Comparison of chest pain, electrocardiographic changes and thallium-201 scintigraphy during varying exercise intensities in men with stable angina pectoris

Comparison of chest pain, electrocardiographic changes and thallium-201 scintigraphy during varying exercise intensities in men with stable angina pectoris

The CORONARY ARTERY DISEASE 1 American Journal SEPTEMBER1, 1991,VOL. 68, NO. 6 of cardiology Comparison of Chest Pain, Electrocardiographic C...

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American Journal

SEPTEMBER1, 1991,VOL. 68, NO. 6



Comparison of Chest Pain, Electrocardiographic Changes and Thallium-201 Scintigraphy During Varying Exercise Intensities in Men with Stable Angina Pectoris Gary V. Heller, MD, PhD, lmtiaz Ahmed, MD, Peter L. Tilkemeier, MD, Marilyn M. Barbour, PharmD, and Carol Ewing Garber, PhD

This study was performed to evaluate the presence of angina pectoris, electrocardiographic changes and reversible thallium-201 defects resulting from 2 different levels of exercise in 19 patients with known coronary artery disease and evidence of exercise-induced ischemia. The exercise protocols consisted of a symptom-limited incremental exercise test (Bruce protocol) followed within 3 to 14 days by a submaximal, steady-state exercise test performed at 70% of the maximal heart rate achieved during the Bruce protocol. The presence and time of onset of angina and electrocardiographic changes (20.1 mV ST-segment depression) as well as oxygen uptake, exercise duration and pressurerate product were recorded. Thallium-201 (2.5 to 3.0 mCi) was injected during the last minute of exercise durlng both protocols, and the images were analyzed using both computer-assisted quantitation and visual interpretations. Incremental exercise resulted in angina1 symptoms in 64% of patients, and electrocardiographic changes and reversible thallium-201 defects in all patients. In contrast, submaximal exercise produced angina1 symptoms in only 26% (p
cant). The locations of the thallium-201 defects, when present, were not different between the 2 exercise protocols. These findings confirm the sequence of the ischemic cascade using 2 levels of exercise and demonstrate that the cascade theory is applicable during varying ischemic intensities in the same patient. (Am J Cardiol 1991;68:569-574)

he temporal sequenceof myocardial ischemia is thought to be initiated by alterations in blood flow or increased myocardial oxygen demand, or both, followed by dysfunction of the myocardium, electrocardiographic ST abnormalities, and finally angina pectoris.l-3 This sequence,termed the “ischemic cascade,”has led someinvestigators to proposethat silent myocardial ischemia occurs in situations in which the ischemic insult is not sufficient to causeangina pectoris.4 Data supporting this model of ischemia have been obtained under conditions in which the individual events of the sequencecan be separately observed by altering the severity and duration of the ischemia.1J,6 Whereasthesestudieshave establishedthe sequence of myocardial responsesduring 1 ischemic challenge, little information is available regarding the effects of varying physiologic conditions on the ischemic cascade. A recent study from our laboratory examined the relation between electrocardiographic changes and angina under markedly different exercise intensities in 33 patients with provocable ischemia.7This study found that a lower work load yielded far lessangina despitecontinued electrocardiographic changesin patients. Although previous studieshave demonstratedthe effects of exercise intensity on clinical features of ischemia, little information regarding myocardial function or blood flow distribution is available. Thallium-201





