{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T23:42:12Z","timestamp":1768347732296,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T00:00:00Z","timestamp":1562889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>A key emerging theme in translational cardiovascular medicine is the need to identify specific causes of arrhythmias and heart failure, defined by phenotype and\/or genotype that will respond to a particular intervention. Unlike other genes implicated in hereditary arrhythmias and cardiomyopathies, pathogenic\/likely pathogenic variants in the cardiac sodium channel alpha subunit gene (SCN5A) produce a remarkably diverse set of electrical and structural phenotypes, one of them being dilated cardiomyopathy. There has been debate about whether left ventricular remodeling is a bona fide phenotypic feature of cardiac sodium channel dysfunction, or a consequence of tachyarrhythmias or conduction disturbances. In light of recent findings, a critical digest of the available experimental and medical literature is necessary. This paper provides a critical appraisal of the evidence linking a dysfunctional cardiac sodium channel to ventricular dysfunction, and discusses the potential mechanisms involved in shaping this phenotype along with implications for precision therapy.<\/jats:p>","DOI":"10.3390\/jcm8071029","type":"journal-article","created":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T11:49:38Z","timestamp":1562932178000},"page":"1029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Cardiac Sodium Channel Dysfunction and Dilated Cardiomyopathy: A Contemporary Reappraisal of Pathophysiological Concepts"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0050-5717","authenticated-orcid":false,"given":"Babken","family":"Asatryan","sequence":"first","affiliation":[{"name":"Department of Cardiology, Inselspital, Bern University Hospital, Freiburgstrasse 10, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/0092-8674(95)90359-3","article-title":"SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome","volume":"80","author":"Wang","year":"1995","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1161\/01.CIR.92.12.3381","article-title":"Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy","volume":"92","author":"Schwartz","year":"1995","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/32675","article-title":"Genetic basis and molecular mechanism for idiopathic ventricular fibrillation","volume":"392","author":"Chen","year":"1998","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/S0008-6363(99)00350-8","article-title":"Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome","volume":"44","author":"Rook","year":"1999","journal-title":"Cardiovasc. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/12618","article-title":"Cardiac conduction defects associate with mutations in SCN5A","volume":"23","author":"Schott","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1161\/hc0302.102592","article-title":"Clinical, genetic, and biophysical characterization of SCN5A mutations associated with atrioventricular conduction block","volume":"105","author":"Wang","year":"2002","journal-title":"Circulation"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1172\/JCI200318062","article-title":"Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A)","volume":"112","author":"Benson","year":"2003","journal-title":"J. Clin. Invest."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1161\/01.RES.0000050585.07097.D7","article-title":"A cardiac sodium channel mutation cosegregates with a rare connexin40 genotype in familial atrial standstill","volume":"92","author":"Groenewegen","year":"2003","journal-title":"Circ. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jacc.2012.02.052","article-title":"Multifocal ectopic Purkinje-related premature contractions: A new SCN5A-related cardiac channelopathy","volume":"60","author":"Laurent","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1111\/j.1540-8167.2006.00411.x","article-title":"SCN5A mutation associated with cardiac conduction defect and atrial arrhythmias","volume":"17","author":"Makynen","year":"2006","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/S0140-6736(99)05277-0","article-title":"Brugada syndrome and sudden cardiac death in children","volume":"355","author":"Priori","year":"2000","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1161\/01.CIR.0000144458.58660.BB","article-title":"SCN5A mutation associated with dilated cardiomyopathy, conduction disorder, and arrhythmia","volume":"110","author":"McNair","year":"2004","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1093\/cvr\/cvw234","article-title":"Multilevel analyses of SCN5A mutations in arrhythmogenic right ventricular dysplasia\/cardiomyopathy suggest non-canonical mechanisms for disease pathogenesis","volume":"113","author":"James","year":"2017","journal-title":"Cardiovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1001\/jama.293.4.447","article-title":"Sodium channel mutations and susceptibility to heart failure and atrial fibrillation","volume":"293","author":"Olson","year":"2005","journal-title":"JAMA"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1016\/j.jacc.2010.09.084","article-title":"SCN5A mutations associate with arrhythmic dilated cardiomyopathy and commonly localize to the voltage-sensing mechanism","volume":"57","author":"McNair","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1566","DOI":"10.1016\/j.jacc.2012.05.050","article-title":"R222Q SCN5A mutation is associated with reversible ventricular ectopy and dilated cardiomyopathy","volume":"60","author":"Mann","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1038\/gim.2016.90","article-title":"Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples","volume":"19","author":"Walsh","year":"2017","journal-title":"Genet. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1172\/JCI200419448","article-title":"Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A\/C-deficient mice","volume":"113","author":"Nikolova","year":"2004","journal-title":"J. Clin. Invest."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.cardiores.2007.04.009","article-title":"Dilated cardiomyopathy is associated with reduced expression of the cardiac sodium channel Scn5a","volume":"75","author":"Hesse","year":"2007","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1161\/CIRCRESAHA.107.164673","article-title":"Divergent biophysical defects caused by mutant sodium channels in dilated cardiomyopathy with arrhythmia","volume":"102","author":"Nguyen","year":"2008","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1093\/europace\/eun202","article-title":"The cardiac sodium channel mutation delQKP 1507-1509 is associated with the expanding phenotypic spectrum of LQT3, conduction disorder, dilated cardiomyopathy, and high incidence of youth sudden death","volume":"10","author":"Shi","year":"2008","journal-title":"Europace"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3389\/fphar.2015.00301","article-title":"Mutations in the Voltage Sensors of Domains I and II of Nav1.5 that are Associated with Arrhythmias and Dilated Cardiomyopathy Generate Gating Pore Currents","volume":"6","author":"Moreau","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1161\/CIRCEP.108.791434","article-title":"Dilated cardiomyopathy due to sodium channel dysfunction: What is the connection?","volume":"1","author":"Bezzina","year":"2008","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1016\/j.hrthm.2014.05.031","article-title":"SCN5A-related dilated cardiomyopathy: What do we know?","volume":"11","author":"Amin","year":"2014","journal-title":"Heart Rhythm."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Gosselin-Badaroudine, P., Keller, D.I., Huang, H., Pouliot, V., Chatelier, A., Osswald, S., Brink, M., and Chahine, M. (2012). A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype. PLoS ONE, 7.","DOI":"10.1371\/annotation\/03304989-b70c-400c-b752-2e3d18851047"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1161\/CIRCEP.107.750752","article-title":"Molecular and clinical characterization of a novel SCN5A mutation associated with atrioventricular block and dilated cardiomyopathy","volume":"1","author":"Ge","year":"2008","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1038\/s41467-017-02262-0","article-title":"Voltage-gated sodium channels assemble and gate as dimers","volume":"8","author":"Clatot","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1161\/CIRCRESAHA.116.305017","article-title":"Ion channel macromolecular complexes in cardiomyocytes: Roles in sudden cardiac death","volume":"116","author":"Abriel","year":"2015","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1016\/j.ymgme.2007.10.009","article-title":"SCN5A variants in Japanese patients with left ventricular noncompaction and arrhythmia","volume":"93","author":"Shan","year":"2008","journal-title":"Mol. Genet. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1161\/CIRCULATIONAHA.105.532614","article-title":"Right ventricular fibrosis and conduction delay in a patient with clinical signs of Brugada syndrome: A combined electrophysiological, genetic, histopathologic, and computational study","volume":"112","author":"Coronel","year":"2005","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3680","DOI":"10.1161\/CIRCULATIONAHA.105.520999","article-title":"Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome","volume":"112","author":"Frustaci","year":"2005","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1976","DOI":"10.1016\/j.jacc.2015.08.862","article-title":"Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome","volume":"66","author":"Nademanee","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1161\/CIRCULATIONAHA.113.003077","article-title":"Missense mutations in plakophilin-2 cause sodium current deficit and associate with a Brugada syndrome phenotype","volume":"129","author":"Cerrone","year":"2014","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.yjmcc.2009.08.025","article-title":"Cardiac sodium channel Na(v)1.5 and interacting proteins: Physiology and pathophysiology","volume":"48","author":"Abriel","year":"2010","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1098","DOI":"10.1161\/CIRCEP.111.969972","article-title":"A novel disease gene for Brugada syndrome: Sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5","volume":"5","author":"Ishikawa","year":"2012","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mlynarova, J., Trentin-Sonoda, M., Gaisler da Silva, F., Major, J.L., Salih, M., Carneiro-Ramos, M.S., and Tuana, B.S. (2019). SLMAP3 isoform modulates cardiac gene expression and function. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214669"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1161\/CIRCEP.110.960807","article-title":"TGF-beta1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging","volume":"4","author":"Hao","year":"2011","journal-title":"Circ. Arrhythm Electrophysiol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Zakrzewska-Koperska, J., Franaszczyk, M., Bilinska, Z., Truszkowska, G., Karczmarz, M., Szumowski, L., Zielinski, T., Ploski, R., and Bilinska, M. (2018). Rapid and effective response of the R222Q SCN5A to quinidine treatment in a patient with Purkinje-related ventricular arrhythmia and familial dilated cardiomyopathy: A case report. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0599-4"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1016\/j.hrthm.2014.04.042","article-title":"Novel SCN5A mutation in amiodarone-responsive multifocal ventricular ectopy-associated cardiomyopathy","volume":"11","author":"Beckermann","year":"2014","journal-title":"Heart Rhythm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1161\/CIRCGENETICS.114.000703","article-title":"Gain-of-function mutation of the SCN5A gene causes exercise-induced polymorphic ventricular arrhythmias","volume":"7","author":"Swan","year":"2014","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ijcard.2017.11.095","article-title":"Multifocal atrial and ventricular premature contractions with an increased risk of dilated cardiomyopathy caused by a Nav1.5 gain-of-function mutation (G213D)","volume":"257","author":"Calloe","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1161\/CIRCULATIONAHA.110.987248","article-title":"Striking In vivo phenotype of a disease-associated human SCN5A mutation producing minimal changes in vitro","volume":"124","author":"Watanabe","year":"2011","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1111\/j.1752-8062.2010.00249.x","article-title":"SCN5A rare variants in familial dilated cardiomyopathy decrease peak sodium current depending on the common polymorphism H558R and common splice variant Q1077del","volume":"3","author":"Cheng","year":"2010","journal-title":"Clin. Transl. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fphar.2010.00144","article-title":"Propranolol blocks cardiac and neuronal voltage-gated sodium channels","volume":"1","author":"Wang","year":"2010","journal-title":"Front. Pharmacol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/7\/1029\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:05:12Z","timestamp":1760187912000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/8\/7\/1029"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,12]]},"references-count":44,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["jcm8071029"],"URL":"https:\/\/doi.org\/10.3390\/jcm8071029","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,12]]}}}