Azimilide decreases defibrillation voltage requirements and increases spatial organization during ventricular fibrillation.
BACKGROUND
Drugs with class III antiarrhythmic properties generally decrease defibrillation threshold (DFT). However, the concentration effect relation for this effect and drug effects on ventricular fibrillation (VF) itself are not well understood. The objectives of this study were to determine the effect of azimilide (NE-10064), a new class III agent, on DFT, and on spatial organization during VF.


METHODS
Defibrillation patch electrodes were sutured to the right and left ventricular epicardium in 12 open-chest anesthetized dogs. The delayed up-down algorithm was used to measure DFT and to estimate the shock strength (voltage) with a 50% probability of successful defibrillation (V50). The magnitude squared coherence (MSC), which measures the spatial relation in the frequency domain, was measured during VF between two unipolar epicardial electrodes 3 mm apart. The V50, MSC, electrophysiologic parameters, and plasma concentrations were determined before and after four cumulative i.v. doses of azimilide (2, 7, 17, and 30 mg/kg).


RESULTS
Azimilide elicited a dose dependent reduction of V50 and increase in MSC. Compared with baseline, azimilide lowered mean V50 by 2 +/- 9%, 10 +/- 18%, 11 +/- 14% and 19 +/- 5%, and increased MSC by 17 +/- 20%, 32 +/- 31%, 20 +/- 44% and 27 +/- 20% (p < 0.05 for dose effect) at 2, 7, 17 and 30 mg/kg, respectively. Mean increases in monophasic action potential duration at 90% repolarization (3-11%), ventricular effective refractory period (6-13%) at 400 msec paced cycle length, and VF cycle length (5-37%) (p < 0.01 for dose effect) were observed with the 4 increasing doses of azimilide, respectively.


CONCLUSIONS
Azimilide significantly decreases DFT and increases coherence in VF in a dose dependent manner.
Qi
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Department of Medicine, St. Michael's Hospital and University of Toronto.
Newman
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Dorian
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D000465:Algorithms; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004554:Electric Countershock; D004567:Electrodes, Implanted; D004594:Electrophysiology / Q000379:methods; D005260:Female; D006339:Heart Rate; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D007275:Injections, Intravenous; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000097:blood / Q000503:physiopathology / Q000628:therapy*
D000889:Anti-Arrhythmia Agents; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; C086123:azimilide