Pediatric Patients Undergoing a Fontan Operation or with a High RACHS-1 Score Require Monitoring for Chronic Kidney Disease in Early Childhood.

Although the number of pediatric patients with long-term survival following cardiac surgery is increasing, concerns regarding chronic kidney disease (CKD) after surgery are growing. We examined the frequency of and risk factors for pediatric CKD development in patients with congenital heart disease (CHD) at least 2 years after cardiac surgery. This was a cross-sectional study of 147 patients who underwent open-heart surgery for CHD at Kagoshima University Hospital from April 2010 to March 2017. Data on demographics, acute kidney injury after cardiac surgery, cyanotic heart disease, Fontan circulation, medications in the perioperative period, and Risk Adjustment for Congenital Heart Surgery-1 (RACHS-1) category were recorded. CKD was defined using the current classification system described in the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative and assessed during early childhood within 2-3 years of cardiac surgery. Statistical analyses were performed using SPSS Statistics for Windows version 25.0. We consecutively enrolled 147 patients, of whom 22 (15.0%) had CKD, all with stage-2 severity. Among patients with CKD, a higher proportion underwent Fontan surgery (P < 0.001), a higher proportion had cyanotic heart disease (P = 0.009), and the RACHS-1 category was high (P = 0.003). Patients with CKD appeared more frequently than patients without CKD in RACHS-1 categories 3, 5, and 6. It is essential to evaluate renal function longitudinally and monitor for CKD, given that patients who underwent Fontan surgery or complicated surgery in infancy have a high rate of developing postoperative CKD in early childhood.

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

Validation of acute kidney injury according to the modified KDIGO criteria in infants after cardiac surgery for congenital heart disease.

AIM: We aimed to validate the incidence of, risk factors for, and postoperative outcomes of acute kidney injury (AKI) according to the modified Kidney Disease Improving Global Outcomes (m-KDIGO) criteria and compare this criteria with both the paediatric Risk, Injury, Failure, Loss, End-stage disease (pRIFLE) and Acute Kidney Injury Network (AKIN) criteria in infants after cardiac surgery. METHODS: We retrospectively enrolled 145 consecutive infants who underwent open-heart surgery at Kagoshima University Hospital. RESULTS: Acute kidney injury was present in 55 (37.9%), 111 (75.9%), and 95 (65.5%) patients according to the m-KDIGO, pRIFLE, and AKIN criteria, respectively. Among these, 71.9% of patients pRIFLE Risk patients and 60.5% of AKIN 1 patients were categorized in the 'no-AKI' group according to the m-KDIGO criteria. Low body weight (m-KDIGO odds ratio [OR], 0.73; P = 0.015; pRIFLE OR, 0.66; P = 0.001; AKIN OR 0.69, P = 0.002) and prolonged cross-clamp time (m-KDIGO OR, 1.02;

Tentative Screening Criteria for Short QT Interval in Children and Adolescents.

BACKGROUND: While the prevalence of short QT syndrome (SQTS) in children and adolescents is low, early detection is important because SQTS can cause life-threatening arrhythmia. The aim of this study was to determine the tentative screening criteria for short QT interval in children and adolescents. Methods and Results: A total of 75,040 digitally stored electrocardiograms (ECG) of participants in a school-based ECG screening program were obtained between 2009 and 2013 in Kagoshima, Japan. ECG with a corrected QT interval (QTc) below the 10th percentile for each grade and sex were selected: 2,581 first graders (M/F, 1,296/1,285); 2,792 7th graders (M/F, 1,400/1,392); and 2018 10th graders (M/F, 979/1,039). Three consecutive QT/RR intervals were manually measured and corrected using Bazett's formula. The prevalence of SQTS was estimated at 1/30,000-1/10,000, which was set compared with the prevalence of long QT syndrome, then the screening points of the prevalence of short QT interval were assumed to be between 1/5,000 and 1/2,000 to exclude the possibility of false negative. We obtained the following tentative criteria based on frequency distribution charts: 325, 315 and 305 ms for male 1st, 7th and 10th graders, respectively; and 320 ms for female 1st, 7th, and 10th graders. CONCLUSIONS: For primary SQTS screening of children and adolescents, the QTc values for short QT interval should be adapted according to grade and sex.

Dexmedetomidine is Associated with an Increased Incidence of Bradycardia in Patients with Trisomy 21 After Surgery for Congenital Heart Disease.

