Nuclear Medicine

Exercise Radionuclide Ventriculography: Practical Considerations and Sensitivity of Coronary Artery Disease Detection1 Thomas J. Brady, M.D., James H. Thrall, M.D., Jean M. Clare, R.T., W. Leslie Rogers, Ph.D., Ka Lo, M.D., and Bertram Pitt, M.D.

Eighty-nine patients were evaluated for coronary artery disease (CAD) with exercise radionuclide ventriculography (ERV) and contrast coronary angiography. In 70 patients with documented lesions the ERV was abnormal in 65 for a sensitivity of 93 %. In patients with normal coronary arteries, the ERV was abnormal in none for a specificity of 100%. Sensitivity of ERV for detecting CAD was affected by the level of exercise achieved. In patients with documented CAD who achieved adequate exercise (i.e., pressure rate product (PRP) greater than 250 or the development of angina or ST segment depression during exercise), the sensitivity was 98% (56 of 57 patients). In those with documented CAD who failed to achieve adequate exercise, the sensitivity was 69% (9 of 13 patients). INDEX TERMS: Coronary angiography, indications. Coronary vessels, diseases • Heart, ejection fraction • Heart, radionuclide studies, 5[1] .1299 • (Coronary vessels, atherosclerosis, 5[4].760)

Radiology 132:697-702, September 1979

HE noninvasive evaluation of patients with cardiac disease has been enhanced by the utilization of radionuclide ventriculography (RNV) (1-4). Patients with coronary artery disease (CAD) may have normal ventricular function at rest only to develop dysfunction during exericse when imbalances between myocardial oxygen supply and demand become evident. To identify stress-induced ventricular dysfunction, Borer et al. (5. 6) extended the period of data acquisition with gated cardiac blood pool imaging to include an exercise phase. Exercise radionuclide ventriculography (ERV) has subsequently been shown to be a sensitive method of detecting patients with CAD (5-8). The study, however, is technically demanding and comprehensive methodology for performing exercise ventriculography has received little attention. Successful implementation of exercise gated blood pool imaging requires the acquisition and proper utilization of new equipment, patient compliance, technical training, coordination of technical personnel. and physician involvement to a degree not found in any other nuclear imaging study. In this paper, we shall review the technique of supine bicycle exercise radionuclide ventriculography and present our experience with this technique in the detection of patients with CAD.

T

MATERIALS AND METHODS

Eighty-nine patients with known or suspected coronary artery disease were evaluated with exercise radionuclide ventriculography. Coronary angiography was performed in all patients within one month of the radionuclide study. This group was selected from a larger group of 400 patients referred for the radionuclide exercise study. In this

Fig. 1.

TABLE

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REASON FOR OBTAINING REST AND EXERCISE RADIONUCLIDE VENTRICULOGRAPHY

% Patients

Reason for Evaluation

78% 15% 7%

Chest pain Valvular heart disease Miscellaneous

larger group, 25 patients could not be studied secondary to arrhythmias. Fourteen patients were not exercised secondary to marked shortness of breath (10 patients). severe intermittent claudication (3 patients) and hysteria (1 patient). Outpatients comprised 47% of all patients studied. The most frequent reason for the study was evaluation of chest pain (TABLE I). Patients were not required to fast during the study. Investigators have shown

1 From the Departments of Nuclear Medicine and Cardiology, University of Michigan Medical Center, Ann Arbor, MI 48109. Presented at the Sixty-fourth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, III., Nov. 26-Dec. 1, 1978. Submitted for publication 26 Jan. 1979; revision requested 2 March 1979; accepted 8 May 1979. shan

697

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THOMAS J. BRADY AND OTHERS

September 1979

that nitrates (6) and propranolol (14) can alter left ventricular response to exercise; therefore, whenever possible, propranolol was tapered and held 48 hours, and long-acting nitrates, 12 hours prior to the exercise study.

Instrumentation and Equipment

Fig. 2. a. Normal sinus rhythm with synchronous R-wave gating signals. b. Atrial fibrillation with synchronous but irregular gating signals. c. Resting artifacts with asynchronous and irregular gating signals. d. Muscle electrical activity causing asynchronous gating signals.

