From the Department of Radiology (M.M.) and the Department of Internal
Medicine (M.S.), Ehime National Hospital; the Department of Radiology (T.M.,
K.M., S.T., J.I.) and the Department of Pediatrics (S.M., M.N.), Ehime
University School of Medicine; and the Department of Radiology, the City of
Yawatahama Hospital (K.H.), Ehime, Japan.
Correspondence to Masao Miyagawa, MD, Department of Radiology, Ehime National Hospital, 366 Yokogawara, Shigenobu, Ehime 791-0281, Japan. E-mail mmiyagaw{at}ehime-nh.go.jp
Methods and Results—Of 459 consecutive patients with Kawasaki
disease, coronary aneurysms were detected in 90 cases
by echocardiography during the acute stage. After
paired studies of selective CAG and SPECT were conducted, all patients
were followed up and monitored for the occurrence of any cardiac events
for
Conclusions—Dipyridamole-thallium SPECT is safely
performed and is useful and important for risk stratification in the
long-term follow-up of patients with Kawasaki disease.
Whereas coronary aneurysms are usually diagnosed by
cross-sectional echocardiography, coronary
stenosis is invasively assessed by coronary angiography
(CAG).3 However, angiography cannot be repeated
very often, especially in infants. Therefore, it is sometimes difficult
to monitor progressive changes from aneurysms to
stenotic lesions. Alternatively,
dipyridamole-thallium single-photon-emission CT (SPECT)
may be applicable to young children who are unable to exercise
adequately.6 Because of the absence of
prospective or retrospective long-term follow-up data, its prognostic
value has not yet been determined. This investigation attempts to
evaluate the prognostic significance of
dipyridamole-thallium SPECT in patients with
Kawasaki disease.
After the paired studies of selective CAG and
dipyridamole-thallium SPECT were conducted, all
patients were seen for routine follow-up visits every 6 months in the
pediatric cardiology unit for at least 8 and at most 14
years after discharge (mean±SD, 8.8±1.2 years). Long-term
antiplatelet therapy with aspirin (3 to 5 mg ·
kg-1 · d-1) was
administered at least until abnormalities resolved. We reviewed the
charts, personally interviewed the parents, or both to determine the
specific occurrence of cardiac events, including myocardial infarction
and cardiac death. We also noted the presence of readmission to the
coronary care unit for medical control of angina. The diagnosis
of myocardial infarction was made according to World Health
Organization criteria. Unstable angina was defined by the presence of
Dipyridamole-Thallium SPECT and
Interpretation
Myocardial uptake of thallium was assessed with a 180°
tomographic acquisition gamma camera (Gamma View T/Harp,
Hitachi). Thirty-two planar views were obtained for 40 seconds
at 1.5 hardware zoom into a 64x64 digital matrix. Tomographic
reconstruction was performed by means of a standard filtered
back-projection technique with a Chestler's filter to generate
transaxial tomograms. No scatter or attenuation correction was applied.
From these transaxial tomograms, the long axis of the left ventricle
was identified, and oblique-angled tomograms were generated (vertical
long-axis, short-axis, and horizontal long-axis sections).
The images were interpreted qualitatively by 2 independent observers
without prior knowledge of the patients' clinical history or
angiographic results. Differences in interpretation between the
observers were resolved by consensus. SPECT images of the left
ventricle were divided into 5 areas (anterior, septal,
inferior, lateral, and apical), and regional thallium
uptake in each area was semiquantitatively graded (0, normal; 1, mildly
reduced; 2, moderately reduced; and 3, severely reduced). Initial
thallium scans showing grade 1 or more perfusion defects on 2
consecutive sections and 2 different projections were considered
abnormal. Perfusion defects were further categorized as showing
redistribution if the defect appeared filled on the delayed images (if
there was improvement by
CAG and Interpretation
Echocardiography
Statistical Analysis
In addition to the above statistical comparisons, a nonlinear, stepwise
logistic regression analysis (BMDPLR, BMDP Statistical Software
Inc) was used to determine the statistical value of several patient
characteristics for the prediction of future cardiac events. In the
initial step (zero), no terms were entered into the model, and the
variables were evaluated independently. After step zero, the
highest predictor, if significant (P<0.10), was then
incorporated into the model, and the stepwise process was repeated
until no terms provided additional significance.
