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EXPERIMENTAL STUDY

Differences in organization between acute and chronic atrial fibrillation in dogs

Haris J. Sih, PhD^*, Douglas P. Zipes, MD, FACC, Edward J. Berbari, PhD^* , David E. Adams and Jeffrey E. Olgin, MD, FACC

^* Department of Electrical Engineering, Indiana University Purdue University, Indianapolis, Indiana, USA
Krannert Institute of Cardiology, Department of Medicine, Indiana University Purdue University, Indianapolis, Indiana, USA

Manuscript received September 13, 1999; revised manuscript received March 15, 2000, accepted April 19, 2000.

Reprint requests and correspondence: Dr. Jeffrey E. Olgin, Indiana University School of Medicine, Krannert Institute of Cardiology, 1111 West 10th Street, Indianapolis, Indiana 46202
jolgin{at}iupui.edu

	Abstract

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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 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.

Abbreviations and Acronyms   AF = atrial fibrillation   ANOVA = analysis of variance   CL = cycle length   LA = left atrium, left atria or left atrial   RA = right atrium, right atria or right atrial

We hypothesized that acutely-induced AF would demonstrate more organized activity than chronic AF after electrical remodeling. As the left atria (LA) and right atria (RA) have different anatomy, autonomic innervation and electrophysiologic properties, we further hypothesized that differences in organization of AF would be heterogeneously distributed. To test these hypotheses, epicardial recordings were made in two canine models of AF. In one model, short-term (<10 s) atrial burst pacing induced acute AF. In the other model, long-term (>6 weeks) rapid atrial pacing induced chronic/self-sustained AF.

	Methods

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Experimental preparation.   Experiments were performed in 15 mongrel dogs weighing 20 to 25 kg. Eight dogs underwent continuous rapid atrial pacing for six weeks to create sustained AF (chronic group). The long-term rapid atrial pacing model is similar to models previously described (6,7,10). In brief, after sedation with sodium thiopental, the animal was intubated and ventilated with oxygen at 2 µl/min with a 2% mixture of isoflurane to maintain anesthesia. The right cervical jugular vein was exposed, and an active fixation permanent pacing lead was inserted and fluoroscopically guided to the RA. After positioning the atrial lead to obtain a diastolic stimulus threshold of less than 2 mA at 4 ms duration, the lead was fixed into place and connected to a pacemaker that continuously paced at 480 beats/min at three times the stimulus threshold. The pacemaker was placed in a subcutaneous pocket in the neck that was subsequently closed in layers. After six weeks of continuous rapid pacing, self-sustained AF was confirmed; the pacemaker was turned off, and the animals underwent mapping studies described below.

In seven dogs (acute group), transient AF was induced by atrial burst pacing, and the atria were epicardially mapped as described below. No autonomic manipulations were performed in either group.

Mapping studies.   Each dog was anesthetized initially with sodium thiopental (30 mg/kg). After intubation the dogs were ventilated with oxygen at 2 µl/min and a 2% concentration of isoflurane. Arterial blood pressure via the femoral artery and surface electrocardiogram lead II were monitored. A median sternotomy was performed, and the heart was exposed and suspended in a pericardial cradle. In the acute AF group, an 8F introducer was placed in the femoral vein, and a catheter was advanced to the RA for atrial pacing. The atria were burst paced from the intraatrial catheter for 2 to 5 s with a pulse frequency of 300 Hz and amplitude of 10 mA to induce AF. Only AF episodes that lasted longer than 15 s were retained for analysis. A 10 s epoch of AF, beginning at least 2 s after AF induction and ending at least 2 s before conversion to sinus rhythm, was analyzed. Further, when several AF recordings were analyzed in the same animal, at least 1 min elapsed between AF episodes.

A custom built set of four epicardial plaques with 240 unipoles was used to map atrial activation during AF (Fig. 1). Two plaques were placed on the medial aspect of both the RA and LA appendages and along Bachmann’s bundle (43 and 50 unipoles, respectively). A plaque with 77 unipoles was placed on the lateral aspect of the appendage and free-wall of the RA, and a plaque with 70 unipoles was placed on the lateral aspect of the appendage and free-wall of the LA. Simultaneous LA and RA maps were recorded at an interelectrode distance of 5.6 mm. All electrodes were stainless steel with a diameter of 1.5 mm and mounted on a thermoplastic backing (Orfit, North Coast Medical, San Jose, California) that, when heated, could be formed to the contours of the epicardial surface.

