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

From the Institut de Pharmacologie Moléculaire et Cellulaire (M.-D.D., I.A., C.C., M.L., G.R., J.B.), CNRS-UPR 411, Valbonne, France, and the Beckman Research Institute of the City of Hope (J.R.M.), Duarte, Calif.

Correspondence to Jacques Barhanin, Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. E-mail barhanin{at}unice.fr

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.

Key Words: long-QT syndrome • KCNE1 • MinK • electrocardiography • sex difference

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