title: Reduced Na(+) and higher K(+) channel expression and function contribute to right ventricular origin of arrhythmias in Scn5a+/- mice.
abstract: Brugada syndrome (BrS) is associated with ventricular tachycardia originating particularly in the right ventricle (RV). We explore electrophysiological features predisposing to such arrhythmic tendency and their possible RV localization in a heterozygotic Scn5a+/- murine model. Na(v)1.5 mRNA and protein expression were lower in Scn5a+/- than wild-type (WT), with a further reduction in the RV compared with the left ventricle (LV). RVs showed higher expression levels of K(v)4.2, K(v)4.3 and KChIP2 in both Scn5a+/- and WT. Action potential upstroke velocity and maximum Na(+) current (I(Na)) density were correspondingly decreased in Scn5a+/-, with a further reduction in the RV. The voltage dependence of inactivation was shifted to more negative values in Scn5a+/-. These findings are predictive of a localized depolarization abnormality leading to slowed conduction. Persistent Na(+) current (I(pNa)) density was decreased in a similar pattern to I(Na). RV transient outward current (I(to)) density was greater than LV in both WT and Scn5a+/-, and had larger time constants of inactivation. These findings were also consistent with the observation that AP durations were smallest in the RV of Scn5a+/-, fulfilling predictions of an increased heterogeneity of repolarization as an additional possible electrophysiological mechanism for arrhythmogenesis in BrS.
authors: Physiological Laboratory, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK. clairemartin@gmail.com
authors: Claire A
authors: CA
authors: Martin
authors: Urszula
authors: U
authors: Siedlecka
authors: Kristin
authors: K
authors: Kemmerich
authors: Jason
authors: J
authors: Lawrence
authors: James
authors: J
authors: Cartledge
authors: Laila
authors: L
authors: Guzadhur
authors: Nicola
authors: N
authors: Brice
authors: Andrew A
authors: AA
authors: Grace
authors: Christof
authors: C
authors: Schwiening
authors: Cesare M
authors: CM
authors: Terracciano
authors: Christopher L-H
authors: CL
authors: Huang
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017136:Ion Transport / Q000235:genetics; D008564:Membrane Potentials; D051379:Mice; D008817:Mice, Mutant Strains; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D024642:Potassium Channels, Voltage-Gated; C568321:Scn5a protein, mouse