title: Arrhythmic substrate, slowed propagation and increased dispersion in conduction direction in the right ventricular outflow tract of murine Scn5a+/- hearts.
abstract: OBJECTIVE
  To test a hypothesis attributing arrhythmia in Brugada Syndrome to right ventricular (RV) outflow tract (RVOT) conduction abnormalities arising from Nav 1.5 insufficiency and fibrotic change.
  
  
  METHODS
  Arrhythmic properties of Langendorff-perfused Scn5a+/- and wild-type mouse hearts were correlated with ventricular effective refractory periods (VERPs), multi-electrode array (MEA) measurements of action potential (AP) conduction velocities and dispersions in conduction direction (CD), Nav 1.5 expression levels, and fibrotic change, as measured at the RVOT and RV. Two-way anova was used to test for both independent and interacting effects of anatomical region and genotype on these parameters.
  
  
  RESULTS
  Scn5a+/- hearts showed greater arrhythmic frequencies during programmed electrical stimulation at the RVOT but not the RV. The Scn5a+/- genotype caused an independent increase of VERP regardless of whether the recording site was the RVOT or RV. Effective AP conduction velocities (CV†s), derived from fitting regression planes to arrays of observed local activation times were reduced in Scn5a+/- hearts and at the RVOT independently. AP conduction velocity magnitudes derived by averaging MEA results from local vector analyses, CV*, were reduced by the Scn5a+/- genotype alone. In contrast, dispersions in conduction direction, were greater in the RVOT than the RV, when the atrioventricular node was used as the pacing site. The observed reductions in Nav 1.5 expression were attributable to Scn5a+/-, whereas increased levels of fibrosis were associated with the RVOT.
  
  
  CONCLUSIONS
  The Scn5a+/- RVOT recapitulates clinical findings of increased arrhythmogenicity through reduced CV† reflecting reduced CV* attributable to reduced Nav 1.5 expression and increased CD attributable to fibrosis.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK; Heart Centre, Northwest Women's and Children's Hospital, Xi'an, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Guzadhur
authors.forename: K
authors.initials: K
authors.lastname: Jeevaratnam
authors.forename: S C
authors.initials: SC
authors.lastname: Salvage
authors.forename: G D K
authors.initials: GD
authors.lastname: Matthews
authors.forename: W J
authors.initials: WJ
authors.lastname: Lammers
authors.forename: M
authors.initials: M
authors.lastname: Lei
authors.forename: C L-H
authors.initials: CL
authors.lastname: Huang
authors.forename: J A
authors.initials: JA
authors.lastname: Fraser
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D015153:Blotting, Western; D053840:Brugada Syndrome / Q000503:physiopathology*; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006329:Heart Conduction System / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D009924:Organ Culture Techniques
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse
keywords: Brugada Syndrome; Na+ channel; conduction velocity; right ventricular outflow tract