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.

Safety of same-day discharge without anticoagulation for left-sided radiofrequency catheter ablations in pediatrics.

BACKGROUND: For left-sided radiofrequency catheter ablation (LCA) in pediatrics, significant practice variability exists regarding anticoagulation and discharge practices. Given the lack of data in pediatric patients, the risks and benefits of these practices are not well defined. OBJECTIVE: The purpose of this study was to evaluate the safety of same-day discharge and use of aspirin (ASA) in pediatric patients following LCA. METHODS: We performed a retrospective cohort study of pediatric patients who underwent LCA from 2010 to 2020 at our institution. Discharge timing and ASA usage were based on operator preference. The primary outcome was incidence of postablation anticoagulation complications reported within 1 month of the procedure. RESULTS: Three hundred seventy-six patients underwent LCA and met inclusion criteria. Median [25th, 75th percentiles] age was 13.9 [10.5, 16.2] years; 18 (4.7%) had a history of structural heart disease. The most common substrates for ablation were Wolff-Parkinson-White syndrome (183 patients [48.7%]), concealed accessory pathway (159 patients [42.3%]), and ectopic atrial tachycardia (10 patients [2.7%]). Three hundred thirty-eight patients (89.9%) were discharged on the day of LCA. Seventy-six patients (20.2%) were prescribed ASA at discharge. Of those who underwent follow-up (273 patients [72.6%]), 7 (2.7%) reported an anticoagulation complication (5 with hematoma, 2 with headache). One of these patients was prescribed ASA; none required readmission. There was no correlation between anticoagulation complications and same-day discharge or with ASA usage. CONCLUSION: Given the rare incidence of anticoagulation complications in pediatric patients undergoing LCAs, same-day discharge from the electrophysiology laboratory without anticoagulation should 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.

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.

IV Sotalol Use in Pediatric and Congenital Heart Patients: A Multicenter Registry Study.

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5-1.8 mg/kg/dose) over a median of 60 minutes (range 30-300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%-62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%-41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early. Conclusions IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.

Exercise Recommendations in Pediatric HCM: Variation and Influence of Provider Characteristics.

Pediatric Hypertrophic Cardiomyopathy (HCM) is associated with sudden cardiac death (SCD) that can be related to physical activity. Without pediatric specific guidelines, recommendations for activity restriction may be varied. Therefore, our aim is to determine the current practice and variability surrounding exercise clearance recommendations (ER) in pediatric HCM referral centers as well as provider and patient characteristics that influence them. We designed a survey that was distributed to the Pediatric Heart Transplant Study (PHTS) providers and members of the Pediatric and Adult Congenital Electrophysiology Society (PACES) querying provider demographics and patient variables from 2 patient vignettes. The study is a multicenter survey of current practice of specialized providers caring for pediatric HCM patients. Survey of PHTS and PACES providers via email to the respective listservs with a response rate of 28% and 91 overall completing the entire survey after self-identifying as providers for pediatric HCM patients at their center. ER varies for pediatric HCM and is associated with provider training background as well as personal and professional history. Of the 91 providers who completed the survey, 42% (N = 38) trained in pediatric electrophysiology (EP), and 40% (N = 36) in pediatric heart failure (HF). Responses varied and only 53% of providers cleared for mild to moderate activity for the patient in Vignette 1, which is more in line with recent published adult guidelines. ER in both vignettes was significantly associated with type of training background. EP providers were more likely to recommend no restriction (27.8% vs 5.9%) than HF providers even when controlling for provider age and time out of training. Syncope with exercise was deemed "Most Important" by 81% of providers when making ER. ER for pediatric HCM are variable and the majority of providers make ER outside of previously published adult guidelines. Furthermore, ER are influenced by provider background and experience. Further study is needed for risks and benefits of physical activity in this population to inform the development of pediatric specific guidelines.

Safety of maximal cardiopulmonary exercise testing in individuals with sickle cell disease: a systematic review.

OBJECTIVE: We evaluated the safety of maximal cardiopulmonary exercise testing (CPET) in individuals with sickle cell disease (SCD). Maximal CPET using gas exchange analysis is the gold standard for measuring cardiopulmonary fitness in the laboratory, yet its safety in the SCD population is unclear. DESIGN: Systematic review. DATA SOURCES: Systematic search of Medline (PubMed), EMBASE, Cochrane, ClinicalTrials.gov and professional society websites for all published studies and abstracts through December 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Two reviewers independently extracted data of interest from studies that assessed safety outcomes of maximal CPET in children and adults with SCD. A modified version of the Newcastle-Ottawa Scale was used to assess for risk of bias in studies included. RESULTS: In total, 24 studies met inclusion/exclusion criteria. Adverse events were reported separately or as part of study results in 36 (3.8%) of 939 participants with SCD undergoing maximal CPET in studies included. Most adverse events were related to transient ischaemic changes on ECG monitoring or oxygen desaturation during testing, which did not result in arrhythmias or other complications. Only 4 (0.43%) of 939 participants experienced pain events due to maximal CPET. CONCLUSION: Maximal CPET appears to be a safe testing modality in children and adults with SCD and can be used to better understand the physiological basis of reduced exercise capacity and guide exercise prescription in this population. Some studies did not focus on reporting adverse events related to exercise testing or failed to mention safety monitoring, which contributed to risk of bias.