Echocardiography and CAG Findings
The interval between the initial echocardiography
and the CAG was 1.6±0.3 years. CAG results were obtained by means of
the Judkins technique in all cases. Of 90 patients, 25 (28%) had
significant coronary stenosis with or without
coronary aneurysms at the time of CAG. Of the 25
patients who had significant coronary stenosis on CAG,
16 had single-vessel, 6 had double-vessel, and 3 had triple-vessel
coronary disease. Forty-one patients (46%) still had
coronary aneurysms on CAG, whereas the
aneurysms in the other 49 patients (54%) had regressed to
normal.
Follow-up Data
Comparative clinical and radionuclide imaging characteristics are
summarized in Table 2
Of 15 patients who had some event, the presence of thallium
redistribution on SPECT was found in 14. The event-free survival rate
was significantly lower in patients with thallium redistribution than
in those without redistribution (P<0.0001) (Figure 3
Prediction of Cardiac Events
Recently, the importance of the management of older children and young
adults has been emphasized.15 The wide spectrum
of clinical outcomes, ranging from no sequelae in the majority of
patients to life-threatening coronary artery abnormalities in a
few, requires various management options. A stress test with ECG
monitoring alone as a method of ischemia detection appears to
have low sensitivity and specificity. Although exercise stress testing
with either a treadmill or bicycle ergometer may be
useful,16 80% of the patients are children
younger than 5 years, and most are children younger than 2 years who
are limited in their capacity to perform an exercise
test.17 Sixty-one (68%) of our study patients
were younger than 4 years at the time of SPECT and were unable to
exercise to an adequate end point.
Pharmacological stress with intravenous infusion of
dipyridamole is an effective strategy for the
evaluation of subjects with known or suspected coronary artery
disease.18 In adult patients, combined
analysis of the dipyridamole test results and
clinical data is useful in identifying high-risk
subsets.19 20 However, the application of
dipyridamole-thallium imaging in children has received
limited attention.6 21 Our prospective data
demonstrated that the presence of thallium redistribution on
dipyridamole-thallium SPECT is a powerful independent
clinical predictor of serious cardiac events in the long-term follow-up
of Kawasaki disease. The number of aneurysms on CAG added
minimal improvement to the logistic regression model.
The presence of significant coronary stenosis on CAG is
not a more significant predictor of cardiac events than the presence of
redistribution on dipyridamole-thallium SPECT. It is
true that CAG offers more detailed definition of coronary
artery anatomy than cardiac ultrasound, making it possible to
detect coronary artery stenosis or thrombotic occlusion
and to determine the extent of collateral artery formation. However,
the usefulness of CAG is limited because the procedure does not
specifically detect intramural changes in the coronary artery.
Postmortem examinations of some patients with angiographically
documented regression of coronary artery aneurysms have
revealed intimal proliferation and fibrosis not apparent on
angiogram.22 Moreover, significant discordance in
findings between stress nuclear imaging and CAG has been
reported.23 24 25 In particular, some patients
without angiographic evidence of coronary abnormalities had an
abnormal scan, suggesting enhanced stiffness of the regressed
coronary artery aneurysms.26
The physician must carefully compare the potential benefit of the
procedure with the risks and cost before recommending that a patient
undergo CAG. The decision should be guided by
echocardiography, clinical and ECG signs, and
especially by radioisotope perfusion studies indicating myocardial
ischemia. In the present study of 90 patients, even
patients younger than 3 years of age could complete the
dipyridamole-thallium SPECT with appropriate use of
sedative drugs, and there were no serious complications either during
or after dipyridamole infusion. Because it is
noninvasive and relatively safe, dipyridamole-thallium
SPECT seems to be an adequate method for the screening and follow-up of
patients with Kawasaki disease who have the possibility of future
cardiac events.
Study Limitations
Conclusions
Received December 8, 1997;
revision received April 1, 1998;
accepted April 27, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Prognostic Value of Dipyridamole-Thallium Myocardial Scintigraphy in Patients With Kawasaki Disease
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Although coronary
artery lesions are critical complications of Kawasaki disease, their
long-term outcome is still unclear. It is sometimes difficult to
monitor progressive changes from aneurysms to stenotic
lesions because coronary angiography (CAG) cannot be repeated
very often, especially in infants. Our prospective study was designed
to evaluate the prognostic value of
dipyridamole-thallium single-photon-emission CT (SPECT)
in the long-term follow-up of patients with Kawasaki disease. 
