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arly voltage/calcium uncoupling predestinates the duration ofentricular tachyarrhythmias during ischemia/reperfusionerman D. Himel IV, PhD,* Gil Bub, PhD,† Yuankun Yue, PhD,* Nabil El-Sherif, MD, FHRS*‡

rom the *VA NY Harbor Healthcare System, Brooklyn, New York, †Oxford University, Oxford, England, and the ‡SUNY

ownstate Medical Center, Brooklyn, New York.

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ACKGROUND Abnormal intracellular calcium (Cai) kinetics dur-ng ischemia/reperfusion (I/R) can alter membrane voltage (Vm)nd destabilize wavefront propagation.

BJECTIVE We used optical mapping to investigate the hypoth-sis that early Vm/Cai uncoupling during a ventricular tachyar-hythmia (VT) can play a primary role in perpetuation of VTpisodes.

ETHODS Seventeen Langendorff-perfused guinea pig heartsere subjected to 15 min I/15 min R. Simultaneous optical re-ordings of Vm and Cai signals were obtained using a dual-photo-iode array. Spatiotemporal entropy (E) was used to quantifyifferences in Vm/Cai kinetics during VT and compare wavefrontopology during the first 500 ms of a VT episode.

ESULTS A total of 39 episodes of VT were analyzed; VT waslassified as self-terminating (ST, n � 28) and non–self-terminat-

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METpimU8cpol.com. (Received April 30, 2009; accepted June 24, 2009.)

547-5271/$ -see front matter. Published by Elsevier Inc. on behalf of the Heart

T/VT (1 to 5 s in duration; n � 16) and long ST/VT (�5 s, n �2). E values for NST/VTs were significantly higher than E valuesor both short and long ST/VTs separately as well as E values forT/VTs as a group. Further, E values for long ST/VTs were signif-cantly higher than E values for short ST/VTs. Wave breaks wereonsistently identified during periods of high E.

ONCLUSION High E during the first 500 ms of the onset of VTthe first 2 to 3 beats) is significantly correlated with long ST orST episodes. This may be related to destabilization of waveropagation that helps to perpetuate VT. Early Vm/Cai uncouplingan predestinate the development of a malignant NST/VT.

EYWORDS Ischemia/reperfusion; Ventricular tachyarrhythmias;ptical mapping; Calcium kinetics; Spatiotemporal entropy.

Heart Rhythm 2009;6:1359–1365) Published by Elsevier Inc. on

ng (NST, n � 11). The ST/VTs were further classified into short behalf of the Heart Rhythm Society.

ntroductionschemia/reperfusion (I/R) is characterized by abnormalalcium kinetics and elevated intracellular Ca2� (Cai).

1–3

owever, the role of Cai in arrhythmogenesis during I/R isot well understood. Alterations in Cai kinetics can alterransmembrane voltage (Vm) and lead to arrhythmogenesisy several mechanisms: Cai alternans,4 focal arrhythmiasriggered by early or delayed afterdepolarizations,5 or aestabilization of wave propagation caused by local uncou-ling of Vm/Cai. Of these 3 mechanisms, the relationshipetween Vm/Cai uncoupling and arrhythmogenesis is theeast understood.

Under normal conditions, Vm and Cai are highly inter-ependent and bidirectionally coupled. Cai reliably tracksm at normal heart rates. Ischemia results in contrasting

ffects on action potential duration (APD) and Cai transienturation.4 Although APD is shortened, the Cai transient isrolonged because of delayed upstroke and slowed decay ofhe transient.4 The changes in APD are spatially heteroge-eous in contrast to a more homogeneous prolongation of

This study was supported by MERIT and REAP grants to Dr. El-Sherifrom the VA Central Research Department. Address reprint requests andorrespondence: Dr. Nabil El-Sherif, VA NY Harbor Healthcare System,00 Poly Place, Brooklyn, New York 11209. E-mail address: nelsherif@

ai transient.4 At fast excitation rates, this can result in localncoupling of Vm/Cai. We hypothesized that during the earlyhase of ventricular tachyarrhythmia (VT) a spatially hetero-eneous uncoupling of Vm/Cai could destabilize wavefrontropagation and play a primary role in perpetuation of theT episode. By contrast, a lesser degree of uncoupling of

m/Cai during the early phase of VT could be associatedith a short VT episode. The duration of a VT episode is ofaramount importance in clinical arrhythmology becauseong VT episodes can cause hemodynamic deterioration andrrhythmic death. To investigate this hypothesis, we intro-uce a novel analytical method based on spatiotemporalntropy6,7 to quantify differences in Vm/Cai kinetics duringT episodes of different durations.