Technical Considerations

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A standard 25.4-cm (10-in.) diameter field of view gamma camera with current high count capability was used for data acquisition. The camera was equipped with a low energy, high sensitivity collimator. The system was interfaced to a dedicated computer (Medical Data Systems, Inc.) with software capabilities for dynamic acquisition, quantitative analysis and cinematic display. Multigated data collection was initiated with an R-wave synchronized gate (Brattle-Model 202). The imaging table was modified from a fixed top table with reinforced legs. The table position was maintained with bayonet clamps that locked into floor receptacles at each leg. Patient stability was maintained with an adjustable shoulder support and a restraining strap across the pelvis. A foam rubber wedge placed under the coccyx provided comfort and prevented migration of the patient during exercise. The bicycle ergometer (Collins Pedal-Mate) provided multiple calibrated work load settings, heart rate and RPM gauge. The ergometer was mounted in a stable position in a cantilever fashion from the end of the imaging table (Fig. 1). This modification has the pedal position much lower than the standard imaging table requiring less hip flexion and eliminating potential interference with the gamma camera head during exercise. A non-fade oscilloscope was used for continuous monitoring of the EGGsignal and a strip chart recorder provided hard copy of the ECG at rest and during exercise. A defibrillator and other emergency equipment should always be present in the exercise laboratory.

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TIME {Minutes)

Fig. 3. Option I-Graded Exercise. In this option multiple sequential studiesare obtainedat progressivework loads (levels of exercise).

A dose of cold stannous pyrophosphate (10 p,g stannous ion per kilogram, maximum dose 620 p,g) for complexing with red blood cells (RBC) was injected intravenously 20 minutes prior to the study (9, 10). Patients were then placed supine on the imaging table with feet taped to the ergometer pedals. Patients tend to migrate during exercise so a short practice session (less than 15 seconds) was obtained prior to imaging to maximize comfort and position. The exercise procedure was carefully explained to all patients and informed consent was obtained. A bipolar V -5 lead system was used to obtain resting rhythm ECG strips (Fig. 2a). Additional lead systems such as an inferior lead can also be obtained. The cardiac rhythm is evaluated prior to the administration of the radionuclide. Atrial fibrillation or chaotic rhythms make multiple gated blood pool imaging impractical (Fig. 2b). Occasional premature ventricular contractions (PVCs)(less than 10 %) do not, however, significantly degrade the im-

Vol. 132

ages. An arrhythmia filter was usedto eliminate these extra beats. Artifacts in gating can also cause deterioration of image quality. Resting artifacts may be caused by inadequate skin preparation before lead placement (Fig. 2c). The skin should be shaved if necessary and vigorously rubbed with an alcohol swab prior to electrode placement. Exercise artifacts are usually due to muscle activity (Fig. 2d). These can be eliminated by repositioning the electrode over bony prominences, for example, sternum and lower ribs. Baseline ECGstrip, heart rate and blood pressure are recorded. Exercise blood pool imaging should not be attempted without direct supervision of a physician experienced in exercise testing, electrocardiographic monitoring, and cardiopulmonary resuscitation. After a normal rhythm was documented, 25 mCi (925 MBq) 99mTc was injected intravenously for in vivo RBC labeling (9, 10). Images were obtained with a low energy, parallel hole, high sensitivity collimator with a 20 % energy window centered at 140 keV. A standard computer program (Medical Data Systems, Inc., MUGX Program) designed for exercise ventriculography was used to acquire 64 X 64 byte mode data. In this program the cardiac cycle is divided into 14 frames with computer calculated optimum time per frame based on the resting and exercise heart rate. For each study, 150,000 to 200,000 counts per frame were obtained. Acquisition time ranged from 60 to 100 seconds; average acquisition time was 75 seconds. (Thetime of the study is dependent upon the count rate per second and this will vary depending upon the amount of radioactivity, window width, type of gamma camera and collimator.) Exercise Protocol A 100 RAO and 2 LAO studies were obtained at rest. The LAO camera position was determined by finding the best separation between the right and left ventricle. The LAO position varied between 30 0 and 60 0 . In the same LAO position, the patients began exercising with the bicycle ergometer at a relatively low workload. There are two options for data collection during exercise. Option I Graded Exercise: With the patient pedalling at a constant rate (50-70 RPM/min.) the workload is increased until a preset heart rate (HR) or pressure rate product (PRP}2 is reached (Fig. 3). It is important to keep the HR relatively constant (±5 beats/min.) during acquisition. Excessive swings in heart rate (HR) during acquisition can cause quantitative changes in ejection fraction (EF)and deterioration of image quality. A constant HR can be achieved by varying the workload appropriately. Once acquisition is completed, the work load is increased until the next level is reached and the acquisition phase repeated. The graded approach continues until maximal effort is reached or until symptoms develop. Blood pressure and ECG traces are obtained at each level.

2

699

EXERCISE RADIONUCLIDE VENTRICULOGRAPHY

PRP = systolic blood pressure X HR/100.

Nuclear Medicine

RADIONUCLIDE VENTRICULOGRAPHY

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Fig. 4. Radionuclide ventriculography. Mean rest and exercise LVEF and standard error of the mean in patients with normal coronaries and patients with CAD.

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WATT LOAD Fig. 5. Patterns of EF response to progressive increases in workload as seen in a patient with normal coronary arteries (normal CAl and in 2 patients with documented CAD. In patient CAD 1# 1, if only the rest and maximal exercise EF were obtained. the study might be called normal.

Option II-Single Study During Maximal Exercise: The patient begins exercising as in Option I. The workload is progressively increased until the desired pressure rate product is reached or until symptoms develop. The HR is again held constant during the exercise acquisition and a single study is obtained. Blood pressure and ECG traces are recorded. If angina develops exercise may be continued with constant ECGand blood pressure monitoring. If severe chest pain, ventricular arrhythmia, or fall in blood pressure develop, the study is discontinued. All patients in this study were exercised to syrnptom-llmlted chest pain, fatigue or shortness of breath. After the exercise, patients are monitored until blood pressure. heart rate and ST

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THOMAS J. BRADY AND OTHERS

TABLE II:

CAD DETECTION

Contrast Angiography

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ERV

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Sensitivity = 93 % Specificity = 100%

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SENSITIVITY OF EXERCISE R.V. FOR SINGLE. DOUBLE AND TRIPLE VESSEL CAD

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segments approach baseline and until chest pain has abated. Data Analysis

The left ventricular ejection fraction (LVEF) was calculated with a semiautomatic edge detection program (MUGE) with varying regions of interest (4). Baseline LVEF was an average of the two resting ejection fractions. A normal LVEF response to exercise was defined as an increase of .05 compared to the resting study. This was based on the original work of Borer and modified by our early experience. Regional wall motion was analyzed by replaying radionuclide ventriculograms in cinematic closed loop display. Simultaneously displayed rest and exercise studies were visually evaluated by three observers using a 5-point grading system (3+ := normal. 2+ := mild hypokinesis. 1+ := marked hypokinesis, 0 := akinesis, -1 := dyskinesis). Normal wall motion required a 3+ grade in all segments at rest and during exercise. RESULTS

Thirty-two per cent of patients evaluated with exercise radionuclide ventriculography (ERV) for CAD underwent coronary angiography. Other cardiac diseases were excluded by history, physical examination. ECG and cardiac catheterization. Of these 89 patients who underwent catheterization and selective coronary angiography. 70 patients had at least a 70% stenosis in a coronary artery. In the 70 patients with significant lesions the ERV was abnormal in 65 for a sensitivity of 93 %. In 19 patients with normal coronaries or 250, developed typical angina pectoris or ST segment depression> 1 mm during exercise. If the patient failed to attain any of these end points then the exercise was graded as inadequate. Eighty-one per cent of patients with CAD and 53 % of patients with normal coronary arteries achieved adequate exercise levels. Of 70 patients with significant CAD. 57 achieved maximal exercise of which 56 had abnormal ERV for a sensitivity of 98 % . Of the 13 patients who were not maximally exercised, 9 had abnormal ERVsfor a sensitivity of 69 % (TABLE IV). Leg fatigue was the universal reason for inadequate exercise. In the 57 patients who achieved adequate exercise, 42 had angina, 22 had ST segment depression, 53 of 57 had either angina or ST segment depression and 7 had a PRP > 250. DISCUSSION

