Vigorous Exercise in Patients With Congenital Long QT Syndrome: Results of the Prospective, Observational, Multinational LIVE-LQTS Study.

BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.

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.

Intracardiac echocardiography in paediatric and congenital cardiac ablation shortens procedure duration and improves success without complications.

AIMS: Common to adult electrophysiology studies (EPSs), intracardiac echocardiography (ICE) use in paediatric and congenital heart disease (CHD) EPS is limited. The purpose of this study was to assess the efficacy of ICE use and incidence of associated complications in paediatric and CHD EPS. METHODS AND RESULTS: This single-centre retrospective matched cohort study reviewed EPS between 2013 and 2022. Demographics, CHD type, and EPS data were collected. Intracardiac echocardiography cases were matched 1:1 to no ICE controls to assess differences in complications, ablation success, fluoroscopy exposure, procedure duration, and arrhythmia recurrence. Cases and controls with preceding EPS within 5 years were excluded. Intracardiac echocardiography cases without an appropriate match were excluded from comparative analyses but included in the descriptive cohort. We performed univariable and multivariable logistic regression to assess associations between variables and outcomes. A total of 335 EPS were reviewed, with ICE used in 196. The median age of ICE cases was 15 [interquartile range (IQR) 12-17; range 3-47] years, and median weight 57 [IQR 45-71; range 15-134] kg. There were no ICE-related acute or post-procedural complications. There were 139 ICE cases matched to no ICE controls. Baseline demographics and anthropometrics were similar between cases and controls. Fluoroscopy exposure (P = 0.02), procedure duration (P = 0.01), and arrhythmia recurrence (P = 0.01) were significantly lower in ICE cases. CONCLUSION: Intracardiac echocardiography in paediatric and CHD ablations is safe and reduces procedure duration, fluoroscopy exposure, and arrhythmia recurrence. However, not every arrhythmia substrate requires ICE use. Thoughtful selection will ensure the judicious and strategic application of ICE to enhance outcomes.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Ventricular arrhythmias following balloon-expandable transcatheter pulmonary valve replacement in the native right ventricular outflow tract.

BACKGROUND: Ventricular arrhythmia incidence in children and adolescents undergoing transcatheter pulmonary valve replacement (TPVR) within the native right ventricular outflow tract (nRVOT) is unknown. We sought to describe the incidence, severity, and duration of ventricular arrhythmias and identify associated risk factors in this population. METHODS: This was a retrospective cohort study of 78 patients <21 years of age who underwent TPVR within the nRVOT. Patients were excluded for pre-existing ventricular arrhythmia or antiarrhythmic use. Study variables included surgical history, valve replacement indication, valve type/size, and ventricular arrhythmia. Univariable logistic regression models were used to evaluate factors associated with ventricular arrhythmias, followed by subset analyses. RESULTS: Nonsustained ventricular arrhythmia occurred in 26/78 patients (33.3%). The median age at the procedure was 10.3 years (interquartle range [IQR]: 6.5, 12.8). Compared with other nRVOT types, surgical repair with transannular patch was protective against ventricular arrhythmia incidence: odds ratio (OR): 0.35 (95% confidence interval [CI], 0.13-0.95). Patient weight, valve type/size, number of prestents, and degree of stent extension into the RVOT were not associated with ventricular arrhythmia occurrence. Beta blocker was started in 16/26 (61.5%) patients with ventricular arrhythmia. One additional patient was lost to follow-up. The median beta blocker duration was 46 days (IQR 42, 102). Beta blocker was discontinued in 10 patients by 8-week follow-up and in the remaining four by 9 months. CONCLUSIONS: Though common after balloon-expandable TPVR within the nRVOT, ventricular arrhythmias were benign and transient. Antiarrhythmic medications were successfully discontinued in the majority at 6- to 8-week follow-up, and in all patients by 20 months.

Advancing the science of management of arrhythmic disease in children and adult congenital heart disease patients within the last 25 years.

This review article reflects how publications in EP Europace have contributed to advancing the science of management of arrhythmic disease in children and adult patients with congenital heart disease within the last 25 years. A special focus is directed to congenital atrioventricular (AV) block, the use of pacemakers, cardiac resynchronization therapy devices, and implantable cardioverter defibrillators in the young with and without congenital heart disease, Wolff-Parkinson-White syndrome, mapping and ablation technology, and understanding of cardiac genomics to untangle arrhythmic sudden death in the young.

Effects of cohort, genotype, variant, and maternal ß-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.

AIMS: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal ß-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS. METHODS AND RESULTS: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal ß-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or ß-adrenergic response) had lower FHR. Maternal ß-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity. CONCLUSION: Genotype, LQT1 variant, and maternal ß-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

Asymptomatic Wolff-Parkinson-White Syndrome: An Ounce of Prevention Is Worth the Risk of Cure.