ethodsxperimental procedurehe experimental model is a Dunkin-Hartley Langendorff-erfused guinea pig heart. The protocol was approved by thenstitutional animal studies subcommittee, and animals wereaintained in accordance with the Guide for the Care andse of Laboratory Animals (National Institutes of Health5-23, revised 1985). Voltage and calcium transients wereaptured using a protocol and equipment fully described

reviously.4,8 Briefly, each heart (n � 17) was collected

Rhythm Society. doi:10.1016/j.hrthm.2009.06.032

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1360 Heart Rhythm, Vol 6, No 9, September 2009

rom guinea pigs (female, 350 to 450 g) after intraperitonealnjection of heparin (200 U/kg) followed by anesthesia withodium pentobarbital (35 mg/kg). The heart was Langen-orff perfused with a modified Tyrode solution (130 NaCl,5 NaHCO3, 1.20 MgSO4, 4.0 KCl, 20 dextrose, 1.25aCl2; at pH 7.4, bubbled with 95% O2–5% CO2) with aow rate of 12 to 16 ml/min, at 70 mm Hg pressure. Theeart was then placed in a custom-made chamber and situ-ted against the imaging surface by positioning a Lexanlunger posterior to the imaged plane to reduce the curva-ure of the imaged surface and motion artifacts. The heartas then stained with a voltage-sensitive dye (RH237, Invitro-en, (Carlsbad, CA), 10 to 20 �l of a 1-mg/ml solution inimethyl sulfoxide, DMSO) and intracellular calcium indicatorRhod-2 AM, Invitrogen, 0.2 mg in 0.2 ml DMSO). Theoltage-sensitive dye RH237 was injected as a single bolusver a 1-min period, whereas the calcium indicator was slowlynjected in 5 separate boluses over a 10-min period. The heartas regularly paced from the right ventricle outflow tract at

ycle lengths (CL) of 400 to 500 ms. After a stabilizationeriod of 15 min, the heart was subjected to 15 min of globalo-flow I followed by 15 min of R.

ptical mappingm and Cai transients were captured using a protocol and

quipment fully described previously.4,8 The optical appa-atus was adjusted so that Vm and Cai transients weremaged from a 16 � 16-mm square area of the left ventricle.lobal no-flow I was applied to the preparation after ac-uiring initial measurements of Vm and Cai during basichythm. Vm and Cai traces were continuously recordeduring both I and R.4,5,8 Traces near the edge of the imagingeld were discarded to limit effects of noise on subsequentnalysis. The data were then mapped to a color scheme bysing a false color filter where red maps to high values ofuorescence, green to intermediate values, and blue to lowalues. Activation maps from 16 � 16 pixels were expandedo 256 � 256-pixel images by linear interpolation. A wavereak was defined as the point where the activation wavefrontnd the repolarization wavefront join together on the map.9

ntropy calculationse used a coherent cluster analysis6,7 to compare spatio-

emporal dynamics of Vm and Cai. Frames of 2-dimensionalaps were stacked along the time axis to create a space-

ime cube. Active sites were determined by comparison to ahreshold, which was set to equal to 65% of the maximumF (fractional change in fluorescence relative to the dia-

tolic level of the fluorescence baseline). Neighboring (inime and/or space) active sites were joined to form space-ime clusters (or simply clusters). Small clusters, whichere likely caused by detector noise, were filtered: clustersere not included in the analysis if they did not persist forminimum time of 50 ms, or were not larger than an area

f 5 pixels at any given instant. Also, clusters that werearger than a maximum area of 10 pixels at time 0 were

emoved to exclude clusters that began before the chosen m

ime window. Spatiotemporal entropy was calculated usinghe following equation:

� � �s

vs · ln vs (1)

here vs is the fraction of the total volume of all clusters forgiven cluster size s, as defined by equation 2.

s � s · ns ⁄ Vtotal (2)

here s is the cluster size for a cluster s, ns is the number oflusters of size s, and Vtotal is the total volume of alllusters. Thus, vs is the fractional volume of all clusters ofgiven cluster size s relative to the volume of all clusters.igure 1 is a simplified schematic illustration of the Eoncept.

se of entropy to quantify uncouplingwas calculated separately for Vm and Cai data sets for

ach VT episode. We did not treat entropy values obtainedeparately for Vm and Cai as an accurate measure of E of thenderlying system. Such a characterization would requirevidence of convergence as well as a careful analysis of theffect of the threshold on E. Rather, we obtained the differ-nce in E, Ed, where Ed � |EVm � ECa| (EVm and ECa are the

values obtained for Vm and Cai data sets, respectively).e propose that Ed is a measure of the difference in com-

lexity between Vm and Cai dynamics in this system.VT episodes were located by visual inspection of the

ata. A 500-ms segment starting at the initiation of each VTpisode was isolated for analysis. The starting point of the00-ms window was chosen to coincide with the site of thearliest activation wavefront in the optical field at the ini-

igure 1 Schematic showing space-time cubes illustrating various lev-ls of entropy. Cube A shows a space-time cube with only 1 clusteromprising 100% of the total volume of all clusters, which by Equations 1)nd 2) gives vs � 1 and E � �ln(1) � 0. Cube B contains 1 clusteromprising 50% of the total volume and 2 others that are 25% of the totalolume each. For this case, there are 2 distinct classes of clusters, both ofhich comprise 50% of the total volume, giving vs � 0.5 and E � �ln(0.5) �.6931. Cube C contains 4 classes of clusters, including 1 with a volume of5%, 2 with a volume of 12.5%, 3 with a volume of 8.33%, and 4 with aolume of 6.25%. Thus, each class comprises 25% of the total volume,iving vs � 0.25 and E � �ln(0.25) � 1.3863. For the sake of simplicity,lasses of clusters in cubes B and C were constructed so that each classomprised an equal proportion of the total cluster volume. Axes for the x-y

apping plane and time are indicated above cube A.

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1361Himel et al Voltage/Calcium Uncoupling and VT Duration

iation of the VT episode. Running E values were calculatedvery 160 ms, where each E value represents the E over the00-ms segment after the value. VT episodes were classifieds self-terminating (ST) and non–self-terminating (NST).T/VTs were further classified into short ST/VT (1 to 5 s inuration) and long ST/VT (�5 s). To examine the possibil-ty that VT duration may be accounted for simply by dif-erences in the CL, we calculated the average CL of all VTsuring the first 500 ms using a simulated volume electro-ardiogram, which reflects the overall excitation rate of thentire heart.

tatistical analysisalues are stated as mean � standard deviation. A 1-way

nalysis of variance was used to determine whether differ-nces existed among groups. The 2-tailed, unpaired Student-test with Bonferroni correction was used post-hoc to deter-ine differences between groups. The test did not assume

qual variance. A corrected critical value of 0.0125 corre-ponded to an alpha value of 0.05, and was considered to beignificant. The Lilliefors test for normality was used to verifyhat each of the groups tested were normally distributed.

esultse analyzed 39 episodes of VT from 17 different hearts (16

hort ST/VTs, 12 long ST/VTs, and 11 NST/VTs). In 11earts, 1 or more ST/VT was observed before the onset ofST/VT. In the remaining 6 hearts, only ST/VTs occurred.he average duration of short ST/VTs (1 to 5 s) was 2.29 �.85 s. The duration of long ST/VTs (5 to 30 s) was 14.26 �.50 s. There was no relationship between the duration of I/Rnd the onset of ST/VTs and NST/VTs. In fact, in 4 exper-ments a NST/VT followed a ST/VT within 1 or a few beats,nd in each case there was a significant difference in Ed

etween the 2 VTs (Figure 2).We investigated the degree of Vm/Cai uncoupling during

he first 500 ms of VT episodes. This interval was carefullyhosen after analysis of the average CL of the overallardiac excitation rate in the volume electrogram of all shortnd long VTs during the first 500 ms. The average CL of50 � 30 would include no less than the first 2 and no morehan the first 3 beats of the VT episode. We then analyzedhe average CLs of short and long VTs separately. Althoughong VTs have slightly shorter CLs of 144 � 46 ms com-ared with 160 � 34 for short VTs, the difference was nottatistically significant. This excluded the possibility that anncreased degree of uncoupling during long VT is related toignificantly shorter CLs during the first 2 or 3 cyclesFigure 2).

E values were calculated separately for Vm and Cai, andhe difference in E values between them (Ed) was consid-red a measure of the difference in complexity between Vm

nd Cai wavefront dynamics. A running E measure in-reased during ST/VT, but E values for Vm and Cai re-ained closely coupled. A running measure of E duringST/VT also increased, but E values of Vm and Cai di-

erged from each other (Figure 3). O

We examined wavefront topology during the early phasef ST and NST/VTs. ST/VTs showed the Cai activationavefront in the optical field following closely the Vm

ctivation wavefront with no evidence of early wavebreak,onsistent with a lower degree of Ed (Figure 4). On the otherand, NST/VTs were associated with frequent wavebreak ofoth Vm and Cai wavefronts during the early phase of theT episode, illustrating a higher degree of Ed (Figure 5).Figure 6 shows Ed values for individual VTs as well as

he average values for each of the separate groups. The Ed

alues for NST/VTs were significantly higher than the Ed

alues for both short and long ST/VTs separately as well ashe Ed values for ST/VTs as a group. Further, the Ed valuesor long ST/VTs were significantly higher than the Ed valuesor short ST/VTs. Finally, Ed values during the basic rhythmreceding the onset of VT were consistently close to 0.

In addition to comparing the absolute value of the en-ropy difference between Vm and Cai signals, we also ex-mined the simple entropy difference, defined by Esd � EVm

ECai. Statistical analysis using Esd was performed in andentical manner as in Figure 6C, and no significant differ-nces were found among any of the groups.

iscussionrevious studies have investigated the role of Vm/Cai un-oupling during VF but have reached different conclusions.

igure 2 A: Control recording of simultaneous optical signals of actionotential (AP, in black) and intracellular calcium transient (CaiT, in red) onhe epicardial surface of a Langendorff-perfused guinea pig heart duringight ventricular pacing at cycle length (CL) of 400 ms. The CaiT tracks theonfiguration of the AP. B: After 9 min of ischemia, the AP duration washortened but the duration of CaiT increased primarily because of delayedelaxation of the transient. Ventricular arrhythmias developed in the formf an isolated premature beat (the fourth beat in the recording, followed by1.2-s short run of self-terminating (ST) ventricular tachyarrhythmia (VT),nd within 2 paced beats by an episode of long non–self-terminating (NST)T. C: The average CLs during the first 500 ms duration of the shortT/VTs and long NST/VTs (highlighted in B) and calculated from theimultaneously recorded simulated volume electrocardiogram shown in Cere similar. However, the NST/VT had a significantly larger Ed comparedith the short VT. The black bar beneath recording A represents a 1-s

nterval.

michi et al10 simultaneously mapped Vm and Cai during

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1362 Heart Rhythm, Vol 6, No 9, September 2009

F in a right ventricular preparation, and found that Cai noonger reliably followed, and often preceded, Vm upstrokesear wavebreaks, suggesting a role for uncoupling in VF.y contrast, Warren et al11 reported that Vm/Cai uncouplingas confined to narrow sites of conduction block, leading

hem to suggest that uncoupling is an artifact caused bynequal penetration of Vm/Cai wavefronts into blocked tis-ue, and that Cai kinetics play no role in driving Vm. How-ver, these studies investigated steady-state VF in perfusedissue, and did not address the contribution of early Vm/Cai

ncoupling to the duration of VT during I/R in a whole-eart preparation.

easurements of Vm /Cai uncouplingny quantitative measure of Cai dynamics during ischemia

hould be able to measure differences in Vm and Cai signalsor both short and long runs of VT. However, the 2 estab-ished measures (dominant frequency analysis [DF] andutual information [MI]) have shortcomings in this regard.

igure 3 Running entropy (E) values during a short ST/VT (A) and aembrane voltage (Vm), and the red trace intracellular calcium (Cai). E wa

ermination of the short ST/VT, and the E values for Vm and Cai were connd NST/VT. However, during the short ST/VT, the E values for Vm andai diverged from each other. The black bar beneath the recordings repre

igure 4 A: Running entropy (E) values for a short ST/VT episode frncreased during the short ST/VT but remained closely coupled. B: V an

m i

nset of VT (see arrow in A). The Vm and Cai activation maps are concordant w

F is defined as the frequency with the maximal power intime series.12 In principle, it is possible to measure Vm/Cai

ynchrony by comparing the DF for Vm and Cai transientsn a pixel-by-pixel basis. However, spectral analysis doesot well characterize aperiodic waveforms, which are ex-ected to exist during fibrillation. Further, the DF measureiscards information: by assigning a single frequency valueo a complex waveform, it is likely that small oscillationsaused by abnormal Cai dynamics would be missed.

