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(Circulation. 1997;96:3013-3020.)
© 1997 American Heart Association, Inc.

Articles

\E Induction of Meandering Functional Reentrant Wave Front in Isolated Human Atrial Tissues

Takanori Ikeda, MD; Lawrence Czer, MD; Alfredo Trento, MD; Chun Hwang, MD; James J. C. Ong, MD; Dustan Hough, BS; Michael C. Fishbein, MD; William J. Mandel, MD; Hrayr S. Karagueuzian, PhD; ; Peng-Sheng Chen, MD

From the Division of Cardiology, Department of Medicine; the Division of Cardiothoracic Surgery, Department of Surgery (A.T.); and the Department of Pathology (M.C.F.), Cedars-Sinai Medical Center and University of California Los Angeles School of Medicine.

	Abstract

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Background The purpose of this study was to test the hypothesis that a single meandering functional reentrant wave front can result in rapid and irregular electrogram activity in human atrial tissues.

Methods and Results The study used the explanted hearts of five human cardiac transplant recipients. Three right and two left atrial tissue samples, 3.4±0.3 mm thick, were excised and trimmed to 3.5x3.0 cm. The isolated atrium was placed endocardial surface down in a chamber with a 477 bipolar recording electrode array built into the bottom of the tissue bath. The interelectrode distance was 1.6 mm. The tissue was constantly superfused with 36.5°C oxygenated Tyrode's solution at a rate of 10 mL/min. After eight baseline stimuli (S₁) delivered at 400- or 600-ms cycle length from the edge of the tissue, a single premature stimulus (S₂) was given at the center of the tissue to induce reentry. A total of nine episodes of reentry were induced with S₁-S₂ coupling intervals of 232±29 ms (range, 190 to 290 ms) and an S₂ strength of 10±3 mA (range, 5 to 15 mA). In all samples, a single meandering reentrant wave front was induced, causing irregular and rapid bipolar electrogram activity. These wave fronts had a mean cycle length of 229±45 ms (160 to 290 ms) and persisted for 1.1±0.3 seconds (0.6 seconds to 2.5 seconds), or 5.2±1.4 (3 to 9) cycles, before spontaneous termination.

Conclusions A single meandering functional reentrant wave front can be induced in human atrial tissues and produce rapid and irregular electrical activity.

Key Words: electrophysiology • fibrillation • arrhythmia • atrium • mapping

	Introduction

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High-density computerized mapping of human atrial fibrillation often reveals the coexistence of multiple coherent or fractionated wavelets,^{1 2 3} compatible with Moe's multiple-wavelet hypothesis of atrial fibrillation.⁴ However, in 40% of the patients mapped in one study,¹ atrial fibrillation was associated with a single broad wave front that propagated uniformly across the right atrium. The authors hypothesized that these patterns of activation may represent activation of the mapped tissue by a reentrant wave front outside the mapped area. Recently, Starmer et al⁵ and Gray et al^{6 7} reported that the presence of a single meandering functional reentrant wave front in both computer simulation and rabbit ventricular tissues could result in rapid and irregular electrical activity. If the same observations are applicable to human atrial tissues, then a single meandering wave front could serve as the source of atrial activation for the remaining part of the atria. Computerized mapping distant from the site of reentry could then reveal only large and broad activations.¹ The study by Gray et al,^{6 7} however, was performed in rabbit ventricular tissue, which has a rather uniform structure. In contrast, human atria have significant structural complexities that may exert significant influences on the propagation of the reentrant wave fronts. The relationship between these structural complexities and the reentrant wave-front propagation is unclear. The purpose of the present study was to test the following hypotheses: that (1) the functional reentrant wave fronts in the human atria are not stationary but rather meander from one place to another, resulting in rapid and irregular electrical activity, and (2) the structural complexities of human atria directly influence the reentrant wave-front propagation.

	Methods

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Tissue Preparation
The native hearts of transplant recipients (n=5) were excised, immersed in cold oxygenated Tyrode's solution, and transported to the research laboratory within 10 minutes. Three right atrial tissues and two left atrial tissues were excised and trimmed to 3.5x3.0 cm. The thickness of each tissue was 3.4±0.3 mm. Each tissue was then placed in a tissue chamber with dimensions of 10.2x7.2x2.7 cm. The irregular surface of the endocardium was placed directly against the electrode array. A recording plaque electrode array was constructed on the bottom of the tissue chamber, with the recording electrodes facing up (Fig 1). These electrodes were made of stainless steel wires with a diameter of 0.4 mm. The wires were fully insulated except at the tips, which served as the tissue contact points. In total, 477 bipolar electrodes were included in the plaque, forming 21 columns and 24 rows. The interelectrode distance was 1.6 mm and the interpolar distance, 0.5 mm. Previous studies have revealed that closely spaced bipoles adequately register local activations,⁸ whereas unipolar electrograms often include far-field signals.⁹ When the cardiac activations are fast and complex, the unipolar electrograms may be difficult to analyze, especially when isoelectrical intervals are not present between activations. Therefore, we have been using bipolar recordings instead of unipolar recordings to map complex cardiac arrhythmias.¹⁰

View larger version (46K): [in this window] [in a new window]   Figure 1. Electrode location and mapping procedure. Electrode array was built at bottom of tissue chamber. It has 21 columns and 24 rows, with a total of 477 electrodes. Interelectrode distance was 1.6 mm and interpolar distance 0.5 mm. Tissue was placed endocardial side down on mapping electrode array. Tissue was continuously superfused with oxygenated Tyrode's solution.

The electrodes protruded from the bottom of the tissue chamber by 3 mm. This 3-mm clearance allowed the oxygenated Tyrode's solution to come into direct contact with the endocardial surface to maintain its viability. The tissue was constantly superfused with Tyrode's solution at a rate of 10 mL/min and maintained at 36.5°C and at a pH of 7.4. The Tyrode's solution had the following ionic composition, in mmol/L: NaCl 125, KCl 4.5, NaH₂PO₄ 1.8, CaCl₂ 2.7, MgCl₂ 0.5, NaHCO₃ 24, and dextrose 5.5, in distilled deionized water.¹¹ Both the bath and the stock Tyrode's solutions were continuously gassed with 95% O₂ and 5% CO₂.

The recording electrodes were connected to a computerized mapping system (EMAP, Uniservices).¹² Electrograms were filtered with a high-pass filter of 0.5 Hz and a low-pass filter of 3 MHz and were acquired at 1000 samples per second with 18 bits of accuracy. The mapping system can continuously acquire 8 seconds of data at a time.

Stimulation Protocol
The isolated atrial tissues were paced with Teflon-coated (except at the tip) bipolar silver wires (0.1-mm tip diameter) with 2-mm interpolar distance. Regular stimuli (S₁) with twice diastolic threshold current at cycle lengths of 400 or 600 ms were applied either at the left edge or at the bottom of the tissue. These pacing cycle lengths were chosen because they were the pacing cycle lengths commonly used during human clinical electrophysiology studies. The refractory period was determined at the S₁ site with the extrastimulus method with 10-ms decrement of coupling intervals. The longest coupling interval that failed to capture the atria was the refractory period. Reentry¹³ was induced with a single premature stimulus (S₂) with increasing current strengths applied near the center of the tissue, roughly 1.5 cm from the S₁ site. The configuration of the electrode for the S₂ stimulus was the same as the S₁ electrode. First, the diastolic interval was scanned with an S₂ of twice diastolic current strength at progressively shorter coupling intervals until tissue refractoriness was reached. Then, this procedure was repeated with progressively increasing S₂ strengths at 0.5- to 2-mA increments up to 10 mA, then by 5-mA increments until reentry was induced. The strength was further increased until reentry was again not inducible.

Data Analyses
The times of activation were determined by the computer according to our previously described algorithm.^{10 11 12} Briefly, the maximal dV/dt of the range for data analysis was first determined by the computer. The S₂ artifact, which had an artificially large dV/dt, was excluded. The investigators then had the option to select the threshold dV/dt value (a percentage of the dV/dt value) and the interval (in milliseconds). The computer selected a time as the time of local activation if the dV/dt at that time exceeded the threshold value and if the interval between that time and the time of previous activation exceeded the selected threshold interval. Because each channel had a different signal-to-noise ratio, the threshold value could vary from channel to channel at the investigator's discretion. Manual editing was then performed for each activation on each channel.

After activation times were determined, the pattern of activation was visualized dynamically on a computer screen on which each electrode site was illuminated when an activation was registered. During each activation when an electrode site was illuminated, the computer directed the corresponding site to be illuminated initially red, then yellow, green, light blue, and finally dark blue before it changed again to the background black color.^{10 11} Each illumination was selected to persist for 10 ms. The total duration of illumination of each dot by one activation could thus be preset at 50 ms. This time was chosen because it was shorter than the refractory period of the atrial tissue and the fastest cycle length of the induced reentry. It did not indicate the actual duration of the action potential, which was not measured during the study. Selected color snapshots were obtained on a hard copy at different moments during reentry.^{10 11}

Trajectory of the Tip of a Reentrant Wave Front
We traced the tip of a reentrant wave front by freezing the motion of the reentry and then advancing it in 30- to 50-ms intervals until the reentrant wave front terminated. The pathway of the tip of the reentrant wave front was traced with a mouse and custom-written software.^{10 11} The tip of the reentrant wave front was the red dot closest to the core during the dynamic display of reentry.

Histological Studies
After the conclusion of the electrophysiological studies, the isolated tissues were fixed in 10% buffered formalin and stored in a refrigerator. The position of the stimulating electrodes and the mapping electrode array were marked with dyes of different colors. Sections (5 µm) parallel to the endocardial surface were made, and the myocardial fiber orientation and the presence of tissue abnormalities were determined in hematoxylin-eosin–stained sections. Five to eight sections were made in each tissue sample. In addition, in each tissue, two to four cross sections from epicardium to endocardium were also made and stained with hematoxylin-eosin to determine tissue thickness, structure, and preservation.¹¹

	Results

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The Table shows the clinical characteristics of patients before transplantation. All patients were treated with digoxin. Otherwise, no antiarrhythmic drugs were used. The total duration of the study lasted 32±11 minutes (mean±SD) (range, 15 to 60 minutes), during which the capturing threshold and the refractory period remained unchanged. The mean refractory period was 204±36 ms.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Morphology of Atrial Tissue Samples
In all tissues studied, the endocardial surface of left or right atrium was not smooth but rather had abundant pectinate muscles. These pectinate muscles exert significant influences on the propagation of reentrant excitation in human atrial tissues. Fig 2 shows a typical example of the left atrial endocardial surface from patient 4. During the study, this endocardial surface was placed face down, directly on the mapping electrode array. The right upper corner of the tissue shown in Fig 2 was placed close to electrode 1 and the left upper corner of the tissue near electrode 21 (see Fig 1). The black box shows the location of the recording electrode array. The white lines and arrows indicate the direction of wave-front propagation in figures that will be presented later. As will be shown in those figures, the pattern of activation during reentry was significantly modified by the structural complexities of the endocardial surface.

View larger version (102K): [in this window] [in a new window]   Figure 2. Endocardial surface of left atrium. Figure is from patient 4. Black box indicates site of recording electrode array, corresponding to that shown in Fig 1. White arrow in center of figure shows direction of impulse propagation during reentrant excitation in Figs 5 and 6.

The cross sections of all atrial tissues show significant variations of the wall thickness. Fig 3 shows an example from the right atrium of patient 2. Fig 3A is a low-power view of the cross section. The thickness of pectinate muscle is usually much greater than the thickness of the surrounding atrial tissues. Significant source-sink mismatch¹⁴ may occur at the junction between pectinate muscle and surrounding tissue, resulting in diminished velocity or safety factor of impulse propagation. Fig 3B is a high-power view of the same atrium, showing that the myocardial fiber orientation was nonuniform and complex, with significant amounts of connective tissues. These findings are characteristic of atrial tissues with anisotropic propagation characteristics reported previously by Spach et al.^{15 16} Although most patients had evidence of atrial enlargement by echocardiogram (Table), the atrial myocardium was normal histologically. There was no evidence of atrial infarction or ischemic injury in any of the tissue samples. Patient 4 is the only patient with a history of AF. However, the atrial size in this patient was not particularly large. There were no histological findings that distinguished this patient from others.

View larger version (142K): [in this window] [in a new window]   Figure 3. Morphological examination. Picture from tissue samples of patient 2. A, Low-power transmural section of right atrial free wall. Bar=5 mm. Thinnest portion of epicardium measured 1 mm, and thickness of pectinate muscles is >5 mm. B, High-power view of same tissue. Myocardial fiber orientation is nonuniform and complex.

Activation Patterns During Regular Pacing
The S₁ capturing threshold averaged 1.2±0.6 mA (range, 0.6 to 2.4 mA). Fig 4 was from patient 4, who had a history of chronic atrial fibrillation. It shows color-coded isochronal activation maps during regular pacing in a representative tissue. Panels A through D show sequential activations. There was no evidence of conduction block. Panel E shows the location of selected bipolar electrograms (panel F) during S₁ pacing. The presence of sequential activation during regular pacing without conduction slowing or block indicates the absence of an anatomic obstacle in our isolated atrial tissues. This finding was confirmed by histological studies. In all tissue studied, no conduction block was observed during S₁ pacing. The average conduction velocity was 0.35±0.03 m/s. In two tissues, pacing was also performed from the center of the tissue and showed no conduction block.

View larger version (62K): [in this window] [in a new window]   Figure 4. Patterns of activation during baseline (S1) pacing. Example from patient 4, who had a history of chronic atrial fibrillation. When an activation is registered, electrode shows red. Color then becomes yellow, green, light blue, and blue before becoming background color (black) again. Each of first five colors persists for 10 ms. Background color persists until next activation occurs. A through D, Propagation of impulses from pacing site in A to rest of tissue without evidence of conduction delay. Onset of S1 stimulus artifact is at time zero. E, Location of electrodes that registered activations in F.

Characteristics of Reentry in Human Atrial Tissues
A total of nine episodes of reentry were induced (1 to 3 episodes per tissue). Reentry was induced with an S₁-S₂ coupling interval of 232±29 ms (range, 190 to 290 ms) and an S₂ strength of 10±3 mA (range, 5 to 15 mA). A single functional reentrant wave front was observed in each episode. The mean cycle length of the reentrant wave fronts was 229±45 ms (160 to 290 ms), and it persisted for 1.1±0.3 seconds (0.6 to 2.5 seconds), or 5.2±1.4 (3 to 9) cycles. The reentrant wave fronts were not stationary. Rather, they meandered from one place to another before spontaneous termination.

Fig 5 is also from patient 4. It shows the patterns of activation of a single meandering functional reentrant wave front. Arrows point in the direction of wave-front propagation. Although the reentry in general rotated in the clockwise direction, the sequence of activation was not continuous throughout the endocardial surface. Rather, there were intermittent prolonged gaps of impulse propagation (between panels D and E and between panels J and K). A time lag of 54 ms was noted between panels D and E. In panel F, the green dots are surrounded by yellow dots, indicating that after this long pause, the impulse propagates in all directions (note that the yellow and green dots are 10 ms apart). In panel J, the propagation of the impulse reached the right lower border. The propagation then reappeared 52 ms later (panel K). The patterns of activation in panel L are also compatible with focal breakthrough, because the green dots are partially surrounded by yellow dots. These prolonged delays of activation show that the impulse propagation in the endocardium is not continuous. Note that Figs 2 and 5 are mirror images, because the endocardial surface of this tissue is placed on top of the mapping electrode array. The gaps of activation that occurred in the right lower border of the mapped tissue (between panels D and E and panels J and K) corresponded to impulse propagation across a large pectinate muscle (Fig 2).

View larger version (149K): [in this window] [in a new window]   Figure 5. Meandering functional reentrant wave front. Example from patient 4. Reentry was initiated by a premature stimulus (S2) and propagated in clockwise direction. Onset of S2 was used as time zero. Arrows indicate direction of wave-front propagation. Reentrant wave front did not propagate smoothly. For example, time difference between D and E was 54 ms, and between J and K 52 ms. During these 54 or 52 ms, impulse propagated only a very short distance, indicating that propagation probably did not occur at mapped surface. Comparing with Fig 2, wave front was propagating across a large pectinate muscle when delay occurred. Wave front shown in K probably was initiated by an activation wave front from epicardial side and not by direct propagation from endocardial surface to right of these electrodes. Letters a through l indicate electrode in leading edge of wave front closest to core (corresponding to tip of spiral). Trajectory of tip is shown in Fig 6.

Fig 6 shows the bipolar electrogram associated with the meandering functional reentrant wave front. This is the same episode as that shown in Fig 5. Panel A shows the trajectory of the tip of the reentrant wave front. As the reentrant wave front rotated clockwise, the trajectory of the tip also meandered in a clockwise direction. Panel B shows selected bipolar electrograms recorded during the same episode. The electrograms show rapid activity with irregular cycle lengths. Panel C shows the actual bipolar recordings made by electrodes m, n, o, p, q, and r (see panel A). Note that electrodes m and n were within the area encircled by the trajectory of the reentrant pathway (near or at the core) for both cycles, showing consistent double potentials. Electrodes o and p were within the area encircled by the first but not the second trajectory. The electrograms showed double potentials only in the first and not in the second cycle of reentry. Electrodes q and r were always outside of the area encircled by the trajectory and did not show double potentials.