View larger version (124K): [in this window] [in a new window]   Figure 1 Four custom-built arrays (240 unipoles) covered the right free wall (RFW), the lateral aspect of the right atrial appendage (RAA), the medial aspect of the RAA, the left free wall (LFW), the lateral aspect of the left atrial appendage (LAA) and the medial aspect of the LAA. BB = Bachmann’s bundle; IVC = inferior vena cava; PV = pulmonary veins; SVC = superior vena cava.

Data analysis.   As the unipolar atrial signals usually contained significant far-field ventricular activity, the far-field ventricular signals were digitally attenuated by subtracting a median ventricular complex (11,12). In brief, QRS-complex fiducial points were determined from the surface electrocardiogram. The timings of those fiducial points were then used to align the far-field ventricular components in the atrial unipolar signals. In each atrial unipolar signal, 60 ms windows around each fiducial point were retained, aligned and averaged to obtain a median ventricular complex for that unipole. After compensating for baseline offsets, the median ventricular complex was subtracted at the timing of each fiducial point.

After subtraction of the far-field ventricular signal, electrogram signal quality was manually assessed from each 10 s recording. Individual channels with poor amplitudes (that is, less than approximately 5 mV peak-to-peak) or channels lacking high frequency deflections during electrograms were eliminated from subsequent analysis.

Atrial cycle lengths (CL) were compared from multiple sites on the LA and RA (Fig. 2). The average CL over the 10 s recording was calculated. As the minimum CL has been shown to correlate to atrial refractoriness (13), the minimum AF CL over 10 s was also calculated.

View larger version (13K): [in this window] [in a new window]   Figure 2 Posterior view of the atria (left) and outline of the mapped regions (right). Numbers indicate the 16 atrial locations from which AF cycle lengths were measured.

Isochronal activation maps of AF were created. Activation times were determined manually from all the epicardial unipoles over a 4 s epoch. An activation time was defined to be the time of the greatest negative downslope of an electrogram. Ten ms isochrones were determined from the activation times over the 4 s epoch and reviewed in sequence.

Statistics.   Cycle lengths and organization were compared between the acute and chronic groups using repeated measures two-way analysis of variance (ANOVA) tests with mixed model assumptions to handle unbalanced data sets (17). When data were compared within either the acute or chronic group, one-way ANOVA tests were used. When the ANOVA was significant, Tukey’s procedure for multiple comparisons was used to identify the differences. Probability values less than 0.05 were considered statistically significant.

	Results

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In the seven dogs in the acute AF group, 21 episodes of AF were analyzed and had duration of 28 ± 16 s. All eight dogs in the chronic group had self-sustained AF at the time of study. In the eight dogs in the chronic AF group, 21 10-s recordings of chronic AF were made. Each episode of multiple recordings in a single animal was at least 1 min apart. In three animals in the acute group, the medial aspect of the LA appendage was considered too small to obtain reliable epicardial maps using our fixed size arrays. Similarly, in two animals, the medial aspect of the RA appendage was considered too small to map. Thus, in these areas for these dogs, only a portion of the appendages was epicardially mapped.

AF cycle length.   Atrial fibrillation CLs were measured from eight sites on the LA and eight sites on the RA. A summary of the CLs for all LA sites versus all RA sites is shown in Figure 3. Average AF CLs in the acute AF group (127 ± 16 ms) were significantly longer than they were in the chronic AF group (109 ± 20 ms) (p < 0.0001). While a small but significant decrease in the average RA CLs from acute AF to chronic AF contributed to this difference (acute = 131 ± 14 ms, chronic = 121 ± 18 ms, p < 0.0001), average LA CLs decreased more dramatically between the two groups (acute = 124 ± 16 ms, chronic = 96 ± 14 ms, p < 0.0001). Similar results were obtained with the minimum AF cycle length. That is, the minimum AF CL in the acute AF group (87 ± 23 ms) was significantly longer than it was in the chronic AF group (65 ± 19 ms) (p < 0.0001), with a small decrease in the RA (acute = 84 ± 20 ms, chronic = 74 ± 21 ms, p < 0.0001) and a more dramatic decrease in the LA (acute = 90 ± 26 ms, chronic = 57 ± 14 ms, p < 0.0001).

