An Alternative Approach to Determining Metabolic Syndrome Component Cutoffs in Children and Adolescents Using Segmental Regression Analysis.

Background: The prevalence of metabolic syndrome is increasing in children and adolescents. Although some diagnostic criteria for metabolic syndrome exist, further research is needed to determine appropriate age-, sex-, and race-specific cutoffs for each component. Methods and Results: Health examinations were conducted in 1,679 children aged 6-15 years in 9 regions of Japan. Participants were divided into 3 age groups for each sex: 6-8, 9-11, and 12-15 years. For metabolic syndrome components in each group, inverse cumulative percentile graphs were drawn and approximated by 3 regression lines using segmented regression analysis. The intersection of each regression line was defined as the breakpoint, and the measured value corresponding to the breakpoint percentile as the breakpoint value. Breakpoint values for waist circumference were age dependent at approximately 60, 70, and 80 cm for ages 6-8, 9-11, and 12-15 years, respectively. Breakpoint values for blood pressure were age- and/or sex dependent, while those for triglycerides, high-density lipoprotein cholesterol, and fasting blood glucose were neither age nor sex dependent. Based on these results, we proposed new cutoffs for diagnosing metabolic syndrome in Japanese children and adolescents. Conclusions: Breakpoint values obtained by segmented regression analysis on inverse cumulative percentile graphs can be useful for determining metabolic syndrome component cutoffs in children and adolescents.

Effects of cohort, genotype, variant, and maternal ß-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

AIMS: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal ß-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. METHODS AND RESULTS: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal ß-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or ß-adrenergic response) had lower FHR. Maternal ß-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. CONCLUSION: Genotype, LQT1 variant, and maternal ß-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

Developmental trajectories at a high risk for childhood overweight/obesity.

BACKGROUND: The associations between developmental patterns (trajectories) in children and maternal factors have been widely investigated, but paternal effects on these trajectories are unclear. This study aimed to determine child and parental factors involved in developmental trajectories at high risk for causing adverse cardiovascular (CV) profiles in children. METHODS: We analyzed longitudinal anthropometric data from birth to the present and CV profiles of 1,832 healthy volunteers (51% girls) aged 3-15 years who participated in a nationwide study between July 2012 and January 2014. Six trajectory latent class growth models were developed using body mass index z- scores. Predictors for being in developmental trajectories at high risk for causing adverse CV profiles were determined by multivariate regression analysis. RESULTS: The mean±standard deviation number of anthropometric data points was 12±3 for both boys and girls. Among the six trajectories, the infantile onset and continual increase groups had significantly worse levels of many CV profiles than those in the remaining groups. Paternal overweight/obesity was an independent predictor for boys being in the infantile onset group and for girls being in the continual increase group. Additionally, maternal pre-pregnancy overweight/obesity in boys and maternal excessive gestational weight gain in girls were independent predictors for being in the infantile onset group. Having no sibling in boys and an older maternal age were independent predictors for being in the continual increase group. CONCLUSIONS: Interventions to prevent childhood obesity should include strategies that focus on fathers and mothers as well as those that focus on children with certain types of familial background.

Efficacy of SubcutAneous implantable cardioVErter-defibrillators in ≤18 year-old CHILDREN: SAVE-CHILDREN registry.

BACKGROUND: In adult patients, subcutaneous implantable cardioverter defibrillators (S-ICDs) have been reported to be non-inferior to transvenous ICDs with respect to the incidence of device-related complications and inappropriate shocks. Only a few reports have investigated the efficacy of S-ICDs in the pediatric field. This study aimed to investigate the utility and safety of S-ICDs in patients ≤18 years old. METHODS: This study was a multicenter, observational, retrospective study on S-ICD implantations. Patients <18 years old who underwent S-ICD implantations were enrolled. The detailed data on the device implantations and eligibility tests, incidence of appropriate- and inappropriate shocks, and follow-up data were assessed. RESULTS: A total of 62 patients were enrolled from 30 centers. The patients ranged in age from 3 to 18 (median 14 years old [IQR 11.0-16.0 years]). During a median follow up of 27 months (13.3-35.8), a total of 16 patients (26.2%) received appropriate shocks and 13 (21.3%) received inappropriate shocks. The common causes of the inappropriate shocks were sinus tachycardia (n = 4, 30.8%) and T-wave oversensing (n = 4, 30.8%). In spite of the physical growth, the number of suitable sensing vectors did not change during the follow up. No one had any lead fractures or device infections in the chronic phase. CONCLUSIONS: Our study suggested that S-ICDs can prevent sudden cardiac death in the pediatric population with a low incidence of lead complications or device infections. The number of suitable sensing vectors did not change during the patients' growth.

Control of Heart Rate in Infant and Child Tachyarrhythmia With Reduced Cardiac Function Using Landiolol (HEARTFUL)　- Results of a Prospective, Multicenter, Uncontrolled Clinical Study.

BACKGROUND: The prospective Control of HEART rate in inFant and child tachyarrhythmia with reduced cardiac function Using Landiolol (HEARTFUL) study investigated the effectiveness and safety of landiolol, a short-acting ß1 selective blocker, in children.Methods and Results: Twenty-five inpatients aged ≥3 months to <15 years who developed supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, and inappropriate sinus tachycardia) were treated with landiolol. The primary endpoint, the percent of patients with a reduction in heart rate ≥20% from the initial rate of tachycardia, or termination of tachycardia at 2 h after starting landiolol, was achieved in 12/25 patients (48.0%; 95% CI 28.4-67.6), which exceeded the predetermined threshold (38.0%). At 2 h after starting landiolol administration, heart rate had decreased by ≥20% in 45.8% (11/24) and recovery to sinus rhythm was achieved in 40.0% (6/15) of the patients. Adverse reactions (ARs) occurred in 24.0% (6/25) of patients, and the study was discontinued in 4.0% (1/25) of the patients; however, none of these ARs were considered serious. The most common AR was hypotension (20.0% [5/25] of patients). CONCLUSIONS: The HEARTFUL study has demonstrated the efficacy of landiolol, by reducing heart rate or terminating tachycardia, in pediatric patients with supraventricular tachyarrhythmias. Although serious ARs and concerns were not identified in this study, physicians should be always cautious of circulatory collapse due to hypotension.

Lung Ultrasound for Predicting the Respiratory Outcome in Patients with Bronchopulmonary Dysplasia.

OBJECTIVE: This study aimed to investigate the utility of lung ultrasound (LUS) with whole chest scanning for predicting respiratory outcomes in patients with bronchopulmonary dysplasia (BPD). STUDY DESIGN: We performed a prospective observational study. Preterm infants of less than 32 weeks' gestational age requiring oxygen therapy at 28 days of life were included. LUS was performed on day 28, at 36 weeks' postmenstrual age, and at the time of discharge. Each lung was divided into three regions by the anterior and posterior axillary lines and received an LUS score of 0 to 3 points; the total score was obtained by adding the six regional scores. The classification of BPD was determined based on the National Institute of Child and Human Development. The outcomes of this study were the development of moderate-to-severe BPD and the need for home oxygen therapy (HOT). RESULTS: We enrolled 87 patients; 39, 33, and 15 infants had mild, moderate, and severe BPD, respectively. The LUS score correlated with BPD severity and exhibited an improvement trend with time toward the point of discharge. LUS at 28 days of life predicted moderate-to-severe BPD with an area under the curve of 0.95 (95% confidence interval: 0.91-0.99) and HOT with an area under the curve of 0.95 (95% confidence interval: 0.81-1.0). CONCLUSION: LUS with whole chest scanning is useful for predicting respiratory outcomes in patients with BPD, as well as for understanding BPD severity or clinical improvement trends. KEY POINTS: · LUS predicts respiratory outcomes in patients with BPD.. · LUS indicates BPD severity.. · LUS can show clinical improvement with time..

Outcomes of hypertrophic cardiomyopathy in Japanese children: a retrospective cohort study.

There has been no multicenter study on the prognosis of pediatric hypertrophic cardiomyopathy (HCM) in Japan. Therefore, we conducted a retrospective multicenter observational study on the long-term survival rate in patients diagnosed with HCM under the age of 18 between 1990 and 2014. Twenty institutions participated. A total of 180 patients were identified. The median age at diagnosis was 5.8 years old and median duration of observation was 8.3 years. Although six patients (3%) deteriorated into the dilated phase of HCM, no patient received heart transplantation. Freedom from death at 1, 5, 10, and 20 years were 97%, 92%, 84%, and 80%, respectively. There were 26 deaths. Among them, 11 patients died suddenly, presumably due to arrhythmia, and 15 patients died of heart failure. The presence of heart failure symptoms and a greater cardiothoracic ratio were significant risk factors for heart failure-related death. There were no significant risk factors identified for arrhythmia-related death. In conclusion, the prognosis of pediatric HCM in Japan is good and similar to those reported in population-based studies in the United States and Australia. Significant risk factors for heart failure-related death were identified in pediatric patients with HCM in Japan.

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.

Outcomes of Dilated Cardiomyopathy in Japanese Children　- A Retrospective Cohort Study.

BACKGROUND: There has been no nationwide survey on the prognosis of pediatric dilated cardiomyopathy (DCM) in Japan. Therefore, we designed this retrospective multicenter study to investigate the long-term survival rate in pediatric patients with DCM in Japan.Methods and Results:In this multicenter retrospective observational study, data were reviewed for 106 patients aged <18 years who had been diagnosed with DCM at any 1 of 18 Japanese institutions between 1990 and 2014. The median age at diagnosis was 2.0 years and the median duration of observation was 3.3 years. Most DCM patients were diagnosed because of symptoms of heart failure. On echocardiography, the median left ventricular end-diastolic dimension z score was 5.4 and fractional shortening was 0.10. Freedom from death or transplantation rates at 1, 3, 5, 10, and 20 years after diagnosis were 76%, 66%, 64%, 58%, and 43%, respectively. Freedom from death rates at 1, 5, 10, and 20 years after diagnosis were 81%, 75%, 72%, and 53%, respectively. The incidence of heart transplantation at 1, 5, 10, and 20 years after diagnosis was 6%, 15%, 20%, and 20%, respectively, suggesting that only 15% of patients in Japan underwent heart transplantation within 5 years of diagnosis. CONCLUSIONS: In Japan, the prognosis of pediatric DCM is poor and the rate of heart transplantation is low.

