Background-Structural and electrophysiological changes of the atria occur with prolonged rapid rates; however, the effects of sustained atrial fibrillation (AF) on autonomic innervation of the atria are unknown. We hypothesized that electrophysiological remodeling from rapid atrial rates is accompanied by altered atrial autonomic innervation. Methods and Results-Six dogs (paced group) underwent atrial pacing at 600 bpm; 9 dogs (control animals) were not paced. All paced dogs developed sustained AF by week 4 of pacing. All 15 animals underwent positron emission tomography imaging of the atria with [C-11] hydroxyephedrine (HED) to label sympathetic nerve terminals. HED retention in the atria was significantly greater in paced dogs compared with control animals (Pϭ0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (Pϭ0.01). The coefficient of variation of HED retention was also greater in paced animals (Pϭ0.05) and was greater in the right atrium than in the left atrium (Pϭ0.004). Epicardial activation maps of AF were obtained in the paced animals at baseline and with autonomic manipulation. Mean AF cycle length was longer in the right atrium (109.2Ϯ5 ms) than in the left atrium (85.8Ϯ5.5 ms) at baseline (Pϭ0.005). AF cycle length did not vary significantly from baseline (97.6Ϯ13.4 ms) with stellate stimulation (100.5Ϯ6 ms) but lengthened with propranolol (107.5Ϯ6.1 ms, Pϭ0.03). Conclusions-Rapid rates of AF produce a heterogeneous increase in atrial sympathetic innervation. These changes parallel disparate effects of rapid pacing-induced AF on atrial electrophysiology.

Atrial fibrillation (AF) has been described as a "random" or "chaotic" rhythm. Evidence suggests that AF may have transient episodes of temporal and spatial organization. We introduce a new algorithm that quantifies AF organization by the mean-squared error (MSE) in the linear prediction between two cardiac electrograms. This algorithm calculates organization at a finer temporal resolution. (approximately 300 ms) than previously published algorithms. Using canine atrial epicardial mapping data, we verified that the MSE algorithm showed nonfibrillatory rhythms to be significantly more organized than fibrillatory rhythms (p < .00001). Further, we compared the sensitivity of MSE to that of two previously published algorithms by analyzing AF with simulated noise and AF manipulated with vagal stimulation or by adenosine administration to alter the character of the AF. MSE performed favorably in the presence of noise. While all three algorithms distinguished between low and high vagal AF, MSE was the most sensitive in its discrimination. Only MSE could distinguish baseline AF from AF with adenosine. We conclude that our algorithm can distinguish different levels of organization during AF with a greater temporal resolution and sensitivity than previously described algorithms. This algorithm could lead to new ways of analyzing and understanding AF as well as improved techniques in AF therapy.

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6 -8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 ϫ 16 photodiode array from 2 ϫ 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD 80) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD80 may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility. atrial conduction; optical mapping ATRIAL FIBRILLATION (AF) is a frequently occurring arrhythmia, present in ϳ5% of people over 65 yr old (5). Among the risk factors predisposing to AF are congestive heart failure (CHF), hypertension, and mitral valve disease, including both stenosis and insufficiency (reviewed in Ref. 5). In general, atrial dilatation is associated with an increased occurrence of AF (17,28).Prevailing theory suggests that inducibility of sustained AF requires either a shortening of refractoriness, increased dispersion of refractoriness, or conduction slowing (1). Other factors that have been implicated in the stabilization of AF include increased conduction heterogeneity and anisotropy (23). The presence of one or more of these proarrhythmic factors would thus represent a "substrate for AF," contributing to increased AF stability. Various animal models of AF have been developed to study AF substrate. Parasympathetic stimulation (either with direct vagal nerve stimulation or circulating cholinergic agents) results in shortening of atrial refractoriness and sustained AF (10, 16). Prolonged rapid atrial pacing (RAP) leads to shortening of refractoriness and sustained AF (18,30). In a dog model of CHF due to rapid ventricular pacing, no changes in refractoriness were found, but increased con...

Background-Heterogeneous electrophysiological properties, which may be due in part to autonomic innervation, are important in the maintenance of atrial fibrillation (AF). We hypothesized that heterogeneous sympathetic denervation with phenol would create a milieu for sustained AF. Methods and Results-After the determination of baseline inducibility, 15 dogs underwent atrial epicardial phenol application and 11 underwent a sham procedure. After 2 weeks of recovery, the animals had repeat attempts at inducing AF and effective refractory period (ERP) testing. Epicardial maps were obtained to determine local AF cycle lengths. ERPs were determined at baseline and during sympathetic, vagal, and simultaneous vagal/sympathetic stimulation.

Acute and chronic AF exhibit heterogeneous differences in CL, organization and activation patterns. The LA in chronic AF is faster and more disorganized than it is in acute AF. Differences in the models may be due to heterogeneous electrophysiologic remodeling and anatomic constraints. The design of future AF therapies may benefit by addressing the patient specific degree of atrial remodeling.