Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1.
Mutations in KCNE1, the gene encoding the beta subunit of the slowly activating delayed rectifier potassium current (IKs) channel protein, may lead to the long QT syndrome (LQTS), a condition associated with enhanced arrhythmogenesis. Mice with homozygous deletion of the coding sequence of KCNE1 have inner ear defects strikingly similar to those seen in the corresponding human condition. The present study demonstrated and assessed the mechanism of ventricular arrhythmias in Langendorff-perfused whole heart preparations from homozygous KCNE1-/- mice compared to wild-type mice of the same age. The effects of programmed electrical stimulation with decremental pacing from the basal right ventricular epicardial surface upon electrogram waveforms recorded from the basal left ventricle were assessed and quantified using techniques of paced electrogram fractionation analysis for the first time in an experimental system. All KCNE1-/-(n = 10) but not wild-type (n = 14) mouse hearts empirically demonstrated marked pacing-induced ventricular arrhythmogenicity. This correlated with significant increases in electrogram dispersion, consistent with a wider spread in conduction velocities, in parallel with clinical findings from LQTS patients with potassium channel mutations. In contrast, introduction of 100 nM isoprenaline induced arrhythmogenicity in both KCNE1-/- (n = 7) and wild-type (n = 6) hearts during pacing. Furthermore, pretreatment with 1 muM nifedipine exerted a strong anti-arrhythmic effect in the KCNE1-/- hearts (n = 12) that persisted even in the presence of 100 nM isoprenaline (n = 6). Our findings associate KCNE1-/- with an arrhythmogenic phenotype that shows an increased dispersion of conduction velocities, and whose initiation is prevented by nifedipine, a finding that in turn may have therapeutic applications in conditions such as LQTS.
Balasubramaniam
Richard
R
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. rnb25@cam.ac.uk
Grace
Andrew A
AA
Saumarez
Richard C
RC
Vandenberg
Jamie I
JI
Huang
Christopher L-H
CL
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D004558:Electric Stimulation; D004562:Electrocardiography; D004567:Electrodes, Implanted; D004594:Electrophysiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009543:Nifedipine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated
D000318:Adrenergic beta-Agonists; D002121:Calcium Channel Blockers; C092068:Kcne1 protein, mouse; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D009543:Nifedipine; D007545:Isoproterenol