title: Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a.
abstract: Voltage-gated sodium channels drive the initial depolarization phase of the cardiac action potential and therefore critically determine conduction of excitation through the heart. In patients, deletions or loss-of-function mutations of the cardiac sodium channel gene, SCN5A, have been associated with a wide range of arrhythmias including bradycardia (heart rate slowing), atrioventricular conduction delay, and ventricular fibrillation. The pathophysiological basis of these clinical conditions is unresolved. Here we show that disruption of the mouse cardiac sodium channel gene, Scn5a, causes intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis whereas heterozygotes show normal survival. Whole-cell patch clamp analyses of isolated ventricular myocytes from adult Scn5a(+/-) mice demonstrate a approximately 50% reduction in sodium conductance. Scn5a(+/-) hearts have several defects including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconcile reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias.
authors.affiliation: Section of Cardiovascular Biology, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom.
authors.forename: G Alex
authors.initials: GA
authors.lastname: Papadatos
authors.forename: Polly M R
authors.initials: PM
authors.lastname: Wallerstein
authors.forename: Catherine E G
authors.initials: CE
authors.lastname: Head
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ratcliff
authors.forename: Peter A
authors.initials: PA
authors.lastname: Brady
authors.forename: Klaus
authors.initials: K
authors.lastname: Benndorf
authors.forename: Richard C
authors.initials: RC
authors.lastname: Saumarez
authors.forename: Ann E O
authors.initials: AE
authors.lastname: Trezise
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: Jamie I
authors.initials: JI
authors.lastname: Vandenberg
authors.forename: William H
authors.initials: WH
authors.lastname: Colledge
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
mesh_terms: D000818:Animals; D002470:Cell Survival; D004562:Electrocardiography; D004594:Electrophysiology; D005091:Exons; D006579:Heterozygote; D006720:Homozygote; D051379:Mice; D008957:Models, Genetic; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010641:Phenotype; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D017180:Tachycardia, Ventricular / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels