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.

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.

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.

Standard Values and Characteristics of Electrocardiographic Findings in Children and Adolescents.

BACKGROUND: Reference values and the characteristics of the electrocardiographic (ECG) findings using a large number of subjects are lacking for children and adolescents.Methods and Results:A total of 56,753 digitally stored ECGs of participants in a school-based ECG screening system were obtained between 2006 and 2009 in Kagoshima, Japan. Each ECG was manually reviewed by 2 pediatric cardiologists and only ECGs with sinus rhythm were included. A final total of 48,401 ECGs from 16,773 1st (6 years old, 50% girls), 18,126 7th (12 years old, 51% girls), and 13,502 10th graders (15 years old, 52% girls) were selected. ECG variables showed differences in age and sex. However, the effects of age and sex on ECG variables such as the PQ interval, QRS voltage, and STJ segment were also different. The 98th percentile values of well-known surrogate parameters for ventricular hypertrophy in the present study were much higher than the conventional criteria. CONCLUSIONS: The present study of a large number of pediatric subjects showed that the effects of age and sex on ECG parameters are different, and that criteria for ventricular hypertrophy should be newly determined by age and sex. We have developed reference data for STJ segment elevation for children and adolescents. These findings are useful for creating guidelines and recommendations for interpretation of pediatric ECG.

Pharmacologic therapy with flecainide for asymptomatic Wolff-Parkinson-White syndrome in an infant with severe left ventricular dyssynchrony.

Some asymptomatic patients with Wolff-Parkinson-White syndrome have severe left ventricular dyssynchrony and dysfunction. We describe a patient who was given a diagnosis of Wolff-Parkinson-White syndrome in infancy and had a complete response to pharmacologic therapy with flecainide. Our findings suggest that flecainide is a suitable resynchronisation therapy for such infants.

Usefulness of real-time three-dimensional trans-oesophageal echocardiography for detection of isolated unroofed coronary sinus.

We report a case of unroofed coronary sinus not associated with the persistent left superior vena cava. Definite diagnosis of the unroofed coronary sinus was obtained by trans-oesophageal echocardiography, which revealed the unroofed portion with left-to-right shunt. Real-time three-dimensional trans-oesophageal echocardiography could show the whole pictures of the defect, which was useful information for surgical repair.

Circumstances and outcomes of out-of-hospital cardiac arrest in elementary and middle school students in the era of public-access defibrillation.

BACKGROUND: Circumstances and outcomes of out-of-hospital cardiac arrest (OHCA) in elementary and middle school students while at school in the era of public-access defibrillation are unknown. METHODS AND RESULTS: We conducted a nationwide hospital-based survey of elementary and middle school students who had had OHCA of cardiac origin and received prehospital resuscitation in 2005-2009. Among 58 cases recruited, 90% were witnessed by bystanders; 86% had ventricular fibrillation as the initial rhythm; 74% were resuscitated by bystanders; 24% were defibrillated by bystanders; 55% occurred at school; 66% were exercise-related; 48% were followed up before the event; 67% had structural heart disease. In total, 53% of overall patients and 79% of those initially defibrillated by bystanders had a favorable neurological outcome. Patients were more likely to be defibrillated by bystanders (38% vs. 8%, P=0.012) and had a more favorable neurological outcome in schools (69% vs. 35%, P=0.017) than in other locations. The majority of arrests in schools were exercise-related (84% vs. 42%, P=0.001), occurred at sports venues, and students were resuscitated by teachers; half of the cases at school occurred in patients with a pre-event follow-up. CONCLUSIONS: After OHCA, children were more likely to be defibrillated by bystanders and had a better outcome in schools than in other locations, which may be relevant to the circumstances of events.

Asparagine repeat function in a Plasmodium falciparum protein assessed via a regulatable fluorescent affinity tag.

One in four proteins in Plasmodium falciparum contains asparagine repeats. We probed the function of one such 28-residue asparagine repeat present in the P. falciparum proteasome lid subunit 6, Rpn6. To aid our efforts, we developed a regulatable, fluorescent affinity (RFA) tag that allows cellular localization, manipulation of cellular levels, and affinity isolation of a chosen protein in P. falciparum. The tag comprises a degradation domain derived from Escherichia coli dihydrofolate reductase together with GFP. The expression of RFA-tagged proteins is regulated by the simple folate analog trimethoprim (TMP). Parasite lines were generated in which full-length Rpn6 and an asparagine repeat-deletion mutant of Rpn6 were fused to the RFA tag. The knockdown of Rpn6 upon removal of TMP revealed that this protein is essential for ubiquitinated protein degradation and for parasite survival, but the asparagine repeat is dispensable for protein expression, stability, and function. The data point to a genomic mechanism for repeat perpetuation rather than a positive cellular role. The RFA tag should facilitate study of the role of essential genes in parasite biology.

Electrocardiographic Changes with Age in Japanese Patients with Noonan Syndrome.

Little information is available on age-related electrocardiographic changes in patients with Noonan syndrome. This single-center study evaluated the electrocardiograms of patients with Noonan syndrome. We divided the patients (n = 112; electrocardiograms, 256) into four groups according to age: G1 (1 month-1 year), G2 (1-6 years), G3 (6-12 years), and G4 (>12 years). Typical Noonan syndrome-related electrocardiographic features such as left-axis deviation, abnormal Q wave, wide QRS complex, and small R wave in precordial leads were detected. A high percentage of QRS axis abnormalities was found in all groups. Significant differences in right-axis deviation (RAD) were noted among the groups: 56.5% of G1 patients showed RAD compared with 33.3% of G2, 21.1% of G3, and 19.2% of G4 patients. The small R was also significantly different among the groups: 32.6% of G1 patients showed a small R wave compared with 14.9% of G2, 8.5% of G3, and 15.4% of G4 patients. Of the 53 patients with Noonan syndrome aged 1 month to 2 years, 18 had T-positive V1 with a higher prevalence of pulmonary stenosis and cardiac interventions. QRS axis abnormalities, small R in V6, and T-positive V1 could help diagnose Noonan syndrome in infants or young children.

Inhibition of phosphodiesterase type 3 dilates the rat ductus arteriosus without inducing intimal thickening.

BACKGROUND: Prostaglandin E(1) (PGE(1)), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE(1) is the sole DA dilator that is used until surgery, but PGE(1) has a short duration of action, and frequently induces apnea. Most importantly, PGE(1) increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE(1). METHODS AND RESULTS: Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE(1) (10µg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients. CONCLUSIONS: Because PDE3 inhibitors induced longer-lasting vasodilation without causing apnea or HA-mediated IT, they may be good alternatives to PGE(1) for patients with DA-dependent CHD.

Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease.

BACKGROUND: The treatment of Kawasaki disease patients who fail to respond to initial i.v. immunoglobulin (IVIG) therapy is controversial. The aim of the present study was to investigate the long-term efficacy of plasma exchange (PE) treatment for refractory Kawasaki disease. METHODS: A total of 125 Kawasaki disease patients refractory to IVIG were treated with PE. Coronary artery lesions (CAL) before PE, in the acute period, and during the late period were examined retrospectively. RESULTS: Residual sequelae requiring medical treatment occurred in six cases in the late period. The outcomes of treatment tended to be better when PE was begun in the early stage. Sequelae remained in 2.8% of patients in whom PE was initiated prior to day 9 after onset, and were present in 15% of patients in whom PE was started on or after day 10. The 105 patients whose coronary arteries were normal before PE had no sequelae (residual sequelae: 0%). Dilatation was present before PE in 14 patients, but remained in only two patients in the late period (residual sequelae, 14.3%). In four of the six patients in whom aneurysms had already formed before PE, the lesions had advanced into giant aneurysms, but in the other two patients they returned to the normal range (residual sequelae, 66.6%). CONCLUSIONS: The outcomes of PE for Kawasaki disease refractory to IVIG are favorable, and the effectiveness of this treatment is excellent, particularly if it is initiated before CAL arise.

