Silent Myocardial Ischemia in Kawasaki Disease
Evaluation of Percutaneous Transluminal Coronary Angioplasty by Dobutamine Stress Testing
Background Myocardial ischemia and myocardial infarction are the most serious complications of coronary artery lesions in children with Kawasaki disease (KD). Therefore, early detection and treatment of myocardial ischemia in patients with KD is essential. We studied the effectiveness of percutaneous transluminal coronary angioplasty (PTCA) in patients with silent myocardial ischemia detected by dobutamine stress 99mTc myocardial scintigraphy (TMS), body surface mapping (BMS), and signal-averaged ECG late potentials (ELP).
Methods and Results Eight of 76 asymptomatic patients with a coronary stenosis>25% and a positive dobutamine stress test were considered to have silent myocardial ischemia. All eight patients had>95% stenoses demonstrated by coronary angiography (CAG) just before PTCA. After PTCA, CAG showed that all of the coronary artery stenoses had been reduced to<50%. Additionally, intravascular ultrasonography (IVUS) performed in five patients before and after PTCA demonstrated adequate dilation of the coronary stenosis after PTCA. All eight patients underwent dobutamine stress TMS, BMS, and ELP 2 to 3 months after PTCA, which demonstrated no regions of myocardial ischemia. Approximately 6 months later, CAG was performed in all eight patients, and only one patient had developed restenosis.
Conclusions PTCA effectively dilates stenotic coronary arteries in children with KD. Moreover, dobutamine stress TMS, BMS, and ELP are useful for detecting silent myocardial ischemia and estimating the effectiveness of PTCA. Furthermore, IVUS is useful for evaluating the severity of coronary artery lesions before and after PTCA in patients with KD.
Myocardial ischemia and myocardial infarction seriously affect the prognosis of children with coronary artery stenoses caused by KD. It has been recently shown that myocardial hibernation and stunning can be detected by exercise myocardial scintigraphy,1,2 echocardiography,3,4 ECG,5,6 and positron emission tomography.7,8 Young children may not be able to tolerate exercise stress tests for the evaluation of myocardial ischemia. As a result, pharmacological stress tests have been used primarily in children.
Pharmacological stress myocardial scintigraphy detects cardiac ischemia with both a high degree of sensitivity and specificity.9,10 Moreover, pharmacological stress ECG testing, such as BSM and signal-averaged ELP, also can be used to detect myocardial ischemia.11,12 Furthermore, exercise mapping and ELP are convenient, reproducible, and objective and therefore can be used to follow patients with known coronary stenoses.
Recently, PTCA has been performed in patients with KD and severe coronary artery stenosis. However, the effectiveness of PTCA in this group of patients is controversial.13–15 This study was designed to determine the effectiveness of PTCA with the use of IVUS imaging in patients with silent myocardial ischemia detected by dobutamine stress TMS, BSM, and signal-averaged ELP.
Seventy-six patients, aged 10 months to 18 years (mean, 60±2 mo), with a history of KD but no symptoms of myocardial ischemia were screened for inclusion in the study. The patients included 57 men and 19 women; they were followed at the outpatient clinic of the Nippon Medical School Hospital. The time from onset of KD to the time of testing for silent myocardial ischemia ranged from 6 months to 17 years (mean, 39±4 months). The patients had between 25% and 75% stenoses demonstrated by CAG performed at least 5 months before inclusion in the present study. Seventy-four of the patients were treated with γ-globulin 200 to 400 mg · kg−1 · d−1 for 5 days during the acute stage of KD. All of the patients were treated with aspirin 30 mg · kg−1 · d−1 during the acute stage of KD and aspirin 5 mg · kg−1 · d−1 either alone or with warfarin after the acute stage of illness.
Informed consent was obtained from each patient or their parents after the study was explained fully.
Estimation of Silent Myocardial Ischemia
DOB Stress Test
DOB was administered at a dose of 5 μg · kg−1 · min−1 for 3 minutes and then increased in 5 μg · kg−1 · min−1 increments every 3 minutes to a maximum dose of 30 μg · kg−1 · min−1. Young children were sedated at the time of the DOB stress test. The 12-lead ECG was monitored continuously during the stress test; the heart rate, blood pressure, and minute oxygen consumption were recorded every 3 minutes. Additionally, the rate-pressure product was calculated.
DOB administration was discontinued if the patient experienced intolerable chest pain, palpitations, headache, nausea, or if the systolic blood pressure increased to>200 mm Hg. Furthermore, DOB infusion was stopped if frequent or sustained ventricular arrhythmias developed.
DOB Stress 99mTc Tetrofosmin Myocardial Scintigraphy
Single-photon emission computed tomography was performed with 99mTc tetrofosmin with the patient at rest and after DOB infusion. Regions of myocardial ischemia were defined by perfusion defects at rest and/or extension of defects during DOB stress.
DOB Stress BSM
ST segment potential mapping (40 ms after the J-point) and ST-T isointegral mapping were performed for 87 leads with a VCM-3000 system (Fukuda Electronics Ltd, Co). The number of leads with 0.1 mV or more of horizontal or down-sloping ST depression that lasted at least 80 ms were calculated. Myocardial ischemia was defined by ST depression ≥0.1 mV at rest in more than one lead during mapping or if the number of leads with significant ST depression increased with DOB stress. In addition, the location of myocardial ischemia was determined by pattern analysis of the ST-T isointegral map as previously described.16,17
DOB Stress Signal-Averaged ECG Ventricular Late Potentials
Signal-averaged ECGs were recorded with a high resolution VCM-3000 system according to the Simson18 method. With a bandpass filter (40 to 300 Hz), the potentials of 200 heart beats were added and averaged. Values for the filtered QRS duration (f-QRSd), the mean potential during the last 40 ms of the filtered QRS (RMS), and the minimal duration of signal ≤40 μV in the terminal portion of the filtered QRS (LAS) were measured based on our body surface area–related criteria.19
Methods of PTCA
Patients were sedated without the use of general anesthesia. The 12-lead ECG was monitored during PTCA. A pacing catheter was placed in the right ventricle with standby pacing activated at rates below 80% of the resting rate. We performed PTCA with a USCI ProCross over-the-wire balloon catheter. The balloon size was based on the diameter of the adjacent, nonstenotic native coronary artery determined by coronary angiography and IVUS. Sheaths 6F were inserted through right femoral artery punctures and 6F-guiding catheters were generally used. However, in two young patients (patients 6 and 7), 6F sheaths and 6F-guiding catheters were too large to be inserted into their femoral arteries. Therefore, 5F sheaths with 5F coronary angiographic catheters were used. In these two patients, the 5F angiographic catheters were advanced to the coronary ostia, and 0.014-inch guidewires were inserted into the coronary artery through the angiographic catheters. The angiographic catheter was then pulled back, and a balloon catheter was inserted over the guidewire and positioned at the stenotic region. Balloons were inflated to 8 bars of holding pressure. If the coronary artery did not dilate adequately, the inflation pressure was increased in a stepwise fashion by 2 bars. Balloons were inflated over a 30-second period, and maximum pressure was maintained for 60 seconds.
IVUS Evaluation of Coronary Stenoses
A 7F sheath was inserted in the right femoral artery, and a 7F right or left guiding catheter was placed at the coronary ostium. An ultrasound 2.8F-imaging catheter with a 20-MHz transducer and a frame rate of 10 per second (EndoSonics) was advanced down the coronary artery over a 0.014-inch guidewire. The location of the tip of the IVUS catheter was confirmed by fluoroscopy. IVUS images were recorded on videotape (S-VHS), and the diameter and character of the coronary arteries were determined.
