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(Circulation. 1996;94:2103-2106.)
© 1996 American Heart Association, Inc.

Articles

Endothelial Dysfunction Late After Kawasaki Disease

Rami Dhillon, MRCP; Peter Clarkson, MRCP; Ann E. Donald; Amanda J. Powe, RN; Margot Nash, FRACP; Vas Novelli, FRCP; Michael J. Dillon, FRCP; John E. Deanfield, FRCP

the Cardiothoracic Unit, Special Pediatric Unit (M.N., M.J.D.), and Infectious Diseases Unit (V.N.), Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.

Correspondence to Dr John E. Deanfield, Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust, Great Ormond Street, London WC1N 3JH, United Kingdom.

	Abstract

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Background Kawasaki disease (KD) is a systemic vasculitis of childhood with widespread vascular endothelial damage in the acute stage. Long-term complications, such as myocardial infarction and death, are recognized, but the extent and nature of late vascular abnormalities that might predispose to these events have not been studied.

Methods and Results We used high-resolution ultrasound to study endothelial function in the brachial artery of 20 patients 5 to 17 years after acute KD (median, 11 years) and compared findings with those in 20 age- and sex-matched control subjects. Vascular responses to reactive hyperemia (with flow increase leading to endothelium-dependent dilation) and to sublingual glyceryl trinitrate (GTN; endothelium-independent dilation) were recorded. The relationship between endothelium-dependent vascular responses and features of the acute illness was examined. There was no difference in baseline vessel diameter, degree of reactive hyperemia, or response to GTN between patients and control subjects. In contrast, flow-mediated dilation was markedly reduced in KD patients compared with control subjects (3.1% versus 9.4%; P<.001). Late endothelium-dependent responses were not related to features of the acute illness.

Conclusions Abnormalities of systemic endothelial function are present many years after resolution of acute KD, even in patients without detectable early coronary artery involvement. Because this may be an important factor in the genesis of late vascular complications, long-term follow-up of all patients with KD is indicated.

Key Words: Kawasaki disease • ultrasonics • endothelium

	Introduction

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Kawasaki disease (KD), a systemic vasculitis of unknown etiology, is a leading cause of acquired heart disease in children from developed countries.¹ In the acute stage, coronary aneurysm formation may occur, and this has been associated with myocardial infarction and death.² Long-term follow-up and aspirin treatment are currently recommended for these patients because structural and functional abnormalities in the coronary arteries, with associated morbidity and mortality, may be found late after resolution of the acute lesions.^{3 4 5} In contrast, long-term management of patients without early coronary artery involvement is less well defined because the nature and extent of late vascular abnormalities in these patients are unknown. KD is associated with widespread vascular endothelial damage in the acute stage.⁶ In the present study, we used a novel, noninvasive technique to characterize endothelium-dependent vascular responses late after KD. We aimed to determine whether there was evidence of abnormal endothelial function in the systemic circulation even in patients without early coronary involvement. We found persistent abnormalities that may have implications for surveillance and treatment strategies.

	Methods

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Subjects
The patients, selected from our hospital population, were all aged >10 years and had had acute KD 5 years previously, diagnosed by standard criteria.⁷ Subjects were excluded if they had potentially confounding risk factors for endothelial damage, such as smoking, elevated LDL cholesterol, hypertension, diabetes mellitus, or a family history of premature cardiovascular disease or if they were taking vasoactive medication. No other selection criteria were applied. Twenty patients (12 males) aged 11 to 19 years (median age, 13 years) were studied 5.3 to 17.1 years after acute KD (median, 11.3 years), which had occurred at 0.4 to 11.7 years of age (median, 2.3 years). During the acute illness, two patients had coronary artery aneurysms (of right and left coronary arteries) and one patient had diffuse dilatation of the proximal left anterior descending and right coronary arteries. In all cases, there was echocardiographic resolution by 14 months of follow-up. Management was determined by the patients' own physicians. Twelve patients received aspirin in a biphasic regimen, with an initial high dose (30 to 100 mg·kg^-1·d^-1) for 2 to 14 days followed by a low dose (3 to 5 mg·kg^-1·d^-1). One patient received only low-dose aspirin from 1 to 6 months after onset of the illness. Only one patient continued taking aspirin for >6 months after the acute illness; this subject was still taking aspirin at the time of the present study. Four of the patients who took aspirin were also treated with dipyridamole (5 mg·kg^-1·d^-1) for 3 months. Three patients received intravenous gamma globulin (400 mg/kg for 4 consecutive days) within 2 weeks of onset of illness. None of the patients with coronary artery lesions received gamma globulin, but one was treated with prednisolone on the basis of diagnostic uncertainty (1 mg·kg^-1·d^-1). Twenty healthy age- and sex-matched control subjects, aged 10 to 16 years (median, 15 years), were also studied. These subjects were normal children without risk factors for endothelial damage as listed above and were recruited from family and friends of hospital staff. None were taking medication or had a history of significant illness. The study was approved by the local ethics committee, and informed consent was obtained from all subjects or their parents.

