Involvement of IsK-Associated K + Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome

Abstract

Abstract —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 .