Minako Hoshiai

Endothelial function evaluated by flow-mediated dilatation in pediatric vascular disease

The endothelial function of children with and without vascular disease, consisting of 41 controls, 24 with Kawasaki disease (KD), and 46 with diabetes mellitus (DM), was examined. Age at examination ranged from 3 to 23 years (mean, 12.0 ± 4.7). The flow-mediated dilatation (FMD) and intima-media complex in the common carotid artery were measured. In controls age at examination was not associated with FMD or intima-media complex. FMD significantly decreased in children with KD and DM compared with the control group (control vs KD or DM: 11.7 ± 14.7 vs 3.0 ± 11.0 or 6.4 ± 8.5%, respectively; p < 0.05). However, there was no significant difference for intima-media complex among the groups. Furthermore, FMD in KD patients with coronary arterial aneurysm was lower than that in KD patients without aneurysm (-0.5 ± 9.2 vs 8.3 ± 9.1%, p < 0.05). In DM patients, FMD in the high HbA1c group (HbA1c = 7%) was lower than that in the normal HbA1c group (HbA1c < 7%) (4.8 ± 8.1 vs 11.4 ± 7.8%, p < 0.05). In conclusion, FMD detected endothelial impairment in children with KD or type 1 DM regardless of overt vascular complications, and FMD impairment occurs prior to intima-media complex thickening. By measuring both FMD and intima-media complex, useful information for predicting vascular complications may be obtained.

Double-Orifice Mitral Valve Associated with Noncompaction of Left Ventricular Myocardium

Double-orifice mitral valve (DOMV) is a rare anomaly commonly associated with other congenital heart diseases. We present two patients with DOMV and noncompaction of the left ventricular myocardium (NLVM). Case 1 was a 5-year-old male diagnosed with dilated cardiomyopathy. His echocardiogram showed thin myocardium with dilatation at the basal of the left ventricle, thick noncompacted myocardium around the apex of the left ventricle, and DOMV (complete bridge type) with mild mitral regurgitation. Case 2 was an 11-year-old male diagnosed with complete atrioventricular block. His echocardiogram showed thick noncompacted myocardium with mild hypokinesis from the posterior to lateral wall and DOMV (complete bridge type) with mild mitral regurgitation. DOMV is commonly associated with congenital anomaly and always has an abnormal subvalvar apparatus. The mitral valve and its apparatus embryologically originate from the endomyocardium, which is thought to be the origin of noncompacted myocardium. We speculate that patients with DOMV may have NLVM.

Cardiac and Haemodynamic Effects of Tacrolimus in the Halothane-Anaesthetized Dog

Tacrolimus (FK506) is a potent immunosuppressant widely used for the treatment of patients with solid organ transplantation and autoimmune diseases. The present study investigated the cardiac, haemodynamic and electrophysiological effects of tacrolimus. Tacrolimus in doses of 0.01 and 0.1 mg/kg was infused over 10 min. with a pause of 20 min. in halothane-anaesthetized dogs under monitoring of plasma drug concentrations (n = 5). Sub-therapeutic dose of 0.01 mg/kg hardly affected any of the cardiovascular variables except that it slightly delayed the repolarization. The clinically relevant dose of 0.1 mg/kg had negative chronotropic, inotropic and dromotropic effects, and lowered blood pressure by 70 +/- 12 mmHg, effects previously ascribed to Ca(2+) channel blocking action. Tacrolimus also delayed the repolarization process in a dose-dependent and reverse use-dependent manner with an increase in electrical vulnerability. The cardiovascular effects of tacrolimus were enhanced after the cessation of drug infusion, despite a decline in the plasma concentrations. In human embryonic kidney 293 cells, however, only supratherapeutic tacrolimus concentrations (>0.1 mumol/l) inhibited hERG K(+) current with a maximum inhibition of 28% at 10 mumol/l, indicating that other mechanisms might have also operated besides direct block of ionic channel function. The present study suggests that tacrolimus has negative chronotropic, inotropic and dromotropic effects in the heart, delays repolarization and lowers blood pressure. Moreover, the monitoring of the actual drug concentration may not necessarily reflect its effects on the cardiovascular system; thus, frequent monitoring of cardiovascular variables may be essential for tacrolimus-treated patients.

