{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:15:56Z","timestamp":1760055356683,"version":"build-2065373602"},"reference-count":27,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"AHA, NIH","award":["TPA963783, TPA34850095, 905880, HL128099 , HL141917 , C06 RR018823, GM103444, HL149696, HL131546, HL173930, F31HL167482"],"award-info":[{"award-number":["TPA963783, TPA34850095, 905880, HL128099 , HL141917 , C06 RR018823, GM103444, HL149696, HL131546, HL173930, F31HL167482"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>Recent evidence demonstrates that mitral valve prolapse (MVP) increases mechanical stress on the subvalvular apparatus and is linked to regional myocardial fibrosis and life-threatening ventricular arrhythmias. However, current surgical guidelines do not account for the extent of myocardial fibrosis or the severity of leaflet involvement, both key features of arrhythmogenic MVP. To address this gap, we conducted histopathological analysis of endomyocardial biopsies from patients with MVP and regionalized myocardial fibrosis (n = 6) who underwent mitral valve repair. Using digital pathology-based quantitative image analysis (QIA), we found that fibrosis in peri-papillary biopsies exhibited a significantly higher Morphometric Composite Score compared with remote biopsies (5.68 \u00b1 0.69 vs. 3.71 \u00b1 0.49, p = 0.042), reflecting larger, more branched, and more assembled collagen fibers, indicative of a mature and persistent fibrotic phenotype. These findings suggest that myocardial scarring in MVP is well-established by the time of surgery and underscore the potential value of earlier surgical intervention to reduce the risk of arrhythmia and preserve post-operative left ventricular function.<\/jats:p>","DOI":"10.3390\/cells14191536","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T07:58:13Z","timestamp":1759305493000},"page":"1536","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Collagen Fiber Maturity and Architecture in MVP-Associated Fibrosis Quantified by Digital Pathology"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0625-2449","authenticated-orcid":false,"given":"Ranan","family":"Phookan","sequence":"first","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan E.","family":"Morningstar","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian","family":"Loizzi","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4412-6337","authenticated-orcid":false,"given":"Antonia","family":"Van Kampen","sequence":"additional","affiliation":[{"name":"Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"},{"name":"University Department of Cardiac Surgery, Leipzig Heart Center, Struempellstrasse 39, 04289 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8492-3536","authenticated-orcid":false,"given":"Cortney","family":"Gensemer","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja-Theresa","family":"Dieterlen","sequence":"additional","affiliation":[{"name":"University Department of Cardiac Surgery, Leipzig Heart Center, Struempellstrasse 39, 04289 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Spampinato","sequence":"additional","affiliation":[{"name":"University Department of Cardiac Surgery, Leipzig Heart Center, Struempellstrasse 39, 04289 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis","family":"Petitjean","sequence":"additional","affiliation":[{"name":"PharmaNest Inc., Princeton, NJ 08540, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3468-7114","authenticated-orcid":false,"given":"Mathieu","family":"Petitjean","sequence":"additional","affiliation":[{"name":"PharmaNest Inc., Princeton, NJ 08540, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1524-5804","authenticated-orcid":false,"given":"Taylor","family":"Petrucci","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roman","family":"Fenner","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6041-0157","authenticated-orcid":false,"given":"Jake","family":"Griner","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn","family":"Byerly","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9484-8218","authenticated-orcid":false,"given":"Robert A.","family":"Levine","sequence":"additional","affiliation":[{"name":"Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1046-1364","authenticated-orcid":false,"given":"Michael A.","family":"Borger","sequence":"additional","affiliation":[{"name":"University Department of Cardiac Surgery, Leipzig Heart Center, Struempellstrasse 39, 04289 Leipzig, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8462-5726","authenticated-orcid":false,"given":"Russell A.","family":"Norris","sequence":"additional","affiliation":[{"name":"Department of Regenerative Medicine and Cell Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29407, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1161\/CIRCULATIONAHA.113.006702","article-title":"Epidemiology and pathophysiology of mitral valve prolapse: New insights into disease progression, genetics, and molecular basis","volume":"129","author":"Delling","year":"2014","journal-title":"Circulation"},{"key":"ref_2","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":"ref_3","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1016\/j.jacc.2022.09.044","article-title":"Research Opportunities in the Treatment of Mitral Valve Prolapse: JACC Expert Panel","volume":"80","author":"Delling","year":"2022","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e020919","DOI":"10.1161\/JAHA.121.020919","article-title":"Mitral Valve Prolapse and Its Motley Crew-Syndromic Prevalence, Pathophysiology, and Progression of a Common Heart Condition","volume":"10","author":"Morningstar","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1007\/s10554-023-02985-w","article-title":"Left ventricular fibrosis and CMR tissue characterization of papillary muscles in mitral valve prolapse patients","volume":"40","author":"Spampinato","year":"2023","journal-title":"Int. J. Cardiovasc. Imaging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e014963","DOI":"10.1161\/CIRCIMAGING.122.014963","article-title":"Abnormal