TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

Outcome of patients with functional single ventricular heart after pacemaker implantation: What makes it poor, and what can we do?

BACKGROUND: Pacemaker implantation in patients with single ventricle is associated with poor outcomes. OBJECTIVE: The purpose of this study was to determine the reasons for the poor outcomes of pacemaker implantation. METHODS: We performed a retrospective chart review of patients with single ventricle who had undergone permanent pacemaker implantation. Patients were categorized into 3 groups based on the site of pacing and the proportion of ventricular pacing (VP) as follows: (1) atrial pacing group with atrial pacing only (n = 11); (2) low VP group with low daily VP proportion (<50%; n = 12); and (3) high VP group with high daily VP proportion (≥50%; n = 15). Pacing leads were placed at the epicardium in all patients. RESULTS: No patients in the atrial pacing or low VP groups died, whereas the survival rate in the high VP group was 58.9% and 39.3% at 10 and 20 years, respectively, after pacemaker implantation. Among the post-Fontan patients, plasma brain natriuretic peptide (BNP) levels significantly increased with the proportion of VP: 11.7, 20.3, and 28.4 pg/mL in the atrial pacing, low VP, and high VP groups, respectively (P = 0.04). In the high VP group, the plasma BNP level was significantly lower in patients with an apical pacing lead than in those with a nonapical pacing lead (27.0 pg/mL vs 82.8 pg/mL, respectively; P = .03). CONCLUSION: A higher proportion of VP was associated with poor outcome and higher plasma BNP levels, probably due to ventricular dyssynchrony. In epicardial ventricular pacing, apical pacing is better to avoid the increase in ventricular stress and plasma BNP level.

Autonomic Function and QT Interval During Night-Time Sleep in Infant Long QT Syndrome.

BACKGROUND: Sudden infant death syndrome mainly occurs during night-time sleep. Approximately 10% of cases are thought to involve infants with long QT syndrome (LQTS). Autonomic function and QT interval in night-time sleep in early infancy in LQTS infants, however, remain controversial.Methods and Results:Holter electrocardiography was performed in 11 LQTS infants before medication in early infancy, and in 11 age-matched control infants. Control infants were re-evaluated in late infancy. The power spectral density was calculated and parasympathetic activity and sympathovagal balance were obtained. Electrocardiograms of a representative hour during night-time sleep, daytime sleep, and daytime activity, were chosen and QT/RR intervals were manually measured. LQTS infants had significantly lower parasympathetic activity and higher sympathovagal balance during night-time sleep than control infants in early infancy. These autonomic conditions in early infancy were significantly depressed compared with late infancy. Corrected QT interval (QTc) during night-time sleep (490±20 ms) was significantly longer than that in daytime sleep (477±21 ms, P=0.04) or daytime activity (458±18 ms, P=0.003) in LQTS infants, and significantly longer than that during night-time sleep in controls. CONCLUSIONS: A combination of the longest QTc and autonomic imbalance during night-time sleep in early infancy may be responsible for development of life-threatening arrhythmia in LQTS infants. Critical cases should be included in future studies.

Cardiac Ventricular Contractile Responses to Chronically Increased Afterload Secondary to Right Ventricular Outflow Obstruction in Patients With Tetralogy of Fallot.

We examined the adaptive mechanism of the pulmonary ventricle (PV) in response to increased afterload secondary to pulmonary stenosis in tetralogy of Fallot (TOF, n = 47) and congenitally corrected transposition of the great arteries (cCTGA, n = 18), where the PV is morphologically different. We also elucidated the effects of such adaptation on systemic ventricular (SV) function. PV contractility, assessed by dp/dtmax, showed significant positive correlations with PV pressure (r = 0.82, p <0.01 for TOF and r = 0.78, p <0.01 for cCTGA) and pulmonary-to-systemic ventricular pressure ratio (r = 0.70, p <0.01 for TOF and r = 0.76, p <0.01 for cCTGA) in patients with both TOF and cCTGA. Notably, the slopes of these correlations were significantly higher in cCTGA than in TOF (p <0.01), suggesting enhanced contractile responses in cCTGA. Moreover, SV dp/dtmax showed significant positive correlations with PV dp/dtmax in patients with both TOF and cCTGA (r = 0.67, p <0.01 and r = 0.61, p <0.01, respectively), indicating positive ventricular-ventricular interaction. In this relationship, the slopes of correlations were significantly higher in TOF than in cCTGA (p = 0.024). These results, indicating different behaviors of PV contractile physiology and its interaction with the SV, may have important therapeutic implications when considering medical, catheter, and surgical interventions for pulmonary stenosis in these diseases. The results may also offer the potential for a new approach for improvement of prognosis, especially in cCTGA.

