title: Sinus node dysfunction following targeted disruption of the murine cardiac sodium channel gene Scn5a.
abstract: We have examined sino-atrial node (SAN) function in hearts from adult mice with heterozygous targeted disruption of the Scn5a gene to clarify the role of Scn5a-encoded cardiac Na+ channels in normal SAN function and the mechanism(s) by which reduced Na+ channel function might cause sinus node dysfunction. Scn5a+/- mice showed depressed heart rates and occasional sino-atrial (SA) block. Their isolated peripheral SAN pacemaker cells showed a reduced Na+ channel expression and slowed intrinsic pacemaker rates. Wild-type (WT) and Scn5a+/- SAN preparations exhibited similar activation patterns but with significantly slower SA conduction and frequent sino-atrial conduction block in Scn5a+/- SAN preparations. Furthermore, isolated WT and Scn5a+/- SAN cells demonstrated differing correlations between cycle length, maximum upstroke velocity and action potential amplitude, and cell size. Small myocytes showed similar, but large myocytes reduced pacemaker rates, implicating the larger peripheral SAN cells in the reduced pacemaker rate that was observed in Scn5a+/- myocytes. These findings were successfully reproduced in a model that implicated i(Na) directly in action potential propagation through the SAN and from SAN to atria, and in modifying heart rate through a coupling of SAN and atrial cells. Functional alterations in the SAN following heterozygous-targeted disruption of Scn5a thus closely resemble those observed in clinical sinus node dysfunction. The findings accordingly provide a basis for understanding of the role of cardiac-type Na+ channels in normal SAN function and the pathophysiology of sinus node dysfunction and suggest new potential targets for its clinical management.
authors.affiliation: University Laboratory of Physiology, University of Oxford, Oxford, OX1 3PT UK. ming.lei@physiol.ox.ac.uk
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Catharine
authors.initials: C
authors.lastname: Goddard
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Léoni
authors.forename: Anne
authors.initials: A
authors.lastname: Royer
authors.forename: Simon S-M
authors.initials: SS
authors.lastname: Fung
authors.forename: Guosheng
authors.initials: G
authors.lastname: Xiao
authors.forename: Aiqun
authors.initials: A
authors.lastname: Ma
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Flavien
authors.initials: F
authors.lastname: Charpentier
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
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials; D000818:Animals; D001683:Biological Clocks; D002478:Cells, Cultured; D003198:Computer Simulation; D005260:Female; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods; D008297:Male; D051379:Mice; D008955:Models, Cardiovascular; D032342:Muscle Cells / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012849:Sinoatrial Node / Q000503:physiopathology*; D015222:Sodium Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels