Measures of organization during atrial fibrillation.

Atrial fibrillation, a rhythm classically described as totally disorganized, is now recognized to have some structure in its activation. Even though that structure may be very complex, it clearly exists, and researchers continue to try to quantify that structure. One problem with this quantification is that "organization" is an ambiguous term that can have many interpretations. Rather than attempt to impose a particular definition of "organization," this review categorizes the methodologies for quantifying atrial fibrillation organization based on the number of recording channels used in the methods. This method of categorization is not only convenient, but is also descriptive of the different "philosophical" definitions of organization that various researchers have.

Differences in organization between acute and chronic atrial fibrillation in dogs.

OBJECTIVES: The purpose of this study was to determine differences in acute and chronic atrial fibrillation (AF) "organization" in canine models. BACKGROUND: Electrophysiologic changes occur during atrial remodeling, but little is known about how remodeling affects AF organization. We hypothesized that atrial remodeling induced by long-term rapid atrial rates heterogeneously decreases AF organization. METHODS: In seven dogs, acute AF was induced by atrial burst pacing, and in eight dogs chronic AF was created by six weeks of continuous rapid atrial pacing. Atrial fibrillation was epicardially mapped from the right atria (RA) and left atria (LA). Atrial cycle length (CL), spatial organization and activation maps were compared. Spatial organization was quantified by an objective signal processing measure between multiple electrograms. RESULTS In acute AF, mean CL was slightly shorter in the LA (124 +/- 16 ms) than it was in the RA (131 +/- 14 ms) (p < 0.0001). In chronic AF, LA CL (96 +/- 14 ms) averaged 24 ms shorter than RA CL (121 +/- 18 ms) (p < 0.0001). Right atria and LA in acute AF had similar levels of organization. In chronic AF, the LA became approximately 25% more disorganized (p < 0.0001) while the RA did not change. In acute AF, a single broad wave front originating from the posterior and medial atrium dominated LA activation. In chronic AF, LA activation was more complex, sustaining multiple reentrant wavelets in the free wall and lateral appendage. CONCLUSIONS: 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.

Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation.

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 (P=0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (P=0.01). The coefficient of variation of HED retention was also greater in paced animals (P=0.05) and was greater in the right atrium than in the left atrium (P=0.004). 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 (109.2+/-5 ms) than in the left atrium (85.8+/-5.5 ms) at baseline (P=0.005). AF cycle length did not vary significantly from baseline (97.6+/-13.4 ms) with stellate stimulation (100.5+/-6 ms) but lengthened with propranolol (107.5+/-6.1 ms, P=0.03). 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.

Evidence of heterogeneous remodeling in canine atrial fibrillation.

Although electrophysiologic changes occur during atrial remodeling, little is known how remodeling affects atrial fibrillation (AF) organization. We hypothesized that, in animals with long-term rapid atrial rates and a rapid ventricular response, AF would be more disorganized than in animals with rapid atrial rates only. In 8 dogs, chronic AF was created by 6 weeks of continuous rapid atrial pacing. In this group, the ventricular response to AF was spontaneous and unaltered. Twenty-one epochs of AF were epicardially mapped from the right and left atria. In 6 dogs, chronic AF was also created with rapid atrial pacing, however, the AV node was ablated and the ventricles were VVI paced at 80 BPM. Only 1 epoch of AF per dog was mapped. Atrial cycle length (CL) and spatial organization were compared. In chronic AF with a spontaneous ventricular rate, left atrial CL (96+/-14 ms) averaged 24 ms shorter than right atrial CL (121+/-18 ms) (P < .0001). With VVI pacing, AF CL was longer than in the dogs with the spontaneous ventricular rate. However, the left atrial CL (109+/-30 ms) was still significantly shorter than the right atrial CL (145+/-43 ms) (P < .001). Spatial organization values showed that during chronic AF with a spontaneous ventricular rate, the left atrium is more disorganized (2593+/-497) than the right atrium (2052+/-732) (P < .0001). With VVI pacing, the left atrium (2202+/-597) is still more disorganized than the right (1620+/-936) (P < .05). However, with VVI pacing, both atria appear less disorganized than dogs with VVI pacing. Atrial remodeling caused by heart failure that is superimposed on the remodeling due to rapid atrial rates causes the atria to be more disorganized than remodeling due to rapid atrial rates alone. However, in either case the left atrium is faster and more disorganized than the right atrium. Atrial fibrosis caused by the heart failure may increase the disorganization of AF activation.

A high-temporal resolution algorithm for quantifying organization during atrial fibrillation.