8 years. During the follow-up interval, there were 15 cardiac
events (1 death, 5 infarctions, 2 coronary artery bypass graft
operations, and 7 occurrences of unstable angina). Of patients who had
some event, thallium redistribution was found on SPECT in 14 (93%,
P<0.001). Of the various clinical and scintigraphic
image variables, the presence of thallium redistribution was the
best multivariate independent predictor of a late
cardiac event (
2=57.8, P<0.0001). The
number of aneurysms detected on CAG added minimal statistical
improvement to the model (2=1.9,
P=0.0009).
Key Words: prognosis • follow-up studies • nuclear medicine • Kawasaki disease
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Kawasaki disease is
an acute febrile illness with mucosal inflammation, skin rash, and
cervical lymphadenopathy recognized most often in children younger than
4 years of age.1 The prognosis of the disease
depends on the extent of associated coronary artery lesions.
Coronary arterial aneurysms develop in
20% of children during the acute stage of untreated Kawasaki
disease, and myocardial infarction may occur as a result of thrombotic
occlusion of the coronary artery even if sufficient
antiplatelet therapy is given.2 The
coronary aneurysms regress spontaneously within 1 to 2
years after onset in more than half of the patients, but some may
progress to obstructive coronary
lesions.3 4 Although coronary artery
lesions are critical complications of Kawasaki disease, their long-term
outcome is still unclear. Recently, coronary artery sequelae of
Kawasaki disease have become one of the most important causes of
coronary artery disease in young
adults.5
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patients and Follow-up
Of 459 consecutive patients with Kawasaki disease who were
admitted to the pediatric cardiology unit at Ehime
University Hospital from 1982 to 1987, coronary
aneurysms were detected in 90 cases (19.6%) by cross-sectional
echocardiography during the acute stage of illness.
The prospective study was conducted with these 90 patients, who all
fulfilled the diagnostic criteria of Kawasaki
disease.2 There were 61 males and 29 females.
From September 1983 to August 1989, these patients underwent paired
studies of selective CAG and dipyridamole-thallium
SPECT, which were performed within a 1-month period. Mean age at the
onset of disease was 2.3±2.2 years, and the interval between onset of
disease and SPECT was 1.6±0.3 years. The study was approved by the
institutional ethics committee for human subjects, and informed consent
was obtained from all parents. 1 of the following features: (1) crescendo angina—more severe,
prolonged, or more frequent anginal attacks, superimposed on chronic
effort angina; (2) angina at rest as well as with minimal exertion; or
(3) angina of recent onset, within 6 weeks, brought on by minimal
exertion.7 In all patients, referral for cardiac
catheterization and subsequent CABG operation
was made by the patient's physician because the patients were
symptomatic, independent of the results of the SPECT.
With the patient in the supine position while ECG and blood
pressure were being monitored, dipyridamole
(Boehringer Ingelheim) was infused intravenously
through the antecubital vein at a rate of 0.14 mg per kg of body weight
per minute for 4 minutes.8 Three minutes after
the infusion, 111 MBq of 201Tl (Nihon
Medi-physics) per 1.7 m2 of body surface area was
injected intravenously. Adverse effects, including ST
depression on ECG, were monitored carefully. We defined >1-mm flat or
downsloping ST-segment depression at 80 ms after the J point as
significant. Parenteral aminophylline was available for treatment of
adverse effects of the dipyridamole infusion. Patients
younger than 4 years who were unable to stay still were sedated 20 to
30 minutes before scintigraphy with high-dose chloral
hydrate (65 to 100 mg/kg) or other short-acting sedatives or hypnotic
agents. The initial images were recorded 5 minutes after the
injection of thallium and the delayed images 3 hours later. 1 grade) or as being fixed if they did not
fill in. The presence of reversible or fixed perfusion defects and, if
present, the number and location of areas having perfusion defects
on the initial images were evaluated in each patient for subsequent
statistical analysis of their prognostic value.
Selective CAG was performed on all patients via the Judkins
femoral approach to assess the diameter of normal, aneurysmal,
and stenotic coronary arteries. The locations of
coronary aneurysms and stenoses were determined
according to the American Heart Association reporting system. We
considered coronary narrowing >50% to be significant. The
percentage of coronary stenosis was calculated with the
nearest normal-appearing portion of the coronary artery (either
distal or proximal to the stenosis) as a standard. The presence
of significant stenoses and the number of aneurysms
were evaluated.
