Shigeru Tateno

Vascular endothelial growth factor in acute Kawasaki disease

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is an important regulator of angiogenesis and blood vessel permeability. Kawasaki disease (KD) is characterized by systemic vasculitis with increased vascular permeability, implying a possible role of VEGF in KD. To elucidate the involvement of VEGF in the pathogenesis of KD, we investigated 30 patients with acute KD, comparing the time course of plasma VEGF levels (n = 123) with clinical symptoms and laboratory findings. Compared with control values, the peak levels of plasma VEGF were significantly elevated (38+/-26 vs 244+/-248 pg/ml, p <0.001). The VEGF levels at the appearance of skin rash and/or edema of hands and feet were also elevated to 176+/-163 pg/ml (p <0.001). In 7 patients (23%), the plasma VEGF levels remained increased after the resolution of the skin rash and peripheral edema. The VEGF levels were independent of gamma globulin therapy and levels of serum albumin and C-reactive protein. We also measured the plasma levels of transforming growth factor-beta1 (TGF-beta1) and tumor necrosis factor alpha, both of which can upregulate VEGF in vitro. The plasma levels of VEGF were highly correlated with those of TGF-beta1 (n = 63, r = 0.73, p <0.001) but not with those of tumor necrosis factor alpha. These findings suggest that the production of VEGF is increased and may be upregulated by TGF-beta1 in acute KD. VEGF may be involved in the hyperpermeability of local blood vessels in acute KD.

Prevalence of adult patients with congenital heart disease in Japan

BACKGROUND Today most patients with congenital heart disease (CHD) can be expected to survive into adulthood. Reports regarding the number of adults with CHD in Japan are scarce. Our study aims to define the number of these adults. MATERIAL AND METHODS The estimated number of infants born in Japan with major CHDs since 1947 was calculated together with mortality rates. We estimated the number of CHD survivors from data on survival rates of unoperated and postoperative patients. The number of deaths from 1968 to 1997 was analyzed using individual death certificates held by the Japanese Government. RESULTS In 1967, 163,058 patients with CHD including 53,846 adults were assumed to be alive. From 1968 to 1997, 548,360 patients with CHD were born and 82,919 died. A total of 622,800 patients, including 304,474 children (49%) and 318,326 adults (51%) were estimated to be alive in 1997. From 1997 to 2007, there has been an estimated increase of 9000 adults every year, and in 2007, 409,101 adults are estimated to be alive. CONCLUSIONS The prevalence in adults with CHD in Japan has explosively increased from 1967 to 2007. There were 409,101 adults with CHD in 2007 with an annual increase of 9000. These data are crucial for planning the establishment in Japan of special facilities and resources necessary for the care of these patients.

Dramatic decrease of circulating levels of monocyte chemoattractant protein-1 in Kawasaki disease after gamma globulin treatment.

Kawasaki disease (KD) is a systemic vasculitis preferentially affecting coronary arteries. Extensive monocytes/macrophages infiltrate in the vascular lesions, implying the involvement of a chemotactic cytokine in their recruitment. We investigated the role of monocyte chemoattractant protein‐1 (MCP‐1, also termed monocyte chemotactic and activating factor) in KD. In the immunohistochemical studies using the cardiac tissues of patients with fatal KD, MCP‐1 but not interleukin (IL) ‐8 or macrophage inflammatory protein‐1α was localized at the extracellular matrix associated with mononuclear cellular infiltration. The sites of MCP‐1 expression correlated with the distribution of the acute inflammation, including early coronary vasculitis. In prospectively studied patients with KD, circulating levels of MCP‐1, IL‐8, tumor necrosis factor a (TNF‐α), and IL‐1α were elevated in 73, 77, 57, and 0% of samples before gamma globulin (GG) treatment (400 mg/kg × 5 days = total 2 g/kg), respectively, compared with respective control values. GG treatment correlated with a rapid decrease in the circulating levels of MCP‐1 (P = 0.001) but not IL‐8 (P = 0.19) or TNF‐α (P = 0.33). In the sensitive Western blotting, MCP‐1 bound to GG. Furthermore, GG inhibited the MCP‐1‐induced Ca2+ influx in a human monocytic cell line in vitro. These findings suggest a role of MCP‐1 in KD, and indicate that GG treatment may block MCP‐1 activity, thus alleviating KD vasculitis. J. Leukoc. Biol. 65: 566–572; 1999.

Measurement of ventricular volumes by cine magnetic resonance imaging in complex congenital heart disease with morphologically abnormal ventricles

This study assessed the validity of cine magnetic resonance imaging (MRI) for measuring right and left ventricular volumes by using Simpsons rule in children with complex congenital heart disease. Forty-five patients with complex congenital heart disease (average age 2.6 years) and 10 controls (average age 2.3 years) were evaluated. The whole heart was encompassed by contiguous transverse sections. Ventricular volumes were calculated by adding luminal areas determined in each section at end diastole and end systole. End-diastolic and end-systolic volumes by MRI in both groups correlated well with those by ventriculography (r>0.89). Comparison of the ejection fraction in both ventricles in both groups yielded a good correlation between MRI and ventriculography (r>0.67). MRI technique in both groups had low intraobserver and interobserver variation (<6%). Cine MRI provides a suitable noninvasive means of quantifying ventricular volume in children with complex congenital heart disease.

Prevalence of arrhythmias and conduction disturbances in large population-based samples of children

The aim of our study is to provide data on the prevalence of disturbances of rhythm in the general population of children. Accurate estimates of true prevalence of such disturbances of rhythm from large samples are mandatory if we are to interpret properly electrocardiographic abnormalities. We analysed prevalence of disturbances of rhythm in a population of 152,322, comprised of 71,855 elementary school students, 36,692 males and 35,163 females, aged from 5 to 6 years, and 80,467 students of junior high school, 41,842 males and 38,625 females, aged from 12 to 13 years. We analysed the prevalence of premature atrial and ventricular contractions, first, second and third degree atrioventricular block, incomplete and complete right bundle branch block, Wolff-Parkinson-White syndrome, and prolongation of the QT interval. The prevalence of disturbances of rhythm in total rose with age, being found in 1.25% of elementary school students and 2.32% of junior high school students, and was higher in males than females, at 2.00% as opposed to 1.38%, both values being statistically significant at a level of less than 0.0001. Prevalences of all types of rhythmic disturbances were higher in junior high school students than elementary school students (p < 0.0001). Premature atrial and ventricular contractions and prolongation of the QT interval were higher in female than male students, at percentages of 0.089, 0.497, and 0.02 for males, and 0.123, 0.534 and 0.027 in females (p < 0.0001). In contrast, incomplete and complete right bundle branch blocks were higher in males than females, at 0.983% and 0.083% in males versus 0.410% and 0.161% in females (p < 0.0001). Disturbances of rhythm increased with age, and conduction disturbances were higher in male students than female, although premature atrial and ventricular contractions and prolongation of the QT interval were more frequent in female. These data may be useful for future comparative studies of disturbance of rhythm in children.

Alleviation of Myocardial Ischemia After Kawasaki Disease by Heparin and Exercise Therapy

Background—Heparin promotes angiogenesis. We evaluated the effects of combined treatment with heparin and exercise on myocardial ischemia in the chronic stage of Kawasaki disease. Methods and Results—This study was conducted in 7 patients (aged 6 to 19 years) who had a totally occluded coronary artery and stress-induced myocardial ischemia in the collateral-dependent areas. Twice-daily exercise using a bicycle ergometer was performed with increments of 0.5 W/kg every 3 minutes up to maximal exertion for 10 days. Heparin, which immediately increased circulating hepatocyte growth factor, was given intravenously 10 minutes before each exercise period. Newly developed myocardial infarction, ventricular tachyarrhythmia, anginal attack, or hemorrhagic complication was not observed in any patient. Dipyridamole-loading single photon emission computed tomography documented improved myocardial perfusion in the collateral-dependent areas and a significant reduction in total defect scores in all patients after the completion of 20 sessions (P =0.01). In control patients who did not receive the heparin-exercise therapy, however, stress defect scores remained unchanged (n=1) or increased (n=2) during follow-up. Computerized quantitative coronary angiography provided evidence that the heparin-exercise therapy increased the diameter of the occluded artery to which collaterals terminated (P =0.001) but not that of the reference artery with which collaterals were not connected (P =0.96). Conclusions—The findings suggest that a series of heparin and exercise treatments over 10 days may have a dramatic effect on the alleviation of myocardial ischemia in collateral-dependent regions. This may be a safe, noninvasive revascularization therapy for patients with coronary artery occlusion in the chronic stage of Kawasaki disease.

Magnetic resonace imaging of heterotaxia in infants

OBJECTIVES This study assessed the usefulness and safety of magnetic resonance imaging (MRI) for systematically diagnosing heterotaxia in infants. BACKGROUND Although it is important to diagnose and treat infants with heterotaxia, which is associated with viscerobronchial cardiovascular anomalies, systematic diagnosis of these anomalies by a single imaging technique is difficult. METHODS Twenty patients with heterotaxia were evaluated. The infants ranged in age from 21 days to 12 months (average 5.2 months, average body weight 4.3 kg). Electrocardiographically gated MRI was performed by spin echo imaging techniques operating at 0.5 tesla. RESULTS In all 20 patients, MRI results were sufficient to evaluate these anomalies without serious complications. In 17 patients, neither a spleen nor splenules were detected, but in 3 patients, a polymorphous spleen was visualized. In all 20 patients, bronchial anatomies were clearly visualized (bilateral eparterial bronchi in 14 patients, bilateral hyparterial bronchi in 2 and normal bronchial patterns in 4). Additionally, in a comparison of 149 observations of cardiovascular anatomy by MRI with those by angiography, discrepancies were found in only 10 observations (6.7%). CONCLUSIONS Magnetic resonance imaging was found to be safe and very useful for the systematic diagnosis of heterotaxia in infants.

Validation of the Proximal Isovelocity Surface Area Method for Assessing Mitral Regurgitation in Children

Abstract. The proximal isovelocity surface area (PISA) method for calculating volume flow through the regurgitant orifice has attracted significant attention. A number of in vitro studies and clinical studies in adults suggest that the method is accurate. However, when applying the method to children it must be noted that the absolute regurgitation volume is small, and the range of body sizes is wide. This study investigated the accuracy of the PISA method for quantitative assessment of the severity of mitral regurgitation in children. Twenty children aged 7 months to 12 years (average 4.7 years) with mitral regurgitation but without interventricular shunt or aortic stenosis were selected for this study. Underlying cardiac diseases included atrioventricular septal defects in nine, isolated mitral regurgitation in five, and association with other heart defects in six. The PISA radius (r) and the duration of regurgitation (T) were measured on color M-mode recordings, with the M line passing through the center of the PISA. Assuming that the PISA is a hemisphere, maximal regurgitant flow rate (MFR: ml/s) was calculated as MFR = 2π×~ r2×~ V (r= maximal radius, V= aliasing velocity), and regurgitant stroke volume (RSVpisa) as RSVpisa = 2π×~ MSR ×~ V×~ T (MSR = mean square of the PISA radius during regurgitation). As a validating standard, total stroke volume (TSV) using two-dimensional echocardiography determined by the area–length volumetry method and forward stroke volume (FSV) by the pulsed Doppler method were measured, and regurgitant stroke volume (RSVD: RSVD= TSV − FSV) and regurgitant fraction (RF: RF = RSVD/TSV) were calculated. A linear correlation was found between MFR, RSVpisa, and RSVD (X) (MFR = 4.2X + 54.0, r= 0.84. RSVpisa = 1.0X + 9.8, r= 0.90), and both RSVpisa and MFR divided by body surface area (BSA: m2) revealed a significant correlation with regurgitant fraction (X) by nonlinear regression analysis (RSVpisa/BSA = 26.2 ×~ X/(1 − X) + 16.8, r= 0.85. MFR/BSA = 121.8 ×~ X/(1 − X) + 92.2, r= 0.79). It is concluded that maximal regurgitant flow rate, regurgitant stroke volume, and regurgitant fraction can be accurately predicted in children using the PISA method by Doppler echocardiography.

The prevalence and risk factors for cholelithiasis and asymptomatic gallstones in adults with congenital heart disease

PURPOSE Cyanosis is considered to be a risk factor for cholelithiasis which is an important complication of cyanotic congenital heart disease (CCHD) in adults. In this study, the prevalence of cholelithiasis and asymptomatic calcium bilirubinate gallstones was evaluated in adults with congenital heart disease (CHD). Furthermore, risk factors for this potentially high risk complication were assessed. MATERIALS AND METHODS Subjects were derived from 114 consecutive congenital patients who visited our center from May 2008 to January 2009. For analyses of risk factors, we divided them into 4 groups: group A, 15 CCHD patients without reparative surgery (7 men, 31.8 ± 7.0 years old); group B, 41 CCHD patients rendered acyanotic by reparative surgery (21 men, 32.5 ± 11.8 years old); group C, 23 unoperated acyanotic CHD patients (11 men, 42.4 ± 16.4 years old); and group D, 35 patients who were acyanotic before and after operation (18 men, 36.3 ± 14.8 years old). Gallstones were identified by abdominal ultrasound and risk factors were analyzed by a multivariate logistic regression model. RESULTS Cholecystectomy was performed in 5/114 (4.3%), asymptomatic gallstones were seen in 16/114 (14%), and symptomatic gallstones except for patients after cholecystectomy were seen in 7/114 (6.1%). In group A, 4 (27%) with gallstones underwent cholecystectomy (p<0.01). Non-cholesterol gallstones were observed in 5 patients (33%) in group A, 12 patients (29%) in group B, nobody in group C, and 3 patients (8.6%) in group D. By a multivariate logistic regression model, CCHD by nature regardless of repair, prolonged cyanosis periods, higher frequency of cardiopulmonary bypass (CPB), and lower platelet counts were significant factors predicting gallstones (odds ratio 4.48, 1.08, 3.96, and 0.87, 95% CI, 1.14-17.5, 1.00-1.18, 1.65-9.54, and 0.75-0.99, respectively). CONCLUSIONS The prevalence of cholelithiasis and asymptomatic gallstones is significantly high in CCHD patients regardless of cardiac repairs. CCHD by nature, prolonged cyanosis durations, high frequency of CPB and low platelet counts have influences on gallstone formation in adults with CHD.

Aortic pressure wave reflection in patients after successful aortic arch repair in early infancy

Despite the apparently successful surgical repair of aortic coarctation, subsequent cardiovascular complications have sometimes been encountered. Aortic pressure wave reflection is one of the risk factors for developing cardiovascular diseases, and an enhancement of the pressure wave reflection has been reported in patients after aortic arch repair. To clarify this issue, the increase in pressure wave reflection was evaluated in patients <15 years old who underwent aortic arch repair. This study enrolled 35 patients after aortic arch repair in early infancy. All patients underwent cardiac catheterization, and in 20 patients, there was no pressure difference within the repaired aortic arch. The aortic pressure waveforms in patients after successful aortic arch repair were recorded using a pressure sensor-mounted catheter, and the augmentation index in the ascending aorta was calculated. The augmentation index in patients after an aortic arch repair was increased compared with control subjects, although there was no pressure difference between the ascending and descending aorta (P<0.0001). The increase in the augmentation index was correlated with the patient’s age (r=0.8932, P<0.0001) and with the left ventricular posterior wall thickness (r=0.4075, P=0.0373). In patients who undergo aortic arch repair, the pressure wave reflection is accelerated, even when the aortic arch repair is ‘successful’. This increase is one of the possible causes of left ventricular hypertrophy.