Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/- murine hearts modelling the Brugada syndrome.
Brugada syndrome (BrS) is associated with a loss of Na+ channel function and an increased incidence of rapid polymorphic ventricular tachycardia (VT) and sudden cardiac death. A programmed electrical stimulation (PES) technique assessed arrhythmic tendency in Langendorff-perfused wild-type (WT) and genetically modified (Scn5a+/-) 'loss-of-function' murine hearts in the presence and absence of flecainide and quinidine, and the extent to which Scn5a+/- hearts model the human BrS. Extra-stimuli (S2), applied to the right ventricular epicardium, followed trains of pacing stimuli (S1) at progressively reduced S1-S2 intervals. These triggered VT in 16 out of 29 untreated Scn5a+/- and zero out of 31 WT hearts. VT occurred in 11 out of 16 (10 microM) flecainide-treated WT and nine out of the 13 initially non-arrhythmogenic Scn5a+/- hearts treated with (1.0 microM) flecainide. Quinidine (10 microM) prevented VT in six out of six flecainide-treated WT and 13 out of the 16 arrhythmogenic Scn5a+/- hearts in parallel with its clinical effects. Paced electrogram fractionation analysis demonstrated increased electrogram durations, expressed as electrogram duration (EGD) ratios, with shortening S1-S2 intervals in arrhythmogenic Scn5a+/- hearts, and prolonged ventricular effective refractory periods (VERPs) in non-arrhythmogenic Scn5a+/- hearts. Flecainide increased EGD ratios in WT (at 10 microM) and non-arrhythmogenic Scn5a+/- hearts (at 1.0 microM), whereas quinidine (10 microM) reduced EGD ratios and prolonged VERPs in WT and arrhythmogenic Scn5a+/- hearts. However, epicardial and endocardial monophasic action potential recordings consistently demonstrated positive gradients of repolarization in WT, arrhythmogenic and non-arrhythmogenic Scn5a+/- hearts under all pharmacological conditions. Together, these findings demonstrate proarrhythmic effects of flecainide in WT and Scn5a+/- murine hearts that recapitulate its clinical effects. They further attribute the arrhythmogenic phenomena observed here to re-entrant substrates resulting from delayed epicardial activation despite an absence of transmural heterogeneities of repolarization, in sharp contrast to recent characterizations in 'gain-of-function' Scn5a+/Delta murine hearts modelling the long-QT(3) syndrome.
Stokoe
Kate S
KS
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Balasubramaniam
Richard
R
Goddard
Catharine A
CA
Colledge
William H
WH
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D053840:Brugada Syndrome / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004594:Electrophysiology; D005260:Female; D005424:Flecainide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011802:Quinidine / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*
D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D011802:Quinidine; D005424:Flecainide