Methods. Cardiovascular Drugs and Therapy 4: , 1990 Kluwer Academic Publishers, Boston. Printed in U.S.A.

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1 Cardovascular Drugs and Therapy 4: , 1990 Kluwer Academc Publshers, Boston. Prnted n U.S.A. A New Semautomated Algorthm to Quantfy Holter-Detected Myocardal schema: Prelmnary Experence n the Trmetazdne European Multcenter Tral (TEMS) Jean-Mare Detry, Robert Fesler, Tony Berckmans, Phlppe Leclercq Dvson of Cardology, Unversty of Louvan, Sant-Luc Unversty Hosptal, Brussels, Belgum Summary. Holter-detected myocardal schema, ether panful or panless, s an mportant ssue n the functonal and prognostc evaluaton of coronary patents. Ths paper descrbes one of the frst attempts to relably quantfy the duraton and severty of the schemc ST-segment changes over a gven perod of tme; the algorthm descrbed here provdes physcans wth a global ndex of schema that s the total schemc area, namely, the ntegral of ST-segment depresson or elevaton over tme (expressed n mm mn). The dagnostc and prognostc power of ths new ndex remans to be establshed and to be compared wth the actually used smple measurements,.e., the number and duraton of schemc events. Key Words. myocardal schema, schemc area, Holter, ST segment torng systems s ther lack of quanttatve and reproducble data. Another parameter stll lackng n the lterature avalable today s a global, duraton- and severty-adjusted ndex of myocardal schema. n order to mprove the presently avalable methodology, we have desgned and tested a sem-automated algorthm that allows the detecton of all schemc epsodes and ther quantfcaton n a global schemc score. t provdes the ntegral of schemc ST-segment depresson over tme durng a gven perod of tme. The Holter system was tested wth an dentcal sgnal recorded on a prevously desgned and descrbed system for the analyss of the exercse-nduced STsegment shfts [6,15,16]. Although panful and slent schema may be mportant markers of the severty and prognoss of patents wth documented coronary artery dsease (CAD), hours of Holter montorng of ST-segment shfts has yet to prove ts real place n the dagnoss of CAD. Ths should be based on hstory (complants), rsk factor evaluaton, and modern (.e., computer-asssted) symptom-lmted maxmal exercse testng combned, whenever clncally useful, wth stress perfuson scntgraphy and late magng [1-6]. On the other hand, Holter montorng has a specfc place n the evaluaton of the total schemc burden, whch s the addton of both the panful and slent (panless) epsodes of myocardal schema [7-12]. Classcal technques rely on the analyss of the number of schemc epsodes and ther total duraton, and allow the dentfcaton of a crcadan varaton n myocardal schema. The latter s strongly remnscent of the crcadan varaton of other major markers of CAD,.e., angna pectors, myocardal nfarcton, and schemc sudden death [12,13]. A major lmtaton of all avalable Holter mon- Methods Holter montorng We use A.M. Avoncs recorders for 24-hour Holter montorng and the Avoncs Trendsetter A for further analyss. Durng the trend operaton of the Holter reader, two analog sgnals, one for ST-segment level (ST) (0.06 or 0.08 seconds after the J pont) and another for heart rate (HR), are dgtzed and stored on the floppy dsc of a homemade mcroprocessor system. The acquston rate s 120 converson by second. As we store only the average of fve successve acqustons and as the playback of the tape s 240 tmes faster than the recordng tme, the real-tme equvalent samplng rate becomes one sample every 10 seconds. Thus, for a 24- hour tape, 8640 ponts for the ST segment and 8640 Address for correspondence and reprnt requests: Professor J.M. Detry, Dvson of Cardology, Clnques Unverstares Sant-Luc, 10, Avenue Hppocrate, B-1200 Brussels, Belgum. 841

2 842 Detry, Fesler, Berckmans and Leclercq ponts for the heart rate (HR) are kept on the floppy dsc. The resoluton of the converson s equal to 0.1 mm for the ST and 1 unt for HR. After ths acquston s performed, the system could be dsconnected from the reader for further processng. The techncan can then access the data curves (ST and HR) on a graphc screen. The curves dsplayed on the screen represent 1 hour of the trend, gvng an mportant enlargement as compared wth the usual paper trend gven by the Holter reader. The use of a mouse on such an enlarged dsplay s very useful for the techncan, who can easly make any correctons on the curves and mark the exact begnnng and end of the ST depresson (or elevaton) events. A short ECG trace can be obtaned from the Holter reader for all suspected ST events gven by the trend, enablng the techncan to classfy or dscard each ST event, e.g., n case of nose. The system can report four dfferent categores of ST events: 1. Symptomatc ST depresson 2. Symptomatc ST elevaton 3. Slent ST depresson 4. Slent ST elevaton (ST - ) (ST + ) (SST - ) (SST + ) Fnally the system computes some parameters, such as the total duraton for each event, the area of depresson,.e., the ntegral of the ST segment (mm ran), the begnnng HR and the mean HR of each event, and the HR correspondng to the maxmal depresson. The system s very flexble. On the one hand, t allows the techncan to dscard all the nosy perods whle, on the other hand, t permts the use of any desrable cut-off ponts n the ST segment (.e., 1, 2, or 3 or... mm of ST depresson or elevaton). The measurements and the results of the computaton are prnted. Exercse testng n order to test the accuracy of the whole Holter system, calbraton sgnals and two leads (X and Y of the Frank system) were smultaneously recorded durng a maxmal bcycle exercse test through the same electrode system on a Holter tape and on our computerzed system for the analyss and nterpretaton of the exertonal ECG [6,15,16]; ths was done n 20 coronary patents, yeldng 47 smultaneous measurements for comparson. Patents The Holter system descrbed above was used n 35 patents who have been ncluded n the TEMS (Trmetazdne European Multcenter Study) and completed the protocol. Brefly, the TEMS s a doubleblnd, randomzed comparson of the antschemc effects of propranolol and trmetazdne; at days -15 and 0, the patents underwent both a symptom-lmted test of maxmally tolerated exercse and 24-hour ambulatory Holter montorng. These tests are repeated 30 and 40 days after ncluson (n = 30), wth an opton to contnue the study for 180 days (n = 5). At the present state of the study, 145 Holter tapes are avalable n the data bank, and ther results have been analyzed blndly. Results Fgure 1 represents the analog dsplay of the output of the Holter system (ST segment 80 ms after the J pont and heart rate) and shows one schemc epsode occurrng at 12 hours 48 mnutes, wth a duraton of 36 mnutes and 20 seconds. The dgtzed output correspondng to these epsodes are shown n Fgure 2, where the tme base has been wdened on the horzontal axs, whch corresponds to only 1 hour. By analyzng the actual ECG recordng n real tme (on the Holter system screen), the techncan can smooth the curve and dscard any nosy records by usng a mouse (+). The methods of calculatng the schemc ST segment area are depcted n Fgure 3, whch ndcates that several defntons of schemc ST-segment depresson can be used. The comparson between exercse-nduced Holter and our computerzed ECG system s depcted n Fgures 4 and 5; the relatonshp between the two measurements s excellent (r = 0.968) wth, however, a systematc dfference of 0.25 mm, whch s more marked on the Holter system than on the computerzed ECG system. Prelmnary Holter data from the TEMS Among the 145 Holter tapes avalable, 103 showed schema (that s 71%, whch s a hgh score due to the selecton of schemc patents). Among the 209 schemc epsodes, 134 (64%) were slent; the crcadan dstrbuton of these slent and panful epsodes s depcted n Fgure 6. Dscusson The algorthm descrbed n ths paper s one of the frst to attempt to really quantfy the electrocardographc sgns of myocardal schema durng a gven perod of tme. Countng only the number and duraton of the

3 - - T..... h 1H., ~5o _+_?_-~_+ 50 ] + +!! H E A R T R A T E - B P M ~ r + + ~ ++-~-- ' 1, : +.+ t t ' v+ +!,!-+ ~+' _~+_+~ _-...,;~ ~ S-T LEVEL m m J, +.~_~- +_ t _++++ Fg. 1. Analog reports from the Holter data (heart rate, upper cha~+t~el a~+d ST segmet~t, lower cha+~t~el). t~ ths example, the patent exhbts an ST-segment depresson+ startng at 12 hours 48 ran a~+d lastt+g./br 36 mt++ttes 20 sec. 12h "4"... J"... *J... J.....t... &...* &... J"... J... J.... ~... &.... ~... &... J" "4'... t... & &... J"... *.a... J , &....x J.... s , &....L... j... j.... t t ST -t... &... J J l... & ::...~... ~..:: ~.'...~...~..~...~..:... :....~... &... J.... a... ~....~.J~ t &... J ,... s... & ~ J.... J... J.... t & ,1.... ~ &......,w ,4,... l... ~... t ,... : :,, HR 290,tee l t....:+... ',,... t, :, o ~-.....J. l l... J.... ~.o...&, ,,... ;-....;.....,.... ~ Fg. 2. Pcture of the screen of the computerzed system, whch allows to analyze the HR (lower chat~nel) and ST-segment sgnals (upper channel) durng one hour; the tme scale s thus consderably ncreased when compared to the usual Holter report. The techncan s able to dentfy by markers t~e start (W ) and the end (7) of the ST segment abuormaltes and to eventaauy smooth the curve; when the tracng s too nosy, t can be dsregarded. Ths dgtal screen output correspo~ds to the schemc epsodes depcted n Fgure

4 9 - ST c..) DH EH c,,o, Dur, Rrea 0, HOLTER-EXERCCE (68ns) f~n bg nn "-- ST CraM) C, Area!! Fg. 3. Schematc representaton of the analyss of the dgtzed Holter ST segment data. BM and EM = the begnnng and the end of the ST-segment shft from the 0 voltage baselne; dur. = the duraton of the schemc epsode; the area s the product of the duraton and of the depth of the schemc shft, expressed n ram.ran; C.Dur. and C.Area = the duraton of area of the schemc ST depresson once the ST segment has crossed (C) the -0.1 mv border (the latter beng consdered by many to be the real schemc epsode). he'an -,25 -,68 -,48 -,28 8,88 4?,20nn Fg. 5. Ths llustrates, pont by pont, the dfference between the two systems compa~'ed n Fgure 4. HOLTER (68ns) versus EXERCTCE (6Ons) nn bg nn COR :,$68 VgR =,16~ n = 47.~ ' ;1~-...- ~". ".. -! -".,-...-'J. " "... Slope =:~57 ~.z, '..- ~ ""," K...-.:...-::.'..-] -Z;88-2,50-2,88-1,58-1,68 -,58 8,00,58 1,0 EXERCCE Fg. 4. Relatonshp between the amount of ST-segment depresson (60 ms, after J. Pont) measured smultaneously and through a strctly dentcal lead system by the Holter Avoncs system and our exercse ECG system. The correlaton s excellent, although there s a systematc dfference.

5 Quantfcaton of Slent schema 845 CRCADAN DSTRBUTON OF PANFUL (') AND SLENT (+) EPSODES (n=35 patents;145 Holter tapea) o Panful (75) Slent (134) + '4" " '4. ' " 4" 4" -- 4, 4" 4" "4. 4.@ O O 4" 4" "+4" "4" O O " C O O O O f f ~, TME n hours y Fg. 6. The fgure llustrates the crcadan varaton of the schemc epsodes (panfm = O; panless = +) wthn 24-hour Holter montorng records (n )from TEMS. t documents the greater frequency of patdess epsodes and the prevo~sly descrbed crcadan dstrbuton. schemc transent events seems to overlook the degree and duraton of the ST-segment shfts. Our new ndex of schemc area over tme, however, needs further documentaton, and ts dagnostc and prognostc nterest remans to be demonstrated [17,18]. The systematc dfference n the severty of the STsegment depresson measured 0.08 seconds after the J pont noted between the Avoncs Holter data and our computerzed exercse data remans largely unexplaned. t s probably due to a systematc error n the detecton of the J pont, whch s determned on a sngle lead, and probably sooner, wth the Holter system, whle t s determned wth a three-lead, spatal velocty curve n our computerzed system for the analyss of the exercse ECG [15,16]. As the dfference s systematc and reproducble, t should not nterfere wth the usefulness of the new algorthm n clncal research. nterestngly, the prelmnary data collected n the TEMS study confrm the mportance of slent schema, whch s, as recently documented, more frequent than panful schema [13,14]. Also, the crcadan varaton of schema, panful or slent, was confrmed by our prelmnary results. Acknowledgments Ths work was supported by grants from the Fonds de la Recherche Scentfque M~dcale (F.R.S.M. no ), the Morgan Guaranty Trust Bank, the A et R. Betlot Fundaton, and the TEMS study, References 1. Detry JMR, Kapta BM, Cosyns J, et al. Dagnostc value of hstory and maxmal exercse electrocardography n men and women suspected of coronary heart dsease. Crculaton 1977;56: Damond GA, Forester JS. Analyss of probablty as an ad n the clncal dagnoss of coronary-artery dsease. N Engl J Med 1979;300: Chatman BR, Waters DD, Bourassa MG, et al. The mportance of clncal subsets n nterpretng maxmal treadmll exercse test results: The role of multple-lead ECG systems. Crculaton 1979;59: Wener DA, Ryan TJ, McCabe CH, et al. Exercse stress testng. Correlatons among hstory of angna, ST-segment response and prevalence of coronary artery dsease n the coronary artery surgery study (CASS). N Engl J Med 1979;301: Meln JA, Pret L J, Vanbutsele RJM, et al. Dagnostc value of exercse electrocardography and thallum myo-

6 846 Detrg, Fesler, Berckma~s and Leclercq cardal scntgraphy n patents wthout prevous myocardal nfarcton: A Bayesan approach. Crculaton 1981;63: Detry JMR, Robert A, Luwaert R J, et al. Dagnostc value of computerzed exercse testng n men wthout prevous myocardal nfarcton. A multvarate, compartmental and probablstc approach. Eur Heart J 1985;6: Stern S, Tzvon D. Early detecton of slent schemc heart dsease by 24-hour electrocardographc montorng of actve subjects. Br Heart J 1974;36: Schang SJ Jr, Pepne CJ. Transent asymptomatc ST segment depresson durng actvty. Am J Cardol 1977;39: Cohn PF. Slent myocardal schema n patents wth a defectve angnal warnng system. Am J Cardol 1980;45: Deanfeld JE, Selwyn AP, Chercha S, et al. Myocardal schema durng daly lfe n patents wth stable angna: ts relaton to symptoms and heart rate changes. Lancet 1983;2: Cecch AC, Dovelln EV. March F, et al. Slent myocardal schema durng ambulatory electrocardographc montorng n patents wth effort angna. J Am Coll Cardol 1983;1: Quyyum AA, Mockus L, Wrght C, et al. Morphology of ambulatory ST segment changes n patents wth varyng severty of coronary artery dsease: nvestgaton of the frequency of nocturnal schema and coronary spasm. Br Heart J 1985;53: Mulcahy D, Cunnngham D, Crean P, et al. Crcadan varaton of total schaemc burden and ts alteraton wth antangnal agents. Lancet 1988;2: Rocco MB, Barry J, Cambell S, et al. Crcadan varaton of transent myocardal schema n patents wth coronary artery dsease. Crculaton 1987;75: Smoons ML, Boom HBK, Smallenburg E. One-lne processng of orthogonal exercse electrocardograms. Comput Bomed Res 1975;8: Fesler R, Derwael-Barchy C, Brohet C, et al. Acquston of exercse-electrocardograms on dgtal cartrdge. n: Wllems JL, ed. MC 79 Proceedngs. Unversty of Leuven, Belgum. Afdelng Medsche nformatca 1979: DetryJMR, Luwaert R J, Meln JA, et al. Prognostc mportance of slent exertonal myocardal schema n coronary patents wthout prevous myocardal nfarcton (abstract). Crculaton 1987;76(Suppt V): Bonow RO, Bacharach SL, Green MV, et al. Prognostc mplcatons of symptomatc versus asymptomatc (slent) myocardal schema nduced by exercse n mldly symptomatc and n asymptomatc patents wth angographcally documented coronary artery dsease. Am J Cardol 1987;60: