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Key Clinical Message: We identified novel compound heterozygous TMEM70 variants in a Japanese patient who had hyperlactacidemia, metabolic acidosis, hyperalaninemia, developmental delay, undescended testicle, and left ventricular noncompaction. The urinary organic acids profile revealed elevated levels of 3‐MGA, and BN‐PAGE/Western blotting analysis and ETC. activity confirmed complex V deficiency. We identified novel compound heterozygous TMEM70 variants in a Japanese patient who had hyperlactacidemia, metabolic acidosis, hyperalaninemia, developmental delay, undescended testicle, and left ventricular noncompaction. The urinary organic acids profile revealed elevated levels of 3‐MGA, and BN‐PAGE/Western blotting analysis and ETC. activity confirmed complex V deficiency. [ABSTRACT FROM AUTHOR]

Background: Developmental status of young infants with congenital heart disease (CHD) is associated with physical and psychosocial factors. With the aim of obtaining basic data to perform developmental support, the study was conducted to examine the development and associated factors among these infants. Methods: The Japanese Denver Developmental Screening Test was performed in 75 infants at 3–5 months of age, and a questionnaire was sent to their mothers about recognition of their child’s development. Infants with and without developmental delay were compared using the characteristics of diagnosis of heart disease, symptoms and surgery, the state of growth of infants, and recognition of a child’s development by its mother. To specify more adequate factors, a multiple logistic regression analysis was conducted. Results: Of 75 infants, 14 (18.7%) had developmental delay. Weight gain of standard weight–2SD, Kaup index, and recognition of a child’s development by mothers were associated with delayed development. In particular, infants gaining weight at <10 g/day were significantly more delayed than those gaining weight at >20 g/day. In addition, infants whose mothers recognized developmental delay were significantly delayed compared to those not recognized. Conclusions: Developmental status of young infants with CHD was found to be strongly associated with growth. In particular, weight gain <10 g/day appeared to be the critical point for delayed development, as well as mothers’ recognition of their child’s development. [ABSTRACT FROM AUTHOR]

Objective: To investigate the morphology and genetics of a fetus at 22 weeks. This fetus demonstrated progressive fetal hydrops and cardiomegaly with retrograde flow in the pulmonary artery and progressive myocardial deterioration and heart failure. Methods: Postmortem examination, light and electron microscopy of the myocardium, karyotyping, fetal DNA analysis, screening for mutations in the G4.5 gene, α-dystrobrevin gene, FKBP 12 gene, Desmin, Syntrophin and Cypher/ZASP genes, which have been described as being associated with noncompaction ventricular myocardium, using single-strand DNA conformation polymorphism analysis and DNA sequencing. Results: The morphological diagnosis was compatible with noncompaction ventricular myocardium or spongyforme myopathy. The karyotype was normal. Mutation analysis in exons and introns of all six genes did not show any known mutation. Conclusion: Noncompaction ventricular myocardium or spongyforme myopathy may be associated with mutations in genes which have previously not been thought to be associated with this phenotype. Alternatively, this disease could be the result of abnormal cardiac hemodynamics. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by numerous excessively trabeculations and deep intertrabecular recesses. This study was performed to investigate Japanese LVNC patients for disease-causing mutations in a series of selected candidate genes. DNA was isolated from the peripheral blood of 79 cases including 20 familial cases and 59 sporadic cases. DNA samples were screened for mutations in the genes encoding G4.5 (TAZ), α-dystrobrevin (DTNA), α1-syntrophin (SNTA1), FK506 Binding protein 1A (FKBP1A or FKPB12: FKBP1A), and LIM Domain Binding protein 3 (Cypher/ZASP: LDB3), using single-strand conformational polymorphism analysis and DNA sequencing. DNA variants were identified in 6 of the 79 cases, including four familial cases and two sporadic cases. A splice acceptor mutation of intron 8 in TAZ (IVS8-1G>C) was identified in one family with isolated LVNC, resulting in deletion of exon 9 from mRNA. In a sporadic case of isolated LVNC and Barth syndrome (BTHS), a 158insC in exon 2 of TAZ resulting in a frame-shift mutation was identified. A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC. A 163G>A polymorphism was identified in LDB3, which changed a valine to isoleucine (V55I) in one patient with isolated LVNC. In addition, in a family with nonisolated LVNC, a 362C>T mutation was identified in DTNA. LVNC, like other forms of inherited cardiomyopathy, is a genetically heterogeneous disease, associated with variable clinical symptoms and can be inherited as an autosomal or X-linked recessive disorder. [Copyright &y& Elsevier]

Determines the appropriate method for the standardization of left ventricular mass in infants, children and adolescents. Number of children and adolescents included in the study; Body length, bodyweight and body surface area exponents in males and females.

Abstract. Epidemiologic and clinical features of Kawasaki disease in 106 patients seen between 1980 and 1986 at The New York Hospital in midtown Manhattan were compared with those in large series from the United States, Canada, and Japan. Dissimilarities in our Kawasaki disease experience included ethnic heterogeneity of our patients (50% white, 18% black, 16% Hispanic, and 16% Oriental) and, in comparison with the Japanese experience, an older mean age (3 1/2 vs 1 1/2 years) with fewer children less than 2 years of age (32% vs 50% to 60%). In comparison with the general population of the geographic urban and suburban referral area for our hospital and in comparison with our general pediatric population, Oriental children with Kawasaki disease were overrepresented (16% vs 2%). More families of children with Kawasaki disease were members of the upper and middle class (73%) than were the population seen in general pediatrics (31.7%) at our hospital. Personal interviews with 63 families of children with Kawasaki disease and 63 control families with children paired for ethnic group, sex, and age revealed no epidemiologic differences except for use of rug shampoo within 1 month of onset in 16 episodes in 15 children with Kawasaki disease in 14 families (22% of families) compared with two families of control children (3%) (P < .001). [ABSTRACT FROM AUTHOR]

Abstract. Following personal interviews with 63 families of children with Kawasaki disease and with 63 control families with children paired for race, sex, and age, no epidemiologic differences were seen except for use of rug shampoo within 1 month of onset in 16 episodes in 15 children with Kawasaki disease in 14 families (24% of children, 22% of families) compared with two families of control children (3%, P < .005). Explanations for this strong association of recent rug shampoo and Kawasaki disease include the question of recall bias as well as the possibility that an agent in the shampooing process does cause or does contribute to illness. [ABSTRACT FROM AUTHOR]