Serial 2-dimensional echocardiographic
examinations with at least 6-month intervals were performed by 2
experienced pediatric echocardiographers for documentation
and follow-up of the coronary sequelae of the patients. The
initial echocardiogram was obtained as soon as the diagnosis of
Kawasaki disease was suspected. This preliminary examination
established a baseline for longitudinal follow-up of coronary
artery morphology. The serial examinations included display of the left
main, anterior descending, and left circumflex coronary
arteries as well as the right coronary artery, and they were
performed by use of a 3.5- or 5-MHz medium-focused transducer (Aloka
Inc). The inner diameters of the vessels were expressed in millimeters
and as percent enlargement relative to the adjacent normal segment.
Care was taken in making the diagnosis of aneurysm because of
considerable normal variations in coronary artery distribution
and dominance.9
Fisher's exact test was used to determine the significance of
differences in rates of occurrence, and all other comparisons between
groups of a single numerical variable were performed by an ANOVA
and appropriate t tests. All results are expressed as
mean±SD. Actuarial event-free rates were analyzed by
Mantel-Breslow survival curves. CIs for binomial proportions were
calculated for each of the survival analysis groups every other
year.10 Differences in event rates were
calculated by the log-rank statistic over the duration of the follow-up
period.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Clinical Response to Dipyridamole
In the 90 patients who underwent
dipyridamole-thallium SPECT, changes of heart rate,
systolic and diastolic blood pressure, and
rate-pressure product that occurred with
dipyridamole infusion are shown in Table 1
. Thirty patients younger than 4 years
required sedative drugs. Both mean heart rate and rate-pressure
product significantly increased, whereas systolic blood
pressure decreased. Significant ST depression on ECG was found in 9
patients (10%). Abdominal pain or discomfort, headache, and chest pain
were observed in 16, 18, and 3 patients, respectively. In patients who
complained of chest pain, aminophylline (3 mg/kg) was infused slowly to
counteract the effects of dipyridamole 2 minutes after
the thallium injection. In these patients, chest pain and ECG changes
disappeared within 2 minutes after the aminophylline infusion. There
were no complications of myocardial infarction, sustained angina, or
death related to this stress test.
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Table 1. Hemodynamic Effects of
Dipyridamole in 90 Patients
The maximal size of aneurysms and the site (right or left
coronary artery) of the largest aneurysm had been
determined by serial echocardiography during the
period between the time of onset and
dipyridamole-thallium SPECT (Table 2). The largest aneurysm was
>8 mm in diameter in 10 patients and >5 mm in 42.
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Table 2. Summary of Clinical and Scintigraphic Results
Of the 90 patients, 15 had some cardiac event over the
8.8±1.2-year follow-up period: 1 cardiac death, 5 acute myocardial
infarctions, 2 CABG operations, and 7 cases of unstable angina pectoris
(event rate: 17%). The remaining 75 patients had no cardiac events
(Table 3). No patients dropped out during
the follow-up period. Only 8 patients (9%) had been treated with
intravenous 
-globulin (400 mg ·
kg-1 ·
d-1)11 during the acute
stage of illness; the remaining 82 patients had been treated with
aspirin (100 mg · kg-1 ·
d-1 orally). Coronary angiograms and
dipyridamole-thallium SPECT images of patient 1 are
shown in Figures 1 and 2, respectively.
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Table 3. SPECT and Angiographic Findings in the 15 Patients
Who Experienced Any Cardiac Event
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Figure 1. Left coronary angiogram (left) shows a
large aneurysm, which was 12 mm in diameter, and severe
postaneurysmatic stenosis at origin of left anterior
descending artery in a 5-and-a-half-year-old boy whose onset of
Kawasaki disease was at 3 years of age. Postaneurysmatic
stenosis (50%) is also seen at origin of left circumflex
artery. Right coronary angiogram (right) shows evidence of
retrograde filling to left anterior descending artery.
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Figure 2. Dipyridamole-thallium SPECT images
of patient in Figure 1 
. Initial image (top) of the
midventricular short axis (Short) shows a perfusion defect
in anteroseptal wall of left myocardium. Vertical long-axis
section (Vertical) shows an anteroapical perfusion defect as well. In
the septal area, the defect had filled in with time, but there may be
some infarcted myocardium at the apex (bottom). This
patient died suddenly while waiting for bypass surgery. DP indicates
dipyridamole stress; RD, redistribution; A, anterior;
S, septal; L, lateral; P, posterior; Ap, apical; and I,
inferior.. Several characteristics were significantly more
frequent in those who had any event, including ST depression with
dipyridamole, presence of significant coronary
stenosis, and presence of redistribution or anterior or
inferior perfusion defects. In addition, the maximal size
of aneurysm, the number of aneurysms, and the number of
defect areas were significantly greater in those who had any event.