Evaluation of FKBP and DHFR based destabilizing domains in Saccharomyces cerevisiae.

Two orthogonal destabilizing domains have been developed based on mutants of human FKBP12 as well as bacterial DHFR and these engineered domains have been used to control protein concentration in a variety of contexts in vitro and in vivo. FKBP12 based destabilizing domains cannot be rescued in the yeast Saccharomyces cerevisiae; ecDHFR based destabilizing domains are not degraded as efficiently in S. cerevisiae as in mammalian cells or Plasmodium, but provide a starting point for the development of domains with increased signal-to-noise in S. cerevisiae.

Intrapericardial and retrocardial implantation of implantable cardioverter-defibrillator lead in a child with type 3 long QT syndrome.

A 6-year-old girl with type 3 long QT syndrome was safely and successfully implanted with an implantable cardioverter-defibrillator (ICD) system. Prior to implantation, she had experienced uncontrollable life-threatening arrhythmia in spite of high-dose administration of mexiletine. An ICD coil lead for transvenous use was placed in the intrapericardial and retrocardial space and was connected to a generator placed in front of the posterior sheath of the right abdominal rectal muscle. Administration of a beta-blocker in addition to atrial pacing almost completely eliminated the patient's life-threatening arrhythmia attacks. Intrapericardial and retrocardial implantation of ICD coil leads might be useful for children.

A case of multisystem inflammatory syndrome in children in a Japanese boy: with discussion of cytokine profile.

The new disease concept of multisystem inflammatory syndrome in children (MIS-C), which is a systemic inflammatory syndrome with multiple organ involvement after SARS-CoV2 infection, was established in 2020. MIS-C is common in Hispanic and black children in Europe and North America, with few reports in East Asians. A significant portion of patients with MIS-C develop Kawasaki disease (KD)-like symptoms. Therefore, differential diagnosis is challenging, especially in East Asia, where KD is most prevalent. No Japanese cases have been reported in the literatures so far. We report a case of MIS-C in Japan with KD-like symptoms. A 9-year-old Japanese boy, who was infected with SARS-CoV2 1 month previously along with his family, was admitted to our hospital owing to fever for 6 d and erythema mainly in the groyne and pubic area. He also had conjunctivitis, strawberry tongue and diarrhoea. His laboratory findings were as follows: WBC, 12,840/µL (lymphocytes, 4%); CRP, 22.6 mg/dL, pro-calcitonin, 1.8 ng/mL (normal, <0.50 ng/mL); NT pro-BNP, 7627 pg/mL (<125 pg/mL); and troponin T, 0.14 ng/mL (<0.01 ng/mL). His cardiac function was normal. We initially diagnosed him with KD. His fever rapidly resolved with intravenous immunoglobulin (IVIG) and there were no coronary artery lesions. Desquamation of the fingers was observed later. Finally, a history of SARS-COV2 infection, his age, atypical skin rash, elevation of markers of inflammation and heart failure and lymphopenia suggested the diagnosis of MIS-C rather than KD. Differentiation between KD and MIS-C is necessary even in Japan, especially in patients with atypical features of KD.

Impact of the T-wave characteristics on distinguishing arrhythmogenic right ventricular cardiomyopathy from healthy children.

BACKGROUND: T-wave inversion (TWI) is not considered useful for diagnosing pediatric arrhythmogenic right ventricular cardiomyopathy (ARVC), because right precordial TWI in ARVC resembles a normal juvenile pattern. OBJECTIVES: The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children. METHODS: Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children. RESULTS: The mean age at the first arrhythmic event or diagnosis was 13.3 ± 4.7 years. Nine patients were asymptomatic initially and were found by ECG screening, but 6 developed severe symptoms during the follow-up. Healthy children had a normal juvenile pattern, while ARVC children, especially symptomatic patients, had a significant tendency to have inferior and anterior TWI. The phenomenon of T-wave discontinuity (TWD) in which the TWI became deeper from V1 to V3 and suddenly turned positive in V5 was significantly more frequent in ARVC (60%) than healthy children (0.55%). Anterior TWI and TWD were also significantly more frequent in those who developed severe symptoms. The sensitivity and specificity of TWD were 60% (95% CI, 31-83%), and 99% (95% CI, 99-99%) to distinguish ARVC from healthy children, as well as 100% (95% CI, 71-100%) and 80% (95% CI, 51-80%), respectively, to predict severe symptoms in the future. CONCLUSIONS: The ECG is useful to distinguish ARVC children, even in the early phase. Anterior TWI and TWD could detect ARVC children and to predict the possible serious conditions.

