Seiichiro Ozawa

Effects of HMG-CoA reductase inhibitors on continuous post-inflammatory vascular remodeling late after Kawasaki disease

BACKGROUND In Kawasaki disease (KD), it has been clinically and experimentally reported that post-inflammatory vascular remodeling would induce the development of arteriosclerosis or early onset of atherosclerosis in the future. The effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on continuous vascular remodeling late after Kawasaki disease were clinically evaluated. PATIENTS AND METHODS We enrolled and treated a total of 11 KD patients (age range, 7-25 years) with fluvastatin (0.5-0.7 mg/kg/day) for 12 months. All of them had significant coronary aneurysmal or stenotic lesions and more than 3 of the following 5 abnormal findings: reduced %flow-mediated dilatation (%FMD), reduced urinary NOx, elevated high-sensitivity C-reactive protein (hs-CRP), reduced urinary 8-isoprostane, and elevated brachial-ankle pulse wave velocity (baPWV; control, ≤1400 cm/s). RESULTS A statistically significant improvement was observed in each biomarker after fluvastatin treatment: %FMD, from 9.29% (3.41)% to 10.55% (3.27)% (p=0.003) after 3 months; NOx/creatinine (cre), from 1.16 (0.54) µmol/mg cre to 1.30 (0.50) µmol/mg cre (p=0.038) after 12 months; baPWV, from 1175.4 (277.3) cm/s to 1031.8 (155.6) cm/s (p=0.009) after 3 months; hs-CRP, from 0.073 (0.035) mg/dl to 0.028 (0.014) mg/dl (p=0.0002) after 3 months; and 8-iso/cre, from 751.8 (241.8) pg/mg cre to 660.0 (198.5) pg/mg cre (p=0.018) after 3 months. No adverse events were clinically observed in the patients. CONCLUSIONS The results of this study suggested that HMG-CoA reductase inhibitors are useful as an alternative therapeutic strategy for stabilizing continuous post-inflammatory vascular remodeling that results in the development of arteriosclerosis late after KD or early onset of atherosclerosis in the future.

The role of apelin on the alleviative effect of Angiotensin receptor blocker in unilateral ureteral obstruction-induced renal fibrosis.

Background: Apelin is a selective endogenous ligand of the APJ receptor, which genetically has closest identity to the angiotensin II type 1 receptor (AT-1). The effects of the apelin/APJ system on renal fibrosis still remain unclear. Methods: We examined the effects of the apelin/APJ system on renal fibrosis during AT-1 blockade in a mouse unilateral ureteral obstruction (UUO) model. Results: We obtained the following results: (1) At UUO day 7, mRNA expressions of apelin/APJ and phosphorylations of Akt/endothelial nitric oxide synthase (eNOS) in the UUO kidney were increased compared to those in the nonobstructed kidney. (2) AT-1 blockade by the treatment with losartan resulted in a further increase of apelin mRNA as well as phosphorylations of Akt/eNOS proteins, and this was accompanied by alleviated renal interstitial fibrosis, decreased myofibroblast accumulation, and a decreased number of interstitial macrophages. (3) Blockade of the APJ receptor by the treatment with F13A during losartan administration completely abrogated the effects of losartan in the activation of the Akt/eNOS pathway and the amelioration of renal fibrosis. (4) Inhibition of NOS by the treatment with L-NAME also resulted in a further increase in renal fibrosis compared to the control group. Conclusion: These results suggest that increased nitric oxide production through the apelin/APJ/Akt/eNOS pathway may, at least in part, contribute to the alleviative effect of losartan in UUO-induced renal fibrosis.

Spiral CT scanning angiography for assessing systemic-to-pulmonary shunt in children

package. The reconstructions were rotated to evaluate stenotic changes. The diameter of grafts was measured with digital computer-assisted calipers (Digitizer KD 4300, Graphtec Co, Japan). Shunt grafts were clearly identified with spiral CT angiography (figure) in all cases. A strong linear correlation between spiral CT angiography and conventional angiography (Y=1·50 –2·28, r=0·93) was found for measurement of the mid-portion diameter of the shunt graft. In four of eight cases, significant stenotic lesions were observed in the angiographic images at the junction of the shunt graft and pulmonary artery, and a strong linear correlation (Y=1·00 –0·62, r=0·82) was also observed in the narrowest diameter of the graft between both angiograms. Spiral CT angiography evaluates graft configuration and diameter, with an accuracy similar to that of conventional invasive angiography.

Neutropenia in the acute phase of Kawasaki disease and prevention of coronary artery aneurysm

Background:  The significance of neutropenia in Kawasaki disease (KD) has not been fully elucidated as yet.

