Paced electrogram fractionation analysis of arrhythmogenic tendency in DeltaKPQ Scn5a mice.
BACKGROUND
Gain-of-function mutations within Scn5a, including the DeltaKPQ 1505-1507 deletion in the inactivation domain compromising myocardial repolarization, are implicated in human long QT 3 syndrome (LQT3), associated with ventricular arrhythmogenesis and sudden death.


RESULTS
Patch clamp studies on isolated ventricular Scn5a+/Delta myocytes from DeltaKPQ mice produced by homologous recombination in embryonic stem (ES) cells confirmed such altered electrophysiological properties of the mutant channel. Programmed electrical stimulation (PES) with decremental pacing from the basal right ventricular epicardial surface and paced electrogram fractionation analysis (PEFA) of electrograms recorded from the basal left ventricular epicardial surface of Langendorff-perfused whole heart preparations demonstrated ventricular tachycardia (VT) in 8 of 9 Scn5a+/Delta mutant (but no Scn5a+/+ (wild-type (WT)) controls; n = 17), with increased electrogram durations (EGD) and more dispersed conduction curves. Isoproterenol (100 nM) was without effect on tachycardic Scn5a+/Delta hearts (n = 9) yet propranolol (1 microM) prevented VT in all isoproterenol-infused WT control (n = 4) but no Scn5a+/Delta hearts (n = 4). Furthermore propranolol itself increased EGD and dispersion in Scn5a+/Delta hearts. In contrast, mexiletine (10 microM) suppressed VTs in 4 of 5 Scn5a+/Delta hearts without altering EGD or dispersion.


CONCLUSIONS
Beta-adrenoreceptor blockade does not confer an antiarrhythmic effect and may even enhance arrhythmogenesis by increasing reentrant substrate in Scn5a+/Delta hearts while mexiletine protects against VT without modifying conduction characteristics. Together these findings permit a scheme where VT in LQT3 is initiated by triggered mechanisms but propagated by reentry.
Head
Catherine E
CE
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, UK.
Balasubramaniam
Richard
R
Thomas
Glyn
G
Goddard
Catharine A
CA
Lei
Ming
M
Colledge
William H
WH
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004558:Electric Stimulation; D017353:Gene Deletion; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics*; D008801:Mexiletine / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015222:Sodium Channels / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000517:prevention & control
D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D008801:Mexiletine