Whole genome sequencing in paediatric channelopathy and cardiomyopathy.

Background: Precision medicine in paediatric cardiac channelopathy and cardiomyopathy has a rapid advancement over the past years. Compared to conventional gene panel and exome-based testing, whole genome sequencing (WGS) offers additional coverage at the promoter, intronic regions and the mitochondrial genome. However, the data on use of WGS to evaluate the genetic cause of these cardiovascular conditions in children and adolescents are limited. Methods: In a tertiary paediatric cardiology center, we recruited all patients diagnosed with cardiac channelopathy and cardiomyopathy between the ages of 0 and 18 years old, who had negative genetic findings with prior gene panel or exome-based testing. After genetic counselling, blood samples were collected from the subjects and both their parents for WGS analysis. Results: A total of 31 patients (11 cardiac channelopathy and 20 cardiomyopathy) were recruited. Four intronic splice-site variants were identified in three cardiomyopathy patients, which were not identified in previous whole exome sequencing. These included a pathogenic variant in TAFAZZIN:c.284+5G>A (Barth syndrome), a variant of unknown significance (VUS) in MYBPC3:c.1224-80G>A and 2 compound heterozygous LP variants in LZTR1 (LZTR1:c.1943-256C>T and LZTR1:c1261-3C>G) in a patient with clinical features of RASopathy. There was an additional diagnostic yield of 1.94% using WGS for identification of intronic variants, on top of conventional gene testing. Conclusion: WGS plays a role in identifying additional intronic splice-site variants in paediatric patients with isolated cardiomyopathy. With the demonstrated low extra yield of WGS albeit its ability to provide potential clinically important information, WGS should be considered in selected paediatric cases of cardiac channelopathy and cardiomyopathy in a cost-effective manner.

Prioritize Variant Reclassification in Pediatric Long QT Syndrome-Time to Revisit.

Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome associated with sudden cardiac death. Accurate interpretation and classification of genetic variants in LQTS patients are crucial for effective management. All patients with LQTS with a positive genetic test over the past 18 years (2002-2020) in our single tertiary pediatric cardiac center were identified. Reevaluation of the reported variants in LQTS genes was conducted using the American College of Genetics and Genomics (ACMG) guideline after refinement by the US ClinGen SVI working group and guideline by Walsh et al. on genetic variant reclassification, under multidisciplinary input. Among the 59 variants identified. 18 variants (30.5%) were reclassified. A significant larger portion of variants of unknown significance (VUS) were reclassified compared to likely pathogenic (LP)/pathogenic (P) variants (57.7% vs 9.1%, p < 0.001). The rate of reclassification was significantly higher in the limited/disputed evidence group compared to the definite/moderate evidence group (p = 0.0006). All LP/P variants were downgraded in the limited/disputed evidence group (p = 0.0057). VUS upgrades are associated with VUS located in genes within the definite/moderate evidence group (p = 0.0403) and with VUS present in patients exhibiting higher corrected QT intervals (QTc) (p = 0.0445). A significant number of pediatric LQTS variants were reclassified, particularly for VUS. The strength of the gene-disease association of the genes influences the reclassification performance. The study provides important insights and guidance for pediatricians to seek for reclassification of "outdated variants" in order to facilitate contemporary precision medicine.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there are limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic patients with CPVT with and without ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with ICD (31.1%) and 162 without ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in the no ICD group and in those not on optimal medical therapy. Patients with ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

Flecainide Is Associated With a Lower Incidence of Arrhythmic Events in a Large Cohort of Patients With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: In severely affected patients with catecholaminergic polymorphic ventricular tachycardia, beta-blockers are often insufficiently protective. The purpose of this study was to evaluate whether flecainide is associated with a lower incidence of arrhythmic events (AEs) when added to beta-blockers in a large cohort of patients with catecholaminergic polymorphic ventricular tachycardia. METHODS: From 2 international registries, this multicenter case cross-over study included patients with a clinical or genetic diagnosis of catecholaminergic polymorphic ventricular tachycardia in whom flecainide was added to beta-blocker therapy. The study period was defined as the period in which background therapy (ie, beta-blocker type [beta1-selective or nonselective]), left cardiac sympathetic denervation, and implantable cardioverter defibrillator treatment status, remained unchanged within individual patients and was divided into pre-flecainide and on-flecainide periods. The primary end point was AEs, defined as sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter defibrillator shock, and arrhythmic syncope. The association of flecainide with AE rates was assessed using a generalized linear mixed model assuming negative binomial distribution and random effects for patients. RESULTS: A total of 247 patients (123 [50%] females; median age at start of flecainide, 18 years [interquartile range, 14-29]; median flecainide dose, 2.2 mg/kg per day [interquartile range, 1.7-3.1]) were included. At baseline, all patients used a beta-blocker, 70 (28%) had an implantable cardioverter defibrillator, and 21 (9%) had a left cardiac sympathetic denervation. During a median pre-flecainide follow-up of 2.1 years (interquartile range, 0.4-7.2), 41 patients (17%) experienced 58 AEs (annual event rate, 5.6%). During a median on-flecainide follow-up of 2.9 years (interquartile range, 1.0-6.0), 23 patients (9%) experienced 38 AEs (annual event rate, 4.0%). There were significantly fewer AEs after initiation of flecainide (incidence rate ratio, 0.55 [95% CI, 0.38-0.83]; P=0.007). Among patients who were symptomatic before diagnosis or during the pre-flecainide period (n=167), flecainide was associated with significantly fewer AEs (incidence rate ratio, 0.49 [95% CI, 0.31-0.77]; P=0.002). Among patients with ≥1 AE on beta-blocker therapy (n=41), adding flecainide was also associated with significantly fewer AEs (incidence rate ratio, 0.25 [95% CI, 0.14-0.45]; P<0.001). CONCLUSIONS: For patients with catecholaminergic polymorphic ventricular tachycardia, adding flecainide to beta-blocker therapy was associated with a lower incidence of AEs in the overall cohort, in symptomatic patients, and particularly in patients with breakthrough AEs while on beta-blocker therapy.

Detection of QT interval prolongation using Apple Watch electrocardiogram in children and adolescents with congenital long QT syndrome.

Background: Apple watch-derived electrocardiogram (awECG) may help identify prolongation of corrected QT (QTc) interval. This study aimed to determine its usefulness for assessment of prolongation of QTc interval in children and adolescents with long QT syndrome (LQTS). Methods: Children and adolescents with and without LQTS were recruited for measurement of QTc intervals based on standard 12-lead (sECG) and awECG lead I, II and V5 tracings. Bland-Altman analysis of reproducibility, concordance assessment of T wave morphologies, and receiver operating characteristic (ROC) analysis of sensitivity and specificity of awECG-derived QTc interval for detecting QTc prolongation were performed. Results: Forty-nine patients, 19 with and 30 without LQTS, aged 3-22 years were studied. The intraclass correlation coefficient was 1.00 for both intra- and inter-observer variability in the measurement of QTc interval. The awECG- and sECG-derived QTc intervals correlated strongly in all three leads (r = 0.90-0.93, all p < 0.001). Concordance between awECG and sECG in assessing T wave morphologies was 84% (16/19). For detection of QTc prolongation, awECG lead V5 had the best specificity (94.4% and 87.5%, respectively) and positive predictive value (87.5% and 80.0%, respectively), and for identification of patients with LQTS, awECG leads II and V5 had the greatest specificity (92.3%-94.1%) and positive predictive value (85.7% to 91.7%) in both males and females. Conclusions: Apple Watch leads II and V5 tracings can be used for reproducible and accurate measurement of QTc interval, ascertainment of abnormal T wave morphologies, and detection of prolonged QTc interval in children and adolescents with LQTS.

Impact and Modifiers of Ventricular Pacing in Patients With Single Ventricle Circulation.