MI is a statistic that quantifies the interdependence of 2ariables by comparing individual and joint probability den-ities of the variables. In the case of Vm/Cai measurements,I represents the amount of information that one can ac-

uire about Cai, given that Vm is known. MI was found toecrease during sustained VF for optically measured Vm

nd Cai traces,10 indicating that Vm and Cai dynamics be-ome uncoupled. However, the statistical power of MI de-ends on the duration of the traces. Vm and Cai need to be

/VT episode (B) from a different experiment. The blue trace represents0 during the basic beats preceding the onset of both VTs as well as aftercoupled. On the other hand, E values increased during both short ST/VT

re closely coupled, whereas during the NST/VT, the E values for Vm and1-s interval.

ifferent experiment. As shown in Figure 3, the E values for Vm and Cai

aps in 4 consecutive frames at 20-ms intervals starting 260 ms from the

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1363Himel et al Voltage/Calcium Uncoupling and VT Duration

ontinuously measured for tens of seconds during VF forI to be accurately assessed. MI is therefore not a reliable

tatistic for the short paroxysmal VT episodes observeduring I/R.

On the other hand, spatiotemporal entropy is a measurehat has been applied to quantify wavefront fractionation inxcitable tissues.6 We have previously used this technique

igure 5 A: Running entropy values (E) for a long NST/VT episode frond diverged from each other. B: Vm and Cai maps in 4 consecutive frameame time from the onset of VT as shown for the short ST/VT episodeavefront topology with evidence of wave break.

igure 6 A: A scatter plot of Ed values for the basic rhythm (B, star shpisodes (diamond). Numbers on the x-axis indicate the duration of the arrasic rhythm preceding VT episodes (B), short ST/VTs (S), long ST/VTsntropy values in a table form calculated for the basic rhythm, short ST/Vorrection was used post-hoc to compare all possible combinations, and th

o an alpha of .05. Asterisks indicate redundant tests or a group tested against its

o analyze spatiotemporal dynamics during the initiation ofpiral waves in a 2-dimensional cardiomyocyte monolayer.7

s opposed to DF and MI measurements, which compareime series on a trace-by-trace basis, E characterizes wave-ronts over a spatiotemporal volume. E is assessed by de-ermining the volume occupied by individual wavefronts inspace-time cube constructed from the data. High E values

me experiment shown in Figure 4. The E values for Vm and Cai increasedms intervals starting at 270 ms following the VT onset (approximately there 4, see arrow in A). The Vm and Cai activation maps show discordant

ort ST/VT episodes (circle), long ST/VT episodes (square), and NST/VTin seconds. B: Bar graphs of means and standard deviations of Ed for the

T/VTs as one group (ST), and NST/VT (NST). C: Statistical analysis ofST/VT, ST/V as one group, and NST/VT. Student t-test with Bonferroniant P values are given. A corrected critical P value of .0125 corresponds

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1364 Heart Rhythm, Vol 6, No 9, September 2009

ndicate that there are a wide range of different-sized wave-ronts, whereas low E indicates that all wavefronts areoughly the same size. When applied to quantifying Vm andai dynamics, E differences between Vm and Cai indicate

hat there are differences in patterns of wave propagation,hich we use as a measure of Vm/Cai uncoupling.Our analysis focused on the magnitude of the difference,

ather than the simple difference, between entropy values.everal factors may influence whether voltage or calcium hasigher E values, some of which include rapid calcium oscilla-ions5 and discrepancies between voltage and calcium alter-ans.4 By taking a simple average, these effects may offsetach other and lead to an underestimation of uncoupling be-ween Vm and Cai signals.

