Kawasaki disease (KD) is an acute febrile disorder with. Pediatric Cardiology

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1 Pediatric Cardiology In Vivo Plaque Composition and Morphology in Coronary Artery Lesions in Adolescents and Young Adults Long After Kawasaki Disease A Virtual Histology Intravascular Ultrasound Study Yoshihide Mitani, MD, PhD; Hiroyuki Ohashi, MD; Hirofumi Sawada, MD, PhD; Yukiko Ikeyama, MD; Hidetoshi Hayakawa, MD, PhD; Shin Takabayashi, MD, PhD; Kazuo Maruyama, MD, PhD; Hideto Shimpo, MD, PhD; Yoshihiro Komada, MD, PhD Background Coronary artery lesions (CALs) late after Kawasaki disease were characterized by endothelial dysfunction and low-grade inflammation, surrogate markers for atherosclerosis. We tested the hypothesis that CALs in patients long after Kawasaki disease are accompanied by atheroma-like features, as assessed by virtual histology intravascular ultrasound, a new method to assess coronary plaque composition and morphology in vivo. Methods and Results Virtual histology intravascular ultrasound was performed in 13 Japanese Kawasaki disease patients (median age, 18.3 years; interquartile range, 16.9 to 23.3 years) an interval after Kawasaki disease (median, 15.9 years; interquartile range, 14.3 to 21.9 years). We investigated 6 sites with localized stenosis, 15 sites with an aneurysm, 29 sites with a regressed aneurysm, and 50 sites with a normal coronary segment. Plaque components were categorized into 4 parts: fibrous, fibrofatty, necrotic core, and dense calcium areas. Qualitatively, the normal segment had no or trivial intravascular ultrasound visible plaque area, whereas the CAL exhibited a heterogeneous plaque area with the 4 components in different amounts and proportions. Quantitatively, a combined group of CALs had a higher absolute value of fibrous, dense calcium, and necrotic core areas than the normal segment. In further analyses of 3 subtypes of CALs, localized stenosis, an advanced lesion, exhibited higher absolute and relative values of dense calcium and necrotic core areas and a lower relative value of the fibrous area than regressed and persistent aneurysms. Conclusion The present limited but initial virtual histology intravascular ultrasound findings give new insight into the potential role of atherogenesis in the evolution of CALs in adolescents and young adults long after Kawasaki disease and therefore warrant further investigation. (Circulation. 2009;119: ) Key Words: atherosclerosis coronary disease imaging pediatrics plaque Kawasaki disease (KD) is an acute febrile disorder with coronary and other systemic vasculitis that occurs predominantly in infancy and early childhood. It is of great concern to pediatricians and cardiologists because up to 25% of KD patients develop coronary aneurysms leading to lethal coronary vascular events. 1,2 To date, patients have been affected by KD in Japan for 40 years 2 ; in the United States, KD is the leading cause of acquired heart disease in childhood. 3 Later in adulthood, angiographic and postmortem studies demonstrated that coronary sequelae persisting long after acute KD vasculitis are predisposed to late coronary events or sudden death. 4,5 Recently, surrogate markers for atherosclerosis, coronary endothelial dysfunction and increased levels of high-sensitivity C-reactive protein, were associated with coronary sequelae long after KD. 6 8 Furthermore, recent case reports demonstrated that young adults long after KD developed coronary events consistent with acute coronary syndrome, an end-stage phenotype of atherosclerosis. 9,10 However, whether atherosclerotic changes are superimposed on such coronary artery lesions (CALs) is poorly understood in patients long after KD. Clinical Perspective on p 2836 Intravascular ultrasound (IVUS) is now the gold standard for the evaluation of coronary plaque, lumen, and vessel dimensions. 11 In fact, gray-scale IVUS is suitable for quantitative evaluation of vessel and luminal areas. Although simple visual interpretation of acoustic reflections indicates the overall composition of large homogeneous regions such as calcified areas in coronary plaques, it is not consistently Received August 31, 2008; accepted March 27, From the Departments of Pediatrics (Y.M., H.O., H. Sawada, Y.I., H.H., Y.K.), Thoracic Cardiovascular Surgery (S.T., H. Shimpo), and Anesthesiology (K.M.), Mie University Graduate School of Medicine, Tsu, Japan. The online-only Data Supplement can be found with this article at Correspondence to Yoshihide Mitani, MD, PhD, Department of Pediatrics, Mie University Graduate School of Medicine, Edobashi, Tsu City, Mie Prefecture, , Japan. ymitani@clin.medic.mie-u.ac.jp 2009 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 2830 Circulation June 2, 2009 able to represent actual histology, especially in differentiating smaller adjacent areas with heterogeneous composition. Recently, spectral analysis of IVUS radiofrequency data, virtual histology (VH) IVUS, has demonstrated the potential to provide detailed quantitative and qualitative information on plaque composition and morphology in atherosclerotic patients. 