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.

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.

OBJECTIVES: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs). BACKGROUND: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/or neonate has been associated with risk for major CEs, but overall outcomes and predictors remain unknown. METHODS: A retrospective study involving 25 international centers evaluated the course of fetuses/newborns diagnosed with congenital LQTS and either 2:1 atrioventricular block or torsades de pointes. The primary outcomes were age at first CE after dismissal from the newborn hospitalization and death and/or cardiac transplantation during follow-up. CE was defined as aborted cardiac arrest, appropriate shock from implantable cardioverter-defibrillator, or sudden cardiac death. RESULTS: A total of 84 fetuses and/or neonates were identified with LQTS (12 as LQT1, 35 as LQT2, 37 as LQT3). Median gestational age at delivery was 37 weeks (interquartile range: 35 to 39 weeks) and age at hospital discharge was 3 weeks (interquartile range: 2 to 5 weeks). Fetal demise occurred in 2 and pre-discharge death in 1. Over a median of 5.2 years, there were 1 LQT1, 3 LQT2, and 23 LQT3 CEs (13 aborted cardiac arrests, 5 sudden cardiac deaths, and 9 appropriate shocks). One patient with LQT1 and 11 patients with LQT3 died or received cardiac transplant during follow-up. The only multivariate predictor of post-discharge CEs was LQT3 status (LQT3 vs. LQT2: hazard ratio: 8.4; 95% confidence interval: 2.6 to 38.9; p < 0.001), and LQT3, relative to LQT2, genotype predicted death and/or cardiac transplant (p < 0.001). CONCLUSIONS: In this large multicenter study, fetuses and/or neonates with LQT3 but not those with LQT1 or LQT2 presenting with severe arrhythmias were at high risk of not only frequent, but lethal CEs.

Melphalan induces cardiotoxicity through oxidative stress in cardiomyocytes derived from human induced pluripotent stem cells.

BACKGROUND: Treatment-induced cardiotoxicity is a leading noncancer-related cause of acute and late onset morbidity and mortality in cancer patients on antineoplastic drugs such as melphalan-increasing clinical case reports have documented that it could induce cardiotoxicity including severe arrhythmias and heart failure. As the mechanism by which melphalan impairs cardiac cells remains poorly understood, here, we aimed to use cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs) to investigate the cellular and molecular mechanisms of melphalan-induced cardiotoxicity. METHODS: hiPSC-CMs were generated and treated with clinically relevant doses of melphalan. To characterize melphalan-induced cardiotoxicity, cell viability and apoptosis were quantified at various treatment durations. Ca2+ transient and contractility analyses were used to examine the alterations of hiPSC-CM function. Proteomic analysis, reactive oxygen species detection, and RNA-Sequencing were conducted to investigate underlying mechanisms. RESULTS: Melphalan treatment of hiPSC-CMs induced oxidative stress, caused Ca2+ handling defects and dysfunctional contractility, altered global transcriptomic and proteomic profiles, and resulted in apoptosis and cell death. The antioxidant N-acetyl-L-cysteine attenuated these genomic, cellular, and functional alterations. In addition, several other signaling pathways including the p53 and transforming growth factor-ß signaling pathways were also implicated in melphalan-induced cardiotoxicity according to the proteomic and transcriptomic analyses. CONCLUSIONS: Melphalan induces cardiotoxicity through the oxidative stress pathway. This study provides a unique resource of the global transcriptomic and proteomic datasets for melphalan-induced cardiotoxicity and can potentially open up new clinical mechanism-based targets to prevent and treat melphalan-induced cardiotoxicity.

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS: Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Recurrent single echo beats after cryoablation of atrioventricular nodal reentrant tachycardia: The pediatric population.