imaging has been used as a marker of coronary blood flow that can identify both the presenceand degree of ischemia.s-10The present study was performed using thallium-201 imaging to evaluate the eventsof the ischemit cascade during varying levels of myocardial demand using both incremental and submaximal, steadystate exercise. METHODS Patients: All male patients referred for exercise thallium-201 studies at the Memorial Hospital of Rhode Island during a 2-year period were screenedfor inclusion in this study. Entry criteria included angina1 symptoms during symptom-limited exercise testing, positive electrocardiographic response (horizontal or downsloping ST segment depression LO.1 mV), a reversible thallium-20 1 defect, previous angina pectoris, and consent to participate. Patients with conduction defects or left ventricular hypertrophy on the electrocardiogram at rest, those receiving digoxin or other medications, or electrocardiographic changes at rest that precluded electrocardiographic interpretation were not included in the study. Coronary artery bypassgraft surgery at any time, percutaneous transluminal coronary angioplasty or myocardial infarction during the interval between the identifying exercisetest and the completion of the research protocol were also exclusion criteria. Women were excluded becauseso few were able to meet entry criteria from our laboratory. Procedures: EXERCISE TESTING: After giving informed consent,the subjectscompleted 2 exercisetests. An incremental exercisetest was administered first, followed 3 to 14 days later by a 20-minute submaximal steady-stateexercisetest. Both tests were performed in the fasting state and at the same time of day. The patients continued their prescribedcardiac medicationson the days of testing and no medication changes were made in the interval between the 2 tests. The incremental exercise test was symptom-limited using a standard Bruce protocol on a Marquette series 1800 treadmill. l l Test termination criteria included ST segment depression 20.3 mV, progressiveangina pectoris, volitional fatigue or other reasonsto stop according to standard criteria.” The submaximal, steady-state test was performed on the same treadmill at a work load that elicited a heart rate of 70% of the peak heart rate (f 5 beats/ min) attained during the incremental exercisetest. This work load was determined by estimating the treadmill speedwithout grade which approximated the MET level at this heart rate during the incremental protocol. The submaximal test began at this work load with adjustments in speed or addition of a slight grade (2 to 4%) made as necessaryduring the first 3 minutes in 570


order to attain the target heart rate. The subject walked at this work load for 20 minutes unless there was a reasonto stop according to the previously describedtest termination criteria. i * Interpretation of the exercisetests was performed in a blinded fashion at the completion of the study. Interpreters included 2 members of the study team as well as a cardiologist not associatedwith the study. PHYSIOLOGICMEASUREMENTS: The electrocardiogram, heart rate, blood pressure,oxygen uptake and ratings of angina1pain (scale of 1 to 4 intensity) were monitored and the pressure-rate product was calculated during both tests. Heart rate was calculated as the mean of 10 R to R intervals. The ischemic electrocardiographic threshold was defined as the time at which horizontal or downsloping ST-segment depression 20.1 mV first appeared.‘l The angina1 threshold was defined as the time of the onset of angina pectoris. The pressure-rate product was calculated as the product of the systolic blood pressureand heart rate. Oxygen uptake was measuredby indirect open-circuit calorimetry using a Douglas bag technique. Mixed expired gas sampleswere collected during the last 30 secondsof each minute during exercise and analyzed for fractional concentrations of oxygen and carbon dioxide (Ametek S-3A oxygen analyzer and Beckman LB-2 carbon dioxide analyzer). Before each test, the analyzers were calibrated with a gas with known concentrations verified by the micro-Scholander technique.I2 Expiratory volumes were measured using a heated digital pneumotach (Hewlett-Packard model no. 47303A). Calculations of oxygen uptake and derived variables were obtained using the equationsof Consolazio et a1.13 THALLIUM-201 IMAGING: For each exercise prOtOCO1, thallium-201 (2.5 to 3.0 mCi) was injected intravenously 1 minute before completion of the exercise.Imaging commenced10 minutes after exercisein the standard planar views: anterior, 45” left anterior oblique and 70“ left anterior oblique view. Patients returned 4 hours later for delayed images.Equipment usedfor this study was an Elscint Corporation large field-of-view gamma camera with an all-purpose parallel-hole collimator. THALLIUM-201 INTERPRETATION: All thallium-201 studies were interpreted visually, using a Sudbury Systems ImageCenter computer system. The studies were read without knowledgeof the patient or exerciseprotocol and included images from normal subjects and patients with coronary artery diseasewho were not part of this study. The coded studies were reviewed by 3 of the investigators and agreement was by consensus.i4The heart contour on each projection was divided into 5 segments, for a total of 15 segments.Each segment was evaluated using a 4-point scale (0 = normal, 1 = slight-


TABLE I Data Obtained at Peak Exercise During Incremental Exercise (Bruce protocol) and Submaximal Steady-State Exercise Testing in 22 Patients ExerciseTest Incremental Exerciseduration (min) Treadmill speed (miles/hour) Treadmill grade (%) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Rate-pressure product (beats/min, mm Hg) Maximal VOn (ml. kg-1 min-1) Angina pectoris (no. of pts.) Patients with ST depression (no. of pts.) Maximal ST depression (mm) Patients with reversible TI-201 defects (no. of pts.) NS = difference not significant;


= thallium-201;

VO? = oxygen consumption


p Value

19.5 + 2.3

8.0 2 2.4 3.2 + 0.5

13.6 ‘1- 1.3 130 i 16 172 f 18

2.3 zk 0.8 1.0 2 2.5

so.01 10.05 SO.01

100 f 13


153 86 15,275 12.7

902 11 22,357 + 3,303 20.7 f 4.0

16 19

+ 2 t f 5

14 6 2,718 3.4


NS so.01

10.01 10.01 so.05 so.05


2.6 k 0.9

1.7 +. 0.8





ly diminished activity, 2 = moderate reduction in activity, and 3 = absent activity equivalent to background). This method has been previously validated for reproducibility.15 If >_2of the 15 segmentshad defects,the study was considered abnormal.“j In addition to visual, blinded interpretation, the planar views were subjected to computerized qualitative analysis, using the procedure of Maddahit7 and Are&at* and their co-workers. This program uses a circumferential profile analysis of pixel counts and comparesthe patient data with those from a group of 32 patients with a very low probability of significant coronary artery disease.These analyseswere performed independent of the visual interpretations. Comparisons between the visual data and computerized analysis of the same views were made with regard to the presence and location of defects. Discrepancieswere resolvedby either identification of artifact, such as breast attenuation, or by accepting the quantitative findings as correct. Disagreement between visual and computerized analysis was <5%. Statistical analyses: Statistical analyseswere completed using a multivariate approach repeated-measures analysis of variance with the Biomedical Statistical Package, program 4V. l9 Post hoc tests were applied when indicated using a Tukey HSD test. RESULTS Nineteen men (mean age f standard deviation 61 f 7 years) completed the study protocol. All patients had stable angina pectoris. Six had prior myocardial infarction. Thirteen patients (68%) were taking antiischemic medications, with 6 receiving combination therapy. Data obtained at peak exerciseduring the 2 exercise protocols are listed in Table I. During submaximal exercise,the maximally achievedheart rate, systolic blood pressure,heart rate-blood pressureproduct and oxygen

uptake were significantly lower than those achieved during the incremental exercise.By protocol design,the 2 exerciseprotocols were also considerably different in work load achieved, and the exercise duration during steady-stateexercisewas significantly longer than with incremental exercise. The prevalence of angina pectoris, significant electrocardiographic changes and reversible thallium-201 defects during the 2 exercise protocols are shown in Figure 1. During the Bruce protocol test, 16 of 19 patients (84%) had angina and all patients exhibited reversible thallium-201 defects and electrocardiographic abnormalities. In contrast, during the low-level, steadystate exercise,only 5 patients had angina (26 vs 84%, p










FIGURE 1. Comparison of prevaknce of angina pectoris, electrocardiographii (ECG) changes ad reversii thallium-201 (Tl-201) defeats during incremental exercise (BIIKS~ protocol) and submaximal, steady-state exercise. ns = not significant. THALLIUM-201




TABLE II Comparison of the Onset of Angina1 Symptoms During Incremental (Bruce protocol) Exercise and Submaximal, Steady-State Exercise Bruce (n = 5) Time (min) 5.6 HR (beatsimin) 115 SBP (mm Hg) 166 DBP (mm Hg) 89 RPP (beats/min, mm Hg) 19,186 i/O2 (ml kg-1 * min-1) 17.1 Speed (miles/hour) 2.7 Grade (%) 12.3

k 2.4 + 13 f 17

2 8 2 3,296 r 3.5

Submaximal (n = 5)

9.3 f 4.7 99 r 3 147 lr 18

p Value

0.05 0.05 0.05

89 ZII5 14,590


NS 0.05

? 2,011

9.9 It: 2.2 2.0 f 0.6


I- 0.8 2 1.8

0.0 f 0.0



DBP = diastolic blood pressure; HR = heart rate; NS = not significant; RPP = rate-pressureproduct;SBP = systolicbloodpressure;VO?= oxygenconsumptionrate.

