1364

Fibrillation is More Complex in the Left Ventriclethan in the Right Ventricle

JACK M. ROGERS. PH.D.,* f UAH HUANG. M.D., Pii.D.,tRAMON W. PEDOTO, M.S.,t ROBERT G. WALKER, B.A.,t

WILLIAM M. SMITH, PH.D.,=i= t and RAYMOND E. IDEKER. M.D., PH.D.n

hrom the Departtncnts of '^Biotnedical Engineering. tMedicine. and ^PhysiologyUniversity of Alabama at Birmingham. Birmingham. Alabama

VF Patterns in the Right and Left Ventricles. Introduction: The mechanisms that maintainventricular fibrillation (VF) are not completely understood. It has been propo.sed that increasedventricular wall thickness destabilizes VF wavefronts and therefore is an important determinant ofVF activation patterns. We hypothesized that if this is tbe case, then VF patterns on the tbin-walledright ventricle (RV) should he simpler than those on the thick-walled left ventricle (LV).

Methods and Results: In seven open chest pigs, we mapped VF simultaneously from two epicardialrecording arrays, one on the RV and one on the LV. Each array contained 504 unipolar electrodes(in a 21 x 24 grid) spaced by 2 mm. We used specialized pattern analysis methods to computequantitative descriptors of RV and LV activation patterns. Our data show that VF is more organizedin the RV than the LV, containing fewer, larger wavefronts that follow fewer distinct pathways andare less likely to fragment or collide with other wavefronts. Tbe incidence, size, and cycle length ofreentrant circuits were similar in the two ventricles, but RV reentry persisted for more cycles. Theseresults are not predicted by the differences in electrophysiologic properties between LV and RV thathave been reported in mammalian hearts.

Conclusion: The geometry of the ventricular wall, particularly wall thickness, is an importantdeterminant of VF activation patterns. (J Cardiovasc Electrophx.siol. Vol. II. p. 1364-1371. December2000)

ventricular Jihrillation. wavefronts, cardiac mapping, organization, thickness

Introduction

Duritig ventricular fibrillation (VF), myocardium isactivated by a multitude of wavefrotits of varying size,duration, speed, and direction.* ' However, the dynatnicsgoverning the initiation and maintenance of this con-fused state are poorly understood. The most commonlyproposed mechanisms attribute the wavelVont fragmen-tation characteristic of VF to tissue properties, either theexistence of patchy heterogeneity' or an action potentialduration (APD) restitution curve with a slope exceeding1.-"' Another potential determinant of VF patterns is the

Supported in pan by American Heart Assi.x;iaiton Gram 9R2OO3nSE. agrant from the Whifaker Foundation. NIH Granls HL-2H429 and Ht,-33637. and NSF Grant BES-90346(i.

Address for correspondence: Jack M. Rogers. Ph.D.. University ofAlabama at Birtningham. 1670 University Boulevard. Valker Hall.BI40. Birmingham. AL .^5294. Fax: 2O5-97.'i-472O: B-mail:crml.uab.edu

Manuscript received 29 February 2000: Accepted for publicationSeptember 2000.

heart's complex geometry. For example, Winfree^ pro-posed that the ihickness tif the ventricular wall destabi-lizes reentrant wavefronts by giving their central "vortexlilament.s" room to lash about and fragment at tissueboundaries. This view has been supported by numericalmodels of reentrant activation that demonstrate modes ofvortex instability that can only occur in three-dimen-sional (3D) tissue.'* '-

If tissue thickness is an important destabilizing factorin VF. then VF activation patterns in the thin-walledright ventricle (RV) should be measurably simpler thanpatterns in the thick-walled left ventricle (LV). To testthis hypothesis, we mapped VF simultaneously on RVand LV epicardial surfaces (1.008 total channels) andused a recently developed suite of pattern analysis algo-ri thms'-" '•* to quantitatively compare the recorded pat-terns.

Materials and Methods

The use of experimental animals in this study wasapproved by the Institutional Animal Care and Use Com-

Rogers et al. VF Patterns in the Right and Left Ventricles 136?

mittee at the University of Alabama at Birmingham. Allstudies were performed in accordance with the guide-lines established in the Position of the American HeartAssociation on Research Animal Use adopted by theAmerican Heart Association on November 11, 1984.

Animal Preparation

Seven pigs (weight 34 to 48 kg) were studied; thehearts weighed 209 ± 30 g. The pigs were anesthetizedwith 25 mg/kg intravenous thiopental sodium and main-tained with isollurane in 100% oxygen. Succinylcholincinitially was given at a dose of I mg/kg and later at 0.25to 0.5 mg/kg in approximately 20-minute intervals todecrease muscle contractions induced by detibrillationshocks. Each pig was intubated with a cuffed endotra-cheal tube and ventilated with a mixture of room air andoxygen through an Ohio anesthesia ventilator (AircoInc.. Madison. WI, USA). A femoral arterial line wasinserted with a catheter connected to a Statham trans-ducer (Gould Inc.. Valley View, OH. USA) to monitorsystemic arterial blood pressure. Blood pressure and thelead II surface ECG were displayed on a monitor(78534C monitor/terminal. Hewlett-Packard. Andover,MA. USA). Body temperature was monitored from theesophagus and maintained within normal limits with aheated circulating water mat placed under each animal.Normal saline was continuously infused (2 to 5 niL/kg/min). Normal metabolic status was maintained through-out the study by taking blood every 30 to 60 minutes,determining pH. pO^. pCO^. base excess., CO^, andHCO,~ contents, and calcium, potassium, and sodiumconcentrations, and correcting any abnormal values.

The chest was opened by a median sternotomy, andthe pericardial sac was opened to expo.se the heart. Atwo-piece electrode plaque was sutured to the anteriorRV epicardium. Each plaque contained 252 electrodes ina 21 X 12 array. The electrodes were 1-mm diametersilver spheres with 2-mm spacing (on centers) in eachdirection. This spatial resolution has been shown to beappropriate for mapping VF.'^ The plaques were con-structed of 2.5-mm thick Plexiglas and were positionedto form a uniform 21 X 24 array. A similar two-pieceplaque was sutured to the anterior LV epicardium. Thisarray was identical to the RV array, except that theplaques were constructed from 2-mm thick Silasticsheeting to accommodate the greater curvature of theLV. The ground reference for the unipolar recordingswas attached to the right leg. A mesh electrode wassutured to the LV apex and a catheter electrode (6.9-cmlength, 6.3-cm"" area) was inserted into the superior venacava for use in rescue defibrillation.

Mapping Data Acquisition

The RV and LV arrays were each connected to a528-channel mapping system."* The two mapping sys-tems were synchronized by a common clock to ensuretime alignment of the two mapping datastreams. The

unipolar electrograms were bandpass filtered from 0.5 to500 Hz. sampled at 2 kHz, and recorded digitally with14-bit resolution.

VF was induced with 1- to 2-second bursts of 60-cycle current. Cardiac pertusion was not maintained dur-ing VF. Four to six VF episodes were Induced andmapped in each animal. A rescue biphasic shock at theminimum reliable dertbrillation strength (typically 400 to500 V) was delivered 30 seconds after each induction. Aminimum of 15 minutes was allowed to elapse before VFinduction was reattempted. For each VF episode, map-ping epochs I second in duration and beginning at 5, 10,and 15 seconds postinduction were recorded. A fourthepoch. 4 seconds in duration, was extracted at 20 secondspostinduction (as described later, the differently sizedepochs were used for different analyses).

Ventricular Wall Thickness

Upon completion of the protocol, the pig was eutha-nized by electrically induced VF. The heart was removedand fixed in 10% formalin. The RV and LV walls di-rectly under the recording arrays were isolated from theheart and mounted rigidly on pins so that both the epi-cardium and endocardium could be accessed by a 3Ddigitizing probe (MicroScribe-3DX, Immersion Corp,San Jose. CA. USA). The 3D coordinates of points oneach epicardial surface were acquired. The points werearranged in a rectangular grid with approximately 4-mmspacing in both directions. A parametric cubic B-splinesurface was fit to these data.'^ The routine used for the tit(parsur, available from the Netlib software repository,http://www.nellib.ofij) automatically places knots basedon the value of a parameter that controls the number ofknots and hence the root mean square (RMS) error in thesurface. To avoid inappropriate oscillations in the sur-face, we set this parameter individually for each surfaceso that the RMS error was approximately 0.5 mm. Wenext acquired the 3D coordinates of approximately 25endocardial points on each block. The points were scat-tered on the endocardium with roughly equal spacing andchosen so that about half were between trabeculae andthe rest on top. The minimum distance between eachpoint and the epicardial surface was computed and takenas the wail thickness at that point. Figure I shows anexample of the surface and thickness measurements forone of the RV blocks. For each block, we computed themean wall thickness and coefficient of variation (stan-dard deviation normalized by the mean).

Action Potential Duration

We measured APD tin both the RV and LV epicar-dium using a monophasic action potential (MAP) probe(EP Technologies, Sunnyvale, CA. USA). The heiut waspaced from the RV outflow tract at cycle lengths of 225,250. and 300 msec, and MAPs were recorded from threerandom sites in or near the mapped region on each of theRV and LV. The durations of four action potentials in

1366 J o u r n a l of C a r d i o v a s c u l a r E l e c t r o p h y s i o l o g y Vol. II. No. 12. December 2000

1 cm

Figure 1. Measurement of veuiriadcir wall ihickness. The f-ray surface i.s a cubic B-spline fit to epicardial data poinl-i. The black spheres areendocardial data points, and the white spheres are the epicurdial suiface points closest to the corresponding endocardia! points.

each recording were computed as the interval hetweenpeak dV/dt during the upstroke and the peak uf d'V/dt^during recovery.'^ VF then was induced in eaeh heart.After approximately 15 seconds, 2-second MAP signalswere recorded successively from one site mid-way be-tween base and apex on each of the RV and LV. Sevento twelve APDs were measured in eaeh MAP signal.

Quantitative Analysis of VF Activation Patterns

VF activation pattern.s were quantified using patternanalysis algorithms we descrihed previously.'-'^'^ Thealgorithms are based on wavefront isolatioti.- Briefly, all504 electrograms in a mapping epoch from the RV or LVwere differentiated using a tive-point digital filler. Asample (the datum corre.sponding to a single temporalsample at a single recording site) was deemed active ifdV/dt was less than -0.5 V/sec, Individual wavefrontswere identified and isolated by grouping together activesamples that were adjacent in space and time. DuringVF. wavefronts frequently fragment into multiple newwavefronts or collide with other wavefronts. In our def-inition of a wavefront. a waveiront ends when it frag-ments, at which time the two or more resultant wave-fronts begin, Conversely, when multiple wavefrontscollide and coalesce, the original wavefronts end. and theresulting wavefront begins.

From this decomposition of the overall activationpattern, we computed several parameters. (1) Total num-ber of wavefronts in the VF epoch.- (2) Mean area sweptout by wavefronts.- In this calculation, tissue that isactivated more than once by a particular wavefront (i.e.,during reentry) is only counted once. Thus, the maxi-mum area that can be activated by a wavefront is the areaof" the recording array. (3) Fraction of wavefronts thatfragmented into two or more child wavefVont.s.- (4) Frac-tion of wavefronts that collided and coalesced with oneor more other wavefronts.- (5) Mean epicardial propaga-tion speed. This speed was estimated by tracking themotion of the centroid of each wavefront.' (6) Multiplic-ity of the activation pattern.i-* MuUiplicity measures thenumber of distinct activation pathways in the VF pattern;

smaller numbers indicate a more organized rhythm. (7)Repeatability of the activation pattern.' This parameterexpresses, in an average sense, how many wavefrontspropagate along each of the distinct pathways indicatedby the multiplicity parameter. For example, if an activa-tion pattern ct>niains 6 wavefVonts, 3 of which follow onepathway and 3 of which follow another, then the multi-plicity of the pattern is 2 and the repeatability is 3. If eaehpathway represents part or all of a reentrant circuit, thenrepeatability expresses the number of cycles for whichreentry persists. Following our previous studies,'•'•* pa-rameters 1 to 6 were computed using the first 0.5 secondof each mapping epoch, and parameter 7 was computedusing the entire first .second.

In addition to computing these parameters, we alsoapplied our recently developed methods that automati-cally identify and quantify sequences of wavefronts thatcomptete at least one cycle of reentry." Briefly, in thisanalysis, wavefronts are grouped into '"families"' consist-ing of wavefronts connected temporally by fragmenta-tion or collision events (in our previous publication,these families were referred to as components). Eachfamily was inspected lo determine if it contained a se-quence of wavefronts that activated tissue more thanonce. If it did, it was deemed reentrant. From this anal-ysis, we computed four additional parameters. (8) Inci-dence of reentry, which was defmed as the fraction offamilies containing a reentrant sequence of wavefronts.Each reentrant sequence then was processed by a net-work optimization algorithm to find the path followed bythe tip of the reentrant wave.'^ This path was divided intoindividual cycles of" reenti'y. from which we computed(he (9) mean number of reentrant cycles completed, (10)mean area circumscribed by the cycles, and (II) meanduration of the cycles. Parameters 8 to 11 were computedusing the 4-second epoch beginning at 20 secondspostinduction.

Activation Rate

We approximated the "global" activation rate on eachof the RV and LV recording arrays. Using the 4 second

Rogers et al. VF Patterns in tht Riyht und Left Venlricles 1367

PiiiiwiM.' I'aranicicr Ditfercnces

Paranu'ttT

Numlvr yt\ wiivcfrontsArea swcpl outFragmentation^Collision^Epicardial propagation speedMultiplicityRcpcatabililyActiviiiion rateReentry incidence^

Mean ± SI)

i].^^ ± 0,31 i-0.13 ± 0,40f

0.35=: 0.7I t0.24 z iny-0.06 ± O.lftt0.26 ± O.33t0.00 =: 0..1A

0.OH2 ± (),(W4t0.32 ± 1.72

* Fractional differences luirniali/cd by I.V datii.t Significant LV-RV tiiilLTencc.X Normalized by mean LV data.

data epocbs, on each plaque, we summed tbe signalsfrom all 504 electrodes. We approximated the powerspectra of tbe resulting time series using the methodreponed by Welch''' with nonoverlapping segments4,000 samples (2 sec) long. With ihis method, the reso-lution of the spectra was 0.5 H/. We defined Ihe activa-tion rate as the frequency with the maximum powerbetween 0 and 50 H/, Tbese calctilations were perfortnedusing Matlab 5.3 (The Mathworks. Inc., Natick. MA.USA).

Statistical Analysis

We tested for LV-RV differences in wall thicknessand fractional standard deviation of wall thickness usingpaired /-tests. We tested for LV-RV APD differencesusing three-way analysis of variance with anitual numberand rate (pacing rale or VF) as blocking lactt)rs. Wetested for an overall LV-RV difference in tbe VF de-scriptors tbat were computed for every data epoch(wavefront isolation parameters 1 to 7) using doublymultivariate repeated measures analysis of variance.-'"We further tested for LV-RV differences in each of tbeseindividual parameters by computing the 95'/f Bonlerronict>iiiidence intervals. We used a sitiiilar analysis to testfor LV-RV differences in the parameters that were com-puted only for the 4-second duration epochs (activationrate and wavefront isolation parameter 8). Wavefrontisolation parameters 9. 10, and 11 were compared usingunpaired /-tests. Differences were considered sigtiilicanlfor P < 0.05. The wa\cfront isolation parameters (exceptfor parameters 3. 4. and 8) and activation rate are listedin Table 1 as mean ± SD of {LV - RV)/LV. wbere LVand RV refer to a set of paired parameter observations.Parameters 3. 4. and S were sometimes equal to 0. Thus,to avoid division by 0. these parameters were normalizedby the mean LV value o\er all epochs.

Results

Ventricular Wall Thickness

The LV was signiticaniiy thicker than the RV (14.8 ±L6 mm vs 6.1 ± 1.2 mtn; P < 0.0001). This is consistent

with reports In the literature.-' Tbe fractional standarddeviation of wall thickness was significantly less for tbeLV than tbe RV (0.18 ± 0.04 vs 0.31 ± 0.07; P < 0.05)indicating ihat the LV is more uniform in Ibickness thanthe RV.

Action Potential Duration

No significant differences in APD between RV andLV were found at any pacing cycle length or during VF(Fig, 2).

