{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:07:47Z","timestamp":1788782867697,"version":"build-2803163510"},"reference-count":129,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T00:00:00Z","timestamp":1788566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Cardiovasc. Dev. Dis.","JCDD"],"abstract":"<jats:p>Mitral valve prolapse (MVP) affects 1\u20133% of the general population and is largely considered benign. However, a small subset of MVP patients develops complex ventricular arrhythmias (VAs) and sudden cardiac death, including patients with nonsignificant mitral regurgitation (MR). This subgroup of arrhythmic MVP (aMVP) is variably associated with features such as mitral annular disjunction, bileaflet myxomatous prolapse, and regional myocardial fibrosis, with arrhythmic risk disproportionate to hemodynamic burden. The EHRA defines aMVP as MVP with complex VAs (frequent premature ventricular contractions, non-sustained or sustained ventricular tachycardia, ventricular fibrillation, or aborted sudden cardiac arrest) in the absence of another defined arrhythmic substrate. This narrative review reframes aMVP as a regional, stretch-induced cardiomyopathy with a distinct fibro-inflammatory signature. We further characterize a two-hit pathogenesis in which abnormal valvular mechanics create regional myocardial stress, while patient-specific vulnerability shapes variable fibro-inflammatory, fibrotic, and electromechanical responses. This narrative review synthesizes contemporary evidence across multimodal cardiac imaging, electrophysiology, surgical outcomes, mechanotransduction biology, and pharmacology, emphasizing a modifiable fibro-inflammatory trajectory underlying the intermediate risk aMVP phenotype and supporting a clinical shift from device-based rescue to substrate-directed prevention. Expanding on this model, we evaluate substrate-modifying pharmacotherapies for mechanistic fit, human cardiac evidence, and trial feasibility. Among these, mineralocorticoid receptor antagonists (MRAs) and sodium\u2013glucose cotransporter 2 (SGLT2) inhibitors demonstrate the strongest convergence of antifibrotic potential and trial readiness.<\/jats:p>","DOI":"10.3390\/jcdd13090437","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:30:46Z","timestamp":1788777046000},"page":"437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Arrhythmic Mitral Valve Prolapse as a Regional Stretch-Induced Cardiomyopathy with Fibro-Inflammatory Signature: A Conceptual Review"],"prefix":"10.3390","volume":"13","author":[{"given":"Mili","family":"Dave","sequence":"first","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaaf","family":"Ahmad","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirkwood","family":"Adams","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8117-0591","authenticated-orcid":false,"given":"Adam","family":"Akerman","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1044-8186","authenticated-orcid":false,"given":"Jinny","family":"Ha","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Ross J.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4209-970X","authenticated-orcid":false,"given":"Faisal F.","family":"Syed","sequence":"additional","affiliation":[{"name":"Department of Medicine, Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2904","DOI":"10.1016\/j.jacc.2018.09.048","article-title":"Arrhythmic Mitral Valve Prolapse: JACC Review Topic of the Week","volume":"72","author":"Miller","year":"2018","journal-title":"J. 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