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

Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model

Introduction: Torsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP. Methods: Dofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline. Results: IVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both p < 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms (p < 0.05 vs. high and middle rate). Conclusion: In CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization