The “false positive” exercise electrocardiogram: Value of time course patterns in assessment of depressed ST segments and inverted T waves

The “false positive” exercise electrocardiogram: Value of time course patterns in assessment of depressed ST segments and inverted T waves John B. Barlow, M.D. Johannesburg,

S. Africa

Despite controversy regarding its role in a variety of clinical situations, exercise stress testing remains extremely useful to the practicing physician. Stress testing continues to arouse much interest and the literature abounds with discussion of many aspects.1-8 Criteria for a positive test for ischemia have related largely to the degree and shape of ST segment and T wave changes during or after effort. These have included a horizontal or downward sloping ST segment of 0.08 second or more from the J point, ST depression at least 1 mm below the isoelectric line, and other features,g-‘3 sometimes depending upon the leads used.14* l5 This report does not discuss elevation of ST segments which may occur during or after exercise.16 It relates solely to depression of ST segments and/or inversion of T waves (ST-T) which, whether or not fulfilling strict criteria of a positive ischemic response, would generally be regarded as abnormal and either suggestive of or compatible with myocardial ischemia. Exercise variables2*6s l7 such as the duration and amount of exercise completed, blood pressure response, extent of ST-T, maximal heart rate attained, development of symptoms, and increased R wave amplitude have contributed to improved sensitivity and specificity. The effects of beta receptor blocking agents have been studied in relation to decreasing the number of false positive tests for ischemia.lh lg Lastly, in recent years a number of workerPz5 have investigated sensitivity, specificity, and predictive values of exercise testing in various population groups and have reported different results, notably in the number of so-called “false positives,” depending on factors From the Cardiovascular Research Unit, Department University of the Witwatersrand and the Johannesburg Received

for publication

July

22, 1985; accepted

of Cardiology, Hospital.

Aug. 12, 1985.

Reprint requests: John B. Barlow, M.D., Dept. of Cardiology, Johannesburg Hospital, Private Bag X39, Johannesburg 2000. South Africa.

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Fig. 1. Lead V, recorded 5 minutes after exercise in two women demonstrating similar ST-T configuration. The time course pattern of the ischemic patient (left) is shown in Fig. 4. The full stress test of the 52-year-old woman (right) with arteriographically normal coronary arteries is published in ref. 41 and conforms to the nonischemic type III time course behavior (see text).

such as age, sex, and symptoms. Observations relating to the times of onset, offset, and maximal change of ST-T have indeed been made,26-33 but the contribution of these time course patterns in differentiating nonischemic from ischemic ST-T has received scant attention.28v 2g,32,33 A positive stress ECG reflects myocardial ischemia and not necessarily coronary artery disease. Thus hemodyamically significant aortic or mitral valve disease may be associated with ischemic post exercise ST-T without anatomic coronary artery disease. ECG signs of previous myocardial infarction and of left ventricular hypertrophy,* including those

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B Fig. 2. Schematic representation of ST-T time course patterns at rest, during, and after exercise. Lines within the rectangular panel reflect normal appearances at the relevant times. Thus the line “Normal” illustrates the ST segment and T wave appearances of completely normal subjects at rest, during exercise, and throughout the lo-minutes after exercise period. The time course patterns of nonischemic ST depression and T wave inversion are drawn above the rectangular panel whereas those of ischemia appear below the panel. The extent of ST depression or T inversion is represented by the vertical distance above (nonischemic) or below (ischemic) the panel. For example (A), the ST segments and T waves of the nonischemic type II time course pattern are normal at rest; maximal ST depression and T inversion occur during or approximately 1 minute after exercise and rapid improvement is demonstrated by the line “Type II” returning toward or entering the panel within 3 minutes after exercise. Deviations of abnormality at rest for nonischemic (types III and IV above the panel) (B), and ischemic (Severe 3a and Very severe 4 below the panel) ST-T are somewhat arbitrary for an individual patient, but the amount of change during and after exercise should be compared to the resting level. Types I and II are represented in (A) and types III and IV in (El) in order to avoid overcrowding of lines during the late post exercise phase. In all other respects, (A) and (B) are identical.

due to hypertrophic

cardiomyopathy,”

influence the

interpretation of ST-T both at rest and with exercise. Complete right or left bundle branch block also complicatea interpretation5 of ST-T. ST-T may be exaggerated by digitalis therapy,35 and their assessment after exercise in the Wolff-Parkinson-White

(WPW) syndrome is invariably unreliable.4 While acknowledging these causes of difficulty in interpretation as well as the contributions of exercise variablea in evaluating the results of stress tests for myocardial ischemia, there remain numerous instances in which none of these factors is applicable

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3. Control and post effort ECGs of a 50-year-old woman with ST segments and T waves simulating ischemia in configuration but not in time course. One minute after a good exercise performance (rate 150/min), the ST segments are depressed but upsloping, compatible with normal or only mild ischemia. Thereafter the ST segments are downsloping until at least 15 minutes after exercise, which is suggestive of severe ischemia. The relatively late onset of the apparently severe ischemic ST segments (4 minutes) with the delayed offset reflect the type I nonischemic time course response to exercise. This patient complained of atypical chest pain and selective coronary arteriography was predictably normal. Fig.

and the “abnormal” resting, during exercise, or post exercise ST-T have to be appraised on their own merits. Physical examination is often normal or inconclusive, and subjects complete the exercise required by the attending physician without the detection of any definite exercise variable.17 Based on a survey of the pertinent literature and a reappraisal of the resting and post exercise 1%lead ECGs of such patients, many of whom had been referred because of an abnormal ECG or suspected mitral valve pro1apse,34*36 it is now apparent that the ST-T time course pattern is as useful as the ST-T configuration in determining the presence or absence of is-

chemia. This report seeks to delineate these time course patterns and to support the suggestions of others2& 2g,32*33that ST-T time course interpretation improves the accuracy of stress electrocardiography. Severity of myocardial ischemia does not always correlate with the coronary arteriographic assessment of the number of vessels involved.5* l3 Nevertheless, most cardiologists agree that an early onset of ischemic ST-T with exercise will persist for at least 8 minutes into the recovery phase and reflects severe myocardial ischemia.12* 32*33*37-3sOn the other hand, post effort ECG evidence of relatively mild

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75/MIN 5. Control, during exercise, and post exercise ECGs of a 53-year-old man with symptoms and signs of mitral valve prolapse. The early onset and short duration of the ST segment and T wave changes reflect the type II nonischemic time course pattern. Fig.

4. Control and post effort ECGs of a 54-year-old woman with severe two-vessel coronary artery disease. Ischemic ST-T are seen immediately after exercise, become worse (downsloping) at 2 and 5 minutes, and remain slightly abnormal at 10 minutes (see also Fig. 1).

Fig.

ischemia, whether due to modest coronary artery stenosis, less than submaximal exercise completed, or therapy with beta-receptor blocking agents, appears relatively later. A positive stress ECG response of ischemia follows the general rule of early onset, late offset and late onset, early offset.33 The ST-T which are associated with normal selective coronary arteriograms are usually regarded as nonischemic in origin. 2a,4oThese “nonspecific” ST-T have been attributed to a number of causes,

depending on the context in which they occurred and the interest or the bias of the investigators.26, 41 Causes include mitral valve prolapse, anxiety, neurocirculatory asthenia, hyperventilation syndrome, atypical chest pain syndrome, athlete’s heart, vasoregulatory T wave changes, and so-called “syndrome X”32 or similar conditions.42 On configuration alone, the nonischemic ST-T may be difficult or impossible to distinguish from those of ischemia (Fig. l), but they have different time course patterns after cessation of exercise. The time course patterns of ischemic (Fig. 2, A or B) and nonischemic ST-T are outlined in Fig. 2. In the absence of previous myocardial infarction, very severe ischemia, “unstable angina,” or discernible

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6. Control and post effort ECGs of a 33-year-old long-distance runner who complained of central chest pain. The type II nonischemic time course pattern and the upward coving of ST segments, immediately post effort, are demonstrated. Electrophysiologic studies have not been undertaken to exclude aberrant conduction, but coronary angiography was normal. Fig.