Abstract. Since January 1980, 110 children having 113 attacks of Kawasaki syndrome were studied. Age at onset was 7 weeks to 12 years (mean 3 6/12 years, median 2 9/12 years); 77% were younger than 5 years of age; the male to female ratio was 1.8; racial distribution was 52% white, 19% black, 14% Hispanic, and 16% Asian. Protocol of management consisted of high-dose aspirin (100 mg/kg/ d) until afebrile, and then 81 mg every day until free of coronary aneurysm. Two-dimensional echocardiograms were done weekly during the acute stage, at 2 and 6 months after onset, and yearly if a coronary abnormality was detected. At I month, 51 coronary arterial abnormalities were present in 25 patients. Risk factors for a coronary abnormality were duration of fever greater than or equal to 2 weeks, level of platelet count, marked elevation of ESR, and age younger than 5 years. No statistically significant difference in incidence of aneurysms was detected between patients on high-dose aspirin and those on medium-or low-dose aspirin. [ABSTRACT FROM AUTHOR]

Describes the potential efficacy of combined administration of inhaled nitric oxide and oral beraprost sodium in preferentially causing pulmonary vasodilation in children with pulmonary hypertension. Blood samples taken from pulmonary vein at baseline; Absence of significant decrease in systemic arterial pressure.

Background: Left ventricular hypertrophy (LVH) is a well-recognized cardiac dysfunction in infants of mothers with gestational diabetes mellitus (GDM). Left ventricular noncompaction (LVNC) is a cardiomyopathy that is morphologically characterized by numerous prominent trabeculations and deep intertrabecular recesses on cardiovascular imaging. However, there have been no case reports on neonates of mothers with GDM showing LVH and LVNC. Case presentation: A patient, with LVH of a mother with GDM, was delivered at 36 weeks of gestation. Prominent trabeculations in the LV, suggesting LVNC, instead of LVH, were apparent 1 week after birth. A heterozygous deletion variant in the MYH7 gene (NM_000257.4: c.1090T>C, p.Phe364Leu) was discovered through genetic testing using a cardiomyopathy-associated gene panel in the patient and his father and the older brother who had LVNC. The patient is now 5 years old and does not have major cardiac events, although LVNC persisted. This is the first case of LVH secondary to a mother with GDM and LVNC with a novel variant in the MYH7 gene. Conclusion: Genetic testing should be conducted to obtain an accurate outcome and medical care in a patient with LVH and subsequently prominent hypertrabeculation in the LV. [ABSTRACT FROM AUTHOR]

The article presents a case study of a full-term male neonate weighing 3,350 g without resuscitation treatment born in a regional hospital in Japan. It notes that novel compound heterozygous TBX5 variants may induce hypoplastic left heart syndrome and how the findings may be characteristic of the pathology underlying the development of HLHS in patients with TBX5 variants.

Background Non-high-density lipoprotein cholesterol (non-HDL-C) is now recognized as a strong predictive factor for cardiovascular disease in adults, but there have been few reports on non-HDL-C in children. Methods A total of 5853 4th and 7th grade schoolchildren were included in the screening for lifestyle-related disease from 2010 to 2011 in Takaoka City. The children underwent anthropometric measurements and non-fasting blood tests to measure total cholesterol (TC), HDL-C, triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C). The relationship between percent overweight and each lipid level was analyzed, and children above the 97th percentile level with respect to both TC (220 mg/dL) and non-HDL-C (152 mg/dL) were compared and assessed. The relationship between non-HDL-C and the prevalence of metabolic syndrome was also analyzed among 150 obese children. Results Non-HDL-C positively correlated with percent overweight and TG rather than did TC ( r = 0.273, 0.360 vs 0.118, 0.179, all P < 0.001). In the screening using TC criteria, several subjects with increased HDL-C were miscategorized as hyperlipidemic, whereas none were miscategorized using the non-HDL-C criteria. The sensitivity of the identification of increased LDL-C was lower when the criteria for TC were used rather than the criteria for non-HDL-C (80.8% vs 98.3%). Among obese children, the prevalence of metabolic syndrome increased significantly and was accompanied by an increase in non-HDL-C ( P = 0.009). Conclusion Instead of TC, non-HDL-C would serve as a better and useful cardiovascular risk screening tool for lifestyle-related disease in school children. [ABSTRACT FROM AUTHOR]

It is not always easy to observe and screen atrial septal defects (ASD) using echocardiography. In addition, there are no established echocardiographic reference indices for screening patients with ASDs. We retrospectively reviewed our database and recruited 151 isolated ASD patients and 2769 healthy subjects. In total, 307 echocardiographic studies were performed for ASD patients. Surgical repairs were done in 75 of the ASD patients. The ratio of right to left ventricular end-diastolic dimensions (RVD/LVD), which was determined by M-mode echocardiography, was used as an index of RV dilatation. After obtaining age- and body surface area (BSA)-related RVD/LVD nomograms in healthy subjects, we calculated the z-scores of RVD/LVD for all subjects and obtained the optimal cut-off values to differentiate patients with ASD from healthy subjects. The optimal cut-off values were high in neonates and gradually decreased with an increase in the age and BSA, but were almost constant in children aged >4 years or whose BSA was >0.65 m. The cut-off values of RVD/LVD for suspected ASD were ≥0.42 in children aged >4 years or those whose BSA was >0.65 m. Those for an ASD operation were ≥0.46 in those whose BSA > 0.65 m. The RVD/LVD determined by M-mode echocardiography is a useful index to evaluate RV dilatation in patients with ASDs. The RVD/LVD ≥ 0.42 is the warning flag for suspecting ASD in preschool children and that ≥0.46 may be a clinical important sign to determine ASD operation. [ABSTRACT FROM AUTHOR]

Chronic myocarditis is a prolonged inflammatory condition in the myocardium and its histological manifestation is defined by the presence of an inflammatory infiltrate. Chronic myocarditis has not been well known and its treatment of chronic myocarditis has not been established. Primary outcome of this study was to assess the efficacy of immunomodulatory treatment in addition to conventional treatment, and secondary outcomes were to clarity the prognosis of natural history of chronic myocarditis and incidence of chronic myocarditis in patients with dilated cardiomyopathy (DCM). We searched for studies in Medline, Embase, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi published between January 1946 and June 2020. Sixteen studies met the inclusion criteria. A meta-analysis revealed that patients receiving immunomodulatory treatment showed an improvement in left ventricular ejection fraction after immunomodulatory treatment compared to the control group (hazard ratio, 16.65; confidence interval, 4.55–28.74; p = 0.007). Five-year survival rate of the patients with inflammatory DCM (iDCM) and DCM was 52.7–70.3% and 51.9–91.1%, respectively. Moreover, 51.5%–62.7% of patients with DCM met the criteria of iDCM. Our systematic review revealed that patients with chronic myocarditis had poor prognosis and immunomodulatory treatment was significantly effective in addition to conventional treatment. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to determine the prevalence of persistent neurodevelopmental sequelae in 1-year-old infants after open heart surgery for congenital heart disease, using the Bayley Scales of Infant Development second edition (BSID-II). A secondary objective was to confirm the applicability and usefulness of the BSID-II in Japanese infants. Methods: Thirty-nine infants who underwent repair of a ventricular septal defect before 6 months of age and 108 normal Japanese infants at 1 year of age were assessed using the BSID-II. Results: In normal infants, scores on the Mental Development Index and the Psychomotor Development Index components of the BSID-II ranged from borderline retardation to very superior following a normal distribution similar to those obtained for US controls. No problems were encountered, either in translation or in following the instructions when the BSID-II was used to evaluate the 1-year-old Japanese infants. On the other hand, the mean scores on the Mental Development Index and the Psychomotor Development Index were significantly lower in Japanese patients than in normal Japanese infants, particularly for gross motor development ( P < 0.001). Linear regression analysis showed that a longer intensive care unit stay was associated with impaired cognitive development at 1 year of age ( P= 0.03). Conclusions: Neurodevelopmental functions in 1-year-old infants with congenital heart disease were lower than those in normal infants, especially for gross motor function using the BSID-II. One risk factor that correlated with neurodevelopmental sequelae was the length of intensive care unit stay. [ABSTRACT FROM AUTHOR]

The article presents a study which investigated circulating soluble receptor for advanced glycation end products (sRAGE) in an acute inflammatory disorder. Results showed decreased levels of sRAGE in patients with Kawasaki disease (KD) and those with systemic-onset juvenile idiopathic arthritis (JIA). The authors said inverse regulation of sRAGE and its proinflammatory ligand seems to be a relevant molecular mechanism promoting systemic inflammation.

Objective: To assess the reliability and validity of the Japanese translation version of the Pediatric Quality of Life Inventory 4.0 Short Form 15 (PedsQL 4.0 SF15).Methods: The PedsQL 4.0 SF15 was administered to 229 schoolchildren aged 6-13 years and 100 pediatric outpatients aged 5-18 years and their parents.Results: Internal consistency reliability exceeded 0.70 for both proxy-reported and self-reported scales. Test-retest reliability demonstrated large values for parent proxy-report (range: 0.68-0.79) and moderate to large values for child self-report (range: 0.46-0.73). Parent proxy-report health-related quality of life (HRQOL) was higher than child self-report in all scales except for School Functioning. The correlations between the reports of the parents and children were moderate to high. Gender differences were observed in Social Functioning, School Functioning, and Psychosocial Health Summary, with girls reporting higher HRQOL than boys. Factor analysis indicated that four factors were extracted from the PedsQL 4.0 SF15 and these four factors corresponded mainly to the four scales. Known groups validity was established for proxy-report and self-report with higher HRQOL being reported for healthy children than those with psychosomatic complaints including headache and abdominal pain.Conclusion: The Japanese translation version of the PedsQL 4.0 SF15 demonstrates good reliability and validity and could be used as a measure of HRQOL for transcultural comparisons of pediatric research in school settings and healthcare services research. [ABSTRACT FROM AUTHOR]

To assess the reliability and validity of the Japanese translation version of the Pediatric Quality of Life Inventory™ 4.0 Short Form 15 (PedsQL™ 4.0 SF15). The PedsQL™ 4.0 SF15 was administered to 229 schoolchildren aged 6–13 years and 100 pediatric outpatients aged 5–18 years and their parents. Internal consistency reliability exceeded 0.70 for both proxy-reported and self-reported scales. Test–retest reliability demonstrated large values for parent proxy-report (range: 0.68–0.79) and moderate to large values for child self-report (range: 0.46–0.73). Parent proxy-report health-related quality of life (HRQOL) was higher than child self-report in all scales except for School Functioning. The correlations between the reports of the parents and children were moderate to high. Gender differences were observed in Social Functioning, School Functioning, and Psychosocial Health Summary, with girls reporting higher HRQOL than boys. Factor analysis indicated that four factors were extracted from the PedsQL™ 4.0 SF15 and these four factors corresponded mainly to the four scales. Known groups validity was established for proxy-report and self-report with higher HRQOL being reported for healthy children than those with psychosomatic complaints including headache and abdominal pain. The Japanese translation version of the PedsQL™ 4.0 SF15 demonstrates good reliability and validity and could be used as a measure of HRQOL for transcultural comparisons of pediatric research in school settings and healthcare services research. [ABSTRACT FROM AUTHOR]

Presents guidelines for the use of palivizumab in infants and young children with congenital heart disease. Indications for the drug; Dosage and dosing plan; Interactions with underlying diseases or other drugs.

Mutations in the gene G4.5, originally associated with Barth syndrome, have been reported to result in a wide spectrum of severe infantile X-linked cardiomyopathies. The purpose of this study was to investigate patients with isolated left ventricular noncompaction (LVNC) for disease-causing mutations in G4.5. In 27 patients including 10 families with isolated LVNC, mutation analysis of G4.5 was performed using single-strand DNA conformation polymorphism (SSCP) analysis and DNA sequencing. A novel splice acceptor site mutation of intron 8 of G4.5 was identified in a family with severe infantile X-linked LVNC without the usual findings of Barth syndrome. This mutation results in deletion of exon 9 from the mRNA, and is predicted to significantly disrupt the protein product. Genotype–phenotype correlation of G4.5 mutations in all 38 cases reported in the literature to date revealed that there was no correlation between location or type of mutation and either cardiac phenotype or disease severity. We suggest that males presenting with cardiomyopathy, particularly during infancy, even in the absence of the typical signs of Barth syndrome, should be evaluated for mutations in G4.5. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy, associated with high morbidity and mortality, but the role of genetics in cases of fetal-onset has not been fully evaluated. The goal of this study was to identify the genetic background in LVNC fetal-onset patients using next-generation sequencing (NGS). Thirty-three fetal-onset Japanese probands with LVNC (20 males and 13 females) were enrolled. In the enrolled patients, 81 genes associated with cardiomyopathy were screened using next-generation sequencing (NGS) retrospectively. Twenty-three patients had congestive heart failure (CHF), and six patients had arrhythmias. Prominent trabeculations were mostly observed in lateral LV, posterior LV, and apex of LV in patients with LVNC. Twelve died; three patients experienced intrauterine death or termination of pregnancy. Overall, 15 variants were found among eight genes in 16 patients. Seven variants were detected in MYH7 and two in TPM1. Sarcomere gene variants accounted for 75.0%. A multivariable proportional hazards model revealed that CHF at diagnosis and a higher ratio of the noncompacted layer/compacted layer in the LV posterior wall were independent risk factors for death in LVNC fetal-onset patients (odds ratio = 4.26 × 106 and 1.36 × 108, p = 0.0075 and 0.0005, respectively). The present study is the first report focusing on genetic background combined with clinical features in LVNC fetal-onset patients using NGS. Sarcomere variants were most commonly identified in fetal-onset patients, and greater attention should be paid to fetal-onset patients with LVNC having prominent trabeculations in the LV because they are more likely to develop CHF. • The first report focusing on genetic background in LVNC fetal-onset patients. • Sarcomere variants were most commonly identified. • Higher noncompacted to compacted ratio of left ventricle was risk factors for death. [ABSTRACT FROM AUTHOR]

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. The aims of this study were to clarify the electrocardiographic (ECG) characteristics of pediatric ARVC to distinguish those patients from healthy children. Between 1979 and 2017, 11 ARVC patients under 18 years old were registered and compared with school screening ECGs from 48,401 healthy children. 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. 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. • This study clarified the frequency of T-wave inversion (TWI) in a large cohort of healthy children. • T-wave discontinuity (TWD), as well as TWI in the inferior and anterior leads could differentiate ARVC children. • TWD and anterior TWI are possible signs to predict a serious prognosis in the future. • ARVC children tend not to have VTs but have PVCs and late potentials. [ABSTRACT FROM AUTHOR]

Presents a pediatric case of plastic bronchitis which occurred five years after a Fontan operation. Background on the patient; Pathologic examination; Background on plastic bronchitis.

Background: Both congenital heart disease (CHD) and very‐low birthweight (VLBW) infants are at a very high risk of neurodevelopmental delay. We investigated neurological development at 3 years in pediatric patients with CHD after surgical intervention, those of VLBW, and healthy controls. Methods: We enrolled pediatric patients with CHD (n = 67), VLBW (n = 67), and healthy controls (n = 81). Infants with CHD were grouped into those with single ventricle and two ventricles, and infants with VLBW were grouped into those with birthweights of <1000 and 1000–1499 g. Neurodevelopmental outcomes at 3 years were evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition. Results: Compared with healthy controls, a significant deficit in the language, cognition, and motor skills scores were observed in infants with CHD and VLBW. Infants with a single ventricle exhibited significantly low scores in language and gross motor skills. No statistically significant difference was observed between the birthweight groups of <1000 and 1000–1499 g. Conclusion: Neurodevelopmental outcomes for infants with both CHD and VLBW showed impairment. Notably, neurodevelopmental delays in infants with a single ventricle were remarkable. Thus, because infants with both CHD and VLBW are at high risk of neurodevelopmental disorders, periodic developmental screenings and support are warranted for these children. [ABSTRACT FROM AUTHOR]

Background: TBX5 is a transcription factor that has an important role in development of heart. TBX5 variants in the region encoding the T-box domain have been shown to cause cardiac defects, such as atrial septal defect or ventricular septal defect, while TBX5 variants have also been identified in a few cardiomyopathy patients and considered causative. We identified a TBX5 variant (c.791G>A, p.Arg264Lys), that is over-represented in cardiomyopathy patients. This variant is located outside of the T-box domain, and its pathogenicity has not been confirmed by functional analyses. Objective: To investigate whether the TBX5 R264K is deleterious and could contribute to the pathogenesis of cardiomyopathy. Methods and results: We developed mice expressing Tbx5 R264K. Mice homozygous for this variant displayed compensated dilated cardiomyopathy; mild decreased fractional shortening, dilatation of the left ventricle, left ventricular wall thinning and increased heart weight without major heart structural disorders. There was no difference in activation of the ANF promotor, a transcriptional target of Tbx5, compared to wild-type. However, analysis of RNA isolated from left ventricular samples showed significant increases in the expression of Acta1 in left ventricle with concomitant increases in the protein level of ACTA1. Conclusions: Mice homozygous for Tbx5 R264K showed compensated dilated cardiomyopathy. Thus, TBX5 R264K may have a significant pathogenic role in some cardiomyopathy patients independently of T-box domain pathway. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Neurodevelopmental disability is the most common complication among congenital heart surgery survivors. The Bayley scales are standardized instruments to assess neurodevelopment. The most recent edition (Bayley Scales of Infant and Toddler Development 3rd Edition, Bayley-III) yields better-than-expected scores in typically developing and high-risk infants than the second edition (Bayley Scales of Infant Development 2nd Edition, BSID-II). We compared BSID-II and Bayley-III scores in infants undergoing cardiac surgery. METHODS We evaluated 2198 infants who underwent operations with cardiopulmonary bypass between 1996 and 2009 at 26 institutions. We used propensity score matching to limit confounding by indication in a subset of patients (n  = 705). RESULTS Overall, unadjusted Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores (90.7 ± 17.2 vs 77.6 ± 18.8, P  < 0.001), and unadjusted Bayley-III composite cognitive and language scores were higher than BSID-II Mental Development Index scores (92.0 ± 15.4 vs 88.2 ± 16.7, P  < 0.001). In the propensity-matched analysis, Bayley-III motor scores were higher than BSID-II Psychomotor Development Index scores [absolute difference 14.1, 95% confidence interval (CI) 11.7–17.6; P  < 0.001] and the Bayley-III classified fewer children as having severe [odds ratio (OR) 0.24; 95% CI 0.14–0.42] or mild-to-moderate impairment (OR 0.21; 95% CI 0.14–0.32). The composite of Bayley-III cognitive and language scores was higher than BSID-II Mental Development Index scores (absolute difference 4.0, 95% CI 1.4–6.7; P  = 0.003), but there was no difference between Bayley editions in the proportion of children classified as having severe cognitive and language impairment. CONCLUSIONS The Bayley-III yielded higher scores than the BSID-II and classified fewer children as severely impaired. The systematic bias towards higher scores with the Bayley-III precludes valid comparisons between early and contemporary cardiac surgery cohorts. [ABSTRACT FROM AUTHOR]

