{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T01:22:26Z","timestamp":1783732946785,"version":"3.55.0"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T00:00:00Z","timestamp":1771372800000},"content-version":"vor","delay-in-days":302,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,4,22]],"date-time":"2025-04-22T00:00:00Z","timestamp":1745280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023794","name":"PLN Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2012-10 PREDICT"],"award-info":[{"award-number":["2012-10 PREDICT"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2015-12 eDETECT"],"award-info":[{"award-number":["2015-12 eDETECT"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"crossref","award":["2018-30 PREDICT2"],"award-info":[{"award-number":["2018-30 PREDICT2"]}],"id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Fondation Leducq Transatlantic Network of Excellence"},{"DOI":"10.13039\/501100023794","name":"Stichting PLN","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100023794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Previous studies have shown that carriers of the pathogenic p.Arg14del variant in phospholamban (PLN) have an increased risk of mortality, heart failure and malignant ventricular arrhythmias. However, there are sparse data on the penetrance of cardiac features in these mutation carriers, and the optimal starting age and intervals of clinical follow-up remain to be defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We collected clinical data from PLN p.(Arg14del) carriers. Cardiac penetrance was defined as the presence of a major event or risk factor. A major event consisted of malignant ventricular arrhythmias or symptomatic heart failure. Risk factors were low-voltage electrocardiogram, repolarization abnormalities, frequent premature complexes, left ventricular ejection fraction &amp;lt;45% or cardiac fibrosis on magnetic resonance imaging. Kaplan\u2013Meier analysis with and without left truncation was used to assess penetrance. We identified 868 p.(Arg14del) carriers, with a median age of 43 (interquartile range [IQR] 29\u201355) years at first cardiac evaluation. Median follow-up was 5.3 (IQR 2.2\u20138.5)\u2009years and 207 (23.8%) carriers had a major event, at a mean age of 51 (\u00b1\u200915) years. Penetrance was age-related, with new cardiac phenotypes emerging from adolescence to senior age. At age 70, penetrance of a major event was 43% to 70%, penetrance of a risk factor was 84% to 100% depending on which Kaplan\u2013Meier method was used.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Penetrance of a major cardiac event is high in PLN p.(Arg14del) carriers, with a penetrance up to 70% at age 70. Penetrance of a cardiac risk factor is nearly complete at older age. Furthermore, cardiac phenotypes can emerge from adolescence to senior age. Life-long cardiac follow-up is needed, starting from adolescence.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejhf.3672","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:27:21Z","timestamp":1745375241000},"page":"3269-3277","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Age-Related Penetrance of Phospholamban p.Arg14del Cardiomyopathy"],"prefix":"10.1093","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4340-6815","authenticated-orcid":false,"given":"Tom E.","family":"Verstraelen","sequence":"first","affiliation":[{"name":"Department of Cardiology, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freyja H.M.","family":"van Lint","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remco","family":"de Brouwer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginnio M.","family":"Proost","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmee","family":"van Drie","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurens P.","family":"Bosman","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Division Heart and Lungs, Department of Cardiology, University of Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Weverink","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Taha","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Division Heart and Lungs, Department of Cardiology, University of Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thais","family":"Bueren","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aeilko H.","family":"Zwinderman","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology and Biostatistics, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathelijne","family":"Dickhoff","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Dijklander Ziekenhuis Hoorn , Hoorn ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toon","family":"Oomen","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Antonius Ziekenhuis Sneek , Sneek ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas A.","family":"Schoonderwoerd","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical Center Leeuwarden , Leeuwarden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tjeerd","family":"Germans","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Noordwest Ziekenhuisgroep , Alkmaar ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan C.","family":"Houweling","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan R.","family":"Gimeno-Blanes","sequence":"additional","affiliation":[{"name":"Virgen de Arrixaca Hospital, Ctra , Murcia ,","place":["Spain"]},{"name":"European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Folkert W.","family":"Asselbergs","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A.","family":"van der Zwaag","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Clinical Genetics, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneline S.J.M.","family":"te Riele","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht, Division Heart and Lungs, Department of Cardiology, University of Utrecht , Utrecht ,","place":["The Netherlands"]},{"name":"European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A.","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Groningen ,","place":["The Netherlands"]},{"name":"European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarten P.