{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:19:32Z","timestamp":1788265172430,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Doctoral School of the Iuliu Ha\u021bieganu University of Medicine and Pharmacy","award":["PCD 1032\/33\/13.01.2021"],"award-info":[{"award-number":["PCD 1032\/33\/13.01.2021"]}]},{"name":"Doctoral School of the Iuliu Ha\u021bieganu University of Medicine and Pharmacy","award":["PCD 882\/30\/12.01.2022"],"award-info":[{"award-number":["PCD 882\/30\/12.01.2022"]}]},{"award":["PCD 1032\/33\/13.01.2021"],"award-info":[{"award-number":["PCD 1032\/33\/13.01.2021"]}],"id":[{"id":"https:\/\/ror.org\/051h0cw83","id-type":"ROR","asserted-by":"publisher"}]},{"award":["PCD 882\/30\/12.01.2022"],"award-info":[{"award-number":["PCD 882\/30\/12.01.2022"]}],"id":[{"id":"https:\/\/ror.org\/051h0cw83","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Bicuspid aortic valve (BAV) is frequently associated with valvular dysfunction and aortic remodeling. This exploratory study examined cross-sectional associations between circulating extracellular matrix-related biomarkers and concurrent echocardiographic characteristics in children with BAV. Methods: We included 43 pediatric participants\u201426 with BAV and 17 with tricuspid aortic valves (TAV). All participants underwent clinical assessment, transthoracic echocardiography, and serum biomarker quantification at the same study visit. MMP-2, MMP-9, TIMP-1, and TGF-\u03b21 were measured using ELISA. Biomarker levels were compared between the BAV and TAV groups and, within the BAV group, according to the presence of concurrent aortopathy, aortic stenosis, and aortic regurgitation. Results: MMP-9, TIMP-1, and the MMP-9\/TIMP-1 ratio were higher in the BAV group than in the TAV comparison group. Within the BAV cohort, none of the investigated biomarkers differed significantly between participants with and without aortopathy. TGF-\u03b21 was higher in BAV patients with aortic stenosis, whereas the MMP-9\/TIMP-1 ratio showed a borderline difference according to aortic regurgitation status; these subgroup findings are exploratory and limited by small sample size and multiple comparisons. Conclusions: In this selected pediatric cohort, circulating MMP-9 and TIMP-1 levels differed between children with BAV and the TAV comparison group. However, none of the investigated biomarkers differed significantly between BAV patients with and without aortopathy. These cross-sectional findings describe exploratory associations with the BAV phenotype but do not establish diagnostic, predictive, or prognostic utility. Larger longitudinal studies including the broader clinical spectrum of BAV and independent validation cohorts are required.<\/jats:p>","DOI":"10.3390\/diagnostics16172812","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:33:32Z","timestamp":1788262412000},"page":"2812","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Circulating Extracellular Matrix-Remodeling Biomarkers in Children with Bicuspid Aortic Valve: An Exploratory Cross-Sectional Study"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2826-3112","authenticated-orcid":false,"given":"Oana Iulia","family":"Man","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1487-0018","authenticated-orcid":false,"given":"Ximena Maria","family":"Mure\u0219an","sequence":"additional","affiliation":[{"name":"Personalized Medicine and Rare Diseases Department, Institute for Biomedical Research\u2013MEDFUTURE, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5626-6911","authenticated-orcid":false,"given":"M\u0103d\u0103lina","family":"Nistor","sequence":"additional","affiliation":[{"name":"Personalized Medicine and Rare Diseases Department, Institute for Biomedical Research\u2013MEDFUTURE, Iuliu Hatieganu University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9783-8317","authenticated-orcid":false,"given":"Andra","family":"Negru","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Bogdan M.","family":"Tarc\u0103u","sequence":"additional","affiliation":[{"name":"Doctoral School of Biological and Biomedical Sciences, University of Oradea, 410087 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"}]},{"given":"Renata","family":"Agoston","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8638-496X","authenticated-orcid":false,"given":"Rares Ilie","family":"Orzan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Crina","family":"\u0218ufan\u0103","sequence":"additional","affiliation":[{"name":"1st Department of Pediatrics, Iuliu Hatieganu University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"C\u0103lin","family":"Laz\u0103r","sequence":"additional","affiliation":[{"name":"1st Department of Pediatrics, Iuliu Hatieganu University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania"},{"name":"1st Pediatrics