factors such as left ventricular hypertrophy, conduction defects, drug therapy, or electrolyte imbalance, the ECG of patients with uncomplicated occlusive coronary artery disease is usually normal, or near normal, at rest. Thus patients with mild ischemia have a normal ECG at rest (Fig. 2, Mild I) and develop abnormal ST-T 2 to 3 minutes post exercise. The ST-T are maximal 4 to 5 minutes post exercise and these return to normal relatively early, at about 6 minutes. Patients with moderate ischemia (Fig. 2, Moderate 2) show earlier onset and later offset of ST-T.. Most patients with severe (Fig. 2, Severe 3) ischemia also have normal ST segments and T waves at rest, but some are slightly abnormal (Fig. 2, Severe 34. In both instances, conclusively abnormal ST-T develop during exercise, maximal changes are seen 3 to 6 minutes post exercise, and the abnormal ST-T persist at 10 minutes. Ischemic ST-T at rest denote very severe ischemia (Fig 2, Very seuere 4, and these increase immediately with exercise and remain more marked at 10 minutes than in the resting tracing. Whereas ischemic ST-T consistently follow a general behavior of early onset, late offset and late

onset, early offset, the time course responses to exercise of nonischemic cases are more variable. Four types of time course behavior for the ST-T have been delineated and arbitrarily enumerated for this report. In type I, the ST segments and T waves are normal at rest (Fig. 2, A, Type I) and are still normal, or become only disputably abnormal, until 2 to 6 minutes post exercise, when definite ST-T supervene that persist for at least 10 minutes into the recovery phase (Fig. 3). The type I nonischemic time course behavior was encountered by Malcolm and Ahuja,% who commented that it “distinctly differed” from that of coronary artery disease. The inappropriately late development of the marked ST-T distinguishes type I from those cases with ischemic time course behavior (Fig. 2, Severe 3), in which abnormal ST-T also remain for 10 minutes or longer after cessation of exercise (Fig. 4). Type II is the other nonischemic pattern in which the resting ECG is normal (Fig. 2, A, Type II). The essential time course features of type II were suggested in 1977 by Lozner and Morganroth, to be of value in identifying subjects without coronary artery disease in whom ST-T occurs during exercise. Ellestad32 has

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7. Example of type IV nonischemic time course pattern in a 37-year-old man. The ST-T are most marked immediately after exercise.

Fig.

observed that the ST segment depression in type II may be considerable, either during or immediately after exercise. The ST segments frequently show a fairly typical configuration with upward coving (Figs. 5 and 6). Although the ST-T usually disappear at 2 minutes, in a minority they improve at that time but remain abnormal for several minutes. Whether or not the ST-T of type II persist for $10, or more minutes, the very early onset of ST-T followed by improvement or normalization within 3 minutes, is not in accord with ischemic time course behavior.29s”3 Type IV (Fig. 2, B, Type IV) has virtually the same time course pattern as type II, except that ST-T are present at rest and throughout the postexercise observation period (Fig. 7). As with type II, the type IV time course pattern of an

immediate increase in the ST-T followed by improvement within 3 or 4 minutes after cessation of exercise should make differentiation from an ischemit response apparent. Some patients can be interchanged between types II and IV, depending on the resting status of the ST segments and T waves at the time of the stress test. It is known that ST-T may be affected by posture26,40 and by hyperventilation,26s40 or may vary spontaneously,4” within minutes or days. Type III (Fig. 2, B, Type III) is also a previously reported34*41 nonischemic pattern and the ST-T of many cases of mitral valve prolapse34*43 and athlete’s heart34*43*44 demonstrate the type III time course behavior. The ECG is abnormal at rest, thereby simulating very severe ischemia (Fig. l), but the ST-T partially or completely normalize during

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8. Type III nonischemic time course pattern. Control and post effort ECGs of a 49-year-old woman complaining of intermittent central chest pain for several years. She had previously been diagnosed as having coronary artery disease and had had several admissions to other institutions. Cardiac catheterization confirmed mitral valve prolapse with arteriographically normal coronary arteries. Fig.