BACKGROUND: Palliation of the single ventricle (SV) circulation is associated with a burden of lifelong complications. Previous studies have identified that the need for a permanent ventricular pacing system (PPMv) may be associated with additional adverse long-term outcomes. OBJECTIVES: The goal of this study was to quantify the attributable risk of PPMv in patients with SV, and to identify modifiable risk factors. METHODS: This international study was sponsored by the Pediatric and Congenital Electrophysiology Society. Centers contributed baseline and longitudinal data for functionally SV patients with PPMv. Enrollment was at implantation. Controls were matched 1:1 to PPMv subjects by ventricular morphology and sex, identified within center, and enrolled at matched age. Primary outcome was transplantation or death. RESULTS: In total, 236 PPMv subjects and 213 matched controls were identified (22 centers, 9 countries). Median age at enrollment was 5.3 years (quartiles: 1.5-13.2 years), follow-up 6.9 years (3.4-11.6 years). Median percent ventricular pacing (Vp) was 90.8% (25th-75th percentile: 4.3%-100%) in the PPMv cohort. Across 213 matched pairs, multivariable HR for death/transplant associated with PPMv was 3.8 (95% CI 1.9-7.6; P < 0.001). Within the PPMv population, higher Vp (HR: 1.009 per %; P = 0.009), higher QRS z-score (HR: 1.19; P = 0.009) and nonapical lead position (HR: 2.17; P = 0.042) were all associated with death/transplantation. CONCLUSIONS: PPMv in patients with SV is associated with increased risk of heart transplantation and death, despite controlling for increased associated morbidity of the PPMv cohort. Increased Vp, higher QRS z-score, and nonapical ventricular lead position are all associated with higher risk of adverse outcome and may be modifiable risk factors.

Medical Management of Infants With Supraventricular Tachycardia: Results From a Registry and Review of the Literature.

Background: Several medication choices are available for acute and prophylactic treatment of refractory supraventricular tachycardia (SVT) in infants. There are almost no controlled trials, and medication choices are not necessarily evidence based. Our objective was to report the effectiveness of management strategies for infant SVT. Methods: A registry of infants admitted to hospital with re-entrant SVT and no haemodynamically significant heart disease were prospectively followed at 11 international tertiary care centres. In addition, a systematic review of studies on infant re-entrant SVT in MEDLINE and EMBASE was conducted. Data on demographics, symptoms, acute and maintenance treatments, and outcomes were collected. Results: A total of 2534 infants were included: n = 108 from the registry (median age, 9 days [0-324 days], 70.8% male) and n = 2426 from the literature review (median age, 14 days; 62.3% male). Propranolol was the most prevalent acute (61.4%) and maintenance treatment (53.8%) in the Registry, whereas digoxin was used sparingly (4.0% and 3.8%, respectively). Propranolol and digoxin were used frequently in the literature acutely (31% and 33.2%) and for maintenance (17.8% and 10.1%) (P < 0.001). No differences in acute or prophylactic effectiveness between medications were observed. Recurrence was higher in the Registry (25.0%) vs literature (13.4%) (P < 0.001), and 22 (0.9%) deaths were reported in the literature vs none in the Registry. Conclusion: This was the largest cohort of infants with SVT analysed to date. Digoxin monotherapy use was rare amongst contemporary paediatric cardiologists. There was limited evidence to support one medication over another. Overall, recurrence and mortality rates on antiarrhythmic treatment were low.