Clinic, Emergency Pediatric Clinical Hospital, 400370 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Lucia","family":"Agoston-Coldea","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"2nd Department of Internal Medicine, Emergency County Hospital, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7649-5308","authenticated-orcid":false,"given":"Cecilia","family":"Lazea","sequence":"additional","affiliation":[{"name":"1st Department of Pediatrics, Iuliu Hatieganu University of Medicine and Pharmacy, 400370 Cluj-Napoca, Romania"},{"name":"1st Pediatrics Clinic, Emergency Pediatric Clinical Hospital, 400370 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Spaziani, G., Girolami, F., Arcieri, L., Calabri, G.B., Porcedda, G., Di Filippo, C., Surace, F.C., Pozzi, M., and Favilli, S. (2022). Bicuspid Aortic Valve in Children and Adolescents: A Comprehensive Review. Diagnostics, 12.","DOI":"10.3390\/diagnostics12071751"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1016\/j.jtcvs.2018.02.115","article-title":"The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve\u2013related aortopathy: Full online-only version","volume":"156","author":"Borger","year":"2018","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e228","DOI":"10.1161\/CIR.0000000000001265","article-title":"Cardiovascular Management of Aortopathy in Children: A Scientific Statement from the American Heart Association","volume":"150","author":"Morris","year":"2024","journal-title":"Circulation"},{"key":"ref_4","first-page":"375","article-title":"Defining ascending aorta dilatation in pediatric bicuspid aortic valve: Comparison of known classical and new z-score nomograms, and anthropometric parameters indexing for its assessment","volume":"87","author":"Collell","year":"2025","journal-title":"J. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"101102","DOI":"10.1016\/j.jocmr.2024.101102","article-title":"Assessment of abnormal transvalvular flow and wall shear stress direction for pediatric\/young adults with bicuspid aortic valve: A cross-sectional four-dimensional flow study","volume":"26","author":"Fujiwara","year":"2024","journal-title":"J. Cardiovasc. Magn. Reson."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1007\/s10554-020-01883-9","article-title":"Left ventricular global longitudinal strain in bicupsid aortic valve patients: Head-to-head comparison between computed tomography, 4D flow cardiovascular magnetic resonance and speckle-tracking echocardiography","volume":"36","author":"Hoven","year":"2020","journal-title":"Int. J. Cardiovasc. Imaging"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Girdauskas, E., Petersen, J., Neumann, N., Naito, S., Gross, T., Jagodzinski, A., Reichenspurner, H., and Zeller, T. (2018). Novel Approaches for BAV Aortopathy Prediction\u2014Is There a Need for Cohort Studies and Biomarkers?. Biomolecules, 8.","DOI":"10.3390\/biom8030058"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"F\u0103g\u0103r\u0103\u0219an, A., and S\u0103s\u0103ran, M.O. (2022). The Predictive Role of Plasma Biomarkers in the Evolution of Aortopathies Associated with Congenital Heart Malformations. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094993"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Nappi, F., Singh, S.S.A., and de Siena, P.M. (2024). Bicuspid Aortic Valve in Children and Young Adults for Cardiologists and Cardiac Surgeons: State-of-the-Art of Literature Review. J. Cardiovasc. Dev. Dis., 11.","DOI":"10.3390\/jcdd11100317"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Katsaros, O., Ktenopoulos, N., Korovesis, T., Benetos, G., Apostolos, A., Koliastasis, L., Sagris, M., Milaras, N., Latsios, G., and Synetos, A. (2024). Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment. J. Clin. Med., 13.","DOI":"10.3390\/jcm13174970"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Krych, S., Gniewek, J., Jurkiewicz, M., Kowalczyk, P., Waniczek, D., and Hrapkowicz, T. (2026). Aortopathy in Bicuspid Aortic Valve: Pathophysiology, Risk Stratification and Surgical Decision-Making\u2014A Narrative Review. J. Clin. Med., 15.","DOI":"10.3390\/jcm15093542"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Shipulina, S., Goncharova, I., Valiakhmetov, N., Milto, I., Sukhodolo, I., Panfilov, D., Kozlov, B., and Nazarenko, M. (2026). Histopathological zonal patterns in ascending aortic aneurysm with bicuspid and tricuspid aortic valves. Sci. Rep.","DOI":"10.1038\/s41598-026-60959-z"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Yassine, N.M., Shahram, J.T., and Body, S.C. (2017). Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00687"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Chen, J., and Chang, R. (2022). Association of TGF-\u03b2 Canonical Signaling-Related Core Genes with Aortic Aneurysms and Aortic Dissections. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.888563"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1007\/s12055-023-01513-8","article-title":"The role of transforming growth factor beta in bicuspid aortic valve aortopathy","volume":"39","author":"Grewal","year":"2023","journal-title":"Indian J. Thorac. Cardiovasc. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"F\u0103g\u0103r\u0103\u0219an, A., S\u0103s\u0103ran, M.O., Gozar, L., Toma, D., \u0218uteu, C., Ghiragosian-Rusu, S., Al-Akel, F.C., Szabo, B., and Hu\u021banu, A. (2024). Circulating Matrix Metalloproteinases for Prediction of Aortic Dilatation in Children with Bicuspid Aortic Valve: A Single-Center, Observational Study. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910538"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"\u015eent\u00fcrk, N.G.K., Karaka\u015f, A., Karada\u011f, H., \u00c7ulpan, H.C., Y\u00fccel, I.K., and Dedeo\u011flu, R. (2026). Aortic elastic properties and circulating matrix biomarkers in children with bicuspid aortic valve: An exploratory study. Pediatr. Res.","DOI":"10.1038\/s41390-026-05261-4"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e009717","DOI":"10.1161\/CIRCIMAGING.119.009717","article-title":"Predictors of Bicuspid Aortic Valve\u2013Associated Aortopathy in Childhood","volume":"13","author":"Grattan","year":"2020","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e200496","DOI":"10.1148\/ryct.2021200496","article-title":"International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes","volume":"3","author":"Michelena","year":"2021","journal-title":"Radiol. Cardiothorac. Imaging"},{"key":"ref_20","unstructured":"(2026, July 15). Clinical Calculators\u2014MSD Manual Professional Edition. Available online: https:\/\/www.msdmanuals.com\/professional\/pages-with-widgets\/clinical-calculators?mode=list."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1097\/HJH.0000000000001039","article-title":"2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents","volume":"34","author":"Lurbe","year":"2016","journal-title":"J. Hypertens."},{"key":"ref_22","unstructured":"Flynn, J.T., Kaelber, D.C., and Baker-Smith, C.M. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics [Internet]. Available online: http:\/\/publications.aap.org\/pediatrics\/article-pdf\/140\/3\/e20171904\/1104403\/peds_20171904.pdf."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1111\/echo.13527","article-title":"Echocardiographic assessment of pediatric semilunar valve disease","volume":"34","author":"Cantinotti","year":"2017","journal-title":"Echocardiography"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.echo.2006.09.001","article-title":"Guidelines and Standards for Performance of a Pediatric Echocardiogram: A Report from the Task Force of the Pediatric Council of the American Society of Echocardiography","volume":"19","author":"Lai","year":"2006","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.echo.2023.11.015","article-title":"Guidelines for Performing a Comprehensive Pediatric Transthoracic Echocardiogram: Recommendations from the American Society of Echocardiography","volume":"37","author":"Lopez","year":"2024","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1136\/hrt.2005.081539","article-title":"Dilatation of the ascending aorta in paediatric patients with bicuspid aortic valve: Frequency, rate of progression and risk factors","volume":"92","author":"Warren","year":"2006","journal-title":"Heart"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","article-title":"Correlation Coefficients: Appropriate Use and Interpretation","volume":"126","author":"Schober","year":"2018","journal-title":"Anesth. Analg."},{"key":"ref_28","first-page":"2358","article-title":"Endotrophin and matrix metalloproteinase-2 levels in bicuspid aortic valve and hypertension associated aortopathy and their relationship with strain parameters of the ascending aorta","volume":"27","author":"Baykiz","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1016\/j.ultrasmedbio.2018.01.012","article-title":"Enlarged Size and Impaired Elastic Properties of the Ascending Aorta are Associated with Endothelial Dysfunction and Elevated Plasma Matrix Metalloproteinase-2 Level in Patients with Bicuspid Aortic Valve","volume":"44","author":"Wang","year":"2018","journal-title":"Ultrasound Med. Biol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2812\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T11:54:16Z","timestamp":1788263656000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/17\/2812"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":29,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["diagnostics16172812"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16172812","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]}}}