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


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.


CONCLUSIONS
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.
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany gerrit.frommeyer@ukmuenster.de.
Gerrit
G
Frommeyer
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Peter
P
Milberg
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Catharina
C
Clauss
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Marco
M
Schmidt
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Shahram
S
Ramtin
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Sven
S
Kaese
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Fabian
F
Grundmann
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Jochen Schulze
JS
Grotthoff
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Christian
C
Pott
Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, 48149 Münster, Germany.
Lars
L
Eckardt
D000083:Acetanilides / Q000633:toxicity; D000200:Action Potentials; D000818:Animals; D000840:Anisoles / Q000633:toxicity*; D000889:Anti-Arrhythmia Agents / Q000633:toxicity*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D022062:Electrophysiologic Techniques, Cardiac; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D023421:Models, Animal; D010477:Perfusion; D010879:Piperazines / Q000633:toxicity; D026902:Potassium Channel Blockers / Q000633:toxicity; D011759:Pyrrolidines / Q000633:toxicity*; D011817:Rabbits; D000069458:Ranolazine; D018570:Risk Assessment; D012307:Risk Factors; D026941:Sodium Channel Blockers / Q000633:toxicity; D013015:Sotalol / Q000633:toxicity; D013997:Time Factors
D000083:Acetanilides; D000840:Anisoles; D000889:Anti-Arrhythmia Agents; D010879:Piperazines; D026902:Potassium Channel Blockers; D011759:Pyrrolidines; D026941:Sodium Channel Blockers; C524581:vernakalant; D013015:Sotalol; D000069458:Ranolazine
Dispersion of repolarization; Polymorphic ventricular tachycardia; Proarrhythmia; Ranolazine; Sotalol; Vernakalant