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Sensitivity, Specificity and Predictive Accuracy of Radionuclide Cineangiography During Exercise in Patients with Coronary Artery Disease Comparison with Exercise Electrocardiography JEFFREY S. BORER, M.D., KENNETH M. KENT, M.D., PH.D., STEPHEN L. BACHARACH, PH.D., MICHAEL V. GREEN, M.S., DOUGLAS R. ROSING, M.D., STUART F. SEIDES, M.D., STEPHEN E. EPSTEIN, M.D., AND GERALD S. JOHNSTON, M.D. with the technical assistance of Bonnie Mack. M.S., and Susan Farkas, B.S. Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 SUMMARY Noninvasive radionuclide cineangiography permits the assessment of global and regional left ventricular function during intense exercise. To assess the sensitivity of the technique in detecting coronary artery disease, we studied 63 consecutive patients with 50% stenosis of at least one coronary artery. Fiftynine (94%) had regional dysfunction with exercise; 56 (89%) developed lower-than-normal ejection fractions during exercise. When both regional dysfunction and subnormal ejection fractions are considered together, the sensitivity was 95%. Each patient also underwent exercise electrocardiography to either angina or 85% of predicted maximal heart rate. Of the 42 patients who developed angina during exercise electrocardiography, 26 (62%) developed I mm ST-segment depression; four additional patients (10%) had Q waves diagnostic of previous myocardial infarction. In contrast, 39 (93%, p < 0.001) developed regional dysfunction during radionuclide study, and one additional patient developed a subnormal ejection fraction without regional dysfunction. To assess specificity, we studied 21 consecutive patients with chest pain who had normal coronary arteries. None developed regional dysfunction; ejection fraction increased in all to levels within the range previously defined as normal. The predictive accuracy in this symptomatic population was 100%. We conclude that radionuclide cineangiography is highly sensitive (more so than exercise electrocardiography), predictive and specific in detecting patients with coronary artery disease. WE HAVE RECENTLY shown that noninvasive radionuclide cineangiography performed during exercise permits the detection of abnormalities in regional left ventricular function and ejection fraction in patients with coronary artery disease (CAD).' In the present study, we assessed the sensitivity and specificity of this technique in detecting CAD, and compared its accuracy with that of exercise electrocar- underwent echocardiographic, coronary arteriographic and contrast left ventriculographic studies at rest, as well as resting and exercise electrocardiography within 2 days of radionuclide scintigraphy. Of the 84 patients, 81 had a history of exertional chest pain, acute myocardial infarction, or atypical angina suggestive of CAD, and three were referred for study because of markedly positive exercise ECGs at other institutions. The study group represented a consecutive series of patients admitted to ongoing natural-history studies specifically because their symptoms were so mild that operation was not considered warranted. Sixty-three of the 84 patients (75%) had angiographically demonstrable CAD, causing . 50% stenosis (as judged by maximal reduction in luminal diameter) of at least one major coronary vessel, and had no evidence of other cardiac disease. Eight patients (13%) had . 50% stenosis of only one major coronary vessel, 24 (38%) had . 50% stenosis of two major vessels, and 31 (49%) had . 50% stenosis of all three major coronary vessels. Six patients had . 50% stenosis of the left main coronary artery; for purposes of analysis, each was considered to have disease of both the left anterior descending and the left circumflex coronary artery. No patient had echocardiographic evidence of asymmetric septal hypertrophy or mitral valve prolapse. Thus, 60 mildly to moderately symptomatic and three totally asymp- diography. Methods We studied 84 patients (72 men and 12 women, ages 29-70 years) who were admitted to the National Heart, Lung, and Blood Institute for evaluation of possible CAD. All studies were performed at least 48 hours after cessation of propranolol and at least 4 hours after nitroglycerin administration. Each patient From the Cardiology Branch, NHLBI, and the Department of Nuclear Medicine, Clinical Center, NIH, Bethesda, Maryland 20014. Dr. Borer's current address: Cardiology Division, New York Hospital-Cornell University Medical Center, 525 East 68th Street, New York, New York 10021. Address for reprints: Jeffrey S. Borer, M.D., Cardiology Branch, NHLBI, Building 10, Room 7B-15, National Institutes of Health, Bethesda, Maryland 20014. Received August 22, 1978; revision accepted March 20, 1979. Circulation 60, No. 3, 1979. 572 ACCURACY OF RADIONUCLIDE ANGIOGRAPHY/Borer et al. Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 tomatic patients with angiographically demonstrable CAD constituted the population used in the study of the sensitivity of radionuclide cineangiography. The remaining 21 patients (14 men and seven women) were found to have normal coronary arteries. Most of these patients had atypical angina and none had suffered a previous myocardial infarction. These 21 patients constitute the population used in the study of the specificity of radionuclide cineangiography. None of these patients had evidence of cardiac abnormality of any kind; in particular, there was no evidence of asymmetric septal hypertrophy by echocardiography, and no evidence of mitral valve prolapse by auscultation, contrast angiography or echocardiography. We also studied 13 normal subjects, ages 19-30 years, who had no clinical, electrocardiographic or echocardiographic evidence of cardiovascular or other systemic disease. Each had normal left ventricular systolic function at rest, as evidenced by an ejection fraction > 60% by echocardiography, and each had normal electrocardiographic patterns during maximal exercise. None of these normal subjects underwent catheterization, but because of their age and lack of symptoms, they were considered not to have CAD. They served as normal controls. An additional 30 normal subjects, ages 31-63 years, were studied. Each was without clinical, electrocardiographic or echocardiographic evidence of cardiovascular or other systemic disease. The data obtained from this older, clinically normal group were analyzed separately from those of the younger group because of the possibility that occult CAD might have been present. Gated cardiac scintigraphy was performed with subjects in the supine position at rest and during exercise, as previously described.2 3 In this procedure, human serum albumin labeled with 10 mCi of radioactive technetium (99mTc) was administered intravenously. After the tracer had equilibrated in the blood pool, a conventional Anger camera (field of view 254 mm in diameter), equipped with a highsensitivity, parallel-hole collimator, was oriented in the modified left anterior oblique position5' 6 to isolate the left ventricle in the field of view. Imaging was carried out at rest and during exercise, and was accomplished by the use of our previously described, computer-based, electrocardiographically gated procedure.5 8 The program has been modified to reduce the data processing time and the interval required to achieve statistical reliability.9' 10 The spatial resolution of this system is 1 cm. Once the data have been collected, the physician identifies the left ventricle and defines a "region of interest" in the end-diastolic movie frame, permitting the computer to analyze the acquired data and produce a left ventricular time-activity curve with a high (10 msec) temporal resolution.5'8, 10 Corrections for background activity are made by defining a crescent of pixels outlining the lateral border of the left ventricular region of interest from apex to base, and located one pixel-width lateral to the region of in- 573 terest. Neither left ventricular nor background regions of interest are changed throughout the cardiac cycle. Because blood radioactivity is proportional to blood volume, after correction for background, the timeactivity curve represents a measure of left ventricular volume vs time. Therefore, the technique permits the quantitation of left ventricular volume change with time and the determination of ejection fraction. Statistically reliable information is obtained by summing the radioactivity in the ventricle during many beats. Immediately after data are- acquired, the length of the RR interval of each cardiac cycle is automatically examined to determine if it lies within a physician-selected RR interval "window." Cycles falling outside this window are rejected to prevent distortion of both the time-activity curve and the movies by premature depolarizations. Ejection fractions obtained by this method correlate well with those obtained by contrast angiography with the patient at rest (r = 0.92, p < 0.01).1" After the images and time-activity curves are obtained at rest, the subjects begin to pedal a bicycle ergometer while in supine position. A restraining harness minimizes patient motion under the camera during exercise. Exercise loads are increased by 25watt increments at 2-minute intervals, culminating in loads that produce symptoms of angina or dyspnea, or fatigue of sufficient severity to limit further exercise. Imaging is begun shortly after the onset of exercise and is continued until the cessation of exercise. After exercise, the portion of the exercise data to be analyzed is determined by the physician who selects the heart rate interval to be analyzed. Generally, 2 minutes of image data were necessary to assess regional function adequately, though occasionally it is possible to define regional abnormalities accurately with 1.5 minutes of image data. Thus, in each case, the data used for analysis included at least those collected over the last 1.5 minutes of exercise. In patients with CAD, symptoms most often develop and exercise is stopped at heart rates considerably lower than those reached by normal subjects at peak exercise. Hence, imaging and analysis were undertaken in the older normal subjects at three intervals during exercise: at two submaximal levels (90-105 beats/min and 105-120 beats/min), as well as at the fatigue-limited load. In all subjects, heart rate and blood pressure, obtained by sphygmomanometry, were recorded during each minute of exercise. In this study, regional left ventricular function at rest and during exercise was determined visually from movies by each of three observers who were unaware of the results of coronary arteriography. A study was considered abnormal if at least two of the three observers noted regional abnormalities during exercise, whether or not these regional abnormalities were also present at rest, or if (one case) the ejection fraction fell during exercise, though no regional abnormality was seen. In many patients, at least one regional abnormality also was seen at rest (see Results). Movies during exercise were constructed from im- 574 CIRCULATION Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 ages obtained in the modified left anterior oblique position. Therefore, function of the anteroseptal and anterolateral ventricular walls was evaluated from the movie. Other surfaces of the heart can be imaged by orienting the camera in positions other than the modified left anterior oblique."0 In the present study, such camera orientations were not used. Rather, we further assessed regional function from count-based "difference images," obtained by subtracting the endsystolic from the end-diastolic image.6 8 The computer is programmed to display the resulting difference image such that the intensity (brightness) of each region of the difference image is proportional to the absolute change in radioactive emissions (volume) between diastole and systole in that region. Normally, the entire difference image appears bright except for relative darkness in the region near the outflow tract, where end-systolic volume is greatest. Thus, in the left anterior oblique view, a region of darkness located centrally in the difference image and surrounded by bright regions represents either a posterobasal or an anterobasal region from which blood is not being ejected normally. In addition to supine radionuclide studies, each patient underwent a standard 12-lead electrocardiographic study at rest, and an electrocardiographic study during upright bicycle ergometry within 2 days of radionuclide study. The work load was increased by 20-watt increments every 2.5 minutes until chest discomfort, limiting dyspnea or fatigue developed, or until the heart rate reached > 85% of predicted maximum for the subject's age and sex. (The submaximal exercise protocol was used because it was the protocol selected when our natural history studies of CAD were initiated in 1972. Since these studies are still in progress, the submaximal protocol was retained to permit appropriate comparisons within the study population.) Electrocardiographic leads were arranged in a modified CM5 system, with a reference electrode over the manubrium and an exploring electrode in the V5 position to assess ST-segment changes with a horizontal vector. A second exploring electrode over the lumbar spine was used to assess ST-segment changes with a vertical vector.12 Both electrocardiographic leads were recorded continuously during exercise and for 5 minutes thereafter. An exercise ECG was considered positive if, 0.08 second after the J point, the ST segment was depressed to 0.1 mV or more below the resting base line level, with the ST-segment slope . 0. The exercise tracings were read independently by two observers who were unaware of radionuclide cineangiographic and cardiac catheterization results. No patient in this series had left or right bundle branch block that precluded assessment of the ECG. Data were analyzed using the Student t test and McNemar's test for paired data. In this study, "sensitivity," "specificity" and "predictive accuracy" are defined according to World Health Organization guidelines, as previously reported.'2 VOL 60, No 3, SEPTEMBER 1979 Results Radionuclide Studies Regional Wall Motion Abnormalities No regional dysfunction was noted in studies from any of the 13 young normal patients, the 30 older normal patients or the 21 patients with chest pain but nor- mal coronary arteries. In contrast, of the 63 patients with angiographically demonstrated CAD, 59 (94%) developed regional dysfunction during exercise that was noted by at least two of three observers. Thirty-four (54%) also had abnormalities at rest. Results of individual observers were similar to those of the three observers as group. Thus, one observer identified 92% of patients as having regional dysfunction, one identified 90% and one identified 89%. In total, 11 different patients received false-negative assessments from at least one observer. Forty-four of the 63 patients developed angina during exercise. Forty-one (93%) of these 44 had regional dysfunction during exercise and 25 (57%) also had dysfunction at rest. Nineteen of the 63 patients were limited by fatigue. Eighteen of these 19 patients (95%) had regional dysfunction during exercise; nine also had regional dysfunction at rest. Thus, most patients had regional abnormalities during exercise, though, as noted, many already had abnormalities at rest. However, most patients with normal function at rest also had regional abnormalities during exercise. Thus, of the 29 patients with coronary artery disease but with normal left ventricular function at rest, 26 (90%) had regional abnormalities during exercise. (In addition, as noted below, one patient with no detectable regional abnormality at rest or during exercise manifested a fall in ejection fraction to a subnormal level with exercise.) Moreover, of the 34 patients with at least one regional abnormality present at rest, 12 (35%) developed abnormalities during exercise in regions that had been normal at rest; 15 (45%) who had hypokinesia at rest developed akinesia or dyskinesia in the same region during exercise. Though the ejection fraction fell in six of the remaining nine patients during exercise, changes in the degree of regional dysfunction could not be reliably perceived by observers when studies at rest and during exercise were compared. Left Ventricular Ejection Fraction Analysis of left ventricular ejection fraction yielded results that were consistent with those obtained by visual assessment of regional function (fig. 1). Among the 13 young normal subjects, the ejection fraction invariably rose during maximal exercise, compared with ejection fraction determined with the