{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T19:59:53Z","timestamp":1781380793242,"version":"3.54.1"},"reference-count":35,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,13]],"date-time":"2020-07-13T00:00:00Z","timestamp":1594598400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009664","name":"Sociedad Espa\u00f1ola de Cardiolog\u00eda","doi-asserted-by":"publisher","award":["(SEC)"],"award-info":[{"award-number":["(SEC)"]}],"id":[{"id":"10.13039\/100009664","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV. Methods: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and\/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism. Results: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve. Discussion: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.<\/jats:p>","DOI":"10.3390\/jcm9072215","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T11:03:23Z","timestamp":1594724603000},"page":"2215","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Plasma Metabolomic Profiling Associates Bicuspid Aortic Valve Disease and Ascending Aortic Dilation with a Decrease in Antioxidant Capacity"],"prefix":"10.3390","volume":"9","author":[{"given":"Neus","family":"Mart\u00ednez-Micaelo","sequence":"first","affiliation":[{"name":"Grup de Recerca Cardiovascular, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Universitat Rovira i Virgili, 43201 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carme","family":"Ligero","sequence":"additional","affiliation":[{"name":"Grup de Recerca Cardiovascular, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Universitat Rovira i Virgili, 43201 Reus, Spain"},{"name":"Servei de Cardiologia, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, 43201 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borja","family":"Antequera-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Grup de Recerca Cardiovascular, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Universitat Rovira i Virgili, 43201 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-0419","authenticated-orcid":false,"given":"Alexandra","family":"Junza","sequence":"additional","affiliation":[{"name":"Metabolomics Platform, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Department of Electronic Engineering, Universitat Rovira i Virgili, 43007 Tarragona, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3695-7157","authenticated-orcid":false,"given":"Oscar","family":"Yanes","sequence":"additional","affiliation":[{"name":"Metabolomics Platform, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Department of Electronic Engineering, Universitat Rovira i Virgili, 43007 Tarragona, Spain"},{"name":"Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6117-5512","authenticated-orcid":false,"given":"Josep","family":"Alegret","sequence":"additional","affiliation":[{"name":"Grup de Recerca Cardiovascular, Institut d\u2019Investigaci\u00f3 Sanit\u00e0ria Pere Virgili (IISPV), Universitat Rovira i Virgili, 43201 Reus, Spain"},{"name":"Servei de Cardiologia, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, 43201 Reus, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1016\/S0735-1097(02)01886-7","article-title":"The incidence of congenital heart disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11","DOI":"10.2459\/01.JCM.0000199777.85343.ec","article-title":"Aortic dilatation in patients with bicuspid aortic valve","volume":"7","author":"Cecconi","year":"2006","journal-title":"J. Cardiovasc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1136\/heartjnl-2017-311560","article-title":"Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease","volume":"104","author":"Evangelista","year":"2018","journal-title":"Heart"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12968-018-0451-1","article-title":"Aortic flow patterns and wall shear stress maps by 4D-flow cardiovascular magnetic resonance in the assessment of aortic dilatation in bicuspid aortic valve disease","volume":"20","author":"Guala","year":"2018","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"938","DOI":"10.3389\/fphys.2017.00938","article-title":"Thoracic aortic aneurysm development in patients with bicuspid aortic valve: What is the role of endothelial cells?","volume":"8","author":"Kurakula","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"800","DOI":"10.1136\/heartjnl-2014-305509","article-title":"Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve","volume":"100","author":"Ali","year":"2014","journal-title":"Heart"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Girdauskas, E., Kaemmerer, H., and von Kodolitsch, Y. (2020). Unravelling the Pathogenetic Mechanisms in Congenital Aortopathies: Need for an Integrative Translational Approach. J. Clin. Med., 9.","DOI":"10.3390\/jcm9010204"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/j.jacc.2015.02.018","article-title":"Metabolic Disturbances Identified in Plasma Are Associated With Outcomes in Patients With Heart Failure","volume":"65","author":"Cheng","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.ijcard.2016.04.184","article-title":"Circulating endothelial microparticles are elevated in bicuspid aortic valve disease and related to aortic dilation","volume":"217","author":"Alegret","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/s12967-017-1176-x","article-title":"Specific circulating microRNA signature of bicuspid aortic valve disease","volume":"15","author":"Baiges","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"648","DOI":"10.3389\/fphys.2017.00648","article-title":"MicroRNAs Clustered within the 14q32 Locus Are Associated with Endothelial Damage and Microparticle Secretion in Bicuspid Aortic Valve Disease","volume":"8","author":"Faiges","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10554-004-3901-9","article-title":"Aortic valve morphology definition with transthoracic combined with transesophageal echocardiography in a population with high prevalence of bicuspid aortic valve","volume":"21","author":"Alegret","year":"2005","journal-title":"Int. J. Cardiovasc. Imaging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1002\/jmri.21547","article-title":"Steady-state free-precession (SSFP) cine MRI in distinguishing normal and bicuspid aortic valves","volume":"28","author":"Gleeson","year":"2008","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1021\/ac051437y","article-title":"XCMS: Processing Mass Spectrometry Data for Metabolite Profiling Using Nonlinear Peak Alignment, Matching, and Identification","volume":"78","author":"Smith","year":"2006","journal-title":"Anal. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"775","DOI":"10.3390\/metabo2040775","article-title":"A Guideline to Univariate Statistical Analysis for LC\/MS-Based Untargeted Metabolomics-Derived Data","volume":"2","author":"Vinaixa","year":"2012","journal-title":"Metabolites"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.cmpb.2016.01.008","article-title":"An R package for the integrated analysis of metabolomics and spectral data","volume":"129","author":"Costa","year":"2016","journal-title":"Comput. Methods Programs Biomed."},{"key":"ref_17","unstructured":"(2020, July 02). Wiener AL and, M. Classification and Regression by randomForest. R News 2. Available online: http:\/\/www.stat.berkeley.edu\/."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Sophocleous, F., Milano, E.G., Pontecorboli, G., Chivasso, P., Caputo, M., Rajakaruna, C., Bucciarelli-Ducci, C., Emanueli, C., and Biglino, G. (2018). Enlightening the Association between Bicuspid Aortic Valve and Aortopathy. J. Cardiovasc. Dev. Dis., 5.","DOI":"10.3390\/jcdd5020021"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.cpcardiol.2005.06.002","article-title":"The bicuspid aortic valve","volume":"30","author":"Braverman","year":"2005","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.3389\/fphys.2018.01921","article-title":"(2019) Bicuspid aortic valve: An update in morphology, genetics, biomarker, complications, imaging diagnosis and treatment","volume":"9","author":"Liu","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_21","unstructured":"Della Corte, A., Michelena, H.I., Citarella, A., Votta, E., Piatti, F., Lo Presti, F., Ashurov, R., Cipollaro, M., and Forte, A. (2019). Risk Stratification in Bicuspid Aortic Valve Aortopathy: Emerging Evidence and Future Perspectives. Curr. Probl. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/s10545-017-0130-7","article-title":"Promises and pitfalls of untargeted metabolomics","volume":"41","author":"Gertsman","year":"2018","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/ajcn\/35.4.691","article-title":"Distribution of \u03b1-tocopherol in human plasma lipoproteins","volume":"35","author":"Behrens","year":"1982","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1002\/biof.1070","article-title":"\u03b1-Tocopherol binding to human serum albumin","volume":"39","author":"Fanali","year":"2013","journal-title":"BioFactors"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/978-1-60761-350-3_14","article-title":"Paraoxonase 1 interactions with HDL, antioxidants and macrophages regulate atherogenesis\u2014A protective role for HDL phospholipids","volume":"660","author":"Efrat","year":"2010","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1016\/j.redox.2014.02.002","article-title":"Regulatory metabolites of vitamin E and their putative relevance for atherogenesis","volume":"2","author":"Wallert","year":"2014","journal-title":"Redox Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"37023","DOI":"10.1038\/srep37023","article-title":"Analysis of Serum Metabolites to Diagnose Bicuspid Aortic Valve","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.3390\/nu6072552","article-title":"The effects of choline on hepatic lipid metabolism, mitochondrial function and antioxidative status in human hepatic C3A cells exposed to excessive energy substrates","volume":"6","author":"Zhu","year":"2014","journal-title":"Nutrients"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Zeisel, S. (2017). Choline, Other Methyl-Donors and Epigenetics. Nutrients, 9.","DOI":"10.3390\/nu9050445"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1097\/MOG.0b013e32834e7b4b","article-title":"Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression","volume":"28","author":"Corbin","year":"2012","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_31","first-page":"1","article-title":"Choline ameliorates cardiovascular damage by improving vagal activity and inhibiting the inflammatory response in spontaneously hypertensive rats","volume":"7","author":"Liu","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"Iii-35","DOI":"10.1161\/circ.102.suppl_3.III-35","article-title":"Bicuspid aortic valves are associated with aortic dilatation out of proportion to coexistent valvular lesions","volume":"102","author":"Keane","year":"2000","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/ehjci\/jes273","article-title":"Wall shear stress and flow patterns in the ascending aorta in patients with bicuspid aortic valves differ significantly from tricuspid aortic valves: A prospective study","volume":"14","author":"Meierhofer","year":"2013","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1016\/j.jbiomech.2013.03.029","article-title":"Difference in hemodynamic and wall stress of ascending thoracic aortic aneurysms with bicuspid and tricuspid aortic valve","volume":"46","author":"Pasta","year":"2013","journal-title":"J. Biomech."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.yjmcc.2019.03.004","article-title":"Bicuspid aortic valve, atherosclerosis and changes of lipid metabolism: Are there pathological molecular links?","volume":"129","author":"Magni","year":"2019","journal-title":"J. Mol. Cell. Cardiol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2215\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:50:53Z","timestamp":1760176253000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/7\/2215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,13]]},"references-count":35,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["jcm9072215"],"URL":"https:\/\/doi.org\/10.3390\/jcm9072215","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,13]]}}}