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Vascular Ehlers-Danlos syndrome (vEDS) is a hereditary connective tissue disorder (HCTD) characterized by arterial dissection/aneurysm/rupture, sigmoid colon rupture, or uterine rupture. Diagnosis is confirmed by detecting heterozygous variants in COL3A1. This is the largest Asian case series and the first to apply an amplification-based next-generation sequencing through custom panels of causative genes for HCTDs, including a specific method of evaluating copy number variations. Among 429 patients with suspected HCTDs analyzed, 101 were suspected to have vEDS, and 33 of them (32.4%) were found to have COL3A1 variants. Two patients with a clinical diagnosis of Loeys-Dietz syndrome and/or familial thoracic aortic aneurysm and dissection were also found to have COL3A1 variants. Twenty cases (57.1%) had missense variants leading to glycine (Gly) substitutions in the triple helical domain, one (2.9%) had a missense variant leading to non-Gly substitution in this domain, eight (22.9%) had splice site alterations, three (8.6%) had nonsense variants, two (5.7%) had in-frame deletions, and one (2.9%) had a multi-exon deletion, including two deceased patients analyzed with formalin-fixed and paraffin-embedded samples. This is a clinically useful system to detect a wide spectrum of variants from various types of samples.

Biplane Area-Length (AL) method by left ventriculography (LVG) has been widely adopted as a standard method to estimate left ventricular volume. However, we have experienced difficulties in adopting the value by AL method for the children with Tetralogy of Fallot (TOF) due to the discrepancy among volumetric modalities. This study validated some limitations of AL method, considering the basic principles of its formulation. A single center retrospective cohort study was conducted for 1 year. The confirmed 22 cases with repaired TOF at our hospital were enrolled. The clinical characteristics, some cardiac MRI analyses, and all the cardiac catheterization studies were collected. Angiographic data were compared with historic cohorts of Kawasaki disease without any coronary artery lesions by using AL method. Cardiac MRI analyses of ten TOF patients were additionally available. LVG studies showed that the length of the long axis on anteroposterior view (AP) was not equal to that on lateral view (LT) due to anatomically apical elevation in TOF, followed by a significant difference found in the sagittal lengths of the LV long axis between AP and LT (P = 0.003). Because the difference critically affected the formula depending on biplane AL method, the calculated LVEDV of TOF group appeared overestimated, compared with the control group (TOF vs control group: 119.5% ± 6.3% vs 96.4 ± 3.5% of Normal, P = 0.006). Available cardiac MRI analyses of some patients in TOF group revealed 55% increase of LVEDV by AL method (angiocardiography 116 ± 7.0 vs CMR 75 ± 3.7 ml/m

Respiratory syncytial virus (RSV) is a common pathogen that causes extremely severe respiratory symptoms in the first few weeks and months of life. In infants with cardiopulmonary diseases, RSV infections have a significant clinical impact. Palivizumab, a humanised monoclonal antibody for RSV, has been shown to significantly reduce the rate of hospitalisation of high-risk infants diagnosed with RSV. However, we have experienced a significant number of RSV infections in our institution that required hospitalisation or intensive care, despite the administration of palivizumab. This study aimed to analyse the risk factors associated with severe RSV despite the use of palivizumab. We retrospectively reviewed the medical records of 688 patients who visited or were admitted to our hospital and received palivizumab. Thirty-seven (5.4%) patients required hospitalisation for RSV, despite receiving palivizumab. In addition, 31 of these patients (83.8%) required hospitalisation out of season for palivizumab injection. Preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia (BPD), and trisomy 21 were risk factors for RSV-related hospitalisation in infected patients, despite receiving palivizumab. Furthermore, subgroup analysis of 69 patients with RSV revealed that hemodynamically significant congenital heart disease (CHD) was also a risk factor for RSV-related hospitalisation. Conclusion: Preterm birth (≤ 28 weeks of gestation), BPD, trisomy 21, hemodynamically significant CHD, and CHD requiring surgery or cardiac catheterisation/intervention during infancy could be considered when determining whether year-round administration of palivizumab is appropriate.

Atrial tachyarrhythmias (ATAs), which may occur after tetralogy of Fallot (TOF) surgery, can cause sudden cardiac death. However, ATAs may also develop in response to electrical substrates. This study aims to examine the predictive factors for ATAs by identifying electrical substrates in the atrium obtained from 12-lead electrocardiogram in patients who underwent TOF repair. A total of 144 patients aged15 years (median, 31.6 years) who underwent TOF repair at Hokkaido University were enrolled. We investigated the correlation between the development of ATAs with age, time interval after initial corrective surgery, brain natriuretic peptide levels, cardiac magnetic resonance parameters (right ventricular end-diastolic volume index, right ventricular end-systolic volume index, right ventricular ejection fraction, right atrial volume index, left ventricular end-diastolic volume index, left ventricular ejection fraction), and 12-lead electrocardiogram parameters (P wave maximum voltage, PR interval, QRS width, number of fragmented QRS). Of the 144 patients, 44 patients (30.6%) developed ATAs. Multivariate analysis revealed time interval after initial corrective surgery (odds ratio 6.7, 95% confidence interval 1.78 to 12.6) and PR interval (odds ratio 2.7, 95% confidence interval: 1.17 to 4.20) as independent risk factors for the development of ATAs. The receiver operating characteristic curve revealed a PR interval cut-off value of200 milliseconds as predictive of the development of ATAs in patients more than 15 years after initial corrective surgery (area under the curve, 0.658; sensitivity, 71.4%; specificity, 66.4%). The present study demonstrated that a prolonged PR interval is a simple and convenient predictor for the development of ATAs in patients who underwent TOF repair.

