title: Criteria for arrhythmogenicity in genetically-modified Langendorff-perfused murine hearts modelling the congenital long QT syndrome type 3 and the Brugada syndrome.
abstract: The experiments investigated the applicability of two established criteria for arrhythmogenicity in Scn5a+/Delta and Scn5a+/- murine hearts modelling the congenital long QT syndrome type 3 (LQT3) and the Brugada syndrome (BrS). Monophasic action potentials (APs) recorded during extrasystolic stimulation procedures from Langendorff-perfused control hearts and hearts treated with flecainide (1 microM) or quinidine (1 or 10 microM) demonstrated that both agents were pro-arrhythmic in wild-type (WT) hearts, quinidine was pro-arrhythmic in Scn5a+/Delta hearts, and that flecainide was pro-arrhythmic whereas quinidine was anti-arrhythmic in Scn5a+/- hearts, confirming clinical findings. Statistical analysis confirmed a quadratic relationship between epicardial and endocardial AP durations (APDs) in WT control hearts. However, comparisons between plots of epicardial against endocardial APDs and this reference curve failed to correlate with arrhythmogenicity. Restitution curves, relating APD to diastolic interval (DI), were then constructed for the first time in a murine system and mono-exponential growth functions fitted to these curves. Significant (P<0.05) alterations in the DI at which slopes equalled unity, an established indicator of arrhythmogenicity, now successfully predicted the presence or absence of arrhythmogenicity in all cases. We thus associate changes in the slopes of restitution curves with arrhythmogenicity in models of LQT3 and BrS.
authors.affiliation: Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Sabir
authors.forename: Lucia M
authors.initials: LM
authors.lastname: Li
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Jones
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Goddard
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Grace
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D053840:Brugada Syndrome / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004562:Electrocardiography; D004699:Endocardium / Q000187:drug effects / Q000503:physiopathology; D005424:Flecainide / Q000633:toxicity*; D006339:Heart Rate / Q000187:drug effects*; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008955:Models, Cardiovascular; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010477:Perfusion; D010496:Pericardium / Q000187:drug effects / Q000503:physiopathology; D011802:Quinidine / Q000633:toxicity*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors