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.

Muñoz MA, Kaur J, Vigmond EJ. Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study. Am J Physiol Heart Circ Physiol 301: H1974-H1983, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00059.2011.-Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (ICa,L) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration Ͼ20 nM and for large ICa,L conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I Ca,L upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry. electrophysiology; reentry; autonomic innervation ATRIAL FIBRILLATION (AF) is the most common and diverse cardiac arrhythmia (21). Experimental observations have illustrated the crucial role that neuronal mechanisms have in its initiation and maintenance (33). Atrial arrhythmias can be induced in dogs by localized electrical stimuli applied to nerve branches of the thoracic vagosympathetic complex (31) or mediastinal nerves (2, 31). Experiments show that acetylcholine (ACh) can trigger reentry and AF in the right atrium (RA) and that adrenergic stimulation facilitates both AF initiation and maintenance (33). Atropine completely abolishes bradycardia and subsequent tachyarrhythmias, indicating that cholinergic efferents play a predominant role in induction (33).Different studies describe a similar sequence of events for arrhythmias originating in the RA that were induced by neural stimulation: cycle length (CL) prolongation, often with leading pacemaker site (LPS) shifting, followed by an atrial premature beat (APB), and subsequent tachyarrhythmia (1, 2, 31, 33). The escape beat initiating the tachyarr...