Cardioversion of persistent atrial fibrillation by a combination of atrial specific and non-specific class III drugs in the goat.
OBJECTIVE
In electrically remodeled atria the effect of blockers of the delayed rectifier K+ current I(Kr) on repolarization is reduced, whereas the efficacy of 'early' class III drugs (I(Kur)/I(to)/I(Kach) blockers) is enhanced. We evaluated the electrophysiological and antifibrillatory effects of AVE0118, dofetilide, and ibutilide (alone and in combination) on persistent atrial fibrillation (AF) in the goat.


RESULTS
The effects of separate and combined administration of AVE0118, dofetilide, and ibutilide were determined before and after 48 h of AF. AVE0118 alone markedly prolonged the atrial refractory period (400 ms cycle length) (AERP400) before and after 48 h of AF. The prolongation of AERP(400) by dofetilide and ibutilide, respectively, was reduced by AF from 22+/-2 to 7+/-2 ms (p<0.01) and 25+/-5 to 5+/-2 ms (p=0.01). Pre-treatment with AVE0118 restored the prolongation of AERP400 by dofetilide or ibutilide (to 20+/-3 and 30+/-6 ms; p<0.01). This effect was atrial specific since the QT-interval was not changed. The antifibrillatory action was evaluated in 10 goats that were in persistent AF for 57+/-7 days. Dofetilide (20 microg/kg/h) or ibutilide (4 mg/h) alone restored sinus rhythm in only 20% of the animals. AVE0118 (1, 3 and 10 mg/kg/h) [DOSAGE ERROR CORRECTED] terminated AF in 11, 30, and 60%, respectively. Additional infusion of I(Kr) blockers caused an additional number of cardioversions, resulting in a final cardioversion rate of 56, 80, and 100%, respectively. AVE0118 alone prolonged the AF cycle length (AFCL) while the conduction velocity during AF (CV(AF)) remained unchanged (70+/-1 vs. 68+/-2 cm/s; p=0.3). Addition of dofetilide or ibutilide caused a synergistic increase in AFCL and a slight increase in CV(AF) to 74+/-1 cm/s (p<0.001). The length of the reentrant trajectories increased from 7.6+/-0.3 (control) to 11.6+/-0.5 cm after AVE0118 alone (p<0.001) and 14.8+/-0.8 cm after addition of dofetilide or ibutilide (p<0.001).


CONCLUSIONS
In electrically remodeled atria, blockade of I(Kur)/I(to)/I(KAch) restored the class III action of I(Kr) blockers. Persistent AF could be effectively cardioverted by infusion of a combination of AVE0118 and dofetilide or ibutilide. This antifibrillatory action was associated with an almost twofold lengthening of the intra-atrial pathways for reentry.
Blaauw
Y
Y
Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
Schotten
U
U
van Hunnik
A
A
Neuberger
H R
HR
Allessie
M A
MA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000628:therapy*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004554:Electric Countershock; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006041:Goats; D010627:Phenethylamines / Q000627:therapeutic use; D013449:Sulfonamides / Q000627:therapeutic use
C501729:AVE 0118; D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D010627:Phenethylamines; D013449:Sulfonamides; C067192:ibutilide; C063533:dofetilide