VF Activation Patterns

We analyzed a total of 40 VF episodes. Six !-secondepocbs and one 4-second epixh were corrupted by tecb-nical problems and could not be analyzed. Tbus. tbedescriptors computed with 0.5- or I.O-secnnd epochs(wavefrtint isolation parameters I to 7) were computedlor both the RV and LV arrays in a total of 154 VFepochs. The teentry descriptors (parameters S to 11) andactivation rate were computed for both the RV and LVarrays in a tolal of 39 VF epochs.

LV and RV values are shown in Figures 3. 4. and 5.Table 1 summarizes LV-RV differences for each param-eter. Tbe number of wavefronts (Fig. 3A). fraction ofwavefronts thai fragmented (Fig. 3C), fVactit)n of wave-fronts tbat collided (Fig, 3D), epicardial propagationspeed (Fig. 3H). multiplicity index (Fig. 3F), and activa-tion rate (Fig. 4A) were all significantly less on tbe RVthan on the LV. The mean area swept out by wavefrontswas larger on the RV than the LV (Fig. 3B), The repeat-ability index was not significantly different (Fig. 3G). Atotal of 94 reentrant circuits were detected on the LV and57 on tbe RV. Tbere was not a significant difference inthe incidence of reentry (Fig. 4B), The LV contained atotal of 143 cycles of reentry and tbe RV a total of 123.Tbere were no signihcant differences between the RV

200

150

100

50

VF 225 250 300Cycle Length (msec)

Figure 2. Mimoplui.\ir iirtum potential durailons on the left ventricle

fLV) and rii;lit ventricle (RV) at various paclnn ratt's and during

veiuricular fihriltatiori (VF). There were no significant differences

between RV ami LV at any rate.

1368 Journal of Cardiovascular Fleetrophysiology Vol. 11. No. 12. December 2000

^ ° p<0.013 7 ,3 6 -

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30:

20,

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25

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Figure 3. Left ventricular (LVl and ri^hi ventricular {RV) ventricular fihrillatinn activation piittem descriptors computed for each muppina epnch.The etidpoints of each vertical line indicate the LV and RV values for a .single mapping epoch. When the LV value is iarse.\t. the lint- (.v black:otherwise it is gray. To improve reitdahility, the lines are ordered by LV value. The p values displayed for parameters with signijicant differencesdo not include Bonferroni correction for multiple comparisons.

and LV lor the area (Fiy. 5A) or duration (Fig. .'iB) ofreentrant cycles. However, reentry in the RV differedfrom the LV in that there were significantly more cotn-

plete cycles per reentrant circuit (Fig. .SO. Thus, byseveral co tuple me titary tneasures, VF pattertis on the RVwere more organized than those on the LV.

Rogers et al. VF Patterns in the Right and Left Ventricles 1369

131211109

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7

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veiiliitiiUii fihiilliiiitiii (.iclivalimi ptitlern

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rv vaniputedfor 4-sectmd iliiruiicii mapping epochs. Plots

Discussion

In the present study, we simultaneously mapped VFactivation patterns from RV and LV epicardial surfaces.RV and LV data were compared quantitatively using arecently developed suite of pattern analysis algo-rithms.'•-•'-'•'•' Our primary finding is that VF patterns inthe RV are signiticantly more organi/cd than those in theLV. The difference in activation patterns could be due togeometric differences between Ihc LV and RV: alterna-tively, they could be due to electrophysiologic differ-ences in RV versus LV tissue. Our data suggest theformer is the case.

Data on electrophysiologic differences between RVand LV tissue in pigs are sparse; however, the data thatdo exist do not explain the differences in VF patterns weobserved. In the present study, we did not find anydifferences in APD at the cycle lengths we tested (VF225, 250. 300 msec; Fig. 2). Similarly, in dogs. Di Diegoet al.-- did not find significant APD differences at cyclelengths between 300 and 2,000 msec. They did find thattransient outward current (If,,) was enhanced in the RVrelative to the LV. In another study in canines. Volders etal.-^ found that APD in LV M-cells was longer than inRV M-cells, and that both I,,, and \^^ (slowly activatingcomponent of delayed rectifier current.) were enhancedin the RV. It is unclear how relevant is the difference inIj . because the presence of M-ceils in pigs is contro-versial.-•'-^ In addition. Ii ^ is unlikely to play a role inrepolarization at the high rates characteristic of VF.'*' If

attenuated 1,,, in the LV were responsible for the in-creased complexity of VF patterns in this region, then wewould expect that agents that block I, , would increasethe complexity of VF. However, this is not the case.Tedisamil. which blocks both 1,,, and 1 ; , channels, hasbeen shown to decrease the complexity of VF.-'

A restitution relationship (APD as a function of dia-stolic interval) with slope exceeding I has been proposedas a mechanism for VF. " According to this hypothesis,wavefront fragmentation during VF is due to growingAPD oscillations culminating in local propagation failureand the formation of new rotors. If the restitution rela-tionship were steeper in the LV than the RV. this couldexplain the differences in VF activation patterns. How-ever, the lack of difference in APD between LV and RVat any activation rate indicates that this was probably notthe case.

The most striking difference between LV and RV isgeometric. In the animals we studied, the LV was about2.5 times thicker than the RV. Based on a literaturesurvey, Winfree' noted that reentrant activation in verythin tissue preparations always circulates stably, whereasreentry in thick preparations degenerates to VF. Fromthis observation. Winfree concluded that VF requiressufficient tissue thickness to admit transmural reentry. Inthick tissue, the central filaments of transmural rotorshave room to deform dynamically, eventually acquiringenough curvature that filament segments are extin-guished at tissue boundaries, cutting filaments in two and

140

.- 120

^ 100

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4

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Figure 5. Left ventricular (LV) and right ventricular (RV) reentry descriptors.

1370 Journal of Cardiovascutar Electrophysiology Vol. 11. No. 12. December 2000

resultitig in rotor proliferation.^ Using nurnerical models,several investigators proposed tnechanistiis that mightgovern this filament delbrmation.'^'- Our data, in whichVF was more complex in the thick-walled LV than thethin-walled RV, are consistent with this notion. Sotiie ofthe mechanisms of lilamenl deformation require the ae-cutnulation of twist along the axis of the 3D rotor.'"" Inaddition, models have shown that twist causes abbrevi-ation of the excitable gap.'"^ In our data, although APDwas not different between the RV and LV during VF. theactivation rate ot the LV was t'lister. This implies that thetemporal excitable gap was shorter in the LV than theRV. This also is consistent with the notit)n that complexrotor dynamics enahled hy the thickness ot the LVplayed a role in the difference between LV and RVaclivation patterns.

Another mechanism hy which ventricular geometrymight influence activation patterns involves variations inventricular wall thickness. When a wavefront encoutitersa tissue expansion, it must depolarize a larger volutne oftissue. If sufficient depolari/ing curtent is not available,local propagation taikirc can occur. This is more likely ifexcitability Is depressed, as, for example, when the ac-tivation rate is high.-'' In this context, increased wallthickness variability might increase the cotiiplexity ofVF patterns by increasing the incidence of wavefrontfragtiientation. However, this did not appear to be theease in our data because wall thickness was more vari-able in the RV than the LV.

The available data suggest that the most likely causeof the LV-RV differences in VF activation patterns is thedifference in wall thickness between the two ventricles,This is not to say thai wall thickness is the primarydeterminant of VF activation patterns. Other factors suchas restitution or electrophysiologie and anatomic heter-ogeneity are probably at work as uell. Further studies areneeded to clarify the mechanisms by which ventriculargeotiietry inlluence VF activatiim patterns.

IJmilations

As we discussed in our previous reports.' " the pri-mary limitations of this .study involve spatial sampling.Our spatial resolution was 2 mm. which is in the upperend of the range recotnmended by Bayly et al.'** Each ofthe recording arrays covcied approximately 2()9c of theepicardial surface; VF patterns in other legions were notstudied. As we discussed previously in detail." our es-timates of reentry incidence (Fig. 4A) and the nutuber ofeyeles of reentr\' (Fig. 4B) probably are underestitiiatesbecause of the finite si/e of the recording arrays. How-ever, because these underestimates are functions of themean size of the reentrant circuits relative to the size ofthe recording array, and because in the presetit study thisratio was the same for both RV and LV, our conclusionsrelating LV and RV data should be unaffected. Finally.

our results highlight the need for intramural trapping ofVF, which was not pcrtbrmed in the current study.

Acknowk'it\inwnt: The aiitlwrs thank Dr. Gregory Walcott for assis-tance in acquiring MAP data.

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