Anti-inflammatory Effects of 3-Hydroxy-3-Methylglutaryl-Coenzyme AReductase Inhibitor on Acute Coronary Arteritis in A Rabbit Model ofKawasaki Disease

Background: Recent observations suggest that some of the clinical benefits associated with statin therapy are pleiotropic, i.e., they are independent of their cholesterol-inhibiting action. In this study, we attempted to evaluate the anti-inflammatory effects of statins on coronary arteritis in a rabbit model of Kawasaki disease (KD). Methods and Results: Allergic vasculitis rabbit models were used in this study and divided into 3 groups as follows: no treatment (A), fluvastatin treatment (B), and pravastatin treatment (C). In group A, histological examinations demonstrated severe panvasculitis with endothelial destruction, marked mononuclear cell infiltration of all layers, and edematous thickening of the medial layer. These inflammatory findings were most prominent on day 3 and were similar to the histopathological features in KD. However, in both groups B and C, the inflammatory findings were significantly suppressed even on day 3 in comparison with those in group A. Conclusions: Our study showed that statins had significant anti-inflammatory effects in a rabbit model of acute coronary arteritis typical of KD. It is suggested that statins may be effective for preventing the development of coronary aneurysmal changes.

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.

P-279 Evaluation of Platelet Activation in Kawasaki Disease by Platelet-Derived Microparticles

retrospectively. Non-responsiveness to IVIG was defined as persistent fever (37.5oC over 1 day) after finishing IVIG. This criterion was met in 38 patients (40%), who were all treated with additional IVIG. WBC, CRP, and sodium concentrations were determined before and within half a day after initial IVIG. Generally, the measurement of these laboratory data has been possible at any time. Results: Multivariate logistic regression analysis selected increased WBC count (p < 0.01), increased CRP (p < 0.05), and low sodium concentration (<135mEq/L, p < 0.01) just after initial IVIG, as independent predictors of non-responsiveness to low-dose IVIG. The criteria for at least one of the three predictors were considered to be useful for detecting non-responsiveness to initial low-dose IVIG for acute KD (Sensitivity = 89%, Specificity = 60%). Conclusion: Using our simple predictive models, we can select non-responder to low-dose IVIG treatment, which decrease a total dosage of IVIG in patients with acute KD.

CLINICAL SIGNIFICANCE OF LINEAR SHADOWS INSIDE CORONARY ARTERIAL LESIONS ON TWO-DIMENSIONAL ECHOCARDIOGRAPHY IN PATIENTS WITH KAWASAKI DISEASE

INTRODUCTION: In Kawasaki disease, we have detected linear shadows inside large- or moderate-sized coronary arterial lesions (CALs) on high-resolution two-dimensional echocardiography (2DE). OBJECTIVE: For this study, we wanted to investigate the origin and clinical significance of these linear shadows compared with findings on coronary angiography (CAG), MRI, and intravascular ultrasound. RESULTS: Linear shadows were detected in 11 CALs on high-resolution 2DE in 9 patients with Kawasaki disease. The outer diameters of CALs on 2DE (7.0 ± 2.1 mm) were larger than those on CAG (4.4 ± 1.6 mm), whereas the inner diameters between linear shadows (3.9 ± 1.6 mm) were almost equal to the diameters of CALs on CAG. There was a statistically significant positive correlation (y = 0.99x − 0.10; r2 = 0.77) between the diameters of CALs on CAG and the inner diameters between linear shadows on 2DE. A thickened intima was revealed in the same regions that showed linear shadows on 2DE, in 7 of 11 lesions on MRI, and in all 4 lesions on which intravascular ultrasound was performed. In 3 patients who had been followed up over 3 years, linear shadows inside CALs on 2DE persisted, and the diameter between linear shadows was almost consistent with the diameter of CALs on CAG. CONCLUSIONS: These results suggest that linear shadows inside CALs on 2DE would reflect the existence of a thickened intima. We expected that following up the changes of linear shadows inside CALs was useful for noninvasive evaluation of coronary arterial remodeling such as intimal hypertrophy or stenotic change.