Impaired sarcoplasmic reticulum function in lipopolysaccharide-induced myocardial dysfunction demonstrated in whole heart.

To clarify the pathophysiological cascade leading to lipopolysaccharide- (LPS) induced myocardial dysfunction, we measured sarcoplasmic reticulum (SR) function, expression of inducible nitric oxide synthase (iNOS), and left ventricular (LV) function in a rat whole heart model. The LV function was evaluated by peak LV pressure and SR function was evaluated by the mechanical restitution (MR) curve, a physiological parameter of SR function. The mechanical restitution curve was constructed by plotting extrasystolic potentiation of LV dP/dt during extrasystoles (100-700 ms) under fixed pacing. Functions were evaluated using the perfusion apparatus at 6 or 24 h after LPS administration. In the 6 h group, LV pressure was depressed to 62% of the control, the SR function was impaired, and iNOS protein was expressed. In the 24 h group LV pressure and SR function remained at the control levels, iNOS was not detected. In the 6 h group dexamethasone co-administration normalized the LPS effect and iNOS was not expressed. LPS-induced myocardial dysfunction appeared to be caused by impaired SR function and NO expression suggesting that NO may act as a trigger.

Infliximab regulates monocytes and regulatory T cells in Kawasaki disease

The effect of infliximab (IFX) on immune cells has not been fully reported in Kawasaki disease (KD). To investigate the mechanism of IFX in KD, we examined changes in the abundance of CD14+CD16+ activated monocytes, regulatory T cells (Treg) cells, and T‐helper type 17 (Th17) cells following treatment with IFX.

Co-occurrence of hypertrophic cardiomyopathy and myeloproliferative disorder in a neonate with Noonan syndrome carrying Thr73Ile mutation in PTPN11

Most cases of Noonan syndrome (NS) result from mutations in one of the RAS‐MAPK signaling genes, including PTPN11, SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1 (MAP2K1), and CBL. Cardiovascular diseases of varying severity, such as pulmonary stenosis and hypertrophic cardiomyopathy (HCM), are common in NS patients. RAF1 mutations are most frequent in NS with HCM, while PTPN11 mutations are also well known. Thr73Ile is a gain‐of‐function mutation of PTPN11, which has been highly associated with juvenile myelomonocytic leukemia and NS/myeloproliferative disease (MPD), but has not previously been reported in HCM. Here, we report a Japanese female infant with NS carrying the PTPN11 T73I mutation with NS/MPD, complete atrio‐ventricular septal defect, and rapidly progressive HCM. No other HCM‐related mutations were detected in PTPN11, RAF1, KRAS, BRAF, and SHOC2. This patient provides additional information regarding the genotype–phenotype correlation for PTPN11 T73I mutation in NS.

Novel curved balloon catheter for dilating postoperative angled lesions associated with congenital heart disease.

OBJECTIVES This study aimed to analyze the surface stress generated by a novel curved balloon and assess its efficacy for treating angular lesions associated with congenital heart disease. BACKGROUND Obstructions at the anastomosis of aortopulmonary shunts and cavopulmonary connections may occur postoperatively. Catheter interventions are often performed for such lesions; however, acute angulation may cause balloon slippage or inappropriate stress on the vessel wall. METHODS We dilated the curved balloon in a curved vessel model and measured the resultant wall stress and its distribution. Clinical evaluations were performed using this balloon in angled lesions. RESULTS In the curved vessel model, curved balloons generated uniform stress on the lesser and greater curvatures (curved type, lesser/greater = 0.343 MPa/0.327 MPa; P = 0.61), whereas straight balloons caused disproportionate stress (straight type, lesser/greater = 0.358 MPa/0.254 MPa; P = 0.19). However, the difference in average stress was not statistically significant. Furthermore, the stress was uniform along the entire length of the curved balloon, but differed between the mid and end portions of the straight balloon. Curved balloon dilations were performed for 10 lesions in 7 patients. The curved balloon conformed well to the angulated lesion without slipping. The median percent change in the minimal lumen diameter (MLD) was 64% (range, 0-206%). In 5 lesions, MLD increased by ≥50%. Oxygen saturation increased by 5% (0-9%). CONCLUSIONS Although further clinical evaluation is necessary, this novel curved balloon may be a reasonable alternative in angled lesions, providing better conformability and preventing excessive stress to the vessel wall adjacent to the stenosis.

