Prognostic Value of Dipyridamole-Thallium Myocardial Scintigraphy in Patients With Kawasaki Disease
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.
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 ≥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 (χ2=57.8, P<0.0001). The number of aneurysms detected on CAG added minimal statistical improvement to the model (χ2=1.9, P=0.0009).
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.
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
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.
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.
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 ≥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.
Dipyridamole-Thallium SPECT and Interpretation
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.
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 64×64 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 ≥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.
CAG and Interpretation
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.
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.
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.
Echocardiography and CAG Findings
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.
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.
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 γ-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.
Comparative clinical and radionuclide imaging characteristics are summarized in Table 2⇑. 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 γ-globulin therapy, location of largest aneurysm, or presence of fixed defects.
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⇓). 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.
Prediction of Cardiac Events
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 (χ2=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 χ2 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%.
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.
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.
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.
- Received December 8, 1997.
- Revision received April 1, 1998.
- Accepted April 27, 1998.
- Copyright © 1998 by American Heart Association
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