Identification of False Positive Exercise Tests With Use of Electrocardiographic Criteria: A Possible Role for Atrial Repolarization Waves

Transcription

1 JACC Vl. 18. N. I July 1991: Identificatin f False Psitive Exercise Tests ith Use f Electrcardigraphic Criteria: A Pssible Rle fr Atrial Replarizatin aves PETER M. SAPIN, MD, GARY KOCH, PHD, MARY BETH BLAUET, BS, JAMES J. McCARTHY, BS, SPENCER. HINDS, MD, LEONARD S. GETTES, MD, FACC Chapel Hill, Nrth Carlina Atrial replarizatin aves are ppsite in directin t P aves, may have a magnitude f 1 t 2 pv and may extend int the ST segment and T ave. It as pstulated that exaggerated atrial replarizatin aves during exercise culd prduce ST segment depressin mimicking mycardial ischemia. The P aves, PR segments and ST segments ere studied in leads,, avf and V 4 t V6 in 69 patients hse exercise electrcardigram (ECG) suggested ischemia (1 pv hrizntal r 15 pv upslping ST depressin 8 ms after the J pint). All had a nrmal ECG at rest. The exercise test in 25 patients (52% male, mean age 53 years) as deemed false psitive because f nrmal crnary arterigrams and left ventricular functin (5 patients) r nrmal stress single phtn emissin cmputed tmgraphic thallium r gated bld pl scans (16 patients), r bth (4 patients). Frty-fur patients ith a similar age and gender distributin, anginal chest pain and at least ne crnary stensis 8% served as a true psitive cntrl grup. The false psitive grup as characterized by 1) markedly dnslping PR segments at peak exercise, 2) lnger exercise time and mre rapid peak exercise heart rate than thse f the true psitive grup, and 3) absence f exercise-induced chest pain. The false psitive grup als displayed significantly greater abslute P ave amplitudes at peak exercise and greater augmentatin f P ave amplitude by exercise in au six ECG leads than ere bserved in the true psitive grup. Multivariable analysis revealed that exercise duratin (p =.1) and dnslping PR segments in the inferir ECG leads (p =.4) ere independent predictrs f a false psitive test. The cmbinatin f dnslping PR segments in t f three inferir leads plus either exercise duratin 4 min r peak heart rate 125 beats/min identified false psitive tests ith a sensitivity f 84% and a specificity f 86% t 89%. These results prvide ECG criteria fr predicting a false psitive exercise test and supprt the hypthesis that exaggerated atrial replarizatin aves may be a cause f a false psitive exercise test. (J Am Cll CardiI1991;18:127-35) The exercise electrcardigram (ECG) is an imprtant first step in the evaluatin f patients ith suspected ischemic heart disease. Despite its pivtal rle in cardiac diagnsis, the exercise ECG has limited specificity, reprted t be apprximately 77% in a recent meta-analysis f 132 studies (1). Factrs knn t be assciated ith a false psitive exercise test (defined as ST segment depressin in the absence f mycardial ischemia) include electrlyte abnrmalities, drug use and replarizatin abnrmalities n the rest ECG. Hever, ften nne f these factrs is present and in this situatin, the cause f stress-induced ST segment depressin in the absence f mycardial ischemia is unclear. Sme authrs (2-7) have suggested that atrial replariza- tin might cntribute t ST segment depressin during exercise testing. Other investigatrs (4,8-14) have demnstrated that atrial replarizatin aves are usually ppsite in directin t the P ave, have a magnitude f :::;2 /LV and extend ell int the ST segment. e pstulated that exaggerated atrial replarizatin aves culd shift the ST segment in the absence f mycardial ischemia and that this phenmenn culd be recgnized by ECG criteria. T test the hypthesis, e studied the P ave, PR segment and ST segment in a grup f patients ith a false psitive exercise test and cmpared them ith findings in a similar grup ith a true psitive test (that is, ST segment depressin due t mycardial ischemia). Frm the Divisin f Cardilgy. Schl f Medicine. University f Nrth Carlina, Chapel Hill. Nrth Carlina. This study as supprted by Grants POI HL-2743 and T32 HL-747 frm the Natinal Heart, Lung. and Bld Institute, Bethesda, Maryland. Manuscript received Nvember I, 199; revised manuscript received December , accepted January Address fr reprints: Lenard S. Gettes. MD. Divisin f Cardilgy. CB#775, Burnett-mack Building. Chapel Hill. Nrth Carlina Methds Patient selectin. In this study, a psitive exercise test as defined as ST depressin 8 ms after the J pint in at least ne standard ECG lead f ::::1 /LV fr hrizntal r dnslping ST segments r 15 /LV fr slightly upslping ST segments (1). Patients ere excluded frm the study if 1991 by the American Cllege f Cardilgy /911$3.5

