Contrasting Efficacy of Dofetilide in Differing Experimental Models of Atrial Fibrillation

Li, Danshi; Bénardeau, Agnès; Nattel, Stanley

doi:10.1161/01.cir.102.1.104

Cited by 98 publications

(90 citation statements)

References 35 publications

(35 reference statements)

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“…20,57 CHF-related AF appears to arise, at least in some instances, from a single macroreentrant source. 58 Further work is needed to evaluate quantitatively the potential mechanisms of AF based on substrates other than increased cholinergic tone.…”

Section: Comparison With Experimental Studies Of Vagal Afmentioning

confidence: 99%

Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties

Kneller

Zou

Vigmond

et al. 2002

Circulation Research

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239

235

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Abstract-Classical concepts of atrial fibrillation (AF) have been rooted in Moe's multiple-wavelet hypothesis and simple cellular-automaton computer model. Recent experimental work has raised questions about the multiple-wavelet mechanism, suggesting a discrete "driver region" underlying AF. We reexplored the theoretical basis for AF with a 2-dimensional computer model of a 5ϫ10-cm sheet of atrial cells with realistic ionic and coupling properties. Vagal actions were formulated based on patch-clamp studies of acetylcholine (ACh) effects. In control, a single extrastimulus resulted in a highly meandering unstable spiral wave. Simulated electrograms showed fibrillatory activity, with a dominant frequency (DF, 6.5 Hz) that correlated with the mean rate. Uniform ACh reduced core meander of the spiral wave by Ϸ70% (as measured by the standard deviation of spiral-wave tip position) and accelerated the DF to 17.0 Hz. Simulated vagally induced refractoriness heterogeneity caused wavefront breakup as accelerated reentrant activity in regions of short refractoriness impinged on regions unable to respond in a 1:1 fashion because of longer refractoriness. In 7 simulations spanning the range of conditions giving sustained AF, 5 were maintained by single dominant spiral waves. On average, 3.0Ϯ1.3 wavelets were present (range, 1 to 7). Most wavelets were short-lived and did not contribute to AF maintenance. In contrast to predictions of the multiple-wavelet hypothesis, but in agreement with recent experimental evidence, our model indicates that AF can result from relatively stable primary spiral-wave generators and is significantly organized. Our results suggest that vagal AF may arise from ACh-induced stabilization of the primary spiral-wave generator and disorganization of the heterogeneous tissue response.

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Section: Comparison With Experimental Studies Of Vagal Afmentioning

confidence: 99%

Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties

Kneller

Zou

Vigmond

et al. 2002

Circulation Research

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239

235

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“…We have recently shown that intravenous dofetilide increases ERP to a greater extent in the LA than in the RA in dogs with a substrate for AF caused by either congestive heart failure or sustained atrial tachycardia. 21 Dofetilide was highly effective in terminating heart failure-related AF but was relatively ineffective in AF associated with atrial tachycardia-induced remodeling. In the latter group, dofetilide largely eliminated reentrant activity in the LA, but persistent reentry in the RA maintained AF.…”

Section: Potential Significancementioning

confidence: 99%

Potential Ionic Mechanism for Repolarization Differences Between Canine Right and Left Atrium

