MR Franz, K Bargheer, W Rafflenbeul, A Haverich and PR Lichtlenelectrocardiograms: direct evidence for the genesis of the T wave

Monophasic action potential mapping in human subjects with normal

ISSN: 1524-4539 Copyright © 1987 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online

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Monophasic action potential mapping in humansubjects with normal electrocardiograms: directevidence for the genesis of the T wave

MICHAEL R. FRANZ, M.D., KLAUS BARGHEER, B. SC., WOLF RAFFLENBEUL, M.D.,AXEL HAVERICH, M.D., AND PAUL R. LICHTLEN, M.D.

ABSTRACT T wave concordance in the normal human electrocardiogram (ECG) generally is ex-

plained by assuming opposite directions of ventricular depolarization and repolarization; however,direct experimental evidence for this hypothesis is lacking. We used a contact electrode catheter torecord monophasic action potentials (MAPs) from 54 left ventricular endocardial sites during cardiaccatheterization (seven patients) and a new contact electrode probe to record MAPs from 23 epicardialsites during cardiac surgery (three patients). All patients had normal left ventricular funtion and ECGswith concordant T waves. MAP recordings during constant sinus rhythm or right atrial pacing were

analyzed for (1) activation time (AT) = earliest QRS deflection to MAP upstroke, (2) action potentialduration (APD) = MAP upstroke to 90% repolarization, and (3) repolarization time (RT) = AT plusAPD. AT and APD varied by 32 and 64 msec, respectively, over the left ventricular endocardium andby 55 and 73 msec, respectively, over the left ventricular epicardium. On a regional basis, thediaphragmatic and apicoseptal endocardium had the shortest AT and the longest APD, and theanteroapical and posterolateral endocardium had the longest AT and the shortest APD (p < .05 to <.0001). RT was less heterogeneous than APD, and no significant transventricular gradients ofRT were

found. In percent of the simultaneously recorded QT interval,- epicardial RT ranged from 70.8 to 87.4(mean 80.7 + 3.9) and endocardial RT ranged from 80 to 97.8 (mean 87.1 4.4) (p < .001). Plottingof APD as a function of AT, independent of the recording site, revealed a close inverse relationship,such that progressively later activation was associated with progressively earlier repolarization Thelinear regression slope of this relationship averaged from all 10 hearts was - 1.32 + 0.45 (r = - .78+ . 10). These data suggest a transmural gradient of repolarization,with earlier repolarization occurringat the epicardium. The negative correlation between AT and APD, which was found at both theendocardial and epicardial surface and had an average slope of greater than unity, may furthercontribute to a positive ventricular gradient and T wave concordance.Circulation 75, No. 2, 379-386, 1987.

IN THE NORMAL electrocardiogram (ECG), the Twave has the same polarity as the QRS complex, al-though on a cellular level depolarization and repolari-zation cause deflections of opposite polarities. Thisparadox of the T wave concordance in the ECG hasbeen explained by assuming that the repolarizationwave travels, at least in some part of the ventricle, in a

direction opposite to that of depolarization.1 Thishypothesis requires that some areas of early activation

From the Division of Cardiology and Cardiovascular Surgery, Han-nover Medical School, Hannover, German Federal Republic.

Address for correspondence: Michael R. Franz, M.D., CardiologyDivision- CVRC 293, Stanford University Medical Center, Stanford,CA 94305.

Received April 30, 1986; revision accepted Oct. 9, 1986.Presented in part at the 58th Annual Scientific Sessions of the Ameri-

can Heart Association, Washington, DC, November 1985.

Vol. 75, No. 2, February 1987

have longer action potentials than do areas excitedlater.

Direct experimental evidence supporting thishypothesis is scarce. Burgess et al.2 determined therecovery of excitability at different ventricular sites asan indirect index of local repolarization; they foundlong functional refractory periods in the endocardiumand the apex and short functional refractory periods inthe epicardium and the base. Spach and Barr3 usedimplanted electrode arrays in dogs to measure the po-tential distribution during depolarization and repolari-zation. They found a relative extracellular positivity onthe epicardial surface, suggesting earlier repolariza-tion, and a prolonged negativity at the apical free wall,suggesting delayed repolarization. Cohen et al.4 andWatanabe et al.5 recorded intracellular action poten-

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tials from small preparations excised from sheep andguinea pig ventricles, respectively. They did not, how-ever, determine the local activation time at these sitesbefore excision and therefore could not define localrepolarization time (RT), which is the sum of activa-tion time (AT) and action potential duration (APD).Autenrieth et al.6 recorded monophasic action poten-tials (MAPs), using a suction electrode technique,from the epicardium of dog ventricles in situ and founda large dispersion ofAPD with a trend for later repolar-ization at the apex than at the base.