Gadolinium-based balloon angioplasty for pulmonary artery stenosis in an infant with a right isomerism

We report here the first described case of utilizing gadolinium‐based contrast material as the contrast agent during a catheter intervention treatment for pulmonary artery stenosis. The patient, a male infant with complex heart disease associated with a right isomerism, had a history of severe allergic reaction to iodine‐containing contrast agents. A combination of digital subtraction angiography and a gadolinium contrast agent, however, provided us with good‐quality images both before and after balloon angioplasty without any associated complications. This method should therefore be considered as an alternative angiographic procedure in children with a high risk of iodine‐related allergic complications. Catheter Cardiovasc Interv 2004;63:346–350.

Mid-term outcome after partial left ventriculectomy in pediatric patients.

From May 1998 to April 2000, we performed partial left ventriculectomy (PLV) in 3 pediatric patients with dilated cardiomyopathy (DCM). At the time of the surgery, their age ranged from eight months to three years. The first patient eventually had to receive a heart transplant, but all patients treated with PLV are alive to this day. Patient #1 was diagnosed with DCM at the age of five months, PLV was done on a semi-urgent basis at the age of eight months, when medium dose IV catecholamine therapy and mechanical ventilation were required. Fraction shortening (FS) as shown by echocardiography increased postoperatively from 8% to 15% along with marked clinical improvement. Her heart failure deteriorated three months after the surgery, and received a heart transplant in the United States when she was one year and two months old. Patient #2 developed severe heart failure two months after correction of a ventricular septal defect. Aggressive medical therapy failed to improve his condition, therefore PLV was done on an elective basis at the age of three years and five months. [The patient was initially hospitalized and underwent low dose catecholamine.] Postoperative course was well. The ventriculography one year after surgery showed an improvement of the left ventricular FS from 12% to 27% after PLV. He was still doing well at his most recent check up. Patient #3 was diagnosed with DCM as a neonate. PLV was done on an elective basis at the age of two years and five months. Her postoperative course was generally well. FS on echocardiography increased postoperatively from 10% to 25% along with marked clinical improvement. The timing of performing PLV is the most essential factor for postoperative course in our experiences. We consider that the best timing is when aggressive catecholamine infusion or mechanical ventilation is required. The mid-term outcome of PLV of pediatric patients is considered to be acceptable. We believe that PLV should be considered as a viable option for severe DCM patients.

Plasma Exchange Downregulates Activated Monocytes and Restores Regulatory T Cells in Kawasaki Disease: Plasma Exchange in Kawasaki Disease

In Kawasaki disease (KD), the effect of plasma exchange (PE) on immune cells has not been fully elucidated. Therefore, we examined the changes in the number of CD14+ CD16+ activated monocytes, regulatory T (Treg), and T‐helper type 17 (Th17) cells in KD patients treated with PE. The percentage of total monocytes and subclasses of lymphocytes, including CD4+ and CD8+ T cells, and CD19+ B cells, showed no significant difference before and after PE. However, the percentage of CD14+ CD16+ monocytes in total leukocytes decreased significantly after PE (1.1% ± 1.5% vs. 2.1% ± 2.3%, P < 0.05). Furthermore, while the percentage of Th17 cells in CD4+ T cells did not change, the percentage of Treg cells in CD4+ T cells increased significantly after PE (11.1% ± 5.1% vs. 8.0% ± 4.4%, P < 0.05). Therefore, PE downregulates activated monocytes and upregulates Treg cells toward normal levels and thus attenuates inflammation in KD.