{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:04:34Z","timestamp":1789747474907,"version":"4.0.1"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Brugada syndrome is usually interpreted through SCN5A genetics, yet many patients with a Brugada phenotype carry no clearly pathogenic SCN5A variant and penetrance among carriers is incomplete. Cardiac sodium-channel function is therefore not a direct readout of coding sequence but an integrated property shaped by the channelosome, transcriptional and epigenetic control, post-translational modification, metabolic state, and inflammatory signaling. Through these routes, oxidative stress, altered glycosylation, and Nedd4-2-dependent ubiquitination can reduce peak sodium current in experimental systems, potentially lowering conduction reserve; inflammatory mediators may additionally modify the regional substrate through other ionic pathways without altering the SCN5A coding sequence in the experimental system, converging on the loss-of-function phenotype that characterizes Brugada syndrome, in contrast to the late-current gain of function of long QT syndrome type 3. Epicardial adipose tissue may provide a regional context for such signals at the right ventricular outflow tract, where conduction reserve is low and the substrate preferentially localizes, and anti-Nav1.5 autoantibodies provide a humoral route to reduced channel availability. We examine sequence-independent modifiers that may dynamically reduce Nav1.5 function and define the experimental framework needed to establish their clinical weight.<\/jats:p>","DOI":"10.1093\/europace\/euag261","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:20:08Z","timestamp":1789672808000},"source":"Crossref","is-referenced-by-count":0,"title":["Nav1.5 Beyond Genetics: Loss of Cardiac Sodium-Channel Function in Brugada Syndrome"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0712-2161","authenticated-orcid":false,"given":"Luigi","family":"Anastasia","sequence":"first","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato , Milan ,","place":["Italy"]},{"name":"School of Medicine, Vita-Salute San Raffaele University , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7886-5467","authenticated-orcid":false,"given":"Giuseppe","family":"Ciconte","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato , Milan ,","place":["Italy"]},{"name":"School of Medicine, Vita-Salute San Raffaele University , Milan ,","place":["Italy"]},{"name":"Arrhythmology Department, IRCCS Policlinico San Donato , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Fuga","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dudie","family":"Gjeci","sequence":"additional","affiliation":[{"name":"School of Medicine, Vita-Salute San Raffaele University , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5653-3741","authenticated-orcid":false,"given":"Tiziano","family":"Dallavilla","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato , Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-2715","authenticated-orcid":false,"given":"Marco","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Institute for Molecular and Translational Cardiology (IMTC), IRCCS Policlinico San Donato , Milan ,","place":["Italy"]},{"name":"School of Medicine, Vita-Salute San Raffaele University , Milan 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