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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/H1489    most recent 01054.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Comtois, P. Articles by Nattel, S. PubMed PubMed Citation Articles by Comtois, P. Articles by Nattel, S.

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

¹Department of Medicine and Research Center, Montreal Heart Institute and Université de Montréal, Montreal; ²Department of Pharmacology, McGill University, Montreal; and ³Department of Electrical and Computer Engineering, University of Calgary, Calgary, Alberta, Canada

Submitted 11 September 2007 ; accepted in final form 29 July 2008

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 89% at 60 µM). 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.

state-dependent channel; cardiac action potential; antiarrhythmic drug therapy; computer simulations; heart arrhythmia models