Electrophysiologic mechanisms of perpetuation of atrial fibrillation

Electrophysiologic Mechanisms of Perpetuation of Atrial Fibrillation Maurits

A. Allessie,

MD, PhD, Karen Konings, MD, Charles and Maurits Wiiffels, MD

J. H. J. Kirchhof,

MD, PhD,

The presence of an excitable gap during atrial fibrillation (AF), although short and variable, may be of potential importance for the development of alternative techniques for termination of AF by rapid pacing. Also the notion that perpetuation of AF may be partly dependent on macroreentry around the natuml atrial orifices, may provide a new thempeutic option for the permanent cure of AF by interrupting the anatomical circular pathways

in the atria by radiofrequency ablation. In our opinion the mpidly growing understanding of the electrophysiologic mechanisms of AF certainly warrants some optimism about the possibility of cure of AF in the near future without causing too much discomfort and without cartying an unacceptable risk. (Am J Cardiol 1996; 77: 1 OA-23A)

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MAPPING

lthough our knowledge and understanding of cardiac arrhythmias has increased coniderably during the last 50 years, it is not until recent years that the interest of experimental and clinical cardiologists is focussing on atria1 fibrillation (AF). Several clinical trials have emphasized that AF is not such a benign arrhythmia as thought for a long time, but actually is associated with a considcrablc morbidity and mortality.1-7 Therefore the insight is growing that it may not be sufficient to control the ventricular rate during AF, but in order to prevent the associated morbidity and mortality, it might be necessary to cure AF itself. Recent studies indicate that AF is a treatable disease.x However, there are still many questions about the pathophysiologic mechanisms of AF which first should be answered before an adequate strategy for prevention and treatment of AF can be designed. AF in itself should not be regarded as a disease since any heart of sufficient size can fibrillate. However the stability of induced AF depends on various factors. In general, large hearts fibrillate longer than small hearts,” but even in one and the same heart the duration of episodes of AF varies considerably.‘” Thus the pathologic substrate of AF should account for tither an abnormally high inducibility (vulnerability) or an abnormally high stability of AF. In this article WCwill focus on the mechanisms related to perpetuation of AF.

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Maurits

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Allessie, Institute,

Maastricht,

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Research The MD,

Department

Maastricht The

CARDIOLOGY

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Mapping of the electrical excitation of the atria during AF is a powerful technique to gain insight into the fibrillatory process and the related abnormalities in intra-atria1 conduction. Until now only a relatively small number of AF mapping studies have been performed. An important limitation of these studies is that most of them have been done in more or less normal atria in which AF was induced either by vagal stimulation and/or clectrical pacing.“-ls So far mapping data of clinical AF are scarce.16-i9Because of this, the possibility exists that the electrical phenomena during clinical AF may be basically different from the mapping data of artificially induced AF-mostly all that has been acquired so far. In 1985, mapping studies on cholinergically induced AF in isolated canine hearts” provided the first experimental evidence supporting Mot’s multiple wavelet hypothesis.20 This hypothesis postulated that perpetuation of AF was based on the continuous propagation of various individual wavelets in the atria. From the experimental study of Allessie et all2 it was estimated that a critical number of 3-6 wavelcts was required for perpetuation of AF. Recently these observations have been confirmed by Wang et a114J5who showed that termination of AF by flecainide, procainamide, or propafenone was preceded by a decrease in the average number of propagating wavelets. In 1991 Cox et al16J7studied 13 Wolff-ParkinsonWhite patients (age 15-36 years) during surgery of the accessory atrioventricular connections. None of these patients showed spontaneous AF during surgery, and AF was induced by burst pacing. In 6 of the 13 patients atrial activation patterns wcrc JANUARY

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1996

found during induced AF that were suggestive of reentry in the right atrium. In some of them functional conduction block seemed to be associated with an atria1 structure like the Crista Terminalis. The cycle length of these right atria1 reentrant circuits was relatively long, in the range of 180-210 msec. The left atrium was activated nonuniformly by wavefronts emerging either from a right atria1 reentrant circuit or from the accessory atrioventricular pathway. Documentation of complete left atria1 reentry was rare. In the remaining 7 patients reentry could not be conclusively demonstrated, but the repetitive sequence of activation of the atria was compatible with a large reentrant pathway, partly through the interatrial septum. Thus, this study showed multiple wavelets wandering around both natural anatomic obstacles and functional arcs of conduction block. In some cases the wavelets seemed to be offsprings of a single reentrant circuit. No evidence of micro-reentry or focal automaticity was found, and it was concluded that AF was maintained on the basis of macroreentry. Furthermore, it was emphasized that the macro-reentrant circuits present during AF were “so fleeting in appearance and location that it would be impossible to use on-line maps to guide surgical therapy.” However, in these studies the investigators had chosen to map both atria as completely as possible (except for the interatrial septum). Since the total number of recording channels was limited (in this case to 156 channels), s,patial resolution of the mapping had to be sacrificed and a relatively large inter-electrode distance of about 1 cm was used. With such a low density of electrodes, functionally determined micro-reentrant circuits can easily be missed. In the high density mapping study of human AF by Konings et all8 the electrical activation of the free wall of the right atrium was mapped during electrically induced AF in 25 patients with the Wolff-Parkinson-White syndrome. The patients (16 men, 9 women) underwent surgical interruption of

their accessory pathway for symptomatic or drugrefractory tachycardias. No cardiac abnormalities other than the Wolff-Parkinson-White syndrome were found in any of the patients. Mapping of the free wall of the right atrium was performed with a high density, spoon-shaped mapping electrode (diameter 3.6 cm), containing 244 unipolar electrodes (interelectrode distance, 2.25 mm) positioned manually on the atria1 wall. Before the patients were put on cardiopulmonary bypass and before cryoablation of the accessory pathway(s) was performed, the electrical activation of the right atrium was mapped during sinus rhythm, rapid pacing, and electrically induced episodes of AF. In 8 patients the free wall of the left atrium was also mapped. Intra-atria1 conduction block was defined as an apparent local conduction velocity <7.5 cmisec associated with a change in direction of propagation distal to the line of block. During sinus rhythm and rapid atria1 pacing (330 beats/min) in all patients the free wall of the right atrium was activated by a single broad, uniformly propagating wave of depolarization. The conduction velocity of this depolarization wave was 73 2 5 cmisec during sinus rhythm and 68 + 3 cm/set during rapid pacing. No areas of slow conduction or conduction block were found. In each patient a single time window of 12 set of AF was analyzed. The average duration of the episodes of AF selected for analysis was 173 + 154 sec. In the 25 patients a wide spectrum of activation patterns was found during AF. In an attempt to classify AF, 3 different categories were defined, based on the degree of complexity of activation of the free wall of the right atrium. In Figure 1 an example of these 3 different patterns of AF is shown. In type.1 AF the surface of the right atrium was activated by a single wavefront propagating uniformly or with only minor local conduction delays not disturbing the main course of the activation wave. During type II AF the area under the mapping

