Heart Rate Adjustment of ST Segment Depression and Performance of the Exercise Electrocardiogram: a Critical Evaluation

1726 JACC Vol. 25, No. 7 June 1995:1726-35 REVIEW ARTICLE

Heart Rate Adjustment of ST Segment Depression and Performance of the Exercise Electrocardiogram: A Critical Evaluation

PETER M. OKIN, MD, FACC, PAUL KLIGFIELD, MD, FACC New York, New York

Analysis of the rate-related change in exercise-induced ST segment/heart rate slope to the presence and extent of coronary segment depression using the exercise ST segment/heart rate artery disease. False positive and false negative test results of the slope and ST segment/heart rate index can improve the accuracy heart rate-adjusted methods are well known in selected popula- of the exercise electrocardiogram (ECG) for the identification of tions and require further clarification. Application of these meth- patients with coronary artery disease, recognition of patients with ods is also highly dependent on the type of exercise protocol, anatomically or functionally severe coronary obstruction and number of ECG leads examined, timing of ST segment measure- detection of patients at increased risk for future coronary events. ment relative to the J point and accuracy and precision of ST These methods provide a more physiologic approach to analysis of segment measurement. These methodologic details have been an the ST segment response to exercise by adjusting the apparent important limitation to test application when traditional proto- severity of ischemia for the corresponding increase in myocardial cols and measurement procedures are required. When applied oxygen demand, which in turn can be linearly related to increasing with attention to required details, the heart rate-adjusted meth- heart rate. Solid-angle theory provides a model for the linear ods can improve the usefulness of the exercise ECG in a range of relation of ST segment depression to heart rate during exercise clinically relevant populations. and a framework for understanding the relation of the ST (J Am Coll Cardiol 1995;25:1726-35)

Poor sensitivity and poor predictive value of standard ST methodologic and population conditions that govern perfor- segment depression criteria have limited the usefulness of the mance of these new measures. exercise electrocardiogram (ECG) (or exercise tolerance test) for the detection and evaluation of coronary artery disease (1-9). In response to these well recognized limitations, new Methods of Heart Rate Adjustment of ST test algorithms based on heart rate adjustment of the magnitude of ST segment depression during exercise have been Segment Depression developed over the past 15 years (10-52). Within defined Heart rate adjustment is a rational, physiologic approach to conditions, these methods improve the accuracy of the exercise interpretation of the exercise tolerance test. ST segment ECG, either for the detection of coronary obstruction (10- depression recorded on the surface ECG during exercise- 12,19-23,25,26,29,30,37,42,46) or for assessment of the ana- induced ischemia results primarily from the separate interac- tomic, functional and prognostic severity of coronary disease tive influences of the extent of coronary obstruction and the (10,11,19-21,24,27,34,37,44,48) in a range of clinically relevant magnitude of excess myocardial oxygen demand (51,62-75). In populations. Application of heart rate-adjusted methods has patients with demand-mediated myocardial ischemia due to been shown to be strongly dependent on population selection, obstructive coronary artery disease, ST depression will be exercise protocol, number of ECG leads and precision and proportional to exercise work load for any degree of obstruc- accuracy of ST segment measurement (29-33,36-38,40- tion. Thus, a patient with 1.0 mm (100/xV) of ST depression 43,46-61). This review examines the value and limitations of during exercise might reach 1.5 or 2.0 mm of ST depression the heart rate-adjusted indexes of ST segment depression in a with further effort, whereas less effort might provoke only theoretic and experimental context (62-75) that focuses on the 0.5 mm of ST depression. Because the underlying extent of coronary obstruction is the same in each of these conditions, the ischemia apparent in ST depression alone cannot be directly related to the presence or extent of disease without From the Divisionof Cardiology,Department of Medicine,The New York adjustment for the corresponding myocardial work load. Hospitat-CornellMedical Center, New York, New York. This study was sup- ported by grants fromthe Elizabethand Robert Rosenman Charitable Founda- Physiologic insights result when exercise-induced ST seg- tion and the Davidand HopeG. SolingerFoundation, Inc., New York,New York. ment depression is plotted against heart rate rather than Manuscript receivedOctober 7, 1994; revisedmanuscript received January against time. At higher exercise work loads, myocardial oxygen 26, 1995, acceptedFebruary 2, 1995. Address for corresnondence:Dr. Peter M. Okin, The New York Hospital- demand is directly proportional to heart rate (70,71,73,75), and Cornell Medical Center, 525 East 68th Street, New York, New York 10021. clinical observations suggest that the relation between ST

Figure 1. Calculation of the ST segment 300 depression/heart rate (STAIR) slope. Pro- gressive ST segment depression in lead 0 CM5 (shown as a positive magnitude on the vertical axis) is plotted against exer- / cise heart rate in a patient with three- 200 vessel coronary artery disease. This case 0 illustrates the linear relation "of ST seg- ST ment depression to heart rate as peak DEPRESSION exercise is approached. As a result, the (uv) lOO / slope of the line relating the final three data points by linear regression is higher 0 ..... ST/HR slope= 10.0 (r= 1.000, pelectrocardiography is tion. Two related but distinct methods of heart rate adjustment improved sensitivity for coronary disease, new tests must also of the magnitude of ST segment depression occurring during perform with high specificity in general populations. Accord- exercise have evolved: the linear regression-based ST segment/ ingly, an ST segment/heart rate slope partition of 2.4/zVfoeat heart rate slope and the simpler ST segment/heart rate index. per min with 95% specificity in clinically normal subjects The ST segment/heart rate slope is calculated from the maxi- correctly identified 90% of patients with nonanginal chest pain mal rate of change of ST depression relative to heart rate and a predictably lower 72% of patients with normal coronary during the period of active ischemia that accompanies end- arteries at catheterization (37). This criterion for identification exercise. The ST segment/heart rate index represents the of coronary disease was found to have a sensitivity of 95% in average change of ST depression relative to heart rate change our first series of patients at catheterization and also 95% in over the entire course of exercise, which therefore underesti- patients with stable angina, compared with only 68% for mates the maximal ST segment/heart rate slope because it standard criteria in these same subgroups (37). includes a large change in heart rate before any ischemia For assessment of the severity of coronary obstruction, occurs. Both of these methods specifically do not consider any perhaps for evaluation of potentially high risk symptomatic ST segment depression that occurs during the postexercise patients for coronary angiography, high test sensitivity is a recovery period (10,11,31,37,39). more critically important feature of test performance than is Regression-based ST segment/heart rate slope calculation. high specificity. An ST segment/heart rate slope partition of Accurate measurement of the ST segment/heart rate slope is 6.0/xV/beat per min, observed in early studies (10-12,27) to be determined by linear regression analysis to relate the measured at the upper range of values in patients with two-vessel disease amount of ST segment depression in each lead to the heart was found to identify 93% of patients with three-vessel or left rate at the end of each stage of exercise and at peak exercise main coronary artery disease, with a specificity of 57% (34), 1728 OKIN AND KLIGFIELD JACC Vol. 25, No. 7 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION June 1995:1726-35 thus providing a usefully sensitive, if imperfect, marker for ischemia at the level of the myocardial cell (62-67). This extensive obstruction in this important subgroup. relation remains proportional under conditions in which major SimpLe ST/HR index calculation. This simplification of the changes in gap junctional conductance do not occur (63-68). ST segment/heart rate slope method, which evolved from During exercise the severity of ischemia is directly propor- separate observations by Detrano et al. (20), is derived by tional to changes in myocardial oxygen demand (70,71), which dividing the maximal change in ST segment depression during in turn can be linearly related to increasing heart rate (AHR) exercise by the total change in heart rate from rest to peak (72-75). As an arithmetic consequence, the ratio AVm/AHR effort (20,33,37,42). An ST segment/heart rate index partition should remain constant when the changing severity of ischemia of 1.6 ~V/beat per rain with 95% specificity in clinically is equilibrated with changing heart rate (51) and under condi- normal subjects had a specificity of 88% in patients with tions in which changes in conductance are proportional or nonanginal chest pain but a specificity of only 61% in patients small: with normal coronary arteries at catheterization (37). The 93% and 88% sensitivity of this partition for identification of AST/AHR = (l)/4~r)(c), [21 coronary disease in our initial series of patients with catheter- where c = a new constant of proportionality (51). Thus, during ization-proved disease and patients with stable angina (37) was exercise-induced transient subendocardial ischemia due to similar to the 95% sensitivity of the ST segment/heart rate increased work load, the instantaneous ratio of changing ST slope and significantly greater than the 68% sensitivity of segment depression to changing heart rate should be directly standard criteria in these groups. However, for identification of proportional to the area of ischemic boundary when the three-vessel or left main coronary artery disease, an ST segment/ severity of ischemia is steadily related to progressive demand. heart rate index partition of 3.3 txV/beat per min, at a Further, this ratio should remain independent of the metabolic specificity of 57% matched to the ST segment/heart rate slope effects of ischemic severity on transmembrane potential differ- partition, identified anatomically severe disease with a sensi- ences across the ischemic boundary. The relations inherent in tivity of only 77%, a value between the 66% sensitivity of a equation 2 provide a strong theoretic basis for the practical markedly positive standard test and the 93% sensitivity of the application of heart rate adjustment to analysis of the ST ST segment/heart rate slope for this purpose (34). Thus, segment response to exercise, whereas equation 1 offers fur- the simple ST segment/heart rate index appeared to approach ther insight into the poor performance of traditional exercise the performance of the ST segment/heart rate slope for test criteria that are based solely on the magnitude and identification of coronary disease only, not for assessment of its configuration of ST segment depression (1-9,76-78), particu- anatomic severity. larly in the presence of limited effort tolerance or beta- adrenoceptor blockade (77-79). Of course, many factors relat- Theoretic and Experimental Background for ing to changing coronary flow might alter these relations (80-88). Heart Rate Adjustment of ST Segment Depression Experimental evidence (62-75) provides a theoretic frame- Clinical Applications of Heart work for a model that relates measured ST segment depression Rate Adjustment to heart rate during exercise (51). According to solid-angle Like standard exercise tolerance test criteria, the ST seg- theory (65), the magnitude of ST depression recorded at a ment/heart rate slope and ST segment/heart rate index can surface electrode (AST) can be related to the product of spatial each be applied to the identification of coronary obstruction and nonspatial determinants as defined by the following rela- and separately to the assessment of the anatomic and function: tional severity of disease (2,3,6,10-12,34,37). Test perfor- AST = (D./4~r)(AVm)K, [11 mance of each method and the performance of each method relative to standard test criteria will vary with these different where AST = magnitude of ST segment depression; 12 = solid major diagnostic purposes of exercise testing, so that the angle subtending the boundary of the ischemic territory; clinical application of the exercise tolerance test must be AVm = difference in transmembrane voltage between the considered in intertest comparison of these methods (2,6,7). ischemic and adjacent nonischemic regions; and K =- correc- Exercise testing for identificationof coronary artery dis- tion term for the differences in intracellular and extracellular ease. False positive and false negative responses of the heart conductivity and changes in gap junctional conductance (63- rate-adjusted methods are well recognized in selected popu- 67). As a consequence, during the transient ischemia associ- lations, which require further clarification, but both the ST ated with exercise, the magnitude of ST depression recorded segment/heart rate slope and the simple ST segment/heart rate by a surface electrode will be proportional to the area of index can improve the identification of coronary disease in ischemic territory subtended by the recording electrode (63- clinically relevant populations. In addition to early reports 69) and to the local transmembrane potential difference, which from Leeds (10-12), findings from Europe (15,16,26), Japan reflects the electrical consequences of the metabolic severity of (21) and several centers in the United States (19,37,41,46,50) JACC Vol. 25, No. 7 OKIN AND KLIGF1ELD 1729 June 1995:1726--35 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION

Table 1. Summary of Studies of ST Segment/Heart Rate Slope for Identification and Quantification of Coronary Artery Disease in Relation to Test Performance and Methodologic Variables No. of ST Segment Measurement ST Segment Measurement Method of ST Segment Study* Patients Point (ms) Precision (~V) Measurement Improved Performance: Identification of Disease Kardash et al. (12) 60 J + 80 10 Magnifying graticnle Sievanan et al. (26) 156 J + 60 NR Computer average Ameisen et al. (29) 135 J + 70 25 Magnifying graticule Ameisen et al. (30) 113 J + 70 25 Magnifying graticute Okin et al. (42) 130 J + 60 10 Computer average Okin and Kligfield (46) 254 J + 60 10 Computer average Improved Performance: Quantification of Disease Okin et al. (27) 50 J + 70 25 Magnifying graticule Okin et al. (34) 128 J + 60 10 Computer average Kligfield et al. (48) 172 J + 60 10 Computer average Improved Performance: Identification and Quantification of Disease Elamin et al. (10) 64 J + 80 10 Magnifying graticule Elamin et al. (11) 206 J + 80 10 Magnifying graticule Finkelhor et al. (19) 64 J + 80 NR Computer average Sato et al. (21) 142 J + 60 10 Computer average Kligfield et al. (37) 300 J + 60 10 Computer average

No Significant Improvement in Performance

Quyyumi et aL (53)t 78 J + 80 10 Magnifying graticule Balcon et al. (54)? 49 J + 80 10 Magnifying graticule Thwaites et al. (55) 60 J + 80 10 Magnifying graticule

*Numbers in parentheses are reference numbers, tProbably no improvement; no direct comparison made with standard ST depression criteria. NR = not reported. have demonstrated greater accuracy of the ST segment/heart when methodologic details are observed. Most studies of the rate slope than of standard ST segment depression criteria for regression-based ST segment/heart rate slope have demon- the detection of significant coronary obstruction (Table 1). strated improved accuracy for the detection of three-vessel Improved sensitivity of the ST segment/heart rate slope rela- coronary artery disease (Table 1) (10-12,15,16,19,21,27,34,48). tive to standard ST segment depression criteria has been most In addition, the ST segment/heart rate slope has been shown to evident among population groups in which false negative be more accurate than standard criteria for assessment of the standard test responses are common, including patients with anatomic extent of coronary obstruction as alternately defined anatomically modest disease (37) and those with submaximal by high Duke jeopardy scores (34,48) or Gensini scores effort tolerance and parallel submaximal heart rate increases (19,34,48). Further, as a functional consequence of extensive during exercise, a group in which exercise ECGs are frequently coronary obstruction, high ST segment/heart rate slopes have considered "nondiagnostic" because of limited effort toler- been found to correlate with large decreases in left ventricular ance. Additional value of the ST segment/heart rate slope for ejection fraction during exercise radionuclide cineangiography identification of coronary disease is highlighted by 1) similar (28). However, the ST segment/heart rate slope has not been test outcomes in patients with and without beta-adrenergic found to improve the exercise ECG assessment of disease blocking agents (12,48); 2) its ability to accurately detect severity in several studies (53-55) (Table 1), and the simple ST coronary disease among subjects with upsloping ST depression >1 mm (100/xV) (37) (frequently considered an "equivocal" segment/heart rate index does not appear to consistently test response); and 3) the similar performance of this method improve the exercise ECG identification of anatomically ex- in men and women (46). Improved accuracy for the detection tensive disease over standard criteria (Table 3). of coronary disease has also been found for the simple ST Exercise testing for prediction of cardiovascular risk. In a segment/heart rate index in most (20,24,25,35,37,42,46) but not totally nonreferred group of asymptomatic subjects within the all studies (56,57,59,61) (Table 2). Framingham offspring cohort (44), an abnormal ST segment/ Exercise testing for assessment of disease severity. Unlike heart rate index significantly concentrated the risk of future the heart rate-adjusted measures for simple identification of cardiovascular events. Improved risk stratification with heart coronary disease, the ST segment/heart rate slope and ST rate adjustment was independent of age, gender and multiple segment/heart rate index do not perform comparably with additional cardiac risk factors (44), but coronary event risk was respect to assessment of the anatomic severity of disease, even not significantly concentrated among subjects with a positive 1730 OKIN AND KLIGFIELD JACC Vol. 25, No. 7 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION June 1995:1726-35

Table 2. Summary of Studies of ST Segment/Heart Rate Index for Identification of Coronary Artery Disease in Relation to Test Performance and Methodologic Variables No. of ST Segment Measurement ST Segment Measurement Method of ST Segment Study* Patients Point (ms) Precision (~V) Measurement Improved Performance

Detrano et al. (20) 303 J + 80 10 Magnifying graticule Deckers et al. (22) 189 J + 80 NR Computer average Deckers et al. (23) 345 J + 80 NR Computer average Robert et at. (25) 135 J + 60 NR Computer average Kligfield et al. (37) 300 J + 60 10 Computer average Okin et ak (42) 130 J + 60 10 Computer average Okin and Kligfield (46) 254 J + 60 10 Computer average

No Significant Improvement in Performance

Lachterman et al. (56) 328 J point NR NR Herbert et al. (57) 200 J point NR NR Morise and Duval (59) 420 J + 80 NR Visual estimation *Numbers in parentheses are reference numbers. NR = not reported. test result according to standard ST segment depression crite- examined in context of the separate effects of methodologic ria. variables that are known to change the performance of exercise test criteria (Table 4). Effect of ST segment measurement timing. The timing of Relationship of Test Performance to ST segment depression measurement relative to the J point Methodologic Variability can have a profound effect on relative test performance of ST segment/heart rate slope and ST segment/heart rate standard and heart rate-adjusted ST depression criteria. index calculations are performed in our laboratory by a Traditionally, ST depression has been measured either at the computerized ECG system that measures ST segment depres- J point or 60 to 80 ms after the J point (2,7,13,14,17,23, sion below the isoelectric baseline to the nearest 10 txV at a 42,49,56,61). Performance of standard ST depression criteria point 60 ms after the J point from a 12-lead recording system will vary with the timing of ST segment measurement relative modified by the addition of bipolar lead CM5 (excluding leads to the J point, but measurements made at 60 ms after the J aVR, aVL and V1 from all analyses), with exercise according to point have generally outperformed J-point measurements for the Cornell protocol. These methodologic details are required the identification of coronary disease (13,14,17,23,42,49). Per- for test accuracy, but they have also been an important formance characteristics of both the ST segment/heart rate limitation to test application where traditional protocols and slope and ST segment/heart rate index are also optimized when measurement procedures are standard practice. Seemingly ST segment depression is measured precisely at 60 ms after the small variations of these details can have large effects on test J point (42). Use of J-point measurements reduces perfor- outcome. Therefore, the relative performance of standard and mance of heart rate-adjusted criteria to the level of standard heart rate-adjusted criteria among different studies must be test criteria (42). These findings provide a partial, reasonable

Table 3. Summaryof Studies of ST Segment/Heart Rate Index for Identificationof AnatomicallySevere CoronaryArtery Disease in Relation to Test Performance and MethodologicVariables No. of ST Segment Measurement ST Segment Measurement Method of ST Segment Study* Patients Point (ms) Precision (~V) Measurement Improved Performance

Detrano et al. (20) 303 J + 80 10 Magnifying graticule Watanabe et al. (24) 42 J + 80 10 Magnifying glass No Significant Improvement in Performance

Okin et al. (34) 128 J + 60 10 Computer average Kligfietd et al. (48) 172 J + 60 10 Computer average Lachterman et al. (56) 328 J point NR NR Herbert et al. (57) 454 J point NR NR Bobbio et al. (60) 2,270 . J + 80 NR NR *Numbers in parentheses are reference numbers. NR = not reported. JACC Vol. 25, No. 7 OKIN AND KLIGFIELD 1731 June 1995:1726-35 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION

Table 4. MethodologicFactors AffectingPerformance of Heart been found to be reduced when fewer than the standard Rate-Adjusted ST Segment Depression Criteria and Recommended 12-leads plus lead CM5 are used, whereas the relative differ- Methodologic Criteria ence in performance between standard and heart rate- Recommended Metbodotogic adjusted criteria appears to narrow with the use of fewer ECG Methodologic Factors Criteria leads (38). These considerations provide an additional expla- 1. Timing of ST segment depression 1. 60 ms after the J point nation for the smaller difference in test accuracy found be- measurement relative to the J tween the ST segment/heart rate index and standard test point criteria when alternative leads are used for heart rate-adjusted 2. Precision and accuracy of ST 2. Accurate computer measurement analyses (59). Further investigation is required to establish the segment measurement to the nearest 10/xV 3. Definition of measurement 3. Measurement of ST segment contribution of specific leads to test performance and the value baseline deviation below the isoelectric of lead-specific criteria during exercise testing. baseline Effect of exercise protocol. Differences in the type of 4. Number and location of 4. Use of standard 12-leads and exercise test protocol used can also have a profound effect on electrocardiographic leads bipolar lead CMs, with exclusion accuracy of the ST segment/heart rate slope (31,32,38). Calcu- of leads aVR, aVL and V 1 from all analyses lation of the ST segment/heart rate slope is highly dependent 5. Exercise protocol 5. Cornell modification of the on small heart rate increments between exercise stages, which Bruce protocol ensures detection of the maximal rate of ST segment depres- 6. Method of heart rate correction 6. ST/HR slope sion as a function of heart rate that occurs during peak (ST/HR slope vs. ST/HR index) exercise-related ischemia (10,11,31,38). Because the average ST/HR = ST segment/heart rate. change in heart rate between stages of the Cornell protocol is 10 beats/min (32), whereas heart rate increments between stages of the Bruce protocol are two to three times larger (38), explanation for reduced accuracy of the ST segment/heart rate test accuracy of the ST segment/heart rate slope decreases, and index that has been reported when J-point measurements of in many instances the ST segment/heart rate slope may not be ST segment depression are used (Table 2) (56,61). calculable when patients exercise according to the Bruce Effects of ST segment measurement precision. In addition protocol (33,38). These factors may in part explain the rela- to the timing of ST segment measurement, precision of tively lower test accuracy of the ST segment/heart rate slope in measurement can have a significant effect on the relative at least one early study (55). Other exercise protocols that performance of standard and heart rate-adjusted ST segment produce a graded heart rate response to exercise (89-91) criteria (43). Because heart rate-adjusted criteria are calcu- might also allow accurate calculation of the ST segment/heart lated as continuous variables, even small differences in the rate slope, but this must be validated because exercise test measured magnitude of ST depression can change test out- performance can vary when different treadmill methods are come (31,37), particularly when the amount of ST depression used (31,32,38). is small. In contrast, standard exercise ECG criteria traditionally are interpreted as discrete variables, so that precise measurement of ST depression when it is <100/xV (1.0 ram) Relation of Test Performance to has no consequence for the routine definition of test outcome (31,37). Because much of the improvement in test sensitivity Population Selection offered by heart rate-adjusted criteria is found in their ability Beyond issues of methodologic variability, population se- to accurately identify coronary disease in patients with lection can have separate and important effects on the relative <100/xV of ST depression (37,42,44), less precise measure- sensitivity and specificity of exercise ECG criteria (50,92-95). ment or visual underestimation of the magnitude of ST de- As a consequence, exercise test performance must be related pression in these patients would be expected to lower test to and adjusted for the populations in which criteria are accuracy. Indeed, it can be shown that use of ST segment defined and in whom the test is to be used (50,92-94). It is measurements less precise than 10/xV can reduce sensitivity of unlikely that normalization of ST segment depression by heart the simple ST segment/heart rate index for detection of rate alone should completely eliminate inaccurate exercise test coronary artery disease by as much as 10% (43). These findings findings in groups characterized by the occurrence of marked suggest possible additional methodologic explanation for the repolarization abnormalities that are known to be dispropor- reduced relative performance of the ST segment/heart rate tionate to the presence or extent of coronary obstruction. index in some studies (Tables 2 and 3). Thus, because factors other than discrete coronary obstruction, Effect of lead selection and lead number. Differences in the such as exercise-provoked epicardial vasoconstriction (87), as number and position of ECG leads used can also affect the well as valvular and myopathic heart disease, can result in accuracy of both standard and heart rate-adjusted ST depres- exercise-induced subendocardial ischemia and ST segment sion criteria (1,38,77). In concordance with these observations, depression, false positive ST segment/heart rate slope and ST performance of both ST segment/heart rate slope and ST segment/heart rate index values in the absence of coronary segment/heart rate index for detection of coronary disease has disease are predictable in these patients (29,96). 1732 OKIN AND KLIGFIELD JACC Vol. 25, No. 7 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION June 1995:1726-35

