Atrial fibrillation in KCNE1-null mice.
Although atrial fibrillation is the most common serious cardiac arrhythmia, the fundamental molecular pathways remain undefined. Mutations in KCNQ1, one component of a sympathetically activated cardiac potassium channel complex, cause familial atrial fibrillation, although the mechanisms in vivo are unknown. We show here that mice with deletion of the KCNQ1 protein partner KCNE1 have spontaneous episodes of atrial fibrillation despite normal atrial size and structure. Isoproterenol abolishes these abnormalities, but vagomimetic interventions have no effect. Whereas loss of KCNE1 function prolongs ventricular action potentials in humans, KCNE1-/- mice displayed unexpectedly shortened atrial action potentials, and multiple potential mechanisms were identified: (1) K+ currents (total and those sensitive to the KCNQ1 blocker chromanol 293B) were significantly increased in atrial cells from KCNE1-/- mice compared with controls, and (2) when CHO cells expressing KCNQ1 and KCNE1 were pulsed very rapidly (at rates comparable to the normal mouse heart and to human atrial fibrillation), the sigmoidicity of IKs activation prevented current accumulation, whereas cells expressing KCNQ1 alone displayed marked current accumulation at these very rapid rates. Thus, KCNE1 deletion in mice unexpectedly leads to increased outward current in atrial myocytes, shortens atrial action potentials, and enhances susceptibility to atrial fibrillation.
Temple
Joel
J
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn 37232-6602, USA.
Frias
Patricio
P
Rottman
Jeffrey
J
Yang
Tao
T
Wu
Yuejin
Y
Verheijck
E Etienne
EE
Zhang
Wei
W
Siprachanh
Chanthaphaychith
C
Kanki
Hideaki
H
Atkinson
James B
JB
King
Paul
P
Anderson
Mark E
ME
Kupershmidt
Sabina
S
Roden
Dan M
DM
D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000503:physiopathology; D004198:Disease Susceptibility; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000502:physiology*
C092068:Kcne1 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D007545:Isoproterenol