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.

Deep Learning-Augmented ECG Analysis for Screening and Genotype Prediction of Congenital Long QT Syndrome.

Importance: Congenital long QT syndrome (LQTS) is associated with syncope, ventricular arrhythmias, and sudden death. Half of patients with LQTS have a normal or borderline-normal QT interval despite LQTS often being detected by QT prolongation on resting electrocardiography (ECG). Objective: To develop a deep learning-based neural network for identification of LQTS and differentiation of genotypes (LQTS1 and LQTS2) using 12-lead ECG. Design, Setting, and Participants: This diagnostic accuracy study used ECGs from patients with suspected inherited arrhythmia enrolled in the Hearts in Rhythm Organization Registry (HiRO) from August 2012 to December 2021. The internal dataset was derived at 2 sites and an external validation dataset at 4 sites within the HiRO Registry; an additional cross-sectional validation dataset was from the Montreal Heart Institute. The cohort with LQTS included probands and relatives with pathogenic or likely pathogenic variants in KCNQ1 or KCNH2 genes with normal or prolonged corrected QT (QTc) intervals. Exposures: Convolutional neural network (CNN) discrimination between LQTS1, LQTS2, and negative genetic test results. Main Outcomes and Measures: The main outcomes were area under the curve (AUC), F1 scores, and sensitivity for detecting LQTS and differentiating genotypes using a CNN method compared with QTc-based detection. Results: A total of 4521 ECGs from 990 patients (mean [SD] age, 42 [18] years; 589 [59.5%] female) were analyzed. External validation within the national registry (101 patients) demonstrated the CNN's high diagnostic capacity for LQTS detection (AUC, 0.93; 95% CI, 0.89-0.96) and genotype differentiation (AUC, 0.91; 95% CI, 0.86-0.96). This surpassed expert-measured QTc intervals in detecting LQTS (F1 score, 0.84 [95% CI, 0.78-0.90] vs 0.22 [95% CI, 0.13-0.31]; sensitivity, 0.90 [95% CI, 0.86-0.94] vs 0.36 [95% CI, 0.23-0.47]), including in patients with normal or borderline QTc intervals (F1 score, 0.70 [95% CI, 0.40-1.00]; sensitivity, 0.78 [95% CI, 0.53-0.95]). In further validation in a cross-sectional cohort (406 patients) of high-risk patients and genotype-negative controls, the CNN detected LQTS with an AUC of 0.81 (95% CI, 0.80-0.85), which was better than QTc interval-based detection (AUC, 0.74; 95% CI, 0.69-0.78). Conclusions and Relevance: The deep learning model improved detection of congenital LQTS from resting ECGs and allowed for differentiation between the 2 most common genetic subtypes. Broader validation over an unselected general population may support application of this model to patients with suspected LQTS.

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.

Infants less than or equal to 2.5 kg have increased mortality and worse motor neurodevelopmental outcomes at 2 years of age after Norwood-Sano palliation.

Objectives: In infants with single-ventricle congenital heart disease, prematurity and low weight at the time of the Norwood operation are risk factors for mortality. Reports assessing outcomes (including neurodevelopment) post Norwood palliation in infants ≤2.5 kg are limited. Methods: All infants who underwent a Norwood-Sano procedure between 2004 and 2019 were identified. Infants ≤2.5 kg at the time of the operation (cases) were matched 3:1 with infants >3.0 kg (comparisons) for year of surgery and cardiac diagnosis. Demographic and perioperative characteristics, survival, and functional and neurodevelopmental outcomes were compared. Results: Twenty-seven cases (mean ± standard deviation: weight 2.2 ± 0.3 kg and age 15.6 ± 14.1 days at surgery) and 81 comparisons (3.5 ± 0.4 kg and age 10.9 ± 7.9 days at surgery) were identified. Post-Norwood, cases had a longer time to lactate ≤2 mmol/L (33.1 ± 27.5 vs 17.9 ± 12.2 hours, P < .001), longer duration of ventilation (30.5 ± 24.5 vs 18.6 ± 17.5 days, P = .005), greater need for dialysis (48.1% vs 19.8%, P = .007), and greater need for extracorporeal membrane oxygenation support (29.6% vs 12.3%, P = .004). Cases had significantly greater postoperative (in-hospital) (25.9% vs 1.2%, P < .001) and 2-year (59.2% vs 11.1%, P < .001) mortality. Neurodevelopmental assessment showed the following for cases versus comparisons, respectively: cognitive delay (18.2% vs 7.9%, P = .272), language delay (18.2% vs 11.1%, P = .505), and motor delay (27.3% vs 14.3%, P = .013). Conclusions: Infants ≤2.5 kg at Norwood-Sano palliation have significantly increased postoperative morbidity and mortality up to 2-year follow-up. Neurodevelopmental motor outcomes were worse in these infants. Additional studies are warranted to assess the outcome of alternative medical and interventional treatment plans in this patient population.

