HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Guest Access | Sign In via User Name/Password

This Article Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (13) Citing Articles via Google Scholar Google Scholar Articles by Tavel, M. E. Search for Related Content PubMed PubMed Citation Articles by Tavel, M. E.

Stress Testing in Cardiac Evaluation^*

Current Concepts With Emphasis on the ECG

^* From the Indiana Heart Institute, Care Group, Inc, and the Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.

Correspondence to: Morton E. Tavel, MD, FCCP, 8333 Naab Rd, Suite 200, Indianapolis, IN 46260; e-mail: mtavel6986{at}aol.com

Key Words: stress testing • treadmill testing

	Introduction

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
The stress test combined with ECG was originally used primarily for the detection of ST changes secondary to myocardial ischemia. Modern exercise testing, however, is not limited to observation of these changes. Important information is derived from exercise capacity, BP response, development of arrhythmias, and whether or not symptoms such as chest pain develop during exercise. This allows for assessment of presence and severity of ischemia, prognosis, overall functional capacity, and efficacy of therapeutic interventions. Although stress testing is often combined with radionuclide or echocardiographic imaging, I shall focus primarily on the ECG component. The proper selection of stress tests in clinical evaluation will also be discussed.

The major indications for performing a stress test are summarized in Table 1 . Table 2 lists the generally accepted contraindications for such testing, as adapted from the guidelines provided by the American College of Cardiology/American Heart Association Task Force in 1997.¹

	Safety of the Exercise Test

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

	Types of Stress Tests

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
The most commonly performed stress test is the graded exercise test, using either the treadmill or cycle ergometer. The patient is generally subjected to increasing workloads at 2- or 3-min intervals. The test is stopped for any of the reasons listed in Table 3 . The ECG is monitored not only during exercise but also afterward, for 5 to 11% of patients with abnormal responses may not display such findings until reaching the recovery period^{4 5} (see below).

	BP Response to Exercise

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
In response to the increased stroke volume and systolic contractile force, the systolic BP normally rises progressively with increasing workloads, reaching approximately 160 to 220 mm Hg with maximum effort. Because exercise lowers overall peripheral vascular resistance, the diastolic pressure exhibits little or no change (< 10 mm Hg). If the systolic pressure fails to rise to 130 mm Hg or falls by 10 mm Hg in response to exercise, this frequently indicates left ventricular dysfunction and often signals the presence of severe coronary artery disease (CAD) associated with extensive myocardial ischemia.^{9 10} However, possibly in a substantial number of patients, myocardial ischemia may produce an abnormal fall in BP, presumably resulting from an excessive vasodilator reflex in nonexercising vascular beds.¹¹ In this instance, cardiac output actually may be increased during exercise.

An abnormal rise in exercise systolic pressure to a level 214 mm Hg in a subject with a normal resting pressure predicts increased risk for future sustained hypertension, estimated at approximately 10 to 26% for the next 5 to 10 years.¹² This is associated with a relatively high prevalence of left ventricular hypertrophy.¹³ Some investigators¹² have found a slightly greater 5- to 10-year rate of subsequent cardiovascular events within this group, but others¹⁴ have not observed this outcome.

Normally, the systolic pressure falls rapidly after cessation of exercise, dropping by an average of 15% at 3 min after stopping. Myocardial ischemia may reduce the rate at which this level falls: a 3-min postexercise level of 90% in comparison with the peak systolic level during exercise suggests the presence of ischemia.^{15 16 17} To minimize the inaccuracies of BP measurement at peak exercise, McHam et al¹⁷ suggested comparing pressures at 1 and 3 min after exercise. Abnormality existed if the value at 3 min equaled or exceeded that at 1 min. Such a retarded pressure drop is an insensitive indicator of ischemia, but it is fairly specific for this disorder, reportedly exceeding 80%.¹⁷ Although the mechanism for this abnormal pressure response is uncertain, it may result from ischemic suppression of left ventricular function during exercise combined with the subsequent recovery of contractility during recovery. This response has been found usually to signal profound and extensive ischemia, with the systolic pressure ratio increasing proportionally with the number of diseased coronary arteries.¹⁶

	Heart Rate Response to Exercise

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
In general, the heart rate rises proportionately with the intensity of the workload. Excessively rapid rises in rate result primarily from reduced left ventricular stroke volume, which, in turn, may be caused by physical deconditioning or cardiac disease. Under such circumstances, the heart rate reaches its peak level relatively early, and this limits maximum exercise capacity. However, when the heart rate response to exercise is excessively attenuated (in the absence of rate-limiting drugs), this condition is termed chronotropic incompetence. Patients showing this response often have significant organic heart disease, and among patients with known or suspected coronary disease, it is independently predictive of higher all-cause mortality.¹⁸ Unfortunately, however, definitions of chronotropic incompetence vary: they range from the inability to achieve 85% of expected maximum heart rate, to failure to achieve 100 beats/min at maximal exertion,¹⁹ to heart rate responses in terms of percentage or standard deviations around a mean heart rate for each stage on the treadmill.^{18 20} Because of such limitations, analysis of cardiac chronotropic responses currently has limited practical applicability.²¹

The rate with which the heart rate slows in the early recovery period can also provide information about ventricular function and prognosis. A recent study by Cole et al²² demonstrated that a drop in rate by 12 beats/min at 1 min after peak exercise during the cool-down phase in early recovery (while walking 1.5 mph at 2.5% grade) signaled a poor prognosis. These subjects were found to have a subsequent 6-year mortality rate four times greater than those have with a more rapid fall in heart rate. The retarded heart rate drop during recovery probably signifies reduced vagal tone, which is often associated with decreased myocardial function and exercise capacity. An abnormal rate drop may add independent prognostic information that extends beyond such factors as effort tolerance and rate response during the exercise period.

	Cardiac Auscultatory Findings

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Cardiac auscultation should be performed before and immediately after exercise. Resting abnormalities, such as murmurs and third and fourth heart sounds, should be noted and compared with postexercise findings. This facilitates recognition of important valvular abnormalities, such as aortic stenosis, that might preclude or modify testing. I have also encountered individuals with hypertrophic subaortic stenosis in whom intense systolic murmurs became manifest only after exercise. The appearance of a third heart sound or mid-diastolic gallop sound after exercise is usually indicative of reduced resting systolic function of the left ventricle, which may be associated with cardiomyopathy or prior infarction, often associated with diabetes mellitus and left bundle branch-block, although extensive stress-induced ischemia is occasionally found.²³

	Recording Techniques

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
The conventional 12-lead ECG is the most widely chosen one for the graded exercise test. Almost all the significant ST-segment changes, however, can be demonstrated in leads I and V₃ through V₆,²⁴ and approximately 90% of that information is contained in lead V₅. Some investigators have suggested that the addition of right precordial leads, ie, leads V₁R through V₄R, may improve the diagnostic accuracy in detection of ischemia in general, especially in the distribution of the right and circumflex left coronary arteries.^{25 26}

Equipment for computer averaging of the ECG signals is commonly available, and this provides assistance in the analysis of various changes—especially ST depression. I agree with others²⁷ who have noted that such records often produce spuriously abnormal ST changes. Thus, the clinician should always evaluate the actual ECG recording strips.

	Criteria for a Positive Exercise Test: Conventional Criteria

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Horizontal or Downsloping ST-Segment Depression of 1 mm
The PR segment is the reference point with which the ST segment is compared (Fig 1 ). The criterion of 1 mm of horizontal or downsloping depression (Fig 1, D and E) is the most generally accepted. Junctional (J point) depression with slowly upsloping ST segments (Fig 1C) also is generally considered to be an abnormal response,^{28 29 30} although the definition of slowly upsloping varies. Various investigators³¹ have reported that including upsloping ST responses that remain 1 to 2 mm below the baseline at 60 to 80 ms after the J point significantly increases test sensitivity without degrading specificity. However, Sansoy et al³² noted that specificity was reduced, especially if 1-mm depression was selected at 80 ms. For this reason and until further data are available, in the case of upsloping ST segments, I agree with others³³ who suggest using 1.5-mm depression at 80 ms after the J point as a reasonable criterion for a positive response.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Schematic representation of various ST-segment patterns potentially produced by exercise. A: normal; B: junctional depression that returns to baseline (level of PR segment) within 0.08 s (arrow); C: junctional depression that remains below baseline at 0.08 s; D: horizontal ST depression; E: downsloping ST depression;. F: ST elevation. See text for explanation.

ST-Segment Elevation
Although horizontal or downsloping ST-segment depression is the typical ischemic response in stress testing (in all leads except aVR), some patients exhibit ST-segment elevation of 1 mm (Fig 1F) . Generally, in the absence of prior infarction, this finding is uncommon but implies severe transmural ischemia exceeding that associated with isolated ST depression.³⁸ The reported incidence among patients with chest pain ranges from 0.2 to 1.7%.^{38 39 40 41 42} High-grade proximal coronary stenosis is usually found, and this combination is associated with an ominous prognosis.³⁸ The correlation between the site of the ST-segment elevation and the artery involved is generally quite good.^{38 39 40 41 42 43} Probably representing a variant of ST elevation, isolated transient increase in height of T waves in the anterior leads (V₁ through V₃) strongly suggests severe narrowing of the left anterior descending coronary artery.⁴⁴

Exercise-induced ST-segment elevation is seen most commonly in patients who have had previous myocardial infarctions.^{40 41} Most studies demonstrated an incidence of 14 to 27%.^{40 41 42 45 46 47 48 49 50} Patients with anterior myocardial infarction are more likely to have exercise-induced ST-segment elevation than are those with inferior myocardial infarction.^{49 51} The ST-segment elevation almost always occurs in the leads with abnormal Q waves.⁵⁰ It also is associated with a left ventricular wall motion abnormality, either dyskinetic or akinetic, in the corresponding site in > 90% of cases.^{41 50 51 52} Overall poor left ventricular systolic function is usually found.^{45 52} Although some studies suggest that such ST changes denote residual myocardial ischemia and contractile reserve within this infarct area,^{53 54} passive segmental left ventricular wall motion abnormality (with or without aneurysm formation) is probably the underlying mechanism for the ST-segment elevation in most cases.⁵⁴ Findings in one study,⁵⁵ however, suggested that residual viability could be found only in those instances in which ST elevation was associated with reciprocal ST depression in those leads taken from the opposite side of the heart. In this context, therefore, ST depression may simply be a secondary response to remote ischemia rather than a primary marker of ischemia in itself—as is the usual interpretation. In the case of prior inferior myocardial infarction, the ST elevation found accompanying the Q waves in the inferior leads (II, III, and aVF) often gives rise to reciprocal ST depression in the high lateral leads (I and aVL).⁵⁶

Ten to 30% of patients with variant angina also may have ST-segment elevation with exercise.⁵¹ The leads that show ST-segment elevation are usually the same leads that record elevation during angina at rest. All studies^{51 57 58} regularly report the occurrence of spasm of a major coronary artery supplying the area of the myocardium corresponding to the site of the ST-segment elevation. Most patients with variant angina and exercise-induced ST-segment elevation, however, also have significant fixed coronary lesions.⁵⁹

Transient, exercise-induced ST elevation has been reported to occur in conjunction with acute pericarditis⁶⁰ and may be mistaken for ischemic pain in the acute care setting. As noted previously, patients with known pericarditis are usually not subjected to stress testing. When the diagnosis is uncertain, however, persistence of ST elevation in response to exercise stress testing may aid in the distinction between pericarditis and early repolarization (a normal variant) inasmuch as in the latter condition, ST elevation returns to the isoelectric line.⁶¹ Exercise-induced resolution of ST elevation, however, although uncommon, may occur in pericarditis as well.⁶²

	Less Commonly Used or Controversial Criteria

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
The degree of ST-segment displacement in relation to the increase in heart rate (ST/HR index) with exercise has been suggested by some investigators to be a more accurate indicator of the presence and severity of CAD.^{63 64 65 66 67} This method requires meticulous or computerized measurement of ST displacement. Other studies^{68 69 70 71} have not demonstrated the superiority of the ST/HR index in the prediction of CAD. The usefulness of changes of the heart rate-adjusted ST-segment depression in the detection of CAD, therefore, remains controversial⁷² and, at best, may add only limited incremental diagnostic value.⁷³ Thus, this method has not gained wide acceptance.

Transient inversion of U waves—even in the absence of an abnormal ST-segment response—has been suggested as a marker of extensive ischemia in the anterior myocardium⁷⁴ or elsewhere.⁷⁵ Analogous to U-wave inversion, others^{76 77} have found that exercise-induced increased magnitude of the U wave in the precordial leads ( 0.05 MV) was strongly suggestive of ischemia in the distribution of the left circumflex or right coronary arteries, presumably representing reciprocal changes from posterior U-wave inversion when myocardial ischemia occurred in this latter location. Detection of all U-wave changes is difficult in the presence of tachycardia, a factor that limits the usefulness of these observations.

Bonoris et al⁷⁸ initially reported an increase in the R-wave amplitude immediately after exercise in patients with severe multivessel coronary artery narrowing and ventricular dysfunction, presumably caused by transient ventricular dilatation. The results of later studies varied, some supporting and others not supporting the original observation.^{79 80 81 82 83 84} Nevertheless, although the sensitivity of this finding is low, when the R-wave amplitude increases by > 2 mm at peak exercise, this has been said to strongly suggest ischemia.⁸⁵ In general, however, analysis of R-wave amplitude is not used in clinical practice.

Normally, the Q-wave depth in lead V₅ increases in response to exercise,^{86 87} presumably because of septal thickening in response to inotropic stimulation. A decrease or no change in this wave has been found with stenosis of the left anterior descending coronary artery, usually in association with multivessel disease.⁸⁶

The P wave shortens normally by approximately 0.02 s in response to exercise, whereas in the presence of ischemia, it may lengthen slightly or remain unchanged.⁸⁸ Transient elevation of atrial and left ventricular filling pressure induced by ischemia is the assumed mechanism for such P-wave prolongation. This interesting observation, if confirmed, may provide a useful secondary means to confirm the significance of other changes, such as ST depression.

The mean frontal plane QRS axis normally shifts toward the right in response to exercise. Exercise-induced leftward axis shift^{89 90} or absence of rightward shift⁸⁹ is reported to be highly specific for narrowing of the left anterior descending coronary artery, presumably caused by ischemia of the left anterior fascicle. However, transient rightward axis shift to > 90° is a rare occurrence, but said to be highly specific for CAD,⁹¹ presumably as a consequence of septal ischemia.

Exercise induction of complete right or left bundle branch block is generally nonspecific. When found together with other evidence of ischemia, however, such as angina pectoris, the conduction abnormality is said to be strongly suggestive of myocardial ischemia, especially in the distribution of the proximal left anterior descending coronary artery.⁹⁰

The QRS duration normally remains unchanged or shortens slightly in response to exercise. In the presence of ischemia, the QRS may lengthen slightly (> 3 to 5 ms) and this may allow detection of ischemia with greater sensitivity and specificity than ST segment changes alone,^{92 93 94 95} even in patients with recent myocardial infarction.⁹⁶ Michaelides et al⁹⁵ found that the QRS prolongation correlated with severity of ischemia, prolonging progressively with one (9.7 ms), two (13.6 ms), and three (16.3 ms) ischemic areas as demonstrated by nuclear scintigraphy. When prolongation of S waves (10 to 12 ms) occurs in subjects with resting right bundle branch block or left anterior hemiblock, this is believed to be highly suggestive of left anterior descending coronary artery stenosis.⁹⁷ Because of the small increments in duration of any of the above intervals, higher recording paper speeds or computer-aided measuring techniques such as signal averaging^{93 95} would be generally required to achieve sufficient accuracy.

Normally, the QT interval (corrected for heart rate) shortens with exercise. Some investigators have found that this interval fails to shorten or lengthens when ischemia is present.^{98 99} Others^{100 101} have suggested that abnormal exercise-induced QT dispersion, ie, the difference between shortest and longest QT intervals when multiple leads are compared, is greater in patients with ischemia. Measurement of this interval, however, is difficult, especially when tachycardia is present, and this limits its potential clinical value.

	Methods to Validate the Presence of Myocardial Ischemia

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Despite its limitations, the coronary arteriogram remains the most common standard against which the diagnostic value (especially sensitivity) of stress testing for CAD is measured. As noted, the use of arteriography as a standard usually suffers from the disadvantages of referral bias, ie, a positive ECG stress test is often involved in the decision to select those referred for subsequent coronary arteriography. The effect of such selective referral is to raise falsely sensitivity estimates, and, conversely, to reduce falsely specificity values.

Noninvasive techniques (eg, stress thallium perfusion imaging or stress echocardiography) have also been used to confirm the presence of coronary disease. When such studies are used to evaluate the performance of stress ECG, referral bias can be minimized, and this usually results in lower sensitivity but relatively high specificity values.

	Accuracy of ST-Segment Depression in Detection of Ischemia

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Stress-induced ST-segment depression is probably caused largely by reduction of perfusion to the subendocardium, the zone most vulnerable to ischemia. The sensitivity of such changes in the detection of coronary disease varies widely in published reports,^{102 103 104} undoubtedly reflecting various confounding factors such as referral bias, severity of disease in the selected population, and so forth. Overall, test sensitivity is most often found to lie in the 60 to 70% range. In studies in which referral bias was minimized, however, lower sensitivity values are reported, falling in the range of 45 to 60%.^{37 105} In general, the greater the degree and extent of ischemia, the more likely will ST depression occur, and, therefore, the higher the sensitivity of the stress ECG. Most investigators have reported a sensitivity in the range of 40%, 66%, and 76% for one-, two-, and three-vessel coronary disease, respectively.^{106 107} We have also found that with larger nuclear perfusion defects in response to stress imaging, ST depression was more often encountered.¹⁰⁵ Notwithstanding the results of smaller studies,¹⁰⁸ we have also found that larger areas of hypoperfusion also increased the average depth of ST depression.¹⁰⁵

In general, the distribution of leads manifesting ST-segment depression does not appear to be helpful in localizing the obstructive coronary lesions,^{105 106 109 110 111 112} for as noted, the lead V₅ is most apt to reflect this change whenever ischemia is present. However, some studies^{43 113} have noted that ST depression of lead V₁—either isolated or associated with other lead changes—suggests the presence of ischemia in posterior myocardial regions, ie, in those areas supplied by the left circumflex or right coronary arteries. Such depression in these leads presumably arises as a reciprocal response to ST elevation posteriorly, a location usually inaccessible to conventional lead systems. Extending these observations further, one group²⁶ has suggested that ST deviation in the right precordial leads (V₃R and V₄R) may not only enhance the recognition of posterior ischemia, but when these changes are combined with abnormalities in the conventional lead systems, the sensitivity of ECG stress testing in general could be greatly enhanced for detection of coronary disease. They claimed a sensitivity ranging from 89% in single-vessel involvement to as high as 95% in triple-vessel coronary disease. To enter the clinical mainstream, however, these latter observations require confirmation.

In contrast to the almost universal changes produced in the left precordial leads (V₄ through V₆), myocardial ischemia seldom produces ST depression confined to the inferior leads (II, III, and aVF), and when one encounters such a limited distribution, this usually denotes a false-positive test response,^{105 114} possibly often attributable to P-wave repolarization (see below).

In general, the myocardial location of ischemia also appears to play no role in the likelihood of ST depression,^{105 110} for we have demonstrated that the likelihood of its appearance depends primarily on the extent of ischemia rather than its location.¹⁰⁵

The configuration, time of onset, and duration of depressed ST segment during and after treadmill exercise have important diagnostic significance.¹¹⁵ Multivessel or left main coronary disease is present in approximately 90% of patients who have changes appearing at low workloads (Bruce stage I or II) or persisting for > 8 min after exercise.^{116 117} Although such early and prolonged ST responses are highly specific for ischemia, some studies suggest that they correlate less well with subsequent prognosis,¹¹⁸ and even arteriographic or scintigraphic severity may be variable.¹¹⁹ Although T-wave changes alone are not helpful in diagnosis, the presence of deep T-wave inversion ( 5 mm) when combined with ST depression has been found to be highly specific for multivessel CAD with multiple severe narrowings.¹²⁰

