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.
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ABSTRACT: Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.Current drug safety. 01/2010; 5(1):65-72.
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ABSTRACT: Atrial fibrillation (AF) is a highly prevalent arrhythmia and responsible for significant morbidity, mortality and health care cost. The prevalence of AF is expected to increase markedly with the aging population. The use of conventional antiarrhythmic agents has been limited by potentially fatal ventricular proarrhythmia. Rhythm control could become the preferred treatment strategy for AF if antiarrhythmic agents that are similarly or more effective, but safer, than currently approved AF agents become available. A subanalysis of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial data showed that normal sinus rhythm confers a survival benefit in AF, suggesting that rhythm control, if achieved without the adverse effects related to current antiarrhythmic medications, may offer a significant survival advantage over rate control. Considerable work has been performed to explore novel, potentially safer antiarrhythmic drug targets for AF therapy, and some of these drug targets are currently being tested in experimental and clinical proof of concept studies. This article summarizes relevant aspects of the cellular electrophysiology of AF and reviews the actions of pharmacological agents being considered for the prevention and treatment of AF, focusing on atrial selective antiarrhythmic agents. A variety of drugs that inhibit the atrium-specific ultra rapid delayed rectifier potassium current (IKur) are being evaluated pre-clinically, but human experience with these agents is limited. The acetylcholine-activated current (IKACh) is another novel candidate target for atrial-specific drug therapy. The constitutively active form of this current is increased in human AF and pharmacological inhibition might be of therapeutic value. Certain drugs have IKACh blocking properties, but similar to IKur-blockers, none have been shown to have pure selectivity for this current. Newer agents being studied also include gap junction modulators and angiotensin-converting enzyme inhibitors. There is great hope that at least some of these agents will ultimately be available for effective and safer clinical treatment and prevention of AF.Cardiovascular & hematological agents in medicinal chemistry 02/2009; 7(1):64-75.
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ABSTRACT: INTRODUCTION: This study was designed to compare the effect of electrical baroreflex stimulation (BRS) at an intensity used in hypertensive patients and renal denervation (RDN) on atrial electrophysiology. BRS and RDN reduce blood pressure and global sympathetic drive in patients with resistant hypertension. Whereas RDN decreases sympathetic renal afferent nerve activity, leading to decreased central sympathetic drive, BRS modulates autonomic balance by activation of the baroreflex, resulting in both reduced sympathetic drive and increased vagal activation. Increased vagal tone potentially shortens atrial refractoriness resulting in a stabilization of reentry circuits perpetuating atrial fibrillation (AF). METHODS AND RESULTS: In normotensive anesthetized pigs (n = 12), we compared the acute effect of BRS and RDN on blood pressure, atrial effective refractory period (AERP), and inducibility of AF. Electrical BRS was titrated to result in comparable heart rate and blood pressure reduction compared to irreversible RDN. BRS resulted in a rapid and pronounced shortening of AERP (from 162 ± 8 milliseconds to 117 ± 16 milliseconds, P = 0.001) associated with increased AF-inducibility from 0% to 82%. This shortening in AERP was completely reversible after stopping BRS. After administration of atropine, AF-inducibility during BRS was attenuated. Ventricular repolarization was not modulated by BRS. In RDN, AF was not inducible; however, it did not prevent BRS-induced shortening of AERP. CONCLUSION: RDN and BRS resulting in comparable blood pressure and heart rate reductions differently influence atrial electrophysiology. Vagally mediated shortening of AERP, resulting in increased AF-inducibility, was observed with BRS but not with RDN.Journal of Cardiovascular Electrophysiology 04/2013; · 3.48 Impact Factor