IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog

Abstract

Introduction: Impaired I_Ks induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and I_Kr inhibitor dofetilide. We tested the proarrhythmic effect of I_Ks inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein.

Methods: Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) I_Ks inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) I_Ks inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10).

Results: JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P < 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dt_max from 1725 ± 273 to 4147 ± 611 mmHg/s, P < 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P < 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2.

Conclusion: Mimicking LQT1 using I_Ks inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. Induction of the more severe arrhythmic events (TdP) demands a combination of I_Ks inhibition with enhanced inotropy or ending the anesthetic regime.

Keywords: CAVB Dog model; Contractility; I(Ks); JNJ303; QT interval; Ventricular arrhythmia.