Study Protocol
A history was obtained from all subjects, and a physical examination was performed, including supine blood pressure. All subjects had an ECG, and KD patients also had an echocardiogram. The medical records of the KD patients were reviewed for details of their acute illness. Nonfasting lipid profile (total cholesterol, LDL cholesterol, and HDL cholesterol levels) was measured in all subjects, and random blood glucose, full blood count, erythrocyte sedimentation rate, and C-reactive protein were also measured in the KD patients. A noninvasive study of brachial artery endothelial function was performed as described below.

Brachial Artery Vascular Study
Our noninvasive technique for assessing systemic arterial vascular responses uses high-resolution ultrasound to compare brachial artery responses with endothelium-dependent and -independent dilator stimuli.⁸ Dilation of the brachial artery in response to increased flow is dependent on intact endothelial function, whereas glyceryl trinitrate (GTN) is a direct smooth-muscle dilator that acts independently of the status of the endothelium.

B-mode ultrasound images of the brachial artery were obtained in longitudinal section 2 to 15 cm above the elbow by use of a 7-MHz linear-array transducer and Acuson 128XP/10. The center of the artery was identified when the clearest picture of the anterior and posterior walls was obtained. The transmit zone (focus) was set to the depth of the near wall, and gain settings were adjusted to optimize images of the lumen-arterial wall interface. Images were magnified by use of a resolution-box function, leading to a line width of 0.065 mm. Machine operating parameters were kept constant throughout the study.

When we found a satisfactory transducer position, the skin was marked and the arm kept in the same position throughout the study. A baseline scan was recorded after 15 minutes of rest. The pneumatic tourniquet was then inflated distal to the arterial segment being imaged to a pressure of 300 mm Hg for 4.5 minutes, followed by release. A second scan was then recorded from 30 seconds before to 90 seconds after cuff deflation. After an additional rest period of 10 to 15 minutes to permit vessel recovery, a repeat baseline scan was recorded. Sublingual GTN was then administered (400 µg) and the final scan recorded 3 to 4 minutes later. We recorded Doppler-derived flow measurements using a pulsed Doppler signal at a 70° angle to the vessel wall, with the range gate (1.5 mm) in the center of the artery. Flow measurements were recorded during the first resting scan (baseline blood flow) and again during the first 15 seconds of reactive hyperemia. The flow increase was expressed as a percentage of the baseline flow. The ECG was monitored continuously throughout the study.

Data Analysis
Arterial diameters were measured directly from super-VHS videotape, in each case by two independent observers blinded to the scan sequence and the identity of the subject. The arterial diameter was measured at a fixed distance from an anatomic marker (such as a bifurcation or fascial plane) by use of ultrasonic calipers. Measurements were taken from the anterior to the posterior "m-line" at end diastole. The mean diameter was calculated from four cardiac cycles incident with the R wave on the ECG. To assess flow-mediated diameter changes in the second scan, diameter measurements were made 50 to 60 seconds after cuff deflation. Changes in diameter were calculated as percentage change relative to the first (baseline) scan. Hence, flow-mediated dilation equaled [(diameter after cuff deflation-resting diameter)/resting diameter]x100%. We have previously shown⁹ that this method is accurate and reproducible, with low interobserver error. Blood flow was calculated by multiplying the angle-corrected velocity time integral of the Doppler flow signal by the heart rate and vessel cross-sectional area (r²). The flow velocity was taken from the center of the artery and therefore gave an overestimated absolute flow, but relative flows before and after cuff inflation were accurate. Flow change (reactive hyperemia) was calculated as [(flow after cuff deflation-resting flow)/resting flow]x100%.

Statistical Methods
Descriptive data are presented as mean (SD) unless otherwise specified. Differences in biological variables between patients in the case group and control subjects were analyzed by use of an independent t test. Standard multivariate regression analysis techniques were used to examine the relation between biological variables and vascular responses to increased flow and GTN. Statistical significance was inferred at P<.05.

	Results

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All subjects were well, with normal ECGs. The KD patients had normal left ventricular function and normal coronary arteries on echocardiography. All KD patients had normal blood glucose, hemoglobin, white cell count, platelet count, and C-reactive protein. Three patients had an erythrocyte sedimentation rate >20 mm in the first hour (KD patients 22, 25, and 35), but all three had a C-reactive protein level of <1 mg/dL. Cholesterol levels and blood glucose values were all within normal limits and were not different from the control subjects (Table 1). No qualitative differences in the appearance of the vessel walls or intima were seen between the KD patients and control subjects. There was no difference in baseline vessel diameter or the increase in flow after cuff inflation and deflation (reactive hyperemia) between KD patients and control subjects (Table 1). However, flow-mediated dilation of the brachial artery (endothelium-dependent response) was markedly reduced in the KD group (3.1% versus 9.4%; P<.001; Figure). In contrast, responses to GTN did not differ between the two groups (23.0% versus 21.7%; P=.58; Figure). Flow-mediated dilation did not differ in the patients who had detectable early coronary artery abnormalities or in those who had received gamma globulin (Figure).

View this table: [in this window] [in a new window]   Table 1. Lipids, Glucose, and Vascular Studies in Kawasaki Disease Patients and Control Subjects

View larger version (31K): [in this window] [in a new window]   Figure 1. Brachial artery flow-mediated dilation (A) and dilation to glyceryl trinitrate (GTN) (B) in 20 Kawasaki disease patients compared with 20 age- and sex-matched control subjects. Marked impairment in flow-mediated dilation was found in Kawasaki disease patients. , patients treated with gamma globulin; , patients with coronary lesions in the acute stage; and , subjects not treated with gamma globulin and without coronary lesions and control subjects.

Determinants of Vascular Responses
The relations between flow-mediated dilation and vessel size, total cholesterol, reactive hyperemia, age, and the presence of KD were explored for the entire group of 40 subjects by use of multivariate analysis (Table 2). Flow-mediated dilation was inversely correlated with vessel size, as previously reported,⁸ but not with total cholesterol, the degree of reactive hyperemia, or age. The strongest determinant of impaired flow-mediated dilation was a history of KD (P<.001). Within the group of KD patients, a further multivariate analysis was performed to examine the relation between flow-mediated dilation and features of the acute KD illness, including peak white cell count, erythrocyte sedimentation rate, and platelet count. None of these markers of disease severity were related to late endothelium-dependent responses.

View this table: [in this window] [in a new window]   Table 2. Multivariate Analysis of Determinants of Flow-Mediated Dilation in all 40 Subjects

	Discussion

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This study has shown that abnormalities of systemic endothelial function are present many years after resolution of acute KD in early childhood. These striking functional abnormalities were found even in patients without detectable coronary artery involvement during the acute illness.

It has long been known that coronary artery aneurysms occur in a minority of children with acute KD,¹⁰ and considerable attention has been focused on the long-term outcome of this subgroup.^{11 12 13} Histopathological findings in acute KD, however, show widespread vascular inflammation with endothelial edema and necrosis and leukocyte infiltration, involving coronary and other medium-sized muscular arteries,^{14 15} even in children without echocardiographically detectable aneurysms. Our finding of late functional abnormalities of the brachial artery endothelium in the majority of our study group may be a consequence of this systemic inflammation and raises concern that the risk of late cardiovascular complications may not be confined to those with detectable early coronary artery abnormalities.

Endothelial dysfunction is a key early event in the process of atherogenesis, as well as being related to cardiovascular risk in established disease.^{16 17} Abnormalities of the L-arginine/nitric oxide pathway lead to abnormal control of vascular tone and blood flow, increased platelet adhesion and aggregation, altered leukocyte/endothelial interaction, and smooth muscle proliferation.¹⁸ Loss of nitric oxide activity may therefore promote atherogenesis. We have studied endothelial function using a novel, noninvasive method. This method compares vascular dilation in response to increased flow with that to GTN. Flow-mediated dilation in experimental models is known to depend on the ability of the endothelium to release nitric oxide in response to shear stress.¹⁹ The response seen with our technique can be blocked by intra-arterial infusion of N-monomethyl-L-arginine, a specific antagonist of nitric oxide production, which strongly suggests that dilation to flow reflects endothelial nitric oxide activity in large arteries.²⁰ We have previously shown⁹ that our technique measures small changes in arterial diameter accurately and reproducibly in children and young adults. A close correlation has been established between endothelial function in the brachial artery, assessed with the use of our method, and endothelial function in the coronary arteries, studied invasively by infusion of acetylcholine in patients with atherosclerosis.²¹ In view of the known propensity of KD to affect the coronary circulation, it is therefore likely that coronary artery endothelial dysfunction may also be present in patients with abnormal brachial artery responses.

We have previously reported^{22 23 24} impaired endothelium-dependent dilation in young subjects with known coronary risk factors including smoking, diabetes, and hypercholesterolemia. Newburger et al²⁵ reported low HDL cholesterol levels early after KD and attributed this to diminished lipoprotein lipase activity as a result of endothelial damage. In the present study, conducted late after KD, we included only subjects with normal cholesterol levels. Our finding of abnormal endothelium-dependent dilation suggests that the late endothelial dysfunction in KD is independent of lipid profile. Furthermore, lipid abnormalities are not sensitive markers of vascular damage in this condition. However, they may contribute to an increased risk of atherosclerotic disease, as in other populations.²⁶

The acute management of KD in our subjects was not standardized. It differs from current recommendations but was representative of practice at the time these patients presented. As a result, our findings are not necessarily applicable to all patients with KD. No relation was found between features of the acute disease or its treatment in this small cohort of patients. It is noteworthy that despite the heterogeneity of the group, evidence of impaired endothelium-dependent responses was detected in the majority. We cannot examine the important question of whether late abnormalities of endothelial function are influenced by early treatment, particularly by the recently introduced use of gamma globulin. This would require a large prospective trial.

Our finding of strikingly common abnormalities of endothelial function at late follow-up of KD has implications for surveillance strategies. It is currently recommended that patients with acute coronary artery involvement should receive long-term antiplatelet medication and cardiac follow-up. In those without demonstrable early coronary artery abnormalities, who form the majority of patients, long-term antiplatelet treatment is not advised and cardiac follow-up is rarely undertaken.²⁷ We have now demonstrated vascular abnormalities of potential clinical importance in this group. It has been <30 years since the first report of KD, and therefore, very few patients with documented KD have reached an age at which coronary artery disease usually becomes apparent. Thus, no firm link can be established between abnormal endothelial function at 5 to 17 years after disease onset and subsequent clinical risk in this population. However, experimental and clinical studies^{28 29} have indicated that endothelial damage is important both in the genesis of atherosclerosis and in increasing the risk in established disease. Prospective research is required to assess the potential benefit of therapeutic approaches in KD patients, which may include risk-factor control and antiplatelet therapy. The availability of a simple, reproducible, and noninvasive technique makes repeated assessment of endothelial function in these patients during follow-up both feasible and ethical.

	Acknowledgments

 
This work was supported by grants from the British Heart Foundation and Coronary Artery Disease Research Association (CORDA). Dr Nash was supported by the John Herring and Friends Fund, Child Health Research Appeal Trust. The authors would like to give special thanks to Teresa Bull for her help with this manuscript.

Received January 17, 1996; revision received May 14, 1996; accepted May 27, 1996.

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