BACKGROUND: Cryoablation for atrioventricular nodal reentrant tachycardia (AVNRT) is effective and safe with a reported limitation of lower success and higher recurrence rates. We have observed cases in which slow pathway conduction was eliminated as demonstrated by atrial extra-stimulus testing within 1 min of cryo-energy delivery but returned following tissue rewarming. Frequently, slow pathway conduction persisted despite multiple acutely successful lesions over a broad anatomic region. We aimed to determine if return of slow pathway conduction after elimination during cryoablation represents a risk for recurrent AVNRT with the same intermediate term results as slow pathway ablation. We hypothesize that remnant single echo beats in the absence of sustained slow pathway conduction and inducible AVNRT is an acceptable end point after clear slow pathway elimination during cryoablation. METHODS: Retrospective chart review of patients undergoing attempted slow pathway ablation for AVNRT using solely cryoablation between January 2015-January 2018. RESULTS: Forty-four patients met inclusion criteria with at-least 2 features of dual AVN physiology. 19 patients had return of slow pathway conduction shortly after clear elimination during cryoablation (Group A) while 25 did not (Group B). All in Group A had recurrent single echo beats but none had sustained slow pathway conduction at the end of the procedure nor AVNRT recurrence at 1 year. CONCLUSION: Recurrent single echo beats with absent sustained slow pathway conduction and non-inducible AVNRT may be an acceptable endpoint for slow pathway ablation of AVNRT using cryoablation when there is elimination of slow pathway demonstrated during energy delivery.

Chemical cardioversion of atrial flutter and fibrillation in the pediatric population with Ibutilide.

INTRODUCTION: Atrial flutter (AFL) and atrial fibrillation (AF) are common in pediatric patients with congenital heart disease and structurally normal hearts as well. Chemical cardioversion is attractive for patients with AFL/AF for a short period of time because of the ability to avoid sedation. We review a single center's experience with Ibutilide in pediatric patients in an effort to report on its safety and efficacy. METHODS: We performed a retrospective chart review of pediatric patients (0-21 years) who underwent chemical cardioversion for AFL/AF with Ibutilide (January 2011-February 2019). Patients on another antiarrhythmic medication or attempted chemical cardioversion with another drug were excluded. RESULTS: There were 21 patients who met inclusion criteria. Thirteen of the 21 (62%) patients were successfully cardioverted with Ibutilide (10 out of 13 had AF and four out of 13 required a second dose). There were no significant differences in baseline characteristics between those who were successfully cardioverted compared to those who were not. Administration of magnesium prior to administration did not appear to have an effect on the success rate. There was a significant increase in rate corrected QT interval (QTc) post Ibutilide administration, which returned to baseline prior to discharge. One patient had symptomatic bradycardia needing intravenous fluids and another had torsades requiring electrical cardioversion during Ibutilide administration. CONCLUSIONS: The success rate of chemical cardioversion with Ibutilide was similar in our experience as compared to studies in the adult population and the other lone pediatric study. Although adverse events were uncommon, Ibutilide administration warrants close monitoring and fully defining its efficacy warrants further pediatric experience.

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. METHODS: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. RESULTS: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P<0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; P=0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], P=0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). CONCLUSIONS: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Myocardial deformation as a predictor of right ventricular pacing-induced cardiomyopathy in the pediatric population.

INTRODUCTION: Right ventricular pacing is associated with pacemaker induced cardiomyopathy and lesser degrees of pacing-induced LV dysfunction (PIVD) manifested by a reduction in left ventricular ejection fraction (LVEF). Our objective was to determine whether apical 4 chamber strain (A4C) by echocardiography can identify patients at risk of PIVD before LVEF declines. METHODS AND RESULTS: A retrospective chart review of patients (0-21 years) who had a pacemaker with a ventricular lead placed between 2011 and 2017 was performed. Patients were divided into group A (LVEF <55% and/or >10% decline in LVEF within 12 months of pacemaker placement) and group B. Data have collected before and 1 and 12 months postpacemaker implantation. There were 30 patients in the group A and 60 in group B. At 1 and 12 months postpacemaker implantation, the LVEF was significantly lower while the A4C and QRS duration on electrocardiogram were significantly higher in the group A. While the LVEF and A4C became markedly abnormal in group A as early as 1 month, the A4C did not seem to demonstrate such marked abnormalities in group B. However, a sub-analysis of patients in the group A with preserved LVEF at 1 month demonstrated significant worsening in their A4C at that time. CONCLUSION: Myocardial deformation imaging may be a clinically useful tool for the prediction of a decline in LV systolic function following pacemaker implantation. Abnormalities in A4C seem to appear before LVEF decline and as soon as 1-month postpacemaker implantation.

Voltage mapping to guide pacemaker placement in patients with CHD.

Transvenous pacemaker implantation for sinus node dysfunction in patients with Fontan palliation presents the difficulty of finding suitable pacing tissue and the potential of causing vascular obstruction in a low-flow circuit. We describe a patient who underwent electro-anatomic voltage mapping to guide a transvenous single chamber lead within her Fontan baffle. This highlights the use of advanced mapping technologies for pacemaker implantation in complex cyanotic heart disease.

Atrioventricular block after congenital heart surgery: Analysis from the Pediatric Cardiac Critical Care Consortium.