Counterclockwise Clockwise Rate-Recovery Loop Rate-Recovery Loop 500- Coronary Artery Disease Clinical Normal Figure2. ST segment deviation as a function of heart rate during exercise and recovery, with ST segment depression shown in the upward direction and ST 200 segment elevation shown in the downward direction. ST Typical rate-recovery loops are shown for a clinically DEPRESSION normal subject (right) and a patient with coronary (uv) 100. artery disease (left). Despite a greater magnitude of ST segment depression at peak exercise in the clini- / • •--• Exercise cally normal subject, there is a clockwisepattern of ST i-• 0 0 segment depression relative to heart rate during recov- 0I•/ O--OR ...... y \ / O ery; the patient with coronarydisease has the opposite, 1O0 counterclockwise pattern of recovery, bpm = beats/ 50 100 150 200 50 100 150 200 min. HEART RATE (bpm)

Similarly, false negative ST segment/heart rate slope values commonly exhibit a counterclockwise loop of ST depression as also are predictable where ST segment depression is minimal a function of heart rate (39). The rate-recovery loop improves or entirely absent with exercise, such as often occurs after sensitivity of the exercise ECG for the detection of coronary recent Q wave myocardial infarction (29,30,97-99). Additional artery disease with no loss in specificity compared with that for factors that can affect the relative performance of heart standard ST segment depression criteria (39). In contrast to rate-adjusted and standard methods are the extent of coronary standard ST depression criteria and heart rate-adjusted crite- disease in the study population (37) and the proportion of ria that are derived from exercise phase data alone, sensitivity patients studied while receiving beta-blockers (48). The recog- of the rate-recovery loop appears to be relatively independent nition of patients and populations in whom unreliably predic- of the extent of coronary artery disease (39). Alone and in tive ST segment/heart rate slope and ST segment/heart rate combination with the ST segment/heart rate index, the rate- index responses may occur is of importance because incorpo- recovery loop can improve the prediction of future cardiovas- ration of such patients in evaluation of these methods may lead cular risk over that with standard ST depression criteria (44). to biased interpretations of potential test accuracy and may explain some of the early discordant observations of ST segment/heart rate slope usefulness (Table 1). Clinical Implications and Future Directions Heart Rate Adjustment in the Postexercise The limitations of exercise electrocardiography require Recovery Period reevaluation and reconsideration. We suggest that sensitivity Additional applications of heart rate adjustment of ST and specificity of the exercise tolerance test can be increased in segment depression can be found in the Hollenberg treadmill clinically important populations by the ST segment/heart rate exercise score (5,100) and the rate-recovery loop (39,44). Both slope and ST segment/heart rate index when careful attention of these methods incorporate work load or heart rate into an is paid to the methodologic criteria that have been found to evaluation of the ST segment response to exercise that extends influence test performance. At the same time, simple demon- into the postexercise recovery phase. The Hollenberg method stration of imperfection of these methods does not obviate has been shown (5) to improve sensitivity of the exercise ECG their value within clinically relevant, context-sensitive diagnos- for detection and quantification of coronary disease and to tic strategies. The selected populations in which the heart improve specificity when screening healthy young men (100). rate-adjusted methods have been derived and tested to date Analysis of the behavior of ST segment depression as a represent only a segment of the possible clinical populations in function of heart rate during both exercise and recovery using which exercise testing can be applied, and it is clear that new the rate-recovery loop (39,44) provides additional insight into test criteria must be developed and test performance examined the value of heart rate adjustment of ST depression. Physio- in the precise population subgroups in which the test will be logic correlates of rate-rec6very loop patterns can be found in used (50,92-95). As a consequence, application of these crite- earlier observations that compared myocardial ischemia during ria requires further evaluation in other important subsets of exercise and recovery (76,101-103). Rate-recovery loops are patients who frequently undergo exercise testing, such as those constructed by plotting ST segment deviation with reference to with atypical angina or nonanginal chest pain syndromes. changing heart rate throughout treadmill exercise and recovery Additional areas of test applicability that require further (Fig. 2). Normal subjects typically exhibit a clockwise loop of clarification include the modulating effects of drugs, circulating ST depression as a function of heart rate during exercise and hormones and additional forms of noncoronary heart disease recovery, whereas patients with coronary artery disease most on the heart rate-adjusted methods and criteria. JACC Vol. 25, No. 7 OKIN AND KLIGFIELD 1733 June 1995:1726-35 HEART RATE ADJUSTMENT OF ST SEGMENT DEPRESSION

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