2 128 SAPIN ET AL. JACC Vl. 18, N.1 July 1991: Table 1. Patient Characteristics False PsitIve True Psitive Exercise Test ExercIse Test (n = 25) (n = 45) N. % N. % p Value Age (yr) ± J ± 1.6 NS Male patients NS Hypertensin Diabetes Cigarette smking NS Family histry NS Hyperlipidemia NS Calcium channel blcking agent Beta-adrenergic blcking agent N. = number f patients analyzed fr each variable: % = percent f patients ith a variable present (age in years given as mean ± SE). they had 1) an abnrmal ECG at rest; 2) ST segment depressin r change in T ave plarity induced by hyperventilatin r a change frm the supine t the standing psitin; 3) knn cardimypathy r valvular disease, including mitral valve prlapse (clinical r echcardigraphic diagnsis); 4) a tracing ith excessive baseline artifact r andering; 5) digitalis r direct-acting antiarrhythmic drug use ithin 8 days f the exercise test; r 6) prir crnary artery bypass surgery. Study patients. Tenty-five retrspectively identified patients ith a psitive exercise test but n diagnsed heart disease r knn cause fr such a test result frmed the false psitive grup. Nineteen patients ere identified cnsecutively by revieing all thse ith a nrmal stress radinuclide study (93 patients) r a nrmal crnary arterigram (158 patients) beteen December 1, 1988 and December 3, Six additinal patients had studies perfrmed befre that time. Five f the 25 patients had crnary arterigraphy shing n crnary stensis f 2:3% and nrmal left ventricular functin. Sixteen patients had a nrmal stress radinuclide study (1 single phtn emissin cmputed tmgraphy thallium and 6 gated bld pl scans) hile exercising t a peak systlic bld pressure-heart rate prduct f 2:25,. Three patients had bth nrmal crnary arterigraphy and a nrmal stress radinuclide study. One patient ith a 5% mid-left anterir descending crnary artery stensis and a nrmal stress radinuclide study as als cnsidered t be in the false psitive grup. Tenty-t patients in the false psitive grup ere tested t evaluate a chest pain syndrme; t ere evaluated because f palpitatin and ne patient as self-referred because f risk factrs fr crnary disease. The true psitive grup cnsisted f 44 patients identified at randm and retrspectively ith a histry cnsistent ith angina pectris, a psitive exercise test and crnary arterigraphy ithin 4 mnths f the exercise test shing at least ne 2:8% stensis in a majr crnary artery. Exercise test files ere revieed cnsecutively by medical recrd number t identify patients meeting these criteria. Because the age and gender distributin f the false psitive grup as already knn, sme ptential true psitive tests ere arbitrarily excluded hen it appeared that the cntrl grup as becming t heavily eighted ith elderly men. Hever, this exclusin tk place befre revie f the exercise ECG. Patient characteristics (Table 1). The false psitive and true psitive grups ere similar in mean age (false psitive 53 ± 1.5 years, true psitive 57 ± 1.6 years) and gender distributin (false psitive 52% male, true psitive 61% male). A histry f hypertensin r diabetes mellitus as significantly mre cmmn in the true psitive grup and mre patients in this grup ere taking a calcium channel r beta-adrenergic blcker. Of the 1 patients ith a false psitive test and a histry f hypertensin, 3 ere receiving a diuretic. In t f these patients, the serum ptassium level determined ithin 1 eek f the exercise test as nrmal. The ptassium level as nt determined in the third patient. The study as apprved by the Cmmittee n the Prtectin f the Rights f Human Subjects f the University f Nrth Carlina, Chapel Hill. Exercise testing. Patients ere exercised n a mtrized treadmill (Marquette mdel 18) using the standard Bruce prtcl. Cntinuus mnitring f ECG leads, V 4 and V 5 as perfrmed, ith a 12 lead tracing perfrmed every minute. End pints fr the test ere the develpment f exertin-limiting symptms (angina, fatigue, dyspnea, claudicatin), a decrease in systlic bld pressure> 1 mm Hg frm the pretest level, ventricular tachycardia r hrizntal ST segment depressin >2 /-LV. Bld pressure as measured by mercury sphygmmanmeter at the end f each 3 min stage, at intermediate intervals hen indicated and at peak exercise. The supine ECG as mnitred in the