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

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

Study design for control of HEART rate in inFant and child tachyarrhythmia with heart failure Using Landiolol (HEARTFUL): A prospective, multicenter, uncontrolled clinical trial.

BACKGROUND: Persistent tachycardia in pediatric patients after congenital heart surgery further deteriorates their hemodynamic condition, and may become fatal. Therefore, immediate control of the tachycardia is mandatory in these patients. For this purpose, quick-acting, short-acting, titratable intravenous agents are required. However, there are no agents with such characteristics among the drugs approved for control of pediatric arrhythmias in Japan, and thus novel and effective medications for these patients are awaited. Landiolol, an ultrashort-acting ß-blocker, was approved in 2013 for tachyarrhythmias in adult patients with heart failure. However, its efficacy and safety in pediatric patients remain unclear. The aim of this prospective, multicenter, open-label phase IIb/III study is to investigate the efficacy and safety of landiolol in pediatric patients with tachyarrhythmias as well as heart failure. METHODS: Eligible patients are aged ≥ 3 months and <15 years, and have tachyarrhythmia (atrial fibrillation, atrial flutter, supraventricular tachycardia) as well as heart failure. The primary endpoint of the study is ≥20% reduction from baseline heart rate or return to normal sinus rhythm within 2h after starting intravenous administration of landiolol. Patients will receive intravenous infusion of landiolol, starting at 1µg/kg/min. The dose will be increased by 1µg/kg/min every 15-20min until the tachycardia rate has decreased by >20% or tachycardia has terminated, and the dose will then be maintained or further increased depending on the patient's condition. The study was started in April 2015 and will end within a few years. CONCLUSIONS: The study was designed and designated the "HEARTFUL study" in the hope of establishing a basis for control of HEART rate in inFant and child tachyarrhythmia Using Landiolol in children with heart failure.

Environmental risk factors for sudden infant death syndrome in Japan.

While the prevalence of sudden infant death syndrome (SIDS) has decreased worldwide, this decline has plateaued recently. Strategies are needed to resume the constant decrease of SIDS in Japan. A prospective electrocardiographic screening program for infants was performed between July 2010 and March 2011. Parents of 4319 infants were asked about environmental factors related to SIDS through questionnaires at a one-month medical checkup and one year. Parental awareness of prone position, smoke exposure, and breast feeding as environmental factors were 81.4 %, 69.0 %, and 47.8 %, respectively. The prevalence of laying infants exclusively in a supine position was 96.7 %. At the one-month medical checkup, smoking prevalence was 41.7 % in fathers and 2.1 % in mothers. Maternal smoking prevalence was significantly increased at one year after (p < 0.001). Multivariate regression analysis showed that risk factors for new or continued maternal smoking habits were maternal smoking habits at one month (p < 0.001), paternal smoking habits one year later (p < 0.001), and younger maternal age (p = 0.02). CONCLUSION: Most parents already avoid laying infants in the prone position, and parental smoking is still a SIDS risk concern in Japan. Smoking cessation programs should be further implemented for parents to decrease risks of SIDS in Japan. What is Known: • The prevalence of sudden infant death syndrome (SIDS) has decreased worldwide, however, this decline has plateaued recently. What is New: • Most infants were laid sleeping in the supine position (96.7 %) and were fed breast milk or a mix of expressed milk and formula (92.7 %), and 2.1 % of mothers smoked at the one-month medical checkup. • Maternal smoking prevalence significantly increased from the one-month medical checkup to one year later, and smoking mothers were more likely to feed infants by formula rather than breast milk. • Independent risk factors for new or continued maternal smoking habits included younger maternal age, maternal smoking habits at one month, and paternal smoking habits one year later.

