Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome

被引:105
作者
Drici, MD
Arrighi, I
Chouabe, C
Mann, JR
Lazdunski, M
Romey, G
Barhanin, J
机构
[1] CNRS, UPR 411, Inst Pharmacol Mol & Cellulaire, F-06560 Valbonne, France
[2] Beckman Res Inst City Hope, Duarte, CA USA
关键词
long-QT syndrome; KCNE1; MinK electrocardiography; sex difference;
D O I
10.1161/01.RES.83.1.95
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 EGG. 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 (I-Ks), 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 I-Ks, 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 I-Ks.
引用
收藏
页码:95 / 102
页数:8
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