title: Atrial arrhythmogenic properties in wild-type and Scn5a+/- murine hearts.
abstract: Loss- and gain-of-function cardiac Na(+) channel (SCN5A) mutations are associated with the Brugada and long QT type 3 syndromes (LQT3), respectively. Both result in ventricular arrhythmias, but have differing atrial effects. We have recently reported decreased incidences of atrial arrhythmias in a murine Scn5a+/Delta cardiac system used to model LQT3. We now explore for atrial arrhythmias in a murine Brugada syndrome model. Programmed electrical stimulation and burst pacing were applied to 10 wild-type (WT) and 10 Scn5a+/- Langendorff-perfused murine hearts. These induced arrhythmias in similar proportions of the Scn5a+/- and WT hearts, in contrast to their decreased incidences previously reported for Scn5a+/Delta. Almost half of the Scn5a+/- hearts displayed spontaneous atrial arrhythmias never observed in WT. Both these WT and Scn5a+/- hearts showed positive critical intervals, given by the difference between action potential durations at 90% recovery (APD(90)) and atrial effective refractory periods, before pharmacological intervention. Both flecainide and quinidine then prevented both induced and spontaneous atrial arrhythmias in all the arrhythmic WT and Scn5a+/- hearts, in contrast to their differing ventricular effects. However, flecainide prolonged APD(90) in WT but not Scn5a+/-, whereas quinidine prolonged APD(90) in both WT and Scn5a+/-. Nevertheless, addition of both agents markedly increased atrial effective refractory periods to values exceeding the corresponding values of APD(90). This resulted in negative critical intervals in both WT and Scn5a+/-. These findings demonstrate a clear-cut relationship between critical interval and atrial arrhythmic tendency for the first time and extend previous reports that had related critical interval to ventricular arrhythmia.
authors.affiliation: Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Yana
authors.initials: Y
authors.lastname: Dautova
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
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 / Q000494:pharmacology; D016275:Atrial Function / Q000187:drug effects; D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D005424:Flecainide / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010477:Perfusion; D011802:Quinidine / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016276:Ventricular Function
chemical_list: D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D011802:Quinidine; D005424:Flecainide