Effect of Atrial Electrical Remodeling on the Efficacy of Antiarrhythmic Drugs: Comparison of Amiodarone with I Kr - and I to /IKur-Blockade In Vivo
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.
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.
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.
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Available from: Charles Antzelevitch
- "It is important to recognize that the atrial selectivity of I Na and I Kr blockers has been demonstrated largely in " healthy " atria and ventricles (Burashnikov et al., 2007; Burashnikov et al., 2008b; Spinelli et al., 1992; Wiesfeld et al., 1996; Baskin & Lynch, Jr., 1998; Wang et al., 1994). Changes associated with AF (electrical and structural remodeling) can significantly modify pharmacologic response of the atria to I Na and I Kr blockers (Duytschaever et al., 2005; Wettwer et al., 2004; Linz et al., 2007), thereby modulating the atrial selectivity of these agents and their ability to suppress AF, an effect well recognized with I Kur blockers (Wettwer et al., 2004). Triangulation of atrial action potential, typically observed in electrically remodeled atria, reduces the ability of I Kr blockers to prolong atrial APD. "
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