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.

Heterogeneous atrial denervation creates substrate for sustained atrial fibrillation.

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. Dogs then underwent PET imaging with either a sympathetic ([11C]hydroxyephedrine, HED) or parasympathetic (5-[11C]methoxybenzovesamicol, MOBV) nerve label. None of the animals had sustained AF (>60 minutes) at baseline. None of the sham dogs and 14 of 15 phenol dogs had sustained AF at follow-up. Sites to which phenol was applied had a significantly shorter ERP (136+/-17.6 ms) than those same sites in the sham controls (156+/-19.1 ms) (P=0.01). Although there was no difference in the ERP change with either vagal or sympathetic stimulation alone between phenol and nonphenol sites, the percent decrease in ERP with simultaneous vagal/sympathetic stimulation was greater in the phenol sites (17+/-8%) than in the nonphenol sites (9+/-9%) (P=0.01). There was a significantly increased dispersion of refractoriness (21+/-6.4 ms in the sham versus 58+/-14 ms in the phenol dogs, P=0.01) as well as dispersion of AF cycle length (49+/-10 ms in the sham versus 105+/-12 ms in the phenol dogs, P=0.0001). PET images demonstrated defects of HED uptake in the areas of phenol application, with no defect of MOBV uptake. CONCLUSIONS: Heterogeneous sympathetic atrial denervation with phenol facilitates sustained AF.

Further observations of "linking" of atrial excitation during clinical atrial fibrillation.

The objective of this article was to look for evidence of nonrandom behavior during atrial fibrillation by examining long (> 15 minutes) recordings. We have previously reported transient "linking" of atrial activation during atrial fibrillation, and showed that activation was not entirely random. Over the few episodes of linking seen during 1 minute, activation directions apparently repeated, indicating a possible anatomical or physiological constraint. In the present study, we examined atrial fibrillation over longer time periods to see if this constancy of direction was stable. Endocardial recordings were made from 12 patients with atrial fibrillation using a catheter with three orthogonal bipoles, allowing measurements of local activation directions in three dimensions. The direction was calculated using Pipberger's half-area method, and episodes of transient linking were identified. An average direction for each episode of linking was calculated and plotted in two dimensions using spherical coordinates (altitude and azimuth). In addition, the nature of initiation and termination of linking was examined. Of the twelve patients, 611 episodes of linking (range 1 to 169 per patient, mean 51) were identified. The episodes for most patients clustered closely in direction. In contrast, directions measured for all activations (i.e., linked and not linked) filled up the entire available range. Linking in most cases subjectively appeared to initiate and terminate suddenly. The results indicate that the local anatomy, pathology, or physiology of the atrium has a strong constraining effect on the electrical activations occurring during atrial fibrillation, and revises our perception of activation during atrial fibrillation as "random." The demonstration that local properties greatly influence conduction during fibrillation has important implications for ablation or pacing therapy.

Epicardial maps of atrial fibrillation after linear ablation lesions.

INTRODUCTION: The purpose of this study was to investigate the mechanisms by which atrial linear ablation lesions eliminate atrial fibrillation (AF). METHODS AND RESULTS: With an array of 112 unipole, epicardial maps of electrically induced AF in 6 dogs (acute group), self-sustained AF in 6 dogs (chronic group), and sinus rhythm and atrial pacing in 3 dogs (control group) were analyzed before and after creating linear radiofrequency ablation lesions in both atria that eliminated the AF. In the acute and chronic groups, activation maps showed multiple wavelets with complex patterns of activation and reentry during AF. Conduction velocity and the number, size, and complexity of wavelets did not change, whereas median fibrillatory cycle length increased with the number of linear lesions. In the control group, refractoriness and conduction velocity were unaffected by the number of lesions. CONCLUSIONS: In these models of AF, linear lesions that eliminate AF increase the cycle length of AF without changing conduction velocity, number of size of wavelets, or complexity of activation patterns.

A method for determining high-resolution activation time delays in unipolar cardiac mapping.