subject at rest (ejection fraction averaged 59 ± 3% at rest, and 71 ± 2% during exercise, p < 0.001) (fig. 1). The results were virtually identical in the 30 older normal subjects: ejection fraction invariably rose during exercise, with ejection fraction averaging 57 ± 2% at rest ACCURACY OF RADIONUCLIDE ANGIOGRAPHY/Borer et al. 575 100 90 80 70 O z 0 cc: 60 50 z LU 40 Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 -J 30 20 10 p<.001 p< .001 0 REST EXERCISE REST EXERCISE p< .001 ,l REST EXERCISE p< .001 REST EXERCISE FIGURE 1. Left ventricular (LV) ejection fraction at rest and during exercise in young normal subjects, older normal subjects, patients with coronary artery disease (CAD) and patients with chest pain and normal coronary arteries. The dashed line represents the lowest ejection fraction (54%) recorded during submaximal exercise in normal subjects. and 71 ± 2% during exercise (p < 0.001). The lowest ejection fraction of any normal subject during exercise (54%) was achieved during submaximal exercise at a heart rate of 96 beats/min. However, ejection fractions developed during submaximal exercise in each subject invariably were higher than those recorded with the subject at rest. Values for ejection fraction during submaximal exercise in the 30 older normal subjects (comparable in age to the patients with coronary artery disease) were: heart rate 90-105 beats/min, ejection fraction 54-79% (average 65 ± 1%, p < 0.001 compared with resting value); heart rate 106-120 beats/min, ejection fraction 55-84% (average 69 + 1%, p < 0.001 compared with resting value). In contrast, for the entire group of 63 patients with CAD, the ejection fraction at rest averaged 49 ± 2% and decreased to 39 + 2% (p < 0.001) during exercise. While only 16 of 63 (25%) patients had ejection fractions at rest below the lowest value recorded from any normal subject, 56 of 63 patients (89%) developed values during exercise that were below the lowest nor- mal value of 54%. Moreover, while all subjects without CAD (regardless of age) had increased ejection fraction during exercise, only seven of the 63 patients with CAD had an increase in ejection fraction during exercise, and only three of these had ejection fractions within the normal range at rest and during exercise. In the 44 patients who developed angina during exercise, the ejection fraction averaged 48 ± 2% at rest and 39 ± 2% during exercise (p < 0.001). The ejection fraction during exercise was below the limits of normal in 39 of the 44 (89%) patients. The ejection fraction fell during exercise in 38, remained unchanged in one and rose in five. Of the 19 patients who did not develop angina during exercise, the ejection fraction averaged 49 ± 3% at rest and 41 ± 3% during exercise (p < 0.001). The ejection fraction during exercise was below the lower limit of normal in 17 of these 19 patients (89%). For the entire group of 19 patients, the ejection fraction fell during exercise in 14, remained unchanged in three and rose in two. 576 CI RCULATION Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 In summary, radionuclide cineangiographic study during exercise revealed that 94% of patients with CAD had regional dysfunction and 89% had subnormal ejection fraction. When both regional dysfunction and subnormal ejection fraction are considered together, 95% of patients (60 of 63) had an abnormal test. Though the sensitivity of radionuclide cineangiography in determining abnormalities in regional function and ejection fraction was high both in the patients who developed angina during exercise and in those who did not, the level of exertion achieved during imaging was significantly higher in patients who did not develop angina. Thus, the average maximum load achieved during exercise was 100 ± 10 watts in patients without angina, but only 50 ± 4 watts in those with symptoms (p < 0.001). The difference in loads achieved was paralleled by the heart rate response. The heart rate during imaging was 128 ± 4 beats/min in those without angina during exercise, and 107 ± 2 beats/min in those who were stopped by angina (p < 0.001). The average peak systolic arterial pressure was 170 ± 5 mm Hg in those without symptoms and 160 ± 4 mm Hg in those with symptoms (NS). Relation of Sensitivity of Radionuclide Cineangiography to Degree of CAD Of the 63 patients with CAD, 31 had . 50% stenosis of all three major coronary arteries. Each of these 31 had regional dysfunction during exercise (fig. 2), and 30 of the 31 developed subnormal left ventricular ejection fraction during exercise. Twenty-four patients had . 50% stenosis of two major coronary arteries; 21 of the 24 had regional dysfunction (fig. 2) and all 24 had a subnormal ejection fraction during exercise. Eight patients had . 