BACKGROUND AND AIMS:Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS:The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS:A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS:These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Importance:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmogenic syndrome in which exercise stress testing is the primary method for provoking adrenergically mediated ventricular arrhythmias. Traditional exercise testing protocols, such as the Bruce protocol, may lack sensitivity, leading to missed diagnoses and undertreatment, whereas early pilot data suggest that a sudden high-intensity Burst protocol may better unmask arrhythmias. Objective:To evaluate the diagnostic yield and therapeutic impact of the Burst exercise stress testing protocol compared with the traditional Bruce protocol in CPVT. Design, Setting, and Participants:This retrospective cohort study included pediatric and adult patients evaluated for CPVT at 2 tertiary referral centers in Vancouver, British Columbia, Canada. Data were collected from May 2017 through May 2024, and data analysis was performed from May 2024 through April 2025. Of 38 screened patients, 28 were included who had undergone consecutive Bruce and Burst exercise tests, with available tracings and a diagnostic phenotype on at least 1 test. Arrhythmia severity was scored using the Ventricular Arrhythmia Score. Exposure:Type of exercise stress testing protocol (Bruce vs Burst). Main Outcomes and Measures:The main outcome was the Ventricular Arrhythmia Score (ranging from 0 = no premature ventricular contractions to 4 = nonsustained ventricular tachycardia). Other outcomes included changes in pharmacologic therapy and adverse events. Results:The cohort included 13 female patients (46%) and 18 probands (64%), including 23 (82%) with a causative RYR2 variant. Median (IQR) age at testing was 19.9 (14.8-33.9) years for Bruce testing and 21.0 (16.1-35.5) years at Burst testing. Bruce and Burst exercise tests were performed a median (IQR) of 1.3 (0.6-2.0) years apart, with all Burst tests performed on equivalent or intensified therapy. The Burst protocol provoked more severe arrhythmias in 20 of 28 patients (71%) with a higher median (IQR) Ventricular Arrhythmia Score (3 [2-4] vs 1 [1-2]; P < .001). These findings prompted β-blocker or flecainide initiation or dose escalation in 13 patients (65%). No adverse safety events occurred. Conclusions and Relevance:In this cohort study, the Burst exercise stress testing protocol detected a greater burden and severity of ventricular arrhythmias than the Bruce protocol in patients with CPVT, frequently prompting treatment escalation without observed safety concerns. These data suggest that incorporating Burst protocol exercise stress testing into the routine care of patients with CPVT is low risk and often informative.

Various medications used to treat psychiatric conditions are associated with prolongation of the QTc interval, which can lead to Torsades de Pointes, a deadly arrhythmia. Despite evidence of QTc prolongation, clinicians increasingly use psychiatric drugs in the pediatric population. Guidelines for prescribing many of these medications in children do not currently exist. To safely prescribe QTc prolonging drugs, especially in children with preexisting cardiovascular conditions, psychiatric providers, primary care physicians and/or pediatricians should conduct a detailed personal and family medical history, medication record, physical examination, and lab work, if clinically indicated, to rule out potential risk factors. Pharmacist input should be sought, if available. If risk factors are present and pre-treatment assessments identify cardiac risk factors, an assessment by a cardiologist may be necessary. To enhance treatment safety and mitigate QTc prolongation risks associated with psychiatric drug use in children, a standardized approach for drug prescribing that takes patient risk factors into account is proposed.

Chest pain is a common complaint among children that has a non-cardiac origin in 99% of pediatric cases. We conducted a literature review of the different proposed etiologies of pediatric chest pain, as well as the evidence base supporting current approaches. Among the non-cardiac causes of chest pain in children, musculoskeletal causes are reported to be the most prevalent. This includes precordial catch syndrome, Tietze's syndrome, and costochondritis. However, these origins of musculoskeletal chest pain were described historically, and their labels are likely applied too broadly. It is important that providers be able to differentiate between benign chest pain that truly has a musculoskeletal origin and that which lacks an identifiable cause. To determine the cause of chest pain, providers should take a detailed history, physical examination, electrocardiogram, and any additional indicated laboratory tests. Musculoskeletal chest pain should only be diagnosed if there is an objective finding of reproducible tenderness during the physical examination or if there is a plausible history. If no cause can be identified, the chest pain may be linked to somatization. As a result, these patients may benefit from psychiatric evaluation and mindfulness-based interventions. To better inform clinical care, providers should be aware of these emerging management approaches.