View larger version (17K): [in this window] [in a new window]   Figure 3 Left atrial (LA) and right atrial (RA) cycle lengths during acute or chronic AF. Top panel = mean AF cycle length; bottom panel = minimum AF cycle length. *p < 0.0001. Cycle length decreases in chronic AF, most significantly in the LA. AF = atrial fibrillation.

View larger version (29K): [in this window] [in a new window]   Figure 4 Comparison of AF cycle lengths for the 16 atrial locations. *p < 0.05. Solid triangles = acute AF; solid circles = chronic AF. Top panel = mean AF cycle length; bottom panel = minimum AF cycle length. Chronic AF cycle lengths are generally shorter, except in or close to the right atrial free wall. AF = atrial fibrillation.

AF organization.   Overall, atrial activation in the chronic AF group was slightly more disorganized than that in the acute AF group, with prediction errors of 2,322 ± 680 and 2,079 ± 651, respectively (p < 0.01). The lower organization in the chronic AF group is attributed to differences in LA organization. Both atria of the acute group (LA = 2,064 ± 718, RA = 2,092 ± 589) and the RA (2,052 ± 732) of the chronic group show similar organization, while the LA of the chronic group is significantly more disorganized, that is, has a higher prediction error (2,593 ± 497) (p < 0.0001).

Figure 5 shows the differences in organization according to atrial location. From acute AF to chronic AF, the largest increases in disorganization occur in the LA free wall and the lateral aspect of the LA appendage (p < 0.001). A small but significant increase in disorganization is also seen in the RA free wall (p < 0.05). Paradoxically, the lateral aspect of the RA appendage becomes less disorganized with chronic AF (p < 0.01).

View larger version (28K): [in this window] [in a new window]   Figure 5 Prediction error/disorganization according to atrial region. Solid triangles = acute AF. Solid circles = chronic AF. AF = atrial fibrillation; FW = atrial free wall; LatAp = lateral atrial appendage; MedAp = medial atrial appendage. *p < 0.05; **p < 0.001.

View larger version (68K): [in this window] [in a new window]   Figure 6 Example activation map sequences over 400 ms during acute and chronic AF. Regions in gray indicate areas either not activated or a portion of the electrode array not in contact with atrial tissue. In the acute AF group, left atrial activation was dominated by repetitive activation originating from the deep posterior and medial atrium. Activation in the right free wall had two to four wavelets that would have a stable pattern for two to three cycles before changing. In the chronic AF group, activation maps showed more complex activation in the left atrium. The right atrium had three to five wavelets that would also have a stable pattern for two to three cycles before changing.

In contrast, the LA of the chronic AF dogs showed more complex activation. Two to four wavelets were usually seen in the LA during chronic AF. Complex wave front interactions, such as wavelet collisions and various reentry patterns, were common in the left free wall and low left appendage. The chronic AF maps in Figure 6 illustrate the more complex activation in the LA as compared with that during acute AF.

Activation in the atrial appendages was typically uniform, especially at the appendage tips. In the acute group, the LA appendage was activated by the same broad wave front that activated the left free wall. In the chronic group, the smooth activation of the left appendage was often a consequence of activation spreading out from a more complex interaction in the free wall. In the RA appendage, the lateral aspect was activated similarly to the right free wall. In the medial aspect, both the chronic and acute groups showed smooth activation for the majority of that epicardial surface. However, closer towards Bachmann’s bundle, some small and well-contained wavelets were often seen. These attributes are also illustrated in Figure 6.

	Discussion

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Major findings.   The results from this study show that there are major differences in CL, organization and activation patterns between AF induced in normal atria by burst atrial pacing and chronic AF induced by long-term rapid atrial pacing. In general, the RA and LA of the acute AF model had similar cycle lengths and organization. However, the LA in the chronic AF model had significantly shorter cycle lengths and was more disorganized than the RA. Results also indicate that organization changes heterogeneously. Activation maps in the acute model revealed that LA activation was usually by a single broad wave front that originated from the deep posterior and medial atrium. In contrast, in the chronic model, activation maps showed an increase in the number of LA wavelets with more complex patterns of activation than in acute AF. Right atrial activation was similar in the two models with a trend towards slightly more wavelets in the chronic model.

Comparison with previous findings.   Several studies have shown differences between LA and RA electrophysiologic properties. In animal models with AF induced by long-term rapid pacing (6,7,18–21), several investigators have shown both shorter atrial effective refractory periods and shorter AF cycle lengths in the LA than in the RA, which is consistent with our observations. In patients Tse et al. (22) have shown shorter atrial refractoriness in the distal coronary sinus in patients with chronic AF as compared with controls, while refractoriness in the high RA did not change. Recently, Lee et al. (23) have shown differences between the LA and RA in the recovery of refractoriness after the cessation of rapid atrial pacing in dogs. In canine sterile pericarditis models of AF, Li et al. (19) described significantly longer atrial effective refractory periods in RA versus LA, while Kumagai et al. (24) noted that epicardial maps of the RA had significantly more wave fronts with more lines of functional block than the LA. In an epicardial mapping study of AF induced in dogs with vagal stimulation, Wang et al. (25) described "more regular and discrete" activation in the LA than in the RA, which is also consistent with observations in our acute AF group. In eight epicardially mapped patients with Wolff-Parkinson-White syndrome, Konings et al. (4) saw no consistent differences in CL or activation maps between the LA and RA during acutely induced AF, while in 6 of 13 patients, Cox et al. (3) observed macroreentrant circuits in the RA, with multiple wave fronts in the LA. In patients with chronic AF and mitral valve disease, Harada et al. (26) concluded from multiple epicardial recordings that the LA acted as a "driving chamber" for AF, with regular and repetitive LA activation and irregular activation in the RA. Jaïs et al. (27) described in humans more disorganized electrograms in the posteroseptal RA than in the anterolateral RA and broadly disorganized electrograms in the LA. In patients undergoing ablation for AF, Gaita et al. (28) showed an association between irregular electrogram morphology and unsuccessful ablation.

Clearly, there is little consensus on activation characteristics during AF, in part due to the varying models of AF studied. Each of these studies shows consistencies with various aspects of our two AF models. Our findings demonstrate important differences in acutely induced AF and that which occurs after long-term pacing induced remodeling. Thus, results from human or animal AF studies must be carefully interpreted with respect to the underlying model.

Mechanisms.   In animal models and in humans, paroxysms of transient AF can increase in duration until AF becomes chronic (7,29,30). In animal models (6,7,10,21,31,32), the development of chronic AF by long-term atrial pacing is accompanied by atrial enlargement, shortening of atrial refractoriness, loss of rate adaptivity of refractoriness, increased dispersion of refractoriness, changes in autonomic innervation and in sinus node function. From our results, long-term high-rate atrial pacing, which is associated with the electrical remodeling of AF, causes a preferential decrease in atrial CL and the organization of activation in the LA. Contributing factors to this heterogeneity include heterogeneous autonomic remodeling, which has been previously demonstrated by our lab (31), and heterogeneous anatomic constraints.

Regardless of the underlying causes of these changes in cycle length, organization and activation maps, our results imply that the different atrial regions remodel heterogeneously and may play different roles in AF maintenance and activation depending on the state of remodeling. Activation maps indicate that most of the LA in acute AF is activated in a passive manner. Since CLs and organization are similar between the LA and RA in acute AF, this suggests that both atria are triggered by some common source that could be located within the RA, the septum or the deep posterior aspects of either atrium. We note that, even though the RA often sustained more wavelets than the LA, the patterns of activation were usually similar over several cycles, and, thus, the degree of synchrony between multiple sites and the resulting spatial organization was still similar to that of the LA.

When analyzed according to a specific atrial region, our results show that remodeling does not affect organization in either the left or right medial appendage and only marginally in the right free wall. These areas roughly correspond to trabeculated regions of the atria where certain anatomic barriers exist. Anatomic barriers, such as Bachmann’s bundle and the crista terminalis, likely constrain activation and maintain the relative degree of spatial organization. For example, it is known that the crista terminalis serves as a conduction barrier that constrains the reentrant circuit of atrial flutter between it and the tricuspid annulus (33–36). During chronic AF, anatomic structures like the crista terminalis can restrict and consequently organize electrical activity. This has been suggested by Roithinger et al. (37) who observed the conversion of AF to atrial flutter in humans and found that, before conversion to atrial flutter, AF "organized" in the RA and usually demonstrated broad activation wave fronts propagating in a craniocaudal direction along the crista. In an earlier epicardial mapping study in dogs and in humans, Cox et al. (3) also showed several instances in which RA activation was dominated by a single broad wave front that propagated in the RA around the area of the crista terminalis. Lastly, a paradoxical change in organization was observed in the lateral aspect of the RA appendage where organization actually increased in chronic AF. While it is not clear why organization increases in this region, it appears that while the lateral aspect of the left appendage becomes more involved in the complexity of activation, the right appendage becomes more passive.

To our knowledge, this is the first study to quantitatively compare the regional organization of AF activation in acute and chronic AF in conjunction with CL and activation maps. Our measure of organization is similar to other previously published algorithms for measuring AF organization (38,39) but is more sensitive to changes in AF organization (14). This feature provides a quantifiable measure of the regional organization of AF that is less subjective than descriptions of isochronal activation patterns.

Clinical implications.   Ablation techniques are emerging as possible therapy for AF. The relative importance of ablating the LA versus the RA is still in debate. If human AF remodeling is similar to the canine AF remodeling described here, treatment of infrequent paroxysmal AF, especially when it is vagally mediated or does not involve remodeling from prolonged rapid rates, may be more successful with RA ablation lesions, while elimination of chronic AF may be more successful with LA ablation lesions. Similarly, other therapies, including electrical cardioversion, pacing therapy and drug therapy, may benefit from analyzing the relative organization of the AF being treated. Assuming that promoting atrial organization would also promote the conversion of AF to sinus rhythm, as inferred in the multiple wavelet hypothesis (5), these other therapies might be more effective if they concentrated their effects on eliminating or reducing the areas of disorganization. Note that these approaches address the substrate of AF rather than its triggers. Our study does not address the role of triggering events for AF, and AF therapies such as ablation may further benefit from considering such events.

Study limitations.   As pointed out by Ideker et al. (40), all epicardial mapping studies have certain basic limitations, of which one is the delineation of electrograms and activation times. We report minimum AF cycle lengths as a correlate of refractoriness (13). The minimum CL may be sensitive to double potentials or similar phenomenon, which may not reflect the true local activation. While we attempted to exclude double potentials in an electrogram by scanning spatially adjacent recordings, no clear criteria exist to distinguish double potentials from a short-duration local AF interval. Another basic limitation concerns the number and density of electrodes. While the mapping plaques covered most of the atrial epicardium, the extreme posterior, endocardial and septal areas of the atria could not be measured from. Further investigation of the roles of these areas in AF and AF remodeling is clearly warranted.

An additional limitation of this study is that the acute AF group and the chronic AF group could not be compared in a paired fashion because our observations were done using multiple epicardial recordings, requiring an open chest procedure. Techniques using multiple endocardial recordings may make paired comparisons feasible but are limited by their number and density of electrodes. Another potential limitation of this study is the differences in atrial size with chronic AF. As has been reported elsewhere (6,7,10,31), chronic rapid pacing causes changes in atrial enlargement. Whether any resulting change in atrial mass by itself is sufficient to cause the changes in atrial CL, activation and organization could not be determined. Finally, autonomic blockade was not performed in these animals. In other work from our lab (31), we have demonstrated that autonomic tone remodels with rapid atrial rates. While the changes in autonomic tone with remodeling are consistent with results presented here, it is not known to what degree the remodeled autonomics are responsible for the organization changes from acute to chronic AF.

	Footnotes

 
This work was supported, in part, by the Herman C. Krannert Fund, a grant from the Indiana Heart Association and grants HL52323 and HL03703 from the National Heart, Lung and Blood Institute of the National Institutes of Health. Dr. Olgin is supported, in part, by grant HL03703 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, and by a grant from the Indiana Heart Association. Drs. Zipes, Berbari and Sih are supported, in part, by grant HL52323 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

	References

Top Abstract Methods Results Discussion References

 