Exercise radionuclide ventriculography has been reported to have a high sensitivity for detection of coronary artery disease. These results are confirmed by the present study. To achieve this high level of sensitivity, patient cooperation, physician involvement, and a detailed exercise protocol are required. Option I is the preferred exercise method in our laboratory. Information can be obtained at low work levels that give an estimate of the severity of ischemia. Additionally. if patients develop arrhythmias or are otherwise unable to complete maximum exercise, submaximal levels can be evaluated. If performance is abnormal at this level, then the test need not be repeated. In 82 % of patient studies the graded exercise (Option I) protocol was used. There was an average of 2.8 exercise levels per patient which required an additional 10 minutes of data processing time. When fatigue is likely, for example in elderly patients, or in patients with chronic lung disease and those with peripheral vascular disease, the physician can use Option II and obtain one study at the highest level of exercise possible. In patients with severe arthritis, claudication, or pulmonary disease, adequate exercise levels may not be achieved. In patients with unstable angina pectoris, recent myocardial infarction, congestive heart failure or pulmo-

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EXERCISE RADIONUCLIDE VENTRICULOGRAPHY

nary hypertension, exercise should be attempted if at all only after cardiology consultation. Regardingour choice of collimator for the exercise study we have evaluated both high and medium sensitivity types. Since these terms are applied by the individual camera manufacturers to their product lines, actual collimator characteristics vary widely for a given sensitivity designation. For example, one high sensitivity collimator (General Electric) has provided images of comparable resolution (both visually and for utilizing the edge detection algorithm) to those obtained with a general all purpose collimator (Ohio Nuclear). The high sensitivity collimator has reduced the imaging time by 45 % which has the obvious advantage of decreased acquisition time during exercise. Patient stability is essential during exercise. Although a small amount of patient motion can be tolerated. excessive motion causes deterioration of image quality and erroneous calculation of LVEF. Patient stability can be insured by using a stable imaging table and a support system to immobilize the patient. The position of the bicycle ergometer is an important factor in patient immobilization. With the ergometer on the top of the table, the patient's legs are elevated and hips flexed. Exercise in this position is uncomfortable and results in trunk motion. With the ergometer mounted in a cantilever position from the end of the exercise table, the legs are lower and there is less hip flexion allowing exercise to be accomplished more comfortably with less trunk motion. In addition,this position minimizes interference between the patient's leg and the detector head, another cause for potential motion artifact. During the exercise phase the physician should be especiaHy alert to electrocardiographic artifacts which may alter gating and should ensure a constant heart rate by adjusting the exercise load so as to achieve a steady state during imaging. Occasionally, at high work loads, the heart rate may fail to increase, pedalling rate decreases and the patient tires. By reducing the work load the patient may be able to increase the pedalling rate and his heart rate. The work load can then be gradually increased until symptoms develop or maximal exercise is achieved. The data in the present study stress the importance of the level of exercise achieved during the study. To ensure maximum sensitivity, adequate exercise must be achieved. While the overall sensitivity for detecting patients with coronary artery disease was 93 %, the sensitivity in those who achieved an adequate level of exercise, determined by pressure rate product of greater than 250, greater than 1 mm ST segment depression, or the development of typical precordial chest discomfort was 98 % (56/57 patients). In patients who failed to achieve adequate exercise levels the sensitivity was only 69% (9/13 patients). Physician involvement and encouragement are essential if adequate exercise levels are to be achieved. Despite this, however, adequate exercise was achieved in only 81 % of our patients with significant CAD and 53 % of those with normal coronary arteries. Patients with CAD more fre-