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Medical Center Groningen, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"Department of Genetics, University Medical Center Utrecht , Utrecht ,","place":["The Netherlands"]},{"name":"European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur A.M.","family":"Wilde","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Amsterdam UMC, University of Amsterdam , Amsterdam ,","place":["The Netherlands"]},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure and Arrhythmias, Amsterdam UMC , Amsterdam ,","place":["The Netherlands"]},{"name":"European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart)"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,22]]},"reference":[{"key":"2026021721530875000_ejhf3672-bib-0001","doi-asserted-by":"crossref","first-page":"e301","DOI":"10.1016\/j.hrthm.2019.05.007","article-title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy","volume":"16","author":"Towbin","year":"2019","journal-title":"Heart Rhythm"},{"key":"2026021721530875000_ejhf3672-bib-0002","doi-asserted-by":"crossref","first-page":"2793","DOI":"10.1093\/eurheartj\/ehv316","article-title":"2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC)","volume":"36","author":"Priori","year":"2015","journal-title":"Eur Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0003","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1111\/his.12963","article-title":"Phospholamban p.Arg14del cardiomyopathy is characterized by phospholamban aggregates, aggresomes, and autophagic degradation","volume":"69","author":"Te Rijdt","year":"2016","journal-title":"Histopathology"},{"key":"2026021721530875000_ejhf3672-bib-0004","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1161\/CIRCGENETICS.113.000374","article-title":"Outcome in phospholamban R14del carriers results of a large multicentre cohort study","volume":"7","author":"Rijsingen","year":"2014","journal-title":"Circ Cardiovasc Genet"},{"key":"2026021721530875000_ejhf3672-bib-0005","doi-asserted-by":"crossref","first-page":"2842","DOI":"10.1093\/eurheartj\/ehab294","article-title":"Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers\u2013reaching the frontiers of individual risk prediction","volume":"42","author":"Verstraelen","year":"2021","journal-title":"Eur Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0006","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1016\/j.jcmg.2020.09.030","article-title":"Early mechanical alterations in phospholamban mutation carriers: Identifying subclinical disease before onset of symptoms","volume":"14","author":"Taha","year":"2021","journal-title":"JACC Cardiovasc Imaging"},{"key":"2026021721530875000_ejhf3672-bib-0007","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1093\/ehjci\/jey047","article-title":"Myocardial fibrosis as an early feature in phospholamban p.Arg14del mutation carriers: Phenotypic insights from cardiovascular magnetic resonance imaging","volume":"20","author":"Rijdt","year":"2019","journal-title":"Eur Heart J Cardiovasc Imaging"},{"key":"2026021721530875000_ejhf3672-bib-0008","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.hrthm.2009.01.016","article-title":"Genetic deletion of arginine 14 in phospholamban causes dilated cardiomyopathy with attenuated electrocardiographic R amplitudes","volume":"6","author":"Posch","year":"2009","journal-title":"Heart Rhythm"},{"key":"2026021721530875000_ejhf3672-bib-0009","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1093\/eurheartj\/ehx596","article-title":"Lamin A\/C cardiomyopathy: Young onset, high penetrance, and frequent need for heart transplantation","volume":"39","author":"Hasselberg","year":"2018","journal-title":"Eur Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0010","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1007\/s12471-019-1270-1","article-title":"The Netherlands Arrhythmogenic Cardiomyopathy Registry: Design and status update","volume":"27","author":"Bosman","year":"2019","journal-title":"Neth Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0011","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/s12968-015-0111-7","article-title":"Normal values for cardiovascular magnetic resonance in adults and children","volume":"17","author":"Kawel-Boehm","year":"2015","journal-title":"J Cardiovasc Magn Reson"},{"key":"2026021721530875000_ejhf3672-bib-0012","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1161\/01.CIR.62.5.1054","article-title":"Echocardiographic measurements in normal subjects from infancy to old age","volume":"62","author":"Henry","year":"1980","journal-title":"Circulation"},{"key":"2026021721530875000_ejhf3672-bib-0013","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1093\/eurheartj\/ehq025","article-title":"Diagnosis of arrhythmogenic right ventricular cardiomyopathy\/dysplasia: Proposed modification of the Task Force Criteria","volume":"31","author":"Marcus","year":"2010","journal-title":"Eur Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0014","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1093\/eurheartj\/ehac180","article-title":"A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy","volume":"43","author":"Cadrin-Tourigny","year":"2022","journal-title":"Eur Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0015","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1016\/j.jacc.2016.09.951","article-title":"Arrhythmogenic right ventricular cardiomyopathy: Clinical course and predictors of arrhythmic risk","volume":"68","author":"Mazzanti","year":"2016","journal-title":"J Am Coll Cardiol"},{"key":"2026021721530875000_ejhf3672-bib-0016","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGEN.117.001797","article-title":"Effect of ascertainment bias on estimates of patient mortality in inherited cardiac diseases","volume":"11","author":"Nannenberg","year":"2018","journal-title":"Circ Genom Precis Med"},{"key":"2026021721530875000_ejhf3672-bib-0017","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s12471-013-0401-3","article-title":"Recurrent and founder mutations in the Netherlands \u2013 Phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy","volume":"21","author":"Zwaag","year":"2013","journal-title":"Neth Heart J"},{"key":"2026021721530875000_ejhf3672-bib-0018","doi-asserted-by":"crossref","DOI":"10.1161\/CIRCGEN.120.003302","article-title":"Clinical findings and diagnostic yield of arrhythmogenic cardiomyopathy through genomic screening of pathogenic or likely pathogenic desmosome gene variants","volume":"14","author":"Carruth","year":"2021","journal-title":"Circ Genom Precis Med"},{"key":"2026021721530875000_ejhf3672-bib-0019","article-title":"Prevalence and disease expression of pathogenic and likely pathogenic variants associated with inherited cardiomyopathies in the general population","volume":"14","author":"Bourfiss","year":"2022","journal-title":"Circ Genom Precis Med"}],"container-title":["European Journal of Heart Failure"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/27\/12\/3269\/66836217\/eurjhf_27_12_3269.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/eurjhf\/article-pdf\/27\/12\/3269\/66836217\/eurjhf_27_12_3269.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,18]],"date-time":"2026-02-18T02:53:18Z","timestamp":1771383198000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/eurjhf\/article\/27\/12\/3269\/8470701"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,22]]},"references-count":19,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,4,22]]},"published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1002\/ejhf.3672","relation":{},"ISSN":["1388-9842","1879-0844"],"issn-type":[{"value":"1388-9842","type":"print"},{"value":"1879-0844","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12]]},"published":{"date-parts":[[2025,4,22]]},"assertion":[{"value":"2024-09-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}