Purpose: We previously demonstrated that the rational pediatric dosage of warfarin can be well-described by a SIZE parameter that includes an allometry exponent of weight. On the other hand, allometry alone is considered to be insufficient to predict drug clearance in neonates and infants. The primary purpose of the present study was to evaluate the effects of incorporation of the maturation process into the analysis model for the dose-response relationship of warfarin in Japanese children. In addition, we evaluated the effect of chronic heart failure (CHF) on the response to warfarin as an independent risk factor for increased anticoagulant effects. Methods: Thirty-eight patients with stable anticoagulation by warfarin were enrolled. During a mean follow-up period of 4.74 ± 3.51 years, 1092 data points including prothrombin time-international normalized ratio (PT-INR) were obtained. The data were subjected to multiple regression analysis to identify covariates related to the anticoagulant effects. Results: Two different models describing the maturation process did not improve the predictive performance for the dose-response relationship in pediatric patients. In addition to the SIZE-normalized daily dose, the vitamin K epoxide reductase complex 1 (VKORC1) genotype, and concomitant use of bosentan, CHF was identified as a covariate increasing the anticoagulant effects of warfarin to 118%. Conclusion: The SIZE parameter was useful even without incorporation of maturation models to describe the response to warfarin in pediatric patients, and our longitudinal follow-up study design with multiple observations was beneficial to detect changes within individual subjects. [ABSTRACT FROM AUTHOR]

Objective: Kawasaki disease (KD) is an acute vasculitis of childhood, predominantly affecting the coronary arteries. S100A12, a granulocyte‐derived agonist of both the receptor for advanced glycation end products (RAGE) and Toll‐like receptor 4 (TLR‐4), is strongly up‐regulated in KD. This study was undertaken to investigate the potential contributions of S100A12 to the pathogenesis of KD. Methods: Serum samples from patients with KD (n = 30) at different stages pre– and post–intravenous immunoglobulin (IVIG) treatment were analyzed for the expression of S100A12, cytokines, chemokines, and soluble markers of endothelial cell activation. Primary human coronary artery endothelial cells (HCAECs) were analyzed for responsiveness to direct stimulation with S100A12 or lipopolysaccharide (LPS), as assessed by real‐time quantitative reverse transcription–polymerase chain reaction analysis of cytokine and endothelial cell adhesion molecule messenger RNA expression. Alternatively, HCAECs were cultured in conditioned medium obtained from primary human monocytes that were stimulated with LPS or S100A12 in the absence or presence of IVIG or cytokine antagonists. Results: In the serum of patients with KD, pretreatment S100A12 levels were associated with soluble vascular cell adhesion molecule 1 titers in the course of IVIG therapy (rs = −0.6, P = 0.0003). Yet, HCAECs were not responsive to direct S100A12 stimulation, despite the presence of appropriate receptors (RAGE, TLR‐4). HCAECs did, however, respond to supernatants obtained from S100A12‐stimulated primary human monocytes, as evidenced by the gene expression of inflammatory cytokines and adhesion molecules. This response was strictly dependent on interleukin‐1β (IL‐1β) signaling (P < 0.001). Conclusion: In its role as a highly expressed mediator of sterile inflammation in KD, S100A12 appears to activate HCAECs in an IL‐1β–dependent manner. These data provide new mechanistic insights into the contributions of S100A12 and IL‐1β to disease pathogenesis, and may therefore support current IL‐1–targeting studies in the treatment of patients with KD. [ABSTRACT FROM AUTHOR]

We found that a female infant presenting with left bundle branch block and left ventricular noncompaction carries uninvestigated gene mutations HCN4(G811E), SCN5A(L1988R), DMD(S2384Y), and EMD(R203H). Here, we explored the possible pathogenicity of HCN4(G811E), which results in a G811E substitution in hyperpolarization-activated cyclic nucleotide-gated channel 4, the main subunit of the cardiac pacemaker channel. Voltage-clamp measurements in a heterologous expression system of HEK293T cells showed that HCN4(G811E) slightly reduced whole-cell HCN4 channel conductance, whereas it did not affect the gating kinetics, unitary conductance, or cAMP-dependent modulation of voltage-dependence. Immunocytochemistry and immunoblot analysis showed that the G811E mutation did not impair the membrane trafficking of the channel subunit in the heterologous expression system. These findings indicate that HCN4(G811E) may not be a monogenic factor to cause the cardiac disorders. [ABSTRACT FROM AUTHOR]

Background A Japanese nationwide survey has reported that Down syndrome ( DS) is a less-frequently occurring comorbidity in Kawasaki disease ( KD). Although altered immune responses are frequently observed in DS, no studies have focused on the treatment response and risk for coronary artery abnormalities ( CAA) in DS patients with KD. The aim of this study was therefore to evaluate the clinical manifestations, treatment response and prevalence of CAA in DS with KD. Methods We retrospectively reviewed the medical records of DS patients with KD from 2005 through 2012. The survey questionnaires were sent to facilities nationwide, and clinical data regarding KD in DS were collected. A control group consisted of non- DS patients with KD who were managed at Toho University. Results Of the 94 233 children diagnosed with acute KD from 2005 to 2012, 16 children with acute KD also had DS (0.017%). The DS- KD patients were significantly older than the non- DS patients (median, 8 years vs 1 year, P < 0.05, respectively). Half of the DS patients had incomplete KD. Although 50% of the DS children were at high risk of immunoglobulin resistance, all children responded to initial treatment and none had CAA. Conclusions All DS- KD patients responded to initial i.v. immunoglobulin ( IVIG) or aspirin despite having a high risk of IVIG resistance, and none of the DS patients had CAA. This suggests that the risk of treatment resistance and development of CAA may be not higher in DS patients with acute KD. [ABSTRACT FROM AUTHOR]

KCNE1 encodes a modulator of KCNQ1 and KCNH2 channels. Although KCNE1(G38S), a single-nucleotide polymorphism (SNP) causing a G38S substitution in KCNE1, is found frequently, whether and how this SNP causes long QT syndrome (LQTS) remains unclear. We evaluated rate-dependent repolarization dynamics using Holter electrocardiogram (ECG) to assess the pathogenicity of KCNE1(G38S). Forty-five patients exhibiting long QT intervals, as assessed by their baseline ECGs, and 16 control subjects were enrolled. KCNE1(G38S) carriers were identified using genome sequencing. LQTS patients were classified into LQT1 or LQT2 using genetic analysis or epinephrine test. QT-RR relations were determined using 24-h Holter ECG recordings. Among the 15 patients (33.3 %) with KCNE1(G38S), four patients without any mutations or amino acid changes in other major cardiac ion channels were categorized as KCNE1(G38S) carriers. In the QT-RR regression lines, the QT-RR slope was greater in the KCNE1(G38S) carriers and the LQT2 patients (0.215 ± 0.021 and 0.207 ± 0.032, respectively) than in the LQT1 patients (0.163 ± 0.014, P < 0.05) and the control subjects (0.135 ± 0.025, P < 0.001). The calculated QT intervals at an RR interval of 1200 ms were longer in the KCNE1(G38S) carriers and LQT1 and LQT2 patients than in the control subjects. Patients with KCNE1(G38S) had a rate-dependent repolarization abnormality similar to patients with LQT2 and, therefore, may have a potential risk to develop lethal arrhythmias. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non-compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6-month-old boy with KD was admitted to hospital. Despite high-dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 ( LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation. [ABSTRACT FROM AUTHOR]

Aim of our study was to evaluate right ventricular (RV) systolic function in neonate using newly developed single-beat three-dimensional echocardiography (sb3DE). We enrolled 15 healthy or premature neonates (0-53 days after birth). We scanned one beat full volume using Siemens ACUSON SC2000 (Siemens AG) echocardiography with 4Z1c full-volume transducer without ECG gating. RV end-diastolic volume (RVEDV) and RV end-systolic volume (RVESV) were computed with special software dedicated to analysis for RV volume. RV ejection fraction (RVEF) and RV stroke volume (3D-RVSV) were calculated. And RV stroke volume was also determined from the recordings of ejection blood flow velocity and diameter at the level of the pulmonary orifice in RV outflow tract (Doppler-RVSV). Tricuspid annular plane systolic excursion (TAPSE) was also measured by 2D echocardiography. RVEDV ranged from 5.1 to 10.7 ml (average 7.5 ml), RVESV ranged from 2.3 to 5.8 ml (average 3.9 ml). There was a good correlation between 3D-RVSV and Doppler-RVSV ( r = 0.77). Bland-Altman plot revealed that 3D-RVSV became underestimation of an average of 1.78 ml compared to Doppler-RVSV. And TAPSE positively correlated with 3D-RVEF ( r = 0.58, P = 0.038). Newly developed sb3DE enables us to perform three-dimensional acquisition of RV volume without ECG gating even in neonate. However, 3D-RVSV currently tends to be underestimated in neonatal measurement. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI), RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P < .001}. Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P < .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources. [ABSTRACT FROM AUTHOR]

Abstract: KCNQ1 encodes the α subunit of the voltage-gated channel that mediates the cardiac slow delayed rectifier K+ current (I Ks). Here, we report a KCNQ1 allele encoding an A590T mutation [KCNQ1(A590T)] found in a 39-year-old female with a mild QT prolongation. A590 is located in the C-terminal α helical region of KCNQ1 that mediates subunit tetramerization, membrane trafficking, and interaction with Yotiao. This interaction is known to be required for the proper modulation of I Ks by cAMP. Since previous studies reported that mutations in the vicinity of A590 impair I Ks channel surface expression and function, we examined whether and how the A590T mutation affects the I Ks channel. Electrophysiological measurements in HEK-293T cells showed that the A590T mutation caused a reduction in I Ks density and a right-shift of the current–voltage relation of channel activation. Immunocytochemical and immunoblot analyses showed the reduced cell surface expression of KCNQ1(A590T) subunit and its rescue by coexpression of the wild-type KCNQ1 [KCNQ1(WT)] subunit. Moreover, KCNQ1(A590T) subunit interacted with Yotiao and had a cAMP-responsiveness comparable to that of KCNQ1(WT) subunit. These findings indicate that the A590 of KCNQ1 subunit plays important roles in the maintenance of channel surface expression and function via a novel mechanism independent of interaction with Yotiao. [Copyright &y& Elsevier]

A letter to the editor is presented "Kawasaki disease patients homozygous for the rs12252-C variant of interferon-induced transmembrane protein-3 are significantly more likely to develop coronary artery lesions" by C. Arrington, A. Brass and T. Kawasaki in the 2014 issue.

ABSTRACT The aims of the present study were to evaluate the variability of pharmacokinetics of flecainide in young Japanese patients and to investigate the mechanisms of renal excretion and intestinal absorption of the drug using cultured epithelial cells. First the plasma concentration data of flecainide was analysed in 16 Japanese patients aged between 0.07 and 18.30 years using a one-compartment model. Considerable interindividual variability was observed in the oral clearance ( CL/ F) and the apparent volume of distribution ( V/ F) of flecainide in the young patients. Flecainide was transported selectively in the basolateral-to-apical direction in P-glycoprotein-expressing renal epithelial LLC-GA5-COL150 cell monolayers. The uptake of flecainide into intestinal epithelial LS180 cells was decreased significantly by acidification of the extracellular medium, and was inhibited by tertiary amines, such as diphenhydramine and quinidine. These findings in the present study suggest that flecainide is excreted by P-glycoprotein in the renal tubule and is taken up by the postulated H+/tertiary amine antiporter in the intestine, and that functional variability of not only the hepatic drug-metabolizing enzymes, but also the transporters in the kidney and intestine, may be responsible for the interindividual variability of systemic clearance ( CL) and/or the bioavailability ( F) of flecainide. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction: The human ether- à- go- go-related gene ( hERG) encodes the α-subunit of a cardiac potassium channel. Various mutations of hERG, including missense mutations, have been reported to cause long QT syndrome (LQTS) and severe arrhythmic disorders such as sudden cardiac death. We identified a novel hERG frameshift mutation ( hERG(ΔAT)) in the S5-pore region from a LQTS patient who died suddenly and analyzed its genetic profile and the molecular and electrophysiological behaviors of the protein product to assess the pathogenicity of hERG(ΔAT). Methods and results: We performed direct sequencing of hERG and evaluated its transcript level by using a whole blood sample from the patient. We performed immunoblotting, immunocytochemistry, and patch-clamp recordings of HEK-293 T cells transfected with hERG(ΔAT), wild-type hERG ( hERG(WT)), or both. The patient demonstrated an AT deletion (c.1735_1736del) in hERG and a decrease in hERG mRNA transcripts. HEK-293 T cells showed lower production and cell surface expression of hERG(ΔAT) compared with hERG(WT) protein. In addition, the hERG(∆AT) protein failed to form functional channels, while the activation kinetics of functional channels, presumably consisting of hERG(WT) subunits, were unaffected. Conclusion: The ΔAT mutation may decrease the number of functional hERG channels by impairing the posttranscriptional and posttranslational processing of the mutant product. This decrease may partly explain the cardiac symptoms of the patient who was heterozygous for hERG(ΔAT). [ABSTRACT FROM AUTHOR]