Neurodevelopmental Outcomes of Infants after Neonatal Surgical Intervention for Tetralogy of Fallot or Pulmonary Atresia.

OBJECTIVE: To determine the 2-year neurodevelopmental outcomes for survivors of neonatal cardiac surgery for the most common right ventricular outflow tract obstructive lesions: tetralogy of Fallot and pulmonary atresia with a ventricular septal defect. STUDY DESIGN: A single-center consecutive cohort of 77 children underwent neonatal surgery for tetralogy of Fallot or pulmonary atresia with a ventricular septal defect at ≤6 weeks of age between 2006 and 2017. The patients underwent a multidisciplinary neurodevelopmental assessment at 18-24 months of age. Survivor outcomes were compared by univariable and multivariable analyses. RESULTS: The 2-year mortality was 7.8% (6/77) with a postoperative in-hospital mortality of 3.9% (3/77). Freedom from reintervention by cardiac catheterization or surgical intervention at 2 years was 36%. Functional and neurodevelopmental assessment for 69 of 71 survivors was completed at a mean age of 22.6 ± 4.0 months using the Bayley Scales of Infant and Toddler Development III. The mean neurodevelopmental outcome scores were 83.4 ± 16.5 for cognitive skills, 82.2 ± 18.7 for language skills, and 81.4 ± 18.1 for motor skills. Cognitive, language, and motor delay, defined as a score of <70, was identified in 25%, 25%, and 23% of patients, respectively. Multivariable analyses for factors associated with worse neurodevelopmental outcomes identified chromosomal anomalies (P < .001) and postoperative complications (P < .03). CONCLUSIONS: Cyanotic tetralogy of Fallot and pulmonary atresia with ventricular septal defect requiring neonatal repair showed similar 2-year neurodevelopmental outcomes below normative values and a high prevalence of cognitive, language and motor delays.

Management of Inherited Arrhythmia Syndromes: A HiRO Consensus Handbook on Process of Care.

Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care.

Les syndromes d'arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L'organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d'améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l'arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d'un guide pratique et simple à l'intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l'utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l'objet d'un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l'arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l'arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L'orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L'objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l'administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d'offrir des soins multidisciplinaires normalisés de grande qualité.

Third Trimester Umbilical Arterial Pulsatility Index is Associated with Neurodevelopmental Outcomes at 2-Years in Major Congenital Heart Disease.

Major congenital heart disease (CHD) is associated with impaired neurodevelopment (ND), partly from prenatal insults. In this study we explore associations between 2nd and 3rd trimester umbilical (UA) and middle cerebral artery (MCA) pulsatility index (PI = systolic-diastolic velocities/mean velocity) in fetuses with major CHD and 2-year ND and growth outcomes. Eligible patients included those with a prenatal diagnosis of CHD from 2007 to 2017 without a genetic syndrome who underwent previously defined cardiac surgeries and 2-year biometric and ND assessments in our program. UA and MCA-PI Z-scores at fetal echocardiography were examined for relationships with 2-year Bayley Scales of Infant and Toddler Development and biometric Z-scores. Data from 147 children was analyzed. Second and 3rd trimester fetal echocardiograms were performed at 22.4 ± 3.7 and 34.7 ± 2.9 weeks (mean ± SD), respectively. Multivariable regression analysis showed an inverse relationship between 3rd trimester UA-PI for all CHD and cognitive - 1.98 (- 3.37, - 0.59), motor - 2.57 (- 4.15, - 0.99), and language - 1.67 (- 3.3, - 0.03) (effect size and 95th confidence interval) ND domains (p < 0.05), with the strongest relationships in the single ventricle and hypoplastic left heart syndrome subgroups. No association was found for 2nd trimester UA-PI or any trimester MCA-PI and ND or between UA or MCA-PI and 2-year growth parameters. Increased 3rd trimester UA-PI, reflecting an altered late gestation fetoplacental circulation, relates to worse 2-year ND in all domains.

