Holter Electrocardiographic Approach to Predicting Outcomes of Pediatric Patients With Long QT Syndrome.

BACKGROUND: This study was performed to clarify the clinical findings of pediatric patients diagnosed with long QT syndrome (LQTS) through electrocardiographic screening programs and to predict their outcome using Holter electrocardiographic approaches.Methods and Results: This retrospective study included pediatric patients with a Schwartz score of ≥3.5 who visited the National Hospital Organization Kagoshima Medical Center between April 2005 and March 2019. Resting 12-lead and Holter electrocardiograms were recorded at every visit. The maximum resting QTc and maximum Holter QTc values among all recordings were used for statistical analyses. To test the prognostic value of QTc for the appearance of cardiac events after the first hospital visit, receiver operating characteristic curves were used to calculate the area under the curve (AUC). Among 207 patients, 181 (87%) were diagnosed through screening programs. The prevalence of cardiac events after the first hospital visit was 4% (8/207). Among QTc at diagnosis, maximum resting QTc, and maximum Holter QTc, only maximum Holter QTc value was a predictor (P=0.02) of cardiac events after the hospital visit in multivariate regression analysis. The AUC of the maximum Holter QTc was significantly superior to that of maximum resting QTc. CONCLUSIONS: The maximum Holter QTc value can be used to predict the appearance of symptoms in pediatric patients with LQTS.

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.

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.

A surviving 24-month-old patient with neonatal-onset carnitine palmitoyltransferase II deficiency.

The early-onset form of carnitine palmitoyltransferase (CPT) II deficiency has severe outcomes; patients typically die during the newborn period. We report a case of neonatal-onset CPT II deficiency with prolonged survival, exceeding 24 months. The patient was successfully treated by continuous hemodialysis (CHD), which enabled her to overcome repeated crises. We suggest that early intensive treatment, including CHD, is a key for prolonged survival in patients with neonatal-onset CPT II deficiency.

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.

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.

Potential risk factors for dexmedetomidine withdrawal seizures in infants after surgery for congenital heart disease.

PURPOSE: Few studies are available on withdrawal seizures about dexmedetomidine (DEX). Thus, we retrospectively evaluated the incidence of withdrawal seizures after discontinuation of DEX and examined potential risk factors in infants after cardiovascular surgery. METHODS: The medical records of 142 infants who had undergone cardiovascular surgery between April 2010 and November 2013 were examined. Clinical characteristics and usage of DEX were analyzed. DEX withdrawal seizures were evaluated using Withdrawal Assessment Tool - version 1 (WAT-1). All the patients and controls were categorized according to DEX discontinuation strategy, which was either gradual or abrupt. RESULTS: Nine patients (6.3%) developed generalized clonic or generalized tonic-clonic seizures accompanied by preceding fever of >38°C approximately four to eight hours following the discontinuation of DEX, and were clinically diagnosed as DEX withdrawal seizures with a median WAT-1 score of 3. Clinical characteristics and operative data were similar, but median cumulative dose and maximum temperature after discontinuation of DEX were significantly higher in infants with withdrawal seizures than in those without (P=0.007 and P<0.001, respectively). Eight of the 9 patients with withdrawal seizures (88.9%) and 20 of the 133 patients (15.0%) with no withdrawal seizures had discontinued DEX abruptly (P<0.001). Cumulative dose and abrupt discontinuation of DEX were significantly associated with DEX withdrawal seizures in infants after cardiovascular surgery (R=0.619, P=0.004). CONCLUSIONS: Physicians should be aware that infants who received DEX after cardiovascular surgery had potential to cause withdrawal seizures accompanied by preceding pyrexia after discontinuation of DEX. Higher cumulative dose and abrupt discontinuation of DEX appears to increase the risk for these withdrawal seizures.

Combination of flecainide and propranolol for congenital junctional ectopic tachycardia.

Congenital junctional ectopic tachycardia is a rare tachyarrhythmia with high mortality. A pharmacological approach in early infancy is regarded as the first-line therapeutic option. Pharmacologically, amiodarone alone or in combination with other drugs is the most commonly reported effective agent for congenital junctional ectopic tachycardia, but it has many adverse effects. Here we report the case of a 40-day-old infant. The clinical course suggests that combined oral flecainide and propranolol is an effective alternative therapy for early infants. Esophageal lead electrocardiography may give a clear diagnosis of junctional ectopic tachycardia.

Current human T-cell lymphotropic virus type 1 mother-to-child transmission prevention status in Kagoshima.

The aim of this study was to assess the current human T-cell lymphotropic virus type 1 (HTLV-I) mother-to-child transmission (MTCT) prevention system in Kagoshima Prefecture. We investigated the rate of carrier pregnant women from obstetrics facilities in Kagoshima by mail in 2012 and compared our results with previous study results. We interviewed carrier pregnant women about their choices for infant nutrition, and we interviewed midwives about the follow-up system. In 2012, 8719 screening tests were performed, covering 58.1% of all pregnant women in Kagoshima; the rate of carrier pregnant women was 1.3%. Of 59 carriers, 39 chose short-term breast-feeding. The HTLV-I carrier rate among pregnant women in Kagoshima has declined. The current HTLV-I MTCT prevention system in Kagoshima is effective, but not sufficient. To bring the nutrition methods to completion, various types of support are needed. Further studies will elucidate many unsolved problems concerning MTCT.

Genetic characteristics of children and adolescents with long-QT syndrome diagnosed by school-based electrocardiographic screening programs.

BACKGROUND: A school-based electrocardiographic screening program has been developed in Japan. However, few data are available on the genetic characteristics of pediatric patients with long-QT syndrome who were diagnosed by this program. METHODS AND RESULTS: A total of 117 unrelated probands aged ≤18 years were the subjects who were referred to our centers for genetic testing. Of these, 69 subjects diagnosed by the program formed the screened group. A total of 48 subjects were included in the clinical group and were diagnosed with long-QT syndrome-related symptoms, familial study, or by chance. Mutations were classified as radical, of high probability of pathogenicity, or of uncertain significance. Two subjects in the clinical group died. Genotypes were identified in 50 (72%) and 23 (48%) of subjects in the screened and clinical groups, respectively. Of the KCNQ1 or KCNH2 mutations, 31 of 33 (94%) in the screened group and 15 of 16 (94%) in the clinical group were radical and of high probability of pathogenicity. Prevalence of symptoms before (9/69 versus 31/48; P<0.0001) and after (12/69 versus 17/48; P=0.03) diagnosis was significantly lower in the screened group when compared with that in the clinical group although the QTc values, family history of long-QT syndrome, sudden death, and follow-up periods were not different between the groups. CONCLUSIONS: These data suggest that the screening program may be effective for early diagnosis of long-QT syndrome that may allow intervention before symptoms. In addition, screened patients should have follow-up equivalent to clinically identified patients.

Risk factors for symptoms in long QT syndrome patients in a single pediatric center.

BACKGROUND: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death due to arrhythmia in the pediatric population. This study aimed to determine risk factors for the presence of LQTS-related symptoms in a single pediatric center. METHODS: Subjects were 146 consecutive LQTS patients (M:F = 72:74) who visited our hospital between April 2005 and August 2012 and during the preceding 24 months. A total of 103 subjects were discovered by the school-based screening, 15 subjects visited because of their symptoms, and the others were 28 subjects. One subject died. RESULTS: Risk factors for the presence of symptoms after diagnosis were longer QTc values (P = 0.01), the presence of history of LQTS-related symptoms (P = 0.04), and longer follow-up periods (P = 0.03). Non-compliance with medicine was the sole risk factor for frequent symptoms after diagnosis (P = 0.02). In subjects discovered by the school-based screening, nine subjects (9%) had LQTS-related symptoms after diagnosis. Longer follow-up periods were the sole risk for the presence of symptoms (P = 0.04). The mean period until the presence of symptoms after diagnosis was 3.1 ± 2.7 years (0.1-7.1 years). CONCLUSION: Good compliance with medicine is essential to prevent recurrent episodes. A new strategy is required to prevent subjects, including school-based screened subjects, from dropping out of hospital visits.

K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival.

A considerable amount of evidence indicates that Ras signaling contributes to the development of endometrial cancer. We previously demonstrated that endometrial cancer cells carrying oncogenic [(12)Val]K-ras were susceptible to apoptosis. The present study examined the role of K-and H-Ras in the induction of apoptosis using rat endometrial cells (RENT4 cells). We found that constitutively activated K-Ras promoted apoptotic cell death, whereas the H-Ras mutant rescued rat endometrial cells from apoptosis. Expression of a constitutively active form of Raf-1 (Raf-CAAX) promoted apoptosis, whereas expression of a constitutively active catalytic subunit of phosphoinositide 3-kinase, p110K227E, allowed cells to escape from apoptosis. Moreover, inhibition of the MEK-MAPK pathway by the specific inhibitor, UO126, rescued the cells from apoptosis, whereas the inhibition of phosphoinositide 3-kinase by its specific inhibitor, LY294002, promoted apoptosis in RENT4 cells expressing activated K-Ras. However, both inhibitors promoted apoptosis in RENT4 cells expressing activated H-Ras. This difference in the regulation of apoptosis by the MEK inhibitor between K-Ras- and H-Ras-expressing cells depended on the interaction of effector proteins downstream of each Ras isoform. Finally, to elucidate the role of downstream K-Ras signal pathways, we generated K-Ras effector domain mutants (K12V35S, K12V40C). We examined the incidence of apoptotic cell death induced by the K-Ras effector domain mutants (K12V35S, K12V40C). The relative ratio of phospho-MAPK to phospho-Akt compared with that of mock cells was higher in K12V35S cells than in K12V40C cells. Ectopic expression of K12V35S protein increased the proportion of apoptotic cells, and in turn, the expression of K12V40C protein decreased compared with the expression of K12V protein without the effector domain mutant. These results demonstrate that K- and H-Ras-mediated signaling pathways exert distinct effects on apoptosis and that K-Ras downstream Raf/MEK/MAPK pathway is required for the induction of apoptosis in endometrial cells. Coordination of the two pathways contributes to endometrial cell survival.