T/VT versus NST/VTne of the least understood issues in clinical arrhythmology

s the difference in the electrophysiological mechanisms ofT/VTs versus NST/VTs. It is not unusual to observe alinical recording showing more than 1 ST/VTs to be fol-owed, sometimes within few seconds, by an NST/VT thatay result in sudden arrhythmic death. Several studies have

ttempted to address this issue using different experimentalodels. In an early study from this laboratory, the electro-

hysiological mechanism of spontaneous termination ofonomorphic reentrant VT was investigated in the canine

ost–myocardial infarction model.13 Two basic mechanismsf spontaneous termination were observed: 1) accelerationf conduction in part of the reentrant circuit associated withlowing of conduction and finally conduction block in theommon reentrant pathway; 2) the activation wavefront inhe common reentrant pathway abruptly broke across atable arc of functional conduction block, resulting in pre-ature activation of the common reentrant pathway and

onduction block. In a later study that used the same ex-erimental model, some VTs were observed to abruptlyerminate without any changes in the pattern of activation orf the cycle length.14 Other VTs terminated by prematurectivation resulting from shortening of the functional arc oflock. In both cases, conduction block occurred in theommon reentrant pathway. A more recent study utilizedptical mapping of activation during acute ischemia in iso-ated canine left ventricle preparations.15 In contrast to theresent study, this study showed that both ST/VTs andST/VTs had similar reentrant circuits in the same prepa-

ation. The difference is that ST/VT terminated abruptly inhe isthmus region with no change in activation sequence.owever, a possible difference in the intramural activationattern could not be excluded. All of the above studies haveimply reported topological data that showed the site andode of termination of VT but have provided little insight

f underlying basic electrophysiological mechanisms.

tudy limitationshere are limitations in both experimental and analyticalspects of this work. First, it is difficult to give a physical

nterpretation to E values obtained for our experimental t

ystem. E measurements in previous studies6,7 are based onracking wavefronts through a 2-dimensional excitable me-ia; however, our measurements are obtained from a small-dimensional window of a considerably larger cardiac tis-ue volume. It is impossible to fully track the origin and fatef most wavefronts propagating through the tissue. Thisimitation also applies to the correlation between high en-ropy and the observation of wavebreaks on the epicardialurface of the optical window. It is possible that someavebreaks may have represented discontinuities of subepi-

ardial wavefronts.It is also difficult to assert that recorded Vm and Cai

ignals originate from the same physical location. Photoncattering effects, driven by the stochastic interaction ofoth emission and excitation light with cardiac tissue, haveonfounding effects. For example, Vm- and Cai-sensitiveyes have different peak emission and excitation spectra.ecause the ability of light to penetrate tissue is stronglyependent on wavelength, we expect that each co-registeredixel from Vm and Cai detectors will be sampling fluores-ence from different spatiotemporal volumes. It is possiblehat a traveling wavefront edge may be detected by only 1f a pair of co-registered pixels. This effect becomes likelyt regions of tissue with conduction block.11 Further, Ealues vary as a function of the activation threshold, whiche believe reflects uncertainty in localizing wavefronts inptical maps during arrhythmic episodes.

However, these considerations may be mitigated as weompare the difference in E between related signals (Vm andai maps) for many arrhythmic episodes in the same exper-

mental system. Because our results are based on a relatives opposed to an absolute measure of E, we believe ouronclusions are valid. Further, we note that E measurementsuring the basic rhythm preceding the onset of VT are stablend the difference in E during the basic rhythm was con-istently 0, suggesting that our measurements reflect thenderlying complexity of the system.

onclusione have shown, for the first time, that differences in wave-

ront topology of Vm and Cai during the first 2 or 3 cyclesf VT, which reflect a higher degree of spatiotemporalntropy, are associated with a long ST/VT or NST/VT. Thetrong statistical difference of Ed values between shortT/VT and NST/VT provide robust proof of our hypothesiss it relates to the clinical situation, at least as it applies torrhythmias during ischemia/reperfusion. On the otherand, although we have shown statistical differences of Ed

alues between long ST/VT and both short ST/VT andST/VT, the value of this finding with reference to the

linical setting should be qualified. In the experimentaletting, coronary perfusion is stable and maintained at allimes; however, in the clinical setting, a long VT episodeay result in coronary hypoperfusion. This could alter the

nderlying electrophysiological substrate resulting in fur-her destabilization of activation wavefronts and degenera-

ion into NST/VT. Finally, strategies to prevent arrhythmic

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1365Himel et al Voltage/Calcium Uncoupling and VT Duration

eath during ischemia will need to take into account ourndings of early predestination of potentially malignantTs.

eferences1. Marban E, Kitakaze M, Koretsune Y, Yue DT, Chacko VP, Pike MM. Quan-

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