title: The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium.
abstract: Cardiac sodium channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of sodium channel expression and function in the myocardium. Sodium channel Scn5a mRNA and Na(v)1.5 protein distribution was investigated in adult and embryonic mouse heart through immunohistochemistry and in situ hybridization. Functional sodium channel availability in subepicardial and subendocardial myocytes was assessed using patch-clamp technique. Adult and embryonic (ED14.5) mouse heart sections showed low expression of Na(v)1.5 in the HCN4-positive sinoatrial and atrioventricular nodes. In contrast, high expression levels of Na(v)1.5 were observed in the HCN4-positive and Cx43-negative AV or His bundle, bundle branches and Purkinje fibers. In both ventricles, a transmural gradient was observed, with a low Na(v)1.5 labeling intensity in the subepicardium as compared to the subendocardium. Similar Scn5a mRNA expression patterns were observed on in situ hybridization of embryonic and adult tissue. Maximal action potential upstroke velocity was significantly lower in subepicardial myocytes (mean +/- SEM 309 +/- 32 V/s; n = 14) compared to subendocardial myocytes (394 +/- 32 V/s; n = 11; P < 0.05), indicating decreased sodium channel availability in subepicardium compared to subendocardium. Scn5a and Na(v)1.5 show heterogeneous distribution patterns within the cardiac conduction system and across the ventricular wall. This differential distribution of the cardiac sodium channel may have profound consequences for conduction disease phenotypes and arrhythmogenesis in the setting of sodium channel disease.
authors.affiliation: Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. c.a.remme@amc.uva.nl
authors.forename: C A
authors.initials: CA
authors.lastname: Remme
authors.forename: A O
authors.initials: AO
authors.lastname: Verkerk
authors.forename: W M H
authors.initials: WM
authors.lastname: Hoogaars
authors.forename: W T J
authors.initials: WT
authors.lastname: Aanhaanen
authors.forename: B P
authors.initials: BP
authors.lastname: Scicluna
authors.forename: C
authors.initials: C
authors.lastname: Annink
authors.forename: M J B
authors.initials: MJ
authors.lastname: van den Hoff
authors.forename: A A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: T A B
authors.initials: TA
authors.lastname: van Veen
authors.forename: M W
authors.initials: MW
authors.lastname: Veldkamp
authors.forename: J M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: V M
authors.initials: VM
authors.lastname: Christoffels
authors.forename: C R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D000200:Action Potentials; D000818:Animals; D001283:Atrioventricular Node / Q000378:metabolism; D002036:Bundle of His / Q000378:metabolism; D002460:Cell Line; D018507:Gene Expression Regulation, Developmental; D006329:Heart Conduction System / Q000196:embryology / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D011690:Purkinje Fibers / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels