{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T17:52:49Z","timestamp":1770745969737,"version":"3.49.0"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2025,7,31]],"date-time":"2025-07-31T00:00:00Z","timestamp":1753920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union - NextGenerationEU"},{"name":"Italian Ministry of University and Research","award":["PNRR - M4C2-I1.3 Project PR_00000019"],"award-info":[{"award-number":["PNRR - M4C2-I1.3 Project PR_00000019"]}]},{"name":"HEAL ITALIA","award":["J33C22002920006"],"award-info":[{"award-number":["J33C22002920006"]}]},{"DOI":"10.13039\/501100002954","name":"University of Milano-Bicocca","doi-asserted-by":"publisher","award":["PNRR M4C2-I1.3 Project PE 00000019"],"award-info":[{"award-number":["PNRR M4C2-I1.3 Project PE 00000019"]}],"id":[{"id":"10.13039\/501100002954","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Loss-of-function (LOF) mutations of the cardiac Na+ channel (SCN5A) are causatively associated with the Brugada Syndrome (BrS). However, the onset of Ventricular Fibrillation (VF) is a rare event, and critical factors favouring the pathological phenotype remain often elusive. This study explores how concomitant triggering conditions may impact on VF onset in a symptomatic proband carrying the S805L\/SCN5A BrS mutation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>Clinical, in-vitro, numerical, and structural analyses were performed. A 67-year-old male was resuscitated after cardiac arrest, and clinical analysis upon hospitalisation revealed severe hypokalaemia (2.5 mEq\/L). The ECG showed a coved type-I BrS pattern and the SCN5A mutation (S805L) was identified. Patch-clamp studies carried out in a heterologous expression system (HEK293 cells) revealed that WT\/S805L channels exhibit two different phenotypes (normal and LOF); the main parameter controlling this distribution is the cell membrane potential. A protected\/normal behaviour was observed at \u221280\u2005mV; conversely, LOF occurred at more negative potentials (\u2212100\/\u2212120\u2005mV). Further analyses in isolated outflow tract ventricular cardiomyocytes showed that hypokalaemia (and bradycardia) induced diastolic potential hyperpolarisation, thus favouring the Na+ current LOF. Computational and molecular modelling confirmed our findings and revealed the structural determinant of this alteration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>WT\/S805L Na+ channels exhibit either a LOF or a wild-type-like behaviour depending on the membrane potential. Since hypokalaemia and slow pacing rate induce cell hyperpolarisation and the associated LOF, they represent concurrent elements creating the scenario responsible for the VF and cardiac arrest. These results may represent an interpretative paradigm applicable to other BrS mutations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/europace\/euaf160","type":"journal-article","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T11:30:34Z","timestamp":1753788634000},"source":"Crossref","is-referenced-by-count":0,"title":["Hypokalaemia and bradycardia unmask the loss-of-function phenotype of a Brugada Syndrome\n                    <i>SCN5A<\/i>\n                    mutation"],"prefix":"10.1093","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7628-989X","authenticated-orcid":false,"given":"Anthony","family":"Frosio","sequence":"first","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2677-9214","authenticated-orcid":false,"given":"Procolo","family":"Marchese","sequence":"additional","affiliation":[{"name":"Cardiology Unit, AST Ascoli Piceno , Ascoli Piceno ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5352-253X","authenticated-orcid":false,"given":"Giorgia","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4355-4508","authenticated-orcid":false,"given":"David","family":"Molla","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6509-4894","authenticated-orcid":false,"given":"Martina","family":"Arici","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Biosciences, Universit\u00e0 degli Studi di Milano Bicocca , Milan ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6231-2980","authenticated-orcid":false,"given":"Chiara","family":"Bartolucci","sequence":"additional","affiliation":[{"name":"Department of Electrical, Electronic and Information Engineering Guglielmo Marconi, University of Bologna , Cesena ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-8402","authenticated-orcid":false,"given":"Chiara","family":"Piantoni","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Guidi","sequence":"additional","affiliation":[{"name":"Department of Electrical, Electronic and Information Engineering Guglielmo Marconi, University of Bologna , Cesena ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Bazzini","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3371-3301","authenticated-orcid":false,"given":"Patrizia","family":"Benzoni","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9513-8878","authenticated-orcid":false,"given":"Raffaella","family":"Milanesi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, MiLab and \u201cCentro Interuniversitario di Medicina Molecolare e Biofisica Applicata\u201d, Universit\u00e0 degli Studi di Milano , Milano 20133 ,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-2998","authenticated-orcid":false,"given":"Antonio","family":"Fortunato","sequence":"additional","affiliation":[{"name":"U.O.C. 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