50% narrowing of one coronary artery. Seven of the eight had regional dysfunction (the single exception was the only patient with single-vessel right coronary artery disease), and five of the eight had subnormal ejection fractions during exercise. Sensitivity in detecting individual diseased coronary arteries in this group of patients, in which 90% had multivessel disease, varied with the arteries involved. For example, 45 patients had > 50% stenosis of both the left anterior descending and the left circumflex coronary arteries, with or without right coronary artery abnormalities; 43 (96%) had anteroseptal dysfunction during exercise, indicative of left anterior descending stenosis, and 26 (59%) had anterolateral dysfunction during exercise, indicative of left circumflex stenosis. Two patients had neither anteroseptal nor anterolateral dysfunction, though one, who also had right coronary artery disease, had an abnormal difference image. Forty-one patients had > 50% stenosis of the right coronary artery and either the left anterior descending, the left circumflex or both. A central abnormality in the difference image was present in 25 (60%) of these patients. Thirty-six of the 41 (88%) had either anteroseptal or anterolateral dysfunction. Three of the 41 patients had neither ab- VOL 60, No 3, SEPTEMBER 1979 31 inn -- 90 WITHOUT ABNORMALITY AT REST 80 70 60 > 50 a) z ) 40 WITH ABNORMALITY AT REST 30 20 10 1 2 3 NUMBER OF STENOTIC MAJOR CORONARY ARTERIES FIGURE 2. Sensitivity of radionuclide cineangiography in detecting coronary artery disease with regard to number of stenotic major vessels. The number ofpatients is given above each bar. normal difference images nor other regional dysfunction. Of the 25 patients with right coronary artery stenosis and abnormal difference images, 24 also had stenosis of the left anterior descending coronary artery which might cause anterobasal dysfunction, with resulting abnormality in the difference image. In addition, four patients had central abnormalities in the difference image and stenosis of the left anterior descending but not of the right coronary artery. Therefore, while central abnormalities in the difference image were present in the majority of patients with > 50% stenosis of the right coronary artery, in this group of patients, it is not possible to ascertain the specificity of a difference image abnormality as an indicator of right coronary artery disease. Six patients had . 50% obstruction of the left main coronary artery. Five of the six also had involvement of other major vessels (table 1). It was not possible to predict involvement of the left main coronary artery either from analysis of regional function or from quantitation of the left ventricular ejection fraction during exercise. Thus, while all six had anteroseptal dysfunction, only four of the six had anterolateral dysfunction, and two of these four had > 50% stenosis in the circumflex system. Ejection fractions at rest were normal in four of the six. During exercise, the ejection fraction invariably diminished. The absolute value of the ejection fraction during exercise was subnormal in all four patients with right coronary artery stenosis. However, in the two patients without right ACCURACY OF RADIONUCLIDE ANGIOGRAPHY/Borer et al. 577 TA-BLE 1. Left Main Coronary Artery Disease Maximal exercise load (watts) 75 Heart rate during peak exercise Ejection fraction Itest Exercise 43 29 Other coronary stenoses LAI) LCC RtCA + + + + + + Itegional dysfunction AS AL D)I Pt. (beats/min) 126 + + 1 + + 2 120 43 35 5)0 + + 109 + 3 72 52 '235 + 88 62 3-4 + 4 50 22 + + + + + 116 13 25 + 110 31 6 50 47 + + + + right coronary artery; LCC left anterior descending coroiiary artery; RtCA Abbreviatioiis: LAI) left Cilculmflex (oioniary artery; AS = aniteroseptal; AL = ajiterolateral; )I = difference image. coronary artery disease, the ejection fraction during exercise was normal in one and only minimally depressed in the other. Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 Patients with Chest Pain and Normal Coronary A rteries In each of the 21 patients with chest pain and normal coronary arteries, the ejection fractions recorded at rest and during exercise were within the limits of normal. Moreover, the ejection fraction invariably rose during exercise (ejection fraction averaged 61 2% at rest and 70 ± 2% during exercise, p < 0.001) (fig. 1). Electrocardiographic Studies During Exercise Use of 85% of the predicted maximal heart rate as a criterion to terminate exercise during electrocardiographic studies in patients who do not develop angina during electrocardiographic exercise testing may diminish the sensitivity of the exercise ECG in detecting patients with CAD. Therefore, use of this end point may invalidate comparison with radionuclide studies in which symptom-limited supine exercise was performed. To avoid this problem, we analyzed separately the results of radionuclide cineangiography and exercise electrocardiography in the 42 patients whose exercise electrocardiographic study was terminated by the development of angina. Because 34 of the 63 patients had regional dysfunction at rest during radionuclide cineangiography, indicative of CAD, we also determined the prevalence of resting electrocardiographic Q waves diagnostic of previous myocardial infarction (table 2, fig. 3). Of the 42 patients who developed angina, 26 (62%) had positive exercise electrocardiographic results, and four additional patients (10%) with normal exercise ECGs had diagnostic Q waves at rest; 30 of the 42 patients (72%) had electrocardiographic abnormalities suggestive or indicative of CAD. In contrast, 39 (93%) had regional dysfunction during radionuclide cineangiography (fig. 3), and 36 of 42 (86%) had subnormal ejection fraction during exercise, one of whom had normal regional function; thus, 40 of the 42 (95%) had radionuclide abnormalities suggestive or indicative of CAD (p < 0.01 compared with electrocar- diography). The three patients with normal regional function also had normal rest and exercise ECGs. Eighteen of the 24 patients (75%) with three-vessel disease had positive electrocardiographic exercise tests, and three additional patients had Q waves at rest; thus 88% had electrocardiographic abnormalities. Six of the 12 patients (50%) with two-vessel disease had positive electrocardiographic exercise tests and one additional patient had Q waves at rest; thus, 58% had electrocardiographic abnormalities. Only one of the five patients (20%) with single-vessel disease had a positive electrocardiographic exercise test, and none had Q waves at rest. The heart rate at peak (anginalimited) exercise in these 42 patients during upright bicycle ergometry was 134 ± 3 beats/min, significantly higher than the 110 ± 2 beats/min recorded in the same patients during symptom-limited supine exercise (p < 0.001). The remaining 21 patients did not develop angina during upright bicycle ergometry and therefore exercised to 85% of predicted maximal heart rate. Eight (38%) developed ST-segment abnormalities during exercise, and five additional patients (24%) had Q waves at rest; thus, 62% had electrocardiographic abnormalities. In contrast, 20 (95%) had regional dysfunction by radionuclide cineangiography (p < 0.02). Nine patients in this group developed neither electrocardiographic abnormalities during upright exercise nor symptoms during supine exercise while radionuclide cineangiography was performed. Of these nine, eight TABLE 2. Comparison of Radionuclide Cineangiographic (RNCA) and Electrodardiographic Results Obtained with Patients at Rest Normal resting RNCA* + normal resting ECGt n = 27 Abnormal resting RNCA + normal resting ECG n = 19 Normal resting RNCA Abnormal resting RNCA + abnormal resting ECG + abnormal resting ECG n = 2 n = 15 *RNCA was abnormal if regional dysfunction (hypokinesia, akenesia, dyskinesia) was apparent. tECG was abnormal if Q waves diagnostic of previous myocardial infarction were present.25 CIRCULATION 578 100 r- 90 p<.Ol 80 70 Exercise ABN Only 60 50K C,) z wL Rest ABN with Additional Exercise ABN 40 Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 30K 20K Rest ABN without Additional Exercise ABN 10 0 ECG RADIONUCLIDE CINEANGIOGRAPHY FIGURE 3. Comparison of the sensitivity of radionuclide cineangiography with resting (Q waves) and exercise (ST segments) electrocardiography in detecting coronary artery disease (CA D) in the 42 consecutive patients whose exercise ECG test was terminated because of chest pain. Both ECG and radionuclide tests indicated CAD if abnormalities (A BN) were present only during exercise, or ifabnormalities were present at rest, even in the absence of new abnormalities during exercise. developed regional dysfunction and a subnormal ejection fraction during exercise. The remaining patient, who did not develop regional dysfunction, developed an ejection fraction of 52% during exercise, slightly below the lower limit of normal. Thus, all nine had abnormalities detectable with radionuclide cineangiography. Four of the nine had Q waves at rest. No patient with CAD had Q waves at rest or abnormalities during exercise electrocardiography in the absence of regional dysfunction during radionuclide cineangiography. Exercise electrocardiographic abnormalities were present in only one of the 21 patients with chest pain and normal coronary arteries. No Q waves were noted patients. Thus, the exercise ECG had a specificity of 95% in this group, which is statistically indistinguishable from the 100% specificity of radionuclide cineangiography. at rest in these 21 VOL 60. No 3. SEPTEMBER 1979 Discussion The results of this study, performed in patients who either had no exertional chest pain or whose exertional chest pain caused only mild-to-moderate symptomatic limitation, indicate that radionuclide cineangiography is highly sensitive in detecting CAD. Thus, 95% of patients with CAD had either regional dysfunction or a subnormal ejection fraction during exercise. The technique is also highly specific in determining the absence of CAD in patients with chest pain that is suggestive of CAD but presumably of noncardiac origin. Thus, we found that all 21 such patients in this study had normal regional function and ejection fraction during exercise. Our results in this study group also demonstrate that radionuclide cineangiography is significantly more sensitive than exercise electrocardiography in detecting the presence of CAD when information from ECGs obtained both at rest (Q waves) and during exercise (ST-segment abnormalities) is considered. This conclusion pertains to results derived from patients who exercised to a symptom-limited (angina) end point during electrocardiography, as well as to those who exercised only to 85% of their predicted maximal heart rate without symptoms. Radionuclide cineangiography and electrocardiographic testing were both highly specific in symptomatic and asymptomatic subjects without coronary or other forms of heart disease. Our results also indicate that, in a symptomatic population, a positive stress scintigram has very high predictive accuracy. Of the 84 consecutive patients admitted to our natural-history study (75% with . 50% coronary stenoses), all those with positive tests had CAD. The relatively low sensitivity of the exercise ECG in patients with CAD, even when data from the ECG recorded at rest also are considered, is consistent with the results of several previous studies.13-15 Our population included patients with relatively mild symptoms, many of whom did not develop angina during exercise. Thus, our patients might be expected to have relatively less ischemia during exercise than was present in previously studied populations, which usually included patients with severe symptoms who would be considered candidates for operative intervention. Even in this mildly symptomatic group, however, radionuclide cineangiography proved highly sensitive in detecting underlying coronary disease. The greater sensitivity of radionuclide cineangiography in comparison to exercise electrocardiography may relate to the observation that abnormalities in myocardial contractile function appear to precede electrophysiologic abnormalities consequent to ischemia.'6 However, the difference in sensitivity may also be partly due to a lower level of stress associated with upright bicycle exercise. Thus, while heart rates at the end of exercise were higher during upright than during supine exercise, the arterial pressure response is higher and the left ventricular volumes are larger when the patient is supine.'7' 18 These factors might account for greater myocardial oxygen demand despite ACCURACY OF RADIONUCLIDE ANGIOGRAPHY/Borer et al. Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 the lower heart rate. The fact that angina pectoris, which indicates an imbalance between myocardial oxygen supply and demand, invariably occurred in each patient at a lower heart rate during supine than during upright exercise is compatible with this concept. It appears that high levels of exertion are important if maximal sensitivity is to be achieved with the radionuclide technique. Unlike the findings previously reported with the exercise ECG,19 maximal exercise intensity did not decrease the specificity of radionuclide cineangiography in this study. Thus, it seems likely that routine use of maximal exercise as the end point of radionuclide testing to achieve maximal sensitivity will not lead to many false-positive results. However, though most patients with CAD have abnormalities during fatigue-limited exertion, even in the absence of symptoms,3 fatigue may occur at a level of exertion not sufficient to produce ischemic dysfunction.20 Radionuclide cineangiography was unsuccessful in detecting regional dysfunction during exercise in four of the 63 patients with CAD (6%), though an abnormal response of ejection fraction (a finding seen in patients with other forms of heart disease as well)21 was seen in one of these patients. The inability to demonstrate regional dysfunction might be attributable to several factors. Ischemia might affect a region too small to be detectable, given the relatively coarse (1 cm) spatial resolution of the radionuclide procedure. In addition, because approximately 2 minutes of imaging are currently required to collect a reliable, visually interpretable series of images, imaging at "maximal stress" often is begun at a heart rate or arterial pressure slightly below that associated with angina. Though ischemic dysfunction is often present, even at these subsymptomatic levels of exercise,3 it is possible, in some patients, that dysfunction is not present during part of the imaging. Consequently, the composite radionuclide cineangiogram may be influenced by images obtained before ischemia, thereby obscuring ischemia-induced changes. The latter limitation might be minimized by techniques that increase the rate of radioactive emission collection during equilibrium procedures. In the present study, we achieved high sensitivity in detecting ischemic heart disease, though only 10 mCi of 99MTc was administered to each patient. In most laboratories, blood pool scanning is performed with > 20 mCi of 99mTc. Such doses, if applied in the context of the computer-based method used in this study, would be expected to cause an increase in the count rate and a decrease in the time required for data collection. Our technique does not allow highly sensitive detection of all diseased vessels in a patient with multivessel CAD. Thus, in patients with both left anterior descending and left circumflex lesions, 96% of left anterior descending lesions were detected compared with only 58% of left circumflex lesions. In patients with multivessel disease, angina leading to cessation of exercise may result from ischemia 579 developing in only one region. In some patients, exercise-limiting ischemic symptoms also may occur as a result of ischemia in regions (inferobasal, anterobasal) that were assessed in our study only from the difference image. Theoretically, an abnormality in the difference image requires a relatively marked reduction in ejection from a non-border region. The difference image, therefore, would be expected to be a less sensitive indicator of ischemic dysfunction than movie analysis of edge motion. The use of biplane collimators and newer techniques in computer processing may eventually obviate this difficulty.22 Though factors such as those noted above may account for the occasional absence of exercise-induced regional dysfunction, the absence of dysfunction may be clinically important. Anatomic abnormalities of the coronary arteries, detectable at coronary arteriography, define regions of potential myocardial ischemia. However, regional myocardial oxygen demand is not known. Moreover, it is impossible to assess accurately the importance of collateral flow in a given patient, or to quantitate precisely the degree of coronary stenosis (or regional coronary flow) from angiographic studies.3 Hence, the severity of myocardial ischemia cannot be determined from the coronary arteriogram alone. It appears reasonable to assume, however, that the degree of functional impairment of the left ventricle during stress reflects the extent and severity of myocardial ischemia. If this is so, the absence of detectable ischemic dysfunction during stress may indicate functionally mild CAD, a finding that might be of prognostic importance. The disparity between anatomic and functional abnormalities is illustrated by the result of studies in our six patients with left main CAD. This anatomic abnormality is a potential cause of near-global ischemia. However, in our patients with left main coronary stenosis, both regional and global function during exercise varied widely, with ejection fraction being best preserved in the two patients without right coronary artery disease. Such patients are known to have considerably better prognosis than those with both left main and right coronary artery stenosis.24 Our results indicate that radionuclide cineangiography is more sensitive than electrocardiography in detecting patients with CAD, and, like electrocardiography, manifests a high specificity in excluding CAD in patients with symptoms suggestive of disease but with normal coronary arteries. The results of this study, however, do not indicate that radionuclide cineangiography, or any objective test, should be applied to every patient with known or suspected CAD. In many patients, the diagnosis of CAD can be made from the history alone, and objective diagnostic tests should be reserved for patients in whom a diagnosis cannot be reached by simpler means. To perform radionuclide cineangiography requires an Anger camera and a minicomputer. Thus, the procedure is relatively costly (though significantly less costly than invasive procedures), a factor that must be considered in deciding upon the patient CI RCULATION 580 groups in which the test is most appropriate at present. Because information relating the results of radionuclide cineangiography and long-term prognosis is not yet available, information from this technique cannot be used to offer accurate prognostic counseling or to decide upon the need for or the appropriate timing of therapy. The test can be used for evaluating therapy,3 I and thus might well be obtained before instituting major therapeutic procedures, as an aid to evaluating symptoms after therapy. Further study is necessary to determine the appropriate application of radionuclide cineangiography in patients with known or suspected CAD. 9. 10. 11. 12. 13. Acknowledgments 14. Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 We gratefully acknowledge the invaluable contribution of John Condit, B.A., in the cardiac catheterization studies. We also acknowledge the valuable assistance of Fred Bullock, B.A., Nancy Condit, R.N., Carolyn Ewels, B.S., Mary Denise Ochsenschlager, B.S., Catherine Quigley, M.S., and Marjorie Rimmer, B.A., in the performance of these studies. 15. References 1. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS: Rapid evaluation of left ventricular function during exercise in patients with coronary artery disease. Circulation 54 (suppl II): 11-6, 1976 2. Borer JS, Bacharach SL, Green MV, Kent KM, Epstein SE, Johnston GS: 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, 1977 3. Borer JS, Bacharach SL, Green MV, Kent KM, Johnston GS, Epstein SE: Effect of nitroglycerin on exercise-induced abnormalities of left ventricular regional function and ejection fraction in coronary artery disease: assessment by radionuclide cineangiography in symptomatic and asymptomatic patients. Circulation 57: 314, 1978 4. Kent KM, Borer JS, Green MV, Bacharach SL, McIntosh CM, Conkle D, Epstein SE: Effects of coronary artery bypass operation on global and regional left ventricular function during exercise. N Engl J Med 298: 1434, 1978 5. Green MV, Ostrow HG, Douglas MA, Myers RW, Scott RN, Bailey JJ, Johnston GS: High temporal resolution ECG-gated scintigraphic angiocardiography. J Nucl Med 16: 95, 1975 6. Green MV, Bacharach SL, Douglas MA, Line BR, Ostrow HG, Redwood DR, Bailey JJ, Johnston GS: The measurement of left ventricular function and the detection of wall motion abnormalities with high temporal resolution ECG-gated scintigraphic angiocardiography. IEEE Trans Nucl Sci NS 23: 1257, 1976 7. Douglas MA, Ostrow HG, Green MV, Bailey JJ, Johnston GS: A computer processing system for ECG-gated radioisotope angiography of the human heart. Comput Biomed Res 9: 133, 1976 8. Green MV, Bailey JJ, Ostrow HG, Douglas MA, Pearlman AS, Brody WR, Itscoitz SB, Redwood DR, Johnston GS: Computerized EKG-gated radionuclide angiocardiography: a noninvasive method for determining left ventricular volumes 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. VOL 60, No 3, SEPTEMBER 1979 and focal myocardial dyskinesia. In Computers in Cardiology, Proceedings of the IEEE Computer Society. Rotterdam, The Netherlands, 1975, pp 137-140 Bacharach SL, Green MV, Borer JS, Douglas MA, Ostrow HG, Johnston GS: A real-time system for multi-image gated cardiac studies. J NucI Med 18: 79, 1977 Bacharach SL, Green MV, Borer JS, Douglas MA, Ostrow HG, Johnston GS: Real-time scintigraphic cineangiography. In Computers in Cardiology, Proceedings of the IEEE Computer Society. 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Circulation 54 (suppl III): III-107, 1976 Friedman HH: Diagnostic Electrocardiography and Vectorcardiography. New York, McGraw-Hill, 1971, pp 207-208 Sensitivity, specificity and predictive accuracy of radionuclide cineangiography during exercise in patients with coronary artery disease. Comparison with exercise electrocardiography. J S Borer, K M Kent, S L Bacharach, M V Green, D R Rosing, S F Seides, S E Epstein and G S Johnston Downloaded from http://circ.ahajournals.org/ by guest on April 29, 2017 Circulation. 1979;60:572-580 doi: 10.1161/01.CIR.60.3.572 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1979 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. 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