Atrial arrhythmogenesis in wild-type and Scn5a+/delta murine hearts modelling LQT3 syndrome.
Long QT(3) (LQT3) syndrome is associated with abnormal repolarisation kinetics, prolonged action potential durations (APD) and QT intervals and may lead to life-threatening ventricular arrhythmias. However, there have been few physiological studies of its effects on atrial electrophysiology. Programmed electrical stimulation and burst pacing induced atrial arrhythmic episodes in 16 out of 16 (16/16) wild-type (WT) and 7/16 genetically modified Scn5a+/Delta (KPQ) Langendorff-perfused murine hearts modelling LQT3 (P < 0.001 for both), and in 14/16 WT and 1/16 KPQ hearts (P < 0.001 for both; Fisher's exact test), respectively. The arrhythmogenic WT hearts had significantly larger positive critical intervals (CI), given by the difference between atrial effective refractory periods (AERPs) and action potential durations at 90% recovery (APD(90)), compared to KPQ hearts (8.1 and 3.2 ms, respectively, P < 0.001). Flecainide prevented atrial arrhythmias in all arrhythmogenic WT (P < 0.001) and KPQ hearts (P < 0.05). It prolonged the AERP to a larger extent than it did the APD(90) in both WT and KPQ groups, giving negative CIs. Quinidine similarly exerted anti-arrhythmic effects, prolonged AERP over corresponding APD(90) in both WT and KPQ groups. These findings, thus, demonstrate, for the first time, inhibitory effects of the KPQ mutation on atrial arrhythmogenesis and its modification by flecainide and quinidine. They attribute these findings to differences in the CI between WT and mutant hearts, in the presence or absence of these drugs. Thus, prolongation of APD(90) over AERP gave positive CI values and increased atrial arrhythmogenicity whereas lengthening of AERP over APD(90) reduced such CI values and produced the opposite effect.
Dautova
Yana
Y
Cardiovascular Biology Group, Physiological Laboratory, University of Cambridge, Cambridge, UK.
Zhang
Yanmin
Y
Sabir
Ian
I
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005424:Flecainide / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011802:Quinidine / Q000008:administration & dosage*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome
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