However, there were no significant differences based on sex, age at
onset, receipt of -globulin therapy, location of largest
aneurysm, or presence of fixed defects. ). The sensitivity and specificity of
presence of redistribution on SPECT for detecting patients who would
have some event were 93% (14/15) and 83% (62/75), respectively. In
addition, the positive and negative predictive values were 52% (14/27)
and 98% (62/63), respectively.
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Figure 3. Event-free survival rate in patients with or
without thallium redistribution. Actuarial event-free survival rate was
significantly better for the 63 patients without than for the 27
patients with thallium redistribution on SPECT.
A stepwise logistic regression analysis was performed to
evaluate the prognostic significance of the 13 clinical and
scintigraphic indexes in the prediction of cardiac events (Table 4). When the indexes were considered as
independent variables (step 0), the presence of thallium
redistribution was seen to be the most significant predictor
(2=54.4, P<0.0001). In addition,
ST depression, maximal size of the aneurysm, number of
aneurysms, presence of coronary stenosis,
presence of anterior or inferior perfusion defects, and
number of defect areas were also seen to be significant. When the
presence of redistribution was entered in step 1 of the model, the
number of aneurysms was a significant predictor, with the
highest 2 value among the remaining
variables. When these 2 variables were entered in step 2 of the
model, no further statistical improvement was attained by the addition
of the remaining variables. After completion of the model, the
presence of thallium redistribution was the best
multivariate independent predictor of a late cardiac
event (relative risk [odds ratio], 57.8). The number of
aneurysms (relative risk, 1.9) added minimal statistical
improvement to the model beyond the presence of thallium redistribution
alone. From this regression analysis, the predictive
probability of a late cardiac event in patients with no thallium
redistribution was determined to be 1.6±1.6%. The presence of
redistribution raised the predictive probability to 51.9±9.6%, and
the additional presence of 2 aneurysms raised it to
62.7±10.4%.
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[in a new window]
Table 4. Stepwise Logistic Regression Model to Predict
Cardiac Events
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In Japan as well as in North America, Kawasaki disease is
presently a leading cause of acquired heart disease in
children.12 Of particular concern are
coronary artery aneurysms, which may precipitate
thrombosis or evolve into segmental stenoses in the chronic
phase. Although Kato et al13 reported follow-up
data of a cohort of 594 children with Kawasaki disease, they followed
up mainly by repeated CAG and echocardiography. CAG
offers no advantage for the majority of patients with Kawasaki disease
during the acute or convalescent phases because the aneurysms
regress within 1 to 2 years in approximately half of the
patients.4 13 14 Moreover, because all systemic
arteries are potentially affected in patients with Kawasaki disease,
cardiac catheterization carries the added risk of
arterial occlusion or pseudoaneurysm formation at
the catheterization site, especially if repetitive
follow-up examinations are performed.
Our 90 patient subjects were selected on the basis of
aneurysms detected by cross-sectional
echocardiography. Our data demonstrated that the
presence of thallium redistribution on
dipyridamole-thallium SPECT is a powerful predictor of
cardiac events in the follow-up of the selected patients. However,
because SPECT data were not available on the remaining 369 patients who
did not have coronary aneurysms on
echocardiography, the prognostic value and the
false-positive rate of dipyridamole-thallium SPECT in
the unselected patients have not been determined. Therefore, the
usefulness of dipyridamole-thallium SPECT for the
entire group of patients with Kawasaki disease has not been shown
clearly.
We prospectively studied the prognostic value of
dipyridamole-thallium SPECT in patients with Kawasaki
disease who had coronary aneurysms detected by
echocardiography. After paired studies of CAG and
SPECT were conducted, all patients were monitored for the occurrence of
any cardiac events for 8 years. Of various clinical and scintigraphic
indexes used in a stepwise logistic regression analysis, the
presence of thallium redistribution was the best independent predictor
of late cardiac events. Thus, dipyridamole-thallium
SPECT is useful and important for risk stratification in the long-term
follow-up of patients with Kawasaki disease.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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