{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T13:53:52Z","timestamp":1775915632320,"version":"3.50.1"},"reference-count":58,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T00:00:00Z","timestamp":1718323200000},"content-version":"vor","delay-in-days":13,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Innovational Research Incentives Scheme Vidi"},{"DOI":"10.13039\/501100001826","name":"Netherlands Organisation for Health Research and Development","doi-asserted-by":"publisher","award":["91714371"],"award-info":[{"award-number":["91714371"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Joint Research Program on Rare Diseases"},{"name":"ZonMw Priority Medicines","award":["113303006"],"award-info":[{"award-number":["113303006"]}]},{"name":"Netherlands CardioVascular Research Initiative","award":["CVON-PREDICT2 2018-30"],"award-info":[{"award-number":["CVON-PREDICT2 2018-30"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Patients with mutations in SCN5A encoding NaV1.5 often display variable severity of electrical and structural alterations, but the underlying mechanisms are not fully elucidated. We here investigate the combined modulatory effect of genetic background and age on disease severity in the Scn5a1798insD\/+ mouse model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>In vivo electrocardiogram and echocardiograms, ex vivo electrical and optical mapping, and histological analyses were performed in adult (2\u20137 months) and aged (8\u201328 months) wild-type (WT) and Scn5a1798insD\/+ (mutant, MUT) mice from the FVB\/N and 129P2 inbred strains. Atrio-ventricular (AV) conduction, ventricular conduction, and ventricular repolarization are modulated by strain, genotype, and age. An aging effect was present in MUT mice, with aged MUT mice of both strains showing prolonged QRS interval and right ventricular (RV) conduction slowing. 129P2-MUT mice were severely affected, with adult and aged 129P2-MUT mice displaying AV and ventricular conduction slowing, prolonged repolarization, and spontaneous arrhythmias. In addition, the 129P2 strain appeared particularly susceptible to age-dependent electrical, functional, and structural alterations including RV conduction slowing, reduced left ventricular (LV) ejection fraction, RV dilatation, and myocardial fibrosis as compared to FVB\/N mice. Overall, aged 129P2-MUT mice displayed the most severe conduction defects, RV dilatation, and myocardial fibrosis, in addition to the highest frequency of spontaneous arrhythmia and inducible arrhythmias.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Genetic background and age both modulate disease severity in Scn5a1798insD\/+ mice and hence may explain, at least in part, the variable disease expressivity observed in patients with SCN5A mutations. Age- and genetic background\u2013dependent development of cardiac structural alterations furthermore impacts arrhythmia risk. Our findings therefore emphasize the importance of continued assessment of cardiac structure and function in patients carrying SCN5A mutations.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/europace\/euae153","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T19:29:41Z","timestamp":1718393381000},"source":"Crossref","is-referenced-by-count":5,"title":["Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in <i>Scn5a<\/i>-1798insD mice"],"prefix":"10.1093","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7353-0235","authenticated-orcid":false,"given":"Gerard A","family":"Marchal","sequence":"first","affiliation":[{"name":"Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"OptoCARD Lab, Institute of Clinical Physiology (IFC-CNR) , Florence , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0680-3483","authenticated-orcid":false,"given":"Mathilde R","family":"Rivaud","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rianne","family":"Wolswinkel","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0195-9753","authenticated-orcid":false,"given":"Cristina","family":"Basso","sequence":"additional","affiliation":[{"name":"Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova , Padua , Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-5924","authenticated-orcid":false,"given":"Toon A B","family":"van Veen","sequence":"additional","affiliation":[{"name":"Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht , Utrecht , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0633-3514","authenticated-orcid":false,"given":"Connie R","family":"Bezzina","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0095-0084","authenticated-orcid":false,"given":"Carol Ann","family":"Remme","sequence":"additional","affiliation":[{"name":"Department of Experimental Cardiology, Heart Centre, Amsterdam UMC location University of Amsterdam , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The Netherlands"},{"name":"Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias , Meibergdreef 15, PO Box 22660, 1100 DD Amsterdam , The 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