Leuprolide Acetate and QTc Interval in Gender-Diverse Youth.

Background: Puberty suppression is a standard of care for gender-affirming therapy in gender-diverse youth. Leuprolide acetate is a gonadotropin-releasing hormone agonist (GnRHa) commonly used for pubertal suppression. There are concerns that GnRHa agents prolong the rate-corrected QT interval (QTc) when used as androgen deprivation therapy in management of prostate cancer; however, there is a paucity of literature regarding the effect of leuprolide acetate on QTc intervals in gender-diverse youth. Aim: To determine the proportion of gender-diverse youth with QTc prolongation on leuprolide acetate therapy. Methods: A retrospective chart review of gender-diverse youth initiated on leuprolide acetate between July 1, 2018 and December 31, 2019 was conducted at a tertiary care pediatric hospital in Alberta, Canada. Youth aged 9-18 years were included if a 12-lead electrocardiogram was completed after initiating leuprolide acetate. The proportion of adolescents with clinically significant QTc prolongation was assessed, defined as QTc >460 milliseconds (ms). Results: Thirty-three pubertal youth were included. The cohort had a mean age of 13.7 years (standard deviation [SD] 2.1) and 69.7% identified as male (assigned female at birth). The mean post-leuprolide acetate QTc was 415 ms (SD 27, range 372-455). Twenty-two (66.7%) of youth were prescribed concomitant medications, including QTc-prolonging medications in 15.2%. None of the 33 youth on leuprolide acetate had QTc prolongation. Only 24.2% patients had a borderline QTc (QTc 440-460 ms). Conclusion: No gender-diverse youth on leuprolide acetate demonstrated clinically significant QTc prolongation.

Combination therapy with simultaneous delivery of spinal cord stimulation modalities: COMBO randomized controlled trial.

Aim: The Combining Mechanisms for Better Outcomes randomized controlled trial assessed the effectiveness of various spinal cord stimulation (SCS) modalities for chronic pain. Specifically, combination therapy (simultaneous use of customized sub-perception field and paresthesia-based SCS) versus monotherapy (paresthesia-based SCS) was evaluated. Methods: Participants were prospectively enrolled (key inclusion criterion: chronic pain for ≥6 months). Primary end point was the proportion with ≥50% pain reduction without increased opioids at the 3 month follow-up. Patients were followed for 2 years. Results: The primary end point was met (n = 89; p < 0.0001) in 88% of patients in the combination-therapy arm (n = 36/41) and 71% in the monotherapy arm (n = 34/48). Responder rates at 1 and 2 years (with available SCS modalities) were 84% and 85%, respectively. Sustained functional outcomes improvement was observed out to 2 years. Conclusion: SCS-based combination therapy can improve outcomes in patients with chronic pain. Clinical Trial Registration: NCT03689920 (ClinicalTrials.gov), Combining Mechanisms for Better Outcomes (COMBO).

Spinal cord stimulation (SCS) is a device-based therapy for chronic pain that delivers electrical impulses to the spinal cord, disrupting pain signals to the brain. Pain relief can be achieved using different SCS techniques that use or do not use paresthesia (stimulation that produces a tingling sensation). These approaches affect patients in different ways, suggesting that different biological processes are involved in enabling pain relief. Research also suggests that better long-term results occur when patients can choose the therapy that is best for their own needs. This clinical study compared pain relief and other functional activities in those receiving combination therapy (simultaneous use of SCS that does and does not produce tingling sensation) against those receiving monotherapy (only SCS therapy producing tingling sensation) for 3 months. In the study, 88% of those receiving combination therapy and 71% with monotherapy alone reported a 50% (or greater) decrease in overall pain (the 'responder rate') without an increased dose of opioid drugs at 3 months after the start of therapy. This responder rate was found to be 84% at 1 year and 85% at 2 years (with all SCS therapy options available). Analysis of functional activities or disability showed that patients improved from 'severely disabled' at study start to 'moderately disabled' after 2 years, indicating that effective long-term (2 year) improvement can be achieved using SCS-based combination therapy for chronic pain.