3 JACC Vl. 18, N.1 SAPIN ET AL. 129 Figure 1. This representatin f an electrcardigraphic (ECG) cmplex indicates the pints used fr ECG measurements. A = P ave amplitude; B = PR segment duratin; C = PR segment slpe; D = J pint depressin; E = ST segment depressin at 8 ms after the J pint. recvery perid, ith 12 lead tracings each minute until the ECG returned t baseline values. Exercise test analysis. Tracings ere analyzed at peak exercise hen ST segment depressin as maximal. In each tracing, leads,, a VF. V 4' V 5 and V 6 ere examined as shn in Figure 1. The P ave amplitude as measured frm the peak f the P ave t the beginning f the PR segment, defined as that pint here there as a change in the dnslpe f the P ave. The PR segment duratin as measured in the lead here the PR segment as mst clearly defined (usually lead 11). The ST segment slpe as classified as fiat, slightly upslping r markedly upslping. The J pint depressin and ST segment depressin ere referred t the PR-Qjunctin, ith ST segment depressin measured at 8 ms after the J pint. The PR segment slpe as determined by visual inspectin and classified as fiat, slightly dnslping r markedly dnslping (Fig. 2). Amplitudes and PR segment duratin ere determined t the nearest 5 p.v r 1 ms. Figure 2. Examples f the three PR segment slpe classificatins taken frm actual electrcardigraphic tracings. Arr indicates PR segment. FLAT SLIGHTLY DONSLOPING MARKEDLY DONSLOPING The reader did nt kn the clinical data. Intrabserver reprducibility as assessed by rereading the same tracings in a similar blinded fashin 1 eek later. A randm sample f 4 false psitive and 12 true psitive tracings (96 separate lead tracings) as assessed by a secnd bserver using the same techniques and criteria. The reprducibility f all ECG measurements as studied by intraclass crrelatin. The reliability cefficients ere abut.7 (range.41 t.92), cnfirming the similarity f the readings by the t bservers. The reliability cefficients fr the PR segment slpe, particularly in leads, and a VF, ere higher (intrabserver r =.86,.92 and.92; interbserver r =.87,.88 and.74, respectively). Cardiac catheterizatin. Selective crnary arterigraphy as perfrmed in multiple prjectins using cranial and caudal angulatin t visualize all parts f the crnary vessels. A ventriculgram as btained in the right anterir blique and in mst cases the left anterir blique prjectin. The films ere analyzed by t bservers h ere aare nly that the exercise test as psitive. Thallium scintigraphy. Exercise as perfrmed using supine bicycle ergmetry, beginning at a rk lad f 2 kilpnd-meters (kp-m)/min, increasing by 1 kp-m/min every minute. hen ne f the end pints described fr exercise ECG as apprached, 2 mci f thallium-21 as injected intravenusly and exercise cntinued fr 9 s. Single phtn emissin cmputed tmgraphic imaging as perfrmed ithin 1 min f injectin (GE Starcam and sftare) ith redistributin images btained 4 h later. Images ere interpreted visually by t bservers aare nly that the exercise test as psitive. The study as cnsidered nrmal if mycardial perfusin as hmgeneus during stress and redistributin imaging. RadinucIide ventriculgraphy. This as perfrmed ith the patient n a supine bicycle and use f the exercise and mnitring prtcl described fr thallium scintigraphy. Stress images ere btained in the right anterir blique vie during the first pass f in viv radilabeled red bld cells (2 mci ftechnetium-99m pertechnetate). After a 1 t 15 min recvery perid, stress as repeated ith the rk lad at a level that culd be maintained fr 3 min and equilibrium images ere btained in a left anterir blique prjectin mdified t best separate the left and right ventricles. The patient as alled t recver and images at rest ere btained in bth psitins by the equilibrium technique. The details f image data acquisitin and analysis have been reprted previusly (15). Cine studies created by display f an endless lp f frame data frm the cardiac study ere used t evaluate all mtin. Studies ere interpreted by t bservers ith knledge nly f a psitive exercise test. A nrmal study as defined as an increase in ejectin fractin f ;?:.5 percent pints plus nrmal all mtin at rest and ith stress. T patients ith an ejectin fractin at rest f >.7, an increase ith stress f <.5 and nrmal all mtin ere cnsidered nrmal (16).