TABLE Ill Comparison of the Onset of Electrocardiographic ST-Segment Changes (21 mm) During incremental (Bruce protocol) Exercise and Submaximal, Steady-State Exercise Bruce (n = 9) Time (min) 4.3 HR (beats/min) 112 SBP (mm Hg) 167 90 DBP (mm Hg) RPP (beats/min, mm Hg) 18,792 i/O2 (ml kg-l min-1) 16.6 Speed (miles/hour) 2.3 Grade (%) 11.5

Submaximal (n = 9)

r 2.1

7.3 2 2.8

zr~16 f 11

97 + 13 150 * 15

f 8

88 2 6

2 3,222 2 3.5

f 0.6 f 1.5

14,564 -1-2,434 12.0 + 3.7

2.4 +- 0.9 0.6 r?:1.7

p Value

0.05 0.05 0.05 NS 0.05

0.05 NS


Abbreviations as in Table II,

The thallium-201 defects with incremental exercise were either partially (5 patients) or totally ( 14 patients) reversedon images 4 hours after exercise.Similarly, of the thallium-201 defects with submaximal exercise,all were either partially (6 patients) or totally (11 patients) reversedwhen imaged 4 hours later. The location of the scintigraphic abnormalities were similar between the 2 tests. Most defects affected the inferior and apical regions. The 5 patients with angina during the low level protocol also had angina and electrocardiographic changes during incremental exercise. Each of these 5 patients had reversible thallium-201 defects during both protocols, and 4 had electrocardiographic changeswith submaximal exercise. Although 9 patients had electrocardiographic changeswith both protocols, the magnitude of the ST segmentdepressionwas significantly lesswith submaximal exercise (Table I). In addition to evaluating the percentageof patients with evidenceof ischemia, the onset of angina and electrocardiographic changesduring both exerciseprotocols were examined (Tables II and III). Angina1 pain that occurred in 5 patients during submaximal exercisebegan significantly later during exercise and at a significantly lower heart rate, rate-pressureproduct and oxygen consumption when compared with the onset of angina during incremental exercise (Table II). Similarly, 572






in the 9 patients with ischemic electrocardiographic changesduring submaximal exercise,the onset was significantly later and was associated with lower heart rate, rate-pressure product and oxygen consumption when comparedwith that observedin the samepatients during incremental exercise (Table III).

DISCUSSION The present study was performed to evaluate the relations among 3 measuresof ischemia during incremental and submaximal exercise in the same patients. With incremental exercise, all patients demonstrated significant electrocardiographic ST segmentabnormalities and reversible thallium-201 defects, whereas 84% of patients developedangina. In contrast, with submaximal exercise only 26% of patients had angina, 47% had electrocardiographic changes, but 89% still developed reversiblethallium-201 defects.The results of this study confirm the concept of the ischemic cascade.1>2 The sequencehas been confirmed in numerous studies which demonstrate blood flow abnormalities early, followed by both systolic and diastolic dysfunction before clinical findings.2°-22 Whereas previous studies described responsesto a single ischemic stimulus, the present study evaluated the same patients under 2 conditions provoking ischemia with use of dissimilar exercise protocols. Assuming the ischemic sequenceconcept to be correct, one would expect the less strenuous protocol, which has a lower energy demand as well as lower myocardial oxygen demand, to produce less angina and fewer electrocardiographic changes than the more intense exercise. Since blood flow alterations have been proposedas one of the first events in the ischemic chain2 thallium-201 changeswould be expectedto be seenin a greater percentage of patients with lesserstressthan would either electrocardiographic changes or angina. Not only do our findings demonstratethis, but the finding of a higher percentage of patients with reversible thallium-201 defects than patients with either angina or electrocardiographic changes provides a physiologic explanation for the greater sensitivity of thallium-201 imaging in detecting coronary artery disease, including low-level exercise.23-26 Currently, it has been assumed that the ischemic cascadefollows a fixed threshold for each event, and that the degreeof the ischemia influences only the presence or absenceof the event. Our data suggest that although the ischemic cascadeoccurs in a set sequence in responseto ischemia, the onset of each physiologic event varies in accordance with the level of ischemia. Thus, it is possibleto hypothesizethat the ischemic cascade may be conceived as a series of curves that respondto both the intensity and duration of the ischemia (Figure 2). For purposesof this hypothesis, ventricular


1. 1991

function has been added in addition to data supported by the present study on blood flow alterations, electrocardiographic and angina1 assessments.Rapid, symptom-limited exercisemay be expectedto elicit all events in the cascadeat an early time in the exercise period but at a high rate-pressure product. Moderately progressing maximal exercise would still bring about all changes,but at a longer time frame after the onset of exercise, and at a lower rate-pressure product. However, submaximal incremental exercisewhich intentionally limits the maximal activity would result in fewer patients exhibiting angina1 symptoms or electrocardiographic changes.Finally, submaximal, steady-stateexercise results in even fewer clinical events and at a reduced rate-pressureproduct. These data also give further support to an energy expenditure relation between “silent” and symptomatic myocardial ischemia. Our data with submaximal exercise demonstrated that many patients who were previously symptomatic continued to show signs of ischemia (thallium-201 imaging, electrocardiographic changes) in the absenceof symptoms. It has been suggestedthat patients with mixed angina1syndromesmay have silent





EGG Changea







cl I/


ischemia in settings in which the work load or stressis not sufficient to cause angina pectoris. These episodes have been theorized to occur in daily situations, particularly with psychological stress or low-level activity.4,27-30 Two studiesnoted the onset of ambulatory ST segment depressionsto be at a lower heart rate than that seenduring laboratory conditions.4,29This discrepancy in the onset of electrocardiographic changes is similar to our findings, and is likely explained by more gradual and prolonged exerciseat a lower work load in the ambulatory setting (Figure 2). Although data from a study by Gasparetti et aP1did not show discrepancies between the time of onset of angina and electrocardiographic changes, they did confirm that patients had fewer angina1 symptoms than electrocardiographic changesin the presenceof thallium-201 defects. The present study was undertaken with a group of patients with stable angina pectoris and evidence of ischemia from exercise tests. Thus, many were receiving antiischemic regimens.Therefore, the specific influence of any of these drugs on our results cannot be ascertained. All medications were held constant throughout the study for each patient, as was the time


Yotlon Flow

RIM [email protected] Abnormautlor



FlGURE 2. Theoretical relation between events of the ischemic cascade and intensity of exercise achieved. Three types of exercise are compared: maximal exercise, either with rapid or moderate incremental exercise (RIM, MIM); submaximal incremental execeise (ISM); and submaximal steady-state exercise (SSM). The relative onset of ischemic events may be compared with relation to time and either rate-pressure product or oxygen uptake. Rapid incremental exercise and submaximal steady-state exe-rcise are based on results of the present study, whereas moderate or submaximal incremental exercise was theoretically derived from prior studies. BP = blood pressure; ECG = electmcardiographic; HR = heart rate. THALLIUM-201



frame between medication administration and exercise testing. In conclusion, the results from the present study provide further support and extend the concept of the ischemic cascadeduring myocardial ischemia using a measureof blood flow during varying physiologic stress in the same persons.The results of this study suggest that, although angina or blood flow alterations may occur in a set sequence,the timing and hemodynamic level at the onset of the ischemic event varies with the physiologic stressor.Finally, these studies confirm that ischemia may occur at low levels of exercisein the absence of symptoms in the same patients who exhibit angina at higher exercise intensities. Acknowledgment: The skillful manuscript preparation by Karen Poissant, and technologic assistance of Andrea Rousseau-Devol, Debra Messinger, Donna Cloutier, Lisa Warren and Alan Ahlberg are gratefully acknowledged.Nathan Harmony, Productions Supervisor, Elscint Corporation, is acknowledgedfor assistance in computerized quantitative analysis of thallium images.

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