Efficacy of primary treatment with immunoglobulin plus ciclosporin for prevention of coronary artery abnormalities in patients with Kawasaki disease predicted to be at increased risk of non-response to intravenous immunoglobulin (KAICA): a randomised controlled, open-label, blinded-endpoints, phase 3 trial.

BACKGROUND: Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. METHODS: We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. FINDINGS: We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25-0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). INTERPRETATION: Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. FUNDING: Japan Agency for Medical Research and Development (grant CCT-B-2503).

Hypoxia induces alteration of bone morphogenetic protein receptor signaling in pulmonary artery endothelial cell.

Reduced expression of bone morphogenetic protein receptors (BMPR) has been implicated in the pathogenesis of pulmonary hypertension (PH), but changes in the intracellular signaling pathway of BMPR have not been fully understood. We hypothesized that BMPR signaling in pulmonary endothelial cells is altered during the development of PH, such as hypoxia-induced PH. We examined the expression of BMPR, BMP-regulated Smads and Id-1 in lung tissues of Sprague-Dawley rats exposed to 2 wk of hypoxia and in isolated lung vascular endothelial cells exposed to hypoxia. BMPRII was predominantly expressed in the endothelial cells (EC) of pulmonary vasculature. In hypoxic rats, reduced expression of BMPRII was observed in the EC of resistance pulmonary arteries. The expression of phosphorylated-Smad1/5/8 and Id-1 in EC was also reduced, whereas the expression of Smad1 as well as activin receptor-like kinase 1 (ALK1) was up-regulated during the development of PH. In in vitro exposure to hypoxia, the expression of mRNA transcripts for BMPRII, Smad8, and Id-1 in EC was reduced, whereas mRNA of Smad1 was not diminished. Our results suggest that hypoxia induces alteration of intracellular BMPR signaling in the EC of resistance pulmonary artery, which is involved in the pathogenesis of PH.

Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment.

Clinical, laboratory, and echocardiographic data were retrospectively analyzed in 112 patients with acute Kawasaki disease who received high-dose (2 g/kg) intravenous gamma-globulin (IVIG) treatment within 2 days and were compared for those who were responsive and non-responsive to initial IVIG treatment. Coronary arteries adjusted for body surface area (BSA) were evaluated quantitatively by comparison with the mean dimensions for 85 normal control subjects. The incidence of coronary abnormalities was higher in IVIG-non-responsive patients as compared to IVIG-responsive patients (71% versus 5%, p<0.0001). Univariate analysis of pre-IVIG data showed that the neutrophil count and serum levels of C-reactive protein (CRP), total bilirubin (TB), aspartate aminotransferase (AST), alanine aminotransferase, and lactate dehydrogenase (LDH) were significantly higher in IVIG-non-responsive versus responsive patients. Multivariate analysis selected CRP (p=0.009), TB (p<0.001), and AST (p=0.002) as independent predictors of non-responsiveness to initial IVIG treatment. By defining predictive values, patients with at least two of three predictors (CRP>or=7.0 mg, TB>or=0.9 mg, or AST>or=200 IU/L) are considered to be non-responsive to IVIG for acute Kawasaki disease. Alternatively, more intense initial therapy may be a promising therapeutic strategy for patients who are predicted to be IVIG-non-responsive.

Application of signal-averaged electrocardiogram to myocardial damage in the late stage of Kawasaki disease.

BACKGROUND: Myocardial damage occurs in the late stage of Kawasaki disease (KD) regardless of whether coronary artery lesions (CALs) are present. METHODS AND RESULTS: A signal-averaged electrocardiogram (ECG) was performed in 23 patients who were in the late stage of KD (CAL was found in 12 and no CAL (non-CAL) was found in 11) and 10 healthy controls. Filtered QRS duration and the root-mean-square voltage in the last 40 ms of the QRS complex were measured using time-domain analysis. Additionally, the area ratio (AR), (area of 20-50 Hz)/(area of 0-20 Hz) x100, was calculated by frequency domain analysis. These findings were compared with the clinical data and histopathological findings. In time-domain analysis, there were no significant differences among the 3 groups. In frequency domain analysis, the AR in CAL was significantly higher than that in the other 2 groups. Furthermore, all 4 patients who underwent an endomyocardial biopsy showed a high AR and abnormal histopathological features. CONCLUSIONS: The findings of the present study suggest that patients in the late stage of KD have abnormal findings on signal-averaged ECG even without stenotic lesions, arrhythmia or ischemia, a condition that might reflect histopathological changes in the myocardium in the late stage of KD.

Beneficial Effect of Oral Bisphosphonate Treatment on Bone Loss Induced by Chronic Administration of Furosemide without Alteration of Its Administration and Urinary Calcium Loss.

Bisphosphonate is widely used to treat patients with primary and secondary osteoporosis. The chronic administration of furosemide is considered a risk factor for osteoporosis mainly due to the increased urinary excretion of calcium, leading to a long-term negative balance of calcium. We describe two patients with mild heart failure who took furosemide for more than 5 yr and developed hyperparathyroidism and lumbago associated with low bone mineral density. Their serum levels of intact parathyroid hormone and bone mineral density (BMD) of the lumbar spine (L2-L4) were 180.8 and 144.3 pg/ml, and 71% and 80% of the mean of healthy women, respectively. The oral administration of alendronate or risedronate was effective for lumbago and improved BMD, although the urinary excretion of calcium and hyperparathyroidism were not changed. For the medical treatment of lumbago and decreased bone mass secondary to the long-term administration of furosemide, bisphosphonate is proposed when the dose of furosemide cannot be reduced. However, it may be important to give sufficient calcium and vitamin D to patients to improve secondary hyperparathyroidism.

A novel mutation in the PTPN11 gene in a patient with Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy.

UNLABELLED: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene. CONCLUSION: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

Determination of timing for reoperation in patients after right ventricular outflow reconstruction.

After right ventricular (RV) outflow reconstruction, patients often develop postoperative outflow tract stenosis or pulmonary regurgitation, or both. The aim of this study was to assess the relation between RV hypertrophy, volume, pressure, and function and to provide indications for repeat surgery. We performed magnetic resonance imaging to measure RV volume, wall mass, and the ratio of mass to volume in 31 patients after RV outflow reconstruction and in 12 controls. Patients were divided into 2 groups, New York Heart Association class I and the repeat surgery group. The RV stress index was defined as RV peak systolic pressure/(mass to volume); RV ejection fraction (EF) was calculated by ventriculography. The RV stress index for the repeat surgery group was significantly higher than for the remaining groups (p <0.01). In the New York Heart Association class I and control groups, a significant inverse correlation was observed between RVEF and the RV stress index (r = -0.59, p <0.01). All patients in reoperation group whose RVEF decreased to <95% confidence limit of regression had symptoms of RV failure. The RV stress index decreased substantially after reoperation, but RVEF remained at <95% limits. These findings suggest that excess RV wall stress contributes to impaired RV performance. The RV stress-RVEF relation may be useful in assessing RV function and in establishing a surgical indication.

Successful stenting for renal artery stenosis in a patient with Alagille syndrome.

A 12-year-old girl with Alagille syndrome manifested severe hypertension caused by renal artery stenosis in a solitary functioning kidney. Percutaneous transluminal angioplasty (PTA) and stenting was performed, but the hypertension persisted. On the next day, acute renal failure occurred with the administration of angiotensin-converting enzyme inhibitor, and migration of the stent was confirmed by angiography. Thus, a second stent was placed with success. Since then, the hypertension has been controlled with anti-hypertensive medication, and the renal function has recovered to normal range.

Impaired vascular endothelium-dependent relaxation in Henoch-Schönlein purpura.

Few reports have focused on vascular endothelial function in children with Henoch-Schönlein purpura (HSP). The purpose of the present study was to assess endothelial function and to follow serial changes from the acute to convalescent phases in children with HSP. Forearm flow-mediated vasodilation was evaluated in 21 patients with HSP, aged 4.0-10.3 years (median 6.2 years), and in 14 control subjects. Vascular dimension, mean velocity, and flow volume were measured by ultrasonography in brachial artery before and after hyperemia, and during incremental infusions of nitroglycerin (0.5, 1.0 microg/kg per min). In the controls, significant increases in dimension, mean velocity, and flow volume were observed in reactive hyperemia ( P<0.01). In contrast, patients in the acute phase of HSP showed a flow velocity profile indicating a highly resistant forearm circulation, and significantly attenuated responses after hyperemia ( P<0.01 vs. control), whereas the responses to nitroglycerin were well preserved. In addition, the impaired hyperemic responses recovered in the convalescent phase, with no significant differences compared with controls. These results clearly suggest that forearm vascular endothelium-dependent relaxation was attenuated in patients with acute HSP.

Serum KL-6 level in newborns with meconium aspiration syndrome.

BACKGROUND: It has been reported that serum KL-6 increases in babies with progressing chronic lung disease (CLD). However, there have been few reports assessing KL-6 in meconium aspiration syndrome (MAS). KL-6 was measured in neonates with respiratory diseases including MAS. METHODS: Thirty-eight neonates with respiratory disease were enrolled in the study. These patients were classified into three groups, 14 patients with respiratory distress syndrome (RDS), 14 with MAS, and 10 with transient tachypnea of the newborn (TTN). The control group consisted of 12 healthy neonates. KL-6 levels were measured 1 day (median) after the birth. In the RDS group, measurement was repeated just prior to 36 weeks' postmenstrual age. RESULTS: The levels of KL-6 were 116 +/- 40 U/mL in the RDS, 281 +/- 138 U/mL in the MAS, and 106 +/- 41 U/mL in the TTN groups. KL-6 levels were significantly higher in the MAS group than in the control group (134 +/- 71 U/mL; P < 0.01). In addition, the levels were significantly higher in those with severe MAS than those with mild MAS (P < 0.05). In patients with RDS, KL-6 increased in patients who developed CLD (P < 0.05), while KL-6 levels did not change in those who did not develop CLD. CONCLUSION: These data confirm the high level of KL-6 in CLD, and suggest that KL-6 is increased in MAS.

Coronary diameter in normal infants, children and patients with Kawasaki disease.

BACKGROUND: The coronary assessments in Kawasaki disease are mainly based on the Japanese Ministry of Health and Welfare criteria, which is simply classified according to the patient's age, over 5 years and less than 4-years-old. METHODS: We obtained normal values of coronary diameters adjusted for the body surface area and for the coronary anatomical site from 71 healthy children using 2-D echocardiography. We also studied patients with Kawasaki disease at three stages from the onset of illness: (i) 43 patients at admission; (ii) the subsequent 2-3 weeks; and (iii) 62 children followed at a clinic, for a median 2.2 years after the onset. No patients showed any coronary abnormalities by several echographic exams. RESULTS: The coronary diameters were strongly correlated with the body surface area (r = 0.81 in left main, r = 0.89 in proximal right, r = 0.89 in left anterior descending artery). The coronary diameters in the patient groups at admission and at 2-3 weeks later were significantly larger than those in the normal group (P < 0.01). Although the coronary diameters in the follow-up group did not show a significant difference compared with those of normal, 19% retained their coronary diameters at greater than two standard deviations above the expected mean in at least one coronary artery. CONCLUSIONS: The more strictly defined criteria adjusted for body size and for the anatomical site should be used to detect the subtle changes and to prevent the misclassification of the coronary artery abnormalities in KD.

P wave signal averaged electrocardiography in patients undergoing the Fontan operation.

OBJECTIVES: Supraventricular arrhythmias are one of the most common and fatal sequelae of the Fontan operation. P wave triggered signal averaged electrocardiography was performed in patients undergoing the Fontan operation to evaluate the presence of atrial degeneration, and to clarify which factors affected the development of atrial arrhythmias. METHODS: P wave triggered signal averaged electrocardiography was recorded in 14 patients after the Fontan-type operation (conventional atriopulmonary connection in 5 and total cavopulmonary connection in 9) and 15 healthy controls. The duration and area of the filtered P wave, and the signal magnitudes (M20, M30) at 20 Hz and 30 Hz obtained from the frequency domain analysis of the P wave (M20, M30) were evaluated and compared with the hemodynamic data. RESULTS: The duration and area of the filtered P wave, M20 and M30 in patients after atriopulmonary connection were significantly greater than in those after total cavopulmonary connection and the control subjects (p < 0.05). M20 was significantly greater in patients after total cavopulmonary connection than in the control subjects. Right atrial volume in patients after atriopulmonary connection was significantly (p < 0.001) larger than in patients after total cavopulmonary connection (p < 0.05). There were no significant differences in other indices including atrial pressure between the two groups. CONCLUSIONS: Our results suggest that the substrate for atrial arrhythmias such as atrial myocardial degeneration and fibrosis is frequently present in patients after the Fontan operation, especially after atriopulmonary connection. Thus, the enlarged right atrium may be involved in the presence of a substrate for atrial arrhythmias. The developmental risk for late atrial arrhythmias seems to be present even in patients after total cavopulmonary connection.