ST-segment depression occasionally begins only after cessation of exercise. The diagnostic and prognostic significance of such a delayed response is generally similar to those occurring during exercise^{121 122 123} ; however, when the onset of such a change is delayed by > 2 to 3 min into recovery, this suggests a false-positive response.¹²⁴ When ST changes during exercise are equivocal, the finding of progressively greater downsloping ST depression during recovery is a fairly specific sign of severe ischemia and also signals a greater incidence of cardiac events in follow-up.¹²⁵

The pattern of regression of ST changes in the recovery period may be useful in distinguishing ischemic responses from those encountered occasionally in normal subjects who are falsely positive.^{124 126} In true ischemia, the major ST depression tends to coincide with the termination of exercise and continues—often intensifying—for 2 to 3 min after cessation.¹²⁴ The persistence of this depression in recovery usually parallels its onset, ie, when it begins early at low workloads, it is more persistent during recovery. When it reaches a maximum later in the exercise phase, it usually regresses relatively early in recovery, but it usually continues for at least 3 min after stopping. In contrast, false-positive ST depression tends to reach its maximum immediately before and at peak exertion but regresses quickly on cessation, frequently returning to normal within 1 to 3 min of recovery. In this latter instance, as the heart rate slows in recovery, the depth of ST depression is less when compared with corresponding cycle lengths during the exercise phase, whereas those subjects with true ischemia usually show equal or greater ST displacement at comparable cycle lengths.¹²⁶

The development of typical anginal chest pain during the test generally signifies fairly extensive ischemia and thus increases the likelihood of ST changes, adding significantly to test sensitivity.¹⁰⁵ Moreover, typical chest pain during testing is almost as predictive of ischemia as is ST-segment depression.¹²⁷

As already noted for test sensitivity, the specificity of ST depression in the evaluation of coronary ischemia has also been found to vary considerably, with a mean value derived from a meta-analysis reported to be 72%.¹⁰² Referral bias, however, probably reduced these values spuriously, for when this type of bias is minimized, these values generally approach or exceed 90%.^{37 128 129}

Differences in results of stress tests between men and women have been the subject of considerable controversy. In general, women are far more likely than men to manifest a false-positive response,^{130 131 132} but the difference may be attributable to the lower rate of CAD in the populations of women subjected to testing. Based on Bayes theorem, the lower general prevalence of CAD among women results in a relatively low predictive value of a positive test in this group. Some investigators¹³³ have suggested that hormonal effects, especially those of progestin, might be responsible for the production of false-positive ST responses. This effect, if present at all, would be small, for the rate of false-positive stress tests in premenopausal women is low¹²⁹ and only marginally greater than that of men.

Test specificity, ie, the percentage of negative responders in a population known to be free of disease, is of utmost importance in clinical evaluation, and many mistakenly believe that this value is unacceptably low in women. For proper determination of test specificity, a group must be defined that is uniformly proven to be free of disease and in which no prior ECG tests have been performed. Coronary cineangiography is often used as the definitive test to rule out CAD. Unfortunately, such a design is basically flawed because it is a rare individual who has not been subjected to prior stress testing and in whom the results of this testing were not instrumental in the decision to obtain the cineangiographic study. This process produces so-called referral bias, ie, the inclusion of an inordinately high percentage of positive test responders in a disease-free group selected in this manner, thus yielding falsely low specificity values. Such bias may produce greater distortions of test specificity in women simply because, as noted above, falsely abnormal stress responders are more plentiful in mixed populations of women (with and without disease) from which these subjects are drawn. When this type of bias is minimized, however, the difference in specificity between the sexes all but disappears, with a false-positive response rate of 10% for each.^{128 129} Therefore, in accordance with Bayesian principles, a negative test result encountered in a subject from an unselected population of women generally carries a high negative predictive value and thus is useful in excluding CAD. These data suggest that, in general, the initial evaluation of an individual woman should be identical to that of a man, ie, accomplished with a standard ECG stress test. It need not involve costly nuclear or echocardiographic techniques unless the former test result is positive—a relatively uncommon occurrence in the absence of coronary disease.