Analysis of the shape of the T-wave in congenital long-QT syndrome type 3 by geometric morphometrics.

The characteristic shape of the T-wave in congenital long-QT syndrome type 3 (LQTS3) is considered a late-onset T-wave. We analyzed the difference in the shapes of the T-waves of V5 in the electrocardiograms (ECGs) of LQTS3 cases and normal subjects using generalized Procrustes analysis. The J and Q points of LQTS3 cases are shifted to the upper left compared to those of normal subjects. SdFmax is the point on the ECG where the second derivative is first maximized. SdFmax is the point where the change in the slope of the ascending limb of the T-wave is maximized. SdFmax in LQTS3 cases is shifted to the lower right compared to normal subjects. The interval from J to SdFmax in LQTS3 cases is expanded compared with that of normal subjects. From principal component analysis of the Procrustes mean shape of the T-wave landmarks, the second principal component shows a shift of SdFmax to the lower right. These results can quantitatively explain why the T-wave of LQTS3 cases looks like a late-onset T-wave. After being fitted to a multivariate logistic regression model, LQTS3 cases and normal subjects can be distinguished by the second independent component.

Soluble thrombomodulin and cardiovascular disease risk factors in Japanese children.

This study aimed to establish standard reference values for soluble thrombomodulin in healthy prepubertal school-aged children and elucidate the relationship between soluble thrombomodulin levels and obesity, metabolic syndrome-associated indices, and other markers of vascular endothelial damage. The participants in this study were healthy Japanese children aged 9-10 years (315 boys and 267 girls). Blood tests for soluble thrombomodulin, leptin, fibrinogen, and general biochemical markers were performed, and the mean and 10th, 50th, and 90th percentiles for each marker were determined. Participants were divided into two groups based on their waist circumference (≥75 vs. <75 cm), and each parameter was compared between the two groups. Analyses were performed to compare subgroups with different numbers of risk factors for cardiovascular disease (CVD). We found that as CVD risk factors accumulated, the levels of total cholesterol, alanine aminotransferase, uric acid, soluble thrombomodulin, fibrinogen, and leptin were significantly elevated, whereas the level of high-density lipoprotein cholesterol significantly decreased. We determined reference values for soluble thrombomodulin in prepubertal children, and our results suggest that soluble thrombomodulin levels contribute to the latent progress of arteriosclerosis from childhood.

Abdominal aortic thrombus formation in a neonate with an interrupted aortic arch.

We note the risk of paradoxical embolism in patients with congenital heart defects with a right-to-left shunt. These patients should be managed to ensure that abdominal aortic thrombi are not overlooked when their clinical conditions change.

Diagnostic value of P-waves in children with idiopathic restrictive cardiomyopathy.

Restrictive cardiomyopathy (RCM) is a rare myocardial disease with an impaired diastolic function and poor prognosis. Almost all RCM patients are reported to have abnormal P-waves due to atrial overloading. This study aimed to reveal the characteristics of the P-waves in RCM patients and to suggest the diagnostic index of RCM in children with a 12-lead electrocardiogram (ECG). We retrospectively investigated 17 ECGs of children with idiopathic RCM during the initial visit at 15 institutes in Japan between 1979 and 2013. The RCM group was divided into four groups based on the age (elementary school [ES] and junior high school [JHS] students) and inception of the diagnosis (abnormal ECG on school-heart-screening [e-RCM] and some cardiovascular symptoms [s-RCM]), the ES/e-RCM (n = 5), ES/s-RCM (n = 4), JHS/e-RCM (n = 4), and JHS/s-RCM (n = 4) groups. As an aged-match control group, school-heart-screening ECGs of 1st-grade ES students (16,770 students) and 1st-grade JHS students (18,126 students) from Kagoshima in 2016 were adopted. For a comparison between the groups, we used the effect size "Hedge's g" by calculating the mean and standard deviation of the two groups. An effect size of 0.8 (or above) had an overlap of 53% (or less). The effect sizes of the sum of the absolute values of the forward and backward amplitudes in lead V1 (P1 + P2 V1) was the largest, and the ES/e-RCM, ES/s-RCM, JHS/e-RCM, and JHS/s-RCM were 15.8, 22.1, 9.4, and 10.3, respectively. A P1 + P2 V1 > 200 µV was able to rule in all RCM patients, thus, we proposed 200 µV as the cutoff value for screening purposes. In conclusion, the P1 + P2 V1 in the school-heart-screening may be useful for detecting asymptomatic or early-stage RCM in school-age children.