12,13 In this system, 4 different plaque components (fibrous, fibrofatty, dense calcium, and necrotic core) can be identified in atheromatous lesions in adults. However, this system has not been applied to evaluating CALs in patients after KD. We therefore hypothesized that CALs in patients long after KD are accompanied by atheroma-like features, as assessed by VH-IVUS. We investigated plaque component and morphology quantitatively and qualitatively in adolescents and young adults long after KD and compared these findings with the concomitant coronary angiographic findings. Methods Study Subjects We investigated consecutive KD subjects who underwent coronary angiography at the Mie University Hospital between March 2007 and June VH-IVUS was performed in patients meeting the following criteria after routine coronary angiography for the follow-up or the clinical diagnosis of CALs: interval between disease onset and the time of the investigation of 10 years and the presence of echocardiographic evaluation of CALs in the acute phase of KD and regular follow-up by use of echocardiography and/or coronary angiography, if indicated, until the time of the examination. Exclusion criteria included coronary angiographic findings, including 50% stenotic lesion, severe vessel tortuosity, and poor runoff of the contrast medium in the vessels, and clinical or hemodynamic instability. The CALs in the long term were described according to standard criteria. 14 A site or segment was determined to be normal or associated with a CAL by ultrasound investigation during the acute illness and in the convalescent phase, and by coronary angiography in the convalescent phase, and in the present coronary angiography. If an enrolled patient was finally diagnosed as having no CALs by ultrasound investigation during the acute illness and in the convalescent phase and by coronary angiography only in the present coronary angiography, a segment in this patient was regarded as normal. The study protocol was approved by the ethics committee of the Mie University Graduate School of Medicine. Written informed consent was obtained from each patient, the patient s parents, or both. Study Protocol During the procedure, heparin was given as a bolus of 150 U/kg with additional boluses to 2000 U/h. After the completion of the diagnostic coronary angiography under the local anesthesia, a 20-MHz, 2.9F phased-array IVUS catheter (Eagle Eye Gold, Volcano Therapeutics, Rancho Cordova, Calif) was placed through a 6F guiding catheter at a distal portion in the right and left main trunk, left anterior descending, or left circumflex coronary arteries when possible. The IVUS catheter was pulled back to the coronary ostium with a motorized pullback system at 0.5 mm/s. During pullback, gray-scale IVUS was recorded, and raw radiofrequency data were captured at the top of the R wave for reconstruction of the color-coded map by a VH-IVUS data recorder (Volcano Therapeutics). 12,13 The grayscale IVUS movie and captured radiofrequency data were written on a CD-R and DVD-R, respectively. Gray-Scale and VH-IVUS Analyses In gray-scale IVUS analysis, the vessel cross-sectional area (CSA), encircled by the media-adventitia interface, and the lumen CSA, encircled by the luminal surface, were determined. Plaque plus media CSA was determined as vessel CSA minus lumen CSA, and percent plaque burden was determined as plaque plus media CSA divided by vessel CSA times 100. In VH-IVUS analysis, the area between the lumen and media-adventitia contours was analyzed automatically with the use of VH-IVUS console (IVG3, Volcano Therapeutics), which used classification trees based on mathematical autoregressive spectral analysis of IVUS backscattered data, as previously described. 12,13,15,16 Each of the 4 plaque components was assigned a respective color and defined as follows: fibrous area (green), the area of densely packed collagen; fibrofatty area (yellow), fibrous tissue with significant lipid interspersed in collagen; necrotic core area (red), necrotic region consisting of cholesterol clefts, foam cell, and microcalcification; and dense calcium area (white), calcium depositing without adjacent necrosis. 12,13 Such tissue classification has been fully validated by the high accuracy of the VH-IVUS findings in predicting pathological findings; the predictive accuracy of each assigned color is 90.4% and 87.1% for fibrous, 92.8% and 87.1% for fibrofatty, 90.9% and 96.5% for dense calcium, and 89.5% and 88.3% for necrotic core, ex vivo and in vivo, respectively. 12,13 The absolute value of total plaque area and the area of these plaque components were also calculated automatically by the software, and percent plaque component, defined as the area of each plaque component divided by the total plaque area times 100, was determined. Geometrical and compositional data were obtained for each cross section. The cross sections for localized stenosis and persistent and regressed aneurysms were obtained from those with the smallest lumen, the largest lumen, and the largest vessel area, respectively. The cross section for the normal coronary artery was taken from the normal portion from the onset. One to 2 lesions in each segment investigated were obtained for the analysis. Gray-scale and VH- IVUS analyses were performed by an experienced analyst blinded to baseline clinical and lesion characteristics. Biochemical Measurements A blood sample was collected from all patients at entry, and serum obtained was stored at 80 C before measurements. Serum concentration of total cholesterol, high-density lipoprotein cholesterol, and high-sensitivity C-reactive protein (Dade Behring, Deerfield, Ill) was measured in the local laboratory. Statistical Analysis All statistical analyses were performed with SPSS 15.0J for Windows (SPSS Inc, Chicago, Ill). Continuous data are reported throughout the text as mean SD or median and interquartile range when appropriate. Categorical data are expressed as a number or the frequency of occurrence. Because absolute and relative values of plaque plus media area, fibrous, fibrofatty, dense calcium, and necrotic core areas have a skewed distribution; median values were computed for these parameters. In addition, per-plaque analysis was performed. The correlation between the percent plaque burden and the absolute and relative values of fibrous, fibrofatty, dense calcium, or necrotic core areas was analyzed by Spearman correlation coefficients. The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written. Results Patient and Lesion Characteristics Sixteen KD patients were screened for the study. Three of these KD patients were excluded because of the short time interval ( 10 years) between acute KD and the time of investigation. The remaining 13 patients late after KD were enrolled in this study. Gender, age at the time of investigation and KD onset, conventional risk factors for ischemic heart disease, and coronary angiographic findings for each patient are described in the Table. Other patient characteristics are described in Table I of the online-only Data Supplement.

3 Mitani et al Virtual Histology IVUS Late After KD 2831 Table. Patient Characteristics CAG Findings Patient Sex Age, y Age at KD, y CV Risk Factors LCA RCA 1 M AN, RA AN 2 M N RA 3 M LS, AN, RA AN 4 M Smoking RA LS, AN, RA 5 F LS, AN, RA LS, AN, RA 6 M RA LS, AN, RA 7 F Smoking RA OC 8 M RA RA 9 M N N 10 F FH AN, RA RA 11 M AN N 12 F AN, RA RA 13 F RA LS, AN, RA CV indicates cardiovascular; CAG, coronary angiography; LCA, left coronary artery; RCA, right coronary artery; AN, persistent aneurysm; RA, regressed aneurysm; N, normal coronary from the onset; LS, localized stenosis; OC, occlusion; and FH, family history of ischemic heart disease. Thirteen Japanese KD patients (8 men, 5 women) 18.3 years of age (interquartile range, 16.9 to 23.3 years), 15.9 years (interquartile range, 14.3 to 21.9 years) after the acute illness, constitute the final patient population. As for risk factors for ischemic heart disease, hypercholesterolemia, hypertension, obesity (body mass index 30 kg/m 2 ), and diabetes mellitus were not found in any patients, whereas overweight (body mass index, 25.0 to 29.9 kg/m 2 ), smoking habit, and the presence of family history of ischemic heart disease were noted in 4, 2, and 1 patients, respectively, despite no overlapping of these risk factors in any patients. Highsensitivity C-reactive protein level in the total patient group was mg/l (interquartile range, to 0.328); in 10 patients with a persistent aneurysm, localized stenosis, or occlusion, high-sensitivity C-reactive protein was mg/l (interquartile range, to 0.344), which is consistent with the levels in a previous study. 8 Patients were categorized into 4 groups with respect to CALs: 1 patient with normal coronary arteries from the onset, 2 patients with regressed aneurysms only, 4 patients with persistent aneurysms without localized stenoses or occlusions, and 6 patients with localized stenoses or occlusions. One patient (patient 7) had a history of silent myocardial ischemia 5 months after KD onset, which was previously related to an occlusion in the right coronary artery in a coronary angiogram (Table 1). Coronary artery bypass graft or percutaneous coronary intervention was not performed in any patients. Aspirin and dipyridamole were administered to 9 and 7 patients, respectively. Left main trunk, left anterior descending, left circumflex, and right coronary arteries were investigated in 12, 13, 4, and 12 patients, respectively. Fifteen normal segments, 29 regressed aneurysms, 15 persistent aneurysms, and 6 localized stenotic lesions (50% stenosis in 4 sites, 25% stenosis in 2 sites) were investigated by VH-IVUS. All patients had at least 1 normal segment measured. Grayscale and VH-IVUS Findings Qualitative Analysis Normal Coronary Arterial Segments From the Onset Of 50 normal coronary segments investigated, 46 had no plaque area visible in the VH-IVUS system (Figure 1A2, A3, and A4; Figure 2A3, A4, B4, B6, and C4; Figure 3B4, C4, and C6; and Figure 4A5). Only trivial plaque area, if any, with mainly fibrous and some fibrofatty components was found in the remaining 4 segments (Figure 1A1; Figure 3A3 Figure 1. VH-IVUS images in a patient (patient 9) with no coronary lesions from the onset of disease (A1 through A4). The 4 major components are shown in green for the fibrous area, yellow for the fibrofatty area, white for dense calcium, and red for the necrotic core area.

4 2832 Circulation June 2, 2009 Figure 2. VH-IVUS images and selected grayscale images in regressed aneurysms (A1, A2, B1, B2, B5, C1, C2, D1, and D3) and normal segments (A3, A4, B4, B6, and C4) from 4 representative patients (A, patient 8; B, patient 10; C, patient 7; and D, patient 4) long after KD. and B7; Figure 4A4), which were adjacent to persistent aneurysms or localized stenoses in patients with CALs or in the left main trunk in a KD patient with no CALs from the acute stage. Regressed and Persistent Aneurysms All 29 regressed aneurysms and 15 persistent aneurysms were associated with plaque area with different amounts and proportions of the 4 plaque components. A mainly fibrous plaque area with relatively small proportions of fibrofatty, superficial dense calcium, and necrotic core components (Figure 2A1, A2, B1, B2, B5, C1, C2, D1, and D3) or a mixed plaque area with varied proportions of fibrous, fibrofatty, superficial dense calcium, and necrotic core components (Figure 3A1, A4, B1, B2, B5, C1, C3, and C5) was found in regressed and persistent aneurysms. Gray-scale images in persistent and regressed aneurysms showed a plaque area composed mostly of an intermediately echogenic component and relatively small calcified and echolucent components (Figure 2B3, C3, and D2) or a mixed plaque area with varied echolucent, intermediately echogenic, calcified components (Figure 3A2, B3, and C2). Localized Stenotic Lesions All 6 stenotic lesions were associated with a relatively large plaque area with dense calcium and necrotic core. A heavily calcified region with a necrotic core component was found under the luminal surface in a representative localized stenotic lesion; a large fibrofatty area was observed beside it (Figure 4A2). A gray-scale image in such a lesion showed heavily calcified and hypoechoic areas (Figure 4A3). A large area of necrotic core was observed in other representative localized stenotic lesions under the luminal surface with some calcified and fibrofatty areas (Figure 4B2 and Figure 3. VH-IVUS images and selected grayscale images in persistent (A1, A4, B1, and C1) and regressed (B2, C3, and C5) aneurysms from 3 representative patients (A, patient 5; B, patient 4; and C, patient 6) long after KD. Normal segments from the onset of disease (A3, B4, B7, C4, and C6) also are shown.

5 Mitani et al Virtual Histology IVUS Late After KD 2833 Figure 4. VH-IVUS images and selected grayscale images in localized stenotic lesions (A2, B2, and B5) from 2 representative patients (A, patient 5; B, patient 3) long after KD. Persistent (B4) and regressed (A1, B1, and B6) aneurysms and normal segments from the onset (A4 and A5) also are shown. B5). A gray-scale image of such a stenotic lesion showed a mixed plaque area with bright, calcified, soft plaque components (Figure 4B3). Quantitative Data Gray-scale and VH-IVUS parameters are shown in Table II of the online-only Data Supplement. Because of clustering of observations within a small sample of patients, the statistical analysis focused on estimation rather than on hypothesis testing. Compared with the normal segment, percent plaque burden was higher in 3 different CALs, including persistent and regressed aneurysms and the localized stenotic lesion. In addition, percent plaque burden in localized stenosis was higher than in regressed and persistent aneurysms (Figure 5A). Compared with the normal segment, the absolute values of fibrous, dense calcium, and necrotic core areas were higher in a combined group of 3 CALs (Figure 5B). In further analyses of 3 different CALs, absolute and relative values of dense calcium and necrotic core areas were higher, whereas the relative, but not absolute, value of fibrous area was significantly lower in localized stenosis than in regressed and persistent aneurysms (Figure 6A and 6B). Percent plaque burden was positively correlated with the absolute value of fibrous (r 0.62), dense calcium (r 0.59), Figure 5. Percent plaque burden was compared among 4 different CALs associated with KD (A). CSA of 4 different plaque components was compared between the normal segment (N) and a combined group of CALs, including regressed aneurysms (RA) and persistent aneurysms (PA), and localized stenoses (LS) altogether (B). Percent plaque burden was defined as follows: (vessel CSA lumen cross-sectional area)/vessel CSA 100. Each box displays the 25th percentile (bottom of box), median (horizontal line in box), and 75th percentile (top of box). The number of each CAL investigated is given in parentheses. Figure 6. CSA (A) and percentage (B) of each plaque component in the plaque area was compared among 3 different CALs associated with KD. Abbreviations as in Figure 5.

6 2834 Circulation June 2, 2009 and necrotic core (r 0.63) areas but not fibrofatty area. In addition, percent plaque burden was correlated positively with percent dense calcium (r 0.46) and percent necrotic core (r 0.39) but negatively with percent fibrous area (r 0.41) and not correlated with percent fibrofatty area. Further analyses of grayscale and VH-IVUS parameters are shown in Figures I and II of the online-only Data Supplement. Discussion The present VH-IVUS study provides 3 novel observations: (1) Qualitatively, the normal segment from the disease onset had no or trivial plaque area detected, whereas the CAL had a heterogenous plaque area with 4 components in different amounts and proportions; (2) quantitatively, a combined group of CALs had higher absolute values of fibrous, dense calcium, and necrotic core areas than the normal segment; and (3) in further analyses of 3 subclasses of CALs, localized stenosis, an advanced lesion, exhibited higher absolute and relative values of dense calcium and necrotic core areas and a lower relative value of the fibrous area than regressed and persistent aneurysms. The small sample size, lack of longitudinal data, and limitations of VH-IVUS itself notwithstanding, 12 the present initial VH-IVUS findings in KD suggest that arteriosclerotic lesions found in CALs but not obvious in the normal segment in patients with KD are characterized by a heterogeneous intimal area, distinct from a purely fibrotic area, and may give new insight into the potential role of atherogenesis in the evolution of CALs long after KD. The present gray-scale and VH-IVUS data seem to be in line with previously reported gray-scale IVUS findings in KD. In the present VH-IVUS study, most normal segments from the disease onset had no obvious plaque areas detected, whereas the remaining 10% of normal segments had trivial plaque areas located mostly in the vicinity of the CALs, which is consistent with the gray-scale IVUS study of Sugimura et al. 17 With respect to CALs, the present IVUS images were consistent with previous gray-scale IVUS studies in which calcified and hypoechoic areas were heterogeneously distributed in regressed and persistent aneurysms and localized stenosis in KD patients In the present study, percent plaque burden in such CALs was higher than in the normal segment. This is in agreement with previously reported gray-scale IVUS findings in which persistent and regressed aneurysms were associated with increased intimamedia complex in KD. 17,18 Therefore, the present VH-IVUS data add new information on plaque composition in CALs associated with KD, for which gray-scale IVUS studies have shown limited diagnostic values. The VH-IVUS findings seem to be in agreement with previously reported pathological findings in KD. In the present study, the normal segment from the onset had no or only trivial IVUS-visible plaque area (Figures 1 through 4), whereas CAL was associated with a plaque area composed mainly of fibrous component and of various proportions of calcified, fibrofatty, and necrotic core components (Figures 2 through 4). Burns et al 5 reported that no atheromatous plaques were found in seemingly normal coronary arteries distal to aneurysms in 10 autopsied adult KD patients. Previous pathological studies in autopsied case series, mostly just a few years after the acute illness, demonstrated that CALs were characterized by intimal thickening composed of fibrous tissue and calcification, not by typical atheromatous components. In contrast, Takahashi et al 25 reported that among 5 Japanese patients with persistent or recanalized coronary arteries, 3 patients who were 15, 20, and 39 years of age had new intimal thickening, including atheroma-like bright areas and foamy macrophages, in such CALs. Negoro et al 9 also showed that a substantial lipid core with cholesterol crystals and macrophages was found in an atherectomy specimen from a stenotic lesion in a 32-year-old Japanese man who presented with acute coronary syndrome. Therefore, it is possible that the normal segment from the disease onset may have no or trivial intimal area in adolescence and early adulthood; that the mainly fibrotic regions with calcification, reported as arteriosclerosis in previous studies, may be accompanied by various degrees of VH-IVUS derived fibrofatty and necrotic core regions in the same period, as shown in our VH-IVUS study; and that some of these regions could be the substrate for the overt atherosclerotic lesions later in adulthood, as reported in the Negoro et al 9 and Takahashi et al 25 patients. However, limitations of the VH-IVUS system in distinguishing necrotic core from microcalcification 12 may not preclude the possibility that VH-IVUS defined necrotic core areas in KD may represent microcalcification-rich necrotic core like regions, not typical necrotic core, in some coronary lesions in KD. Localized stenosis was characterized by a higher percent plaque burden, a larger amount of dense calcium and necrotic core areas, and a lower proportion of fibrous component, which has mechanistic implications. The present findings demonstrated quantitatively that percent plaque burden in localized stenosis was higher than in persistent and regressed aneurysms, consistent with previous qualitative findings in pathological and gray-scale IVUS studies. 19,24 Such findings are consistent with the hypothesis that localized stenosis is caused by increased intimal thickening, potentially induced by rheological changes associated with aneurysms, although the additional contribution of positive or negative remodeling to the lesion formation remains to be determined Although the highly calcified region was observed in localized stenotic lesions and persistent and regressed aneurysms in KD patients, especially 8 years after the acute illness, as reported previously in IVUS 17 19,26 and histological studies, 21,23,25 the present findings newly demonstrated quantitatively that the absolute and relative values of dense calcium area are higher in localized stenosis than in aneurysms. Because the calcified region was sometimes found under the luminal surface of CALs in the present study, it is possible that such spatial distribution of calcified regions in CALs might trigger thrombosis and coronary vascular events in KD. 27 Localized stenosis also was associated with an increase in the absolute and relative values of necrotic core area. Necrotic core component was sometimes located under the luminal surface in localized stenosis. This is important with respect to the prediction of cardiac events because thin-cap fibroatheroma, defined as a lesion with percent necrotic core 10% and percent plaque burden 40% without evidence of

7 Mitani et al Virtual Histology IVUS Late After KD 2835 fibrous cap in 3 consecutive frames of the lesion, seems to be related to coronary vascular events in adults. 28 However, we could not find any lesions fulfilling such criteria, although the localized stenosis in Figure 4B exhibits percent necrotic core 10% and percent plaque burden 40% without evidence of fibrous cap in 3 consecutive frames. Therefore, an increase in percent plaque burden and dense calcium and necrotic core areas, in parallel with decreased proportions of fibrous component and nondecreased fibrofatty areas, may contributes to the progression of localized stenosis in patients long after KD, although the pathological features of the necrotic core component in KD should be critically evaluated in future studies. 12 Mechanisms involved in inducing intimal calcification and potential atherosclerosis in localized stenosis in KD are unknown in the absence of obvious coronary risk factors. However, because intimal calcification and necrotic core in vessels have been correlated with atherogenesis in several disease conditions, the development of such intimal components in localized stenosis may be mediated by atherogenesis-related pathways, endothelial dysfunction, inflammation, and modulated shear stress. 6 8,27 Taken together, the present gray-scale and VH-IVUS findings may represent pathobiological features of localized stenosis long after KD. Study Limitations Several limitations should be considered in the interpretation of our results. First, no data are available to correlate the VH-IVUS findings with the pathological findings in the corresponding vessels in KD, although interpretation of VH-IVUS findings has been well validated in atherosclerotic or healthy human coronary arteries in vivo and ex vivo. Second, the present VH-IVUS system is not able to differentiate thrombosis from other plaque components and fibrous and fibrofatty components. 15 Third, we have no healthy referents in this study. Considering the lack of or trivial intimal area in the normal segment in the present study, it is possible that most of the normal segments in healthy referents may have no or trivial plaque in the age- and risk factor matched Japanese control subjects in the present method. Fourth, the study sample may be biased; 46% of the patients investigated had stenotic or occlusive lesions in some segments, and an additional 31% of patients had persistent aneurysms in other segments. Because our data in normal segments or regressed aneurysms in patients without any other lesions are limited, it is possible that such mild lesions might have VH-IVUS findings distinct from the present findings. Fifth, because this is a cross-sectional study, the prognostic significance of the value of each plaque component was undetermined. Conversely, although no or only trivial plaque area was observed in the normal coronary segment in KD, these findings do not preclude the possibility that such a vessel may be predisposed to more severe atherosclerosis in KD patients than in healthy referents at advanced ages. Cohort studies incorporating serial VH-IVUS studies may be important in this regard. Clinical Implications The present limited but initial VH-IVUS study suggests that arteriosclerotic lesions found in CALs, but not obvious in the normal segment, may be accompanied by some VH-IVUS derived atheroma-like features in adolescents and young adults long after KD. Although we do not know whether plaque composition and morphology are major determinants for coronary events in patients late after KD, these VH-IVUS findings, together with endothelial dysfunction and chronic low-grade inflammation, may account for coronary events and lesion formation in patients associated with CALs late after KD. Therefore, VH-IVUS could potentially be clinically useful in various ways in KD. Specifically, VH-IVUS findings could be a modality used to predict the prospective coronary events. VH-IVUS could be a gold standard for plaque imaging by noninvasive imaging modalities such as multislice computed tomography and magnetic resonance imaging. VH-IVUS derived compositional changes in CALs could be surrogate end points in clinical trials (ie, emerging antiatherosclerotic drugs). VH-IVUS findings before catheter interventions could be used to predict procedure-related complications such as the slow-flow phenomenon. 16 Therefore, VH-IVUS could be a promising and feasible modality for coronary vessel wall imaging in KD. Further studies using VH-IVUS, in conjunction with verification of this system in refined pathological studies in larger adult KD series, are warranted. Acknowledgments We would express our appreciation to Dr Kaoru Dohi, Department of Cardiology, Mie University Graduate School of Medicine, for his technical guidance in performing the IVUS study; to Hideki Miyagi, Department of Radiology, Mie University Graduate School of Medicine, for his technical assistance; and to Professor Yoshikazu Nakamura, Department of Public Health, Jichi Medical University, for assistance with the statistical analysis. Source of Funding This study was supported in part by a grant from Japanese Society for Kawasaki Disease Pathogenesis Research (2008). 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Circulation. 2000;101: Takahashi K, Oharaseki T, Naoe S. Pathological study of postcoronary arteritis in adolescents and young adults: with reference to the relationship between sequelae of Kawasaki disease and atherosclerosis. Pediatr Cardiol. 2001;22: 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: Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: pathobiological mechanisms and clinical implications. Circ Res. 2006;99: Rodriguez-Granillo GA, Garcia-Garcia HM, Mc Fadden EP, Valgimigli M, Aoki J, de Feyter P, Serruys PW. In vivo intravascular ultrasoundderived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis. J Am Coll Cardiol. 2005;46: CLINICAL PERSPECTIVE Kawasaki disease (KD) is an acute febrile disorder with coronary and other systemic vasculitis in infancy and early childhood. It is of great concern to pediatricians and cardiologists because up to 25% of KD patients develop coronary aneurysms leading to lethal coronary vascular events. To date, patients have been affected by this disorder in Japan for 40 years; in the United States, KD is the leading cause of acquired heart disease in childhood. Recent studies on endothelial function and low-grade inflammation have suggested that coronary sequelae persisting long after KD may be predisposed to premature atherosclerosis. Recently, spectral analysis of intravascular ultrasound radiofrequency data, virtual histology intravascular ultrasound, was demonstrated to provide detailed quantitative and qualitative information on plaque components (fibrous, fibrofatty, necrotic core, and dense calcium areas) in atherosclerotic patients. The present study reports the initial results in 13 adolescents and young adults long after KD by using this method. The normal segment from the onset had no or trivial intravascular ultrasound visible plaque area, whereas the coronary artery lesion had a heterogeneous intimal area with 4 components in different amounts and proportions. Higher percent plaque area, absolute and relative values of dense calcium and necrotic core areas, and a lower relative value of fibrous area were associated with the presence of localized stenosis, an advanced lesion. The present limited but initial virtual histology intravascular ultrasound findings provide new insight into the potential role of atherogenesis in the evolution of coronary artery lesions long after KD and therefore warrant further investigation.