The Relation between Calcification and Restenosis of Coronary Artery after Percutaneous Transluminal Coronary Rotational Ablation (PTCRA) in Kawasaki Disease

Background: Severe calcification in the coronary lesions has been frequently revealed in Kawasaki disease (KD). Therefore, PTCRA has been performed as an effective intervention for obstructive coronary lesions. However, restenosis after PTCRA in KD has not been clear. So, we assessed the relation between calcification and restenosis after PTCRA in KD using the intravascular ultrasound (IVUS) in two KD patients. Case reports: Case1; 13 year-old boy, 9 years after the onset of KD, developed 90% stenosis both at AHA segments 2 and 6 on CAG. PTCRA was performed for these stenotic lesions, and consequently stent implantation was added at segment 6 because of intimal dissection after additional PTCA. Stenosis at segments 2 and 6 reduced to 25% and 0%, respectively. IVUS revealed partial circumferential calcification at segment 2, and total calcification at segment 6. Three months later, the follow-up CAG and IVUS showed 50% restenosis and partial circumferential calcification with intimal thickning at segment 2. On the other hand, they showed no restenosis and total calcification without intimal thickning at segment 6. Case2; 16 year-old boy, 14 years after onset of KD, developed 90% stenosis at segment 6, and total occlusion of RCA with recanalization. Stenotic lesion at segment 6 was improved to 50% by PTCRA. Three months later, follow-up CAG and IVUS showed no restenosis and total calcification without intimal thickning. Conclusion: PTCRA was performed for three calcified stenotic lesions in 2 KD patients. One, with partial circumferential calcification, caused a restenotic change with developed intimal thickning. On the other hand, other 2 lesions with total calcification did not develop restenosis. These results suggest that total calcification could protect intimal proliferation contributing to coronary restenosis after PTCRA.

Randomized-prospective Study of a Single Infusion of 1g|[sol]|kg Gammaglobulin for Reducing a Total Dose of Gammaglobulin in Kawasaki Disease Treatment

A high-dose (2g/kg) gammaglobulin (IVIG) treatment has been well established as a standard therapy for Kawasaki disease (KD). However, it has been clinically and economically expected to reduce a total dose of IVIG because the gammaglobulin is a blood preparation and very expensive. To assess the efficacy of a single infusion therapy of 1g/kg IVIG for preventing the cardiac sequelae, we attempted a multicentral prospective study using our own protocol. Method: 77 KD patients in the acute phase were randomly divided into 2 groups as follows: Group A, a single infusion of 2g/kg IVIG (an additional therapy: 2g/kg), Group B, a single infusion of 1g/kg IVIG (1st additional therapy: 1g/kg, and 2nd 2g/kg). The initial IVIG therapy was started in the 5-7th day of illness in all patients. The additional IVIG was performed in the cases who satisfied with 2 or more items of the following criteria at 24-36h after the first treatment: 1) body temperature >= 37.5 oC, 2) CRP >= 3.0g/dl, 3) neutrophils >= 7500/mm3. Serial echocardiograms were taken until 60 days of illness. Results: 36 were assigned to Group A and 41 to Group B. At enrollment the patients in each group had similar demographic characteristics and laboratory data before treatment. In Group A, no coronary arterial involvement was observed. In Group B, 2 patients with additional 2nd therapy showed temporary coronary dilatation (N.S. vs. Group A, X2 test). 32% in Group B patients were treated only with a single infusion of 1g/kg gammaglobulin. Conclusion: This prospective study suggests that a single infusion of 1g/kg gammaglobulin is clinically effective to prevent coronary sequelae as well as 2g/kg IVIG.Background: The efficacy of high-dose intravenous gamma-globulin (IVGG) treatment in Kawasaki disease (KD) is well known. But it is unclear whether the IVGG products manufactured by various companies are equally efficacious in treatment of KD and whether they are equally safe. Purpose: To compare the efficacy and safety of various IVGG products in patients with KD. Methods: We studied 142 patients with KD who had no coronary artery complications on admission and within the first 9 days of illness. Using a random number table, 50 patients were selected to receive freeze-dried, sulfonated product (Venilon-I; product A), 56 patients were selected to receive pH4-treated product (Polyglobin-N; product B), and the remaing 36 patients were selected to receive polyethyleneglycol-treated product (Venoglobulin-IH; product C). The doses of IVGG (2g/kg X 1 day or 1g/kg X 1 day) were determined by Haradas score. All patients were treated with IVGG in combination with aspirin. Results: There were no significant differences among the 3 groups in regard to age, gender, Haradas score, and illness days when IVGG was initiated. The incidence rate of patients who needed additional IVGG treatment was similar in all groups (product A.26.0%, B 21.4%, C 30.6%). The incidence of coronary artery complications was similar in all groups (product A 10.0%, B 8.9%, C 2.8%). The adverse effects of IVGG were seen in 4 patients, but all patients recovered after IVGG was discontinued. There were no significant differences among the 3 groups in regard to adverse effects (product A 0%, B 1.8%, C 5.6%). Conclusion: We concluded that there are no significant differences among 3 IVGG products in regard to their efficacy and safety.