Zhang

Kneller

et al. 2001

Circulation Research

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171

175

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Abstract-Experimental and clinical evidence suggests a critical role for the left atrium (LA) in atrial fibrillation (AF). In animal models, repolarization is faster in the LA than in the right atrium (RA), leading to more stable reentry circuits with a shorter intrinsic period in the LA. The ionic mechanisms underlying LA-RA repolarization differences are unknown. Therefore, we evaluated ionic currents and action potentials (APs) with the whole-cell patch clamp in isolated canine atrial myocytes. The density of the rapid delayed rectifier current (I Kr ) was greater in the LA (eg, 1.83Ϯ0.10 pA/pF at ϩ20 mV) than in the RA (1.15Ϯ0.07 pA/pF, PϽ0.01; nϭ16 cells per group). The slow and ultrarapid delayed rectifier, the inward rectifier, L-type Ca 2ϩ , and transient outward K ϩ currents were all comparable in the LA and RA. There were no differences in kinetic or voltage-dependent properties of currents in LA versus RA. Western blots of ether-a-go-go-related gene (ERG) protein in three RA and corresponding LA regions showed significantly greater ERG expression in LA. AP duration (APD) was shorter in the LA versus RA in both isolated cells and multicellular preparations, and the effective refractory period (ERP) was shorter in the LA compared with the RA in vivo. Dofetilide had significantly larger APD-and ERP-increasing effects in the LA compared with RA, and LA-RA repolarization differences were eliminated by exposure to dofetilide. We conclude that LA myocytes have larger I Kr than do RA myocytes, contributing importantly to the shorter APD and ERP in LA. The larger LA I Kr may participate in the ability of the LA to act as a "driver region" for AF, with potentially important implications for understanding AF mechanisms and antiarrhythmic therapy. Key Words: channels Ⅲ heterogeneity Ⅲ electrophysiology S everal lines of evidence point to a particularly important role of the left atrium (LA) in maintaining atrial fibrillation (AF). Animal models 1,2 and clinical studies 3 suggest the presence of LA "driver regions" in AF. In an isolated sheep-heart model of AF, rotors maintaining the arrhythmia were always located in the LA. 4 Linear LA lesions appear particularly important for the success of radiofrequency ablation procedures directed against AF. 5 LA refractoriness is shorter than right atrial (RA) refractoriness, 6 -8 potentially explaining, at least in part, the preferential role of LA reentry in AF. Despite the evidence for differences between LA and RA refractoriness that might be important in the pathophysiology of AF, there are no published studies comparing the cellular ionic electrophysiology of LA with RA myocytes. The present work was designed to evaluate action potential (AP) properties and ionic currents governing repolarization in canine cells isolated from the LA free wall and to compare them with RA cells. Because our findings pointed to an important role for differences in rapid delayed rectifier current (I Kr ) between LA and RA, we also evaluated the effect of the I Kr blocker dofetilide on dif...

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“…[1][2][3][4][5][6][17][18][19][20] All studies showed strong ERP reduction and loss of rate adaptation. Changes in CV with long-term (several-week) atrial pacing have been variable, with some studies suggesting a decrease in CV 2,4,5 and others no change 1 ; however, no studies have shown that AT slows conduction significantly in normal hearts over a 1-week period.…”

Section: Relationship To Previous Observations Regarding Atrial Tachymentioning

confidence: 96%

Consequences of Atrial Tachycardia-Induced Remodeling Depend on the Preexisting Atrial Substrate

Shinagawa

Leung

et al. 2002

Circulation

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Background-All animal studies of atrial tachycardia (AT) remodeling to date have been performed in normal hearts, but clinical atrial fibrillation (AF) often occurs in the setting of heart disease. This study evaluated the effects of a pathological AF substrate on AT-induced remodeling. Methods and Results-Fourteen control dogs, 12 AT-only dogs (400 bpm for 1 week), 14 congestive heart failure (CHF) dogs (CHF only, ventricular tachypacing, 220 to 240 bpm for 5 weeks), and 13 CHFϩAT dogs (ventricular tachypacing-induced CHF, 1 week of AT superimposed on the last week of ventricular tachypacing) were studied for evaluation of AT effects in normal hearts (AT-only versus control dogs) and CHF hearts (CHFϩAT versus CHF-only dogs). In normal hearts, AT strongly decreased the effective refractory period (ERP) and abolished ERP rate adaptation, whereas conduction velocity was unaltered. In CHF dogs, AT reduced ERP to a significantly lesser extent, did not alter ERP rate adaptation, and reduced conduction velocity. AT alone increased atrial vulnerability to extrastimuli and prolonged AF. In the presence of CHF, AT had no clear effect on atrial vulnerability but increased the prevalence of prolonged AF. Conclusions-The

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Contrasting Efficacy of Dofetilide in Differing Experimental Models of Atrial Fibrillation

Cited by 98 publications

References 35 publications

Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties

Cholinergic Atrial Fibrillation in a Computer Model of a Two-Dimensional Sheet of Canine Atrial Cells With Realistic Ionic Properties

Potential Ionic Mechanism for Repolarization Differences Between Canine Right and Left Atrium

Consequences of Atrial Tachycardia-Induced Remodeling Depend on the Preexisting Atrial Substrate

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