Conduction System Pacing Versus Conventional Cardiac Resynchronization Therapy in Congenital Heart Disease.

BACKGROUND: Dyssynchrony-associated left ventricular systolic dysfunction is a major contributor to heart failure in congenital heart disease (CHD). Although conventional cardiac resynchronization therapy (CRT) has shown benefit, the comparative efficacy of cardiac conduction system pacing (CSP) is unknown. OBJECTIVES: The purpose of this study was compare the clinical outcomes of CSP vs conventional CRT in CHD with biventricular, systemic left ventricular anatomy. METHODS: Retrospective CSP data from 7 centers were compared with propensity score-matched conventional CRT control subjects. Outcomes were lead performance, change in left ventricular ejection fraction (LVEF), and QRS duration at 12 months. RESULTS: A total of 65 CSP cases were identified (mean age 37 ± 21 years, 46% men). The most common CHDs were tetralogy of Fallot (n = 12 [19%]) and ventricular septal defect (n = 12 [19%]). CSP was achieved after a mean of 2.5 ± 1.6 attempts per procedure (38 patients with left bundle branch pacing, 17 with HBP, 10 with left ventricular septal myocardial). Left bundle branch area pacing [LBBAP] vs HBP was associated with a smaller increase in pacing threshold (Δ pacing threshold 0.2 V vs 0.8 V; P = 0.05) and similar sensing parameters at follow-up. For 25 CSP cases and control subjects with baseline left ventricular systolic dysfunction, improvement in LVEF was non-inferior (Δ LVEF 9.0% vs 6.0%; P = 0.30; 95% confidence limits: -2.9% to 10.0%) and narrowing of QRS duration was more pronounced for CSP (Δ QRS duration 35 ms vs 14 ms; P = 0.04). Complications were similar (3 [12%] CSP, 4 [16%] conventional CRT; P = 1.00). CONCLUSIONS: CSP can be reliably achieved in biventricular, systemic left ventricular CHD patients with similar improvement in LVEF and greater QRS narrowing for CSP vs conventional CRT at 1 year. Among CSP patients, pacing electrical parameters were superior for LBBAP vs HBP.

Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

Evaluating the Prevalence and Factors Associated With an Optimal Neurodevelopmental Outcome in 4- to 6-Year-Old Children With Fontan Circulation.

BACKGROUND: We sought to evaluate the prevalence and factors associated with "optimal" neurodevelopmental outcomes in 4- to 6-year-old children with Fontan circulation. METHODS: Patients followed through the Western Canadian Complex Pediatric Therapies Follow-Up Program, and born between September 1996 and December 2015, were included. Optimal neurodevelopmental outcome was defined as full-scale intelligence quotient; visual-motor integration; adaptive behaviour assessment system-general adaptive composite scores of ≥ 80 each; and the absence of chronic motor disability, permanent hearing loss, visual impairment, and seizure disorder. Multivariable regression models and decision algorithms evaluated variables associated with optimal outcomes. RESULTS: The Fontan procedure was completed on 225 children, with neurodevelopmental outcome data available for 205 (mean [standard deviation]) age at Fontan 3.4 (0.9) years, 37% female). Optimal neurodevelopmental outcome was identified in 55% (112 of 205). Factors independently associated with optimal neurodevelopmental outcome were female sex (odds ratio [OR], 2.1; 95% confidence interval [CI] 1.1-4.1), years of maternal schooling (OR, 1.2 [1.1-1.4]), age at Fontan (years) (OR, 0.97 [0.94-1.0]), need for concomitant atrioventricular valve (AVV) intervention (OR, 0.4 [0.2-1.0]), and time (hours) for lactate to be ≤ 2 mmol/L (OR, 0.9 [0.8-1.0]). Of those with Fontan completion < 3.25 years, without concomitant AVV intervention and lactate normalization within 8 hours post-Fontan, 87% (27 of 31) had optimal neurodevelopmental outcomes. CONCLUSIONS: Optimal neurodevelopmental outcome was present in more than one-half of 4- to 6-year-old children with Fontan circulation in this cohort study, with important associated factors identified, including potentially modifiable factors such as younger age at Fontan surgery and lack of concomitant AVV intervention.

Identification and in-silico characterization of splice-site variants from a large cardiogenetic national registry.

