unreliability of exercise-induced r wave changes as indexes of coronary artery disease

Unreliability of Exercise-Induced R Wave Changes as

Indexes of Coronary Artery Disease

STEPHEN WAGNER, MD, FACC

KEITH COHN, MD, FACC

ARTHUR SELZER, MD, FACC

San Francisco. California

From the Division of Cardiology, Presbyterian Hospital of Pacific Medical Center, San Francisco, California. Manuscript received May 1, 1979; re- vised manuscript received June 26, 1979, ac- cepted July 1, 1979.

Address for reprints: Arthur Seizer, MD, Division of Cardiology, Presbyterian Hospital, Box 7999, San Francisco, California 94120.

To investigate the diagnostic value of exercise-related QRS amplitude changes, the responses of 40 young normal subjects and 28 patients with &hest pain and no significant coronary arterial obstruction were compared with those of 73 patients with coronary arterial narrowing of various de- grees of severity. All underwent submaximal, multiple lead multistaged treadmill exercise testing. The combined normal group showed an average decrease in R wave amplitude between rest and exercise of 1.1 f 2.8 mm (mean f standard deviation) in lead V6; those with coronary artery dis- ease had an increase of 0.6 f 3.4 mm (P = 0.001). Similar but less pro- nounced differences were observed in lead II (a decrease of 1.9 f 2.3 mm in normal subjects versus a decrease of 0.5 f 3.1 mm in those with coronary disease, P = 0.01). When derived R wave criteria were used, the test sensitivity averaged 52 percent and the specificity 63 percent; these values were inferior to the sensitivity of 88 percent and specificity of 72 percent of S-T segment criteria in the same group of patients. No significant relation was found between the extent of coronary artery disease and R wave changes, and an analysis of multiple variables sug- gested possible correlation6 with factors not directly related to ischemia. It is concluded that exercise-induced QRS amplitude change6 are unre- liable predictors of the presence, absence or severity of coronary artery disease.

It has recently been suggested that exercise-related changes in QRS amplitude can be used to provide better discrimination between persons with and without significant coronary artery disease. This study was undertaken to test that hypothesis and to examine the variables that might influence the reversible exercise-induced QRS changes.

Methods

Study group: Group IA consisted of 40 healthy volunteers, 29 men and 11 women with an average age of 30 years, who had no known disease, were taking no cardiac medications, and had normal electrocardiograms at rest and during exercise. They underwent treadmill exercise tests to at least 90 percent of pre- dicted maximal heart rate, achieving a mean peak heart rate of 185 beats/min and exercised for a total mean duration of 11 minutes and 13 seconds.

A “patient”group included 101 persons selected from 250 consecutive patients who were referred to Pacific Medical Center with suspected coronary artery disease between February 1975 and November 1978 and who underwent multiple lead treadmill stress testing and selective coronary angiography performed less than 5 months apart. Of these 101 patients, 28 (Group IR) had no significant coronary arterial obstruction, The mean age of the group was 47 years; 17 were men and 11 women and the average age was 47 years. They achieved a mean peak heart rate of 166 beats/min and exercised for a mean duration of 7 minutes, 26 seconds.

Group II included 73 patients, 63 men and 10 women with an average age of 53 years, who had significant coronary arterial narrowing. They achieved a mean

December 1979 The American Journal of CARDIOLOGY Volume 44 1241

EXERCISE-INDUCED R WAVE CHANGES-WAGNER ET AL.

peak heart rate of 139 beats/min and exercised for a mean duration of 6 minutes. Twenty-six patients had evidence of a prior infarction in the electrocardiogram at rest. Thirty of the 73 had single vessel, 24 had double vessel and 14 had triple vessel disease, and 5 had left main coronary stenosis.

Exercise testing: Graded multistaged treadmill exercise testing was performed using a modified Bruce’ protocol. Ex- ercise was continued until diagnostic S-T depression occurred or the patient reached 90 percent or greater of the age- and sex-predicted maximal heart rate or had limiting signs or symptoms. A satisfactory test for inclusion in the study group required either a positive response (1 mm or greater horizontal or downsloping S-T segment depression 0.08 second after the J point) or achievement of the target heart rate. Nine patients were included who exercised maximally but had uninterpre- table S-T changes. No patients were taking a digitalis prep- aration or had left bundle branch block. A 12 lead electro- cardiogram was taken with the patient at rest in the supine and standing positions. Leads II, Vi and V5 (see Appendix) were monitored in the standing position during hyperventi- lation and exercise and in the seated position immediately after exercise and 30 seconds and 1, 2, 3, 6 and 9 minutes during recovery.

QRS analysis: The height of the R wave and depth of the S wave were measured in millimeters (1 mm = 0.1 millivolt) using the isoelectric line as a reference. Values were obtained by averaging up to 20 consecutive QRS complexes in an at- tempt to minimize the sometimes marked respiratory varia- tions. Measurements were made without knowledge of the angiographic findings. R and S wave amplitudes were mea- sured in leads II and Vs; lead Vi was not quantitated because of excessive respiratory variation. To eliminate the influence of change in body position,2 we compared values during rest

- Normal

o--o Coronary Artery Disease R-Wave

(mm) * p7.05

+1 0

Lead Vs- 1

32 S-Wave

(mm)

I

Rest Hyper- Exer- Recov- Recov- venti- cise ery lation (End) (Onset)

ery (End)

FIGURE 1. Comparison of R and S wave amplitude changes with ex- ercise in leads II and Vs in normal subjects and patients with coronary artery disease. Asterisk indicates a statistically significant mean de- viation from the value at rest. p = probability.

and exercise using the values obtained during standing rest and peak exercise.

Angiography: Selective coronary angiography was per- formed using the Judkins or Sones technique, and biplane left ventriculography was performed in the routine manner. The results were interpreted independently by experienced cardiac radiologists. A significant obstruction was defined as an es- timated 70 percent or greater internal diameter narrowing of at least one coronary artery or a major branch; only two pa- tients had as their only disease arterial narrowing of more than 50 and less than 70 percent. Left ventricular motion was judged abnormal if segmental or diffuse hypokinesia was noted.

Statistical analysis: Multiple variables were analyzed by computer using the SPSS program.” Mean changes in the R and S waves at rest and exercise were compared between groups using the paired two-tailed Student’s t test.4 Proba- bility (P) value of 10.05 was considered significant. Variables such as age were correlated with the QRS response on exercise and correlation coefficients were calculated and expressed as r values.

Results

QRS response to exercise in normal subjects: The healthy volunteers (Group IA) were younger and exer- cised to a higher heart rate for a longer duration (all differences significant at P <O.OOl) than did those in Group IB with no or insignificant coronary arterial narrowing. However, there were no statistically signif- icant differences between the groups in QRS amplitudes at rest or in exercise-related changes in R or S waves and therefore the data were pooled to compose a single normal group of 68 subjects.

Figure 1 depicts the sequence of R and S wave alter- ations during the exercise protocol. In normal subjects there is a significant decrease in R wave height and an increase in S wave depth at peak exercise and onset of recovery with a return to near baseline at end re- covery.

QRS response to exercise in the group with cor- onary artery disease: The R wave response in this group was blunted, the only significant average devia- tion from baseline occurring in lead V5 at end recovery (Fig. 1). The S wave increased with exercise in both the normal subjects and those with coronary artery disease. Table I indicates the magnitude of the differences be-

TABLE I

Average Exercise Change in R and S Wave in Normal Subjects Compared With Patients With Coronary Artery Disease (mean f standard deviation)

R wave (mm) Lead II Lead Vs

Normal CAD (no. = 68) (no. = 72)

-1.9 f 2.3 -0.5 f 3.1 -1.1 f 2.8 0.6 f 3.4

P Value”

0.025 0.001

S wave (mm) Lead II Lead Vs

1.5 f 1.4 0.7 f 1.6 0.01 2.5 f 1.7 2.3 f 1.8 NS

l Probability value for difference between mean changes in normal subjects and patients with coronary artery disease subtracting values at standing rest with those during standing exercise.

CAD = coronary artery disease; NS = not significant.

1242 December 1979 The American Journal of CARDIOLOGY Volume 44

tween the resting and exercise values in the normal versus abnormal groups.

To determine if more severe coronary disease was associated with a more dramatic R wave response, subsets of patients in Group II were chosen to compare the milder versus more severe indexes of coronary artery disease (Table II). In no instance was there a statisti- cally significant difference in average R wave change with exercise either between the pairs of subsets or be- tween any individual group compared with the entire group with coronary artery disease.

Use of R wave criteria to predict coronary artery disease: Figure 2 displays the considerable overlap of the R wave responses to exercise in the normal group and patients with coronary artery disease. The deter- mination of the line separating a normal from an ab- normal response is arbitrary; it can be seen that a cri- terion chosen to reduce false positive results will result in a relatively greater number of false negative results. In Table III two different R wave criteria are compared with the accuracy of S-T segment criteria in diagnosing coronary artery disease in patients in Groups IB and II, all those who underwent coronary angiography. The relatively low specificity of the S-T segment criteria is explained by the high prevalence rate (72 percent) of coronary artery disease in the combined group and by the existence in Group IB of some patients who were referred for angiography because of atypical chest pain and electrocardiographic abnormalities at rest; such patients tend to have a high rate of false positive results. However, the overall diagnostic accuracy was clearly enhanced using S-T rather than R wave criteria for ischemia.

A further comparison is seen in Table IV. Of the true positive responders as judged using S-T criteria, only

TABLE II

Response of R Wave During Exercise in Subsets of Patients With Coronary Artery Disease

Group II (coronary artery disease)

Single vessel disease versus

Triple vessel or main left disease

Cases AR Amplitude (mm) (no.) Lead II Lead Vs

73 -0.5 0.6

26 -1.1 1.0

19 -0.3 0.7

Normal left ventriculogram versus

Abnormal ventriculogram

No chest pain with exercise

versus Chest pain

No S-T changes on treadmill (false negative)

versus lschemic S-T changes

(true positive)

34 -1.1 0.8

39 0.1 0.5

26 -0.6 0.5

47 -0.2 0.7

8 -0.8 0.5

58 -0.3 0.8

AR. II, Vs = average R wave difference in millimeters between values at rest and during exercise in lead II and lead Vs.

EXERCISE-INDUCED R WAVE CHANGES-WAGNER ET AL.

NORMAL C.A.D. f I

1 +12

10 8 6 i

.

:.. . . . . . -::..---__---_

. . . ( y:*e

:. .

2 4. .g +2

= 0 -: . . . .._ __ _---_

n

i

. . . . . . . . . . . .

2 -2 . . . . . . . . .

2 4 l *

61 l *

+12 10 a

1 6 l

-2 ‘i E.2 >” 0 i ‘D 4 -2 f 4 1

6

a -10

I

: . . . . . . . . . . . . . . . . - . . . . . . . . . . . . . . . . . . . . g:,‘:::..

::*“’ j’

.

I

.

FIGURE 2. Frequency distribution of exercise-induced R wave amplitude changes in normal subjects and patients with coronary artery disease (C.A.D.).

69 percent had a positive response with use of the op- timal R wave criterion; of the 18 true negative re- sponders with S-T criteria only 44 percent had a nega- tive response with the R wave criterion. Three of the seven false positive responders with S-T criteria were correctly classified as having a negative response using the R wave criterion. Use of the R wave response ap- peared to improve diagnosis only in the eight patients with coronary artery disease who had no ischemic S-T

TABLE III

Test Accuracy* of R Wave and S-T Segment Criteria for Diagnosing lschemia in Patients Undergoing Coronary Angiography (groups IB and II)

Sensi- tivity (%)

Speci- ficity (%)

Predictive Accuracy Correct

of Classifi- Positive cation

Test Rate (%) (%)

R wave criteria Lead II

R <O z: 80 51 R 10 92 46

Lead Vs R <0 68 46 77 62 R 10

S-T seoment criteria z 61 72 ;9” 8”:

* For definition of terms see Appendix. R <0 = normal response defined as R wave decrease with exercise:

R 50 = normal response defined as R wave that remains unchanged or decreases with exercise: S-T segment criteria = responses de- scribed in Methods section.

December 1979 The American Journal of CARDIOLOGY Volume 44 1243

~xmc~sum~cm R WAVE CHANGE-WAGNER ET AL

TABLE IV

Comparison of Diagnostic Accuracy of S-T Segment Criteria Versus Optimal R Wave Criterion for lschemia in Groups IB and II

Classification Based on Exercise

S-T Segment Classification Based on Response Exercise R Wave Response’

True positive Positive (correct) 40of58(69%) (no. = 58) Negative (incorrect) 18of58(31%)

True negative Negative (correct) 8 of 18 (44%) (no. = 18) Positive (incorrect) 10 of 18 (56%)

False positive Negative (correct) 3of7(43%) (no. = 7) Positive (incorrect) 4 of 7 (57%)

decrease or actually increased in 9 to 61 percent of’

normal subjects. The factors hypothesized or shown to influence reversible QRS voltage changes include:

1. Cardiac position and QRS axis shifts. The change during exercise in the anatomic or electric position of the heart, with respect to the recording electrode may affect QRS voltage.Cj~aJ’18 An increase in the depth of the S wave in lead Vs suggests a rightward and posterior axis shift, and such shifts have been associated with a decrease in R wave voltage in the lateral precordial leads.‘”

2. Intracardiac blood volume. The phenomenon often referred to as the “Brody effect”2oJl postulates a positive correlation between ventricular blood volume and the magnitude of the dominant QRS forces.“‘-“* It remains to be proved that important R wave amplitude changes during exercise are related to this theory, which is based on a hypothetical model.

3. Ventricular performance. QRS voltage may be influenced as a result of alterations in end-diastolic volume”” through the Brody effect or, as other investi- gators have suggested,“eJ7 increased contractility in itself may alter QRS voltage. This hypothesis is also unproved.

Role of ischemia: Myocardial ischemia has not been shown to have a direct, reversible influence on QRS magnitude with the exception of the precipitous in- crease in the R wave and loss of the S wave seen when severe ischemia produces the “variant angina” ef- fect.‘sJY No cases of variant angina were encountered in our study group.

Recent reports have suggested that patients with coronary artery disease may manifest an abnormal R wave response to exercise, namely an increase rather than a decrease. Some investigators’ 1~1:1~30~3i have suggested that use of this deviation enhances the diag- nostic value of stress testing, although other investiga- tors have found the R wave changes less predictable. Most investigators speculated that the exercise-induced increase in voltage, when present, was related to isch- emia-precipitated subnormal ventricular function al- though one group :I8 found, as we did, no correlation between left ventricular function and changes in QRS voltage during exercise. Reversible disturbances of left ventricular function can occur in patients with coronary artery disease in the form of ischemia-induced seg- mental wall motion abnormality with elevation of left ventricular pressure. If the R wave amplitude changes are related to left ventricular ischemia one would expect a close relation between these changes and the isch- emia-precipitated S-T segment abnormalities. One might, in addition, expect the development and mag- nitude of R wave changes to correlate with the extent of coronary artery disease. Neither circumstance oc- curred in our study. Finally, it should be emphasized that reversible exercise-induced abnormalities of left ventricular performance are not specific for coronary artery disease; therefore, secondary R wave voltage changes, if present, would similarly not be expected to

False negative Positive (correct) 6 of 8 (75%) (no. = 8) Negative (incorrect) 2 of 8 (25%)

* lschemic response defined as R wave in lead Vs that remains un- changed or increases with exercise.

depression with exercise; six of these eight had a positive R wave response. It is unlikely that this finding reflects an increased sensitivity of R wave change in detecting ischemia because all eight patients had the mildest degree of disease (single vessel) and, as noted previously, the overall sensitivity of S-T criteria for diagnosing ischemia greatly exceeded that of R wave criteria.

Regression analysis: To determine if variables other than those relating directly to coronary artery disease influenced exercise-related QRS changes, age, peak heart rate, duration of exercise and R wave height at rest were plotted against the changes in R and S wave am- plitudes with exercise (AR, AS). No comment can be made about the QRS response to lower levels of exercise in normal subjects because only peak exercise values were measured in this group.

In the normal subjects, suggestive, although non- statistically significant, correlations were noted: peak heart rate versus AR (r = -0.4), duration of exercise versus AR (r = -0.3). In patients with coronary artery disease no relation could be demonstrated between variables of exercise performance (heart rate and du- ration of exercise) and the R wave change with exercise despite the broad range of peak heart rates (90 to 190 beats/min) and total duration of exercise (1 minute, 20 seconds to 10 minutes, 45 seconds) in this group. When the entire study group was examined, age was not found to relate to AR or AS although the baseline height of the R wave correlated with the exercise change in R wave: the taller the resting amplitude the greater the decrease with exercise (r = -0.5).

Discussion

Factors influencing QRS amplitude changes after exercise: Reversible exercise-related changes in QRS amplitude have previously been described”p1° and include, as we found, a decrease in the height of the R wave in leads X, Y and Vs and an increase in the depth of the S wave. However, considerable variability exists, and in reported series,leml* the R wave either failed to

1244 December 1979 The American Journal of CARDIOLOGY Volume 44

EXERCISE-INDUCED R WAVE CHANGES-WAGNER ET AL.

be specific. We are unable to comment further on this latter point because patients with other forms of cardiac disease are not ordinarily subject to submaximal stress tests at our institution.

The interpretation of our results permits the fol- lowing points to be made: (1) When inferior and lateral leads are used, the mean values of R wave amplitude change with exercise show a significant difference be- tween normal subjects and persons with coronary artery disease, but there is considerable overlap between the groups. The S wave depth increased with exercise in both groups and was not a helpful discriminator. (2) We and other investigators not only found R wave changes-claimed to be characteristic of coronary artery disease-in normal subjects, but also that the changes occurred as well with frequency in the false positive and false negative stress test responders using S-T criteria. (3) We found no significant relation between R wave changes and the extent of coronary arterial obstruction. (4) Variables such as body position, R wave amplitude at rest, axis shift, hyperventilation, heart rate and du- ration of exercise probably have some influence on ex- ercise-related QRS amplitude changes and thus com- plicate attempts to separate groups solely on the basis of ischemia or left ventricular performance.

Clinical implications: The mechanisms for QRS amplitude changes with exercise are mutlifactorial and these QRS changes have little or no clinical value in predicting the presence, absence or severity of coronary artery disease in an individual patient. The variations in amplitude are small (approximately 1 to 2 mm), te- dious and technically difficult to measure and are likely to be induced by other forms of cardiac disease and to be influenced by factors unrelated to cardiac disease. We suggest that these criteria be discarded for diag- nostic exercise testing.

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2.

3.

4.

5.

6.

APPENDIX

Electrode Lead Placement

Two different lead systems were used during the study period. Sixty subjects were monitored using a modified Mason-Likar system with electrodes at the right and left shoulders, adjacent to the right and left anterior iliac crests and at the standard precordial positions. Eighty-one subjects were monitored using an “orthogonal” three lead system with leads VI (anterior-posterior), VF, (right-left), and II (supe- rior-inferior). Although mean baseline R wave magnitude differed slightly between the two systems there were no sta- tistically significant differences in exercise-related QRS changes between them. Moreover, when standard S-T criteria for ischemia were used, virtually identical sensitivity, speci- ficity and predictive accuracy were obtained. For these reasons the data from patients monitored by the two lead systems were pooled.

Definitions of Test Accuracy

Sensitivity = True positive

True positive + False negative .

Specificity = True negative

True negative + False positive ’

Predictive accuracy of positive test

= True positive

True positive + False positive .

Correct classification rate

True positive + True negative = True positive f True negative + False positive +

False negative.

Acknowledgment

We thank Andrea Fox for assistance in the preparation of this manuscript.

References

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