or shortly after exercise, and later either return to the resting pattern (Fig. 8) or become more abnormal.34,41There is thus an important difference in the time course patterns of type III and marked ischemia (Fig. 2, B, III; 34, and 4). Selective coronary arteriography is currently a commonly accepted “gold standard” on which ST-T are designated as nonischemic or ischemic. Although stress tests on many patients not subjected to that investigation have also been evaluated, both in our laboratory and by others,32 the recognition and delineation of the nonischemic time course patterns for this report have been based principally on the premise that a normal coronary arteriogram

reflected or confirmed a nonischemic cause of the ST-T. It is appreciated that this criterion might be fallacious,45 but it is inappropriate in this paper to consider the possibilities of angiographic underestimation of coronary lesions,46*47 of small vessel disease causing myocardial ischemia,45 or of myocardial dysfunction occurring in some of the conditions32,42,48 which have a nonischemic ST-T time course response to exercise. It is also not relevant to discuss the postulated explanations for the ST-T which may occur with those conditions. What is of importance is that the post exercise nonischemic ST-T can frequently not be distinguished from the ST-T of ischemia with angiographically abnormal

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coronary arteries on criteria based upon configuration, but that they can be differentiated by their time course behavior. The four types of nonischemic time course patterns are, in fact, true negatives and should not be regarded as false positives for myocardial ischemia. Our own previous errors of interpretation, several examples of which have been publishedt4, 4swould have been avoided by an improved judgment of time course behavior. Literature on false positive ischemic stress tests often fails to demonstrate examples of the ECGs or does not illustrate the ST-T throughout a 10 lminute recovery phase. We have not detected a published example of a definite false positive test in which the time course pattern and other factors could be fully evaluated. Inevitably there are cases in which the appraisal of symptoms, clinical examination, selective coronary arteriography, and ECG appearances reflect a coexistence34s 41 of occlusive coronary artery disease with one of the prevalent causes of nonischemic ST-T. Nevertheless, it is now our ongoing clinical experience that estimation of ST-T time course behavior combined with the generally accepted practice of evaluating the history, clinical examination, exercise variables, and ST-T configuration enhances the diagnostic value of an exercise test and in many instances, depending on the clinical setting, avoids the necessity for expensive additional investigations such as radionucleotide studies or coronary arteriography. Irrespective of the age, sex, symptoms, or risk factors of a patient, stress testing remains a most practicable and cost-effective method for detecting ischemic heart disease. This useful investigation should not be judged unreliable because of the reputedly high prevalence,“3 of false positive results. It is we, the observers, whose reliability is suspect. REFERENCES

1. Stuart RJ, Ellestad MH: Upsloping S-T segments in exercise stress testing. Six year follow-up study of 438 patients and correlation with 248 angiograms. Am J Cardiol 37:19, 1976. 2. Ellestad MH, Savitz S, Bergdall D, Teske J: The false positive stress test: Multivariate analysis of 215 subjects with hemodynamic angiographic and clinical data. Am J Cardiol 40:681, 1977. 3. McHenry PL: The actual prevalence of false positive STsegment responses to exercise in clinically normal subjects remains undefined. Circulation 55683, 1977. 4. Fortuin NJ, Weiss JL: Exercise stress testing. Circulation 56:699, 1977. 5. Ellestad MH, Cooke BM Jr, Greenberg PS: Stress testing: Clinical application and predictive capacity. Prog Cardiovasc Dis 21:431, 1979. 6. Wiens RD, Lafia P, Marder CM, Evans RG, Kennedy HL: Chronotropic incompetence in clinical exercise testing. Am J Cardiol 54:74, 1984. 7. De Busk RF, Dennis CA: “Submaximal” predischarge exercise testing after acute myocardial infarction: Who needs it? Am J Cardiol 55499, 1985.

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8. Ho SW-C, McComish MJ, Taylor RR: Effect of betaadrenergic blockade on the results of exercise testing related to the extent of coronary artery disease. Am d Cardiol55258, 1985. 9. Erikssen J, Enge I, Forfang K, Storstein 0: False positive diagnostic tests and coronary angiographic findings in 105 presumably healthy males. Circulation 54:371, 1976. 10. Chahine RA. Awdeh MR. Mnaver M. Ftaizner AE. Luchi R,J: The evolutionary pattern of exercise-induced ST segment depression. Original communications J Electrocardiol 12:236, 1979. 11. Fox K: Editorial note: Upsloping ST segment and R wave analysis in the diagnosis of coronary artery disease. Int. ?J Cardiol 5:703, 1984. 12. Hamby RI, Davison ET, Hilsenrath J, Shanies S, Young M, Murphy DH, Hoffman I: Functional and anatomic correlates of markedly abnormal stress tests. J Am Co11 Cardiol 3:1375, 1984. 13. Okin PM, Kligfield P, Ameisen 0, Goldberg HL, Borer JS: Improved accuracy of the exercise electrocardiogram: Identification of three-vessel coronary disease in stable angina pectoris by analysis of peak rate-related changes in ST segments. Am J Cardiol 55:271, 1985. 14. Santinga JT, Flora J, Maple R, Brymer JF, Pitt 23: The determination of the post-test likelihood for coronary disease using Bayes theorem. J Electrocardiol ‘1561, 1982. 15. Van Tellingen C, Ascoop CA, Rijneke RD: On the clinical value of conventional and new exercise electrocardiographic criteria: A comparative study. Int J Cardiol 5:689, 1984. 16. Specchia G, de Servi S, Falcone C, Angoli L, Mussini A, Bramucci E, Marioni GP, Ardissino D, Salerno d, Bobba P: Significance of exercise-induced ST-segment elevation in patients without myocardial infarction Circulation 63:46, 1981. 17. Sheffield LT, Reeves TJ, Blackburn H., Ellestad MH, Froelither VF, Roitman D, Kansal S: The exercise test in perspective. Circulation 55681, 1977. 18. Taggart P, Carruthers M, Joseph S, Kelly HB, Marcomichelakis J, Noble D, O’Neill G, Somerville W: Electrocardiographic changes resembling myorardial ischaemia in asymptomatic men with normal coronary arteriograms. Rr Heart ,J 41:214, 1979. 19. Ahinader EG, Shahar J: Exercise testing in mitral valve prolapse before and after beta blockade. Br Heart ,J 48:1X), 1982. 20. Fisher LD, Ward Kennedy d, Chaitman RR, Ryan TJ, McCabe C, Weiner D, Tristani F, Schloss M, Warner HR: Diagnostic quantification of CASS (Coronary Artery Surgery Study) clinical and exercise test results in determining presence and extent of coronary artery disease. A multivariate approach. Circulation 63:987, 1980. 21. Melin JA, Piret LJ, Vanbutsele RJM, Rousseau MF. Cosyns J, Brasseur LA, Beckers C, Detry JR: Diagnostic value of exercise electrocardiography and thallii!m myocardial scintigraphy in patients without previous myocardial infarction: A Bavesian anDroach. Circulation 63:lOlY. 1980. 22. Uhl GS, Froehcher V: Screening for asymptomatic coronary artery disease. J Am Co11 Cardiol 1:946, 1983. 23. Detry JMR: Is stress testing useful when ischaemic heart disease is unlikely? Eur Heart J 5184, 1984. 24. McCarthy DM: Stress electrocardiography in women. Int. ,I Cardiol 5:727, 1984. 25. Pool J, Schetfer MG, Simoons ML, Patijn M: Clinical value of exercise testing in elderly patients. Eur Heart J 547, 1984. 26. Friesinger GC, Biern RO, Likar I, Mason RE: Exercise electrocardiography and vasoregulatory abnormalities. Am J Cardiol 30~733, 1972. 27. Froelicher VF Jr, Yanowitz FG, Thompson AJ, Lancaster MC: The correlation of coronary angiography and the electrocardiographic response to maximal treadmill testing in 76 asymptomatic men. Circulation 48:597. 1973. 28. Lozner EC, Morganroth J: New criteria to enhance the

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predictability of coronary artery disease by exercise testing in asymptomatic subjects. Circulation 56:799, 1977. 29. Malcolm AD, Ahuja SP: The electrocardiographic response to exercise in 44 patients with mitral leaflet prolapse. Eur J Cardiol 6:359, 1978. 30. Morris SN, McHenry PL: Role of exercise stress testing in healthy subjects and patients with coronary heart disease. Controversies in cardiology. 1. Am J Cardiol 42:659, 1978. 31. Engel PJ, Alpert BL, Hickman JR: The nature and prevalence of the abnormal exercise electrocardiogram in mitral valve prolanse. AM HEARTJ 96:716, 1979. 32. Ellestad MH: Stress testing. Principles and practice. 2nd ed. Philadelphia, 1980, F A Davis Company, pp 203-218. 33. Hollenbere M. Budge WR. Wisneski JA. Gertz EW: Treadmill score quantifies electrocardiographic response to exercise and improves test accuracy and reproducibility. Circulation 61:276, 1980. 34. Barlow JB, Pocock WA: Mitral valve prolapse, the athlete’s heart, physical activity and sudden death. Int J Sports Cardiol 1:9, 1984. 35. Sketch MH, Mooss AN, Butler ML, Nair CK, Mohiuddin SM: Digoxin-induced positive exercise tests: Their clinical and prognostic significance. Am J Cardiol 48:655, 1981. 36. Barlow JB, Pocock WA: The mitral valve prolapse enigmatwo decades later. Mod Concepts Cardiovasc Dis 53:13, 1984. 37. Goldschlager N, Selzer A, Cohn K: Treadmill stress tests as indicators of presence and severity of coronary artery disease. Ann Intern Med 85:277, 1976. 38. Schamroth L: The electrocardiology of coronary artery disease. 2nd ed. Boston, 1984, Blackwell Scientific Publications, p 177. 39. Mukharji J, Kremers M, Lipscomb K, Blomqvist CG: Early positive exercise test and extensive coronary disease: Effect of antianginal therapy. Am J Cardiol 55:267, 1985. 40. McHenry PL, Richmond HW, Weisenberger BL, Rodway JS, “,

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Perry GF, Jordan JW: Evaluation of abnormal exercise electrocardiogram in apparently healthy subjects: Labile repolarization (ST-T) abnormalities as a cause of false positive responses. Am J Cardiol47:1152, 1981. Barlow JB, Pocock WA, Obel IWP: Mitral valve prolapse: Primary, secondary, both or neither? AM HEARTJ 102:140, 1981. Berger HJ, Sands MJ, Davies RA, Wackers FJTH, Lachman AJ, Williams BW, Zaret BL: Exercise left ventricular performance in patients with chest pain, ischemic appearing exercise electrocardiograms, and angiographically normal coronary arteries. Ann Intern Med 94:186, 1981. Barlow JB, Pocock WA: The problem of nonejection systolic clicks and associated mitral systolic murmurs: Emphasis on the billowing mitral leaflet syndrome. AM HEART J 90:636, 1975. Zeppilli P, Pirrami MM, Sassara M, Fenici R: T wave abnormalities in top-ranking athletes: Effects of isoproterenol, atropine, and physical exercise. AM HEART J 100:213, 1980. Cannon RO III: Myocardial ischemia due to dynamic small vessel coronary artery disease. Int J Cardiol 7:198, 1985. Isner JM. Kishel J. Kent KM. Ronan JA. Ross AM. Roberts WC: Accuracy of angiographic determination of left main coronary arterial narrowing. Angiographic-histologic correlative analysis in 28 patients. Circulation 63:1056, i981. White CW. Wright CB. Dotv DB. Hiratza LF. Eastham CL. Harrison DG, Marcus ML: Does visual interpretation of the coronary arteriogram predict the physiologic importance of a coronary stenosis? N Engl J Med 310:819, 1984. Malcolm AD: Mvocardial mvsteries surrounding mitral leaflet prolapse. AM"HEARTJ 100:265, 1980. Barlow JB, Pocock WA: Mitral valve prolapse, the specific billowing mitral leaflet syndrome, or an insignificant nonejection systolic click. AM HEART J 97:277, 1979.