View larger version (37K): [in this window] [in a new window]   Figure 6. Meandering functional reentry causing rapid and irregular activations. Same episode of functional reentry as in Fig 5. A, Points a through l represent location of red dots closest to core of reentry in A through L of Fig 5, respectively. Trajectory of functional reentry represented by these points shows that reentry meanders in a clockwise direction. Dotted line connecting points j and k indicates that activations at these points were not continuous (see Fig 5 legend). B, Actual activations registered at these recording electrodes. Arrows indicate direction of wave-front propagation. These bipolar electrograms show that atrial activations were rapid and irregular, similar to that registered during atrial fibrillation. C, Actual bipolar recordings made by electrodes m, n, o, p, q, and r. Arrows point to double potentials when electrodes are within area encircled by trajectory.

In the other 8 episodes of reentry, the discontinuous propagation was observed in all episodes. The time lag at the gaps of impulse propagation averaged 46±7 ms. Histological examination showed that these gaps were due to conduction across the pectinate muscle in all episodes.

	Discussion

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Meandering Functional Reentrant Wave Front and Mechanisms of Atrial Fibrillation
The multiple wavelet hypothesis of atrial fibrillation^{4 17} posits that atrial fibrillation is sustained by multiple wandering wavelets. These wandering wavelets can result in reentry (reexcitation) and form "circuits." These circuits may shift in position, frequency, and direction with time. These circuits can also die and be replaced by others. These complex activation patterns and the coexistence of multiple wandering wavelets contribute to the rapid and irregular electrocardiographic appearance of atrial fibrillation. This hypothesis is supported by computerized mapping studies¹ that demonstrate both multiple wandering wavelets and shifting circuits during electrically induced atrial fibrillation in humans.

However, not all atrial or ventricular fibrillation activations are formed by multiple wavelets. For example, Janse et al¹⁸ demonstrated that ventricular fibrillation is not always due to multiple wavelet reentry. In the atria, several groups of investigators^{1 2 3} have demonstrated large and coherent wave fronts during atrial fibrillation in humans by computerized mapping techniques. These large wave fronts could have come from a single reentrant wave front or a focal activation outside the mapped area. In patients with preexcitation syndrome, there is an increased risk for atrial fibrillation.^{19 20} However, after either surgical or radiofrequency ablation, the incidence of atrial fibrillation is much decreased.^{21 22 23 24} These studies suggest that atrial fibrillation could originate from a localized area in patients with preexcitation. When that area is destroyed, the incidence of atrial fibrillation is markedly reduced.

In the present study, we demonstrate that a premature stimulus could reliably induce a single functional reentrant wave front in human atrial tissues. These reentrant wave fronts could serve as the source of the broad wave front in other parts of the atria. Furthermore, because these wave fronts were not stationary but rather meandered from one location to another, they could produce polymorphic and rapid atrial activations similar to that registered during human atrial fibrillation in vivo.^{1 3} We propose that in addition to the coexistence of multiple wavelets, the presence of a single meandering reentrant wave front can also result in atrial fibrillation in human patients.

Mechanisms of Meandering
Several factors may contribute to the meandering of functional reentrant wave fronts. The first is the intrinsic activation and recovery properties of the myocytes.^{25 26 27 28 29} Using the FitzHugh-Nagumo model, Winfree²⁵ reported that the spiral tip path can be stationary or meandering, depending on the relative rates of excitation and recovery parameters of the model. Starmer et al⁵ reported that the stability of the tip of spiral wave depends on the potassium conductance. When potassium conduction is decreased from 1.13 to 0.70 (arbitrary units), the spiral tip destabilized and began to meander. In rabbit^{6 7 28 30} and canine¹⁰ ventricular tissues, nonstationary vortex-like reentrant activity has been demonstrated. Based on the theory of general excitable media, it was proposed that the mechanisms of meandering of the tip of the scroll waves were based on continuous media in which there was a gradient of excitability. Gradient in the diastolic outward current was also found by Kogan et al²⁹ to promote meandering in excitable media. The nonstationary nature of the core produces wave-front movement changes by means of the Doppler effect.

Normal rabbit or canine ventricular tissues, however, are quite different from human atrial tissues. Although the ventricular muscle approximated a continuous medium because of its uniform anisotropic properties, the human atrial muscle, as shown in Fig 2, is very complex at microscopic, macroscopic, and gross anatomic size scale. Spach et al^{15 16} also reported that the anisotropic structure in human atrial tissue can result in marked changes in electrogram morphology and conduction velocity. More recently, Gray et al³¹ showed that the endocardial structure may affect the patterns of activation during AF in sheep heart.

In the present study, we have demonstrated that the reentrant wave fronts are irregular. Furthermore, large gaps of activations are present between adjacent sites. Some of these large gaps of time corresponded to propagation across a large pectinate muscle in the mapped (endocardial) surface. These findings are compatible with the hypothesis that the interaction of structural loading effects and inhomogeneities of repolarization account for the mechanisms of meandering of reentrant wave fronts in human atrial tissues.¹⁵

Limitations of the Study
One limitation of the study is that atrial tissues were superfused and not perfused. Over time, an ischemic core may develop in the middle layer of the tissue, thereby altering the patterns of activation. However, the functional reentrant wave fronts even at the very beginning of the study showed evidence of meandering. These latter findings support the major conclusions of this study. A second limitation is that, because of time constraints, we were not able to perform pacing from different sites of the preparation in all tissues to observe whether or not fixed anatomic conduction block was present. However, histological studies did not reveal evidence of infarction or other anatomic barriers. In two tissues, pacing was performed both from the edge and from the center. No conduction block was observed in these two tissues.

A third limitation is that these atrial tissues were obtained from patients with severe congestive heart failure. The results of this study may not be helpful in explaining the observations made by mapping atrial fibrillation in otherwise healthy patients with preexcitation syndrome.^{1 2 3} However, because fibrillation often occurs in patients with preexisting heart diseases, our findings are still valuable in understanding the fundamental mechanisms of atrial fibrillation in human patients.

A fourth limitation is that the cycle length of reentrant excitation in the present study averaged 232 ms, longer than the activation cycle lengths during human atrial fibrillation in patients with preexcitation syndrome.^{1 3} This finding could indicate that our data are more pertinent to atrial tachycardia than to atrial fibrillation. However, it is also possible that the longer cycle length observed in this study is related to the presence of congestive heart failure in our patient population. Alternatively, it is also possible that tissue size reduction alone can result in longer activation cycle lengths. The latter hypothesis is based on a recent observation made by Kim et al³² in perfused swine ventricular tissues. The results of that study showed that tissue size reduction alone could result in significant prolongation of the cycle lengths.

Clinical Relevance
Although significant advances have been made in the prevention and in the treatment of cardiac arrhythmia, atrial fibrillation remains a major public health problem, especially in patients with organic heart diseases.^{33 34} However, few data are available on the basic mechanisms of atrial fibrillation in these patients. In this study, we demonstrated that, in the absence of multiple wavelets, a single reentrant wave front in diseased human atrial tissue can meander and cause rapid and irregular activity. It is conceivable that in some patients, the same mechanism may underlie the generation or the maintenance of atrial fibrillation. If this mechanism can be accurately diagnosed, therapeutic maneuvers such as catheter ablation targeted to a small area may result in a cure in these patients. Further studies will be necessary to determine whether or not a single meandering reentrant wave front is a major mechanism of atrial fibrillation in human patients.

	Acknowledgments

 
This study was done during the tenure of a Cedars-Sinai Burns and Allen Research Institute Fellowship Award (Dr Ikeda), an ACC/Merck Fellowship (Dr Ong), an NIH Individual Research Service Award (Dr Ong), a Cedars-Sinai ECHO Foundation Award (Dr Karagueuzian), and an AHA Wyeth-Ayerst Established Investigatorship Award (Dr Chen) and was supported in part by an NIH SCOR grant (HL-52319), an NIH FIRST Award (HL-50259), and the Ralph M. Parsons Foundation, Los Angeles, Calif. We thank Paul Nusser, RN, Deborah Harasty, RN, Avile McCullen, and Meiling Yuan for their technical assistance and Elaine Lebowitz for her secretarial assistance. The authors also wish to thank Peter Hunter, PhD, David Bullivant, PhD, Sylvain Martel, and Serge LaFontaine for constructing the mapping system used in this study.

	Footnotes

 
Reprints requests to Peng-Sheng Chen, MD, Room 5342, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048.

Received March 26, 1997; revision received May 15, 1997; accepted May 28, 1997.

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