Coronary Computed Tomographic Angiographic Findings in Patients With Kawasaki Disease B. Kelly Han, MDa,b,c,*, Andrew Lesser, BAc, Kristi Rosenthal, RTRc, Kirsten Dummer, MDa, Katharine Grant, PhDd, and Marc Newell, MDc Kawasaki disease (KD) is the leading cause of acquired coronary disease in children and may lead to subsequent myocardial ischemia and infarction. Because coronary computed tomographic angiography (CTA) is the most sensitive noninvasive test in patients with atherosclerosis, the aim of this study was to retrospectively evaluate coronary CTA performed in patients with KD for aneurysm, stenosis, and calcified and noncalcified coronary artery disease (CAD). Clinical histories and prior stress and imaging test results were reviewed. Thirty-two patients underwent coronary CTA for KD, and 385 coronary segments were evaluated. Twenty-three of 32 patients had ‡1 diseased coronary segment. There were 20 aneurysms, 7 lesions, and 75 segments (20%) with nonobstructive CAD (16% noncalcified, 2% calcified, and 2% mixed). All nonobstructive and obstructive CAD was in patients with histories of acute-phase coronary artery dilatation or aneurysm (echocardiographic z score 4 to 44), and were almost always associated with normal stress imaging test results on followup. No lesion or CAD was found in coronary computed tomographic angiographic studies performed in a control group referred for other indications (n [ 32, 422 segments evaluated). The median coronary computed tomographic angiographic dose-length product was 59 mGy cm (interquartile range 32 to 131), the median unadjusted radiation dose was 0.8 mSv (interquartile range 0.4 to 1.8), and the median age- and size-adjusted radiation dose was 1.3 mSv (interquartile range 0.7 to 2.3). In conclusion, high-risk patients with histories of KD had nonobstructive and obstructive CAD not visualized by other noninvasive imaging tests. In properly selected high-risk patients with KD, coronary CTA may identify a subset at increased risk for future coronary pathology who may benefit from medical therapy. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;114:1676e1681) Kawasaki disease (KD) was first described in 1967 and is the leading cause of acquired coronary disease in children in the developed world.1 The small subset of patients who have persistent coronary aneurysms require lifelong follow-up, and the risk for coronary intervention continually increases with age.2 The current guidelines for the care and management of patients with KD recommend routine echocardiography and perfusion imaging for long-term evaluation of coronary pathology in high-risk patients who may require intervention.3 Coronary angiography is recommended within the first year for those with giant aneurysms at the highest risk for morbidity and mortality and in patients with symptoms suggestive of coronary ischemia. Coronary computed tomographic angiography (CTA) is the most sensitive noninvasive test for detecting a coronary stenosis and identifies obstructive and nonobstructive coronary artery disease (CAD) that may cause ischemia or predict a future cardiac event in patients with atherosclerosis.4,5 There are no previous reports of coronary CTA analysis of CAD a The Children’s Heart Clinic; bThe Children’s Hospitals and Clinics of Minnesota; cAdvanced Cardiac Imaging, The Minneapollis Heart Institute and Foundation, Minneapolis, Minnesota; and dSiemens Healthcare, Malvern, Pennsylvania. Manuscript received June 7, 2014; revised manuscript received and accepted September 2, 2014. See page 1680 for disclosure information. *Corresponding author: Tel: (612) 813-8800; fax: (612) 813-8825. E-mail address: [email protected] (B.K. Han).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.09.004
with low Hounsfield unit (HU) attenuation in patients with previous KD. We investigated whether coronary CTA may demonstrate coronary disease in these patients not otherwise identified by currently recommended diagnostic techniques. Methods This was a retrospective descriptive cohort study of consecutive subjects who underwent coronary CTA for evaluation of KD associated CAD at a single institution from April 2007 to August 2013. The KD group was compared with a gender-, age-, and size-matched control group randomly selected from coronary computed tomographic angiographic studies performed for other indications. Institutional review board approval was obtained. All patients with KD were followed by a pediatric cardiologist and were treated according to national consensus guidelines from 1994 and revised in 20043,6 and clinical judgment. Patients were referred to coronary CTA on the basis of a clinician’s discretion. Charts were reviewed for KD history, including age at diagnosis, treatment, acutephase reactants, and clinical course. All previous echocardiographic, angiographic, exercise tests or stress perfusion imaging results were reviewed and correlated with the anatomic coronary artery findings. Z scores were calculated for coronary artery measurements obtained by echocardiography during the acute phase of illness. Patients 7 years of age were able to cooperate with a breath hold for image acquisition (n ¼ 23). All patients were scanned on a first-generation dual-source (Siemens Definition, temporal resolution 83 ms; Siemens Healthcare, Forchheim, Germany) or second-generation dual-source (Siemens Definition Flash, temporal resolution 75 ms) scanner. Retrospective electrocardiographic gating (Mindose protocol) was used for patients on the firstgeneration dual-source scanner (from 2007 to 2009). Prospectively electrocardiographically triggered scan mode was used for patients who underwent coronary CTA on the second-generation dual-source scanner (from 2009 to 2013). A high-pitch scan mode (pitch 3.4) was used when the heart rate was 10 beats/min. Scanner output adjustment for body weight, b blockade, and contrast injection protocol were previously described.7 A pediatric and/or adult cardiologist experienced in coronary CTA was in attendance for all scans. All coronary computed tomographic image data sets (KD and control groups) were evaluated using curved multiplanar reformatted images with the use of a commercially available image postprocessing workstation (Vitrea 4; Vital Images, Minnetonka, Minnesota). Coronary arteries were divided into 16 segments per patient, as recommended by