1. Moe GK, Abildskov JA. Atrial fibrillation as a self-sustaining arrhythmia independent of focal discharge. Am Heart J. 1959;58:59–70[CrossRef][Medline]
2. Allessie MA, Lammers WJEP, Bonke FIM, Hollen J. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. Zipes DP, Jalife J. Cardiac Electrophysiology and Arrhythmias. Orlando, Florida: Grune and Straton, Inc; 1985. p. 265–275
3. Cox JL, Canavan TE, Schuessler RB, et al. The surgical treatment of atrial fibrillation: II. Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atrial flutter and atrial fibrillation. J Thorac Cardiovasc Surg. 1991;101:406–426[Abstract]
4. Konings KTS, Kirchhof CJHJ, Smeets JRLM, Wellens HJJ, Penn OC, Allessie MA. High-density mapping of electrically induced atrial fibrillation in humans. Circulation. 1994;89:1665–1680[Abstract/Free Full Text]
5. Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Int Pharmacodyn Ther. 1962;140:183–188
6. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial pacing: structural, functional and electrophysiological characteristics of a new model of sustained atrial fibrillation. Circulation. 1995;91:1588–1595[Abstract/Free Full Text]
7. Wijffels MCEF, Kirchhof CJHJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92:1954–1968[Abstract/Free Full Text]
8. Daoud EG, Bogun F, Goyal R, et al. Effect of atrial fibrillation on atrial refractoriness in humans. Circulation. 1996;94:1600–1606[Abstract/Free Full Text]
9. Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation: time course and mechanisms. Circulation. 1996;94:2968–2974[Abstract/Free Full Text]
10. Elvan A, Wylie K, Zipes DP. Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs: electrophysiological remodeling. Circulation. 1996;94:2953–2960[Abstract/Free Full Text]
11. Slocum J, Byrom E, McCarthy L, Sahakian A, Swiryn S. Computer detection of atrioventricular dissociation from surface electrocardiograms during wide QRS complex tachycardias. Circulation. 1985;72:1028–1036[Abstract/Free Full Text]
12. Shkurovich S, Sahakian AV, Swiryn S. Detection of atrial activity from high-voltage leads of implantable ventricular defibrillators using a cancellation technique. IEEE Trans Biomed Eng. 1998;45:229–234[CrossRef][Medline]
13. Kim K-B, Rodefeld MD, Schuessler RB, Cox JL, Boineau JP. Relationship between local atrial fibrillation interval and refractory period in the isolated canine atrium. Circulation. 1996;94:2961–2967[Abstract/Free Full Text]
14. Sih HJ, Zipes DP, Berbari EJ, Olgin JE. A high-temporal resolution algorithm for quantifying organization during atrial fibrillation. IEEE Trans Biomed Eng. 1999;46:440–450[CrossRef][Medline]
15. Bayly PV, Johnson EE, Wolf PD, Greenside HS, Smith WM, Ideker RE. A quantitative measurement of spatial order in ventricular fibrillation. J Cardiovasc Electrophysiol. 1993;4:533–546[Medline]
16. Sih HJ, Sahakian AV, Arentzen CE, Swiryn S. A frequency domain analysis of spatial organization of epicardial maps. IEEE Trans Biomed Eng. 1995;42:718–727[CrossRef][Medline]
17. Littell RC, Milliken GA, Stroup WW, Wolfinger RD. SAS System for Mixed Models. Cary, NC: SAS Institute Inc; 1996.
18. Power JM, Beacom GA, Alferness CA, et al. Susceptibility to atrial fibrillation: a study in an ovine model of pacing-induced early heart failure. J Cardiovasc Electrophysiol. 1998;9:423–435[Medline]
19. Li H, Hare J, Mughal K, et al. Distribution of atrial electrogram types during atrial fibrillation: effect of rapid atrial pacing and intercaval junction ablation. J Am Coll Cardiol. 1996;27:1713–1721[Abstract]
20. Sih HJ, Berbari EJ, Zipes DP. Epicardial maps of atrial fibrillation after linear ablation lesions. J Cardiovasc Electrophysiol. 1997;8:1046–1054[Medline]
21. Gaspo R, Bosch RF, Talajic M, Nattel S. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation. 1997;96:4027–4035[Abstract/Free Full Text]
22. Tse H-F, Lau C-P, Ayers GM. Heterogeneous changes in electrophysiologic properties in the paroxysmal and chronically fibrillating human atrium. J Cardiovasc Electrophysiol. 1999;10:125–135[Medline]