This study aimed to evaluate adverse cardiac events using dexmedetomidine in infants with trisomy 21 and those without (controls) and examined potential risk factors in infants after cardiovascular surgery. We conducted a single-center retrospective cohort study. The medical records of 124 consecutive infants who had undergone cardiovascular surgery between April 1, 2013, and October 31, 2015, were enrolled. Clinical characteristics, usage of dexmedetomidine, and perioperative medications were analyzed. Adverse cardiac events were assessed with the Naranjo score and World Health Organization-The Uppsala Monitoring Centre (WHO-UMC) criteria. In total, 124 consecutive infants (30 patients and 94 controls) met the inclusion criteria. Eight of 30 (26.7 %) patients with trisomy 21 and 12 of 94 (12.8 %) controls experienced adverse cardiac events (i.e., hypotension, transient hypertension, and bradycardia) during dexmedetomidine with median Naranjo score of 6, and causality categories of WHO-UMC criteria were "certain" or "probable." Of those, the incidence of bradycardia occurred at a higher rate in patients with trisomy 21 than in controls (P = 0.011). Multiple logistic regression analysis revealed that the presence of trisomy 21 was an independent risk factor for adverse cardiac events of dexmedetomidine after cardiovascular surgery (odds ratio 4.10, 95 % CI 1.17-11.19, P = 0.006). Dexmedetomidine is associated with an increased incidence of bradycardia in patients with trisomy 21 after surgery for congenital heart disease. Physicians using dexmedetomidine should know a great deal about the characteristics of patients with trisomy 21, and hemodynamic monitoring should be closely observed.

Successful coil embolization for pediatric internal mammary artery aneurysm after the Fontan procedure: A case report and literature review.

We herein describe the first pediatric case of an internal mammary artery (IMA) aneurysm caused by a median sternotomy. He was a 2-year-old with tricuspid atresia who underwent an extracardiac conduit Fontan procedure. On the 36th postoperative day, an asymptomatic left IMA aneurysm was detected via contrast computed tomography, which was successfully treated with coil embolization. The patient had no underlying disease such as vasculitis, connective tissue disease, or other hereditary diseases, and there were no episodes of infection or hypertension before or after the onset of the IMA aneurysm. Because the left IMA ran medially to the periphery and was in a vulnerable position during median sternotomy, we considered the IMA aneurysm was caused by the median sternotomy. We pediatric cardiologists should be aware that IMA aneurysms can occur in pediatric cardiac surgery, and we should be proactive in performing postoperative imaging studies in cases where the preoperative internal thoracic artery runs medially toward the periphery. Learning objective: Internal mammary artery (IMA) aneurysm is a rare vascular disease, especially in children. One-third of adult IMA aneurysms have been reported to be caused by sternotomy, but not in children. We report the first pediatric case of an IMA aneurysm caused by sternotomy. We should recognize that there is a potential risk of IMA aneurysms in pediatric cardiac surgery as well.

Platelet vascular endothelial growth factor is a useful predictor for prognosis in Kawasaki syndrome.

Kawasaki syndrome (KS) is an acute febrile vasculitis of childhood. Coronary artery abnormalities (CAA) are a significant problem in KS patients. High dose intravenous immunoglobulin (IVIG) is effective for reducing the occurrence of CAA. Clinical and histopathological findings suggest that vascular endothelial growth factor (VEGF) is involved in CAA. In circulating blood, newly activated platelets are the major source of VEGF, which is released in large amounts in vascular inflammation. The present study analysed 80 KS patients (69 IVIG responders and 11 IVIG non-responders) and evaluated the role of platelet VEGF in KS vasculitis. Serum VEGF and platelet VEGF levels were significantly higher in KS patients than controls (P < 0.001). Platelet VEGF reflected the reactivity of IVIG treatment and was decreased in responders (P < 0.001), but remained increased in non-responders (P = 0.01). Platelet VEGF levels, but not serum VEGF levels, before IVIG were significantly correlated with the maximum CAA z-score (r = 0.524, P = 0.02). Our findings demonstrate that platelet VEGF may reflect the severity of vasculitis related to the pathological development of CAA in KS. Platelet VEGF may be an important feature of KS pathophysiology.

A severe form of Kawasaki disease presenting with only fever and cervical lymphadenopathy at admission.

OBJECTIVE: To examine the characteristics of patients with Kawasaki disease (KD) presenting with only fever and cervical lymphadenopathy at admission. STUDY DESIGN: The laboratory and clinical findings of patients with definite KD presenting with only fever and cervical lymphadenopathy at admission (KDiL) were compared with those of all other patients with KD. RESULTS: Sixteen patients with KDiL (8.6%) and 171 patients without KDiL were examined. The patients with KDiL were significantly older (KDiL/non-KDiL: 4.9+/-2.5/2.2+/-1.9 years) and admitted earlier (3.0+/-1.2/3.9+/-1.3 days of illness) than the patients without KDiL. They also showed significantly elevated white blood cell counts and C-reactive protein levels. Patients with KDiL were treated with the same dose of intravenous immunoglobulin as the patients without KDiL but were treated slightly later and had significantly higher frequency of additional intravenous immunoglobulin treatment (38%/10%) and coronary artery abnormalities (25%/5%). After adjustment for age, white blood cell count, and day of illness at admission or first intravenous immunoglobulin administration, the presence of KDiL significantly increased the risk of being a nonresponder to IVIG treatment or development of a coronary artery abnormality. CONCLUSIONS: KDiL indicates a severe form of KD associated with increased risks of additional intravenous immunoglobulin treatment and coronary artery abnormalities. Patients with KDiL may require heightened surveillance and more aggressive treatment.

Cut-offs for screening prolonged QT intervals from Fridericia's formula in children and adolescents.

BACKGROUND: The corrected QT interval (QTc) according to Bazett's formula (QTc = QT/RR(1/2)) has been used in clinical practice. Bazett's formula, however, overcorrects the QT interval at fast heart rates and undercorrects it at low heart rates. Guidelines and some investigators have recommended using Fridericia's formula (QTc = QT/RR(1/3)) in these cases, especially in tachycardic subjects. The aim of the present study was to determine cut-offs for QTc suitable for screening pediatric subjects with prolonged QT intervals, based on manually measured values corrected by Fridericia's formula in a large number of subjects. METHODS AND RESULTS: Three consecutive QT and RR intervals were measured in 4,655, 4,655, and 5,273 1st, 7th, and 10th graders, aged 6, 12, and 15 years, respectively. Each QT interval was corrected by Fridericia's formula, and mean values were calculated. Determination of the cut-offs for screening was based on the prevalence of abnormal electrocardiographic phenotypes of 1:1,164 and on the upper 0.025 percentile in the QTc distribution derived from previous studies. The tentative cut-offs suitable for screening subjects with prolonged QT intervals were 430 ms for 1st graders, 445 ms for 7th graders, and 440 and 455 ms for 10th grade boys and girls, respectively. CONCLUSIONS: These tentative cut-offs can be used to screen subjects with prolonged QT intervals in the clinical setting. Further studies are needed to confirm their validity.

Prevalence of childhood obesity from 1978 to 2007 in Japan.

BACKGROUND: There are few cross-sectional and longitudinal studies on identification of the age of onset of obesity. The purpose of the present study was therefore to investigate 30 years of cross-sectional and longitudinal changes in the prevalence of obesity from 1978 to 2007 in Japanese children and adolescents between 5 and 17 years of age, using population-based samples. METHODS: Subject data were obtained from the Annual Reports of the School Health Survey published by the Ministry of Education, Culture, Sports, Science and Technology, Japan. Obesity was defined as a body mass index (BMI) at or above the 95th percentile for age and gender based on the reference years from 1979 to 1981 in Japan. The BMI was calculated as weight in kg/(height in m)(2). RESULTS: Cross-sectional analysis of 5-, 8-, 11-, 14-, and 17-year-olds showed that the prevalence of obesity has gradually decreased since the early 2000s, with the highest prevalence in the late 1990s to early 2000s, except for in 17 year-old boys. Longitudinal studies showed that the critical periods for developing obesity were in late infancy (between 5 and 6 years of age) and in the high school period in boys, and mainly in late infancy in girls. CONCLUSIONS: Intervention to prevent obesity should be focused on late infancy in both genders and male adolescents in Japan.

Risk factors for development of ventricular tachycardia in patients with ventricular premature contraction with a structurally normal heart.

BACKGROUND: We examined risk factors for development of ventricular tachycardia (VT) in pediatric patients with ventricular premature contractions (VPCs) and a structurally normal heart. METHODS: The subjects were 81 844 first graders and 88 244 seventh graders of Kagoshima City School-based cardiovascular screening (SCV-screening) between 2001 and 2015. We retrospectively reviewed the clinical data of students who were diagnosed as having VPC. RESULTS: Ventricular premature contractions were observed in 134 first graders (0.16%) and 270 seventh graders (0.31%). On the screening electrocardiograms (ECGs), 43 patients (11%) showed bi-/trigemini, three patients (0.7%) showed a couplet, and one patient showed VT. We obtained 166 patients' follow-up information and evaluated 59 patients (36%) as improved, 97 patients (58%) as no change, and 10 patients (6%) as worsened (couplets, five; triplets, two; VT, three). We assumed that these worsened patients have risk factors for development of VT. Comparing the findings of SCV-screening ECGs of risk patients with the others, a significant difference was observed only in the number of VPCs (per 10 seconds) (mean ± SD; 4.3 ± 2.6 vs 1.8 ± 1.4, P < .0001). A logistic regression analysis revealed that the number of VPCs was significant (P < .001, odds ratio; 2.01, 95% confidence intervals; 1.46-2.93). Receiver operating characteristics analysis showed an adequate cut-off number of three VPCs for the risk, the sensitivity was 89% and the specificity was 77%. CONCLUSIONS: Of the patients with VPC and a structurally normal heart, a few patients developed VT. Careful observation is important in patients who had three or more VPCs on SCV-screening ECG.

An elevated value of high mobility group box 1 is a potential marker for poor response to high-dose of intravenous immunoglobulin treatment in patients with Kawasaki syndrome.

We examined the serum values of high mobility group box 1 (HMGB1) in 36 patients with Kawasaki syndrome (KS) (29 responders and 7 poor-responders to initial intravenous immunoglobulin treatment). A mean value of HMGB1 of poor-responders was significantly elevated compared with those of responders (P = 0.0042). Among the 6 factors showing significant differences between responders and poor-responders including HMGB1 (admission illness day, white blood cell counts, C-reactive protein, aspartate aminotransferase, lactate dehydrogenase), values of HMGB1 showed the widest area under the receiver operating characteristic curve. In conclusion, an elevated HMGB1 value could be a potential marker for poor-responders.

Disruption of Endothelial Cell Homeostasis Plays a Key Role in the Early Pathogenesis of Coronary Artery Abnormalities in Kawasaki Disease.

Disruption of endothelial cell homeostasis may be associated with the pathogenesis of coronary artery abnormalities (CAA) in Kawasaki disease (KD). We sought to clarify the poorly understood pathogenic role of endothelial cell survival and death in KD vasculitis. Human umbilical vein endothelial cells (HUVECs) stimulated with sera from KD patients, compared with sera from patients with bacterial infections, exhibited significant increases in cytotoxicity, high mobility group box protein 1 (HMGB-1), and caspase-3/7 and a decrease in phosphorylated Akt/Akt (pAkt/Akt) ratios. HUVECs stimulated with sera from KD patients treated with immunoglobulin (IG) showed significantly decreased cytotoxicity, HMGB-1, and caspase-3/7 levels and increased pAkt/Akt ratios, as compared with results for untreated HUVECs (P < 0.001, P = 0.008, P = 0.040, and P < 0.001, respectively). In HUVECs stimulated with sera from KD patients, the increased cytotoxicity levels and the suppression of increased pAkt/Akt ratios after subsequent IG treatment were closely related to the development of CAA (P = 0.002 and P = 0.035). Our data reveal that shifting the balance toward cell death rather than survival appears to perturb endothelial cell homeostasis and is closely related to the development of CAA. The cytoprotective effects of IG treatment appear to ameliorate endothelial cell homeostasis.

Central diabetes insipidus as a very late relapse limited to the pituitary stalk in Langerhans cell histiocytosis.

Central diabetes insipidus (CDI) and relapse are frequently seen in multifocal Langerhans cell histiocytosis (LCH). We present two females with multifocal LCH who developed CDI 9 and 5 years after the initial diagnosis, respectively, as a relapse limited to the pituitary stalk. Combination chemotherapy with cytarabine reduced the mass in the pituitary stalk. Although CDI did not improve, there has been no anterior pituitary hormone deficiency (APHD), neurodegenerative disease in the central nervous system (ND-CNS) or additional relapse for 2 years after therapy. It was difficult to predict the development of CDI in these cases. CDI might develop very late in patients with multifocal LCH, and therefore strict follow-up is necessary, especially with regard to symptoms of CDI such as polydipsia and polyuria. For new-onset CDI with LCH, chemotherapy with cytarabine might be useful for preventing APHD and ND-CNS.