FIGURE 1. Illustration of the three types of activation during atrial fibrillation. The mapping electrode had a diameter of 3.6 cm and was positioned on the free wall of the right atrium. During type I fibrillation the free wall of the right atrium was activated by single broad, uniformtv orooaaating waves. In contrast, d&&g tyie Ill fibrillation a hiah dearee of dissociation was pr&ent &d the right atrium was activated by multiple wandering wavelets. (Adapted from Circulation.ls)

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electrode was activated either by a single wavefront showing major local conduction delay or by 2 different activation waves separated by a line of functional conduction block. During type III AF the right atrium was activated by multiple wavelets (23) separated by multiple lines of conduction block or areas of slow conduction ( < 10 cm/set). Generally, during AF a mixture of these diffcrent types of activation was seen. If more than 50% of the “beats” was of type I, II, or III, the patient was classified as having AF of type I, II, or III, respectively. From the analysis of a total of 1500 maps, 10 patients were classified as type I (40%), 8 patients as type II (32%), and 7 patients as having type III fibrillation (28%). There was no statistical significant difference among the three groups of patients with respect to age, sex, location of the accessory pathway(s), incidence of documented AF, or the duration of electrically induced AF. Also the conduction velocity of the uniformly propagating activation waves during sinus rhythm, rapid atria1 pacing, or AF did not differ in patients with type I, II, or III fibrillation. However there was a clear correlation between the type of fibrillation and the rate of AF. In type I AF the average median fibrillation interval was 174 * 28 msec, compared with 150 + 14 and 136 + 16 msec in types II and III fibrillation, respectively (p < 0.05). As the median fibrillation interval was shorter, the variation in fibrillation intervals was larger. In type I fibrillation the difference between the 5th and 95th percentile was 54 2 25 msec whereas in type II and III these values were 94 k 21 and 104 2 22 msec, respectively (p < 0.005). During AF the intra-atria1 conduction velocity was slower than during sinus rhythm (53 + 12 cm/set compared with 73 + 5 cm/set). In patients with type I fibrillation the average median conduction velocity was still relatively high (61 2 6 cm/ set). During type II fibrillation the average conduction velocity was 54 ZL4 cm/set (p < 0.02) whereas during type III fibrillation intra-atria1 conduction was as slow as 38 ? 10 cm/set (p
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Random Reentry

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J FIGURE 2. An example of random reentry during atrial fibrillation. The sites of the unipolar electrograms given next to the maps are indicated on the maps. During mndom reentry a wavelet reenters tissue which shortly before has been activated by another wavelet. Note that the local cycle length at the first site of reentry (electrode 3) is vey short (76 msec). Due to the opposite direction of activation of the reentering and the reentered wavelet, the local cycle length from electrodes 3 to 1 progressively increased from 76 to 136 msec. See ted for discussion. (Adapted from Circulotion.lB)

electrical activity were also observed. During type III fibrillation continuous right atria1 activity was predominant, and complete absence of propagating wavelcts in the free wall of the right atrium was rare, occurring only in 8 + 4% of the time (p
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Epicardial

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FIGURE 3. An example of leading circle reentry during atrial fibrillation. The sites of the unipolar electrograms are indicated on the maps. During leading circle reentry the impulse circulates around a central line of functional conduction block. During atrial fibrillation these functional circuits are not stationary but continuously shift in position. See text for discussion. (Adapted from Circulation.l*)

FIGURE 4. An example of a focal type of activation during atrial fibrillation. The sites of the unipolar electrograms are indicated on the maps. The eadiest electrogram recorded from the “focus” showed a small r-wave preceding its large intrinsic negative deflection. Repetitive “focal” beats were never observed. (Adapted from Circu/ation.J*)

ferences in local cycle length will arise. At the site of first reentry (electrode 3) the local cycle length is very short (in this case 76 msec) and is determined by the local refractory period (no excitable gap). However, due to the opposite direction of propagation of the reentering wavelets (from electrode 3 to electrode l), the local cycle length progressively increases when the reentering wavelet propagates away. In this example the local AF interval increases, within the relatively short distance between electrodes 3 and 1, from 76 to 136 msec. Thus, assuming that the local atria1 refractory periods are more or less the same, due to random reentry, at electrode 1, an excitable gap of about 50-60 msec must exist. Fixed reentrant circuits were never observed in the free wall of the right atrium. As a rule, leading circle reentry was not stable but drifted through the atria1 myocardium before it died out (Figure 3). The incidence of random reentry and leading circle reentry was different in the different types of fibrillation. In type I, random reentry was not observed and leading circle reentry occurred in only 2 patients, persisting for only a small number of cycles (2.4 + 1.4). In type II fibrillation, random reentry occurred in 8 f 8% of the beats and also shifting leading circle reentry was more common (in 28 + 25% of beats). In type III fibrillation, random reentry occurred in 33 + 10% of the beats whereas a shifting leading circle was observed

during 66 ? 29% of the fibrillation cycles. The average persistence of a shifting leading circle was also higher (5.4 ? 3.1 cycles). Frequently offspring from such a wandering circuit propagated away from the mapping area, while at the same time other fibrillation waves entered the mapping area to collide or fuse with the continuously circulating wavefront. Incidentally a “new” wavelet seemed to originate somewhere in the free wall of the right atrium when the surrounding epicardial electrograms showed no sign of propagation toward such an earliest site of activation (Figure 4). The incidence of these “focal” patterns of activation was rather low, however (0% in type I, < 1% in type II, and 2-3% during type III fibrillation) and always occurred as a solitary event. Repetitive focal responses were never observed. Although abnormal automaticity can not be completely excluded, the most likely explanation for these “focal” beats is epicardial breakthrough of a fibrillation wave propagating in deeper layers like a free running endocardial trabeculum.21 This is in agreement with the observation that the electrograms at the earliest sites of activation exhibited a small r-wave before their intrinsic negative deflection. Using the surface electrocardiogram, AF was first divided into “coarse” and “fine” fibrillation.23,24Later Wells and Waldo et a125,26 identified 4 different types of clinical AF based on the characteristics of a single bipolar atria1 electroA SYMPOSIUM: ATRIAL FIBRILLATION

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gram. In type I the electrogram showed discrete trical coupling of the cardiac fibers, and stimulating complexes of variable morphology separated by a efficacy of the depolarization wave may lead to clear isoelectric baseline. Type II was also charac- local conduction block of a premature impulse. terized by discrete atria1 beat-to-beat complexes of However, after the occurrence of local conduction variable morphology, but differed from type I in block a second requirement must be fulfilled for that the bipolar electrogram showed continuous the induction of reentry. The conduction time of perturbations of the baseline. During type III the impulse travelling around the area of block fibrillation highly fragmented atria1 electrograms must be long enough to allow the fibers proximal to were recorded showing no discrete complexes or the line of block to restore their excitability. The isoelectric intervals. Type IV fibrillation was char- significance of the wavelength for circus movement acterized by alternation between types III and the in the heart has been explicitly discussed by Lewis33 other types. In our opinion, however, type IV and later defined by Wiener and Rosenblueth34 as should not be regarded as a separate type of the distance traveled by the depolarization wave fibrillation, but rather, temporal variations in rate during the duration of the refractory period and degree of irregularity should be considered as (wavelength = conduction velocity x refractory pea general property of AF. Although we used the riod). In 2 previous studies35,36we have shown that same terminology as Wells and Waldo et a12s,26 the inducibility of reentrant arrhythmias and the (i.e., types I, II, and III), our criteria for classifica- size of functionally determined intra-atria1 circuits tion of AF were different. Instead of the morpholdepends on the wavelength of the atria1 impulse. ogy of a single bipolar atria1 electrogram, we used When the wavelength of a premature impulse is the complete pattern of activation of the free wall long, a large area of conduction block is required of the right atrium as obtained by high resolution for reentry to occur. However, when the length of a mapping (244 points). In both studies the mean premature impulse is short, either by depressed atrial rate increased from type I to type III. conduction, shortened refractoriness, or both, relaHolm et ali9 mapped the impulse propagation tively small areas of conduction block may already during AF in 12 patients with chronic AF using an be sufficient to set up reentrant circuits. Because a electrode array of 56 atria1 bipolar electrodes. The small arc of intra-atria1 conduction block is more distance between the electrodes in each pair was 3 likely to occur than a block involving a large mm and the distance between the electrode pairs portion of the myocardium, in normal hearts AF is was 3.1 mm in one direction and 5.9 mm in the exclusively induced under conditions in which the other direction. Their data emphasize the possibil- wavelength is short. In the canine heart, a critical ity that in chronic AF preferential directions of value of 7.8 cm was found for the induction of propagation may exist due to impulses originating AF.36 from distinctly localized areas. In 3 of 11 patients In 19 dogs in which the wavelength was varied with chronic AF, their data show clear evidence of by the administration of different drugs, the overall single or multiple “foci” of repetitive impulses correct prediction of the wavelength was 75% originating in the free wall of the right atrium. compared with 48% and 38% for the refractory period and intra-atria1 conduction velocity. The wavelength was also the most sensitive (88100%) THE WAVELENGTH Although it has become clear that AF is based and most specific (80-96%) index for the inducibon multiple reentrant circuits, it is still not known lity of arrhythmias. In Figure 5 the correlation is shown between the inducibility of atria1 arrhythto what extent the anatomic and electrophysiologic mias and the refractory period, the conduction properties of the atrium contribute to the initiation and perpetuation of fibrillation. Heterogeneity of velocity, and the wavelength of the provoking structural and electrophysiologic properties are premature impulse. The refractory period is plotthought to play a major role in the initiation of ted on the abscissa, the conduction velocity on the reentry because of the increased likelihood of ordinate, and the various wavelengths are given by unidirectional block of premature impulses.27-28 the curved “isowave”-lines (product of refractory Also the microarchitecture and anisotropic proper- period and conduction velocity; panel A). In panel ties of the myocardium may cause heterogeneous B all measurements of refractory periods and and discontinuous propagation of the impulse.29-32 conduction velocities of early premature impulses, both during control and during the administration Together with these structural heterogeneities, spatial dispersion in electrophysiologic properties of various drugs, are plotted together (n = 750). In such as refractory period, excitability, passive elec- panels C to F the different responses to premature 14A

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stimulation are separated in four subpopulations (no arrhythmias, rapid repetitive responses, atria1 flutter, and AF). The critical wavelengths for the different atria1 arrythmias are indicated on the various panels. Because of the use of a variety of drugs such as acetylcholine, propafenone, lidoCaine, ouabain, quinidine, and d-sotalol, the values of the atria1 refractory period and conduction velocity varied widely. From this graph one can see that the duration of the refractory period alone is not a specific parameter for the prediction of atria1 arrhythmias. The same holds true for the conduction velocity. For each of these 2 parameters there is considerable overlap between the different subpopulations. However, if one uses the wavelength as an index for the vulnerability to atria1 arrhythmias, a clear separation between the four subpopulations becomes evident. Three wavelength bands can be distinguished. A band of rapid repetitive responses (panel D, wavelength 9.7-12.3 cm), a “flutter band” of 7.8-9.7 cm (panel E), and a zone of AF at wavelengths < 7.8 cm (panel F). In Figure 6, the critical values of refractory period, conduc-

FIGURE 5. Relation between induction of atrial arrhythmias and refractory period, conduction velocity and wavelength of the initiating premature beat. Panel A: The refractory period is plotted on the abscissa and the conduction velocity on the ordinate. “Isowavelength” curves are drawn as the product of refractory period and conduction velocity. Panel 8: 750 responses to a single early premature stimulus obtained in 19 dogs both during control and after administartion of various drugs. Because of the natural spatial dispersion in electrophysiologic properties, and because of the effects of the different drugs, a wide range of values of refmctory period, conduction velocity, and wavelength was achieved. Panels C-F: The four different types of responses (no arrhythmia, rapid repetitive responses, atrial flutter and atrial fibrillation) plotted separately, together with the calculated critical wavelength. At long wavelengths no arrhythmias occurred. At a critical wavelength between 9.7 and 12.3 cm repetitive responses were induced, whereas between 7.8 and 9.7 cm atrial flutter was the prevailing arrhythmia. At a wavelength <7.8 cm atrial fibrillation was induced in 82% of the cases. (Adapted from Circ Res.36)

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tion velocity, and wavelength for the induction of atria1 arrhythmias are plotted during control and the administration of the various drugs. The critical values of both refractory period and conduction velocity varied widely under the influence of these drugs. In contrast, the critical value of the wavelength was strikingly constant, despite the different electrophysiologic effects of the different drugs. Administration of quinidine (10 mg/kg) prolonged the shortest possible wavelength of the premature beat to 9.1 cm. Since this was longer than the critical wavelength for AFib (7.8 cm), AF could no longer be induced. d-Sotalol (8 mg/kg) prolonged the shortest wavelength even further, to 9.6 cm, and prevented the induction of both atria1 flutter and fibrillation. Since for AF a critical number of wandering wavelets is required, the wavelength is also important for perpetuation of fibrillation. If during fibrillation the wavelength is relatively long, fewer waves can circulate through the atria, and fibrillation will tend to self-terminate. However, when the wavelength is short, a greater number of wavelets

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LIOOCAINE

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OUINIDINE

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THE EXCITABLE GAP DURING ATRlAL FIBRILLATION

FIGURE 6. Critical values of refractory period! conduction vebcii, and wavelength for induction of rapld repetitiie responses (squares), atrial flutter (triangles), and atrial fibrillation (dots) as determined during control and after adminktratii of various drugs. Both the critical values of the atrial refractory period and conduction velocity for induction of arrhythmias varied during administration of drugs. However, the critical value of the wavelength for induction of arrhythmias was remarkably constant during all the different drugs. ACh, ocetyfcholine. (Adapted from Circ Res.%)

can be present, and fibrillation will be sustained. As suggested by Rensma et al,“” a critical wavelength of the atria1 impulse might bc the vulnerable parameter for induction and perpetuation of AF. Consequently the antifibrillatory action of antiarrhythmic drugs can be described in terms of effects of these drugs on the wavelength of the atria1 impulse. Drugs that shorten the wavelength arc arrhythmogenic, whereas agents that prolong the wavelength posses antifibrillatory properties. An increase in wavelength is most effectively accomplished by a combined increase in refractory period and conduction velocity. Compounds whose action on one variable is partially counteracted by an Atrial Fibrillation

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opposite effect on the other variable are less e&tive. Recently Wang et a114,15 have studied the effects of flecainidc, procainamide, propafenone, and sotalol on electrically induced AF in vagally stimulated dogs. Mapping of termination of AF by these drugs showed that termination was associated with a reduction of the number of wavelets during AF. AI1 drugs increased the refractory period and the wavelength during rapid pacing of the atria. The antifibrillatory action was influenced to a great extent by the use dependence or reverseuse dependence of the different drugs. A clinical dosage of sotalol, for instance, was ineffective in terminating AF because its effect on the atria1 refractory period and wavelength showed a strong reverse use dependency.

As a result of the wandering multiple wavelets during AF, local atria1 electrograms show a high activation rate and a beat to beat variation in configuration and cycle length. This variation in local cycle lengths might represent changes in the duration of the local refractory period, depending on factors like the direction of impulse propagation (anisotropy),“’ the length of the previous interval, and electrotonic modulation of the action potential by neighboring wavelets or local intra-atria1 conduction block. On the other hand, the variation in local fibrillation interval might also be explained if, after recovery of their excitability, the fibers are not always immediately activated by one of the wandering fibrillation waves. In that case, especially during the relatively long AF cycles, an excitable gap may exist, and the fibrillation interval is determined by the sum of the local refractory period and the duration of the “waiting time.” This possibility implies that during AF the atria1 fibers are not always activated at their maximal rate, and that a volley of perfectly timed and spaced stimuli deliv-

Onset of Capture

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FIGURE 7. Three unipolar electrograms recorded simultaneously during atrial fibrillation in a conscious dog demonstrating local capture of the left atrium by rapid pacing. The electrogmms were reco&d from the bundle of Bachmannat1,2,and3cmfromthe pacing site. At the moment indicated by the asterisk the eiectrograms suddenly became phaselocked to the stimuli. V = ventricular response. (Adapted from Circulation.39)

ered in resonance with the fibrillatory wavelets theoretically should be able to interfere with the fibrillatory process.38 Both in chronically instrumented39 and in openchest dogs13 the presence of an excitable gap during AF was explored, and the effects of local electrical stimulation on the fibrillatory process was evaluated with high resolution mapping techniques. AF was induced by burst pacing of the left atrium. In conscious dogs a pair of electrodes sutured to the left atria1 appendage was used for pacing, whereas in the open-chest study the atrium was paced through a pair of stimulating electrodes in the center of a 248-lead mapping electrode. The duration of the episodes of fibrillation varied from several minutes to >3 hours. After AF had persisted for at least 15 minutes, high rate pacing was started at a cycle length of about 10 msec longer than the median fibrillation interval at the site of pacing. Subsequently, the pacing interval was gradually shortened in steps of 1 msec until atria1 capture occurred or the shortest fibrillation interval was reached. This procedure was repeated several times during each experiment. Figure 7 shows electrograms recorded at 1, 2, and 3 cm from the site of stimulation during AF in a conscious, chronically instrumented dog. In this example the left atria1 appendage was stimulated with a cycle length of 78 msec. The three unipolar electrograms were recorded simultaneously from

Atrial

adjacent electrodes on the bundle of Bachmann at distances of 1, 2, and 3 cm from the stimulating electrodes. During AF (left part of the tracings) the electrograms varied in morphology and cycle length. The first 8 stimuli did not affk ct the fibrillatory process, obviously since they were given during the refractory period of the fibrillatory impulses activating the pacing site. At a certain moment, however (asterisk), the electrogram recorded at 1 cm from the pacing site suddenly became phaselocked to the stimulus and at the same time the configuration of the electrogram became constant. Two cycles later the electrogram recorded 2 cm from the site of stimulation showed the same phenomenon suggesting regional capture of the fibrillating atria. During capture the difference in activation time between the first and second electrogram was constant (11 msec), indicating regular radial spread of propagation from the site of pacing with a conduction velocity of 91 cm/set. The electrogram recorded at a distance of 3 cm from the pacing site showed a different response. During some cycles the electrogram seemed to be in phase with the stimulus artefact. However, at other moments it was thrown out of phase, and also the configuration of the electrogram did not become constant. Apparently, 3 cm away from the site of stimulation the atrium was not always activated by the wavefront originating from the pacing site but still by the fibrillation waves. On the

Fibrillation

+

Capture

123456

FIGURE 8. Epicardial mapping of the free wall of the left atrium during capture of atrial fibrillation by rapid pacing. The 6 consecutive maps show the transition between atrial fibrillation and regional capture by local stimulation at the center of the mapping electrode. The unipolar electrogram (top) was recorded at the asterisk in map 1. In each map t = 0 corresponds to the moment of stimulation. See text for description. (Adapted from Circulation.13)

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average, in the chronically instrumented dog, the left atrium could be captured over a distance of 3.1 ? 0.8 cm from the site of pacing. The time window for obtaining and maintaining capture was very small, often not more than a few milliseconds. Termination of AF by local pacing was never observed. The presence of a narrow, excitable gap during AF is further illustrated in Figure 8. In this example the atria were paced from the center of the mapping electrode, which was positioned on the free wall of the left atrium. In each map, time zero coincides with the moment of stimulation (interval 86 msec). The median fibrillation interval at the site of pacing was 91 msec (P5-95: 32 msec). The top electrogram Was recorded close to the pacing site (asterisks in upper left map). At the moment indicated by the arrow, the electrogram became phase-locked to the stimuli and the electrogram became constant in configuration. Prior to onset of capture the atrium under the mapping electrode was activated in an irregular manner by multiple wavelets from various directions (maps l-3). During the first map the pacing site in the center of the mapping electrode was activated 10 msec before the stimulus was scheduled. Thus at the moment of the stimulus (t = 0) the fibers under the stimulating electrodes were refractory and the stimulus was ineffective. During the next beat (map 2) the site of pacing was activated 6 msec prior to the moment of stimulation and again the stimulus fell in the absolute refractory period. The third stimulus (map 3) was given simultaneously with activation of the pacing site by a broad fibrillation wave propagating from the upper left to the lower right part of the electrode and the stimulus did not seem to affect the spread of activation of this fibrillation wave. The fourth stimulus however (map 4) clearly seemed to capture the area under the pacing electrode and as a result the lower right quadrant of the mapping area was activated by a wavefrontoriginating from the pacing site. Capture was obtained because the next fibrillation wave did not enter the mapping area until 10 msec before the stimulus. Since the conduction time from the periphery to the center of the electrode was more than 10 msec, the stimulus could excite the tissue before it was activated by this incoming fibrillation wave. If the stimulus would not have been given, the fibrillation interval between beats 3 and 4 in the center of the mapping electrode would have been approximately 102 msec. Since the stimulus given at t = 86 msec was successful, the excitable gap during the interval between beats 3 and 4 would 18A

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have been about 16 msec. During the subsequent beats (maps 5 and 6) almost the entire mapping area was activated by a single wavefront originating from the pacing site. Only a small segment of the upper part of the electrode was not captured and remained activated by incoming fibrillation waves. In all dogs the average median fibrillation interval at the site of pacing was 89 f 10 msec. The shortest cycle of stable entrainment was 81 2 11 msec and on the average coincided with the P30 of the fibrillation interval histograms. This implies that during at least 70% of all fibrillation intervals an excitable gap must exist. Since the average P95 of the fibrillation intervals was 101 2 10 msec, during the longer fibrillation intervals the excitable gap might be as long as 20 msec. Thus, the variation in local fibrillation cycle length can be explained in two different ways. First, if the mechanism of AF is based solely on functional reentry of the leading circle type,40 it might reflect temporal fluctuations in the functional atria1 refractory period. Due to the complex and fragmented excitation during fibrillation the duration of the action potential can be expected to vary because of electrotonic modulation by the passage of neighboring wavelets and/or local intra-atria1 conduction block.41 In addition, the variation in local AF cycle length in itself might cause oscillations in the duration of the action potential. A second explanation for the temporal variation in local fibrillation intervals is the assumption of a variable excitable gap. In leading circle reentry a short partially excitable gap may arise, if the amount of excitatory current generated by the fibrillation wave at the pivot points of the central line of functional conduction block is insufficient to excite the large number of cells distal to the pivot point (impedance mismatch).42 During random reentry an excitable gap may arise if the cells are not immediately activated by one of the wandering wavelets after they have regained their excitability. In that case the local cycle length will be determined by the local refractory period plus the time the cells have to wait until they are excited by the next fibrillation wave. Only the shortest cycle lengths during fibrillation then represent the local refractory period, whereas the longer AF cycles contain a shorter or longer partially excitable gap. The studies of Allessie and Kirchhof et al13j39on regional entrainment of AF demonstrate that such an excitable gap actually does exist. This implies that the temporal variation in local fibrillation intervals, at least partly, is due to variation in the duration of an excitable gap. JANUARY 25. 1996

This raises the questions (1) what causes the excitable gap during AF and (2) how may antitibrillatory drugs affect it? At present, three causes for the creation of an excitable gap during AF are recognized: (1) the involvement of a gross anatomic obstacle in the reentrant pathway (such as the natural orifices of the caval and pulmonary veins and the mitral and tricuspid rings); (2) a low safety factor for conduction at the sharp U-turns in a reentrant circuit due to a high curvature of the depolarization wave (anisotropy)“3,44; and (3) random reentry (Figure 2). At present it is unknown to what extent these 3 possible mechanisms contribute to the creation of an excitable gap during AF. During type III fibrillation, random reentry might bc a primary source for the creation of an excitable gap, whereas during type I fibrillation the longer AF cycle lengths may be caused by anatomic reentry. The mapping data on AF collected so far, are certainly in agreement with the concept that AF is perpetuated by a mixture of functionally determined reentry, leading circle as well as random reentry causing the shorter AF cycle lengths, and macro-anatomic reentrant circuits creating the longer ones. Class I antiarrhythmic agents, then, can be expected to enlarge the excitable gap during AF, both by slowing of the conduction velocity in fixed anatomic circuits and by exaggerating the delay of functional circuits when the impulse makes a sharp U-turn (low safety factor for conduction due to high curvature of the depolarization wavc).43

ATRIA1 FIBRILLATION FIBRIUATION

BEGETS ATRIA1

Chronic AF is often preceded by episodes of paroxysmal AF.’ The transition from paroxysmal to chronic fibrillation may be due to a further progression of an underlying ctiologic process, or fibrillation itself may cause changes in the myocardium that favor its irrcvcrsibi1ity.‘0.45 Recent clinical studies have rcvcalcd that atria1 defibrillation, either electrically or by intravenous administration of class I or class III drugs, has a higher success rate if AF is of recent onset ( < 24 hours), compared to AF of longer duration. 4(*s3These clinical observations support the possibility that AF by itself may lead to a tachycardiomyopathy of the atria1 myocardium, promoting the occurrence and perpetuation of AF. Such a positive feed back mechanism, if it exists, of course would offer a plausible explanation for the clinical observation that AF becomes more persistent with time. The hypothesis that AF begets AF was recently tcstcd by Wijffels et a1’o.4sin the chronically instru-

mented goat. This experimental study showed that cvcn during the first days of AF, marked electrophysiologic changes took place in the atria that clearly favored the induction and perpetuation of AF. The artificial maintenance of AF by a fibrillation pacemaker led to sustained AF (lasting >24 hours) in 10 of 11 goats. After conversion to sinus rhythm the fibrillation-induced clcctrophysiological changes turned out to be fully reversible within about 1 week of sinus rhythm. The dcvclopment of an animal model of chronic AF was based on the idea that artificial maintenance of AF for some prolonged period of time (weeks) would exert proarrhythmic effects on the atria that would lcad finally to sustained AF. A total of 27 unipolar electrodes wcrc chronically implanted on the left and right free atria1 wall and on Bachmann’s bundle from the left to the right atrial appendage. After about 1-2 weeks, when the goats had fully recovered from surgery, an extensive electrophysiologic study of the atria was done, including measurements of the atrial refractory period at different pacing intervals (150-500 mscc) at multiple atrial sites. The basic stimuli had a stimulus strength of 2 x threshold, and the single premature test stimuli were of 4 x diastolic threshold. Also the atria1 conduction velocity was measured at various pacing rates by pacing one of the atrial appendages and measuring the conduction times along the row of electrodes along Bachmann’s bundle. The inducibility of AF was tested by applying single early premature stimuli (4 x threshold) at different atria1 sites. After having performed a complete electrophysiologic study during sinus rhythm, the goats (n = 12) were connected to an external fibrillation paccmakcr. This fibrillation pacemaker (dcvcloped in-house) automatically induced AF by dclivering a 1-set burst of stimuli (50 Hz) immediately upon detection of sinus rhythm. The detection algorithm that was used continuously measured the maximal length of the isoelectric scgmcnt in a bipolar atria1 electrogram. Typically, during sinus rhythm the isoelectrical interval is >250 msec, whereas during AF the isoelectrical segment is <80 msec. Thus, this parameter provides an easy and reliable way to continuously monitor the atrial rhythm and to dctcct instantly when spontaneous conversion of AF into sinus rhythm occurs. In the normal goat (not having been in AF before), a I-set burst of stimuli of 50 Hz invariably induces an episode of AF, which as a rule self-terminates within < 10 sec. The median AF interval of “acute” fibrillation was relatively long and avcragcd about A SYMPOSIUM:

ATRIAL

FlBRlLlATlON

19A

burst pacing -

AF -

b

I

AF

after 24 hour

Sustained

l

AF

after

2 weeks

maintained atrial fibrillation. (Adapted from Circulation.45)

This episode -

of atrial fibrilkttion

was sustained

160 msec. Because the fibrillation pacemaker reinduces AF within 1 set after conversion to sinus rhythm, in this way AF could be maintained almost continuously during 24 hours a day, 7 days a week. During sinus rhythm the episodes of electrically induced AF were very short and terminated after only 6 +- 3 sec. In the 12 animals, the median interval of these short runs of AF was 113-176 msec (mean 145 + 18 msec). After 24 hours of maintained AF the average duration of AF had increased to 2.2 & 3.0 minutes, and the fibrillation interval had shortened to 108 +- 8 msec. After 48 hours in 2 goats AF had become sustained (lasting > 24 hours) while in the remaining 10 goats fibrillation lasted for 7.8 ? 9.7 minutes. The mean fibrillation interval was 105 + 8 msec. After 1 week, in 5 of 11 goats AF had become sustained and in the 6 other animals fibrillation lasted for 241 2 459 minutes. The fibrillation interval was 100 2 5 msec (one goat dropped out due to a serious sepsis). After 2 weeks in 9 of 11 goats, and within 3 weeks in 10 of 11 goats, fibrillation lasted > 24 hours (Figure 9). In the goat in which AF did not become sustained the longest episode of AF lasted for 13.5 hours. When after 3 weeks the goats were disconnected from the automatic fibrillation pacemaker, most of them remained in chronic AF. During sustained AF ( > 24 hours) the average AF interval was 99 +- 10 msec compared with 145 + 18 msec for the short lasting episodes of AF induced during sinus rhythm. From this observation it can be concluded that the long-term existence of AF must cause changes in the atria1 electrical substrate in such a’ way that short paroxysms of AF with a relatively long AF interval are replaced by more

20A

FIGURE 9. Prolongation of the duration of episodes of electrically induced atrial fibrillation after maintaining atrial fibrillation for respectively 24 hours and 2 weeks. The three tracings show a single atrial electrogram recorded from the same goat during induction of atrial fibrillation by a 1 -set burst of stimuli (50 Hz, 4 x thresh20 sec. old). In the upper tracing the goat has been in sinus rhythm all the time and atrial fibrillation self-terminated within 5 sec. The second tracing was recorded after the goat had been connected to the 224 hours fibrillation pacemaker for 24 hours showing a prolongation of the dumtion of atrial fibrillation to 20 sec. The third tracing was recorded after 2 weeks of electrically and did not terminate spontaneously anymore. Duration of Fibrillation

Sinus Rhythm

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persistent AF with a higher atria1 rate. Or in other words, this study strongly supported the hypothesis that “atria1 fibrillation begets atria1 fibrillation.”

ELECTRICAL REMODELING ATRIA1 FIBRILLATION

DUE TO

To evaluate which electrophysiologic changes of the atria1 myocardium might be responsible for the prolongation of AF duration and the increase in the atria1 rate of fibrillation, we measured the electrophysiologic properties of the atria1 tissue at various moments during maintenance of AF. Effective atria1 refractory periods (ERP) were measured during pacing at various rates with an interpolated extra-stimulus (Sz) after every fifth basic stimulus (Sr; biphasic stimuli, 2 msec duration, 4 times diastolic threshold). The shortest Sr-S2 interval resulting in a propagated atria1 response was taken as the ERP. Intra-atria1 conduction velocity was determined while pacing at one of the atria1 appendages from the average conduction times between the electrodes covering the bundle of Bachmann. Repetitive induction of AF did not change the conduction velocity along the bundle of Bachmann. The average conduction velocity during slow pacing (400 msec) was 126 f 13 cm/set during control (goat in sinus rhythm) compared with 129 2 12 after 24 hours of maintained AF. During rapid atria1 pacing with 200 msec impulses, conduction velocity increased slightly from 111 + 9 to 118 2 9 cm/set. In contrast, AF gave rise to marked changes in the atria1 ERP. After 24 hours of AF, the ERP during pacing with 400 msec intervals had decreased from 146 rt 19 msec to 95 -t 20 msec

JANUARY 25, 1996

(-35%). At a higher pacing rate (200 ms.ec interval) the ERP decreased from 131 + 11 msec to 106 + 17 msec (-19%). Because the atria1 refractory period had shortened more at lower than at higher heart rates, the physiologic adaptation of the refractory period to heart rate was diminished and in some cases even reversed, resulting in a paradoxical shortening of ERP at a slowing of the heart rate. Figure 10 gives a typical example of the changes in refractory period induced by AF. In this example during control, the refractory period showed the physiologic rate adaptation of the ERP, which increased from 132 msec during rapid pacing (180 msec interval) to 150 msec during slow pacing (500 msec interval). After 6 hours of AF, the adaptation curve had already shifted downward, indicating a general shortening of the refractory period. After 24 hours of AF the adaptation curve was shifted further downward and the refractory period at the 500-msec pacing interval had shortened by about 50 msec to < 100 msec. At the higher pacing rates the adaptation curve had become flat and the normal prolongation of the refractory period upon slowing of the heart rate was abolished. At the slower heart rates (right part of the curve), the refractory period actually became shorter when the pacing interval was prolonged (inversed rate adaptation). In 1982 Attuel et a154,55 measured the atria1 refractory period in 39 patients during pacing at 23 cycle lengths. They found that in patients in which sustained atria1 tachyarrhythmias could be provoked with l-3 premature stimuli, the atria1 refractory period either failed to adapt or adapted poorly to changes in heart rate. On the basis of these observations they suggested that a poor or absent rate adaptation of the atria1 refractory period may constitute a clinical entity and might be a marker of atria1 pathology causing a propensity to AF. These observations were extended by Le Heuzey et a156who measured the effects of changes in heart rate on the duration of the action potential recorded from isolated strips of human atria1 myocardium. From these studies it was suggested that a maladaptation of refractoriness might be the cause of AF in humans. However, from the goat study of Wijffels et a1,45in which similar observations were made, it seemed that the maladaptation of the atria1 refractory period is the result of AF rather than the cause of it. No matter what the cause-and-effect relationships are, however, these studies point to the possibility that a fibrillationinduced maladaptation of the refractory period

ERP (ms) 160

80-

-

, 100

200

I 300

I 400 Pacing

I 500 Interval

(ms)

FIGURE 10. An example of the changes in atrial refractoriness in the course of the first 24 hours of atrial fibrillation. The refractory period shortened markedly at all pacing intervals. In general the amount of shortening was higher at slower heart rates. As a result, the normal physiological rate adaptation of the refractov period was attenuated or even reversed. (Adapted from Circulation.45)

may play an important role in the perpetuation of AF.

CONCLUSIONS The recent finding that “AF begets AF” might have some important implications. If it is true that the long-term shortening of atria1 refractoriness during fibrillation is based on a fundamental change in composition of the ion channels responsible for the repolarization of the atria1 cells (electrical remodeling), the action of antiarrhythmic drugs on fibrillating atria may be different from expected, and it may be necessary to re-evaluate the effects of antifibrillatory drugs in chronically fibrillating atria. On the other hand it opens the possibility that new drugs can be discovered that specifically target those ion channels that are abnormally expressed by AF. At this moment however, these implications are still speculative and more information about the ionic mechanisms of the fibrillation-induced shortening of repolarization is needed before any firm conclusions can be drawn. The anomalous rate adaptation of the atria1 refractory period observed after a couple of days of AF may play an important role in the spontaneous recurrence of AF, which is so frequently seen clinically during the first week after electrical or chemical defibrillation.52 Directly after cardioversion the atria1 interval suddenly prolongs from about loo-150 msec during AF to about 1000 msec during sinus rhythm. When the atria1 refractory period fails to respond to such a sudden slowing in heart rate with a prolongation of the refractory period, or even worse, when it

A SYMPOSIUM: ATRIAL FIBRILLATION

218

becomes shorter due to reversed rate adaptation, the atria will be left with a dangerously short refractory period after conversion to sinus rhythm. Without the natural protection of a long refractory period, the atria1 wavelength will be very short and on the first occasion an atria1 premature beat may reinduce AF. In the goat the shortening of the atria1 refractory period and the maladaptation to heart rate was reversible within a couple of days of sinus rhythm. If this is also true in humans, protection against the fibrillation-induced maladaptation of the refractory period during the first week after conversion might help to prevent early recurrences of AF. The short atria1 refractory period might also explain the diminished success rate of pharmacologic and electrical cardioversion in patients with long-lasting AF. The complete reversion of the AF-induced electrophysiologic changes within 1 week of sinus rhythm also implies that the role of electrical remodeling in patients with paroxysmal AF occurring less than once a week seems limited. Due to the reversibility of the AF-induced electrical remodeling, each paroxysm of AF is independent of the previous one. In general, however, the occurrence of electrical remodeling implies that the best prevention of AF is to terminate AF as quickly as possible. In that way the electrophysiologic sequellae of AF will be interrupted before they get a chance to lead to chronic AF. 1. Godtfredsen .I. Atria1 Fibrillation. Etiology, course and prognosis.A followup study of 1,212cases.Dr Med thesis,Univ. Copenhagen,Munksgaard, 1975. 2. Petersen P, Godtfredsen J. Atria1 Fibrillation-a review of course and prognosis.Acta Med Scami 1984,216:5-9. 3. Alpert JS, Petersen P, Godtfredsen J. Ahial fibrillation: natural history, complicationsand management.Ann Rev Med 1988;39:41-52. 4. EvansW, SwarmP. Lone amicular fibrillation. BrHeart.l1954;16:18~194. 5. Kannel WB, Abbott RD, SavageDD, McNamara PM. Epidemiologic features of chronic atrial fibrillation. The Framingham Study. N Engl J Med 1982;307:lOlMO22. 6. Brand FN, Abbott RD, Kannel WB, Wolf PA. Characteristicsand prognosis of lone atrial fibrillation. 30-Year follow-up in the Framingham study. J. 1982254344%3453. 7. Kopecky SL, Gersh BJ, Mffioon MD, Whisnant JP, Holmes DR, Ilstrup DM, Frye RL. The natural history of lone atrial fibrillation. A populationbasedstudy over three decades.N EnglJMed 1987;317:669-674. 8. In: Kingma JH, Van Hemel NM, Lie KI, eds. Atrial fibrillation, a treatable disease?Amsterdam:Kluwer Academic Publishers1992: 9. Moore EN, Spear JF. Natural occurrence and experimental initiation of atria1 fibrillation in different animal species. In: Kulbertas HE, Olsson SB, Schlepper M, eds. Atrial Fibrillation. Molndal, Sweden: Lmdgren and Saner, 1982:3wl. 10. Wijffels MCEF, Kirchhof CJHJ, Boersma LVA, Allessie MA. Atrial fibrillation begets atrial fibrillation. In: Olsson SB, Allessie MA, Campbell RWF, eds.Atrial fibrillation-Mechanisms and Therapeutic Strategies.Armor&, New York: Futura Publishing,1994;195-201. 11. Allessie MA, Iammers WJEP, SmeetsJRLM, Bonke FIM, Hollen .I. Total mapping of atrial excitation during acetylcholine-induced atrial flutter and fibrillation in the isolated canine heart. In: Kulbertus HE, Olsson SB, Schlepper M, eds. Atriai fibrillation. Molndal, Sweden: Lmdgren and Saner, 1982; 44-52.