	Causes of Positive Results of Exercise Tests in the Absence of CAD

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Numerous situations appear to give rise to exercise-induced ST depression in the absence of obstruction to the major coronary arteries. Mechanical lesions that place a greater burden on left ventricular dynamics and oxygen requirements include such abnormalities as mitral or aortic valvular dysfunction,^{134 135} pulmonary hypertension,¹³⁵ pericardial constriction,¹³⁶ and left ventricular hypertrophy.^{136 137} Relative coronary insufficiency is probably also the responsible mechanism in patients with left ventricular hypertrophy. The frequency of positive test results in such cases has been found to be as high as 38%.¹³⁸ Patients with increased left ventricular mass, even in the absence of standard ECG voltage criteria for this diagnosis, may have false-positive ECG exercise responses.^{137 138}

A wide variety of miscellaneous situations has also been associated with falsely positive ST responses to exercise.¹³⁹ These include digitalis administration,^{140 141} hypokalemia,^{142 143} normal postprandial changes,¹⁴⁴ hyperventilation,^{145 146} postural changes,¹⁴⁷ vasoregulatory abnormalities,^{148 149} mitral valve prolapse,^{150 151} pectus excavatum,¹⁵² and intraventricular conduction defect including left bundle branch block and Wolff-Parkinson-White syndrome.^{153 154 155} There is undoubtedly no common mechanism for ST shifts in these diverse situations; however, effects brought about by electrolyte shifts and sympathetic nervous stimulation at the cellular level may play an important role.

Digitalis is known to cause a false-positive exercise test result in both normal subjects and in patients with heart disease,^{140 141 156} occurring as often as 25% in healthy subjects,¹⁴¹ showing a greater prevalence with increasing age. Hamasaki et al¹⁵⁶ found that digitalis-induced ST-segment depression occurs gradually as the heart rate increases in response to exercise, a pattern differing from that usually seen in myocardial ischemia, in which the ST depression progresses more rapidly as peak heart rates are approached. This might aid in distinguishing between drug effect and ischemia.

Hypokalemia is often associated with abnormal exercise responses,¹⁴² and these changes can be abolished after potassium repletion. Therefore, in patients who are taking diuretics, the results of the ECG stress test should be interpreted with caution.

Food intake may induce ST-segment and T-wave changes in the resting ECG.¹⁵⁷ Significant ST depression also may develop after glucose ingestion in subjects who otherwise had normal exercise ECGs.¹⁴⁴ For this reason, exercise testing should be proscribed until 2 h after a meal to avoid this source of variability.

Although usually causing changes primarily confined to the T waves, hyperventilation is known to produce ST-segment changes in response to exercise that mimic those of myocardial ischemia.^{145 146 158} If this cause is suspected in a given individual with suspicious stress-induced ST changes, that subject may be instructed to voluntarily hyperventilate for a period of 2 to 3 min during rest and with ECG monitoring. If ST changes are produced by this maneuver, they are compared with those encountered during the stress test, and if similar, this suggests a false-positive result induced by hyperventilation. This maneuver, however, should be selectively performed only after the standard stress test, for routine performance before the test is usually unnecessary and may produce dizziness and discomfort and interfere with the proper execution of the standard test.

A peculiar syndrome, sometimes labeled syndrome X, is occasionally encountered, especially in young and middle-aged women, consisting of anginal-type chest pain and abnormal exercise ECG but normal coronary arteriograms.¹⁵⁹ Exercise-induced coronary spasm and microvascular disease¹⁶⁰ are possible causes of this syndrome. Therefore, in this context, the abnormal ECG stress test result may not be truly false positive.

Patients with the mitral valve prolapse and normal coronary arteriograms may have false-positive exercise responses.¹⁵⁰ This phenomenon is clinically important because chest pain and vasoregulatory abnormalities are occasionally encountered in these patients.