the Society of Cardiovascular Computed Tomography.8 An adult cardiologist (MN) experienced in coronary CTA evaluated all coronary artery segments in the first 4 cm of each vessel for the presence of stenosis on the basis of the percentage of luminal narrowing (none, mild [70%]), as well as the presence of noncalcified (low attenuation, 30 to 149 HU), calcified (high attenuation, >149 HU), and mixed CAD. The segments contained in the proximal 4 cm of each coronary artery considered abnormal were additionally evaluated with a plaque software evaluation tool on the basis of HU attenuation (surePlaque; Vital Images) designed for patients with CAD. The outer vessel boundary and inner luminal boundary of the abnormal segments were automatically traced and subsequently manually adjusted in a cross-sectional view. Single-pixel HU attenuation was measured in multiple points within each segment with possible coronary disease. The median and range of HU attenuation for all abnormal segments were calculated.9 Aneurysm was defined as a coronary vessel >3 mm in patients 4 mm in patients >5 years of age. A coronary artery z score was calculated for all echocardiographic measurements meeting this criterion and was compared with measurements obtained from the coronary computed tomographic angiographic scans. Descriptive statistics are displayed as medians and interquartile ranges for continuous variables. CAD was
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Figure 1. (A) Severe stenosis (arrow) of the left main coronary artery in a 4-year-old male patient 3 months after the diagnosis of KD. Initial echocardiograms showed ectasia without aneurysm. (B,C) Echocardiographic 2-dimensional image (short arrow) and color Doppler image of the proximal left main coronary artery (long arrow) suggesting no obstruction immediately after CTA.
Figure 2. A giant left anterior descending coronary artery aneurysm (short arrow) in an 18-month-old female patient. There is thrombus and stenosis (long arrow) at the distal end of the aneurysm.
analyzed per segment; the number of affected segments compared with total segments analyzed is described as a percentage. Noncalcified and calcified CAD, lesion, and aneurysm size were described per patient and compared with controls. Categorical variables are displayed as number and percentages. Groups were compared using Pearson’s chi-square or Fisher’s exact tests. Continuous variables were analyzed using Student’s t test or analysis of variance for normally distributed variables and Kruskal-Wallis tests for continuous variables not normally distributed. Aneurysm measurement by echocardiography versus coronary CTA was compared using a correlation coefficient. A p value 6 mg/L, sedimentation rate >75 mg/L), requiring >1 dose of immunoglobulin, steroids, or infliximab for resolution of symptoms. Initial laboratory data were not available for 6 patients diagnosed at outside institutions and referred for follow-up after the acute phase of illness. The control group consisted of 32 patients randomly selected from age-, size-, and gender-matched patients who underwent coronary CTA for other indications. Control group and KD group comparisons are listed in Table 1. The proximal 4 cm of all coronary segments in the KD and control group coronary computed tomographic angiographic studies were evaluated for the presence of stenosis and calcified and noncalcified CAD. In the 32 patients with KD, 22 (69%) had 1 coronary segment with CAD. Three hundred eighty-five segments were included in the proximal 4 cm of the 32 data sets. Seventy-five segments (20%) were determined to have calcified and noncalcified CAD by visual estimate. Of those, 61 segments had noncalcified CAD, 7 segments had calcified CAD, and 7 segments had mixed CAD. All segments qualitatively determined to have CAD were also documented by the automated plaque analysis tool. Twenty coronary aneurysms and 7 coronary lesions (2 occlusion, 3 severe, 1 moderate, and 1 mild) were present. Representative examples are shown in Figures 1-4. Of the 23 patients with abnormal findings, 8 patients had CAD and aneurysms, 7 patients had isolated CAD, 2 patients had lesions with additional CAD but no aneurysm, 5 patients had CAD, aneurysms, and coronary lesions, and 1
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Figure 3. (A) 2-dimensional representation of total left anterior descending coronary artery occlusion at the proximal end of a previous aneurysm in a 23-yearold patient (short arrow). (B) 3D representation of the occlusion (long arrow) with collateral filling of the coronary artery distal to the calcified aneurysm. (C) Diffuse calcification of the right coronary artery in the same patient. The left main coronary aneurysm had resolved during echocardiographic follow-up.
Figure 4. Eccentric plaque deposition (arrow) with an intact lumen of normal size. This is an example of positive remodeling (Glagov effect). Note the left anterior descending coronary artery is ectatic in the area of prior aneurysm.
patient had an isolated aneurysm. Patients with KD with normal results on coronary CTA had acute-phase echocardiograms showing normal coronary arteries or diffuse dilatation of the coronary arteries without aneurysms (z ¼ 2.5 to 9) that resolved during follow-up. All patients with abnormal results on coronary CTA had acute-phase echocardiograms showing profound coronary artery dilatation or aneurysm, with echocardiography-based coronary artery z scores ranging from 4.7 to 44. Four hundred twenty-two segments were included in the first 4 cm of the control group coronary CTA, and no coronary aneurysms, lesions, or calcified or noncalcified CAD was found. The difference between the number of coronary lesions and coronary segments with CAD in the KD versus control group was statistically significant (p 5 mg/L) and sedimentation rate (100% to >50 mg/L) at the time of diagnosis. The presence of CAD was increased in those treated after 10 days of illness. Coronary disease was present in only 47% of patients diagnosed and treated in the first 10 days of illness compared with 89% of those diagnosed after 10 days of illness (p ¼ 0.036). A higher percentage of patients given >1 dose of intravenous immunoglobulin had disease (85.7%) compared with patients given 1 dose of intravenous immunoglobulin (58.8%), but the association was not statistically significant (p ¼ 0.132).
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Discussion We identified obstructive and nonobstructive CAD by coronary CTA in a highly select group of patients with KD with acute-phase coronary artery dilatation, resolved coronary aneurysms, or persistent coronary aneurysms. Coronary disease was present at the time of coronary CTA, with and without persistent coronary aneurysms. Stress imaging studies rarely suggested the presence of physiologically important CAD in those with or without obstruction. The risk stratification of patients with KD is determined primarily by the extent of coronary artery involvement during the initial phase of illness. Patients with giant or residual aneurysms are known to have an ever increasing risk for coronary obstruction during long-term follow-up.2 Coronary arterial intimal proliferation and fibrosis have been found on postmortem examinations of patients with KD who died of noncardiac causes with angiographically documented regression of previous coronary artery aneurysms.10 Recent investigation of computed tomographyebased calcium scoring in patients with histories of KD validates these findings and shows that some patients with previous or persistent aneurysms had calcium scores >0.11,12 These findings suggest that chronic coronary changes occur in a subset of patients after the acute inflammation of disease onset. The initial mechanism of coronary arterial injury in KD is thought to be different from adult atherosclerosis.13,14 Despite the potential difference in the mechanism, medical therapy with statin agents has been helpful in limiting inflammatory-mediated coronary vasculopathy in disease processes such as postecardiac transplantation.15,16 Importantly, the appearance and location of coronary disease in the patients with KD in our small cohort are similar in appearance to plaque associated with atherosclerotic heart disease and transplant coronary vasculopathy in adults.15 The current guidelines are designed primarily to identify patients potentially requiring intervention. There are conflicting reports of the sensitivity of stress imaging tests for obstructive disease identification in this patient population.17e19 Our results agree with studies showing poor correlation between the severity of a coronary lesion and physiologic testing.18,19 Current recommendations for follow-up of asymptomatic patients with KD may not be adequate to detect nonobstructive or obstructive coronary artery lesions with collateral circulation that have been shown to increase the risk for future coronary events in patients with atherosclerosis.4,20 Coronary computed tomographic angiographic characterization of plaque presence and extent and stenosis severity has been shown to be a strong predictor of major adverse coronary events in the adult population with atherosclerosis.4,21 Identification of similar pathology in the KD population may allow the identification of a high-risk subset of patients who may benefit from medical therapy that would not otherwise be offered. The major limitation of coronary CTA in the pediatric patient population has been the exposure to ionizing radiation. On our current-generation scanner, the median doselength product for a coronary CTA scan was 59 mGy cm. Using the standard adult chest conversion factor estimates
an effective radiation dose of 0.8 mSv, which is equivalent to several months of background radiation at sea level in the United States. This study was retrospective, with a small patient cohort. There is incomplete clinical follow-up and variability of clinical practice regarding the use of coronary CTA and stress perfusion imaging. Older patients were diagnosed before the development of standard consensus treatment guidelines in 1994. Our coronary computed tomographic angiographic analysis was able to determine the presence of disease within the coronary wall but did not quantify total disease burden. Although we discovered previously unrecognized nonobstructive and obstructive coronary disease, it is presently unknown if this finding alone predisposes patients to excess risk that could be modified by medical therapy. Noninvasive assessment of low-HU CAD cannot differentiate between coronary atheroma and intimal hyperplasia. Disclosures Dr. Han is a member of the speakers’ bureau of Siemens and has received grant support. Dr. Newell is a member of the speakers’ bureau of Siemens. Dr. Grant is an employee of Siemens. 1. Taubert KA, Rowley AH, Shulman ST. Nationwide survey of Kawasaki disease and acute rheumatic fever. J Pediatr 1991;119:279e282. 2. Suda K, Iemura M, Nishiono H, Teramachi Y, Koteda Y, Kishimoto S, Kudo Y, Itoh S, Ishii H, Ueno T, Tashiro T, Nobuyoshi M, Kato H, Matsuishi T. Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience. Circulation 2011;123:1836e1842. 3. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004;114:1708e1733. 4. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 5. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O’Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358: 1336e1345. 6. Dajani AS, Taubert KA, Takahashi M, Bierman FZ, Freed MD, Ferrieri P, Gerber M, Shulman ST, Karchmer AW, Wilson W. Guidelines for long-term management of patients with kawasaki disease. Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 1994;89:916e922. 7. Han BK, Lindberg J, Overman D, Schwartz RS, Grant K, Lesser JR. Safety and accuracy of dual-source coronary computed tomography angiography in the pediatric population. J Cardiovasc Comput Tomogr 2012;6:252e259. 8. Raff GL, Abidov A, Achenbach S, Berman DS, Boxt LM, Budoff MJ, Cheng V, DeFrance T, Hellinger JC, Karlsberg RP. SCCT guidelines
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9.
10. 11. 12. 13.
14.
15.
for the interpretation and reporting of coronary computed tomographic angiography. J Cardiovasc Comput Tomogr 2009;3:122e136. Rinehart S, Vazquez G, Qian Z, Murrieta L, Christian K, Voros S. Quantitative measurements of coronary arterial stenosis, plaque geometry, and composition are highly reproducible with a standardized coronary arterial computed tomographic approach in high-quality CT datasets. J Cardiovasc Comput Tomogr 2011;5:35e43. Naoe S, Takahashi K, Masuda H, Tanaka N. Coronary findings post Kawasaki disease in children who died of other causes. Prog Clin Biol Res 1987;250:341e346. Dadlani GH, Gingell RL, Orie JD, Roland JM, Najdzionek J, Lipsitz SR, Pieroni DR, Lipshultz SE. Coronary artery calcifications in the long-term follow-up of Kawasaki disease. Am Heart J 2005;150:1016. Kahn AM, Budoff MJ, Daniels LB, Jimenez-Fernandez S, Cox AS, Gordon JB, Burns JC. Calcium scoring in patients with a history of Kawasaki disease. JACC Cardiovasc Imaging 2012;5:264e272. Suzuki A, Miyagawa-Tomita S, Nakazawa M, Yutani C. Remodeling of coronary artery lesions due to Kawasaki disease: comparison of arteriographic and immunohistochemical findings. Jpn Heart J 2000;41:245e256. Suzuki A, Miyagawa-Tomita S, Komatsu K, Nishikawa T, Sakomura Y, Horie T, Nakazawa M. Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease: immunohistochemical study. Circulation 2000;101:2935e2941. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, Steinbeck G, Seidel D, Reichart B. Simvastatin initiated early after
16. 17. 18.
19.
20.
21.
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heart transplantation: 8-year prospective experience. Circulation 2003;107:93e97. Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation 2008;117:2131e2141. Shiraishi I, Onouchi Z, Hayano T, Hamaoka K, Kiyosawa N. Asymptomatic myocardial infarction in Kawasaki disease: long-term prognosis. Pediatr Cardiol 1991;12:78e82. Fu YC, Shiau YC, Tsai SC, Kao A, Hwang B, Chi CS. Discordance between dipyridamole stress technetium-99m tetrofosmin single photon emission computed tomography and coronary angiography in patients with Kawasaki disease. Int J Cardiovasc Imaging 2002;18: 357e362. Lee PC, Shiau YC, Fu YC, Kao A, Lin CC, Lee CC. Discordance between dipyridamole technetium-99m-sestamibi myocardial perfusion single photon emission computed tomography and two-dimensional echocardiography in Kawasaki disease—a preliminary report. Int J Cardiovasc Imaging 2002;18:343e348. Hadamitzky M, Taubert S, Deseive S, Byrne RA, Martinoff S, Schomig A, Hausleiter J. Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease. Eur Heart J 2013;34:3277e3285. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49e57.
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2014.09.004
with low Hounsfield unit (HU) attenuation in patients with previous KD. We investigated whether coronary CTA may demonstrate coronary disease in these patients not otherwise identified by currently recommended diagnostic techniques. Methods This was a retrospective descriptive cohort study of consecutive subjects who underwent coronary CTA for evaluation of KD associated CAD at a single institution from April 2007 to August 2013. The KD group was compared with a gender-, age-, and size-matched control group randomly selected from coronary computed tomographic angiographic studies performed for other indications. Institutional review board approval was obtained. All patients with KD were followed by a pediatric cardiologist and were treated according to national consensus guidelines from 1994 and revised in 20043,6 and clinical judgment. Patients were referred to coronary CTA on the basis of a clinician’s discretion. Charts were reviewed for KD history, including age at diagnosis, treatment, acutephase reactants, and clinical course. All previous echocardiographic, angiographic, exercise tests or stress perfusion imaging results were reviewed and correlated with the anatomic coronary artery findings. Z scores were calculated for coronary artery measurements obtained by echocardiography during the acute phase of illness. Patients 7 years of age were able to cooperate with a breath hold for image acquisition (n ¼ 23). All patients were scanned on a first-generation dual-source (Siemens Definition, temporal resolution 83 ms; Siemens Healthcare, Forchheim, Germany) or second-generation dual-source (Siemens Definition Flash, temporal resolution 75 ms) scanner. Retrospective electrocardiographic gating (Mindose protocol) was used for patients on the firstgeneration dual-source scanner (from 2007 to 2009). Prospectively electrocardiographically triggered scan mode was used for patients who underwent coronary CTA on the second-generation dual-source scanner (from 2009 to 2013). A high-pitch scan mode (pitch 3.4) was used when the heart rate was 10 beats/min. Scanner output adjustment for body weight, b blockade, and contrast injection protocol were previously described.7 A pediatric and/or adult cardiologist experienced in coronary CTA was in attendance for all scans. All coronary computed tomographic image data sets (KD and control groups) were evaluated using curved multiplanar reformatted images with the use of a commercially available image postprocessing workstation (Vitrea 4; Vital Images, Minnetonka, Minnesota). Coronary arteries were divided into 16 segments per patient, as recommended by
the Society of Cardiovascular Computed Tomography.8 An adult cardiologist (MN) experienced in coronary CTA evaluated all coronary artery segments in the first 4 cm of each vessel for the presence of stenosis on the basis of the percentage of luminal narrowing (none, mild [70%]), as well as the presence of noncalcified (low attenuation, 30 to 149 HU), calcified (high attenuation, >149 HU), and mixed CAD. The segments contained in the proximal 4 cm of each coronary artery considered abnormal were additionally evaluated with a plaque software evaluation tool on the basis of HU attenuation (surePlaque; Vital Images) designed for patients with CAD. The outer vessel boundary and inner luminal boundary of the abnormal segments were automatically traced and subsequently manually adjusted in a cross-sectional view. Single-pixel HU attenuation was measured in multiple points within each segment with possible coronary disease. The median and range of HU attenuation for all abnormal segments were calculated.9 Aneurysm was defined as a coronary vessel >3 mm in patients 4 mm in patients >5 years of age. A coronary artery z score was calculated for all echocardiographic measurements meeting this criterion and was compared with measurements obtained from the coronary computed tomographic angiographic scans. Descriptive statistics are displayed as medians and interquartile ranges for continuous variables. CAD was
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The American Journal of Cardiology (www.ajconline.org)
Figure 1. (A) Severe stenosis (arrow) of the left main coronary artery in a 4-year-old male patient 3 months after the diagnosis of KD. Initial echocardiograms showed ectasia without aneurysm. (B,C) Echocardiographic 2-dimensional image (short arrow) and color Doppler image of the proximal left main coronary artery (long arrow) suggesting no obstruction immediately after CTA.
Figure 2. A giant left anterior descending coronary artery aneurysm (short arrow) in an 18-month-old female patient. There is thrombus and stenosis (long arrow) at the distal end of the aneurysm.
analyzed per segment; the number of affected segments compared with total segments analyzed is described as a percentage. Noncalcified and calcified CAD, lesion, and aneurysm size were described per patient and compared with controls. Categorical variables are displayed as number and percentages. Groups were compared using Pearson’s chi-square or Fisher’s exact tests. Continuous variables were analyzed using Student’s t test or analysis of variance for normally distributed variables and Kruskal-Wallis tests for continuous variables not normally distributed. Aneurysm measurement by echocardiography versus coronary CTA was compared using a correlation coefficient. A p value 6 mg/L, sedimentation rate >75 mg/L), requiring >1 dose of immunoglobulin, steroids, or infliximab for resolution of symptoms. Initial laboratory data were not available for 6 patients diagnosed at outside institutions and referred for follow-up after the acute phase of illness. The control group consisted of 32 patients randomly selected from age-, size-, and gender-matched patients who underwent coronary CTA for other indications. Control group and KD group comparisons are listed in Table 1. The proximal 4 cm of all coronary segments in the KD and control group coronary computed tomographic angiographic studies were evaluated for the presence of stenosis and calcified and noncalcified CAD. In the 32 patients with KD, 22 (69%) had 1 coronary segment with CAD. Three hundred eighty-five segments were included in the proximal 4 cm of the 32 data sets. Seventy-five segments (20%) were determined to have calcified and noncalcified CAD by visual estimate. Of those, 61 segments had noncalcified CAD, 7 segments had calcified CAD, and 7 segments had mixed CAD. All segments qualitatively determined to have CAD were also documented by the automated plaque analysis tool. Twenty coronary aneurysms and 7 coronary lesions (2 occlusion, 3 severe, 1 moderate, and 1 mild) were present. Representative examples are shown in Figures 1-4. Of the 23 patients with abnormal findings, 8 patients had CAD and aneurysms, 7 patients had isolated CAD, 2 patients had lesions with additional CAD but no aneurysm, 5 patients had CAD, aneurysms, and coronary lesions, and 1
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Figure 3. (A) 2-dimensional representation of total left anterior descending coronary artery occlusion at the proximal end of a previous aneurysm in a 23-yearold patient (short arrow). (B) 3D representation of the occlusion (long arrow) with collateral filling of the coronary artery distal to the calcified aneurysm. (C) Diffuse calcification of the right coronary artery in the same patient. The left main coronary aneurysm had resolved during echocardiographic follow-up.
Figure 4. Eccentric plaque deposition (arrow) with an intact lumen of normal size. This is an example of positive remodeling (Glagov effect). Note the left anterior descending coronary artery is ectatic in the area of prior aneurysm.
patient had an isolated aneurysm. Patients with KD with normal results on coronary CTA had acute-phase echocardiograms showing normal coronary arteries or diffuse dilatation of the coronary arteries without aneurysms (z ¼ 2.5 to 9) that resolved during follow-up. All patients with abnormal results on coronary CTA had acute-phase echocardiograms showing profound coronary artery dilatation or aneurysm, with echocardiography-based coronary artery z scores ranging from 4.7 to 44. Four hundred twenty-two segments were included in the first 4 cm of the control group coronary CTA, and no coronary aneurysms, lesions, or calcified or noncalcified CAD was found. The difference between the number of coronary lesions and coronary segments with CAD in the KD versus control group was statistically significant (p 5 mg/L) and sedimentation rate (100% to >50 mg/L) at the time of diagnosis. The presence of CAD was increased in those treated after 10 days of illness. Coronary disease was present in only 47% of patients diagnosed and treated in the first 10 days of illness compared with 89% of those diagnosed after 10 days of illness (p ¼ 0.036). A higher percentage of patients given >1 dose of intravenous immunoglobulin had disease (85.7%) compared with patients given 1 dose of intravenous immunoglobulin (58.8%), but the association was not statistically significant (p ¼ 0.132).
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The American Journal of Cardiology (www.ajconline.org)
Discussion We identified obstructive and nonobstructive CAD by coronary CTA in a highly select group of patients with KD with acute-phase coronary artery dilatation, resolved coronary aneurysms, or persistent coronary aneurysms. Coronary disease was present at the time of coronary CTA, with and without persistent coronary aneurysms. Stress imaging studies rarely suggested the presence of physiologically important CAD in those with or without obstruction. The risk stratification of patients with KD is determined primarily by the extent of coronary artery involvement during the initial phase of illness. Patients with giant or residual aneurysms are known to have an ever increasing risk for coronary obstruction during long-term follow-up.2 Coronary arterial intimal proliferation and fibrosis have been found on postmortem examinations of patients with KD who died of noncardiac causes with angiographically documented regression of previous coronary artery aneurysms.10 Recent investigation of computed tomographyebased calcium scoring in patients with histories of KD validates these findings and shows that some patients with previous or persistent aneurysms had calcium scores >0.11,12 These findings suggest that chronic coronary changes occur in a subset of patients after the acute inflammation of disease onset. The initial mechanism of coronary arterial injury in KD is thought to be different from adult atherosclerosis.13,14 Despite the potential difference in the mechanism, medical therapy with statin agents has been helpful in limiting inflammatory-mediated coronary vasculopathy in disease processes such as postecardiac transplantation.15,16 Importantly, the appearance and location of coronary disease in the patients with KD in our small cohort are similar in appearance to plaque associated with atherosclerotic heart disease and transplant coronary vasculopathy in adults.15 The current guidelines are designed primarily to identify patients potentially requiring intervention. There are conflicting reports of the sensitivity of stress imaging tests for obstructive disease identification in this patient population.17e19 Our results agree with studies showing poor correlation between the severity of a coronary lesion and physiologic testing.18,19 Current recommendations for follow-up of asymptomatic patients with KD may not be adequate to detect nonobstructive or obstructive coronary artery lesions with collateral circulation that have been shown to increase the risk for future coronary events in patients with atherosclerosis.4,20 Coronary computed tomographic angiographic characterization of plaque presence and extent and stenosis severity has been shown to be a strong predictor of major adverse coronary events in the adult population with atherosclerosis.4,21 Identification of similar pathology in the KD population may allow the identification of a high-risk subset of patients who may benefit from medical therapy that would not otherwise be offered. The major limitation of coronary CTA in the pediatric patient population has been the exposure to ionizing radiation. On our current-generation scanner, the median doselength product for a coronary CTA scan was 59 mGy cm. Using the standard adult chest conversion factor estimates
an effective radiation dose of 0.8 mSv, which is equivalent to several months of background radiation at sea level in the United States. This study was retrospective, with a small patient cohort. There is incomplete clinical follow-up and variability of clinical practice regarding the use of coronary CTA and stress perfusion imaging. Older patients were diagnosed before the development of standard consensus treatment guidelines in 1994. Our coronary computed tomographic angiographic analysis was able to determine the presence of disease within the coronary wall but did not quantify total disease burden. Although we discovered previously unrecognized nonobstructive and obstructive coronary disease, it is presently unknown if this finding alone predisposes patients to excess risk that could be modified by medical therapy. Noninvasive assessment of low-HU CAD cannot differentiate between coronary atheroma and intimal hyperplasia. Disclosures Dr. Han is a member of the speakers’ bureau of Siemens and has received grant support. Dr. Newell is a member of the speakers’ bureau of Siemens. Dr. Grant is an employee of Siemens. 1. Taubert KA, Rowley AH, Shulman ST. Nationwide survey of Kawasaki disease and acute rheumatic fever. J Pediatr 1991;119:279e282. 2. Suda K, Iemura M, Nishiono H, Teramachi Y, Koteda Y, Kishimoto S, Kudo Y, Itoh S, Ishii H, Ueno T, Tashiro T, Nobuyoshi M, Kato H, Matsuishi T. Long-term prognosis of patients with Kawasaki disease complicated by giant coronary aneurysms: a single-institution experience. Circulation 2011;123:1836e1842. 3. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, Shulman ST, Bolger AF, Ferrieri P, Baltimore RS, Wilson WR, Baddour LM, Levison ME, Pallasch TJ, Falace DA, Taubert KA. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004;114:1708e1733. 4. Min JK, Dunning A, Lin FY, Achenbach S, Al-Mallah M, Budoff MJ, Cademartiri F, Callister TQ, Chang HJ, Cheng V, Chinnaiyan K, Chow BJ, Delago A, Hadamitzky M, Hausleiter J, Kaufmann P, Maffei E, Raff G, Shaw LJ, Villines T, Berman DS. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol 2011;58:849e860. 5. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, Liu K, Shea S, Szklo M, Bluemke DA, O’Leary DH, Tracy R, Watson K, Wong ND, Kronmal RA. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med 2008;358: 1336e1345. 6. Dajani AS, Taubert KA, Takahashi M, Bierman FZ, Freed MD, Ferrieri P, Gerber M, Shulman ST, Karchmer AW, Wilson W. Guidelines for long-term management of patients with kawasaki disease. Report from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation 1994;89:916e922. 7. Han BK, Lindberg J, Overman D, Schwartz RS, Grant K, Lesser JR. Safety and accuracy of dual-source coronary computed tomography angiography in the pediatric population. J Cardiovasc Comput Tomogr 2012;6:252e259. 8. Raff GL, Abidov A, Achenbach S, Berman DS, Boxt LM, Budoff MJ, Cheng V, DeFrance T, Hellinger JC, Karlsberg RP. SCCT guidelines
Coronary Artery Disease/CT Plaque Analysis in Kawasaki Disease
9.