Corresponding data from the human ventricle arestill lacking because it has not been possible to map theduration and configuration of transmembrane actionpotentials in the clinical setting. We have developed anew contact electrode technique for endocardial7 andepicardial' mapping ofMAPs in vivo and have demon-strated that these MAPs accurately indicate the time ofactivation and the entire repolarization time course ofthe transmembrane action potential.' In this study, werecorded MAPs and determined local AT, APD, andRT at multiple endocardial and epicardial sites in thehuman left ventricle. We detected an inverse correla-tion between AT and APD, which is compatible with apositive ventricular gradient and T wave concordancein the surface ECG.

MethodsPatients. Seven patients referred to the Hospital of the Han-

nover Medical School underwent endocardial MAP mappingduring normal sinus rhythm or during right atrial pacing at aconstant rate. The clinical indication for cardiac catheterizationwas suspected coronary artery disease in five patients and evalu-ation of aortic valve disease and aortic coarctation, respectively,in the other two patients. Epicardial MAP recordings were ob-tained in an additional three patients who underwent cardiacsurgery for coronary artery bypass grafting. The nine male andone female subjects had a mean age of 49.5 years (range 16 to61). All had normal PR, QRS, and QT intervals and normalelectrical axes with concordant T waves. Resting cardiac func-tion, ventricular dimensions, and motility, as assessed by Mmode and two-dimensional echocardiography or ventriculog-raphy, were normal; ejection fractions ranged from 55% to79%. None of the patients received any cardioactive drug regi-men in the days before or during cardiac catheterization orsurgery. All patients gave written informed consent before thestudy, which had been approved by the University's Committeeon Human Investigation.

Endocardial MAP mapping. Studies were performed withthe patient in the nonsedated, postabsorptive state during sinusrhythm. If sinus rate varied by more then 5 beats/min, the heartwas paced from the right atrium at the slowest rate required tooverdrive the spontaneous rhythm. MAPs were recorded with acontact electrode catheter similar to that described previously.7This catheter has two nonpolarizable electrodes, one formingthe catheter tip and the other located on the sidewalls 5 mmproximal to the tip. The MAP catheter was inserted percutane-ously into the femoral artery and advanced to the left ventricleunder fluoroscopic guidance. The left ventricular mapping

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4FIGURE 1. Endocardial mapping schema used to allocate MAP re-cordings to individual segments in the heart. RAO = right anterioroblique projection; LAO = left anterior oblique projection. There were11 individual segments that were combined to six larger areas as fol-lows: segments 2 and 3 = anteroapical; segment 4 = inferoapical;segment 5 = diaphragmatic; segments 6 and 7 = basoseptal; segment 8= apicoseptal; segments 9 and 10 = posterolateral. Segments 1 and 11situated just behind the aortic valve, were difficult to reach; only fourendocardial recordings were obtained from these areas, which thereforewere not included in the statistical analysis.

scheme used is shown in figure 1. The catheter sites wereverified by multiple-plane fluoroscopy. All MAP signals wererecorded with a high-impedance, direct-current coupled, differ-ential preamplifier. The preamplified MAP and three standardECG leads (usually lead II, III, and V,) were displayed simulta-neously on a multichannel recorder and recorded at paper speedof 100 or 250 mm/sec.

Epicardial MAP mapping. Epicardial MAP recordingswere obtained during open-chest cardiac surgery just beforeinitiation of cold cardioplegic heart-lung bypass. The deviceused to record epicardial MAPs is depicted schematically infigure 2. Two nonpolarizable silver-silver chloride electrodesare mounted on the distal end of a ribbonlike bar. The centerelectrode protrudes to contact the epicardial surface directly,whereas the peripheral (reference) electrode has electrical con-tact with the heart through a small piece of saline-soaked foamrubber. The ribbon is made from copper-steel alloy that allows itto be bent easily into the curvature required to reach the record-ing site while maintaining elasticity for stable "spring-loaded"contact of the center electrode with the epicardium. Because ofthe flatness and changeable curvature of the ribbon, the elec-trode head can be advanced between pericardium and epicardi-um to the posterior and inferior aspects of the left ventriclewithout dislodging the heart from its physiologic position.