Mechanics Relate to Myocardial Fibrosis and Ventricular Arrhythmias in Patients with Mitral Valve Prolapse","volume":"16","author":"Nagata","year":"2023","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Dieterlen, M.T., Klaeske, K., Spampinato, R., Marin-Cuartas, M., Wiesner, K., Morningstar, J., Norris, R.A., Melnitchouk, S., Levine, R.A., and van Kampen, A. (2023). Histopathological insights into mitral valve prolapse-induced fibrosis. Front. Cardiovasc. Med., 10.","DOI":"10.3389\/fcvm.2023.1057986"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e022332","DOI":"10.1161\/JAHA.121.022332","article-title":"Mitral Valve Prolapse Induces Regionalized Myocardial Fibrosis","volume":"10","author":"Morningstar","year":"2021","journal-title":"J. Am. Heart Assoc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/S0735-1097(20)32174-4","article-title":"Myocardial Fibrosis Relates to Abnormal Myocardial Mechanics in Patients with Mitral Valve Prolapse","volume":"75","author":"Nagata","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.jacc.2018.11.018","article-title":"Atrial Fibrillation and Mitral Valve Prolapse: Time to Intervene?","volume":"73","author":"Borger","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.jacc.2018.07.006","article-title":"Mitral Valve Prolapse: A Disease of Valve and Ventricle","volume":"72","author":"Levine","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e005113","DOI":"10.1161\/CIRCIMAGING.115.005113","article-title":"Basal Left Ventricular Dilatation and Reduced Contraction in Patients with Mitral Valve Prolapse Can Be Secondary to Annular Dilatation: Preoperative and Postoperative Speckle-Tracking Echocardiographic Study on Left Ventricle and Mitral Valve Annulus Interaction","volume":"9","author":"Fukuda","year":"2016","journal-title":"Circ. Cardiovasc. Imaging"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.jacc.2018.06.048","article-title":"Myocardial Fibrosis in Patients with Primary Mitral Regurgitation with and Without Prolapse","volume":"72","author":"Kitkungvan","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.jacc.2013.02.060","article-title":"Malignant bileaflet mitral valve prolapse syndrome in patients with otherwise idiopathic out-of-hospital cardiac arrest","volume":"62","author":"Sriram","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"952","DOI":"10.1161\/CIRCULATIONAHA.118.034075","article-title":"Mitral Valve Prolapse, Ventricular Arrhythmias, and Sudden Death","volume":"140","author":"Basso","year":"2019","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1016\/j.jacc.2018.07.069","article-title":"Mitral Annulus Disjunction: Emerging Role of Myocardial Mechanical Stretch in Arrhythmogenesis","volume":"72","author":"Basso","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1161\/CIRCULATIONAHA.115.016291","article-title":"Arrhythmic Mitral Valve Prolapse and Sudden Cardiac Death","volume":"132","author":"Basso","year":"2015","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1016\/j.jacc.2018.07.070","article-title":"The Mitral Annulus Disjunction Arrhythmic Syndrome","volume":"72","author":"Dejgaard","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1016\/j.jtcvs.2020.01.086","article-title":"A novel cross-species model of Barlow\u2019s disease to biomechanically analyze repair techniques in an ex vivo left heart simulator","volume":"161","author":"Paulsen","year":"2021","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e70166","DOI":"10.1111\/liv.70166","article-title":"Digital Pathology Quantification of the Continuum of Cirrhosis Severity in Human Liver Biopsies","volume":"45","author":"Petitjean","year":"2025","journal-title":"Liver Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/liv.15768","article-title":"Liver fibrosis phenotyping and severity scoring by quantitative image analysis of biopsy slides","volume":"44","author":"Watson","year":"2024","journal-title":"Liver Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.jhep.2023.10.015","article-title":"Artificial intelligence-assisted digital pathology for non-alcoholic steatohepatitis: Current status and future directions","volume":"80","author":"Ratziu","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/HEP.0000000000000723","article-title":"Artificial intelligence scoring of liver biopsies in a phase II trial of semaglutide in nonalcoholic steatohepatitis","volume":"80","author":"Ratziu","year":"2024","journal-title":"Hepatology"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Fukushima, M., Miyaaki, H., Nakao, Y., Sasaki, R., Haraguchi, M., Takahashi, K., Ozawa, E., Miuma, S., Akazawa, Y., and Soyama, A. (2024). Characterizing alcohol-related and metabolic dysfunction-associated steatotic liver disease cirrhosis via fibrotic pattern analysis. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-73739-4"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kostadinova, R., Strobel, S., Chen, L., Fiaschetti-Egli, K., Gadient, J., Pawlowska, A., Petitjean, L., Bieri, M., Thoma, E., and Petitjean, M. (2024). Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-55438-2"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1016\/j.jtcvs.2014.07.029","article-title":"Left ventricular dysfunction after mitral valve repair\u2014The fallacy of \u201cnormal\u201d preoperative myocardial function","volume":"148","author":"Quintana","year":"2014","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eadd3949","DOI":"10.1126\/scitranslmed.add3949","article-title":"An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis","volume":"15","author":"Wang","year":"2023","journal-title":"Sci. Transl. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1536\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T04:10:33Z","timestamp":1759983033000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/14\/19\/1536"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":27,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["cells14191536"],"URL":"https:\/\/doi.org\/10.3390\/cells14191536","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2025,9,30]]}}}