Abstract: Background: There are few articles on mortality and morbidity of adult patients with Eisenmenger's syndrome (ES) in the current era when disease targeting therapy (DTT) has been available. Methods and results: 198 patients (a median age 35years, 64% female) with ES who visited the 16 participating institutes in Japan and Korea from 1998 to 2009 were enrolled. Clinical data during adulthood were collected from each institutional chart and analyzed centrally. During a median follow-up of 8years, 30 patients died including 14 sudden deaths. 89 patients took oral medication of DTT and clinical improvement was observed in 54 of them. However, survival rate in patients taking DTT was not different from those without (87% vs 84%, p=0.55). When the clinical data in between first and last clinic visits were compared in 85 patients, the patients with NYHA ≧ III increased from 24% to 48% (p<0.001), SpO2 decreased from 89% to 85% (p=0.008) and hematocrit increased from 51.4% to 52.9% (p=0.04). Non-survivors had poorer NYHA function class, lower body weight (BW), lower body mass index (BMI), and higher serum level of Cr at the first visits than survivors. Conclusions: Long term survival and clinical status of adult patients with ES remains unsatisfactory even in the current era of DTT. Poor NYHA functional class, low BW, low BMI and high serum level of Cr were related to mortality. DTT therapy improved clinical status in many patients with Eisenmenger's syndrome, but no significant impact on survival could be shown. [Copyright &y& Elsevier]

Abstract: Background: Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by a prominent trabecular meshwork and deep intertrabecular recesses, and is thought to be due to an arrest of normal endomyocardial morphogenesis. However, the genes contributing to this process remain poorly understood. 14-3-3ε, encoded by YWHAE, is an adapter protein belonging to the 14-3-3 protein family which plays important roles in neuronal development and is involved in Miller–Dieker syndrome. We recently showed that mice lacking this gene develop LVNC. Therefore, we hypothesized that variants in YWHAE may contribute to the pathophysiology of LVNC in humans. Methods and results: In 77 Japanese patients with LVNC, including the probands of 29 families, mutation analysis of YWHAE by direct DNA sequencing identified 7 novel variants. One of them, c.−458G>T, in the YWHAE promoter, was identified in a familial patient with LVNC and hypoplasia of the corpus callosum. The −458G>T variant is located within a regulatory CCAAT/enhancer binding protein (C/EBP) response element of the YWHAE promoter, and it reduced promoter activity by approximately 50%. Increased binding of an inhibitory C/EBPβ isoform was implicated in decreasing YWHAE promoter activity. Interestingly, we had previously shown that C/EBPβ is a key regulator of YWHAE. Conclusions: These data suggest that the −458G>T YWHAE variant contributes to the abnormal myocardial morphogenesis characteristic of LVNC as well as abnormal brain development, and implicate YWHAE as a novel candidate gene in pediatric cardiomyopathies. [Copyright &y& Elsevier]

Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene and the activin receptor–like kinase 1 (ALK1) gene have been reported in heritable pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH). However, the relation between clinical characteristics and each gene mutation in IPAH and HPAH is still unclear, especially in childhood. The aim of this study was to determine, in a retrospective study, the influence and clinical outcomes of gene mutations in childhood IPAH and HPAH. Fifty-four patients with IPAH or HPAH whose onset of disease was at <16 years of age were included. Functional characteristics, hemodynamic parameters, and clinical outcomes were compared in BMPR2 and ALK1 mutation carriers and noncarriers. Overall 5-year survival for all patients was 76%. Eighteen BMPR2 mutation carriers and 7 ALK1 mutation carriers were detected in the 54 patients with childhood IPAH or HPAH. Five-year survival was lower in BMPR2 mutation carriers than mutation noncarriers (55% vs 90%, hazard ratio 12.54, p = 0.0003). ALK1 mutation carriers also had a tendency to have worse outcome than mutation noncarriers (5-year survival rate 64%, hazard ratio 5.14, p = 0.1205). In conclusion, patients with childhood IPAH or HPAH with BMPR2 mutation have the poorest clinical outcomes. ALK1 mutation carriers tended to have worse outcomes than mutation noncarriers. It is important to consider aggressive treatment for BMPR2 or ALK1 mutation carriers. [ABSTRACT FROM AUTHOR]

The article presents a randomised, open label and blinded-endpoints trial of the efficacy of immunoglobulin with prednisolone to prevent coronary artery abnormalities in severe Kawasaki disease in Japan. A minimisation method was used to randomly assign patients with severe Kawasaki disease to receive intravenous immunoglobulin plus prednisolone or intravenous immunoglobulin alone. Results show that the addition of prednisolone in intravenous immunoglobulin enhances coronary artery outcomes.

Barth syndrome is an X-linked disorder usually diagnosed in infancy. It is characterized by hypotonia, dilated cardiomyopathy, neutropenia, growth retardation, and 3-methylglutaconic aciduria. The syndrome is typically caused by mutations in the TAZ (G4.5) gene, which encodes a novel protein family called the tafazzins. We report the case of two brothers with Barth syndrome and left ventricular noncompaction (LVNC) caused by a splice donor mutation in TAZ. Both had impaired sucking ability at the age of 2 months. The elder brother was diagnosed with LVNC at the age of 4 months; by that time he had developed severe heart failure with metabolic decompensation. He died at 12 months of age due to intractable heart failure despite pharmacological therapy with diuretics, an angiotensin-converting enzyme inhibitor, and a beta-blocker. However, the younger brother, who was diagnosed as having Barth syndrome and LVNC with heart failure at the age of 2 months, received early medical treatment and demonstrated normal echocardiographic findings. Conclusion: The clinical courses of Barth syndrome observed in our cases show the phonotypic variability of this syndrome and suggest that early therapy may be beneficial for maintaining cardiac function. [ABSTRACT FROM AUTHOR]

Abstract: Left ventricular noncompaction (LVNC) is a cardiomyopathy morphologically characterized by 2-layered myocardium, numerous prominent trabeculations, and deep intertrabecular recesses communicating with the left ventricular cavity. The purpose of this study was to investigate patients with LVNC for possible disease causing mutations. We screened 4 genes (TAZ, LDB3, DTNA and TPM1) in 51 patients with LVNC for mutations by polymerase chain reaction and direct DNA sequencing. A novel missense substitution in exon 1 of TPM1 (c.109A>G: p.Lys37Glu) was identified in three affected members of a family with isolated LVNC. The substitution brings about a change in amino acid charge at a highly conserved residue and could result in aberrant mRNA splicing. This variant was not identified in 200 normal control samples. Pathologic analysis of a right ventricular myocardial specimen from the proband''s maternal aunt revealed endocardial and subendocardial fibrosis with prominent elastin deposition, as well as the presence of adipose tissue between muscle layers, pathologic changes that are distinct from those seen in patients with HCM or DCM. Screening of the proband and her mother for variants in other sarcomeric protein-encoding candidate genes, MYH7, MYBPC3, TNNT2, TNNI3, ACTC, MYL2, and MYL3, did not identify any other non-synonymous variants or variants in splice donor–acceptor sequences that were potentially disease causing. We conclude TPM1 is a potential candidate disease-causing gene for isolated LVNC, especially in patients experiencing sudden death. [Copyright &y& Elsevier]

Abstract: TAZ (G4.5) was initially identified as the gene associated with Barth syndrome and left ventricular noncompaction (LVNC). The purpose of this study was to investigate patients with LVNC for disease-causing mutations in TAZ. In 124 Japanese patients, including 50 families, mutation analysis of TAZ was performed using DNA sequencing. A splice donor mutation was identified in two brothers with Barth syndrome and LVNC, and a sister who was asymptomatic. However, the variant was not identified in either parent or the maternal grandparents, all of whom were asymptomatic. Due to the recurrent inheritance of this variant by each of the children we concluded that this was evidence of gonadal mosaicism in the obligate carrier mother, the first reported occurrence of this in Barth syndrome. [Copyright &y& Elsevier]

Severe motor and intellectual disabilities (SMID) syndrome is a heterogeneous group of disorders with severe physical disabilities and mental retardation. Higher incidence of sudden death is also known in these patients. However, little is known about the cardiovascular features of patients with SMID. We examine the patients with severe motor and intellectual disabilities using echocardiogram and clarify their characterization of ventricular function. We performed electrocardiographic and echocardiographic analyses in SMID patients. In all patients, two-dimensional echocardiography with tissue Doppler analysis in the pulsed Doppler mode was performed. Of 121 patients, 104 patients had abnormal findings: 81 had poor R-wave progression, and 15 patients had low-voltage QRS on ECG. These findings strongly correlated with the degree of physical disability. However, on echocardiography, most patients had LVEF in the normal range, while LV Tei indices were significantly higher (0.43 vs 0.31 cm/s) and left ventricular end-diastolic dimension significantly smaller than healthy controls ( P < 0.05 for each comparison). Patients had significantly decreased early diastolic tissue Doppler velocities at the lateral mitral (5.3 vs 6.7 cm/s), tricuspid (6.7 vs 9.2 cm/s), and septal (5.9 vs 8.8 cm/s) annuli compared with controls ( P < 0.05 for each comparison). We show for the first time that SMID patients have low E/Ea ratios on tissue Doppler imaging while LV contractions are normal, suggesting the existence of latent diastolic dysfunction. This may be one of the reasons why the incidence of sudden death is higher in SMID patients. [ABSTRACT FROM AUTHOR]

Abstract: Left ventricular noncompaction (LVNC) is a genetically heterogenous disorder. Mutations in the human cardiac sodium channel alpha-subunit gene (SCN5A) are involved in the pathophysiology of cardiac arrhythmias and cardiomyopathies. This study was performed to compare the frequency of SCN5A variants in LVNC patients with or without arrhythmias, and to investigate the relationship between variants and disease severity. DNA was isolated from the peripheral blood of 62 Japanese probands with LVNC, comprising 17 familial cases and 45 sporadic cases. Blood samples were screened for variants in SCN5A using single-strand conformational polymorphism analysis (SSCP) and DNA sequencing. Seven variants, rs6599230:G>A, c.453C>T, c.1141-3C>A, rs1805124:A>G (p.H558R), rs1805125:C>T (p.P1090L), c.3996C>T, and rs1805126:T>C were identified in 7 familial and 12 sporadic cases. The frequency of SCN5A variants was significantly higher in the patients with arrhythmias than those without (50% vs 7%: P =0.0003), suggesting these variants represent a risk factor for arrhythmia and supporting the hypothesis that genes encoding ion channels are involved in LVNC pathophysiology. The LVNC patients with heart failure also had high occurence of SCN5A variants, suggesting the presence of SCN5A variants and/or arrhythmias increase the severity of LVNC. [Copyright &y& Elsevier]

Background: The purpose of the present study was to establish the normal values of flow propagation velocity (FPV) in healthy children and examine the variables that affect FPV in clinical situations. Methods: Two hundred and thirty- five healthy children and adolescents were assessed (aged 0–22.6 years, mean age 7.4 ± 5.4 years; male, n = 142; female, n = 93). FPV was obtained from an apical four-chamber view and determined as the slope of aliasing velocity of early diastolic transmitral flow on the color M-mode using Aloka SSD-5500 with 5.0 MHz transducer. Aliasing velocity was set at 50–70% of the peak transmitral flow velocity. Peak transmitral flow velocities in early diastole (E) and during atrial contraction (A), and the ratio of early to late peak velocity (E/A) were obtained. Tei index was also measured for analysis of general left ventricular performance. Left ventricular mass index (LVMI) was obtained from conventional echo measurement. E, E/A, Tei index and LVMI were compared with FPV in healthy subjects. Results: FPV obtained from all subjects ranged from 23.7 to 96.0 cm/s (61.3 ± 13.6 cm/s). Normal value of FPV was less dependent on age, body size, heart rate and left ventricular dimension. In contrast, although there was no significant correlation between FPV and ejection fraction, statistically significant correlation was found between FPV, LVMI ( P = 0.0008) and Tei index ( P = 0.025). Conclusions: FPV is independent of age, body size and heart rate and is useful to assess left ventricular relaxation in children. [ABSTRACT FROM AUTHOR]