OBJECTIVES: Our primary aims were to describe the contemporary epidemiology of postoperative high-grade atrioventricular block (AVB), the timing of recovery and permanent pacemaker (PPM) placement, and to determine predictors for development of and recovery from AVB. METHODS: Patients who underwent congenital heart surgery from August 2014 to June 2017 were analyzed for AVB using the Pediatric Cardiac Critical Care Consortium registry. Predictors of AVB with or without PPM were identified using multinomial logistic regression. We used these predictors to model the probability of PPM for the subgroup of patients with intraoperative complete AVB. RESULTS: We analyzed 15,901 surgical hospitalizations; 422 (2.7%) were complicated by AVB and 162 (1.0%) patients underwent PPM placement. In patients with transient AVB, 50% resolved by 2 days, and 94% resolved by 10 days. In patients who received a PPM, 50% were placed by 8 days and 62% were placed by 10 days. Independent risk factors associated with PPM compared with resolution of AVB were longer duration of cardiopulmonary bypass (relative risk ratio, 1.04; P = .023) and a high-risk operation (relative risk ratio, 2.59; P < .001). Among patients with complete AVB originating in the operating room, those with the highest predicted probability of PPM had a PPM placed only 77% of the time. CONCLUSIONS: In this cohort, postoperative AVB complicated almost 3% of congenital heart surgery cases and 1% of patients underwent PPM placement. Because almost all patients (94%) with transient AVB had resolution by 10 days, our results suggest there is limited benefit to delaying PPM placement beyond that time frame.

Safety of Sports for Young Patients With Implantable Cardioverter-Defibrillators: Long-Term Results of the Multinational ICD Sports Registry.

BACKGROUND: Despite safety concerns, many young patients with implantable cardioverter-defibrillators (ICDs) participate in sports. We undertook a prospective, multinational registry to determine the incidence of serious adverse events because of sports participation. The primary end points were death or resuscitated arrest during sports or injury during sports because of arrhythmia or shock. Secondary end points included system malfunction and incidence of ventricular arrhythmias requiring multiple shocks for termination. METHODS: Athletes with ICDs aged ≤21 years were included in this post hoc subanalysis of the ICD Sports Registry. Data on sports and clinical outcomes were obtained by phone interview and medical records review. ICD shocks and clinical details of lead malfunction were classified by 2 electrophysiologists. RESULTS: A total of 129 young athletes participating in competitive (n=117) or dangerous (n=12) sports were enrolled. The mean age was 16 years (range, 10-21; 40% female; 92% white). The most common diagnoses were long QT syndrome (n=49), hypertrophic cardiomyopathy (n=30), and congenital heart disease (n=16). The most common sports were basketball and soccer, including 79 varsity/junior varsity high school and college athletes. During a median follow-up of 42 months, 35 athletes (27%) received 38 shocks. There were no occurrences of death, arrest, or injury related to arrhythmia, during sports. There was 1 ventricular tachycardia/ventricular fibrillation storm during competition. Freedom from lead malfunction was 92.3% at 5 years and 79.6% at 10 years. CONCLUSIONS: Although shocks related to competition/practice are not uncommon, there were no serious adverse sequelae. Lead malfunction rates were similar to previously reported in unselected pediatric ICD populations. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00637754.

The utility of combined cardiopulmonary exercise stress testing in the evaluation of pediatric patients with chest pain.

INTRODUCTION: A cardiac cause is an extremely rare etiology of pediatric chest pain. Despite its low sensitivity/specificity, exercise stress testing (EST) is widely used to determine the prognosis in patients with suspected/established coronary disease. We aimed to look at the utility of a combined cardiopulmonary EST in the evaluation of pediatric patients with chest pain. METHODS: After institutional review board approval, a retrospective chart review was performed of all pediatric patients who were referred for an EST for chest pain from January 2014 to 2017. Patients with incomplete records, severe congenital heart disease, and a prior EST were excluded. RESULTS: A total of 389 patients met the inclusion criteria. Echocardiogram (ECHO) was performed on 333 (85.6%) patients and 43 (11%) previously unknown structural cardiac anomalies were identified. A total of 76 (19.5%) patients had an abnormal EST with the 3 most common causes being related to the respiratory system. Only four patients had both an abnormal exercise stress test and an incidental structural anomaly on ECHO but none of them had their symptoms recreated during the EST. CONCLUSION: Only 1% of patients previously undiagnosed with heart disease had an abnormal stress test and an incidental anomaly on ECHO. These ECHO anomalies were unlikely to be the cause of chest pain. Furthermore, since the majority of abnormal stress tests were secondary to a pulmonary cause, a complete cardiopulmonary EST may be an effective screening tool for certain patients presenting with chest pain. Our study emphasizes the need for performing a complete cardiopulmonary EST instead of an isolated cardiac stress test to maximize diagnostic efficiency and yield.