This paper presents a method for determining activation time delays in unipolar cardiac mapping data to resolutions considerably smaller than the sample interval. The method involves taking two filtered, differentiated electrograms and computing the Hilbert transform of their cross correlation, which exhibits a negative-to-positive zero crossing at the delay time between the signals. Simultaneous endocardial/epicardial recordings of sinus rhythm were made in the swine right atrium using identical, precisely superpositioned electrode arrays. Data were amplified, lowpass filtered, and digitized at 1000 Hz. A window of data was chosen around each electrogram in an endocardial/epicardial electrogram pair. The windowed electrograms were differentiated and highpass filtered, and the Hilbert transform of the cross correlation between the electrograms was computed. The activation time delay was taken to be the first negative-to-positive zero crossing. Average activation time delays (+/- SD) were computed for 4-s sinus rhythm recordings from each endocardial/epicardial electrode pair. For a representative site, the average transmural activation time delay was 0.71 +/- 0.06 ms (n = 10 electrograms). Time delays estimated using the Hilbert transform method were compared with time delays estimated using the maximum negative slope criterion. The Hilbert transform results exhibited much smaller standard deviations, indicating that the Hilbert transform method may produce more accurate time delay estimates than the maximum negative slope method.

A frequency domain analysis of spatial organization of epicardial maps.

Mapping of organized rhythms like sinus rhythm uses activation times from individual electrograms, and often assumes that the map for a single activation is similar to maps for subsequent activations. However, during fibrillation, activation times and electrograms are not easy to define, and maps change from activation to activation. Volume and complexity of data make analysis of more than a few seconds of fibrillation difficult. Magnitude Squared Coherence (MSC), a frequency domain measure of the phase consistency between two signals, can be used to help interpret longer data segments without defining activation times or electrograms. Sinus rhythm, flutter, and fibrillation in humans and swine were mapped with an array of unipolar electrodes (2.5 mm apart) at 240 sites on the atrial or ventricular epicardium. Four-second data segments were analyzed. One site near the center of the array was chosen ad hoc as a reference. MSC maps were made by measuring mean MSC from 0-50 Hz between every point in the array relative to the reference. Isocoherence contours were drawn. The effects of bias in the coherence estimate due to misalignment were investigated. Average MSC versus distance from the reference was measured for all rhythms. Results indicate that in a 4-s segment of fibrillation, there can exist some phase consistency between one site and the reference and little or none between a second site and the reference even when both sites are equidistant from the reference. In fibrillation, isocoherence contours are elongated and irregularly shaped, reflecting long-term, but nonuniform, spatial organization. That is, activation during fibrillation cannot be considered as random over a 4-s interval. Bias in the coherence estimate due to misalignment is significant for sinus rhythm and flutter, but can be corrected by manual realignment. Average MSC drops with distance for all rhythms, being most pronounced for fibrillation, MSC maps may provide insights into long-term spatial organization of rhythms that would otherwise be cumbersome and difficult to interpret with standard time domain analysis.

Observations from intraatrial recordings on the termination of electrically induced atrial fibrillation in humans.

BACKGROUND: The circulating wavelet hypothesis suggests that atrial fibrillation could terminate by either progressive fusion or simultaneous block of all wavelets. METHODS: Intraatrial recordings from the right atrial free wall were made during procainamide induced (n = 8) or spontaneous (n = 7) termination of electrically induced atrial fibrillation in 14 patients. Atrial rate, mean magnitude squared coherence, and direction of activation during sequential electrograms were measured. Rate and coherence were calculated from the earliest point within 5 minutes prior to termination as well as from the 4-second interval just prior to termination. RESULTS: Termination was directly to sinus rhythm (13 episodes) or to atrial flutter (2 episodes). For the eight procainamide induced terminations, rate decreased between the first measurement and the measurement just prior to termination, from 443 +/- 127 beats/min to 322 +/- 119 beats/min. For the seven spontaneous terminations, rate also decreased from 373 +/- 119 beats/min to 323 +/- 88 beats/min; however, a slight increase in atrial rate prior to termination was observed in three episodes. No specific patterns of atrial cycle lengths were seen during the final few seconds of fibrillation. No increase in coherence was observed. In seven episodes, recordings were made using orthogonal bipoles in the x, y, and z directions, allowing direction of activation of wavefronts to be measured. Three episodes showed multiple instances where direction of activation remained similar over several electrograms as we have previously reported for chronic fibrillation. However, no such instances precipitated termination in any of the seven episodes. CONCLUSIONS: Atrial fibrillation usually terminates directly to sinus rhythm and does so abruptly and without forewarning. While we and others have previously reported that the rate of atrial fibrillation decreases with procainamide infusion, a decrease in the rate of atrial fibrillation is not required for the rhythm to terminate and consequently may not be a part of the termination process at all. Coherence does not demonstrate a progressive increase in the organization of atrial fibrillation prior to termination. Lack of stabilization in the direction of activation of wavefronts in the final few seconds also fails to support fusion of wavefronts as the mechanism of termination of atrial fibrillation. Simultaneous block of all wavelets is consistent with, but not proven by, our observations.