Splice-site variants in cardiac genes may predispose carriers to potentially lethal arrhythmias. To investigate, we screened 1315 probands and first-degree relatives enrolled in the Canadian Hearts in Rhythm Organization (HiRO) registry. 10% (134/1315) of patients in the HiRO registry carry variants within 10 base-pairs of the intron-exon boundary with 78% (104/134) otherwise genotype negative. These 134 probands were carriers of 57 unique variants. For each variant, American College of Medical Genetics and Genomics (ACMG) classification was revisited based on consensus between nine in silico tools. Due in part to the in silico algorithms, seven variants were reclassified from the original report, with the majority (6/7) downgraded. Our analyses predicted 53% (30/57) of variants to be likely/pathogenic. For the 57 variants, an average of 9 tools were able to score variants within splice sites, while 6.5 tools responded for variants outside these sites. With likely/pathogenic classification considered a positive outcome, the ACMG classification was used to calculate sensitivity/specificity of each tool. Among these, Combined Annotation Dependent Depletion (CADD) had good sensitivity (93%) and the highest response rate (131/134, 98%), dbscSNV was also sensitive (97%), and SpliceAI was the most specific (64%) tool. Splice variants remain an important consideration in gene elusive inherited arrhythmia syndromes. Screening for intronic variants, even when restricted to the ±10 positions as performed here may improve genetic testing yield. We compare 9 freely available in silico tools and provide recommendations regarding their predictive capabilities. Moreover, we highlight several novel cardiomyopathy-associated variants which merit further study.

Sex Differences and Utility of Treadmill Testing in Long-QT Syndrome.

Background Diagnosis of congenital long-QT syndrome (LQTS) is complicated by phenotypic ambiguity, with a frequent normal-to-borderline resting QT interval. A 3-step algorithm based on exercise response of the corrected QT interval (QTc) was previously developed to diagnose patients with LQTS and predict subtype. This study evaluated the 3-step algorithm in a population that is more representative of the general population with LQTS with milder phenotypes and establishes sex-specific cutoffs beyond the resting QTc. Methods and Results We identified 208 LQTS likely pathogenic or pathogenic KCNQ1 or KCNH2 variant carriers in the Canadian NLQTS (National Long-QT Syndrome) Registry and 215 unaffected controls from the HiRO (Hearts in Rhythm Organization) Registry. Exercise treadmill tests were analyzed across the 5 stages of the Bruce protocol. The predictive value of exercise ECG characteristics was analyzed using receiver operating characteristic curve analysis to identify optimal cutoff values. A total of 78% of male carriers and 74% of female carriers had a resting QTc value in the normal-to-borderline range. The 4-minute recovery QTc demonstrated the best predictive value for carrier status in both sexes, with better LQTS ascertainment in female patients (area under the curve, 0.90 versus 0.82), with greater sensitivity and specificity. The optimal cutoff value for the 4-minute recovery period was 440 milliseconds for male patients and 450 milliseconds for female patients. The 1-minute recovery QTc had the best predictive value in female patients for differentiating LQTS1 versus LQTS2 (area under the curve, 0.82), and the peak exercise QTc had a marginally better predictive value in male patients for subtype with (area under the curve, 0.71). The optimal cutoff value for the 1-minute recovery period was 435 milliseconds for male patients and 455 milliseconds for femal patients. Conclusions The 3-step QT exercise algorithm is a valid tool for the diagnosis of LQTS in a general population with more frequent ambiguity in phenotype. The algorithm is a simple and reliable method for the identification and prediction of the 2 major genotypes of LQTS.

Return of Results Policies for Genomic Research: Current Practices and the Hearts in Rhythm Organization (HiRO) Approach.

Research teams developing biobanks and/or genomic databases must develop policies for the disclosure and reporting of potentially actionable genomic results to research participants. Currently, a broad range of approaches to the return of results exist, with some studies opting for nondisclosure of research results and others following clinical guidelines for the return of potentially actionable findings from sequencing. In this review, we describe current practices and highlight decisions a research team must make when designing a return of results policy, from informed consent to disclosure practices and clinical validation options. The unique challenges of returning incidental findings in cardiac genes, including reduced penetrance and the lack of clinical screening standards for phenotype-negative individuals, are discussed. Finally, the National Hearts in Rhythm Organisation (HiRO) Registry approach is described to provide a rationale for the selective return of field-specific variants to those participating in disease-specific research. Our goal is to provide researchers with a resource when developing a return of results policy tailored for their research program, based on unique factors related to study design, research team composition, and availability of clinical resources.

