Effect of atrial electrical remodeling on the efficacy of antiarrhythmic drugs: comparison of amiodarone with I(Kr)- and I(to)/IKur-blockade in vivo.
BACKGROUND
Amiodarone is the gold standard in the prevention of recurrence of atrial fibrillation (AF), but the causes for its superior clinical efficacy are not understood. We hypothesized that atrial electrical remodeling increases the atrial efficacy of amiodarone.


RESULTS
We investigated the effect of an acute intravenous dose of amiodarone on atrial refractory periods (AERP) in sinus rhythm (SR) and after 5, 24, and 72 hours of atrial tachypacing in comparison with the I(Kr) blocker dofetilide and the I(to)/IKur blockers AVE1231 and AVE0118 in five instrumented goats. Electrical remodeling progressively increased the AERP-prolonging effect of 3 mg/kg of AVE1231 and AVE0118 (2-fold increase in AERP at 72 hours vs SR, P < 0.01), but strongly decreased that of 10 mug/kg dofetilide (<0.5-fold, P < 0.05, at 300 and 400 ms basic cycle length). After 5 and 24 hours of tachypacing, the effect of 3 mg/kg amiodarone strongly increased (2-fold, P < 0.01 after 24 hours vs SR). This early gain in AERP prolongation was confirmed in anesthetized pigs with 3.5 hours of atrial tachypacing (2.4-fold increase, P < 0.01). At 72 hours of atrial tachypacing in the goat, however, the early gain was lost and the effect of amiodarone was similar again to that in SR.


CONCLUSIONS
Atrial electrical remodeling changed the efficacy of the antiarrhythmic agents in a different way. The favorable efficacy profile of amiodarone during electrical remodeling, particularly the marked increase in AERP prolongation in early electrical remodeling, may explain its superior clinical efficacy over existing antiarrhythmic drugs.
Linz
Dominik K
DK
Sanofi-Aventis Deutschland GmbH, Frankfurt, Germany.
Afkham
Freni
F
Itter
Gabi
G
Rütten
Hartmut
H
Wirth
Klaus J
KJ
D000638:Amiodarone / Q000008:administration & dosage*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage*; D016275:Atrial Function / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006041:Goats; D006329:Heart Conduction System / Q000187:drug effects / Q000502:physiology*; D007275:Injections, Intravenous; D008297:Male; D010627:Phenethylamines / Q000008:administration & dosage*; D026902:Potassium Channel Blockers / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D013552:Swine
C501729:AVE 0118; D000889:Anti-Arrhythmia Agents; D001713:Biphenyl Compounds; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; D000638:Amiodarone; C063533:dofetilide