Contexte: De nombreux choix de médicaments existent pour le traitement aigu et prophylactique de la tachycardie supraventriculaire (TSV) réfractaire chez les nourrissons. Or, il n'y a presque pas d'essais contrôlés à ce sujet, et les choix de médicaments ne sont pas nécessairement fondés sur des données probantes. Notre objectif était de faire état de l'efficacité des stratégies de prise en charge de la TSV chez les nourrissons. Méthodologie: Un registre des nourrissons admis à l'hôpital pour une TSV par réentrée, sans cardiopathie d'importance hémodynamique, a été tenu de façon prospective dans 11 centres de soins tertiaires à l'échelle mondiale. De plus, une revue systématique des études sur la TSV par réentrée chez le nourrisson a été effectuée dans MEDLINE et EMBASE. Des données sur les caractéristiques démographiques, les symptômes, les traitements aigus et d'entretien, et les résultats ont été recueillis. Résultats: Un total de 2 534 nourrissons ont été inclus : n = 108 du registre (âge médian de 9 jours [0-324 jours], 70,8 % de sexe masculin) et n = 2 426 de la revue de la littérature (âge médian de 14 jours; 62,3 % de sexe masculin). Le propranolol était le traitement de soins aigus (61,4 %) et d'entretien (53,8 %) le plus fréquent dans le registre, alors que la digoxine a été utilisée occasionnellement (respectivement dans 4,0 % et 3,8 % des cas). Dans la littérature, le propranolol et la digoxine étaient fréquemment utilisés en soins aigus (31 % et 33,2 %) et en traitement d'entretien (17,8 % et 10,1 %) (p < 0,001). Aucune différence n'a été observée entre les médicaments au chapitre de l'efficacité du traitement de soins aigus ou du traitement prophylactique. Le taux de récurrence était plus élevé dans le registre (25,0 %) que dans la littérature (13,4 %) (p < 0,001), et 22 (0,9 %) décès ont été signalés dans la littérature, mais aucun dans le registre. Conclusion: Il s'agit de la plus grande cohorte de nourrissons atteints de TSV analysée à ce jour. De nos jours, les cardiologues pédiatriques prescrivent rarement la digoxine en monothérapie. Peu de données probantes favorisent l'utilisation d'un médicament par rapport à l'autre. Dans l'ensemble, les taux de récurrence et de mortalité sous traitement antiarythmique étaient faibles.

Evaluation of age at symptom onset, proband status, and sex as predictors of disease severity in pediatric catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for sudden death, and a risk stratification tool does not exist. OBJECTIVE: The purpose of this study was to determine whether proband status, age at symptom onset, and/or sex are independent predictors of cardiac events. METHODS: A multicenter, ambispective, cohort of pediatric CPVT patients was categorized by sex, proband status, and age at symptom onset (D1: first decade of life [symptom onset <10 years] or D2: second decade of life [symptom onset 10-18 years, inclusive]). Demographics, therapy, genetics, and outcomes were compared between groups. RESULTS: A total of 133 patients were included and stratified into 58 D1 and 75 D2 patients (68 female and 65 male; 106 probands and 27 relatives). Localization of RYR2 variants to hotspots differed based on proband status and age at symptom onset. The cardiac event rate was 33% (n = 44/133), inclusive of a 3% (n = 4/133) mortality rate, over a median of 6 years (interquartile range 3-11) after time of symptom onset. Proband status, rather than age at of symptom onset or sex, was an independent predictor of time to first cardiac event (P = .008; hazard ratio = 4.4). The 5-, 10- and 15-year event-free survival rates for probands were 77%, 56%, and 46%, respectively, and for relatives were 96%, 91%, and 86%, respectively. Event risk after diagnosis was 48% (32/67) in patients on ß-blocker or flecainide alone vs 10% (5/48) in patients on ß-blocker plus flecainide and/or left cardiac sympathetic denervation (P <.001). CONCLUSION: Proband status, but not age at symptom onset or male sex, independently predicted an earlier onset of cardiac events. A larger sample size would enable a comprehensive investigation of other risk factors.

Subcutaneous Implantable Cardioverter-Defibrillators in Pediatrics and Congenital Heart Disease: A Pediatric and Congenital Electrophysiology Society Multicenter Review.

OBJECTIVES: The primary goal of this study was to evaluate the implant experience and midterm results of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in pediatric patients and those with congenital heart disease. BACKGROUND: The S-ICD was developed to avoid the lead-related complications associated with transvenous systems. The absence of intravascular or intracardiac components offers potential advantages to pediatric patients and those with congenital heart disease. METHODS: This international, multicenter, retrospective, standard-of-care study was conducted through the Pediatric & Congenital Electrophysiology Society. Complications at 30 and 360 days, inappropriate shocks, and delivery of appropriate therapy were assessed. RESULTS: The study included 115 patients with a median follow-up of 32 (19 to 52) months. Median age was 16.7 years (14.8 to 19.3 years), 29% were female, and 55% had a primary prevention indication. Underlying disease substrate was cardiomyopathy (40%), structural heart disease (32%), idiopathic ventricular fibrillation (16%), and channelopathy (13%). The complication rate was 7.8% at 30 days and 14.7% at 360 days. Overall, inappropriate shocks occurred in 15.6% of patients, with no single clinical characteristic reaching statistical significance. At implant, 97.9% of patients had successful first shock conversion with 96% requiring ≤65 J. Appropriate therapy was delivered to 11.2% of patients with an annual incidence of 3.9% and an acute first shock conversion success rate of 92.5%. CONCLUSIONS: This study found that in a heterogeneous population of pediatric patients and those with congenital heart disease, the S-ICD had comparable rates of complications, inappropriate shocks, and conversion efficacy compared with previously published studies on transvenous systems in similar populations.

Milrinone Acts as a Vasodilator But Not an Inotrope in Children After Cardiac Surgery-Insights From Wave Intensity Analysis.

OBJECTIVES: Milrinone is an inodilator widely used in the postoperative management of children undergoing cardiac surgery. The literature supporting its inotropic effect is sparse. We sought to study the effect of milrinone on the vasculature and its effects on the ventricular function using wave intensity analysis. We also intended to evaluate the feasibility of using wave intensity analysis by the bedside. DESIGN: prospective single-center observational study. SETTING: PICU of a tertiary children's hospital. PATIENTS: Children (< 18 yr) admitted to PICU following cardiac surgery who required to be commenced on a milrinone infusion. INTERVENTIONS: Echocardiography and Doppler ultrasound assessments for wave intensity analysis were performed prior to commencing milrinone and 4-6 hours after milrinone infusion. MEASUREMENTS AND MAIN RESULTS: Wave intensity analysis was successfully performed and analyzed in 15 of 16 patients (94%). We identified three waves-a forward compression wave, backward compression wave, and forward decompression wave. The waves were described with their cumulative intensity and wave-related pressure change. There was a 26% reduction in backward compression wave cumulative intensity following the introduction of milrinone. Other variables (backward compression wave cumulative intensity/forward compression wave cumulative intensity ratio, backward compression wave wave-related pressure change, backward compression wave wave-related pressure change/forward compression wave wave-related pressure change ratio) consistent with vasodilation also decreased after milrinone. It also decreased the vascular wavespeed by 7.1% and increased the distensibility of the vessels by 14.6%. However, it did not increase forward compression wave cumulative intensity, a variable indicating the systolic force generated by the ventricle. Forward decompression wave cumulative intensity indicating ventricular early diastolic relaxation also did not change. CONCLUSIONS: In a cohort of children recovering in PICU after having undergone cardiac surgery, we found that milrinone acted as a vasodilator but did not demonstrate an improvement in the contractility or an improved relaxation of the left ventricle as assessed by wave intensity analysis. We were able to demonstrate the feasibility and utility of wave intensity analysis to further understand ventriculo-vascular interactions in an intensive care setting.

Missing pouches in high-density mapping of atrial tachyarrhythmia in congenital heart diseases.

BACKGROUND: The use of high-density electroanatomical mapping in the Chinese population for congenital heart disease (CHD) is not well reported. METHODS: Retrospective review of consecutive transcatheter ablation of atrial tachyarrhythmia using high-density mapping for CHD patients (at least moderate complexity) in the only tertiary congenital heart center in the territory from January 2017 to January 2019 was conducted. Orion mapping catheter in Rhythmia system (Boston Scientific) was used to create activation and voltage maps. Parameters including mechanism of arrhythmia, acute success, and follow-up data were recorded. RESULTS: Eight patients were identified (median age 35.5 years) who underwent transcatheter ablation of atrial arrhythmia. More than one reentry circuits of IART were identified in five patients. It took a median of 32.4 minutes with 15,952 (IQR 13,395-18,530) mapping points per map. Cavo-annulus isthmus-dependent mechanism was the predominant reentry mechanism. Acute success with the elimination of all inducible tachycardia was achieved in six patients (75%), and partial success in two patients. There was recurrence of atrial arrhythmia in four patients (50%), in which three patients could be maintained in sinus rhythm with low-dose antiarrhythmic medication. Targeted substrate ablation was performed in six patients with multiple IART circuits. Critical anatomical pouches were identified in three patients, which were missed in the initial mapping using Orion basket mapping catheter. CONCLUSIONS: High acute success rate of atrial arrhythmia ablation can be achieved using high-density anatomical mapping in CHD. Substrate ablation was required with multiple IART circuits identified. Vigilance should be sought to identify anatomical pouches.

The different facets of "culture" in genetic counseling: A situated analysis of genetic counseling in Hong Kong.

In this article, we problematize the concept of "culture" in genetic counseling. With globalization and increased mobility of both genetic professionals and clients, there is an increased acknowledgement of the impact of "culture" on a counseling process. There is, however, little agreement on what "culture" is. The essentialist understanding that has long been dominant in the medical literature views culture as a set of shared beliefs, attitudes and practices among a group of people. Such an approach does not account for the individual differences and the dynamic nature of genetic counseling encounters. Following Zayts and Schnurr (2017), we use the distinction between two orders of culture: culture1 that refers to the static, generalized understanding of culture that is external to the specific context, and culture2 , an analytic concept that denotes dynamic enactments of culture, emerging in the interaction. We use empirical data from genetic counseling sessions to illustrate these different facets of culture and to consider how and why speakers draw on them. The clinical implications of the study include highlighting the importance of cultural awareness among counselors, including cultural self-awareness, and demonstrating how authentic interactional data could be used to enhance cultural training in genetic counseling.

Fifty-Five Years Follow-Up of 111 Adult Survivors After Biventricular Repair of PAIVS and PS.

There is paucity of long-term data on adult survivors after biventricular repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS). This study aimed to determine the cardiac and non-cardiac outcomes of adult survivors after biventricular repair of PAIVS and PS. The cardiac, neurodevelopmental and liver problems of 111 adults, 40 with PAIVS and 71 with PS, were reviewed. The median follow-up duration of our patients was 26.5 years (range 14.8-55 years). The freedom from reintervention at 30 years was 17.4% and 73.3% for PAIVS and PS patients (p < 0.001), respectively. Compared with PS patients, PAIVS patients had significantly greater prevalence of right atrial and right ventricular (RV) dilatation, and moderate to severe tricuspid and pulmonary regurgitation (all p < 0.05), and cardiac arrhythmias (22.5% vs. 8.5%, p = 0.047). The freedom from development of cardiac arrhythmias at 30 years of 68.4% and 91.6%, respectively, in PAIVS and PS patients (p = 0.03). Cox proportional hazards model identified PAIVS as an independent risk factor for reintervention (HR 4.0, 95% CI 2.1-7.6, p < 0.001) and development of arrhythmias (HR 4.1, 95% CI 1.1-14.4, p = 0.03). Neurodevelopmental problems were found in 17.5% of PAIVS patients and 7.0% of PS patients (p = 0.11). Liver problems occurred in 2 (5%) PAIVS patients, both of whom required conversion to 1.5 ventricular repair. In conclusion, long-term problems, including the need for reinterventions, cardiac arrhythmias, RV dilation, pulmonary regurgitation, and neurodevelopmental and liver issues are more prevalent in adult PAIVS than PS survivors.

SCN5A mutations in 442 neonates and children: genotype-phenotype correlation and identification of higher-risk subgroups.

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification. Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE. Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Left ventricular mass of persistent masked hypertension in Hong Kong Chinese adolescents: a 4-year follow-up study.