An International Multicenter Cohort Study on ß-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. ß-Blockers decrease this risk, but studies comparing individual ß-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of ß-blocker in a large cohort of symptomatic children with CPVT. METHODS: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before ß-blocker initiation and age at start of ß-blocker therapy <18 years), treated with a ß-blocker were included. Cox regression analyses with time-dependent covariates for ß-blockers and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. RESULTS: We included 329 patients (median age at diagnosis, 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary outcome and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 (interquartile range, 2.8-12.5) years. Two-hundred sixteen patients (66.0%) used a nonselective ß-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a ß1-selective ß-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial ß-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for ß1-selective compared with nonselective ß-blockers (HR, 2.04 [95% CI, 1.31-3.17]; and HR, 1.99 [95% CI, 1.20-3.30], respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68 [95% CI, 1.44-4.99]), bisoprolol (HR, 3.24 [95% CI, 1.47-7.18]), and metoprolol (HR, 2.18 [95% CI, 1.08-4.40]) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68 [95% CI, 1.30-5.55]). CONCLUSIONS: ß1-selective ß-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective ß-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred ß-blocker for treating symptomatic children with CPVT.

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.

Development and Evaluation of Decision Aids to Guide Families' Predictive Testing Choices for Children at Risk for Arrhythmia or Cardiomyopathy.

BACKGROUND: Assessing the issues surrounding predictive genetic testing for children at risk of an inherited arrhythmia or cardiomyopathy is complex. The objective of this study was to design and evaluate 4 cardiac decision aids. The decision aids were developed to assist families with a genetic diagnosis of long QT syndrome, hypertrophic cardiomyopathy, dilated cardiomyopathy, or arrhythmogenic right ventricular cardiomyopathy in deciding between predictive genetic testing and cardiac screening for their children. METHODS: The decision aids were developed with the use of the International Patient Decision Aid Standards framework and revised based on feedback from individuals with lived experience, genetic counsellors, and other health professionals. RESULTS: Response to the decision aids was positive, and acceptability and understandability scores were high. CONCLUSIONS: The decision aids can be used before, during or after a genetic counselling appointment as a resource or to guide discussion. These tools permit a balanced and consistent approach to the decision-making process, with a focus on the importance families place on the advantages and disadvantages of each option.

Outcomes of Pediatric Patients With Defibrillators Following Initial Presentation With Sudden Cardiac Arrest.

BACKGROUND: Implantable cardioverter defibrillators (ICD) are recommended for secondary prevention after sudden cardiac arrest (SCA). The outcomes of pediatric patients receiving an ICD after SCA remain unclear. The objective of this study is to evaluate outcomes, future risk for appropriate shocks, and identify characteristics associated with appropriate ICD therapy during follow-up. METHODS: Multicenter retrospective analysis of patients (age ≤21 years) without prior cardiac disease who received an ICD following SCA. Patient/device characteristics, cardiac function, and underlying diagnoses were collected, along with SCA event characteristics. Patient outcomes including complications and device therapies were analyzed. RESULTS: In total, 106 patients were included, median age 14.7 years. Twenty (19%) received appropriate shocks and 16 (15%) received inappropriate shocks (median follow-up 3 years). First-degree relative with SCA was associated with appropriate shocks (P<0.05). In total, 40% patients were considered idiopathic. Channelopathy was the most frequent late diagnosis not made at time of presentation. Neither underlying diagnosis nor idiopathic status was associated with increased incidence of appropriate shock. Monomorphic ventricular tachycardia (hazard ratio, 4.6 [1.2-17.3]) and family history of sudden death (hazard ratio, 6.5 [1.4-29.8]) were associated with freedom from appropriate shock in a multivariable model (area under the receiver operating characteristic curve, 0.8). Time from diagnoses to evaluation demonstrated a nonlinear association with freedom from appropriate shock (P=0.015). In patients >2 years from implantation, younger age (P=0.02) and positive exercise test (P=0.04) were associated with appropriate shock. CONCLUSIONS: The risk of future device therapy is high in pediatric patients receiving an ICD after SCA, irrelevant of underlying disease. Lack of a definitive diagnosis after SCA was not associated with lower risk of subsequent events and does not obviate the need for secondary prophylaxis.