title: The age-dependence of atrial arrhythmogenicity in Scn5a+/- murine hearts reflects alterations in action potential propagation and recovery.
abstract: 1. In the present study, we investigated the effect of age on atrial electrophysiological properties in Scn5a(+/-) hearts used to model corresponding increases in atrial arrhythmic tendency in human Brugada syndrome. 2. Atrial action potential initiation, propagation and recovery were compared in young (3 month old) and aged (12 month old), wild-type (WT) and Scn5a(+/-) hearts. Multielectrode array recordings assessed the spatial propagation of intrinsic electrical activity in superfused atrial preparations, whereas bipolar electrogram recordings measured basic cycle lengths (BCL) in Langendorff preparations. The duration of electrogram activity (EGD) during regular and extrasystolic stimulation with programmed electrical stimulation provided EGD ratios and atrial effective refractory periods (AERP). Monophasic recordings measured action potential durations (APD). 3. Systematic statistical explorations for independent and interacting effects of age and the Scn5a(+/-) condition demonstrated that both young and aged Scn5a(+/-) mice exhibited slowed propagation of atrial excitation relative to corresponding WT mice, with the greatest effects in aged Scn5a(+/-) mice, which additionally exhibited increased intrinsic BCL. 4. Young Scn5a(+/-) mice exhibited greater EGD and EGD ratios, as well as APD/AERP ratios, suggesting increased arrhythmic tendency compared with WT mice. 5. Aged Scn5a(+/-) mice exhibited normal EGD, EGD ratios and APD compared to aged WT and young Scn5a(+/-), and increased AERP and smaller APD/AERP ratios compared with young Scn5a(+/-). 6. These electrophysiological findings indicate increased atrial arrhythmogenicity with maximal effects on both conduction and repolarization characteristics in young compared with aged Scn5a(+/-) mice.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Laila
authors.initials: L
authors.lastname: Guzadhur
authors.forename: Wenhui
authors.initials: W
authors.lastname: Jiang
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Pearcey
authors.forename: Kamalan
authors.initials: K
authors.lastname: Jeevaratnam
authors.forename: Rudy M
authors.initials: RM
authors.lastname: Duehmke
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D053840:Brugada Syndrome / Q000235:genetics / Q000503:physiopathology*; D006321:Heart / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000502:physiology*; D009924:Organ Culture Techniques; D020127:Recovery of Function / Q000502:physiology*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse