Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome.

AIMS: The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). METHODS AND RESULTS: Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0.5 µM, n = 14) after obtaining baseline data. Thereafter, vernakalant (10 µM) was additionally infused. Infusion of erythromycin or veratridine significantly increased action potential duration (APD90) and QT interval. Erythromycin and veratridine also significantly augmented spatial dispersion of repolarization (erythromycin: +43 ms; veratridine: +55 ms, P < 0.01, respectively) and temporal dispersion of repolarization. After lowering extracellular [K+] in bradycardic hearts, 11 of 15 erythromycin-treated hearts and 4 of 14 veratridine-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with vernakalant resulted in a significant reduction of spatial dispersion of spatial dispersion in both groups (erythromycin: -32 ms; veratridine: -35 ms, P < 0.05 each) and a stabilization of temporal dispersion. After additional treatment with vernakalant, only 5 of 15 erythromycin-treated hearts (P = 0.07) and 1 of 14 veratridine-treated hearts (P = 0.32) presented polymorphic VT. CONCLUSION: Vernakalant has antiarrhythmic effects in this experimental model of acquired LQTS. A reduction of spatial dispersion of repolarization and a stabilization of temporal dispersion in hearts showing polymorphic VT represent the major underlying electrophysiological mechanisms.

Electrophysiological profile of vernakalant in an experimental whole-heart model: the absence of proarrhythmia despite significant effect on myocardial repolarization.

AIM: The most recent European Society of Cardiology (ESC) update on atrial fibrillation has introduced vernakalant (VER) for pharmacological cardioversion of atrial fibrillation. The aim of the present study was to investigate the safety profile of VER in a sensitive model of proarrhythmia. METHODS AND RESULTS: In 36 Langendorff-perfused rabbit hearts, VER (10, 30 µM, n = 12); ranolazine (RAN, 10, 30 µM, n = 12), or sotalol (SOT, 50; 100 µM, n = 12) were infused after obtaining baseline data. Monophasic action potentials and a 12-lead electrocardiogram showed a significant QT prolongation after application of VER as compared with baseline (10 µM: +25 ms, 30 µM: +50 ms, P < 0.05) accompanied by an increase of action potential duration (APD). The increase in APD90 was accompanied by a more marked increase in effective refractory period (ERP) leading to a significant increase in post-repolarization refractoriness (PRR, 10 µM: +30 ms, 30 µM: +36 ms, P < 0.05). Vernakalant did not affect the dispersion of repolarization. Lowered potassium concentration in bradycardic hearts did not provoke early afterdepolarizations (EADs) or polymorphic ventricular tachycardia (pVT). Comparable results were obtained with RAN. Hundred micromolars of SOT led to an increase in QT interval (+49 ms) and APD90 combined with an increased ERP and PRR (+23 ms). In contrast to VER, 100 µM SOT led to a significant increase in dispersion of repolarization and to the occurrence of EAD in 10 of 12 and pVT in 8 of 12 hearts. CONCLUSION: In the present study, application of VER and SOT led to a comparable prolongation of myocardial repolarization. Both drugs increased the PRR. However, VER neither affect the dispersion of repolarization nor induce EAD and therefore did not cause proarrhythmia.

Further insights into the underlying electrophysiological mechanisms for reduction of atrial fibrillation by ranolazine in an experimental model of chronic heart failure.

AIMS: Ranolazine (RAN) was reported to be effective and safe in converting atrial fibrillation (AF) to sinus rhythm by administration of a single dose ('pill in the pocket') to patients with structural heart disease. This study examines the underlying mechanisms for the antiarrhythmic benefit of RAN application in chronic heart failure (CHF). METHODS AND RESULTS: In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1 µM) and isoproterenol (1 µM) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of RAN (10 µM) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. RAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, RAN application moderately increased interatrial conduction time. CONCLUSION: RAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to development of atrial post-repolarization refractoriness and a moderate increase in conduction time. The described electrophysiological mechanisms remain preserved in the setting of CHF.