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

Milou Daniel Drici, Isabelle Arrighi, Christophe Chouabe, Jeffrey R. Mann, Michel Lazdunski, Georges Romey, Jacques Barhanin

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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 (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).

Original languageEnglish
Pages (from-to)95-102
Number of pages8
JournalCirculation Research
Issue number1
Publication statusPublished - 13 Jul 1998
Externally publishedYes


  • Electrocardiography
  • KCNE1
  • Long-QT syndrome
  • MinK
  • Sex difference

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