10. 11. 12. 13.
14.
15.
for the interpretation and reporting of coronary computed tomographic angiography. J Cardiovasc Comput Tomogr 2009;3:122e136. Rinehart S, Vazquez G, Qian Z, Murrieta L, Christian K, Voros S. Quantitative measurements of coronary arterial stenosis, plaque geometry, and composition are highly reproducible with a standardized coronary arterial computed tomographic approach in high-quality CT datasets. J Cardiovasc Comput Tomogr 2011;5:35e43. Naoe S, Takahashi K, Masuda H, Tanaka N. Coronary findings post Kawasaki disease in children who died of other causes. Prog Clin Biol Res 1987;250:341e346. Dadlani GH, Gingell RL, Orie JD, Roland JM, Najdzionek J, Lipsitz SR, Pieroni DR, Lipshultz SE. Coronary artery calcifications in the long-term follow-up of Kawasaki disease. Am Heart J 2005;150:1016. Kahn AM, Budoff MJ, Daniels LB, Jimenez-Fernandez S, Cox AS, Gordon JB, Burns JC. Calcium scoring in patients with a history of Kawasaki disease. JACC Cardiovasc Imaging 2012;5:264e272. Suzuki A, Miyagawa-Tomita S, Nakazawa M, Yutani C. Remodeling of coronary artery lesions due to Kawasaki disease: comparison of arteriographic and immunohistochemical findings. Jpn Heart J 2000;41:245e256. Suzuki A, Miyagawa-Tomita S, Komatsu K, Nishikawa T, Sakomura Y, Horie T, Nakazawa M. Active remodeling of the coronary arterial lesions in the late phase of Kawasaki disease: immunohistochemical study. Circulation 2000;101:2935e2941. Wenke K, Meiser B, Thiery J, Nagel D, von Scheidt W, Krobot K, Steinbeck G, Seidel D, Reichart B. Simvastatin initiated early after
16. 17. 18.
19.
20.
21.
1681
heart transplantation: 8-year prospective experience. Circulation 2003;107:93e97. Schmauss D, Weis M. Cardiac allograft vasculopathy: recent developments. Circulation 2008;117:2131e2141. Shiraishi I, Onouchi Z, Hayano T, Hamaoka K, Kiyosawa N. Asymptomatic myocardial infarction in Kawasaki disease: long-term prognosis. Pediatr Cardiol 1991;12:78e82. Fu YC, Shiau YC, Tsai SC, Kao A, Hwang B, Chi CS. Discordance between dipyridamole stress technetium-99m tetrofosmin single photon emission computed tomography and coronary angiography in patients with Kawasaki disease. Int J Cardiovasc Imaging 2002;18: 357e362. Lee PC, Shiau YC, Fu YC, Kao A, Lin CC, Lee CC. Discordance between dipyridamole technetium-99m-sestamibi myocardial perfusion single photon emission computed tomography and two-dimensional echocardiography in Kawasaki disease—a preliminary report. Int J Cardiovasc Imaging 2002;18:343e348. Hadamitzky M, Taubert S, Deseive S, Byrne RA, Martinoff S, Schomig A, Hausleiter J. Prognostic value of coronary computed tomography angiography during 5 years of follow-up in patients with suspected coronary artery disease. Eur Heart J 2013;34:3277e3285. Motoyama S, Sarai M, Harigaya H, Anno H, Inoue K, Hara T, Naruse H, Ishii J, Hishida H, Wong ND, Virmani R, Kondo T, Ozaki Y, Narula J. Computed tomographic angiography characteristics of atherosclerotic plaques subsequently resulting in acute coronary syndrome. J Am Coll Cardiol 2009;54:49e57.