OBJECTIVE: In our previous study, the prevalence of childhood masked hypertension was 11%. This study aims to assess the left ventricular mass index of persistent masked hypertension and determine the factors of elevated left ventricular mass index in Hong Kong Chinese adolescents from a community cohort. DESIGN: Community prospective cohort study, follow-up of a case-control study in community. SUBJECTS: Patients with masked hypertension at baseline were invited to recheck ambulatory blood pressure for the persistence of masked hypertension. RESULTS: A total of 144 out of 165 patients with masked hypertension in the 2011/2012 ambulatory blood pressure survey consented to participate in the study. In all, 48 patients were found to have persistent masked hypertension by ambulatory blood pressure rechecking and were matched with normotensive controls by sex, age, and body height. The left ventricular mass (117.3±39.9 g versus 87.0±28.2 g versus 102.0±28.2 g) and left ventricular mass index (30.1±8.4 g/m2.7 versus 23.9±6.3 g/m2.7 versus 25.1±5.7 g/m2.7) were significantly higher in the persistent masked hypertension group (p<0.0001) compared with the patients without persistent masked hypertension and controls. In multivariate linear regression analysis, left ventricular mass index was found to be higher in male gender (ß=4.874, p<0.0001) and the patients with persistent masked hypertension (ß=2.796, p=0.003). In addition, left ventricular mass index was positively associated with body mass index z-score (ß=3.045, p<0.0001) and low-density lipoprotein cholesterol concentration (ß=1.634, p=0.015). CONCLUSIONS: Persistent masked hypertension in adolescents is associated with elevated left ventricular mass index.

Ten-year experience in atenolol use and exercise evaluation in children with genetically proven long QT syndrome.

BACKGROUND: Due to its availability, atenolol is the primary beta-blocker used in Australia for children with long QT syndrome. There is limited data on long-term follow-up of its use. METHODS: A single-tertiary-center, retrospective, observational study investigating all children and adolescents who had genetically proven long QT syndrome type 1 (LQT1) and type 2 (LQT2) was conducted. Their pretreatment exercise tests were evaluated for QTc intervals into the recovery phase of exercise. RESULTS: Eighty six patients were identified (LQT1, 67, and LQT2, 19) from 2004 to 2014. The majority (86%) of patients were initially referred for family screening. Atenolol was administered at a mean dose of 1.58 ± 0.51 mg/kg/day. During the median follow-up period of 4.29 years, only one proband developed ventricular arrhythmia whilst taking atenolol, No patient had cardiac arrest or aborted cardiac arrest. With respect to side effects of atenolol, only two patients had intolerable side effects necessitating changes of medication. Evaluation of exercise tests (pretreatment) demonstrated that corrected QT (QTc) intervals at 2-3 min into the recovery phase of exercise were significantly prolonged for LQT1 patients. LQT1 patients with transmembrane mutation had longer QTc intervals than their C-terminus mutation counterparts, reaching statistical significance at 3 min into the recovery phase of exercise. CONCLUSIONS: Atenolol is an effective treatment for genetically proven LQT1 and LQT2 children and adolescents, with good tolerability. In LQT1 patients, QTc intervals at 2-3 min into the recovery phase of exercise were significantly prolonged, particularly in patients with transmembrane mutations.

Ventricular mechanics after repair of subarterial and perimembranous VSDs.

BACKGROUND: Emerging data suggest impaired biventricular function in adults late after repair of ventricular septal defect (VSD). We assessed and compared right (RV) and left ventricular (LV) mechanics in adolescents and adults after surgical closure of doubly committed subarterial and perimembranous VSDs. METHODS: A total of 75 subjects were studied: 29 patients after subarterial VSD repair (group I), 17 patients after perimembranous VSD repair (group II) and 29 age-matched controls (group III). RV and LV mechanics were assessed using tissue Doppler and speckle-tracking echocardiography, while RV outflow systolic function was quantified by systolic excursion and fractional shortening (FS). RESULTS: Compared with group III, groups I and II had significantly reduced tricuspid annular systolic and diastolic velocities, isovolumic myocardial acceleration, RV global longitudinal systolic and diastolic deformation parameters and RV outflow systolic excursion (all P < .05). Group I, but not II, had reduced RV outflow FS (P = .008) and the lowest global LV longitudinal systolic strain (P = .008) and systolic strain rate (P = .014). In group I, postoperative aortic regurgitation was associated with lower LV longitudinal systolic strain (P = .009) and early diastolic strain rate (P = .002), while right bundle branch block was associated with lower RV systolic strain rate (P = .048). As a group, RV outflow excursion (P < .001) and FS (P = .001) were correlated with LV global systolic strain. CONCLUSION: Adolescents and adults late after repair of subarterial and perimembranous VSDs show impairment of RV systolic and diastolic myocardial deformation. The RV outflow function and LV systolic deformation appear to be worse after repair of subarterial defects.