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

Introduction: Impaired IKs 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 IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs 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) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs 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/dtmax 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 IKs 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 IKs inhibition with enhanced inotropy or ending the anesthetic regime

Remodeling in the AV block dog is essential for tolerating moderate treadmill activity

Background: A preclinical model standardized at different remodeling stages after AV block induction in awake state is suitable for the evaluation of improved cardiac devices. We studied exercise-induced cardiorespiratory parameters at three different timepoints after inducing AV block in dogs. Methods: Mongrel dogs (n = 12) were placed on a treadmill with a 10% incline and performed a moderate exercise protocol (10-minute run at 6 km/h). Dogs ran at sinus rhythm (SR), at two days (AVB2d, initiation of remodeling), three weeks (CAVB3) and six weeks (CAVB6, completed remodeling) after AV block. Results: All dogs completed the exercise protocol at SR, CAVB3 and CAVB6, while 6/12 dogs at AVB2d failed to complete the exercise protocol. The atrial rate was higher at all AV block timepoints (126 ± 20 to 141 ± 19 bpm at rest and 221 ± 10 to 231 ± 13 bpm during exercise) compared to SR (100 ± 29 bpm at rest and 162 ± 28 bpm during exercise, p < 0.05). Upon exercise, stroke volume increased from 66 ± 15 ml at SR, to 96 ± 21 ml at AVB2d (p < 0.05), 91 ± 13 ml at CAVB3 (p < 0.05) and 85 ± 24 ml at CAVB6 but failed to compensate for the AV block-induced bradycardia. Therefore, cardiac output was lower after AV block compared to SR. Exercising dogs at AVB2d showed most arrhythmic events, lowest VO2, and signs of desaturation and acidification in venous blood. Conclusion: Dogs with limited remodeling after AV block have a reduced exercise tolerance, which is reflected in changes in cardiorespiratory parameters