Background. Total anomalous pulmonary venous connection (TAPVC) is a critical congenital heart disease for which emergency surgery is required after birth. In cases of no intervention, TAPVC is associated with a high mortality rate in the first year of life. Although foetal echocardiographic techniques for diagnosing TAPVC have improved, TAPVC remains one of the most difficult congenital heart diseases to diagnose via foetal echocardiography. Here, we report a case of TAPVC with pulmonary venous obstruction (PVO), which was diagnosed via foetal echocardiography. Case Presentation. On foetal echocardiography at 32 weeks’ gestation, a large atrial septal defect, enlarged superior vena cava, and continuous flow pattern in the vertical vein from the common chamber were observed in the foetus. Paediatric cardiologists and cardiac surgeons, neonatologists, and obstetricians planned to perform a caesarean section and emergency heart surgery. The male infant was born at 37 weeks’ gestation via caesarean section, and postnatal echocardiography revealed PVO at the confluence of the superior vena cava and common chamber. Similarly, chest computed tomography confirmed the foetal diagnosis. The postnatal diagnoses were TAPVC type Ib, PVO, atrial septal defect, and patent ductus arteriosus. Surgical repair of the TAPVC was initiated within the first 3 hours of life. Screening brain echocardiography and head computed tomography revealed intracranial haemorrhage and hydrocephalus. Therefore, the patient underwent emergency bilateral external drainage on day 13. On day 48, a ventriculoperitoneal shunt was inserted owing to progressive brain ventricular dilatation. The patient was discharged home on postoperative day 68. Conclusions. Although the prognosis of TAPVC with PVO remains poor, continuous observation through foetal echocardiography and early interdepartmental collaboration can result in good outcomes.

Childhood hypertrophic cardiomyopathy; Outcomes; Phenotype Miocardiopatía hipertrófica infantil; Resultados; Fenotipo Miocardiopatia hipertròfica infantil; Resultats; Fenotip Background Up to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. Objectives The aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. Methods Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. Results At baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. Conclusions Early-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages. This work was supported by the British Heart Foundation (grant FS/16/72/32270) to Drs Norrish and Kaski. This work is (partly) funded by the National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre. Dr Norrish is supported by Great Ormond Street Hospital Children’s Charity. Drs Field and Kaski are supported by Max’s Foundation and Great Ormond Street Hospital Children’s Charity. Dr Kaski is supported by a Medical Research Council–National Institute for Health Research Clinical Academic Research Partnership award. This work was financially supported by the Foundation for Paediatric Research of Finland (Dr Ojala). Dr Fernandez has received speaker fees from Sanofi-Genzyme. Dr Kubus is supported by MH CZ – DRO, Motol University Hospital (00064203). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aims Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. Methods and results A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81). Conclusions This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

AimsMitochondrial cardiomyopathy (MCM) is difficult to make a definite diagnosis because of various cardiovascular phenotypes and no diagnostic criteria in the pathology examination. We aim to add myocardial pathology to the diagnostic criteria for mitochondrial respiratory chain disorders.MethodsQuantitative analysis of mitochondria using electron microscopy and immunohistopathological analysis with respiratory chain enzyme antibodies were performed in 11 patients with hypertrophic or restrictive cardiomyopathy who underwent endomyocardial biopsy for possible MCM . Respiratory chain enzymatic assay in biopsied myocardium and genetic studies were also performed in all the subjects to define MCM.ResultsFour patients were diagnosed with MCM according to the recent criteria of mitochondrial respiratory chain disorders. Using electron microscopy with quantitative analysis, the volume density of mitochondria within cardiac muscle cells was significantly increased in the MCM group compared with the non-MCM group (p=0.007). Immunohistopathological results were compatible with the result of the respiratory chain enzymatic assay.ConclusionsPathological diagnosis of MCM could be confirmed by a quantitative study of electron microscopy and immunohistopathological analysis using the mitochondrial respiratory chain enzyme subunit antibody.

Background: Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort. Methods: The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1–16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids). Results: MLVWT Z score was Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3–9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk. Conclusions: In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Background We report a rare case of left ventricular inflow obstruction from a branch of the left circumflex coronary artery to the right atrium caused by a coronary arteriovenous fistula (CAVF) in a young Japanese male child. Case presentation The patient was diagnosed with CAVF following a heart murmur shortly after birth. The left-to-right shunt caused right ventricular volume overload and pulmonary congestion. An emergency surgical intervention was performed for the CAVF on day 6 after birth. However, by 5 years of age, his left ventricular inflow obstruction worsened. We found an abnormal blood vessel originating from the proximal part of a branch of the left circumflex coronary artery, circling the outside of the mitral valve annulus along the medial side of the coronary sinus. As the child gets older, the blood inflow into the left ventricle might get restricted further, resulting in left-sided heart failure. Conclusion Our findings suggest that even after CAVF closure surgery, it is essential to monitor for complications caused by progressive dilatation of a persistent CAVF.

Recent reports suggested that cardiopulmonary bypass (CPB) time is one of the risk factors for postoperative complications after Fontan conversion. Although Fontan conversion may be performed for the patients with hepatic fibrosis after initial Fontan procedure, there is no predictive indicator regarding the liver function associated with hemostasis which can affects CPB time. Thirty-one patients who underwent Fontan conversion using the same surgical procedure (extracardiac conduit conversion with right atrium exclusion) were enrolled. In multivariate analyses including age at Fontan conversion, interval from initial Fontan to conversion, hemodynamic data such as right atrial pressure, ventricular end-diastolic pressure, and cardiac index, hepatic data such as platelet count, prothrombin time international normalized ratios, serum total bilirubin, hyaluronic acid levels, five known indices for hepatic fibrosis (Forns Index, APRI, FIB4, FibroIndex, and MELD-XI), and liver stiffness measured by ultrasound elastography, only the Forns Index remained independently associated with the CPB time (P 0.01) and blood transfusions (plasma transfusions and platelet concentrations: P 0.01 for both). The cutoff level for Forns Index to predict the prolonged CPB time (exceeding 240 min) was 4.85 by receiver-operating characteristic curve (area under the curve 0.823, sensitivity 76.9%, and specificity 72.2%). Three patients with Forns Index 7.0 had poor outcomes with long CPB time and massive blood transfusions in contrast with the other 28 patients. In conclusion, Forns Index could serve as a practical predictor of CPB time and is associated with blood transfusion volume in Fontan conversion.

Respiratory syncytial virus (RSV) is a common pathogen that causes extremely severe respiratory symptoms in the first few weeks and months of life. In infants with cardiopulmonary diseases, RSV infections have a significant clinical impact. Palivizumab, a humanised monoclonal antibody for RSV, has been shown to significantly reduce the rate of hospitalisation of high-risk infants diagnosed with RSV. However, we have experienced a significant number of RSV infections in our institution that required hospitalisation or intensive care, despite the administration of palivizumab. This study aimed to analyse the risk factors associated with severe RSV despite the use of palivizumab. We retrospectively reviewed the medical records of 688 patients who visited or were admitted to our hospital and received palivizumab. Thirty-seven (5.4%) patients required hospitalisation for RSV, despite receiving palivizumab. In addition, 31 of these patients (83.8%) required hospitalisation out of season for palivizumab injection. Preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia (BPD), and trisomy 21 were risk factors for RSV-related hospitalisation in infected patients, despite receiving palivizumab. Furthermore, subgroup analysis of 69 patients with RSV revealed that hemodynamically significant congenital heart disease (CHD) was also a risk factor for RSV-related hospitalisation.Conclusion: Preterm birth (≤ 28 weeks of gestation), BPD, trisomy 21, hemodynamically significant CHD, and CHD requiring surgery or cardiac catheterisation/intervention during infancy could be considered when determining whether year-round administration of palivizumab is appropriate. What is Known: • Respiratory syncytial virus causes severe respiratory symptoms in infants, particularly those with cardiopulmonary diseases. • The use of palivizumab has reduced the rate of hospitalisation of infants diagnosed with RSV. Despite this, the rate of hospitalisation is still high. What is New: • We identified that preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia, trisomy 21, and hemodynamically significant congenital heart disease were risk factors for RSV-related hospitalisation, even after receiving palivizumab treatment. • High-risk infants should be closely monitored and the prolonged use of palivizumab should be considered.

Restrictive cardiomyopathy (RCM) is a rare cardiomyopathy in children, and its prognosis until now, has been poor. Recently some sarcomeric mutations have been reported as disease-causing genes of RCM. However, the genotype-phenotype correlation is not fully understood. Additionally, prognostic factors including sudden death in patients with RCM have not been elucidated. We report our experience in treating twin sisters with RCM or hypertrophic cardiomyopathy with RCM phenotype, both carriers of the same mutation in TNNI3, which encodes one of the major sarcomeric proteins in myofibrils. They were both diagnosed with RCM by cardiac catheterization at the age of 11 years. Despite appropriate follow-up and medical treatment, one died suddenly at the age of 11 years and the other also died at the age of 15 years due to heart failure while awaiting heart transplantation. In addition to our cases, other reports of younger fatal cases with RCM carrying TNNI3 mutations may suggest it as one of the prognostic factors. Genetic diagnosis is important in the clinical diagnosis, management, and treatment of cardiomyopathy.

A case of hypertrophic cardiomyopathy in the transition from childhood to adulthood, which was low risk by the conventional risk assessment model, medium risk by the adult risk prediction model, and high risk by the paediatric risk prediction model, was inserted an implantable cardioverter-defibrillator. Three years post-implantation, the patient was resuscitated with an appropriate discharge of cardioverter-defibrillator.

Mitochondrial cardiomyopathy (MCM) is usually recognized as one of the phenotypes of systemic mitochondrial disease. However if there are no cardiac symptoms, it is difficult to make a definite diagnosis because of various cardiovascular phenotypes and no diagnostic criteria in pathological examination. To add myocardial pathology to the diagnostic criteria for mitochondrial respiratory chain disorders, which is the gold standard in the diagnosis of mitochondrial diseases, we performed quantitative analysis of mitochondria using electron microscopy and immunohistopathologic analysis with respiratory chain enzyme antibodies. Ten patients with hypertrophic or restrictive cardiomyopathy who had undergone endomyocardial biopsy were studied. Respiratory chain enzymatic assay and genetic study were performed and four patients were diagnosed with MCM. Using electron microscopy with quantitative analysis, volume density of mitochondria within cardiac muscle cells was significantly increased in the MCM group compared to the non-MCM group (p=0.013). Immunohistopathologic results were compatible with the result of the respiratory chain enzymatic assay. These advanced pathological tests can distinguish MCM from other cardiomyopathies. Results of immunopathologic study Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development, AMED.

We described a 15-year-old boy who underwent the catheter ablation for the nodoventricular (NV) tachycardia that had difficulty in differentiation from atrioventricular nodal reentrant tachycardia with upper common pathway. The modification of the fast pathway revealed an anterograde conduction of the NV fiber. We successfully performed the catheter ablation targeting for the right ventricular insertion site of the NV fiber.

We described a 15-year-old boy who underwent the catheter ablation for the nodoventricular tachycardia that had difficulty in differentiation from atrioventricular nodal reentrant tachycardia with upper common pathway. The slow pathway ablation revealed an anterograde conduction of nodoventricular fiber. We successfully performed the catheter ablation targeting for the right ventricular insertion site of the nodoventricular fiber.

Congenital heart disease-associated pulmonary arterial hypertension (CHD-PAH) is one of the major complications in patients with CHD. A timely closure of the left-to-right shunt will generally result in the normalization of the pulmonary hemodynamics, but a few patients have severe prognosis in their early childhood. We hypothesized that wide-ranging pathological mechanism in PAH could elucidate the clinical state of severe CHD-PAH. Using electronic medical records, we retrospectively analyzed six infants with severe CHD-PAH who had treatment-resistant PH. All patients were born with congenital malformation syndrome. After starting on a pulmonary vasodilator, five of the six patients developed complications including pulmonary edema and interstitial lung disease (ILD), and four patients had alveolar hemorrhage. After steroid therapy, the clinical condition improved in four patients, but two patients died. The autopsy findings in one of the deceased patients indicated the presence of recurrent alveolar hemorrhage, pulmonary venous hypertension, ILD, and PAH. Based on the clinical course of these CHD-PAH in patients and the literature, CHD-PAH can occur with pulmonary vascular obstructive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH), ILD, and/or alveolar hemorrhage. The severity of CHD-PAH may depend on a genetic disorder, respiratory infection, and upper airway stenosis. Additionally, pulmonary vasodilators may be involved in the development of PVOD/PCH and ILD. When patients with CHD-PAH show unexpected deterioration, clinicians should consider complications associated with PVOD/PCH and/or pulmonary disease. In addition, the choice of upfront combination therapy for pediatric patients with CHD-PAH should be selected carefully.

An interventricular septal hematoma is a rare complication after patch closure of a ventricular septal defect (VSD). We describe three cases of interventricular septal hematomas following patch VSD and discuss their management.

Elevated right atrial (RA) pressure and progressive RA dilation are thought to play pivotal roles in the development of late complications after atriopulmonary connection (APC) Fontan surgery. However, no clear cut-off value for RA pressure or RA volume has been determined for stratifying the risk of developing Fontan complications. We hypothesized that RA tension, which incorporates information about both RA pressure and volume, might help predict the risk of developing complications. We retrospectively studied 51 consecutive APC Fontan patients (median postoperative period 14 years). RA tension was computed from the RA pressure and RA radius, which was calculated from RA volume measured by RA angiography. The correlation between the cardiac catheterization hemodynamic data and the complications of APC Fontan was investigated. Of the 51 patients, 28 had complications, including liver fibrosis (n = 28), arrhythmia (n = 8), protein-losing enteropathy (n = 1), and RA thrombosis (n = 1). Among the hemodynamic data, RA volume and RA tension, but not RA pressure, were significantly higher in patients with complications than in those without (P = 0.004 and P = 0.001, respectively). The cut-off level for RA tension to predict Fontan complications was 26,131 dyne/cm by receiver operating characteristic curve (area under the curve 0.79, sensitivity 71.4%, and specificity 73.9%). The present study demonstrated the significance of RA tension rather than high venous pressure for the development of Fontan complications. Amid the uncertainty about clinical outcomes, the present results, subject to further validation, may contribute to the indications for Fontan conversion.

Although some studies have attempted to find useful prognostic factors in hypertrophic cardiomyopathy (HCM), those results are not fully helpful for use in actual clinical practice. Furthermore, several genetic abnormalities associated with HCM have been identified. However, the genotype-phenotype correlation in HCM remains to be elucidated. Here, we attempted to assess patients with different types of gene mutations causing HCM and investigate the prognosis. A total of 140 patients with HCM underwent a screening test for myofilament gene mutations by direct sequencing of eight sarcomeric genes. Patients with a single mutation in cardiac troponin T, cardiac troponin I, α-tropomyosin, and regulatory and essential light chains were excluded from the study because the number of cases was too small. The clinical presentations and outcomes of the remaining 127 patients with HCM, 31 β-myosin heavy chain (MYH7) mutation carriers, 19 cardiac myosin-binding protein C (MYBPC3) mutation carriers, and 77 mutation non-carriers were analyzed retrospectively. MYBPC3 mutation carriers had a high frequency of ventricular arrhythmia and syncope. Kaplan-Meier curves revealed no significant difference in prognosis among the three groups, but a lack of family history of sudden death (SD) and a past history of syncope were significantly related to poor prognosis. An absence of family history of SD and past history of syncope are useful prognostic factors in patients with HCM. MYH7 and MYBPC3 mutations did not significantly influence prognosis compared to non-carriers. However, patients with the MYBPC3 mutation should be closely followed for the possibility of SD.

Long QT syndrome (LQTS) can cause syncope, ventricular fibrillation, and death. Recently, several disease-causing mutations in ion channel genes have been identified, and compound mutations have also been detected. It is unclear whether children who are carriers of compound mutations exhibit a more severe phenotype than those with single mutations. Although predicting phenotypic severity is clinically important, the availability of prediction tools for LQTS is unknown. To determine whether the severity of the LQTS phenotype can be predicted by the presence of compound mutations in children is needed. We detected 97 single mutations (Group S) and 13 compound mutations (Group C) between 1998 and 2012, age at diagnosis ranging 0-19 years old (median age is 9.0) and 18.0 years of follow-up period. The phenotypes and Kaplan-Meier event-free rates of the two groups were compared for cardiac events. This study investigated phenotypic severity in relation to the location of mutations in the protein sequence, which was analyzed using two sequence homology-based tools. In results, compound mutations in children were associated with a high incidence of syncope within the first decade (Group S: 32 % vs. Group C: 61 %), requiring an ICD in the second decade (Group S: 3 % vs. Group C: 56 %). Mortality in these patients was high within 5 years of birth (23 %). Phenotypic prediction tools correctly predicted the phenotypic severity in both Groups S and C, especially by using their coupling method. The coupling prediction method is useful in the initial evaluation of phenotypes both with single and compound mutations of LQTS patients. However, it should be noted that the compound mutation makes more severe phenotype.

Childhood obstructive sleep apnoea syndrome (OSAS) secondary to adenoid hyperplasia is known to give rise to pulmonary hypertension. However, we present a case of a toddler with pulmonary hypertension (PH) and right heart failure due to OSAS, the cause of which is difficult to identify. After the patient underwent an adenotonsillectomy, OSAS disappeared and the PH eventually resolved. Both paediatricians and otolaryngologists should know that paediatric OSAS can occur even in the setting of mild, clinically insignificant palatine tonsil hypertrophy and adenoid hyperplasia. Surgical intervention should be considered without losing the opportunity if it could be the cause of PH.

This study examined the progression of left ventricular dysfunction and myocardial fibrosis in patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) to evaluate the effects of angiotensin-converting enzyme inhibitor (ACEI). Ninety-eight cardiovascular magnetic resonance (CMR) studies in 34 consecutive patients with DMD (n = 21) or BMD (n = 13) were retrospectively reviewed. Left ventricular ejection fraction (LVEF) and the extent of myocardial late gadolinium enhancement (LGE) were semiautomatically quantified. During the study period, five patients had already been treated with ACEI at the first CMR; five were started on ACEI at LVEF ≥ 55% and 10 at LVEF

Pathological left ventricular hypertrophy (LVH) with myocardial fibrosis is an independent risk factor for cardiovascular mortality. Previous studies indicated that patients with coarctation of the aorta (CoA) have increased left ventricular mass (LVM) including LVH, even after successful CoA repair. It is unclear whether the increased LVM is pathological one with cardiac fibrosis. Group A consisted of 17 patients with successfully repaired CoA. Group B consisted of 17 postoperative subjects who matched the age and postoperative periods of group A. Group C comprised 28 subjects for the geometric standard of the left ventricle. The LVM index (LVMI) and the relative wall thickness (RWT) of group A and B were compared with the values of 17 age-matched subjects from group C. The serum concentration of procollagen type III amino-terminal peptide (P-III-P), a biomarker for myocardial fibrosis, in group A was compared with the concentration in group B. The correlations between the serum P-III-P concentration and LVMI and RWT were studied in group A and non-A group. In group A, RWT and LVMI were significantly higher than those in group C (0.37 ± 0.05 vs. 0.31 ± 0.02, p

Despite the apparently successful surgical repair of aortic coarctation, subsequent cardiovascular complications have sometimes been encountered. Aortic pressure wave reflection is one of the risk factors for developing cardiovascular diseases, and an enhancement of the pressure wave reflection has been reported in patients after aortic arch repair. To clarify this issue, the increase in pressure wave reflection was evaluated in patients

Barth syndrome (BTHS) is an X-linked disorder characterized by skeletal myopathy, neutropenia, growth delay, and cardiomyopathy. It is caused by mutations in the tafazzin gene (TAZ). Although early diagnosis is critical to prevent the progression of heart failure, this disease remains unrecognized when heart failure is not clinically significant. Here we report on a 13-year-old boy with no family history of BTHS who was diagnosed with the syndrome in the subclinical stage of heart failure. The clues to the diagnosis of BTHS in this patient were the findings of lipid storage myopathy in the skeletal muscle biopsy, elevated plasma brain natriuretic peptide, and the diagnosis of isolated noncompaction of the ventricular myocardium in echocardiography. Genetic studies of TAZ revealed a disease-causing mutation (p.Gly216Arg) in this patient. Physicians should be aware of the possibility of this disease and carry out genetic studies when it is considered.

Aortic pressure wave reflection is one of the risk factors for developing cardiovascular disease in adults, and the degree of pressure wave reflection increases with aging. However, enhanced pressure wave reflection has also been reported in infants and children. The purpose of this study was to clarify pressure wave reflection during childhood and to determine the reference for the augmentation index, which is one of the most useful parameters used to represent the degree of aortic pressure wave reflection in children. This study enrolled 72 patients with normal aortic circulation. The aortic pressure waveform was recorded using a pressure sensor-mounted catheter, and the augmentation index was thus calculated. The augmentation index tended to decrease with increasing age until around 15 years of age and then increased thereafter. For children below 15 years of age, multiple regression analysis revealed a significant negative correlation between body height and augmentation index. In children, increases in aortic pressure wave reflection are probably attributable to changes in body height.

Background Tolvaptan, a vasopressin V2-receptor antagonist, has been reported to improve congestion in adult patients with heart failure. However, it has not been fully clarified whether tolvaptan is also effective and safe for pediatric patients as well as adult. Methods This trial was a multicenter, retrospective, observational study, and was led by the Japanese Society of PEdiatric Circulation and Hemodynamics (J-SPECH). Thirty-four pediatric patients who received tolvaptan to treat congestive heart failure were enrolled in this study. Results An increment in the urinary volume and decrease in the body weight from baseline were significant at day 1 (+106.7±241.5%, p=0.008 and −2.30±4.17%, p=0.01), day 3 (+113.5±261.9%, p=0.02 and −2.30±4.17%, p=0.01), week 1 (+56.3±163.5%, p=0.01 and −1.55±4.09%, p=0.03) and month 1 (+91.1±171.6%, p=0.01 and −2.95±5.98, p=0.03). The significant predictive factors in responders, who was defined as patients who achieved an increase in the urinary volume at day 1, were older age (p=0.03), larger body weight before exacerbation (p=0.04), higher weight at one day before the first administration of tolvaptan (p=0.03), higher aspartate aminotransferase levels (p=0.03) and higher urinary osmolality levels (p=0.03). A logistic regression analysis showed that the urinary osmolality was the only significant predictive factor for responders to tolvaptan. Adverse drug reactions were observed in 7 patients (20.6%). Six patients had thirst and a dry month, and 1 had a mild increase in the alanine aminotransferase and aspartate aminotransferase. Conclusion Tolvaptan can be effectively and safely administered in pediatric patients. Because the kidneys in neonates and infants are resistant to arginine vasopressin, the efficacy of tolvaptan may be less effective compared to older children.

Sirs: The incidence of hypertrophic cardiomyopathy (HCM) is 0.2 %, and this condition is considered the most common genetic cardiovascular disease. In addition, HCM is one of the most common causes of sudden cardiac death (SCD) in young people [1]. An implantable cardioverter defibrillator (ICD) is a highly effective device for inhibiting ventricular tachyarrhythmias. It is generally agreed that the indications for an ICD strongly support the secondary prevention of SCD [2]. However, the indications for primary preventive ICD placement for SCD remain controversial. Recently, it has been shown that late gadolinium enhancement magnetic resonance imaging (LGE-MRI) can be used to evaluate myocardial fibrosis as an arrhythmic substrate [3, 4]. Here, we report a familial case of HCM in which we decided to place an ICD as primary prevention for SCD based on the LGE-MRI findings. The cases described are two brothers whose father and grandmother were diagnosed with HCM, and the elder brother of the father had a sudden death. Gene analysis was carried out in the father and the two brothers described here. An Ala63Val mutation in exon 2 of TPM1 gene, which encodes alpha tropomyosin, was found (Fig. 1a). The eldest brother in our two cases was 18 years old. He was diagnosed with HCM following medical screening at age 13. The interventricular septum diameter (IVSd) on echocardiography was 18.2 mm (Z-score was 8.5), which is far from the SCD risk criteria (over 30 mm) at age 18. LGE-MRI demonstrated diffuse contrast enhancement in the left ventricular myocardium. The extent of LGE was 8 % of the LV mass using previously reported methods [1] (Fig. 1b). The patient had been managed with mild limitation of physical activity. At the age of 18, he had syncope due to ventricular tachycardia (Fig. 1c) and was successfully resuscitated without any complications. Then, an ICD was implanted for secondary prevention of SCD. The youngest brother of the above-mentioned case was also diagnosed with HCM following medical screening at age 6. He has been managed by mild mobility limitation and treated by beta-blockers because a left ventricular outflow tract obstruction was detected by echocardiography. Though the extent of myocardial fibrosis using LGE-MRI was only 1 % of the LV mass at age 10, it markedly progressed to 16 % in 2 years (Fig. 1d). In addition, LGEMRI demonstrated a diffuse pattern of enhancement, similar to that observed in the elder brother. Because the presence of LGE was seen more strongly in the younger brother than in the elder brother, the younger brother was scheduled for the placement of a prophylactic ICD. The selection of patients for the primary prevention of SCD with an ICD has been predicated on the assessment of well-known five key risk factors, which were reported previously [2]. Recently, ACCF/AHA guidelines indicated primary prevention with the ICD a class IIa indication, based on the presence of one or more conventional key risk factors [5]. However, it is difficult to determine whether our case represents a form of primary prevention of SCD with an ICD because it was unclear whether the cause of sudden death in a family member was related to hypertrophic cardiomyopathy. In addition, there was no case of sudden death in a first-degree relative [2]. Recently, myocardial fibrosis detected by LGE-MRI was reported as a candidate for a new risk factor that may be able to predict SCD. Green et al. [6] mentioned that H. Yamazawa (&) A. Takeda K. Takei T. Furukawa Department of Pediatrics, Hokkaido University School of Medicine, North 15 West 7, Kitaku, Sapporo, Hokkaido 060-8638, Japan e-mail: h-yamazawa@umin.org

UNLABELLED Barth syndrome (OMIM #302060) (BTHS) is an X-linked disorder of lipid metabolism characterized by skeletal myopathy, neutropenia, growth delay, and cardiomyopathy. It is caused by mutations in the tafazzin gene (TAZ), which lead to decreased production of an enzyme required to produce cardiolipin, a component of the inner mitochondrial membrane necessary for proper functioning of the electron transport chain. The most common initial presentation of BTHS is significant heart failure due to cardiomyopathy, which is the main cause of death in infancy or childhood. On the other hand, some patients have limited clinical features of BTHS. These patients may be overlooked or misdiagnosed with unclassified congenital myopathy, especially when heart failure is not clinically significant. However, these patients could also develop significant heart failure or life-threatening arrhythmias during or even after childhood. Heart failure in BTHS is often responsive to standard medical therapy, indicating early diagnosis is critical. Diagnostic clues of BTHS in the subclinical stage of heart failure include family histories, findings of lipid storage myopathy in the skeletal muscle biopsy, and elevated plasma brain natriuretic peptide levels. The genetic analysis of TAZ is the only confirmatory method for the diagnosis of BTHS. CONCLUSION physicians should be aware of the possibility of this disease and carry out genetic studies when it is considered.

Patients after surgical repair of tetralogy of Fallot (TOF) may experience various complications that result in neurohormonal activation, including plasma B-type natriuretic peptide (BNP) elevation. Right ventricular (RV) dilation is a frequent complication, and few treatments are available. This study aimed to identify the factor or factors leading to BNP elevation and to clarify the effects of angiotensin-converting enzyme inhibitor (ACE-I) on changes in BNP levels in patients with repaired TOF. Plasma BNP levels and hemodynamic data derived from cardiac catheterization were analyzed. In addition, longitudinal BNP levels and ACE-I dosages were analyzed for patients administered ACE-I. For 31 patients with repaired TOF, who mainly had RV dilation, log BNP levels were significantly correlated with the RV end-diastolic volume index (P = 0.02) as well as ventricular volume and pressure (P < 0.01). For 11 patients medicated with ACE-I, BNP levels were significantly lower at the time of maximal ACE-I dosage than at the time of minimal dosage (P < 0.01). Furthermore, BNP levels decreased as the ACE-I dosage per body weight increased (P < 0.01). In conclusion, elevation of BNP in patients after TOF repair could reflect volume and pressure load in the RV end-diastolic phase, and ACE-I may reduce BNP levels in a dose-dependent manner.

The Doppler echocardiography derived peak instantaneous systolic pressure gradient (peak instantaneous Doppler PG), the mean PG (mean Doppler PG) and the aortic valvular area are the accepted standard for determining the prognosis and optimal timing of intervention because of good agreement between Doppler-derived and catheter-measured PGs in adult patients with aortic valvular stenosis. However, several investigators reported that pressure recovery can cause discrepancies between Doppler-derived and catheter-measured PGs, so that the correction for pressure recovery has been proposed. In pediatric patients with aortic valvular stenosis, the discrepancy between Doppler-derived and catheter-measured PGs and the correction for pressure recovery have not been studied well. Therefore, the purpose of current study was to clarify the role of echocardiography for estimating the prognosis and optimal timing of intervention and to assess the influence of pressure recovery on the Doppler-derived PG in pediatric patients with aortic valvular stenosis. Thirteen pediatric patients with aortic valvular stenosis were studied with echocardiography and cardiac catheterization. PG determined by the catheterization was compared with PG determined by the echocardiography with linear regression and Bland and Altman analysis. As result, Doppler-derived PGs corrected for pressure recovery did not correlated well with catheter-measured PGs. By contrast, Doppler-derived PGs correlated well with catheter-measured PGs. In particular, the mean Doppler PG correlated excellently with the mean catheter PG. In conclusion, the mean Doppler PG demonstrated an excellent correlation with the mean catheter PG without the correction for pressure recovery. Thus, the mean Doppler PG is useful in order to determine the prognosis and optimal timing of intervention in pediatric patients with aortic valvular stenosis.

Objectives We sought to provide a new method for quantifying collateral aortopulmonary flow in patients subsequent to construction of a bidirectional cavopulmonary shunt, and to clarify the clinical advantages of the new method. Methods We performed lung perfusion scintigraphy and cardiac catheterization in 10 patients subsequent to construction of a bidirectional cavopulmonary shunt. First, the ratio of collateral to systemic flow was determined by whole-body images of lung perfusion scintigraphy, dividing the total lung count by the total body count minus the total lung count. Second, we integrated lung perfusion scintigraphy and cardiac catheterization data using a formula derived from the Fick principle, taking the ratio of pulmonary to systemic flow to be 1 plus the ratio calculated above and multiplied by the systemic saturation minus the inferior caval venous saturation divided by the pulmonary venous saturation minus the inferior caval venous saturation. Finally, the amount of collateral flow was obtained from the ratio of pulmonary to systemic flow. We evaluated the impact of collateral flow on the calculation of pulmonary vascular resistance. Results The median age at bidirectional cavopulmonary shunt was 1.41 years, and the median age at catheterization was 2.33 years. The mean amount of collateral flow was 1.75 +/- 0.46 litres/min/m(2). The pulmonary vascular resistance calculated without considering the collateral flow was overestimated by an average of 57 +/- 23%, compared to the resistance calculated with our new method. Conclusions The use of scintigraphy combined with catheterization allows accurate determination of aortopulmonary collateral flow, and avoids overestimation of pulmonary vascular resistance in these candidates for the Fontan circulation.

Several modifications to the original Fontan procedure have been proposed in order to decrease postoperative morbidity. Lateral tunnel and extracardiac total cavo-pulmonary connection are 2 such modifications.Between August 2005 and December 2005, the extracardiac lateral tunnel procedure was performed in 5 patients. The age at operation ranged from 19 to 59 months (median 24 months) and the weight ranged from 9.2 to 16.1 kg (median 11.4 kg).There was no mortality. The mean operation time was 466 +/-118 minutes. The mean cardiopulmonary bypass time was 198 +/- 61 minutes. The mean durations of intubation, intensive care unit stay, drainage tube use, and hospital stay were 1 +/- 1, 7 +/- 3, 12 +/- 5 and 30 +/- 2 days, respectively. Postoperative catheterization findings demonstrated that the mean superior venous caval pressure, inferior venous caval pressure, ventricular volume and ventricular ejection fraction were 10.0 +/- 1.4 mmHg, 11.0 +/- 2.4 mmHg, 140 +/- 47% of normal and 58.0 +/- 6.8% , respectively.The short-term results of the extracardiac lateral tunnel compared favorably with the results of different types of Fontan operation. In addition this procedure has the potential for growth and anticoagulation therapy is unnecessary.