Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome.
The Jervell and Lange-Nielsen (JLN) syndrome affects the human cardioauditory system, associating a profound bilateral deafness with an abnormally long QT interval on the ECG. It results from mutations in KVLQT1 and ISK genes that encode the 2 subunits forming the K+ channel responsible for the cardiac and inner ear slowly activating component of the delayed rectifier K+ current (IKs). A JLN mouse model that presents typical inner ear defects has been created by knocking out the isk gene (isk-/-). This study specifically reports on the cardiac phenotype counterpart, determined in the whole animal and at mRNAs and cellular levels. Surface ECG recordings of isk-/- mice showed a longer QT interval at slow heart rates, a paradoxical shorter QT interval at fast heart rates, and an overall exacerbated QT-heart rate adaptation compared with wild-type (WT) mice. A 300-ms increase in the heart rate cycle length induces a 309+/-21% increase in the QT duration of the WT mice versus a 500+/-50% in isk-/- mice (P<0.001). It is concluded that the isk gene product and/or IKs, when present, blunts the QT adaptation to heart rate variations and that steeper QT-RR relationships reflect a greater susceptibility to arrhythmias in patients lacking IKs.
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411, Valbonne, France.
M D
MD
Drici
I
I
Arrighi
C
C
Chouabe
J R
JR
Mann
M
M
Lazdunski
G
G
Romey
J
J
Barhanin
D000375:Aging / Q000502:physiology; D000818:Animals; D015152:Blotting, Northern; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004553:Electric Conductivity; D004562:Electrocardiography; D004594:Electrophysiology; D005260:Female; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008133:Long QT Syndrome / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012727:Sex Characteristics
D002316:Cardiotonic Agents; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D007545:Isoproterenol