12. Allessie MA, LammersWJEP, Bonke FIM, HoUen J. wrimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In: Zipes DP,

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13. Kirchhof CJHJ, Chorro F, Scheffer GJ, Brugada J, Konings K, Zetelaki Z, Allessie MA. Regional entrainment of atria1 fibrillation studied by highresolution mapping in open-chestdogs.Cticulatiorr 1993;88:736-749. 14. Wang Z, Pag6P, Nattel S. Mechanismof flecainide’s antiarrhythmic action in experimental atria1fibrillation. Circ Res 1992;71:271-287. 15. Wang J, Bourne GW, Wang Z, Villemaire C, Talajic M, Nattel S. Comparative mechanismof antiarrhflhmic drug action in experimental atrial fibrillation. Importance of use dependent effects on refractoriness. Circulation 1993;88: 1030-1044. 16. Cox JL, Canavan TE, SchuesslerRB, Cain ME, Lindsay BD, Stone C, Smith PK, Corr PB, Boineau JB. The surgical treatment of atrial fibrillation II: Intraoperative electrophysiologic mapping and description of the electrophysiologic basis of atria1 flutter and atrial fibrillation. J Thorac Cardkmsc Swg 1991;101:40&426. 17. Cox JL, Boineau JP, SchuesslerRB, Kater KM, Iappas DG. Surgical interruption of atrial reentry as a cure for atria1 fibrillation. In: Olsson SB, Allessie MA, Campbell RWF, eds.Atrial Fibrillation-Mechanisms and Therapeutic Strategies.Armonk, New York: Futura Publishing,1994;37+lO4. 18. Konings KTS, Kirchhof CJHJ, Smeets JRLM, Wellens HJJ, Penn OC, Allessie MA. High density mapping of electrically induced atrial fibrillation in man. Circulation 1994;89:1665-1680. 19. Hahn M, Blomstrom P, Brandt J, Johansson R, Luhrs C, Olsson SB. Determination of preferable directions of impulse propagation during atria1 fibrillation by time averaging of multiple electrogram vectors. In: Olsson SB, Allessie MA, Campbell RWF, eds.Atria1 Fibrillation-Mechanisms and Therapeutic Strategies Armonk, New York: Futura Publishing,lw67-80. 20. Moe GK. On the multiple wavelet hypothesisof at&l fibrillation. Arch Irzt Phamlacodyn Ther 1%2;140:183-188. 2 1. Hoffman BF, Rosen MR. Cellular mechanismsfor cardiac arrhythmias. Circ Res 1981;49:1-15. 22. SchuesslerRB, Kawamoto T, Hand DE, Mitsuno M,Bromberg BI, Cox JL, Boineau JP. Simultaneousepicardial and endocardial activation sequencemapping in the isolated canine atrium. Circulation 1993,88;25&263. 23. Hewlett AW, Wilson FN. Coarse auricular fibrillation in man.Arch Inton Med 1915;15:78&793. 24. Nelson RM, Jensen CB, Davis RW. Differential atrial arrhythmias in cardiac surgicalpatients.J Thorac Cardiovasc Swg 1969;58:581-587. 25. Wells JL, Karp RB, Kouchoukos NT, MacLean WAH, JamesTN, Waldo AL. Characterization of atrial fibrillation in man: studies following open heart surgery.PACE 1978;1:42&438. 26. Waldo AL. Atrial fibrillation following open heart surgery. In: Olsson SB, Allessie MA, Campbell RWF, eds.Atrid, Fibrillation-Mechanisms and Therapeutic Strategies.Arma& New York: Futura Publishing,1994;211-223. 27.AUessie MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia. II. The role of nonuniform recovery of excitability in the occurrence of unidirectional block as studied with multiple microelectrodes.Cim Res 1976;39:168-177. 28. Boineau JP, SchuesslerRB, Mooney CR Miller CB, Wylds AC, Hudson RD, Borremans JM, Brockus CW. Natural and evoked atria1 flutter due to circus movementin dogs.Am J Cardiol1980;45:1167-1181. 29. Spach MS, Miller WT, Geselowitz DB, Barr RC, Kootsey JM, Johnson EA. The discontinuousnature of propagation in normal canine cardiac muscle. Circ Res 1981;48:39-54. 30. SpachMS, Kootsey JM, Sloan JD. Active modulation of electrical coupling between cardiac cells of the dog: A mechanismfor transient and steady state variations in conductionvelocity. Circ Res 1982;51:347-362. 31. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopiclevel in human cardiac muscIe. Cite Res 1986;58:356-371. 32. Spach MS, Josephson ME. Initiating reentry: The role of nonuniform anisotropy in small circuits.J Cardiovasc Electropt@~l1994;5:182-209. 33. Lewis T. The Mechanism and Graphic Registration of the Heart Beat. London: Shaw & Sons,1925: 34. Wiener N, Rosenblueth A. The mathematicalformulation of the problem of conduction of impulses in a network of connected excitable elements, specifically in cardiac muscle.Arch Imt Cardi Mm 1946;16:205-265. 35. SmeetsJLRM, Allessie MA, LammersWJEP, Bonke FIM, HoUen SJ.The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. Circ Res 1986;58:9&108. 36. Rensma PL, Allessie MG Iammers WJEP, Bonke FIM, Schalij MJ. The length of the excitation wave as an index for the susceptibility to reentrant atrial arrhythmias.Ciz Res 1988;62:395410. 37. Spach MS, Dolber PC, Heidlage JF. Interaction of inhomogeneities of

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sion of acute supraventricular tachycardia to sinus rhythm. Am J Cardbl 1987;59:607-. 48. Crijns HJGM, Van Wijk LM, Van G&t WH, Kingma HJ, van Gelder IC,

Lie KI. Acute conversion of atrial fibrillation to sinus rhythm: clinical efficacy of flecainide acetate. Comparison of hvo regimens.European Heati J 1988;9: 634638. 49. Bianconi L, BoccadamoR, PappaIardoA, Gentili C, F’iitolese M. Effective-

nessof intravenous propafenone for conversion of atriaI fibrillation and flutter of recent onset.Am J Cardiof 1989;63:1275-1278. 50. Suttorp MJ, Kingma JH, Lie-A-Huen L, Mast EG. Intravenous Flecainide versusverapamil for acute conversion of paroxysmal atria1fibrillation or flutter to sinusrhythm.Am J Cardtil1989;63:693696. 51. Suttorp MJ, Kingma JH, Jessuran ER, Lie-A-Huen L, van Hemel NM, Lie KI. The value of class lc antiarrhythmic drugs for acute conversion of paroxysmal atria1 fibrillation or flutter to sinus rhythm. J Am Coil Cardiol 1990;16:1722-1727. J Cardiovasc E.!arophysio[ 1994;5:945-960. 52. Van Gelder IC, Crijns HJGM, Van G&t WH, Verwer R, Lie KI. Predic42. Joyner RW, Overholt ED, Ramza B, Veenstra RD. Propagation through tion of uneventful cardioversion and maintenanceof sinus rhythm from directelectricaIIy coupled cells: Two inhomogeneouslycoupled cardiac tissue layers. current electrical cardioversion of chronic atrial fibrillation and flutter. Am J Am J Physiol1984$47:59fXO9. Cardiol1991;68:41+l6. 43. Allessie MA, Schalij MJ, Kirchhof CJHJ, Boersma L, Huybers.M, Hollen 53. Bjerkelund C, Oming 0. An evaluation of DC shock treatment of atrial SJ. Experimental electrophysiology and arrhythmogenecity. Anisotropy and arrhythmias.Acta Med Stand 1968;184:481491. ventricular tachycardia.Eur Heart J 1989;1O(suppl):2-8. 54.Attuel P, ChiIders R, Cauchemez B, Poveda J, Mugica J, Coumel P. 44. Davidenko JM, Pertsw AV, Salomonsz& Baxter W, JaIife J. Stationary Failure in the rate adaptation of the atria1 refractory period: its relationship to and driftiig spiral wavesof excitation in isolated cardiac muscle.Natrrre 1992,355: vulnerability. Int J Cardiol1982;2:179-197. 34%351. 55. Attuel P, Childers RW, HaissaguerreM, Leclercq J, Mugica J, Coumel R. 45. Wijffels MCEF, Kirchhof CIHJ, Dorland R, AUessieMA. AtriaI fibriIIaFailure in the rate adaptation of the atrial refractory period: new parameter to tion begets atria1 fibriuation. A study in awake chronically instrumented goats. assessatrial vulnerability. PACE 1984;7:1382. Circulation 1995;92:1954-1968. 56. Le Heuzey JY, Boutjdir M, Gagey S, Lavergne T, Guize L. Cellular 46. Gold RL, Haffajee CI, Charos G, Sloan K, Baker S, Alpert JS. Amiodaaspects of atrial vulnerability. In: Attuel P, Coumel P, Janse MJ, eds. The rone for refractory atria1fibrillation. Am .J Cardiol1986;57:124-127. Atrium in Health and Disease. Mount Kisco, New York: Futura Publishing, 47. Crazier IG, Ikram H, Kenealy M, Levy L. Flecainide acetate for conver- 1989;81-94.

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