Serial Cardioversion by Class IC Drugs During 4 Months of Persistent Atrial Fibrillation in the Goat

Eijsbouts, Sabine; Ausma, Jannie; Blaauw, Yuri; Schotten, Ulrich; Duytschaever, Mattias; Allessie, Maurits A.

doi:10.1111/j.1540-8167.2006.00407.x

Cited by 36 publications

(31 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These observations suggest that factors that reduce APD, thereby increasing the angular velocity and functional anchoring of rotors, should reduce the ability of Na ϩ channelblocking drugs to terminate AF. This has, in fact, been the clinical observation with AF-related electrical remodeling, which both reduces APD and induces resistance to Na ϩ channel blocker-induced AF termination (7,39).…”

Section: Interactions Among Ach Concentrations/distributions and Tissmentioning

confidence: 95%

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates

Comtois

Sakabe²,

Vigmond³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding Na(+) channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding I(Na) blockers affect AF, we developed realistic mathematical models of state-dependent Na(+) channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two- and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulated-receptor theory and maximum affinity for activated Na(+) channels. Lidocaine produced frequency-dependent Na(+) channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum approximately 89% at 60 microM). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source Na(+) current in the face of large ACh-sensitive K(+) current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF.

show abstract

Section: Interactions Among Ach Concentrations/distributions and Tissmentioning

confidence: 95%

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates

Comtois

Sakabe²,

Vigmond³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Of note, V 0.5 of I Na inactivation is shifted by +10 mV in cells isolated from AF versus sinus rhythm patients,46 which may reduce the sensitivity to I Na blockers. The potency of Class IC agents appears not to be altered by atrial remodeling in goats 47. Thus, there are many possible permutations that could develop with disease states that could affect the atrial selectivity of sodium channel blockers.…”

Section: Unanswered Questionsmentioning

confidence: 99%

Atrial-Selective Sodium Channel Blockers: Do They Exist?

Burashnikov

Antzelevitch

2008

Journal of Cardiovascular Pharmacology

View full text Add to dashboard Cite

The risk of developing severe ventricular arrhythmias and/or organ toxicity by currently available drugs used to treat atrial fibrillation (AF) has prompted the development of atrial-selective antiarrhythmic agents. Until recently the principal focus has been on development of agents that selectively inhibit the ultra-rapid delayed rectifier outward potassium channels (I Kur ), taking advantage of the presence of these channels in atria but not ventricles. Recent experimental studies have demonstrated important atrioventricular differences in biophysical properties of the sodium channel and have identified sodium channel blockers such as ranolazine and chronic amiodarone that appear to take advantage of these electrophysiologic distinctions and act to specifically or predominantly depress sodium channel-mediated parameters in "healthy" canine atria versus ventricles. Atrial-selective/predominant sodium channel blockers such as ranolazine effectively suppress AF in experimental models of AF involving canine isolated right atrial preparations at concentrations that produce little to no effect on ventricular electrophysiologic parameters. These findings point to atrial-selective sodium channel block as a new strategy for the management of AF. The present review examines our current understanding of atrioventricular distinctions between atrial and ventricular sodium channels and our understanding of the basis for atrial selectively of the sodium channel blockers. A major focus will be on the ability of the atrialselective sodium channel blocking properties of these agents, possibly in conjunction with I Kur and/or I Kr blocking properties, to suppress and prevent the reinduction of AF.

show abstract

“…12 In parallel, the success rate of pharmacological cardioversion decreases until it is no longer possible to cardiovert AF in most goats (permanent AF). 13 To investigate the transition from persistent to permanent AF, we have studied goats after 3 weeks of maintained AF (short-term AF [ST]) and goats after 6 months of AF (long-term AF [LT]). We characterized conduction patterns in the atrial free walls during pacing and AF using high-resolution epicardial mapping and a new method to describe fibrillation patterns.…”

Section: Clinical Perspective On P 599mentioning

confidence: 99%

“…Eijsbouts et al 13 showed that the cardioversion efficacy of flecainide gradually decreases from 60% after 1 month to 17% after 4 months of AF. In another study, we reported a 100% success rate of cardioversion with a combination of AVE0118 and dofetilide in goats after 46Ϯ17 days of AF.…”

Section: Time Course Of Af Stabilizationmentioning

confidence: 99%

Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation

Verheule

Tuyls

Hunnik

et al. 2010

Circ: Arrhythmia and Electrophysiology

Self Cite

View full text Add to dashboard Cite

Background-Over a time course of months, the stability of atrial fibrillation (AF) gradually increases and the efficacy of pharmacological cardioversion declines both in humans and in animal models. Changes in fibrillatory conduction over this period largely are unexplored. Methods and Result-Goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. AF was maintained for 3 weeks (short-term AF [ST], nϭ10) or 6 months (long-term AF [LT], nϭ7). AF could be cardioverted pharmacologically at the early time point (persistent AF), but not at the later time point (permanent AF). At follow-up, a high-resolution mapping electrode was used to record epicardial conduction patterns in the free walls of the right atrium (RA) and left atrium (LA). A new method for mapping of fibrillation waves was used to describe AF conduction patterns. Wavefronts propagated uniformly during slow pacing in both groups, although conduction velocity was significantly lower in the LT group (LA, 93Ϯ14 versus 72Ϯ10 cm/s; RA, 94Ϯ8 versus 78Ϯ8 cm/s). Median AF cycle length (AFCL) was not significantly different between the groups. However, the LT group showed highly complex activation patterns during AF, with an increased number of simultaneously propagating waves (LT group RA, 8.4Ϯ3.0 waves/AFCL; LA, 12.8Ϯ2.4 waves/AFCL; versus ST group RA, 4.3Ϯ2.2 waves/AFCL; LA, 4.5Ϯ2.5 waves/AFCL). Fibrillation waves in the LT group showed pronounced dissociation with large activation time differences. The incidence of waves newly appearing within the recording area also was increased in both atria. These alterations in conduction were accompanied by myocyte hypertrophy and increased endomysial fibrosis. Conclusions-Long-term AF in goats leads to dissociated conduction in the atrial free walls that may contribute to increased AF stability. (Circ Arrhythm Electrophysiol. 2010;3:590-599.)

show abstract

Serial Cardioversion by Class IC Drugs During 4 Months of Persistent Atrial Fibrillation in the Goat

Cited by 36 publications

References 28 publications

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates

Atrial-Selective Sodium Channel Blockers: Do They Exist?

Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation

Contact Info

Product

Resources

About

Serial Cardioversion by Class IC Drugs During 4 Months of Persistent Atrial Fibrillation in the Goat

Cited by 36 publications

References 28 publications

Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates

Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates

Atrial-Selective Sodium Channel Blockers: Do They Exist?

Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation

Contact Info

Product

Resources

About

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates

Mechanisms of atrial fibrillation termination by rapidly unbinding Na⁺ channel blockers: insights from mathematical models and experimental correlates