PURPOSE OF REVIEW: With increased electrocardiogram screening, asymptomatic preexcitation has become more prevalent. Historically, the asymptomatic-symptomatic dichotomy has directed management. This approach warrants scrutiny, as asymptomatic Wolff-Parkinson-White (WPW) syndrome is not without risk. Children may be unreliable symptom reporters, have atypical arrhythmia symptoms, yet have years to become symptomatic. RECENT FINDINGS: In a large WPW study, symptomatic patients were more likely to undergo ablation than asymptomatic patients, yet, except for symptoms, there were no differences in clinical or electrophysiology study (EPS) characteristics. Present data confirm real risk in asymptomatic WPW-sudden death can be the first symptom. Although malignant arrhythmias correlate better with EPS risk stratification than with symptoms, EPS data are imperfect predictors. Unlike adults with WPW, children have yet to prove survivorship. Asymptomatic children must be treated differently than adults. Sudden death risk is low but front-loaded in the young. An aggressive approach to asymptomatic WPW is warranted in this era of highly successful, low-risk catheter ablations.

Patterns of Electrocardiographic Abnormalities in Children with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM), a common cardiomyopathy in children, is an important cause of morbidity and mortality. Early recognition and appropriate management are important. An electrocardiogram (ECG) is often used as a screening tool in children to detect heart disease. The ECG patterns in children with HCM are not well described.ECGs collected from an international cohort of children, and adolescents (≤ 21 years) with HCM were reviewed. 482 ECGs met inclusion criteria. Age ranged from 1 day to 21 years, median 13 years. Of the 482 ECGs, 57 (12%) were normal. The most common abnormalities noted were left ventricular hypertrophy (LVH) in 108/482 (22%) and biventricular hypertrophy (BVH) in 116/482 (24%) Of the patients with LVH/BVH (n = 224), 135 (60%) also had a strain pattern (LVH in 83, BVH in 52). Isolated strain pattern (in the absence of criteria for hypertrophy) was seen in 43/482 (9%). Isolated pathologic Q waves were seen in 71/482 (15%). Pediatric HCM, 88% have an abnormal ECG. The most common ECG abnormalities were LVH or BVH with or without strain. Strain pattern without hypertrophy and a pathologic Q wave were present in a significant proportion (24%) of patients. Thus, a significant number of children with HCM have ECG abnormalities that are not typical for "hypertrophy". The presence of the ECG abnormalities described above in a child should prompt further examination with an echocardiogram to rule out HCM.

Variation in provider compliance with sports restriction guidelines in children with an isolated bicuspid aortic valve.

BACKGROUND: Published guidelines for sports restriction for children with a bicuspid aortic valve remain controversial. We sought to describe practice variation and factors influencing sports restrictions in these children. METHODS: This retrospective single-centre study included children (7-18 years old) with an isolated bicuspid aortic valve at baseline from 1 January, 2005 to 31 December, 2014. Sports restrictions, factors potentially influencing decision-making, and outcomes were collected. Descriptive statistics and multivariable mixed-effects logistic regression models were performed with providers and patients as random effects. Provider variation was estimated using intraclass correlation coefficients. Odds ratios, 95% confidence intervals, and p-values were reported from the models. RESULTS: In 565 encounters (253 children; 34 providers), 41% recommended no sports restrictions, 40% recommended high-static and high-dynamic restrictions, and 19% had no documented recommendations. Based on published guidelines, 22% of children were inappropriately restricted while 30% were not appropriately restricted. The paediatric cardiology provider contributed to 37% of observed practice variation (p < 0.001). Sports restriction was associated with older age, males, greater ascending aorta z-score, and shorter follow-up interval. There were no aortic dissections or deaths and one cardiac intervention. CONCLUSION: Physicians frequently fail to document sports restrictions for children with a bicuspid aortic valve, and documented recommendations often conflict with published guidelines. Despite this, no adverse outcomes occurred. Providers accounted for a significant proportion of the variation in sports restrictions. Further research to provide evidence-based guidelines may improve provider compliance with activity recommendations in this population.

The high-density grid catheter: A safe adjunctive tool in pediatric and complex congenital heart disease patients.