FIGURE 2. Schematic presentation of the contact electrode probe usedto generate and record MAPs from the human epicardium during open-chest surgery. Further details in text and in ref. 8.

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When the center electrode was pressed slightly against theepicardium, MAPs developed and stabilized within 2 to 6 beats.Recordings were made during stable sinus rhythm or duringright atrial pacing at a constant rate. A detailed map of the leftventricular surface was used to identify the location from whicheach recording was made. MAPs were recorded only from thelateral, posterior, and inferior aspects of the left ventricle. Theseareas were covered by pericardium or lung tissue and not ex-posed to the cooling effect of room air. All patients appeared tobe free from subepicardial ischemia at the recording sites at thetime of study, as judged by previously identified indexes ofischemia in the MAP.8Data analysis. Because of the sequential spread of excita-

tion, activation at different left ventricular recording sites doesnot occur simultaneously but with varying delay. The delayfrom the earliest QRS deflection (in any lead) to the rapidupstroke of the MAP was defined as the AT. APD was theduration of the MAP from the upstroke to 90% repolarization.7RT was the time from the onset of the QRS complex to 90%repolarization at the recording site (AT + APD) (figure 3). Theaccuracy of the measured intervals was within 5 msec, as deter-mined by repeated measurements made by two different observ-ers. Only measurements made during regular sinus rhythm ( +5beats/min) or during regular atrial pacing were analyzed. Atleast five consecutive MAP recordings were assessed at eachsite, and intervals at a single site were found reproducible withless than 1% variation. The maximum difference between allrecordings in each patient, averaged for the patient group, wasused as a measure of dispersion.'0 To examine the relationshipbetween the intracardiac recordings and the body surface ECG,AT, APD, and RT were also evaluated in percent of the simulta-neously recorded QRS and QT durations, respectively. Un-paired Student's t tests and Pearson's correlation coefficientswere used to evaluate the significance of all results.

ResultsIn the seven patients undergoing cardiac catheteriza-

tion, MAP recordings were obtained from five to 11(mean 7.7 + 1.8) different left ventricular endocardialsites and in one patient from an additional eight rightventricular endocardial sites. In the three patients un-dergoing cardiac surgery, MAPs were recorded fromfive to 10 different left ventricular sites. All MAPs hadsmooth configurations and stable amplitudes rangingfrom approximately 20 to 40 mV.

Endocardial recordings. Data from an individual pa-tient are shown in figure 4. Values for AT, APD, andRT showed a relatively large variability. Recordings atthe apical region (segment 3 and 4) include both earlyand late activation and shorter and longer APD. Differ-ences in AT and APD within these apical regions werenearly as large as those along the apicobasal axis.Despite this variability of AT and APD within the leftventricular endocardium, it was noted consistently thatsites with early activation had longer APDs than sitesactivated later. Because of this inverse relationship ofAT and APD, RT (the sum of AT and APD) was lessheterogeneous than APD (figure 4). Figure 5 furtherexemplifies this finding by two sets of original MAP

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APDL90%

1 ATI_R

RTFIGURE 3. Method used to analyze local ventricular AT, APD, andRT. Details in text.

recordings, each comprising one with early and lateAT.

Data from all seven patients who underwent cath-eterization are listed in tables 1 and 2. Table 1 lists therange of AT, APD, and RT for each individual patientand the average range (dispersion) of these indexes forthe patient group as a whole. With respect to the simul-taneously recorded surface ECG, left ventricular endo-cardial ATs ranged from 0 to 34.7% of the QRS dura-tion and thus fell within the first third of globalventricular activation. AT varied by up to 32 msec inindividual patients, with an average dispersion of 24.9± 6.1 msec. APD varied by up to 64 msec in individ-ual patients, with an average dispersion of 41.4 ±14.6 msec. Similar to the individual data presented infigure 4, endocardial RT in the entire group was lessheterogenous than APD. The average dispersion ofRTwas 26.4 ± 12.0 msec. This was significantly lessthan the dispersion of APD (p < .05) (table 1).

Table 2 gives the comparative analysis of AT, APD,and RT for the six different left ventricular endocardialregions described in figure 1. The shortest endocardialATs were measured at the diaphragmatic and apico-septal region. Anteroapical and posterolateral regionshad relatively late activation, and basoseptal and in-feroapical regions had intermediate ATs. Because dif-ferent patients had different heart rates, APDs and RTs

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14/250 (264)6/266 (272)

RAO17/245 (262)

19/250 (269)18/252 (270)

16/252 (268)

8/280 (268)

FIGURE 4. Numerical data from endocardial MAP recordings in an

individual patient (No. 5). The left ventricular mapping scheme is thesame as in figure 1. AT and APD separated by slash, RT in parentheses(all msec).

were expressed in percent of the longest value mea-sured in each patient. Significant differences in aver-age APD were found between the diaphragmatic andapicoseptal areas, which had the longest average APD,and the anteroapical and posterolateral areas, whichhad the shortest average APD. Between these areas,average AT was also significantly different, in a direc-tion opposite to that of APD. RT did not demonstratesignificant differences among the six left ventricularendocardial regions; there was a trend for later repolar-ization only in the diaphragmatic and apicoseptal re-gions as compared with the other regions (table 2).This is consistent with the findings that regions withshorter ATs have longer APDs and vice versa; thereciprocal relationship between AT and APD tends tosynchronize repolarization in the ventricle. In one pa-tient, recordings were obtained from both the left andright ventricles. Average ATs were longer and averageAPDs shorter in the right as compared with the leftventricle.

Regional APD and RT were also compared by ex-pressing them in percent of the simultaneously record-ed QT interval. The results from this type of normal-ization confirmed those described above.

Epicardial recordings. ATs of left ventricular epicar-dial recordings in three patients ranged from 25 to 80msec (table 1) or from 26.3% to 64.8% of the simulta-neous QRS duration. The degree of heterogeneity ofepicardial APD was similar to that of endocardial ATs,with a maximum difference of 73 msec between theshortest and longest APD in one patient (table 1). Be-cause of the limited sample size of epicardial record-

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ings, a statistical comparison of different epicardialregions was not performed.To compare epicardial and endocardial RT, mea-

surements from the three surgical patients and the sev-en patients undergoing cardiac catheterization wereexpressed in percent of the simultaneously recordedQT interval. Epicardial RTs ranged from 70.8% to87.4% (mean 80.7 + 3.9%) of the QT interval, whichwas markedly shorter than endocardial RTs, rangingfrom 80% to 97.8% (mean 87.1 ± 4.4%) of the QTinterval (p < .001). Thus, based on this global com-parison, the epicardium had later activation but repo-larized earlier than the endocardium.

Relation between AT and APD. To examine the rela-tion between AT and APD independently of the area,we plotted all APD values as a function of AT, regard-less of the site from which the recordings were ob-tained. Linear regression analysis of these data showeda significant inverse correlation between AT and APD,such that progressively later activation was associatedwith progressively shorter APD (figure 6 and table 3).The average slope of the regression lines, derived fromthe seven endocardial and three epicardial data sets,was - 1.32. This slope, which is greater than negativeunity, indicates that the increase in AT along the acti-vation pathway was more than compensated by a short-ening of the action potential.

DiscussionIn this study, we recorded MAPs from multiple en-

docardial and epicardial sites in the human ventricle insitu by means of the contact electrode technique.7 8The contact electrode has a tip diameter of 1 mm and

(A) (B)

\\J, \=__

FIGURE 5. Original MAP recordings from left ventricular endocar-dium exemplifying the relation between AT and APD. Two sets ofrecordings (each set from a different patient) were superimposed so thatthe concomitant QRS complexes align. A, One MAP (recorded from theleft ventricular mid septum) was activated 34 msec before the other(recorded from the anterior wall), yet repolarized after the MAP withlater activation; B, One MAP (apex) was activated 42 msec before theother (posterolateral), yet repolarized at nearly the same time.

