl. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1056\/NEJMoa1109034","article-title":"Genetic associations with valvular calcification and aortic stenosis","volume":"368","author":"Thanassoulis","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s11010-020-03797-5","article-title":"Plasma lipoprotein(a) concentration as an independent predictor of hemodynamic progression of aortic valve stenosis","volume":"472","author":"Tomova","year":"2020","journal-title":"Mol. Cell Biochem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1093\/eurheartj\/ehab395","article-title":"2021 ESC\/EACTS Guidelines for the management of valvular heart disease","volume":"43","author":"Vahanian","year":"2022","journal-title":"Eur. Heart J."},{"key":"B25","doi-asserted-by":"publisher","first-page":"3569","DOI":"10.3390\/ijms22073569","article-title":"Metabolomics in severe aortic stenosis reveals intermediates of nitric oxide synthesis as Most distinctive markers","volume":"22","author":"van Driel","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"16135","DOI":"10.2147\/JIR.S540540","article-title":"Cross-Disease identification of FBP1 in atherosclerosis and calcific aortic valve disease via integrated bioinformatics and validation: functional analysis and therapeutic target exploration","volume":"18","author":"Xu","year":"2025","journal-title":"JIR"},{"key":"B27","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s10020-022-00433-4","article-title":"Pro-inflammatory mediators released by activated monocytes promote aortic valve fibrocalcific activity","volume":"28","author":"Zhang","year":"2022","journal-title":"Mol. Med."},{"key":"B28","doi-asserted-by":"publisher","first-page":"100830","DOI":"10.1016\/j.jlr.2025.100830","article-title":"Conjugated bile acids are elevated in severe calcific aortic valve stenosis","volume":"66","author":"Zhang","year":"2025","journal-title":"J. Lipid Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"2150","DOI":"10.1016\/j.jacc.2019.01.070","article-title":"Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis","volume":"73","author":"Zheng","year":"2019","journal-title":"J. Am. Coll. Cardiol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1934998\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:49:16Z","timestamp":1790142556000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2026.1934998\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,23]]},"references-count":29,"alternative-id":["10.3389\/fphar.2026.1934998"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2026.1934998","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,23]]},"article-number":"1934998"}}