Matrix metalloproteinase-9 in vascular lesions and endothelial regulation in Kawasaki disease.

BACKGROUND: Matrix metalloproteinases (MMPs) contribute to extracellular remodeling in Kawasaki disease (KD). MMP-9 is an essential vasculature-remodeling factor but its role in the vascular lesions of KD is not understood. This study focused on MMP-9 regulation via cytokines in endothelial cells (ECs). METHODS AND RESULTS: Plasma and peripheral blood mononuclear cells were obtained from 30 KD patients, and 15 non-febrile and 25 febrile children. Plasma MMP-1, -2, -9, and tissue inhibitor of MMP (TIMP)-1 and -2 were measured by 2-step sandwich ELISA. Immunohistology was performed on coronary arterial lesions (CAL) from a patient who died of KD in the acute phase. MMP-9 mRNA expression in human umbilical ECs (HUVECs) treated with plasma or cytokines, and in mononuclear cells was measured by semi-quantitative reverse transcription-polymerase chain reaction. Plasma MMP-1, -2 and TIMP-2 levels were normal for KD. Plasma MMP-9 and TIMP-1 levels increased during the acute phase of the disease (P<0.001 vs each control). MMP-9 stained diffusely in CAL. MMP-9 mRNA levels were higher in HUVECs treated with plasma in the acute and convalescent phases. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha stimulated MMP-9 expression, whereas interferon (IFN)-gamma suppressed it. There was no MMP-9 mRNA elevation in mononuclear cells. CONCLUSIONS: ECs are a source of MMP-9 in the vascular lesions of KD. MMP-9 is regulated by cytokines IL-1beta, IL-6, TNF-alpha and IFN-gamma.

Endothelial dysfunction in adult patients with a history of Kawasaki disease.

To assess the existence of endothelial dysfunction and the possibility of the early onset of atherosclerosis in the chronic stage of Kawasaki disease (KD), we examined endothelial function in adult patients late after the onset of KD. We evaluated two age-matched groups: 35 adult KD patients (KD group) (mean age, 27.0 years; mean interval time, 24.1 years), and 36 healthy adults (control group). To assess vascular endothelial function, flow-mediated dilatation (%FMD) of the brachial artery and urinary nitrites and nitrates (NOx) were examined. We also measured adhesion molecules and several coagulation-fibrinolysis markers. In addition, we measured high-sensitive C-reactive protein (hs-CRP) as a chronic inflammatory marker, and brachial-ankle pulse wave velocity (baPWV) as a marker for arterial stiffness. %FMD was significantly reduced in the KD group when compared with that of the control group (KD group, 10.4 +/- 2.6%; control group, 14.4 +/- 3.2%, p<0.05), particularly in patients with coronary artery lesions. Thrombin-antithrombin III complex values were higher in the KD group, although no significant differences were observed in the other markers for endothelial function. Hs-CRP was significantly elevated only in the patients with coronary aneurysms. Furthermore, in the male KD patients, the baPWV values were significantly higher than those in the control subjects. This study revealed that the adult patients with a history of KD had systemic vascular endothelial dysfunction, and also suggested that a history of KD was possibly one of the risk factors for early onset of atherosclerosis.

[Kawasaki disease and atherosclerosis].

The existence of endothelial damage in impaired coronary arteries, both aneurysms and regressed aneurysms, even during the chronic stage of Kawasaki disease (KD) has been reported by morphologic and functional studies. In addition, based on our results of endothelial-dependent dilatation in systemic arteries or the pathological findings in weaning rabbits in the chronic stage of KD-like allergic coronary arteritis by administering a hypercholesterol diet, it is suggested that vascular endothelial dysfunction, not only in coronary arteries but also in systemic arteries, could exist in the KD patients even in a chronic stage, and also suggested that a history of KD was possible to be one of the risk factor for the early onset of atherosclerosis.

Linear shadows inside coronary arterial lesions on two-dimensional echocardiograhpy in Kawasaki disease patients.

BACKGROUND: Conventional two-dimensional echocardiography (2DE) is not adequately sensitive enough for the detection of stenotic or occlusive coronary lesions that occur in Kawasaki disease. Recently, linear shadows have been detected inside large- or moderate-sized coronary artery lesions (CALs) by high-resolution 2DE at a convalescent or chronic stage. PURPOSE AND METHODS: We evaluated the clinical significance of the linear shadows detected by 2DE and compared the findings with those obtained using coronary angiography (CAG), magnetic resonance imaging (MRI), and intravascular ultrasound (IVUS). RESULTS: From December 2001 to November 2006, linear shadows were detected in 11 out of 18 CALs in 9 patients at our institution. The outer diameters of the CALs by 2DE were larger than the diameters of CALs by CAG, while the inner diameters between the linear shadows by 2DE correlate with the diameters of CALs by CAG. Remarkably thickened intima was confirmed in 7 out of 9 CALs by MRI, and in every lesion that was examined using IVUS. CONCLUSIONS: The results of this study suggest that linear shadows by 2DE would indicate the existence of a thickened intima. We consider that linear shadows may be useful to estimate the development of stenotic lesions during the process of regression or remodeling of CALs.

A randomized prospective study on the use of 2 g-IVIG or 1 g-IVIG as therapy for Kawasaki disease.

A single, 2 g/kg dose of immune globulin (IG), denoted 2 g-intravenous (IV)IG, has become a standard regimen for treating Kawasaki disease (KD) because of its highly preventive effect on coronary arterial lesions (CAL). However, IG is obtained from blood specimens, a drawback to many patients, and is also very expensive. This randomized prospective study reported here was carried out with the aim of developing a treatment regimen that would reduce the total dose of IG. The study tested two protocols (A: 2 g-IVIG; B: 1 g-IVIG) that included the strategy of administering additional IVIG to IVIG-resistant patients based on the criteria we described previously. In protocol A, an additional 2 g-IVIG was administered only once; in protocol B, the first additional IVIG was 1 g-IVIG and the second was 2 g-IVIG. One hundred and nine patients who were admitted before the seventh day of illness and had no CAL at the time of admission were enrolled in the study (protocol A: 54 patients; B: 55 patients). In the protocol A group, 7.4% (4/54) of the patients received 4 g/kg IG. In protocol B, 41.8% (23/55) were treated only with 1 g/kg IG, and 10.9% (6/55) received 4 g/kg IG. No significant differences were observed between the patients of the two subgroups receiving 4 g/kg IG in each protocol group. Discriminate analysis also suggested that 52.4% of the patients in the protocol A group could be treated only with 1 g/kg IG. On the other hand, no significant difference was observed in the incidence of aneurysms between patients in the protocol A group (1/54) and those in the protocol B group (4/55). Our protocol based on 1 g-IVIG, including additional IVIG, was assessed to be an effective treatment and to provide a considerably useful means to reduce the total dose of IG.

Renal function and cardiac angiography.

OBJECTIVE: To study the effect of non-ionic contrast medium on renal function in children with cardiovascular disease. METHODS: Analysis of renal function in 98 children with cardiovascular disease before and after the use of Iopamidol, Iohexol, and Ioversol was done for angiography. Serum creatinine (s-Cre), urinary N-acetyl-beta-D-glucosaminase (u-NAG), urinary beta 2-microglobulin (u-BMG), and urinary alpha 1-microglobulin (u-AMG) levels were evaluated. RESULTS: Although s-Cre levels remained unchanged, u-NAG/Cre, u-AMG/Cre and u-BMG/Cre significantly increased 12 hours after angiography. Levels of u-NAG/Cre, u-BMG/Cre, and u-AMG/Cre after angiography were significantly higher in neonates and infants (age< 12-months, n=32) than in children (age>1-year, n=61), in patients with more than 5 ml/kg of contrast medium (n=25) than in those with less than 5 ml/kg (n=70) and in cyanotic patients (n=13) than in non-cyanotic (n=80) patients. CONCLUSION: Transient renal tubular dysfunction occurred in all of these three non-ionic contrast mediums. Although renal tubular function was intact on a long-term basis, one should be careful of contrast medium-induced nephropathy, especially in neonates and infants, in patients receiving more than 5 ml/kg of contrast mediums in total, and in patients with cyanotic heart disease in using non-ionic contrast mediums.

Characteristics of brachial-ankle pulse wave velocity in Japanese children.

BACKGROUND: Measurement of pulse wave velocity (PWV) is a useful approach for evaluating the severity of atherosclerosis in adults, and, in particular, the measurement of brachial-ankle PWV (baPWV) has been commonly reported as a simple and practicable method. We attempted to investigate how baPWV in healthy children changes with age and gender, in order to assess baPWV in children with risk factors for the early progression of systemic atherosclerosis. METHODS: We measured baPWV in 970 healthy Japanese children (500 boys and 470 girls), and set up the normal baPWV values of children on the basis of age and gender. We also performed linear regression analysis and step-wise multiple regression analysis for evaluating its correlation with baPWV and independent variables for baPWV in children. RESULTS: The values of baPWV in children were higher in boys than in girls, and baPWV increased with age in both genders. Age, blood pressure and heart rate (HR) were significant determinants of baPWV in both male and female subjects, while the obesity index had no correlation with baPWV. CONCLUSION: On the basis of these results, we suggest that baPWV in children is largely influenced by age and gender, and that baPWV gradually increased with age in both genders.