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TABLE 1Range of left ventricular AT, APD, and RT in 10 patients

AT APD RT HRPatient n (msec) (msec) (msec) (beats/min)

Endocardial1 7 3-34 271-311 300-315 852 7 12-42 286-347 318-362 763 8 0-22 277-317 298-318 953 RVA 8 10-39 262-286 282-309 954 5 0-25 306-336 306-330 725 7 6-19 245-266 262-272 996 9 0-32 239-273 252-275 1017 11 7-28 284-348 312-358 64Mean±SDB 24.9±6.1 41.4± 14.6 26.4± 12.0

Epicardial8 5 25-49 247-320 296-354 979 8 37-68 261-306 322-355 7610 10 50-80 270-330 348-380 81Mean ± SD 28.4 ± 3.8 59.3 ± 11.4 41.0± 12.0

HR = heart rate during the recording period.APatient 3 had an additional eight recodrdings from right ventricular (RV) endocardium (not included in mean values).BThe average of the range of values for each patient in the group, a measure of dispersion.

thus samples the electrical activity of probably severalhundred cells. Despite this local averaging effect, thecontact electrode MAP reproduces the AT and theAPD of adjacent transmembrane potentials with highaccuracy.9 In contrast to the intracellular microelec-trode, the contact electrode technique produces stablerecordings in the beating heart and is safely employedin the clinical setting.7 These features combined makethe contact electrode MAP a unique tool for measuringboth the AT and the APD at various sites in the humanventricle. The sum ofAT and APD at an individual siteyields the local RT, which can be used to map the

sequence of ventricular repolarization with respect toventricular activation. We will first discuss our resultsindividually for each index and then relate them to theelectrocardiographic T wave.

AT. Earliest endocardial activation occurred in thediaphragmatic, apicoseptal, and basoseptal regions.This agrees well with data previously obtained in re-

suscitated perfused isolated human hearts'1 and, more

recently, in normal human hearts in situ.'2 Durrer etal. noticed the latest activation (above 30 msec) of theleft ventricular endocardium in the posterobasal re-

gion, and we also measured only relatively long ATs

TABLE 2Average AT, APD, and RT in six left ventricular endocardial regions and the right ventricleA

AT Signif. diff. APD Signif. diff. RTRegion n (msec) from region (%) from region (%)

D 7 6.4 ± 5.0 AApB,pLB 96.3 ± 3.1 AApD,PLD 96.8 ± 2.6ApS 10 8.2±8.4 AApc,PLc 95.7±4.8 AApD,PLD 97.1±3.4BS 8 10.5±3.7 AApc,PLC 95.0±2.8 95.8±3.0IAp 11 11.9±8.2 AApD,PLD 93.9+4.1 95.9±2.4AAp 17 19.9±8.0 DB,ApSC 91.3±5.3 DD,ApSD 95.6±4.0PL 19 20.4± 8.4 DB,ApSC 91.8± 5.5 DD,ApSD 95.1±4.3RV 8 25.9±9.8 n/a 86.5±2.4 n/a 94.3±2.9

Data expressed as mean ± SD.D = diaphragmatic; ApS = apicoseptal; BS = basoseptal; IAp = inferoapical; AAp = anteroapical; PL = posterolateral;

RV = right ventricular.AData are summarized from all seven patients with endocardial recordings. To eliminate the effect of heart rate, APD and RT

are expressed as percent of the maximal value in a given patient.Bp < .0001; Cp < .005; Dp < .05. There were no significant differences in average RT among any of the six left ventricular

regions.

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275

270

265 r=0 889

260

255\*0

250 * \

245 *

240o) 5 10 15 20 25 30

320

310* r=0.840

300 X290

o

280 o0@

270 0 0

260 . >0 10 20 30 40

Activation Time (ims)

FIGURE 6. Relationship between AT and APD demonstrated by linear regression analysis of data from three representativepatients. Open circles in right panel denote right ventricular data.

(above 20 msec) in the posterolateral endocardium.Epicardial ATs, measured in three patients' left ven-

tricles, ranged from 25 to 80 msec, which was consid-erably greater than the range of endocardial ATs. Thisagrees with measurements in isolated human hearts`1 inwhich epicardial ATs ranged from 40 to 70 msec withearly breakthrough points at 20 to 25 msec.

APD. Previous animal studies have suggested sever-al partly conflicting geographic gradients of APD. Co-hen et al.4 using microelectrode records from excisedtissue of sheep ventricle, suggested a shortening ofAPD from the base to the apex. Autenrieth et al.,6 whoused epicardial suction-electrode recordings in intactdog ventricles, and Watanabe et al.'2 who recordedintracellular potentials in partially dissected guinea pigventricles, reported action potential shortening fromthe apex to the base. Watanabe et al.5 found a signifi-

TABLE 3Data from linear regression analysis for the relationship betweenAT and APD in all patients

Patient s slope r p value

1 - 1.27 -.96 <.00012 - 1.48 -.76 <.013 - 1.16 -.84 <.00014 - 0.83 -.66 <.055 - 1.24 -.89 <.00016 -0.82 -.73 <.0057 - 2.11 -.79 <.00018A - 2.00 -.67 NS9A -0.90 -.65 <.0510A - 1.43 -.83 <.005Mean -1.32 -0.78+SD 0.45 0.10

AMAP recordings taken from the left ventricular epicardium; all oth-ers from left ventricular endocardium and patient 3 also from rightventricular endocardium.

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cantly shorter average APD at the lateral free wall as

compared with the septum and papillary muscles.Our data do not verify these gradients for the human

left ventricular endocardium. Although our samplesize was limited, a uniform gradient in, for instance,an apicobasal direction, should not have gone unde-tected. We instead noted that APDs were markedlydisparate, even within a given region. This agrees withresults of previous animal investigations, which indi-cated that inhomogeneities of APD or refractory peri-ods occur within very small distances over the entiresurface of the ventricle.2'5 6. 13 14 In our study, thelongest average APD was measured in the septal anddiaphragmatic area and the shortest at anteroapical andposterolateral sites. There are no endocardial data froma large mammalian species with which to compare thisgradient.

RT. The T wave is a reflection of regional differ-ences in RT, not APD. Ventricular repolarization gra-

dients deduced from regional differences in APD4' 5, 10may be invalid because they ignore the varying delaywith which different sites are activated in the wholeventricle. In this study, the RT, i.e., the interval withwhich a given ventricular site repolarizes after the ear-

liest deflection of the QRS complex, was obtained byadding the APD to the corresponding AT. RT was

found to be more evenly distributed over the left ven-

tricular endocardium than APD; the average dispersionof repolarization, estimated from the RT range in allpatients, was significantly smaller than the average

dispersion of APD. In contrast to APD, we could notdetect statistically significant differences in mean RTamong the six endocardial regions; there was only a

trend of longer RTs in the diaphragmatic and apicosep-tal regions as compared with the other regions.

Endocardial and epicardial RT, expressed in percent

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of the simultaneously recorded QT interval, showedthat in the sampled areas average epicardial RTs weresignificantly shorter than endocardial RTs. This agreeswith measurements of refractory periods"4 15 and extra-cellular field potentials3 in canine hearts and supportsthe concept of a transmural gradient of repolarizationthat may contribute to the T wave genesis.

Watanabe et al.5 found endocardial and epicardialAPDs in guinea pig ventricles too short to account forthe entire T wave duration and postulated longer APDsin the intramural myocardium. In our study, the long-est endocardial RTs were nearly as long (97.8%) as thesimultaneously recorded QT interval. Thus, in keepingwith previous canine data,6 there is no need to assumelonger action potentials in the intramural myocardiumthan on either its endocardial or epicardial surface.

Relation between AT and APD. We found a close nega-tive correlation between AT and APD, such that sitesactivated early had longer action potentials than didsites activated late. The dependence of APD on ATappeared independent of the location in the heart fromwhich the measurements were obtained. This raises theintriguing question of whether regional differences inAPD are caused by intrinsic electrophysiologic differ-ences between myocardial cells or whether they aresecondary to the sequence of activation. Does a myo-cardial cell "know" when to repolarize, just because ofits site within the ventricle, or does an overridingmechanism "tell" the cell when to repolarize?One mechanism that could relate APD to activation

sequence is electrotonic interaction. Studies in isolatedventricular muscle and Purkinje fiber preparationshave shown that repolarizing (anodal) currents appliedduring repolarization shorten the action potential"$'8and that depolarizing (cathodal) currents applied dur-ing repolarization prolong the action potential.'7 AsHoffman'9 suggested, "During the cycle of ventriculardepolarization and repolarization, electrotonic currentfrom the area to be excited last may retard repolariza-tion of areas excited earlier in the activation sequence,and current from the first area to repolarize may speedrepolarization in areas not yet repolarized." Evidencefor electrotonic interaction in the canine heart in situwas obtained by Toyoshima and Burgess,20 who foundthat recovery of excitability was delayed when activa-tion was initiated at or near the site at which it wasmeasured, as compared with stimulation at a distantsite. Autenrieth et al.6 and Toyoshima et al.2' recordedMAPs with suction electrodes from the canine epicar-dium and also noticed that action potentials activatedearlier had longer durations than did those activatedlater.

