{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:52:14Z","timestamp":1793040734079,"version":"4.5.0"},"reference-count":24,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T00:00:00Z","timestamp":1754611200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Italy","award":["BIRD 2024"],"award-info":[{"award-number":["BIRD 2024"]}]},{"name":"Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Italy","award":["PNRR-MR1-2022-12376614"],"award-info":[{"award-number":["PNRR-MR1-2022-12376614"]}]},{"name":"PNRR Next-Generation EU","award":["BIRD 2024"],"award-info":[{"award-number":["BIRD 2024"]}]},{"name":"PNRR Next-Generation EU","award":["PNRR-MR1-2022-12376614"],"award-info":[{"award-number":["PNRR-MR1-2022-12376614"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disorder characterized by structural and functional myocardial alterations, often accompanied by ventricular arrhythmias (VAs), which may ultimately result in sudden cardiac death (SCD). While mutations in genes coding for desmosomal components are commonly identified in affected individuals, genetic variants involving non-desmosomal proteins have recently been recognized as contributors to the disease\u2019s etiology. In 2008, a mutation in the transmembrane protein 43 (TMEM43) was identified as being responsible for a fully penetrant, sex-related, and severe form of ACM. This review aimed to systematically synthesize the current evidence on the natural history, electrocardiographic, and imaging findings as well as the clinical outcomes of TMEM43 cardiomyopathy. Methods: A systematic search was performed in the PubMed, Scopus, and Web of Science databases, following the PRISMA guidelines, using the terms \u201cTMEM43\u201d AND \u201ccardiomyopathy\u201d. After an initial screening of 144 retrieved articles, 80 were considered relevant. Upon a full-text review and eligibility assessment, 12 studies involving 903 individuals harboring TMEM43 variants were selected for inclusion. Results: Male patients more frequently carried the pathogenic TMEM43 variant (n = 505, 55.9%) and exhibited an earlier arrhythmic onset of the disease (33.2 years old versus 46.2 years old in female patients), supporting the need for earlier implantable cardioverter\u2013defibrillator implantation (30.4 versus 42.2 years old). Palpitations, chest pain, and syncope were the most common presenting symptoms. Baseline electrocardiograms commonly demonstrated poor R wave progression, QRS prolongation, and premature ventricular contractions (PVCs). Arrhythmic events, including malignant VAs and SCD, were early manifestations of the disease, especially in male patients. Frequent PVCs and left ventricular dilation were considered early markers of the disease and were predictive of arrhythmic events. Conversely, heart failure was reported as a late clinical outcome, requiring heart transplantation in a minority of cases (1.5%). Conclusions:TMEM43 cardiomyopathy is a fully penetrant autosomal dominant form of ACM, characterized by a well-defined clinical phenotype that is more severe and presents earlier in male patients.<\/jats:p>","DOI":"10.3390\/jcm14165611","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T11:41:53Z","timestamp":1754653313000},"page":"5611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Natural History and Clinical Outcomes of Transmembrane Protein 43 Cardiomyopathy: A Systematic Review"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5587-1215","authenticated-orcid":false,"given":"Annagrazia","family":"Cecere","sequence":"first","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0522-8408","authenticated-orcid":false,"given":"Marika","family":"Martini","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9601-3671","authenticated-orcid":false,"given":"Maria","family":"Bueno Marinas","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Rigato","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-8233","authenticated-orcid":false,"given":"Alessandro","family":"Parodi","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3646-0669","authenticated-orcid":false,"given":"Kalliopi","family":"Pilichou","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7357-293X","authenticated-orcid":false,"given":"Barbara","family":"Bauce","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic, and Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1056\/NEJMra1509267","article-title":"Arrhythmogenic Right Ventricular Cardiomyopathy","volume":"376","author":"Corrado","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"132571","DOI":"10.1016\/j.ijcard.2024.132571","article-title":"The \u201cPadua classification\u201d of cardiomyopathies: Combining pathobiological basis and morpho-functional remodeling","volume":"418","author":"Corrado","year":"2025","journal-title":"Int. J. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1093\/eurheartj\/ehad194","article-title":"ESC Scientific Document Group. 2023 ESC Guidelines for the management of cardiomyopathies","volume":"44","author":"Arbelo","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bueno Marinas, M., Cason, M., Bariani, R., Celeghin, R., De Gaspari, M., Pinci, S., Cipriani, A., Rigato, I., Zorzi, A., and Rizzo, S. (2024). A Comprehensive Analysis of Non-Desmosomal Rare Genetic Variants in Arrhythmogenic Cardiomyopathy: Integrating in Padua Cohort Litera-ture-Derived Data. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25116267"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Siragam, V., Cui, X., Masse, S., Ackerley, C., Aafaqi, S., Strandberg, L., Tropak, M., Fridman, M.D., Nanthakumar, K., and Liu, J. (2014). TMEM43 mutation p.S358L alters intercalated disc protein expression and reduces conduction velocity in arrhythmogenic right ventricular cardiomyopathy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109128"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1016\/j.ajhg.2008.01.010","article-title":"Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a mis-sense mutation in the TMEM43 gene","volume":"82","author":"Merner","year":"2008","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.jacc.2004.08.068","article-title":"The impact of implantable cardioverter-defibrillator therapy on survival in autosomal-dominant arrhythmogenic right ventricular cardiomyopathy (ARVD5)","volume":"45","author":"Hodgkinson","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1111\/j.1399-0004.2012.01919.x","article-title":"The natural history of a genetic subtype of arrhythmogenic right ventricular cardiomyopathy caused by a p.S358L mutation in TMEM43","volume":"83","author":"Hodgkinson","year":"2013","journal-title":"Clin. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1093\/eurheartj\/ehu077","article-title":"The TMEM43 Newfoundland mutation p.S358L causing ARVC-5 was imported from Europe and increases the stiff-ness of the cell nucleus","volume":"36","author":"Milting","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e003589","DOI":"10.1161\/CIRCEP.115.003589","article-title":"Long-Term Clinical Outcome of Arrhythmogenic Right Ventricular Cardiomyopathy in Individuals With a p.S358L Mutation in TMEM43 Following Implantable Cardioverter Defibrillator Therapy","volume":"9","author":"Hodgkinson","year":"2016","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/jce.13353","article-title":"Ventricular tachycardia ablation in arrhythmogenic right ventricular cardiomyopathy patients with TMEM43 gene mutations","volume":"29","author":"AbdelWahab","year":"2018","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1016\/j.hrthm.2020.01.035","article-title":"Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5","volume":"17","author":"Dominguez","year":"2020","journal-title":"Heart Rhythm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1016\/j.hrthm.2020.02.028","article-title":"Exercise and arrhythmic risk in TMEM43 p.S358L arrhythmogenic right ventricular cardiomyopathy","volume":"17","author":"Paulin","year":"2020","journal-title":"Heart Rhythm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12947-021-00270-1","article-title":"Myocardial strain measured via two-dimensional speckle-tracking echocardiography in a family diagnosed with arrhythmogenic left ventricular cardiomyopathy","volume":"19","author":"Ma","year":"2021","journal-title":"Cardiovasc. Ultrasound"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e230155","DOI":"10.1148\/ryct.230155","article-title":"Cardiac MRI and Clinical Outcomes in TMEM43 Arrhythmogenic Cardiomyopathy","volume":"5","author":"Matos","year":"2023","journal-title":"Radiol. Cardiothorac. Imaging"},{"key":"ref_16","first-page":"e013145","article-title":"Electro-physiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy","volume":"17","author":"Gasperetti","year":"2024","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1016\/j.jacc.2013.01.073","article-title":"Genetics of arrhythmogenic right ventricular cardiomyopathy: A practical guide for physicians","volume":"61","author":"Marcus","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1172\/JCI27751","article-title":"Suppression of canonical Wnt\/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy","volume":"116","author":"Lombardi","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1242\/jcs.019281","article-title":"LUMA interacts with emerin and influences its distribution at the inner nuclear membrane","volume":"121","author":"Bengtsson","year":"2008","journal-title":"J. Cell. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e21994","DOI":"10.1096\/fj.202100800R","article-title":"Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy","volume":"35","author":"Shinomiya","year":"2021","journal-title":"FASEB J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/jce.12858","article-title":"VT Recurrence after ablation: Incomplete ablation or disease progression? A multicentric European study","volume":"27","author":"Berte","year":"2016","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1007\/s00330-004-2387-0","article-title":"Assessment of ventricular function and mass by cardiac magnetic resonance imaging","volume":"14","author":"Alfakih","year":"2004","journal-title":"Eur. Radiol."},{"key":"ref_23","first-page":"326","article-title":"Dilated cardiomyopathy and arrhythmogenic left ventricular cardiomyopathy: A comprehensive genotype-imaging phenotype study","volume":"21","author":"Augusto","year":"2020","journal-title":"Eur. Heart J. Cardiovasc. Imaging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1056\/NEJM199912023412302","article-title":"Missense mutations in the rod domain of the lamin A\/C gene as causes of dilated cardiomyopathy and conduction-system disease","volume":"341","author":"Fatkin","year":"1999","journal-title":"N. Engl. J. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5611\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:18Z","timestamp":1760034378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5611"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,8]]},"references-count":24,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jcm14165611"],"URL":"https:\/\/doi.org\/10.3390\/jcm14165611","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,8]]}}}