Download Sensitivity, Specificity and Predictive Accuracy of Radionuclide

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.
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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.
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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
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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.
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-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
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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
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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.
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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
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30K
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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.
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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.
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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.
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J S Borer, K M Kent, S L Bacharach, M V Green, D R Rosing, S F Seides, S E Epstein and G
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Circulation. 1979;60:572-580
doi: 10.1161/01.CIR.60.3.572
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