4 13 SAPIN ET AL. JACC Vl. 18, N. I Table 2. Exercise Variables in False Psitive Versus True Psitive Grups False Psitive Exercise Test True Psitive Exercise Test Value N. Value N. p Value Exercise duratin (min) All patients 8.1 ± ± OJ 44.3 Excluding Ca and beta 8.8 ± ± Peak exercise HR (beats/min) All patients 156 ± ± Excluding Ca and beta 158 ± ± Exercise chest pain 24 ± ± <.1 (% experiencing) Baseline systlic BP 132 ± ± NS (mmhg) Peak systlic BP (mm Hg) 179 ± ± 4J 41 NS Beta = patients taking a beta-adrenergic blcking agent; BP = bld pressure; Ca = patients taking a calcium channel blcking agent; HR = heart rate; N. = number in each grup r subset. Statistical analysis. The distributin f baseline and exercise variables ere described fr each grup, using frequencies and percents fr categric variables and mean and SE fr cntinuus variables. The grups ere cmpared by using the ilcxn rank sum test fr cntinuus variables and the chi-square test fr categric variables. Pairise assciatins fr rdered categric variables and cntinuus variables ere evaluated ith Spearman rank crrelatin methds. Baseline and exercise P ave amplitudes ere cmpared ith use f the ilcxn signed rank and paired t tests. Stepise linear regressin methds ere used t develp the predictive mdel fr discriminating beteen false psitive and true psitive tests, and sensitivity and specificity calculatins ere used fr its evaluatin. Results Exercise variables (Table 2). The false psitive grup had a lnger mean exercise duratin (8.1 ±.7 vs. 5 ± OJ min, p =.3) and higher peak heart rate (156 ± 3.4 vs. 127 ± 3 beats/min, p =.(1). These differences persisted (p <.1) hen patients in each grup receiving a beta-blcking r calcium channel blcking drug ere excluded frm analysis. The false psitive grup als had a significantly smaller number f patients experiencing chest pain during exercise (24% vs. 82%, p <.1). There as n significant difference beteen baseline r peak systlic bld pressure in the t grups. Baseline ECG variables. There ere n differences in rest heart rate r P ave amplitude. There as a eak but significant assciatin in all ECG leads beteen the baseline PR segment slpe and exercise test results, such that a dnslping PR segment classificatin in the rest tracing as assciated ith a subsequent false psitive exercise test (leads,, avf r =.46,.33 and.39, p <.1; leads V 4, V5 and V6 r =.26,.29 and 34, p <.5 respectively,). Exercise ECG variables. In additin t the differences in exercise duratin, maximal heart rate and the presence r absence f chest pain, the t grups ere distinguished n the basis f P ave amplitude, PR segment duratin and slpe, J pint depressin and ST segment slpe. The grups ere nt distinguished n the basis f ST segment depressin. P ave amplitude. The mean P ave amplitude at peak exercise as greater in each lead in the false psitive grup and this difference as statistically significant in leads, V 4' V 5 and V 6 (Fig. 3A). The false psitive grup demnstrated a significantly greater increase in P ave amplitude frm baseline t peak exercise in all six leads (Fig. 3B). The false psitive grup did attain a higher mean exercise heart rate and there as a eak crrelatin beteen P ave amplitude and heart rate that as significant nly in leads, V 4 and V 6 (r =.26, 31 and 3, p <.5, respectively). PR segment duratin. The mean PR segment duratin as significantly shrter in the false psitive grup (43 ± 1.5 vs. 55 ± 1.6 ms, p =.1). This may have been due t the higher mean heart rate in the false psitive grup because PR segment duratin crrelated inversely ith heart rate (that is, the faster the rate, the shrter the PR segment; r =.52, p =.1). PR segment slpe. There as a very strng assciatin beteen PR segment slpe and a false psitive test such that in any given lead, the mre dnslping the classificatin f PR segment slpe (Fig. 2), the mre likely a false psitive test (leads, and avf r =.57,.57 and.62; leads V 4, V5 and V 6 r =.57,.5 and.46, respectively, p <.1). There as als a relatin beteen higher heart rate and a mre dnslping PR segment, but this as nt as strng as that beteen PR segment slpe and a false psitive exercise test (leads, and avf r =.44,.42 and.47; leads V 4, V5 and V6 r =.53,.42,.41, respectively, p <.(1). Of the six ECG leads studied in each patient, an increase in the

5 JACC Vl. 18, N, I SAPIN ET AL. 131 :> 3 ::1. 25 ::> I- :J 2 el: 15 el: Il. 1 VI U a:: 5 )( A :> 2 :::l _ ::>u Il.)( ::E el: el: > el: Il. 1 Il. 5 VI VI el:el: ill a:: U B FALSE POSITIVE TRUE POSITIVE Pc.5 AVF V4 V5 V6 LEAD AVF V4 LEAD FALSE POSITIVE TRUE POSITIVE Pc.5 V5 Figure 3. A, Mean P ave amplitude (±SE) in each electrcardigraphic lead at peak exercise. B, Mean increase in P ave amplitude (±SE) frm rest t peak exercise in each lead. number f PR segments classified as "markedly dnslping" as strngly assciated ith a false psitive test (r =.63, p =.1). The false psitive grup demnstrated markedly dns lping PR segments in 3.8 ±.4 f six leads cmpared ith.8 ±.2 f six leads fr the true psitive grup, ith the changes tending t cncentrate in the three inferir ECG leads (Fig. 4). Figure 5 demnstrates markedly dns lping PR segments in the inferir and lateral ECG leads f a false psitive exercise test. J pint depressin. The magnitude f J pint depressin as significantly greater in the false psitive grup in leads,, avf and V 4 (Fig. 6). ST segment slpe. The false psitive grup had slightly feer psitive leads ith hrizntal ST depressin (3 ±.4 vs. 4 ±.2 leads, p =.4) and mre leads ith upslping ST depressin (1.5 ±.4 vs..5 ±.2 leads, p =.6). Only 3 f 25 patients in the false psitive grup and 1 f 44 patients in the true psitive grup had a psitive exercise test ith nly upslping and n hrizntal ST segment depressin. Figure 5 illustrates the significant hrizntal ST depressin in the false psitive grup. V6 <.:l VIZ 1- zll. :::E <.:lvl Z VI a:: Il. ::r::> I- _ VIa:: Oel: :::E VI u..el: a:: ii: 111- :::EVI ::>VI z5 u '--- ALL SIX FALSE POSITIVE TRUE POSITIVE PcO.OOl INF ONLY LEADS SIUlING CHANGES Figure 4. Mean number f leads (±SE) at peak exercise ith PR segments classified as markedly dnslping. ALL SIX = electrcardigraphic leads,, avf plus V 4 Vs and V 6 ; INF ONLY = inferir leads, and avf. ST segment depressin. The grups ere similar in mean number f leads ith diagnstic ST segment depressin (4.5 ± OJ vs. 4.5 ±.2 leads in the false psitive vs true psitive grup, respectively). The magnitude f ST depressin measured at 8 ms after the J pint as similar in bth grups in every lead except lead, in hich the false psitive grup had mre ST depressin (Fig. 7). Multivariable analysis. Althugh sme f the ECG changes that characterized the false psitive tests ere als crrelated ith the higher heart rate attained by the patients ith these tests, the appearance f markedly dnslping PR segments in the inferir ECG leads as an independent predictr f a false psitive test. Multivariable analysis using a linear regressin mdel including exercise and ECG variables revealed that the independent predictrs f a false psitive test ere exercise duratin (p =.1) and the presence f markedly dnslping PR segments in the inferir leads (p =.4). Peak exercise heart rate did nt enter the mdel as an independent predictr f a false psitive test. The results f multi variable analysis ere applied retrspectively t identify false psitive exercise tests ith ptimal sensitivity and specificity. The cmbinatin f exercise time 2:4 min plus markedly dns lping PR segments in t f three inferir leads identified a false psitive test ith a sensitivity f 84% and a specificity f 89% (Fig. 8). hen a peak exercise heart rate 2: 125 beats/ min as substituted fr exercise duratin, the t variables alled predictin f a false psitive test ith a sensitivity f 84% and a specificity f 86%. If nly the patients attaining a heart rate f 125 beats/min r an exercise duratin f 4 min are examined, the sensitivity f the PR segment slpe criterin remains apprximately 85%, althugh the specificity decreases t apprximately 75% (Fig. 8 and 9).

6 132 SAPIN ET AL. JACC Vl. 18, N. I FALSE FALSE POSITIVE TRUE POSITIVE EXERCISE TEST EXERCISE TEST Figure 5. Lead by lead cmparisn f true and false psitive exercise tests at similar heart rates. In the false psitive test, the PR segments, particularly in electrcardigraphic leads, and avf, are mre dnsl?ping cmpared ith the hrizntal PR segmets the true psitive test. Als nte significant hnzntal ST segment depressin in the false psitive test. Discussin Causes f false psitive ST depressin. Depressin f the ST segment due t subendcardial mycardial ischemia is the result f lcal changes in cellular membrane ptential at rest and the shape f the actin ptential (17). These changes result in current fl that causes TQ segment elevatin and ST segment depressin, bth f hich are registered n the bdy sulface ECG as ST depressin (17). Depressin f the ST segment in the absence f mycardial ischemia may be due t alteratins in the actin ptential prduced by electrlyte abnrmalities, cardiactive drugs, pericarditis and nnischemic mycardial disease (17). Catechlamine and autnmic influences affect the duratin f replarizatin and primarily influence the T ave but have nt been shn t cause islated ST segment abnrmalities (18,19). The electrphysilgic basis fr stress-induced ST segment depressin in the absence f heart disease r ther factrs knn t influence the actin ptential is bscure. e Figure 6. Mean J pint depressin (±SE) in each electrcardigraphic lead at peak exercise. examined the hypthesis that the ECG manifestatins f atrial replarizatin culd prduce ST segment shifts mimicking ischemia. Previus investigatins f atrial replarizatin. Several features f the atrial replarizatin ave have been examined (4,8-14), mstly in patients r animals ith atriventricular (A V) blck. The atrial replarizatin ave has been fund t be almst alays directed ppsite t the P ave (8,9). Thus, the atrial replarizatin ave is nrmally inverted in leads in hich the P ave is upright. The magnitude f the atrial replarizatin ave crrelates directly ith the amplitude f the P ave (8,1). Hayashi et al. (8) fund the average atrial replarizatin ave amplitude t be.38 times the P ave amplitude, ith a range f.22 t.45 in patients ith cmplete A V blck and an therise nrmal heart. This uld indicate that a 25 p, V psitive P ave uld be flled by a negative atrial replarizatin ave f Figure 7. Mean ST segment depressin (±SE) 8 ms after the J pint in each electrcardigraphic lead at peak exercise in false and true psitive (POS) tests. :;- :::L Z iii a: Q. c z (5 Q FALSE POSITIVE TRUE POSITIVE P <.5 AVF V4 V5 V6 LEAD :;- :1.. Z iii a: Q. c z CI FALSEPOS TRUEPOS P <.5 AVF V4 V5 V6 LEAD

7 JACC Vl. 18. N. I SAPIN ET AL. 133 '2 g c:.5:! i;j "- ::J ( 15 1 I ' 5... i...?.6.?.... " ( )( False Psitive True Psitive Figure 8. Exercise duratin cmbined ith PR segment slpe t identify false psitive tests. Open circles = nne r ne PR segment in electrcardigraphic leads, r avf classified as markedly dnslping; filled circles = t r three PR segments in leads. r avf classified as markedly dnslping. The cmbinatin f exercise duratin ;::::4 min and markedly dnslping PR segments in t r mre inferir leads identifies 21 f 25 false psitive tests (sensitivity 84%) and misclassifies 5 f 44 true psitive tests (specificity 89%). 6 t 12 /-LV. The P ave amplitude increases ith exercise (2,21) and the rest amplitudes f bth P and atrial replarizatin aves increase as heart rate increases (8, t, 13). In ne study (4), negative atrial replarizatin aves :::;19 /-LV ere bserved during exercise at a heart rate f 12 beats/ min. The duratin f the atrial replarizatin ave has been reprted (8,11,12) t be cnsiderably lnger than that f the P ave. Hayashi et al. (8) shed the duratin f interval frm the nset f the P ave t the end f the atrial replarizatin ave t be 2.7 t 4 times the P ave duratin (mean P ave and atrial replarizatin ave duratin 45 ms). Other investigatrs (11) reprted atrial replariza- Figure 9. Peak exercise heart rate cmbined ith PR segment slpe t identify false psitive tests. The cmbinatin f peak heart rate ;::::125 beats/min and PR segments classified as markedly dns lping in t r mre inferir electrcardigraphic leads identifies 21 f 25 false psitive tests (sensitivity 84%) and misclassifies 6 f 44 true psitive tests (specificity 86%). Frmat as in Figure 8. E D 18 e! f! 16 1:: I/) )( False Psitive True Psitive 1_ Figure 1. Illustratin f the extent t hich an exaggerated atrial replarizatin ave might influence the ST segment. The lead electrcardigraphic cmplex is frm a false psitive test at a heart rate f 134 beats/min. The dtted line indicates the hypthetical atrial replarizatin ave. The duratin f the P ave plus the atrial replarizatin ave (363 ms) represents the 95% upper cnfidence limit abve the mean P ave and atrial replarizatin ave duratin at that heart rate, derived frm the data f Kesselman et al. (12). tin aves lasting up t 6 ms after the nset f the P ave. It has als been fund (8,15) that the atrial replarizatin ave shrtens predictably as heart rate increases. The ptential extensin f the atrial replarizatin ave int the ST segment can be estimated. In 2 patients in the false psitive grup ith an ECG recrded at a heart rate beteen 145 and 155 beats/min, the mean (±SD) interval frm the nset f the P ave t the nset f the ST segment as 22 ± 22 ms. Regressin equatins predicting P ave and atrial replarizatin ave duratin frm atrial rate ere develped (8,12). These equatins predict mean P ave and atrial replarizatin ave duratins f 272 and 276 ms, respectively, at a heart rate f 15 beats/min. A retrspective analysis f the data f Kesselman et al. (12), hich includes measurements at PP intervals <3 ms, alls calculatin f 95% cnfidence intervals abut the mean P ave and atrial replarizatin ave duratin at a heart rate f 15 beats/min. The 95% upper cnfidence limit value is 34 ms. hen the measured P ave and QRS duratin is cmpared ith these estimates f P ave and atrial replarizatin ave duratin, the mean extentin f the atrial replarizatin ave beynd the end f the QRS cmplex is 56 ms ( ms). In sme patients ith a lnger perid f atrial replarizatin and a shrter PR interval, the atrial replarizatin ave culd extend up t 14 ms (34-2 ms) beynd the end f the QRS cmplex. Thus, it might be expected that nly a small number f nrmal individuals ill develp an atrial replarizatin ave during exercise that is f sufficient duratin and magnitude t cause hrizntal ST segment depressin (Fig. 1). The PR segment represents the plateau phase f the atrial actin ptential, much as the ST segment reflects the plateau phase f the ventricular actin ptential. Because the plateau f the atrial actin ptential is shrter and mre dnslping than that f the ventricular actin ptential (22), the PR segment is nt iselectric and merges ith the atrial replarizatin ave.

8 134 SAPIN ET AL. JACC Vl. 18, N. I Other investigatrs have addressed the effect f atrial replarizatin aves n the exercise ECG in nrmal individuals ithut exercise-induced ST segment depressin by studying P ave and ST segment vectrs using rthgnal lead ECGs (2) r changes in bdy surface isptential maps (23). These investigatrs (2,23) cncluded that the influence f atrial replarizatin aves n the ST segment is minimal. Cnversely, these studies (2,23) did nt assess atrial replarizatin in individuals ith ST depressin, h are the subject f this investigatin. The present study. Given this infrmatin, ne uld predict characteristic ECG changes in patients ith false psitive ST depressin due t large atrial replarizatin aves. First, a test that is false psitive because f atrial replarizatin uld be expected t ccur at mre rapid heart rates hen P ave and atrial replarizatin ave amplitudes are augmented. Secnd, such a false psitive test might have a shrter PR segment duratin, shifting the deepest part f the atrial replarizatin ave further int the ST segment and tending t cause hrizntal ST segment depressin. Third, because f the characteristics f the atrial actin ptential and the shrt transitin segment beteen the P ave and the atrial replarizatin ave, a deep atrial replarizatin ave uld be expected t be accmpanied by a dns lping PR segment in leads in hich the P ave is tallest (that is, inferir ECG leads). Furthermre, ne uld expect these false psitive tests t demnstrate taller P aves and perhaps a greater augmentatin f P ave amplitude ith exercise. Finally, ne might als expect patients ith a false psitive test t sh indicatins f exaggerated atrial replarizatin aves n the rest tracing. The results f this study agree ith these predictins. The patients ith a false psitive test achieved a significantly higher heart rate than did patients ith a true psitive test. The PR segments ere shrter in the false psitive than in the true psitive tests. A false psitive test as assciated ith dns lping PR segments in all leads, particularly leads, and a VF. Althugh these features ere t sme extent a functin f the higher heart rate attained by patients ith a fal'le psitive test, a dnslping PR segment carried independent predictive value fr a false psitive test. ith exercise, the false psitive grup demnstrated taller P aves in all six ECG leads studied, althugh the difference as significant in nly fur. The increase in P ave amplitude ith exercise as significantly greater in all leads in the false psitive grup. Furthermre, there as a significant assciatin beteen a dnslping PR segment at rest and a subsequent false psitive test. The finding f a mean value fr J pint depressin t be slightly greater than that fr ST depressin at 8 ms after the J pint in a false psitive test is als cnsistent ith the effects f atrial replarizatin. Previusly reprted data (4,8,12) suggest that in mst individuals, the duratin f atrial replarizatin is such that its effects ill be maximal at the J pint and the ST segment ill be upslping. Indeed, upslping ST depressin is ell knn t carry a l specificity fr the presence f crnary artery disease (24). Our study suggests that atrial replarizatin may als cause hrizntal ST segment depressin identical t that seen in patients ith mycardial ischemia (Fig. 5). This mst likely reflects the psitining f the deepest prtin f the atrial replarizatin ave late in the ST segment as a result f either a shrt PR segment r a prlnged atrial replarizatin ave, r bth. Patients ith mycardial ischemia during exercise testing may als reflect the effects f atrial replarizatin, particularly if they are able t attain a high heart rate. Thus, a true psitive test in patients h attained a higher peak exercise heart rate as als mre likely t sh dnslping PR segments (Fig. 9). Limitatins. One limitatin f this study is the ptential fr unrecgnized ischemia in the patients ith a test termed "false psitive." If a large prprtin f the patients classified as having a false psitive test had ischemia (that is, the test as, in fact, true psitive), the characteristic PR segment changes seen t separate false psitive and true psitive tests uld be much less useful as a marker fr a genuine false psitive test. In this study, the exclusin f patients h did nt attain a high rate-pressure prduct during the stress radi nuclide test (nly ne patient did nt attain 85% f the maximal predicted heart rate) makes it unlikely that a significant number f ur patients classified as nrmal by stress radinuclide tests alne had functinally significant crnary artery disease (25,26). It is imprtant t nte that the standard fr the demnstratin f functinally significant crnary artery disease is nt yet clarified (27). The demnstratin f a >5% crnary artery stensis in a patient ith a nrmal radi nuclide study at an adequate exercise end pint des nt necessarily imply that the radi nuclide study missed an ischemia-prducing lesin. Hever, ther data suggest (28,29) that f the five patients ith angigraphically nrmal crnary arteries h did nt underg functinal testing, nly t might have had an abnrmal radinuclide study implying "micrvascular ischemia." The measurement techniques utilized ere nt cmputerized and sme ere qualitative. The key variable, PR segment slpe, as assessed qualitatively, althugh nly markedly dnslping PR segments turned ut t be imprtant in the final analysis, thus decreasing reliance n mre subtle changes in this difficult t visualize prtin f the exercise ECG. Finally, the highly selected nature f the t study grups (designed t btain clearly ischemic and nnischemic grups) prevents the applicatin f the study findings t all patients referred fr exercise testing. Cnclusins. The implicatins f ST depressin during an exercise test are significant. Patients may be made aare f an adverse prgnsis, treated empirically fr crnary artery disease r referred directly fr crnary angigraphy ith its attendant risks and expense. This study suggests sme simple clinical and ECG criteria that might be used t predict a false psitive exercise test in patients ith a nrmal rest ECG and n apparent reasn fr a false psitive result. Our

9 JACC Vl. 18, N.1 SAPIN ET AL. 135 findings are in accrd ith ther reprts assciating a higher exercise heart rate, lnger exercise time and absence f chest pain during exercise ith a ler prbability that a psitive exercise test is caused by mycardial ischemia (3-34) and ith a favrable lng-term prgnsis (35). In this setting, the finding f shrt, steeply dnslping PR segments, particularly in the inferir ECG leads, is an independent marker f a false psitive exercise test even in the presence f significant hrizntal ST segment depressin. Patients ith these clinical and ECG exercise findings perhaps require additinal nninvasive effrts t prve they have stress-induced mycardial ischemia befre empiric treatment r invasive testing is recmmended. Finally, the utility f these criteria needs t be assessed prspectively in a large number f patients underging exercise testing. e thank David Sheps, MD, MPH and ayne Casci, MD fr a critical revie f the manuscript, Kirk Adams, MD fr assistance ith statistical analysis and Leslie Rgers fr expert secretarial assistance. References 1. Gianrssi R, Detran R, Mulvihill D, et al. Exercise-induced ST depressin in the diagnsis f crnary artery disease. Circulatin 1989;8: Kattus AA. Exercise electrcardigraphy: recgnitin f ischemic respnses, false psitive and negative patterns. Am J Cardil 1974;33: Mnpere C. False psitive exercise tests and right atrial hypertrphy. J Cardipul Rehab 1989;9: RiffDP, Carletn RA. Effect f exercise n the atrial recvery ave. Am Heart J 1971 ;82: Myers GB, Talmers FN. The electrcardigraphic diagnsis f acute mycardial ischemia. Ann Intern Med 1955;43: Scherf D, Schaffer AI. The electrcardigraphic exercise test. Am Heart J 1952;43: Lepeschkin E, Suraicz B. 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