BackgroundCatecholaminergic 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.ObjectiveTo compare the risk of arrhythmic events in pediatric CPVT patients with and without ICDs.MethodsWe compared the risk of SCD in RYR2 variant and phenotype positive symptomatic CPVT patients with and without ICDs, who were <19 years of age and had no history of sudden cardiac arrest (SCA) at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite incidences of SCD, SCA, appropriate ICD shocks, with/without arrhythmic syncope.ResultsThe study included 235 patients, 73 (31.1%) with ICDs and 162 (68.9%) without ICDs. Over a median follow-up of 8.0 years (IQR 4.3-13.4), SCD occurred in 7 (3.0%) patients, of which 4 (57.1%) were non-compliant with medications and none had an ICD. ICD patients had a higher risk of both secondary composite outcomes (without syncope: HR 5.85 (CI 3.40-10.09); p<0.0001; with syncope: HR 2.55 (CI 1.50-4.34); p=0.0005). Thirty-one (42.5%) patients with an ICD experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications.ConclusionsSCD events occurred only in the no ICD group, in those not on optimal medical therapy. ICD patients had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common and risks versus benefits of ICDs need to be considered.

Supplementary Figure 4A from YB-1 Bridges Neural Stem Cells and Brain Tumor–Initiating Cells via Its Roles in Differentiation and Cell Growth

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.

Background:Our objective was to examine the clinical presentation, echocardiographic findings, and outcomes of newborns presenting with left ventricle (LV) dysfunction in the first 48 hours of life without perinatal asphyxia or structural heart disease. We hypothesize that LV dysfunction may occur due to maladaptation to extrauterine life.Methods:This is a retrospective cohort analysis including infants born in a quaternary perinatal centre. Late preterm and term neonates who were diagnosed with left ventricular dysfunction at less than 48 hours of life were identified using an echocardiography clinical laboratory's database and extracorporeal life support database. LV dysfunction was defined as m-mode fractional shortening (FS) <28% or ejection fraction (EF) <50% on echocardiography or reduced function reported by a cardiologist. Data extracted included patient & maternal demographics, echocardiogram parameters, clinical status, and medications. The primary outcome measure was time to recovery of LV function based on echocardiography.Results:Of the 69 patients identified, 19 patients were included in the final analysis. The mean gestational age was 38 weeks. Thirteen (68%) infants did not have an underlying cause identified despite extensive work-up. Four (21%) infants had exposure to maternal illicit drug use during pregnancy. Three infants died, and all infants without identifiable etiologies had recovery of LV function within 14 days of life.Conclusions:LV dysfunction can occur during the abrupt transition from fetal to neonatal circulation and can be associated with maternal illicit drug use.

Catecholaminergic polymorphic Ventricular Tachycardia (CPVT) is a rare inherited arrhythmia disorder characterized by adrenergic-induced polymorphic ventricular tachycardia (VT). Physical activity (PA) restriction was once a mainstay of therapy. Although an individualized, shared decision approach to PA is recommended, the amount activity considered safe remains unknown.

Sudden cardiac death (SCD) is a rare and devastating event in children and remains a leading cause of death in young athletes. Channelopathies and cardiomyopathies, in particular long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), and arrhythmogenic cardiomyopathy (ACM) are associated with exercise-related SCD. Implantable cardioverter-defibrillators (ICDs) are often placed for secondary prevention for athletes with cardiomyopathy or channelopathy. There remains concern regarding the safety of return to participation with an ICD in place. Guidelines have historically recommended that patients with inherited heart rhythm disorders be restricted from competitive sports participation. Increasing evidence suggests a lower risk of exercise-related cardiac events in young athletes with inherited heart rhythm disorders. In this review, we highlight current knowledge, evolving guidelines, and present a multidisciplinary approach involving shared decision-making and appropriate planning for safe sports participation of children with inherited heart rhythm disorders.

Congenital heart disease (CHD) is linked to an increased incidence of neurodevelopmental impairments in young patients. Given the number of published studies on this topic, a synthesis of the literature is timely and needed. We performed a systematic review and meta-analysis of the medical literature to assess the evidence linking CHD to incidence of autism spectrum disorder (ASD). A systematic review of studies on CHD and ASD in PubMed, Cochrane and Institute for Scientific Information (ISI) from 1965 to May 2021 was conducted. Quantitative estimates of association between CHD and ASD were extracted from eligible studies for the meta-analysis. Pooled estimates were obtained using a random effect models fit by a generalised linear mixed model. We screened 2709 articles and 24 articles were included in this review. Among the 24 studies, there was a total of 348,771 subjects (12,114 CHD, 9829 ASD and 326,828 controls). Seven of 24 studies were eligible for the meta-analysis, which included information on a total of 250,611 subjects (3984 CHD, 9829 ASD, and 236,798 controls). The summary estimate indicated that having CHD is associated with almost double the odds of ASD compared with patients without CHD (OR 1.99, 95

Importance Calcium-release deficiency syndrome (CRDS), which is caused by loss-of-function variants in cardiac ryanodine receptor 2 (RyR2), is an emerging cause of ventricular fibrillation. However, the lack of complex polymorphic/bidirectional ventricular tachyarrhythmias during exercise stress testing (EST) may distinguish it from catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, in the first clinical series describing the condition, mouse and human studies showed that the long-burst, long-pause, short-coupled ventricular extra stimulus (LBLPS) electrophysiology protocol reliably induced CRDS ventricular arrhythmias. Data from larger populations with CRDS and its associated spectrum of disease are lacking. Objective To further insight into CRDS through international collaboration. Design, Setting, and Participants In this multicenter observational cohort study, probands with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine their functional impact. Data were collected from September 1, 2012, to March 6, 2021, and analyzed from August 9, 2015, to March 6, 2021. Main Outcomes and Measures The functional association of RyR2 variants found in putative cases of CRDS and the associated clinical phenotype(s). Results Of 10 RyR2 variants found in 10 probands, 6 were loss-of-function, consistent with CRDS (p.E4451del, p.F4499C, p.V4606E, p.R4608Q, p.R4608W, and p.Q2275H) (in 4 [67%] male and 2 [33%] female probands; median age at presentation, 22 [IQR, 8-34] years). In 5 probands with a documented trigger, 3 were catecholamine driven. During EST, 3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 could not undergo EST (deceased). Relatives of the decedents carrying the RyR2 variant did not have EST results consistent with CPVT. After screening 3 families, 13 relatives were diagnosed with CRDS, including 3 with previous arrhythmic events (23%). None had complex ventricular tachyarrhythmias during EST. Among the 19 confirmed cases with CRDS, 10 had at least 1 life-threatening event at presentation and/or during a median follow-up of 7 (IQR, 6-18) years. Two of the 3 device-detected ventricular fibrillation episodes were induced by a spontaneous LBLPS-like sequence. β-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to β-blocker therapy (19%) had breakthrough events. Conclusions and Relevance The results of this study suggest that calcium-release deficiency syndrome due to RyR2 loss-of-function variants mechanistically and phenotypically differs from CPVT. Ventricular fibrillation may be precipitated by a spontaneous LBLPS-like sequence of ectopy; however, CRDS remains difficult to recognize clinically. These data highlight the need for better diagnostic tools and treatments for this emerging condition.

Background:Patients after ablation for tachyarrhythmias may continue to experience palpitations in the setting of sinus rhythm. The objective of our study was to investigate if patients who have undergone ablation for tachyarrhythmia have palpitations and other somatic complaints more frequently than healthy controls.Methods:Paediatric patients after ablation for tachyarrhythmia at BC Children's Hospital from 2009 to 2020 and healthy controls were invited to participate in a survey about palpitations. Demographics, palpitation symptoms, frequency, duration, and need for medical attention were collected and compared between patients and controls.Results:We received responses from 111 patients (response rate of 27.5%; mean age = 20.0 ± 4.6 years, 52% male) and 62 controls (age = 19.8 ± 5.7 years, 40% male). Sixty-two (56%) patients experienced palpitations beyond the initial 4 weeks after ablation, of whom 77% (n = 48/62) reported their palpitations feeling different. Tachyarrhythmia recurrence rate after ablation was 7.2%. There was no difference in the prevalence of palpitations experienced between patients and controls (P = 0.74). Patients after ablation sought medical attention more often for their palpitations (P = 0.003) and chest symptoms (P = 0.001) compared to controls.Conclusion:The prevalence of palpitations did not differ in ablation patients compared to healthy controls. Patients reported that their palpitations felt different after ablation and were more likely to seek medical attention for their palpitations. Paediatric patients with tachyarrhythmias may have heightened awareness due to their history. Clinicians can incorporate this into procedural counselling to reduce patient concern and need for medical attention.

Long QT Syndrome (LQTS) is a familial ion channelopathy associated with a structurally normal heart and risk of sudden cardiac death. Most cases are associated with variants in KCNQ1 and KCNH2 genes. Ion channel variants have been implicated in neurodevelopmental disorders (NDDs), yet the link between LQTS and NDDs in children has not been well characterized.