Effect of atrial electrical remodeling on the efficacy of antiarrhythmic drugs: Comparison of amiodarone with I-Kr- and I-to/IKur-blockade in vivo
ABSTRACT 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.
- SourceAvailable from: Charles Antzelevitch
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- "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. "
ABSTRACT: Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due to the use of catheter ablation techniques), anti-arrhythmic agents (AADs) remain first line therapy for rhythm control management of AF for most AF patients. When considering efficacy, safety and tolerability, currently available AADs for rhythm control of AF are less than optimal. Ion channel inhibition remains the principal strategy for termination of AF and prevention of its recurrence. Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for rhythm control of AF compared to ion channel-selective blockers. Recent studies suggest that atrial-selective sodium channel block can lead to safe and effective suppression of AF and that concurrent inhibition of potassium ion channels may potentiate this effect. An important limitation of the ion channel block approach for AF treatment is that non-electrical factors (largely structural remodeling) may importantly determine the generation of AF, so that "upstream therapy", aimed at preventing or reversing structural remodeling, may be required for effective rhythm control management. This review focuses on novel pharmacological targets for the rhythm control management of AF.Pharmacology [?] Therapeutics 08/2011; 132(3):300-13. DOI:10.1016/j.pharmthera.2011.08.002 · 7.75 Impact Factor
Conference Paper: Coordination of networked multi-vehicle systems[Show abstract] [Hide abstract]
ABSTRACT: In this paper we present a predictive control strategy for the supervision of networked multi-vehicle systems subject to coordination constraints. Such a constrained dynamic network paradigm is characterized by a set of spatially distributed dynamic systems, connected via communication channels and with possibly dynamic coupling amongst them, which need to be controlled and coordinated in order to accomplish their overall objective. The significance of the method is that it is capable of ensuring no constraints violation and loss of stability regardless of any, possibly unbounded, time-delay occurrence. The method can be specialized to deal more efficiently either with random round-trip time-delays, such as the case over the Internet, or constant/bounded time-delays, typically encountered in space and underwater applications. An application to the coordination of two autonomous vehicles under input-saturation and formation accuracy constraints is presented.Intelligent Vehicle Symposium, 2002. IEEE; 07/2002