vernakalant and Long-QT-Syndrome

In this review we discuss mechanisms of antiarrhythmic and adverse proarrhythmic action of class III drugs. Special attention is given to ionic currents and channels which determine specific features of their effects (IKr, IKa, IKur). We consider general patterns of changes of bioelectrical activity in atria and ventricles leading to development of arrhythmias or stabilization of rhythm. We also discuss value of QT interval as predictor of torsade de pointes. Perspectives and limitations of development of novel class III antiarrhythmic drugs are discussed as well. We present consideration of efficacy and mechanisms of action of such compounds as dronedarone and vernacalant suggested for termination of atrial fibrillation and maintenance of sinus rhythm. Special attention is given to RG 2 - a novel compound with class III activity.

Topics: Amiodarone; Animals; Anisoles; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Dronedarone; Electric Impedance; Electrocardiography; Heart Atria; Heart Rate; Heart Ventricles; Humans; Ion Channels; Long QT Syndrome; Mutation; Myocytes, Cardiac; Pyrrolidines; Rabbits; Rats

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).. 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.. 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.

Topics: Animals; Anisoles; Anti-Arrhythmia Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Conduction System; In Vitro Techniques; Long QT Syndrome; Pyrrolidines; Rabbits; Tachycardia, Ventricular; Treatment Outcome