Favorable Effects of Oxygen Inhalation in Patients After Bidirectional Glenn Procedure as Assessed by Cardiovascular Magnetic Resonance Flow Measurement.

BACKGROUND: Home oxygen therapy (HOT) is used to adapt patients to the bidirectional Glenn (BDG) physiology. However, the precise cardiovascular effect of oxygen inhalation is still unknown. We used phase-contrast MRI to evaluate the cardiovascular effects of oxygen inhalation in young patients with BDG physiology. METHODS AND RESULTS: The 56 sessions of cardiac MRI were performed in 36 patients with BDG circulation. Oxygen saturation (SpO2) and heart rate (HR) were monitored under both room air and nasal 100% oxygen inhalation, and the blood flow volumes of the ascending aorta (AA), superior vena cava (SVC), and inferior vena cava (IVC) were measured by phase-contrast MRI. Systemic-to-pulmonary collateral flow (SPCF) volumes were calculated by subtracting the sum of flow volumes through the SVC and IVC from the flow volume through the AA, and used for further comparative examination. Under nasal oxygen inhalation, SpO2significantly increased from 82% to 89%, while HR decreased from 115 to 110 beats/min. AA (5.0 vs. 4.9 L·min(-1)·m(-2)), SVC (1.85 vs. 1.77 L·min(-1)·m(-2)), and systemic blood flow volume (=SVC+IVC) significantly decreased (3.60 vs. 3.46 L·min(-1)·m(-2)). In contrast, SPCF and the pulmonary-to-systemic blood flow ratio (Qp/Qs) remained unchanged. CONCLUSIONS: Oxygen inhalation improved arterial blood oxygenation and lowered HR in patients with BDG circulation without an increase in Qp/Qs. HOT would be protective of the cardiovascular system in patients with BDG circulation. (Circ J 2016; 80: 1378-1385).

Results of extracardiac conduit total cavopulmonary connection in 500 patients.

OBJECTIVES: This single-institution study aimed to evaluate the early to mid-term outcomes of extracardiac conduit total cavopulmonary connection (EC-TCPC). METHODS: Between March 1994 and March 2014, 500 patients (median age, 3.4 years) underwent EC-TCPC at our hospital. One hundred and twenty-three patients (24.6%) showed heterotaxy, and fenestration was created in 6 patients (1.2%). The standard institutional treatment policy included postoperative anticoagulation and individualized cardiovascular medication. The mortality and morbidity rates, haemodynamic status, cardiopulmonary exercise capacity and liver examination results during the follow-up period (median, 6.7 years) were retrospectively reviewed. RESULTS: There were 2 early and 17 late deaths. The Kaplan-Meier estimated survival rate was 96.2% at 10 years and 92.8% at 15 years. Bradyarrhythmia and tachyarrhythmia occurred in 19 and 13 patients, respectively. Other late-occurring morbidities included protein-losing enteropathy in 8, thromboembolism in 5, bleeding complications in 6 and liver cirrhosis in 1 patient. The rate of freedom from late-occurring morbidities was 82.1% at 15 years. In the multivariate analysis, heterotaxy was found to be a predictor for mortality (P = 0.02), whereas age at operation was a predictor for new-onset arrhythmias (P = 0.048). In the cardiopulmonary exercise test (n = 312), the peak VO2 was 84.9 ± 17.3% of the predicted value, which tended to decrease with age (R(2) = 0.32) and elapsed time since operation (R(2) = 0.21). Postoperative cardiac catheterization (n = 468; time from surgery, 3.6 ± 4.3 years) showed central venous pressure of 9.9 ± 2.4 mmHg, ventricular end-diastolic pressure of 5.2 ± 3.3 mmHg, cardiac index of 3.4 ± 0.8 l/min/m(2) and arterial oxygen saturation of 94.2 ± 4.8%. In 101 patients who were followed up for ≥10 years, amino-terminal type III procollagen peptide and collagen type IV levels exceeded the normal ranges in 52.9 and 75.2% of patients, respectively, and liver ultrasonography revealed hyper-echoic spots in 43.3% of patients. CONCLUSIONS: The early to mid-term outcomes of post-EC-TCPC patients managed with individualized pharmacotherapy were excellent, with low mortality and morbidity rates; however, development of late-occurring morbidities specific to Fontan physiology, including exercise intolerance and liver disease, must be carefully monitored during the long-term follow-up.

Current trends in use of implantable cardioverter defibrillators and cardiac resynchronization therapy with a pacemaker or defibrillator in Japanese pediatric patients: results from a nationwide questionnaire survey.

BACKGROUND: In Japan, the use of implantable cardioverter defibrillators (ICDs), cardiac resynchronization therapy with a biventricular pacemaker (CRTP) and CRT with a defibrillator (CRTD) in children has not been studied statistically, and dual-chamber (DDD) pacemakers are still used for pediatric CRT because of current government regulations. METHODS AND RESULTS: Data were obtained from 15 children's and 74 general hospitals through a questionnaire survey regarding the aforementioned therapies performed before 2012 in Japanese children (<16 years old). ICD, CRT with DDD, CRTP and CRTD were used in 64 (42%), 47 (31%), 34 (22%) and 7 (5%), respectively, of all cases reported (n=152). Among all CRTP and CRT-DDD cases (n=81), the use of DDD accounted for 41% in general hospitals vs. 89% in children's hospitals, and CRT-DDD and CRTP were effective in 67 cases (83%). Of 64 ICD cases, appropriate shocks were experienced in 28 cases (44%), and inappropriate shocks in 19 cases (29%). Additionally, data from the Japan Arrhythmia Device Industry Association obtained for overall device usage analysis revealed that CRTP was more commonly used in children than in adults. CONCLUSIONS: There is an increasing need for pediatric device therapy, especially CRTP. However, many children's hospitals were still using DDD pacemakers in 2012. Although the demand for device therapy in children may be small, it is indispensable in pediatric cardiology.

Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction.

AIMS: Ryanodine receptor gene (RYR2) mutations are well known to cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, RYR2 exon 3 deletion has been identified in patients with dilated cardiomyopathy (DCM) and/or CPVT. This study aimed to screen for the RYR2 exon 3 deletion in CPVT probands, characterize its clinical pathology, and confirm the genomic rearrangement. METHODS AND RESULTS: Our cohort consisted of 24 CPVT probands. Polymerase chain reaction (PCR)-based conventional genetic analysis did not identify any mutations in coding exons of RYR2 in these probands. They were screened using multiplex ligation-dependent probe amplification (MLPA). In probands identified with RYR2 exon 3 deletion, the precise location of the deletion was identified by quantitative PCR and direct sequencing methods. We identified two CPVT probands from unrelated families who harboured a large deletion including exon 3. The probands were 9- and 17-year-old girls. Both probands had a history of syncope related to emotional stress or exercise, exhibited bradycardia, and were diagnosed with left ventricular non-compaction (LVNC). We examined 10 family members and identified six more RYR2 exon 3 deletion carriers. In total, there were eight carriers, of which seven were diagnosed with LVNC (87.5%). Two carriers under the age of 4 years remained asymptomatic, although they were diagnosed with LVNC. Using quantitative PCR and direct sequencing, we confirmed that the deletions were 1.1 and 37.7 kb in length. CONCLUSION: RYR2 exon 3 deletion is frequently associated with LVNC. Therefore, detection of the deletion offers a new modality for predicting the prognosis of patients with LVNC with ventricular/atrial arrhythmias, particularly in children.

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

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

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

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

Electrocardiographic screening of 1-month-old infants for identifying prolonged QT intervals.

BACKGROUND: Neonatal electrocardiographic screening is used to screen infants with prolonged QT intervals, as previously shown in whites. However, this procedure needs to be confirmed in other ethnic groups. METHODS AND RESULTS: In 8 areas in Japan, an ECG was recorded in 4285 infants at 1-month medical checkup. A prospective study showed that a provisional criterion of QTc≥470 ms was appropriate for infants. To assess the validity of the criterion, all infants with a QTc between 460 and 470 ms were followed up. Five infants had a QTc≥470 ms. Four infants were diagnosed with prolonged QT intervals from follow-up ECGs. Four infants showed no symptoms and did not have a family history of long-QT syndrome. Two infants showed progressive prolongation of QT intervals, and medication was started. Genetic testing was performed in 3 of 4 infants with prolonged QT intervals, and it revealed a KCNH2 mutation (3065 delT, L1021fs+34X) in 1 infant. One infant with a QTc≥470 ms and 2 infants with a QTc between 460 and 470 ms showed a decline in their QTc values during follow-up. The study screened another infant with Wolff-Parkinson-White syndrome who was diagnosed with noncompaction before symptoms appeared. CONCLUSIONS: Neonatal electrocardiographic screening can identify infants likely to be affected by long-QT syndrome in the Japanese population, as already shown in whites. This screening may also be useful in identifying other important cardiac diseases.

Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan.

BACKGROUND: The genetic background of catecholaminergic polymorphic ventricular tachycardia (CPVT) has been extensively investigated for the last decade in Western countries, but it remains unstudied in the Asian population. METHODS AND RESULTS: In 50 Japanese probands from unrelated families who satisfied clinical criteria for CPVT, genetic testing was conducted in all exons on 3 CPVT-related genes: cardiac ryanodine receptor 2 (RYR2), calsequestrin 2 (CASQ2) and inward rectifier potassium channel 2 (KCNJ2), and the clinical features between RYR2-genotyped and -non-genotyped patient groups were compared. Genetic and clinical evaluation was also done in 46 family members. In the genetic screening, 28 (18 novel) RYR2 (56.0%), 1 compound heterozygous CASQ2 (2.0%) and 1 KCNJ2 (2.0%) mutation carriers were identified. In the RYR2 mutation-positive group, the frequency of bidirectional ventricular tachycardia and the use of ß-blockers were significantly higher than in the mutation-negative group. In contrast, there was no significant difference in supraventricular arrhythmias between the 2 groups. With regard to disease penetrance, the number of family members of RYR2-genotyped probands with a clinical diagnosis of CPVT was high. CONCLUSIONS: Thirty gene mutation carriers were found for 3 genes in 50 probands clinically diagnosed as having CPVT. The penetrance of CPVT phenotype was significantly higher in RYR2 mutation carriers, thus RYR2 gene screening in CPVT patients would be indispensable to prevent unexpected cardiac sudden death of young family members.

Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan.

BACKGROUND: Data on the clinical presentation and genotype-phenotype correlation of patients with congenital long-QT syndrome (LQTS) diagnosed at perinatal through infantile period are limited. A nationwide survey was conducted to characterize how LQTS detected during those periods is different from that in childhood or adolescence. METHODS AND RESULTS: Using questionnaires, 58 cases were registered from 33 institutions. Diagnosis (or suspicion) of LQTS was made during fetal life (n=18), the neonatal period (n=31, 18 of them at 0 to 2 days of life), and beyond the neonatal period (n=9). Clinical presentation of LQTS included sinus bradycardia (n=37), ventricular tachycardia/torsades de pointes (n=27), atrioventricular block (n=23), family history of LQTS (n=21), sudden cardiac death/aborted cardiac arrest (n=14), convulsion (n=5), syncope (n=5), and others. Genetic testing was available in 41 (71%) cases, and the genotype was confirmed in 29 (71%) cases, consisting of LQT1 (n=11), LQT2 (n=11), LQT3 (n=6), and LQT8 (n=1). Ventricular tachycardia/torsades de pointes and atrioventricular block were almost exclusively observed in patients with LQT2, LQT3, and LQT8, as well as in those with no known mutation. In LQT1 patients, clues to diagnosis were mostly sinus bradycardia or family history of LQTS. Sudden cardiac death/aborted cardiac arrest (n=14) was noted in 4 cases with no known mutations as well as in 4 genotyped cases, although the remaining 6 did not undergo genotyping. Their subsequent clinical course after aborted cardiac arrest was favorable with administration of beta-blockers and mexiletine and with pacemaker implantation/implantable cardioverter-defibrillator. CONCLUSIONS: Patients with LQTS who showed life-threatening arrhythmias at perinatal periods were mostly those with LQT2, LQT3, or no known mutations. Independent of the genotype, aggressive intervention resulted in effective suppression of arrhythmias, with only 7 deaths recorded.