The secondary ST-segment and T-wave changes in patients with intraventricular conduction defects such as left bundle branch block, ventricular paced rhythm, and Wolff-Parkinson-White (preexcitation) syndrome interfere with proper interpretation of the exercise response.^{153 154 155 161 162} Both false-positive and false-negative responses may be seen in patients with left bundle branch block. Studies in a limited number of patients, however, suggested that the exercise test might be useful even if this latter conduction abnormality is present.^{163 164} Recently, Ibrahim et al¹⁶⁵ found that additional exercise-induced J point depression in leads II, aVF, and V₅ was suggestive of ischemia in this group. Most useful in their study was a change of 0.5 mm in lead II. This finding, if confirmed, would be of significant clinical value. False-positive changes are particularly common in patients with the Wolff-Parkinson-White syndrome,¹⁵⁴ being observed in as many as 100% of such cases.¹⁵⁵

In the case of right bundle branch block, the resting anterior ST-T changes secondary to this conduction abnormality interfere with interpretation of the exercise response. Thus, changes in leads V₁ through V₃ often falsely suggest ischemia.¹⁶⁶ The test is still reliable if the ST segment depression is recorded in leads V₄ through V₆. In one small study,¹⁶⁷ however, this conduction abnormality was found to be capable of masking the usual ischemic ST depression in these latter leads, thus producing false-negative ST responses to stress.

Exaggerated atrial repolarization waves may produce spurious depression of ST segments.^{168 169 170} The atrial repolarization wave is directionally opposite to the P wave and can extend well into the ST segment. Thus, with exercise-induced tachycardia, P wave and atrial repolarization wave amplitudes increase, and the PR segment shortens, thus shifting the atrial repolarization wave toward the ST segment. In practice, this phenomenon may be suspected when apparent ST depression is found together with a prominent P wave with a short, sharply downsloping PR segment, especially notable in the inferior leads.

	Causes of False-Negative Response

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
Apart from the inherent limitations of sensitivity of the exercise test in the detection of myocardial ischemia, certain drugs are known to limit its value even further. Drugs which limit the heart rate response to exercise (ß-adrenergic blocking agents, diltiazem, and verapamil) reduce the heart rate and maximum systolic arterial BP during exercise, thus decreasing the left ventricular work and myocardial oxygen requirements and reducing or eliminating the ST-segment depression.¹⁷¹ In the process of increasing exercise capacity, nitrates may also prevent or minimize changes in exercise ECG.¹⁷² In general, if one wishes to maximize test sensitivity, treatment with any of the drugs noted above should be withdrawn for a sufficient period to allow removal from the body before testing. Depending on the information desired from the test and the need for continued medication, however, the clinician may decide to perform the test in selected cases without drug withdrawal.

	Exercise Testing in Patients With Abnormal Resting ECGs

TOP Introduction Safety of the Exercise... Types of Stress Tests BP Response to Exercise Heart Rate Response to... Cardiac Auscultatory Findings Recording Techniques Criteria for a Positive... Less Commonly Used or... Methods to Validate the... Accuracy of ST-Segment... Causes of Positive Results... Causes of False-Negative... Exercise Testing in Patients... Prognostic Value of Exercise... Exercise Testing After... Exercise ECG in Risk... Relationship Between Exercise... Selection of a Stress... Concluding Remarks References

 
A number of reports suggest that exercise testing may be of value even when the resting ECG is abnormal.^{173 174 175} Most of the patients with abnormal resting ECGs show nonspecific ST-segment and T-wave changes. In general, additional ST depression of 1 mm with exercise has a diagnostic accuracy approaching that found in the absence of resting changes.^{173 174 175} Such changes also have been found to have similar prognostic significance as those found in patients with a normal resting ECG.¹⁷⁵

In the presence of resting T-wave inversion, normalization of this abnormality in response to exercise may occur in different clinical settings^{176 177 178} : it may result from regional myocardial ischemia or abnormal left ventricular wall motion, but may also occur in normal subjects. Thus, in general, this finding has little specificity. However, if such normalization occurs in conjunction with an infarcted dysfunctional myocardial zone, it may indicate higher coronary flow reserve, and this in turn suggests better preservation of coronary microcirculatory function and the likely presence of myocardial viability.^{176 177} This concept, however, has been challenged by others.⁵²

ST-segment elevation may be seen in the resting ECGs of healthy subjects because of early repolarization. In such cases, the ST segment returns to the isoelectric baseline with exercise, whereas those with significant CAD may have horizontal ST-segment depression.¹⁷⁹ Therefore, even in the presence of ST elevation in the baseline ECG, the usual criteria for the interpretation of the exercise test are probably still applicable. As noted above, persistent or increasing ST elevati