Arrhythmogenic substrate and its modification by nicorandil in a murine model of long QT type 3 syndrome.
The gain-of-function Scn5a+/DeltaKPQ mutation in the cardiac Na(+) channel causes human long QT type 3 syndrome (LQT3) associated with ventricular arrhythmogenesis. The K(ATP) channel-opener nicorandil (20muM) significantly reduced arrhythmic incidence in Langendorff-perfused Scn5a+/Delta hearts during programmed electrical stimulation; wild-types (WTs) showed a total absence of arrhythmogenicity. These observations precisely correlated with alterations in recently established criteria for re-entrant excitation reflected in: (1) shortened left-ventricular epicardial but not endocardial monophasic action potential durations at 90% repolarization (APD(90)) that (2) restored transmural repolarization gradients, DeltaAPD(90). Scn5a+/Delta hearts showed longer epicardial but not endocardial APD(90)s, giving shorter DeltaAPD(90)s than WT hearts. Nicorandil reduced epicardial APD(90) in both Scn5a+/Delta and WT hearts thereby increasing DeltaAPD(90). (3) Reduced epicardial critical intervals for re-excitation; Scn5a+/Delta hearts showed greater differences between APD(90) and ventricular effective refractory period than WT hearts that were reduced by nicorandil. (4) Reduced APD(90) alternans. Scn5a+/Delta hearts showed greater epicardial and endocardial alternans than WTs, which increased with pacing rate. Nicorandil reduced these in Scn5a+/Delta hearts to levels indistinguishable from untreated WTs. (5) Flattened restitution curves. Scn5a+/Delta hearts showed larger epicardial and endocardial critical diastolic intervals than WT hearts. Nicorandil decreased these in Scn5a+/Delta and WT hearts. The presence or absence of arrhythmogenesis in Scn5a+/Delta and WT hearts thus agreed with previously established criteria for re-entrant excitation, and alterations in these precisely correlated with the corresponding antiarrhythmic effects of nicorandil. Together these findings implicate spatial and temporal re-entrant mechanisms in arrhythmogenesis in LQT3 and their reversal by nicorandil.
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK. ssh26@cam.ac.uk
Sandeep S
SS
Hothi
Stephen W
SW
Booth
Ian N
IN
Sabir
Matthew J
MJ
Killeen
Fergus
F
Simpson
Yanmin
Y
Zhang
Andrew A
AA
Grace
Christopher L-H
CL
Huang
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020108:Nicorandil / Q000627:therapeutic use*; D010477:Perfusion; 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; D020108:Nicorandil