title: Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome.
abstract: Deletion of amino-acid residues 1505-1507 (KPQ) in the cardiac SCN5A Na(+) channel causes autosomal dominant prolongation of the electrocardiographic QT interval (long-QT syndrome type 3 or LQT3). Excessive prolongation of the action potential at low heart rates predisposes individuals with LQT3 to fatal arrhythmias, typically at rest or during sleep. Here we report that mice heterozygous for a knock-in KPQ-deletion (SCN5A(Delta/+)) show the essential LQT3 features and spontaneously develop life-threatening polymorphous ventricular arrhythmias. Unexpectedly, sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early afterdepolarization and triggered arrhythmias in Scn5a(Delta/+) mice. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results show the possible risk of sudden heart-rate accelerations. The Scn5a(Delta/+) mouse with its predisposition for pacing-induced arrhythmia might be useful for the development of new treatments for the LQT3 syndrome.
authors.affiliation: Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Nuyens
authors.forename: M
authors.initials: M
authors.lastname: Stengl
authors.forename: S
authors.initials: S
authors.lastname: Dugarmaa
authors.forename: T
authors.initials: T
authors.lastname: Rossenbacker
authors.forename: V
authors.initials: V
authors.lastname: Compernolle
authors.forename: Y
authors.initials: Y
authors.lastname: Rudy
authors.forename: J F
authors.initials: JF
authors.lastname: Smits
authors.forename: W
authors.initials: W
authors.lastname: Flameng
authors.forename: C E
authors.initials: CE
authors.lastname: Clancy
authors.forename: L
authors.initials: L
authors.lastname: Moons
authors.forename: M A
authors.initials: MA
authors.lastname: Vos
authors.forename: M
authors.initials: M
authors.lastname: Dewerchin
authors.forename: K
authors.initials: K
authors.lastname: Benndorf
authors.forename: D
authors.initials: D
authors.lastname: Collen
authors.forename: E
authors.initials: E
authors.lastname: Carmeliet
authors.forename: P
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D002304:Cardiac Pacing, Artificial; D004562:Electrocardiography; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000235:genetics; D008564:Membrane Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D017384:Sequence Deletion; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D000318:Adrenergic beta-Agonists; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D012964:Sodium; D007545:Isoproterenol