PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1095-1099

Noninvasive Assessment of the Early Progression of Atherosclerosis in Adolescents With Kawasaki Disease and Coronary Artery Lesions

Nobutaka Noto, MD, Tomoo Okada, MD, Masao Yamasuge, MD, Kazuo Taniguchi, MD, Kensuke Karasawa, MD, Mamoru Ayusawa, MD, Naokata Sumitomo, MD, and Kensuke Harada, MD

From the Department of Pediatrics and Cardiology, Nihon University School of Medicine, Tokyo, Japan.

	ABSTRACT

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Objectives.  The severity of carotid arteriosclerosis, defined as increased intima-media thickness (IMT) visible with B-mode ultrasound, is correlated with risk factors for coronary heart disease. Little is known, however, about the relation of IMT, the stiffness of the common carotid artery, and the progression of atherosclerosis in children with Kawasaki disease (KD) and coronary artery lesions (CAL).

Design.  We investigated the associations among total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) , low density lipoprotein cholesterol (LDL-C), triglyceride, TC/HDL-C, ApoE genotype, glycohemoglobin, IMT, and arterial stiffness by high resolution ultrasound in 20 adolescents with KD and CAL (age: 16.6 ± 4.1 years, males: 60%) and 20 sex- and age-matched healthy controls (Cont).

Results.  No significant differences were observed in the values of body mass index and blood pressure between the 2 groups. Also no significant differences were observed in the levels of TC, LDL-C, HDL-C, triglyceride, TC/HDL-C within normal values, or the allele frequency of Apo E4 between the 2 groups. However, the values of IMT, stiffness, and glycohemoglobin in patients with KD were significantly higher than those in Cont (0.53 ± 0.07 vs 0.46 ± 0.05 mm, P < .05; 4.11 ± 0.86 vs 2.94 ± 0.91, P < .001; 5.0 ± 0.4 vs 4.6 ± 0.2%, P < .05). A significant relationship was observed between sex and the mean IMT (r = 0.46) in Cont; however, no significant correlation was found between mean IMT and other variables in either group. Although the arterial stiffness was strongly related to body mass index (r = 0.58) and systolic blood pressure (r = 0.55) in Cont, no significant relationship was observed between the stiffness and any variable tested in patients with KD.

Conclusions.  The less distensible carotid wall in patients with KD compared with that in Cont without major alteration of the lipid profile is likely to be secondary to the changes in arterial walls after a diffuse vasculitis involving noncoronary arteries. These results indicate that the coronary arteries may be predisposed to accelerated atherosclerosis in patients with KD and CAL.  Key words:  Kawasaki disease, atherosclerosis, carotid artery, adolescent.

Kawasaki disease (KD) is an acute inflammatory process affecting the arterial wall that results in panvasculitis in infants and young children. Although current therapy with intravenous -globulin has been demonstrated to reduce the prevalence of coronary artery lesions during the acute phase of the illness, coronary aneurysm still develops in ~10% of children with this disease, and may be followed by myocardial ischemia during the convalescent phase.^1,2 Recent studies revealed that alterations in lipid profile and generalized endothelial cell dysfunction persisted for a long time after the clinical resolution of KD.³ This is important because the vasculitis of KD has a predilection for the coronary arteries at sites identical to those most often affected in atherosclerosis that generally occurs at a later age.

The severity of carotid atherosclerosis, defined as intima-media thickening (IMT) visible with B-mode ultrasound, is correlated with risk factors for coronary heart disease in both young and adult patients with hypercholesterolemia.^4,5 So far, however, no studies have been published on the effect of vasculitis induced by KD on arterial wall properties in adolescents. The authors postulated that coronary artery atherosclerosis might be accelerated in some patients with KD, particularly in patients with coronary artery lesions, in comparison with healthy participants.

The objectives of present study were to compare IMT and the stiffness of the carotid arteries between patients with KD and coronary artery lesions and well-matched healthy controls (Cont), and to determine the relationships among some clinical and blood variables.

	MATERIALS AND METHODS

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Participants

We studied 40 adolescents between 11 and 22 years old (mean: 16.6 ± 4.1 years). Twenty children had a history of KD and coronary aneurysms in either the proximal or middle portion of the left anterior descending coronary artery or right coronary artery in the acute phase or the convalescent phase documented by previous 2-dimensional echocardiography or coronary angiography. The interval from the initial onset of illness ranged from 6 to 20 years (mean: 9.8 ± 4.0 years).

All patients with KD were receiving concurrent medical therapy; 14 patients were receiving aspirin only, while 5 patients were receiving both aspirin and warfarin for prevention of coronary thrombosis. One patient was receiving -blocker and calcium channel blocker besides aspirin for control of ventricular tachycardia. All patients were free of symptoms during their routine daily activities. Two patients had a clinical history or electrocardiogram signs of a previous myocardial infarction. All patients had normal ventricular function and no echocardiographic evidence of left ventricular hypertrophy or valvular heart disease. Twenty age- and sex-matched participants served as Cont. They were normolipidemic according to the age-dependent recommended values of blood lipids.⁶ None was a daily smoker. None had hypertension, diabetes, or a family history of premature ischemic heart disease, defined as 1 or more of the following events before the age of 50 years: sudden cardiac death, typical exercise-induced angina, myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, cardiac transplant, or cerebral infarction.

Height and weight were measured in all participants by the same observer with a wall-mounted stadiometer and an electronic scale. Body mass index (BMI) was calculated from the ratio: body weight/(body height)² in kg/m². Systolic and diastolic blood pressure (BP) were measured in the right arm with a Dinamap automated vital-signs monitor (Criticon Inc, Tampa, FL). The lowest value of the 3 measurements was used in the analysis.

The study was approved by the Human Research Ethics Committee of our institution, and written informed consent for participation in the study was obtained from all parents or legal guardians of the patients.

Laboratory Methods

After an overnight fast, blood samples were obtained by venipuncture from all participants. Serum total cholesterol (TC), triglyceride, and high-density lipoprotein (HDL-C) were determined by conventional enzymatic methods. The concentration of low-density lipoprotein (LDL-C) was calculated by the Friedewald formula. Glycosylated hemoglobin A1c was measured by electrophoresis. Apo E genotyping was performed by the method described by Eiklid and Leren.⁷

Carotid Ultrasonography

All examinations were done by the same sonographer (N.N.), who was blinded to the participant's case status and risk factor levels. High-resolution B-mode ultrasonography of the right carotid artery was performed with an Acuson Sequoia (Acuson, Mountain View, CA) or Toshiba SSA-380A (Toshiba, Tokyo, Japan) ultrasound scanner equipped with a linear 5- to 7.5-MHz transducer. The participants were examined in the supine position with the head turned slightly to the left. Longitudinal images of the common carotid artery were obtained by combined B-mode and color Doppler ultrasound examinations. The IMT of the common carotid artery far wall was measured with the electronic calipers of the machines, as described by Pignoli.⁸ The mean IMT was calculated for each patient as the average of 3 consecutive measurements of maximum far wall thickness obtained from the common carotid artery ~20 mm below the corotid bulb.

M-mode ultrasound examinations were recorded on-line. The maximal end-diastolic carotid lumen diameter was measured at the R wave of the electrocardiogram. Three measurements each of systolic and diastolic diameters were averaged. The diameter change was calculated as the difference between the systolic and diastolic averages. Arterial wall stiffness (S) was defined as S = [ln(systolic BP/diastolic BP)×D/ D], where D = diastolic internal diameter of the vessel(cm) and D = the change in arterial diameter with each pulse.

Statistical Analysis

Variables showing a normal distribution were expressed as means and standard deviations and differences between groups were tested with Student's t test. Other variables were expressed as median and range and the differences between groups were analyzed by the Mann-Whitney U test. For correlation analysis, Pearson's correlation coefficient was calculated for normally distributed variables and Spearman's rank-correlation coefficient for other variables. A possible association among risk factors, mean IMT, and stiffness were analyzed by standard multiple regression analysis. Two-sided values of P < .05 were considered statistically significant. Interobserver and intraobserver variability studied in our laboratory with repeated recordings has shown coefficients of variance for mean IMT of 7.3% and 5.0%, and for stiffness (S) of 9.1% and 6.9%, respectively.

