Document Detail


Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/- murine hearts modelling the Brugada syndrome.
MedLine Citation:
PMID:  17303635     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Kate S Stokoe; Richard Balasubramaniam; Catharine A Goddard; William H Colledge; Andrew A Grace; Christopher L-H Huang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-02-15
Journal Detail:
Title:  The Journal of physiology     Volume:  581     ISSN:  0022-3751     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2007 May 
Date Detail:
Created Date:  2007-05-15     Completed Date:  2007-07-23     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  255-75     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Action Potentials / drug effects,  physiology
Animals
Anti-Arrhythmia Agents / pharmacology*
Brugada Syndrome / genetics,  physiopathology*
Disease Models, Animal
Electric Stimulation
Electrophysiology
Female
Flecainide / pharmacology*
Gene Expression Regulation / drug effects
Heart / physiology*
Male
Mice
Mice, Inbred Strains
NAV1.5 Voltage-Gated Sodium Channel
Quinidine / pharmacology*
Sodium Channels / genetics,  physiology*
Grant Support
ID/Acronym/Agency:
G0100186//Medical Research Council; G0100188//Medical Research Council; //Wellcome Trust
Chemical
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/NAV1.5 Voltage-Gated Sodium Channel; 0/SCN5A protein, human; 0/Scn5a protein, mouse; 0/Sodium Channels; ITX08688JL/Quinidine; K94FTS1806/Flecainide
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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