23. Lee S-H, Lin F-Y, Yu W-C, et al. Regional differences in the recovery course of tachycardia-induced changes of atrial electrophysiological properties. Circulation. 1999;99:1255–1264[Abstract/Free Full Text]
24. Kumagai K, Khrestian C, Waldo AL. Simultaneous multisite mapping studies during induced atrial fibrillation in the sterile pericarditis model: insights into the mechanism of its maintenance. Circulation. 1997;95:511–521[Abstract/Free Full Text]
25. Wang Z, Pagé P, Nattel S. Mechanism of flecainide’s antiarrhythmic action in experimental atrial fibrillation. Circ Res. 1992;71:271–287[Abstract/Free Full Text]
26. Harada A, Sasaki K, Fukushima T, et al. Atrial activation during chronic atrial fibrillation in patients with isolated mitral valve disease. Ann Thorac Surg. 1996;61:104–112[Abstract/Free Full Text]
27. Jaïs P, Haïssaguerre M, Shah DC, Chouairi S, Clèmenty J. Regional disparities of endocardial atrial activation in paroxysmal atrial fibrillation. Pacing Clin Electrophysiol. 1996;19:1998–2003[CrossRef][Medline]
28. Gaita F, Riccardi R, Calò L, et al. Atrial mapping and radiofrequency catheter ablation in patients with idiopathic atrial fibrillation: electrophysiological findings and ablation results. Circulation. 1998;97:2136–2145[Abstract/Free Full Text]
29. Kopecky SL, Gersh BJ, McGoon MD, et al. The natural history of lone atrial fibrillation: a population-based study over three decades. N Engl J Med. 1987;317:669–674[Abstract]
30. Takahashi N, Seki A, Imataka K, Fujii J. Clinical features of paroxysmal atrial fibrillation: an observation of 94 patients. Jpn Heart J. 1981;22:143–149[Medline]
31. Jayachandran JV, Sih HJ, Winkle W, Zipes DP, Hutchins GD, Olgin JE. Atrial fibrillation produced by prolonged rapid atrial pacing is associated with heterogeneous changes in atrial sympathetic innervation. Circulation (in press).
32. Fareh S, Villemaire C, Nattel S. Importance of refractoriness heterogeneity in the enhanced vulnerability to atrial fibrillation induction caused by tachycardia-induced atrial electrical remodeling. Circulation. 1998;98:2202–2209[Abstract/Free Full Text]
33. Kalman JM, Olgin JE, Saxon LA, Fisher WG, Lee RJ, Lesh MD. Activation and entrainment mapping defines the tricuspid annulus as the anterior barrier in typical atrial flutter. Circulation. 1996;94:398–406[Abstract/Free Full Text]
34. Olgin JE, Kalman JM, Fitzpatrick AP, Lesh MD. Role of right atrial endocardial structures as barriers to conduction during human type I atrial flutter: activation and entrainment mapping guided by intracardiac echocardiography. Circulation. 1995;92:1839–1848[Abstract/Free Full Text]
35. Arenal A, Almendral J, Alday JM, et al. Rate-dependent conduction block of the crista terminalis in patients with typical atrial flutter: influence on evaluation of cavotricuspid isthmus conduction block. Circulation. 1999;99:2771–2778[Abstract/Free Full Text]
36. Tai CT, Chen SA, Chen YJ, et al. Conduction properties of the crista terminalis in patients with typical atrial flutter: basis for a line of block in the reentrant circuit. J Cardiovasc Electrophysiol. 1998;9:811–819[Medline]
37. Roithinger FX, Karch MR, Steiner PR, SippensGroenewegen A, Lesh MD. Relationship between atrial fibrillation and typical atrial flutter in humans: activation sequence changes during spontaneous conversion. Circulation. 1997;96:3484–3491[Abstract/Free Full Text]
38. Ropella KM, Sahakian AV, Baerman JM, Swiryn S. The coherence spectrum: a quantitative discriminator of fibrillatory and nonfibrillatory cardiac rhythms. Circulation. 1989;80:112–119[Abstract/Free Full Text]
39. Botteron GW, Smith JM. A technique for measurement of the extent of spatial organization of atrial activation during atrial fibrillation in the intact human heart. IEEE Trans Biomed Eng. 1995;42:579–586[CrossRef][Medline]
40. Ideker RE, Smith WM, Blanchard SM, et al. The assumptions of isochronal cardiac mapping. Pacing Clin Electrophysiol. 1989;12:456–478[CrossRef][Medline]

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