Leucine-rich alpha-2-glycoprotein 1 and angiotensinogen as diagnostic biomarkers for Kawasaki disease.

OBJECTIVE: Kawasaki disease (KD) is a systemic vasculitis in childhood that can lead to coronary artery lesions (CALs). Although early diagnosis and treatment is important for preventing KD patients from development of CALs, diagnosis depends on the clinical features of KD. We studied the usefulness of leucine-rich alpha-2-glycoprotein 1 (LRG1) and angiotensinogen (AGT), previously reported as KD-related proteins, for KD diagnosis and estimation of intravenous immunoglobulin (IVIG) efficacy. METHODS: We undertook a prospective cohort study with patients having two or more KD symptoms in multiple centers in Japan, between July 2017 and February 2019. RESULTS: Two hundred forty-two patients were included. In multivariable analysis, one unit increase in LRG1 was associated with higher odds of KD diagnosis (Odds ratio [OR] 1.02 [95% confidence interval (CI) 1.001-1.03]). Double-positivity for AGT (≥ 26 µg/mL) and LRG1 (≥ 123.5 µg/mL) was an independent biomarker for KD diagnosis in both the total cohort and the subgroup of patients with two to four KD symptoms (OR 5.01 [95% CI 1.86-13.50] and 3.71 [95% CI 1.23-11.16], respectively). There was no association between LRG1/AGT and IVIG efficacy. CONCLUSION: Double-positivity for LRG1 and AGT is an biomarker for KD diagnosis, especially useful in diagnosing incomplete KD from non-KD. Future studies with larger cohorts should seek to determine whether LRG1 and AGT are valuable as definitive data referred at the diagnosis of KD and for estimating the risk of CALs.

Fully automated rapid quantification of Hepatitis C Virus RNA in human plasma and serum by integrated on-chip RT-qPCR and capillary electrophoresis.

The quantification of hepatitis C virus (HCV) is essential for the management of chronic hepatitis C therapy. We have developed a fully automated microfluidic RT-qPCR system for rapid quantitative detection of HCV RNA in human EDTA-plasma and serum, and the performance of the method was assessed. The platform for the assay, µTASWako g1 Fully Automated Genetic Analyzer, performs automated sample preparation and RNA extraction, followed by amplification and detection on an integrated RT-qPCR-CE (capillary electrophoresis (CE)) microfluidic chip. The total assay time from sample input to data output is less than 120 minutes. The HCV assay has a linear quantitative range of 15 to 107 IU/mL, with a limit of detection (LOD) of 10.65 IU/mL in EDTA-plasma and 12.43 IU/mL in serum. The assay has a reproducibility of SD ≤ 0.16 log10 IU/mL and an accuracy of ≤ 0.22 log10 IU/mL difference when compared to the assigned values. The main HCV genotypes 1 to 6 are detected with an accuracy of ± 0.3 log10 IU/mL. The assay is specific for HCV RNA and is free of interference from non-HCV pathogens, elevated levels of anti-viral and anti-bacterial drugs, and common endogenous interferents. In the linear quantitative range, the assay is highly correlated with the Roche cobas AmpliPrep/cobas TaqMan HCV Test, version 2.0 (r2 = 0.949). As the assay is highly sensitive, accurate and specific, and provides reliable quantification of HCV in plasma and serum, it can potentially be applicable for monitoring the therapy and management of HCV infection.