Detection of Silent Myocardial Ischemia
DOB stress tests were performed in 76 patients who had stenotic coronary lesions, which had been documented previously. All patients received the maximum dose of DOB 30 μg · kg−1 · min−1, and no one experienced side effects from the DOB. The rate-pressure product was>20 000 in all patients. We defined silent myocardial ischemia as at least two positive DOB stress tests (TMS, BSM, or ELP). Eight of 76 patients had positive DOB stress TMS. Nine patients had positive stress BSM tests, and 10 of them had positive stress ELP tests. If the results of DOB stress myocardial scintigraphy were considered the gold standard, the sensitivity and specificity of DOB stress mapping to detect myocardial ischemia were 88.9% and 100%, respectively. The sensitivity and specificity of DOB stress ELP were 80% and 100%, respectively. Moreover, localization of myocardial ischemia by ST-T isointegral mapping was 75%, coincident (6 of 8 patients) with the region of ischemia determined by DOB stress scintigraphy.
Coronary angiography was performed in the eight patients with positive DOB stress scintigraphy and demonstrated stenoses>95%. The lesions had become more severe compared with the findings of the CAG performed at least 5 months before the DOB stress test (Table 1⇓).
The period from the onset of KD to the time of PTCA ranged in age from 6 months to 16 years old. None of the patients had complaints or abnormal ECG findings either during or after PTCA. After revascularization, there was no ECG evidence of reperfusion injury. Furthermore, there was no release of myocardial enzymes such as CPK-MB, GPT, LDH, or aldolase. PTCA was performed without complication in all eight patients. Immediately after PTCA, coronary angiography revealed that the stenotic lesions were reduced to<50% by PTCA (Fig 1⇓, Table 2⇓).
Evaluation of Coronary Artery Lesions by IVUS Before and After PTCA
Five of the eight patients underwent IVUS before and after PTCA. IVUS performed before PTCA showed that all of the hemodynamically significant lesions had evidence of calcification and intimal-medial thickening. These changes were not only present at the sites of the stenotic lesions but also in nonstenotic regions. Immediately after PTCA, IVUS revealed intimal-medial flaps and/or tears and dilation of the stenotic lesions (Fig 2⇓). IVUS was not performed in three patients because their femoral arteries were too small for the insertion of the guiding catheters for IVUS.
Estimation of Myocardial Ischemia by DOB Stress TMS, BSM, and ELP After PTCA
Two to 3 months after PTCA, all eight patients were reevaluated for the presence of myocardial ischemia with DOB stress testing. The three DOB stress tests (TMS, BSM, and ELP) showed no evidence of ischemia in seven of the patients, suggesting that myocardial blood flow was improved by PTCA (Figs 3⇓ and 4⇓). However, in one patient (patient 4) with a large coronary aneurysm (8×12 mm) in segment 6, a 99% restenosis proximal to the giant aneurysm was noted during CAG 6 months after PTCA. The DOB stress ELP suggested that myocardial ischemia was present after PTCA in this patient.
Coronary Angiograpic Findings 6 Months After PTCA
Seven of the patients had similar CAG findings after PTCA. In the patient (patient 4) with the large coronary aneurysm, the stenosis had improved to only 50% after PTCA. This patient underwent CABG with the left internal mammary artery.
Myocardial ischemia and/or myocardial infarction are the most serious complications that occur in children who have coronary artery disease in the setting of KD. Therefore, early detection of myocardial ischemia with noninvasive, convenient, and reproducible methods followed by appropriate treatment is necessary in such patients.
Myocardial hibernation and stunning can be detected by exercise echocardiography3,4 and exercise myocardial scintigraphy.1,2 However, exercise myocardial scintigraphy cannot be repeated frequently. Moreover, in young children there are age-related changes in the normal radionuclide distribution pattern for myocardial scintigraphy. Therefore, false-negative or false-positive results may occur.20,21 Exercise scintigraphy is not an appropriate method for detecting myocardial ischemia in young children, especially in those<1 year old. Furthermore, it is difficult to evaluate myocardial ischemia in children with exercise echocardiography, as left ventricular wall motion cannot be adequately evaluated because of high heart rates in young patients. In contrast, exercise mapping and ELP tests are objective, noninvasive, convenient, and reproducible.11,12
In this study, both DOB stress mapping and ELP had high sensitivity and specificity in detecting myocardial ischemia when compared with DOB stress TMS. These data indicate that DOB stress mapping and ELP can localize regions of myocardial ischemia without requiring DOB stress scintigraphy. The present results also indicate that DOB stress TMS, BSM, and ELP are useful for both detecting the existence of myocardial ischemia and in the determination of the effectiveness of treatment with PTCA. Additionally, these data demonstrate that DOB stress mapping and ELP may be adequate for detecting myocardial ischemia and therefore the use of DOB stress TSM is avoided. We believe that these two stress tests can be used to detect myocardial ischemia both in patients with known coronary artery disease and those without documented coronary stenoses in the outpatient setting.
One of the eight patients developed coronary restenosis in the proximal portion of a large aneurysm after PTCA. In this patient, PTCA was successful, but severe restenosis was demonstrated 6 months later, and the results of a DOB stress ELP suggested myocardial ischemia 3 months after PTCA. These findings suggest that coronary restenosis occurred by 3 months after PTCA. We hypothesize that a coronary lesion just proximal to the large aneurysm easily restenosed after PTCA because of intimal-medial hypertrophy and thrombus formation that resulted from decreased coronary artery pressure and coronary blood flow in the aneurysm. After the patient underwent CABG, the DOB stress ELP showed no evidence of ischemia.
Intravascular ultrasound imaging was used both to determine the dimensions of the stenotic lesions and the adjacent nonstenotic artery and to assess the vascular wall itself. IVUS demonstrated that the lesions were calcified and that there was intimal-medial thickening not only at the stenotic lesions but also in the nonstenotic regions. These findings are in agreement with previously reported observations.22 If intimal-medial thickening is significant, it may not be possible to dilate the stenotic lesion with PTCA. Similarly, severe calcification may affect the results of PTCA. In this study, high balloon pressures (8 to 14 bars) were required for effective dilation of stenotic lesions. Because of these two factors, IVUS permits decisions to be made about which treatment for coronary artery stenosis is most appropriate.
In the present study, the success of treatment with PTCA could be because the PTCAs were performed relatively early in the course of KD, and the degree of calcification of the stenotic lesions was minimal. PTCA may be contraindicated in patients with severe calcification. Calcification of the coronary arteries in patients with KD is usually detectable 6 years after the onset of the disease.23 In this study, six of the eight patients underwent PTCA within 6 years after the onset of the disease. Moreover, five patients underwent PTCA after the severity of calcification was evaluated by IVUS. Therefore, PTCA should be performed on patients in the early stages of KD and in patients in whom the severity of calcification has been determined by IVUS.
DOB stress TMS, BSM, and ELP are useful for detecting silent myocardial ischemia and estimating the effectiveness of PTCA. Moreover, PTCA is effective in dilating coronary stenoses in children with KD. However, high balloon pressures (8 to 14 bars) are required for effective dilation. Furthermore, IVUS is useful in the evaluation of coronary lesions before and after PTCA.
Selected Abbreviations and Acronyms
|BMS||=||body surface mapping|
|ELP||=||ECG late potentials|
|TMS||=||99mTc myocardial sinctigraphy|
- Received April 8, 1997.
- Revision received June 26, 1997.
- Accepted July 3, 1997.
- Copyright © 1997 by American Heart Association
Cigarroa CG, deFilippi CR, Brickner ME, Alvarez LG, Wait MA, Grayburn PA. Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization. Circulation. 1993;88:430–436.
Afridi I, Kleiman NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation. Optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation. 1995;91:663–670.
Margonato A, Ballarotto C, Bonetti F, Cappelletti A, Sciammarella M, Cianflone D, Chierchia SL. Assessment of residual tissue viability by exercise testing in recent myocardial infarction: comparison of the electrocardiogram and myocardial scintigraphy. J Am Coll Cardiol. 1992;19:948–952.
Lekakis JP, Prassopoulos V, Kostamis P, Moulopoulos S. Dobutamine-induced ST-segment elevation in patients with healed myocardial infarction: a marker of myocardial viability. J Electrocardiol. 1995;28:95–97.
Schwaiger M, Hicks R. The clinical role of metabolic imaging of the heart by positron emission tomography. J Nucl Med. 1991;32:565–578.
Gropler RJ, Geltman EM, Sampathkumaran K, Perez JE, Schechtman KB, Conversano A, Sobel BE, Bergmann SR, Siegel BA. Comparison of carbon-11-acetate with fluorine-18-fluorodeoxy glucose for delineating viable myocardium by positron emission tomography. J Am Coll Cardiol. 1993;22:1587–1597.
Dilsizian V, Perrone-Filardi P, Arrigi JA, Bacharach S, Quyyumi AA, Freedman NMT, Bonow RO. Concordance and discordance between stress-redistribution-reinjection and rest redistribution thallium imaging for assessing viable myocardium: comparison with metabolic activity by positron emission tomography. Circulation. 1993;88:941–952.
Marwick T, Willemart B, D’Hondt A, Baudhuin T, Wijins W, Detry J, Melin J. Selection of the optimal nonexercise stress for the evaluation of ischemic regional myocardial dysfunction and mal-perfusion: comparison of dobutamine and adenosine using echocardiography and 99mTc-MIBI single photon emission computed tomography. Circulation. 1993;87:345–354.
Seki T, Zhang J, Yuge K, Ogawa S, Watanabe M, Hino Y, Katsube Y, Kamisago M, Hirayama T. Dobutamine stress body surface mapping in Kawasaki disease. Eur Heart J. 1994;15:1–185.
Ogawa S, Zhang J, Genma Y, Yuge K, Hino Y, Kamisago M, Seki T, Ohkubo T, Yamamoto M. The clinical evaluation of myocardial ischemia by dobutamine stress late potentials in children with Kawasaki disease. Circulation. 1995;92(suppl I):I-582.
Ino T, Akimoto K, Ohkubo M, Nishimoto K, Yabuta K, Takaya J, Yamaguchi H. Application of percutaneous transluminal coronary angioplasty to coronary arterial stenosis in Kawasaki disease. Circulation. 1996;93:1709–1715.
Fukazawa R, Ogawa S, Hino Y, Jimbo O, Nagai Y, Kamisago M, Seki T, Ohkubo T, Takechi N, Yamamoto M. Assessment of myocardial ischemia before and after percutaneous transluminal coronary angioplasty by dobutamine stressed 99mTc myocardial scintigraphy, body surface mapping and late potentials to the children with Kawasaki disease. Circulation. 1996;94:(suppl I)I-482.
Kubota I, Hanashima K, Ikeda K, Tsuiki K, Yasui S. Detection of diseased coronary artery by exercise ST-T maps in patients with effort angina pectoris, single-vessel disease, and normal ST-T wave on electrocardiogram at rest. Circulation. 1989;80:120–127.
Simson MB. Use of signals in the terminal QRS complex in identifying patients with ventricular tachycardia after myocardial infarction. Circulation. 1980;64:235–242.
Ogawa S, Nagai Y, Zhang J, Yuge K, Hino Y, Jimbo O, Fukazawa R, Hayashi R, Kamisago M, Seki T, Genma Y, Ohkubo T, Takechi N, Yamamoto M. Evaluation of myocardial ischemia and infarction by signal-averaged electrocardiographic late potentials in children with Kawasaki disease. Am J Cardiol. 1996;78:175–181.
DePasquale EE, Nody AC, DePeuey EG, Garacia EV, Pilcher G, Bredlau C, Roubin G, Gober A, Gruentzig A, D’Amato P, Berger HJ. Quantitative rotational thallium-201 tomography for identifying and localization of coronary artery disease. Circulation. 1988;77:316–327.
Kondo C, Hiroe M, Nakanishi T, Takao A. Detection of coronary artery stenosis in children with Kawasaki disease. Circulation. 1989;80:615–624.
Sugimura T, Kato H, Inoue O, Fukuda T, Sato N, Ishii M, Takagi J, Akagi T, Maeno Y, Kawano T, Takagishi T, Sasaguri Y. Intravascular ultrasound of coronary arteries in children: Assessment of the wall morphology and the lumen after Kawasaki disease. Circulation.. 1994;89:258–265.