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Several limitations apply to this clinical study. (1)Because of T wave results from many simultaneousvoltage gradients during repolarizaiton, even a rela-tively small net gradient in a predominant directionmay determine the polarity of the T wave.' It is possi-ble that a larger sample size would have revealed fur-ther endocardial or epicardial repolarization gradients.Also, endocardial areas located near the aortic valvewere difficult to reach and are underrepresented in thisstudy. (2) We pooled data from different patients withdifferent heart rates by expressing APD and RT as apercentage of the longest APD sampled in each pa-tient. Although the range of APDs recorded per patientwas large, we may have missed the longest APD pres-ent in a given patient. Also, it cannot be excluded thatheart rate alters APD nonuniformly over the heart.These factors may have increased the variability ofAPD and RT in our analysis of the patient group as awhole but not the dispersion found in an individualpatient. We tested our method of normalization byexpressing all data also as a percentage of the simulta-neously recorded QT interval and obtained essentiallyidentical results. (3) Local AT was determined as theinterval between the onset of QRS and the MAP up-stroke. Because of the limited number of ECG leadsrecorded, it is possible that we have missed the veryearliest beginning of ventricular activation. However,because all measurements were referenced to the earli-est QRS deflection in the same lead, the relationshipbetween AT and APD or RT, respectively, should notbe affected. (4) We do not know to what extent thedifferent conditions in patients undergoing cardiaccatheterization and open-chest surgery influence thequantitative comparison of endocardial and epicardialmeasurements. By recording epicardial MAPs onlyfrom areas covered by pericardium or lung tissue, weattempted to minimize the effect of cooling on theAPD. If cooling did occur, it should have resulted in anunderestimation of the transmural repolarization gradi-ent found in this study.T wave concordance. A model often used to explain

the T wave concordance of the normal ECG is based ontwo assumptions: (1) activation and repolarization ofthe ventricle both have relatively uniform and closedwavefronts, and (2) both wavefronts propagate in op-posite directions. Our data from endocardial and epi-cardial measurements, although obtained in differentpatients, strongly support for the human heart the con-cept of a transmural gradient of repolarization with adirection opposite to that of depolarization. A trans-ventricular gradient of repolarization was not detectedin this study. This may have been a result of the limited

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sample size or of nonuniformity of the repolarizationwavefront. In the canine heart, the activation wave-front has been shown to follow a very complex, non-uniform pattern.22 Because of the close (inverse) cou-pling of repolarization and activation, one mightexpect a similarly complex repolarization wavefront.The relatively large variability of RT within andamong different ventricular regions in previous animalexperiments'614 and our human study is consistentwith this hypothesis. Electric field mapping in the ca-nine heart demonstrated that transmural gradients arethe probable cause of T waves during sinus rhythm buttransventricular gradients are responsible during ecto-pic stimulation.23 Regional gradients may therefore beexpected to be either absent or less important duringsinus rhythm. The inverse correlation between AT andAPD, noticed at both the endocardial and epicardialsurface independent of the area, still supports the con-cept of opposite directions of depolarization and repo-larization. The linear regression between AT and APDhad an average slope of greater than - 1, and this maycontribute to a net ventricular gradient and T waveconcordance even in the absence of continuous de-polarization and repolarization wavefronts.

The inverse correlation between AT and APD notonly helps to explain the genesis of the concordant Twave, but also has implications for arrhythmogenesis.Dispersion of ventricular repolarization predisposes toreentrant excitations. 10 Progressive action potentialshortening with progressively later activation, pre-viously recognized in the canine heart2' 24 and corrobo-rated in this human study, tends to synchronize ven-tricular repolarization. This may be an importantphysiologic mechanism in the prevention of ventricu-lar reentrant arrhythmias.

We thank Drs. Howard B. Burchell and William T. Clusinfor discussion and advice during the preparation of the manu-script.

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