	RESULTS

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Table 1 shows the clinical data and results of blood tests. No significant differences were observed in the values of BMI, systolic BP, or diastolic BP between the 2 groups. Also, no significant differences were observed in the levels of triglyceride, TC/HDL-C, and allele frequency of Apo E4 in the 2 groups. The values of TC, LDL-C, and HDL-C in KD, which were all within the range of normal values, were slightly higher than those in Cont, but not significantly so. In contrast, the values of hemoglobin A1c in patients with KD were significantly higher than those in Cont (4.92 ± 0.38 vs 4.65 ± 0.24%; P < .05).

None of the participants in either group had atherosclerotic plaques. The values of mean IMT in patients with KD were significantly higher than those in Cont (0.54 ± 0.09 vs 0.48 ± 0.08 mm; P < .05), however, there was some overlap (Fig 1). Also, the stiffness in patients with KD was significantly higher than that in Cont (4.11 ± 0.86 vs 2.94 ± 0.91; P < .001) (Fig 2). In Cont, males had significantly greater mean IMT and systolic BP than females (0.50 ± 0.08 vs 0.42± 0.04 mm; P < .05, 117.8 ± 7.0 vs 109.2 ± 6.1 mm Hg; P < .05). No such sex-dependent difference was found in patients with KD ( 0.57 ± 0.08 vs 0.51 ± 0.08 mm; not significant, 115.2 ± 11.6 vs 108.5 ± 9.5 mm Hg; not significant).

View larger version (16K): [in this window] [in a new window]   Fig. 1.   Mean carotid IMT in patients with KD and in Cont. The mean IMT in patients with KD was 0.54 ± 0.09 mm, and in Cont it was 0.48 ± 0.08 mm (P < .05).

View larger version (16K): [in this window] [in a new window]   Fig. 2.   Carotid arterial wall stiffness in patients with KD and Cont. Stiffness in KD was 4.11 ± 0.86, and in Cont it was 2.94 ± 0.91 (P < .001).

The correlations of mean IMT and the stiffness with some clinical and laboratory variables are shown in Tables 2 and 3. In univariate analysis, a significant relation was observed between sex and the mean IMT (r = 0.46) in Cont; however, no significant correlation was found between any other variable and the mean IMT in either group. On the other hand, the stiffness was strongly correlated with BMI (r = 0.58) and systolic BP (r = 0.55) in Cont. In patients with KD, however, no significant relation was observed between the stiffness and any variable tested. The variables that were significant or approached statistical significance in the univariate analysis were included in stepwise multivariate analysis. When BMI, systolic BP, and sex were entered into the model, only BMI (r = 0.59, P < .05) emerged as an independent determinant of the stiffness in the Cont. This model accounted for 30% of the variation of the stiffness. No such relationships were found in patients with KD.

	DISCUSSION

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We found that the carotid artery wall in patients with KD and coronary artery lesions was less distensible and thicker than that in Cont. These changes of arterial properties in patients with KD were not associated with major alterations of the lipid profile.

Because of the association between coronary and carotid artery atherosclerosis and the ease of examination of the carotid arteries by ultrasound scanning, the examination of extracranial carotid arteries can be used to predict the extent of atherosclerotic involvement of the coronary arteries.^9-11 Similarly, early atherosclerotic changes of the arterial wall in young patients with familial hypercholesterolemia detected as increased IMT can be studied by ultrasonography.^4,5,12 In the present study, the values of mean IMT were <0.6 mm in all 20 healthy controls aged from 11 to 22 years. Therefore, 0.6 mm was taken as the upper limit of the normal mean IMT, which is compatible with the recently published reference values of mean IMT for this age group.^4,5,11

Univariate correlation analysis showed that the mean IMT was correlated only with sex, and stiffness was correlated with BMI and systolic blood pressure within the normal range of mean IMT in Cont. No significant correlation was found between stiffness or the mean IMT and any of the tested variables, including the serum lipid risk factors for atherosclerosis, in patients with KD. Recent studies showed that in young patients with familial hypercholesterolemia, IMT was significantly correlated with serum total cholesterol, LDL-C, homocystine, fibrinogen, and sex, and inversely correlated with HDL-C.^4,5,13 Also, stiffness was significantly correlated with TC, LDL-C, and age.^12,13 The reason for these differences between our results and the previous studies are uncertain, however, perhaps partially attributable to the small number of participants with KD, who had almost normal values in most variables except for anthropometric values. In addition, our results may indicate that early atherosclerotic changes in the arterial wall properties may include the appearance of changes in the stiffness earlier than in mean IMT in patients with KD. Because the stiffness depended primarily on the anthropometric variables in Cont, its contribution to the atherosclerogenic risk factors, even within so-called normal limits, may be predominant over that of the mean IMT.

The elastic characteristics of the common arteries are determined by both passive (elastin and collagen) and active factors.^14,15 The distensibility of the carotid wall may decrease linearly with age, and may also be affected by the disease state, such as hypercholesterolemia, diabetes, arterial hypertension, and so forth.^15-17 With regard to the histopathologic findings in patients with KD and regressed coronary artery aneurysms, fibrous intimal thickening is evident despite normal coronary artery diameter.¹⁸ Furthermore, intimal thickening and fibrosis have been observed in the coronary arteries of children who died because of causes unrelated to KD during the convalescent phase.¹⁹ The less distensible carotid wall in participants with KD than in Cont is likely to be responsible for the changes in arterial walls after a diffuse vasculitis involving noncoronary arteries, ie, increased amounts of collagen and extracellular matrix material. These histologic abnormalities have raised concerns that after KD, the coronary arteries may be predisposed to accelerated atherosclerosis.^20,21

Several limitations might have influenced the results of this study. First, we cannot exclude the possibility that differences of the interval from the initial onset of illness in KD might be related to the histopathologic changes in arterial walls. Differences in these passive components could account for a portion of the interindividual variation in stiffness. In addition, neural, hormonal, and physical stimuli can activate smooth muscle cells, leading to a reduction of distensibility in participants with KD.

Second, we could not adjust for the pubertal stage in patients with KD and Cont. Moreover, we could not eliminate the influence of the Apo E genotype, which has been reported to affect LDL cholesterol levels. Although some lipid levels are influenced by the pubertal stage and Apo E genotype,^4,22 we had no participants with abnormal lipid levels in this study.

Third, there is no evidence that arterial walls of KD are different from those of normal adolescents, and this is a potential limitation of this study. Arterial fibrous plaques have been found in autopsy specimens from children,^23,24 but no data are available on noninvasive evaluation of the arterial wall in patients with KD, which could allow an anatomically based screening of children with early signs of atherosclerosis.

	CONCLUSIONS

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Because arterial wall stiffness seems to reflect the degree of early atherosclerotic change in the arterial tree, when the effects of the risk factors for cardiovascular events are being evaluated, measurements of the stiffness by carotid ultrasound may be warranted, especially in patients with KD and CAL who have a greater future risk of coronary artery disease and greater benefit of early intervention. Additional ongoing prospective studies are necessary to assess whether or not the detectable modification of carotid ultrasound imply an increased risk of future cardiovascular events in adolescents with KD and CAL.

	ACKNOWLEDGMENT

This work was supported in part by a grant for Kawasaki disease from the Ministry of Health and Welfare of Japan.

	FOOTNOTES

Received for publication May 4, 2000; accepted Oct 3, 2000.

Reprint requests to (N.N.) Department of Pediatrics and Cardiology, Nihon University School of Medicine, 30-1 Oyaguchi, Itabashi-ku, Tokyo 173-0085, Japan. E-mail: nnoto{at}med.email.ne.jp

	ABBREVIATIONS

KD, Kawasaki disease; IMT, intima-media thickening; Cont, control group; BMI, body mass index; BP, blood pressure; TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.

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