title: Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome.
abstract: Mutations in SCN5A, the gene encoding the pore-forming subunit of cardiac Na(+) channels, cause a spectrum of arrhythmic syndromes. Of these, sinoatrial node (SAN) dysfunction occurs in patients with both loss- and gain-of-function SCN5A mutations. We explored for corresponding alterations in SAN function and intracardiac conduction and clarified possible mechanisms underlying these in an established mouse long QT syndrome type 3 model carrying a mutation equivalent to human SCN5A-ΔKPQ. Electrophysiological characterizations of SAN function in living animals and in vitro sinoatrial preparations were compared with cellular SAN and two-dimensional tissue models exploring the consequences of Scn5a+/ΔKPQ mutations. Scn5a+/ΔKPQ mice showed prolonged electrocardiographic QT and corrected QT intervals confirming long QT phenotypes. They showed frequent episodes of sinus bradycardia, sinus pause/arrest, and significantly longer sinus node recovery times, suggesting compromised pacemaker activity compared with wild-type mice. Electrocardiographic waveforms suggested depressed intra-atrial, atrioventricular node, and intraventricular conduction in Scn5a+/ΔKPQ mice. Isolated Scn5a+/ΔKPQ sinoatrial preparations similarly showed lower mean intrinsic heart rates and overall slower conduction through the SAN to the surrounding atrium than did wild-type preparations. Computer simulations of both single SAN cells as well as two-dimensional SAN-atrial models could reproduce the experimental observations of impaired pacemaker and sinoatrial conduction in terms of changes produced by both augmented tail and reduced total Na(+) currents, respectively. In conclusion, the gain-of-function long QT syndrome type 3 murine Scn5a+/ΔKPQ cardiac system, in overlap with corresponding features reported in loss-of-function Na(+) channel mutations, shows compromised SAN pacemaker and conduction function explicable in modeling studies through a combination of augmented tail and reduced peak Na(+) currents.
authors.affiliation: Department of Cardiovascular Diseases, Union Hospital, Huazhong University of Sciences and Technology, Wuhan, Peoples' Republic of China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xinzhao
authors.initials: X
authors.lastname: Zhang
authors.forename: Longxian
authors.initials: L
authors.lastname: Cheng
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Lammers
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: James A
authors.initials: JA
authors.lastname: Fraser
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
mesh_terms: D000465:Algorithms; D000758:Anesthesia; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D001283:Atrioventricular Node / Q000502:physiology; D003198:Computer Simulation; D004562:Electrocardiography; D004567:Electrodes, Implanted; D055724:Electrophysiological Phenomena; D000431:Ethanol / Q000031:analogs & derivatives / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006329:Heart Conduction System / Q000502:physiology*; D066298:In Vitro Techniques; D007649:Ketamine / Q000494:pharmacology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D062554:NAV1.5 Voltage-Gated Sodium Channel; D012849:Sinoatrial Node / Q000502:physiology*; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology*
chemical_list: D000778:Anesthetics, Dissociative; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; C062527:tribromoethanol; D000431:Ethanol; D007649:Ketamine