Nuclear Medicine

quently developed chest pain or ST segment changes while those without CAD more often stopped exercise prematurely because of fatigue. Patients who fail to achieve adequate exercise levels should be reported as having an inadequate exercise test, suggesting the need for further diagnostic study. The relatively high percentage of patients who fail to achieve adequate exercise levels emphasizes the need for the technique of graded exercise. Firstly, the ejection fraction can be evaluated over a wide range of rate pressure products. Patients without coronary artery lesions tend to increase the LVEF early during exercise and plateau at maximum exercise levels while in patients with CAD a variable response is seen (Fig. 5). Some patients show early and continued decreases in left ventricular ejection fraction with increasing levels of exercise. Other patients with CAD show an initial rise in ejection fraction followed by a decrease at higher levels of exercise. If an exercise protocol is used in which a single exercise value is recorded, some of these patients might be called normal since their ejection fraction may have been increased> .05 above resting values. However, if graded exercise is performed, the fact that they decrease the EF after a certain peak value suggests the presence of CAD. If computer programs can be developed for on-line calculation of ejection fraction the graded exercise program could be used to identify abnormal responses at submaximal levels of exercise while the study is still in progress, thereby negating the need for and the risk of greater levels of exercise. Despite the high specificity for detecting patients with CAD by ERV in this study, an abnormal exercise radionuelide ventriculography study is not specific for CAD. Abnormal studies may be seen in patients with valvular heart disease and myocarditis (11-13). Any condition which results in myocardial damage can result in abnormal exercise performance. With increasing clinical application, the use of radionuclide ventriculography is rapidly becoming widespread but the excellent results found in current work and those of other investigators demand careful attention to equipment and exercise procedures. ACKNOWLEDGMENT: The authors would like to thank Mrs. Pamela Hendee for her secretarial and editorial assistance.

REFERENCES 1. Zaret Bl, Strauss HW. Hurley PJ, et al: A noninvasive sctntiphotographic method for detecting regional ventricular dysfunction in man. N Engl J Mea 284: 1165-1170, 27 May 1971 2. Secker-Walker RH, Resnick L, Kunz H, et al: Measurement of left ventricular ejection fraction. J Nucl Med 14:798-802, Nov

1973 3. Berman OS, Salel AF, DeNardoGL, et al: Clinical assessment of left ventricular regional contraction patterns and ejection fraction by high-resolution gated scintigraphy. J Nucl Med 16:865-874, Oct

1975 4. Burow RD, Strauss HW, Singleton R, et al: Analysis of left ventricular function from multiple gated acquisition cardiac blood pool

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imaging. Comparison to contrast angiography. Circulation 56:10241028, Dec 1977 5. Borer JS, Bacharach SL, Green MV, et al: Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary-artery disease. N Engl J Med 296:839-844, 14 Apr 1977 6. Borer JS, Bacharach SL, Green MV, et ai: Effect of nitroglycerin on exercise-induced abnormalities of left ventricular regional function and ejection fraction in coronary artery disease. Circulation 57:314-320, Feb 1978 7. Bodenheimer MM, Banka VS, Fouche CM, et at: Comparative sensitivity of the exercise electrocardiogram, thallium imaging and stress radionuclide angiography to detect the presence and severity of coronary disease (abst). Circulation 58:11:139, 1978 8. Frischknecht JK, Steele PP, Kirch DL, et al: Effect of exercise on left ventricular ejection fraction in patients with coronary disease (abst). Am J CardioI41:430, 1978 9. Pavel DG, Zimmer AM, Patterson VN: In vivo labeling of red blood cells with 99mTc: a new approach to blood pool visualization. J Nucl Med 18:305-308, Mar 1977 10. Thrall JH, Freitas JE, Swanson 0, et al: Clinical comparison of cardiac blood pool visualization with technetium-99m red blood cells

September 1979

labeled in vivo and with technetium-99m human serum albumin. J Nuel Med 19:796-803, Jul 1978 11. Borer JS, Bacharach SL, Green MV, et at: Left ventricular function during exercise before and after aortic valve replacement (abst). Circulation 56:98, 1977 12. Borer JS, Bacharach SL, Green MV, et al: Left ventricular function in aortic stenosis: response to exercise and effects of operation (abst). Am J Cardiol 41:382, 1978 13. Das SV, Brady TJ, Thrall JH, et al: Evidence of cardiac dysfunction in asymptomatic patients with prior myocarditis. Circulation 58:11-24, 1978 14. Marshall RC, Wisenberg G, Schelbert H, et al; Radionuclide evaluation of the effect of oral propranolol on left ventricular function during exercise in patients with coronary artery disease. Am J Cardiol 43:398, Feb 1979

Thomas J. Brady, M.D. Department of Nuclear Medicine University of Michigan Medical Center 1405 East Ann Street Ann Arbor, MI 48109