INTRODUCTION: The safety and utility of the Advisor™ High-Density Grid mapping catheter (HDGC) in children and congenital heart disease (CHD) patients are not well described. METHODS: A single-center retrospective cohort study of pediatric and CHD patients undergoing electrophysiology study and ablation to determine the effect of HDGC use on outcomes including complications, fluoroscopy use, procedure duration, acute ablation success, and arrhythmia recurrence. RESULTS: HDGC was used in 74/261 (28.3%) cases. HDGC subjects differed by median age (17 vs. 13 years; p < 0.001), weight (68 vs. 50 kg; p < 0.001), and prevalence of significant CHD (42% vs. 3%; p < 0.001). Arrhythmia substrates were dissimilar: HGDC cases had higher frequencies of intra-atrial re-entrant tachycardia (25.7% vs. 0.5%), atrial flutter (8.1% vs. 1.1%), ectopic atrial tachycardia (13.5% vs. 3.7%), and premature ventricular contractions (9.5% vs. 0.5%), and lower incidences of atrioventricular re-entrant tachycardia (16.2% vs. 46.1%). Complications were rare (n = 5, 1.9%) with no significant difference between groups (p = 1.00). Procedure duration-but not fluoroscopy exposure-was significantly longer in HDGC cases (median 256 vs. 216 min, p < 0.001). Acute success was lower (93.2% vs. 99.4%; p = 0.01) and recurrences higher (13.2% vs. 3.8%; p = 0.016) in HDGC compared to non-HDGC cases. CONCLUSION: HDGC use in children and CHD patients is safe and not associated with higher complication rates. The lower acute success and higher recurrence rates in HDGC cases likely reflect a bias toward HDGC use in more complex arrhythmia substrates rather than less favorable ablation outcomes.

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.

Calmodulinopathies: throwing back the veil on the newest life-threatening genetic arrhythmia syndrome.

PURPOSE OF REVIEW: This review provides a basic understanding of the calmodulin gene and its role in calcium homeostasis. We outline the functional effects and clinical expression of CALM mutations and review disease expression and management. RECENT FINDINGS: Calmodulinopathies are rare life-threatening arrhythmia syndromes affecting young individuals. They are caused by mutations in any of the three genes (CALM 1-3) that encode calmodulin (CaM), a ubiquitously expressed Ca signaling protein with multiple targets that in the heart, modulates several ion channels. Patients express varied phenotypes: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, sudden death, idiopathic ventricular fibrillation, hypertrophic cardiomyopathy, or mixed disease. This is severe disease. Over half of 2019 International Calmodulin Registry patients experienced recurrent cardiac events despite management strategies that included: monotherapy and combination therapy with beta blockers, sodium channel blockers, other antiarrhythmics, sympathetic denervation, and pacing. Induced pluripotent stem cell-derived cardiomyocytes from patients harboring CALM mutations have provided a platform for better understanding pathogenic mechanisms and avenues for therapy. SUMMARY: Calmodulinopathies are among the more novel inherited arrhythmia syndromes. These are rare but highly lethal diseases with diverse clinical expressions. The practicing electrophysiologist should be aware these conditions, how to recognize them clinically, and understand the challenges in management.

MRI in pediatric and congenital heart disease patients with CIEDs and epicardial or abandoned leads.

BACKGROUND: Heart Rhythm Society guidelines outlining magnetic resonance imaging (MRI) in patients with cardiac implantable electronic devices (CIEDs) excluded children and epicardial or abandoned leads due to theoretical risks of harm. Research investigating these risks is lacking. The primary objective of our study is to determine the incidence of adverse events to patients or CIEDs from MRI imaging. The secondary objective is to describe CIED-related artifact on MRI images. METHODS: A single-center retrospective review was performed on all patients with CIEDs who underwent 1.5 Tesla MRI between July 2007 and May 2019. We subdivided patients among four cohorts: (1) patients <18 years of age, (2) epicardial leads, (3) abandoned endocardial leads, and (4) abandoned epicardial leads. Descriptive statistics pre- and post-MRI and at follow-up within 1.5 years were conducted. RESULTS: Fifty-four MRIs were performed on 40 patients. Median age was 21.2 years (IQR 12.0-25.0). Eighteen (33%) MRIs contained abandoned leads; 20 (37%) contained epicardial leads. Three patients, one with abandoned epicardial leads and two with abandoned endocardial leads, experienced mild discomfort at the CIED site. One adult with endocardial leads experienced a pause in the heart rate while programmed in a nonpacing mode. No clinically important changes to CIED parameters occurred. Nine MRIs (17%), especially those with functional cardiac imaging, were uninterpretable due to image artifact. CONCLUSION: In this study, pediatric and adult CHD patients with CIEDs, many with epicardial or abandoned leads, underwent MRIs without clinically significant complications. In some, CIED artifact reduced cardiac MRI image quality due to CIED position.

Calmodulin mutations and life-threatening cardiac arrhythmias: insights from the International Calmodulinopathy Registry.

AIMS: Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1-3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. METHODS AND RESULTS: A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1-5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0-8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. CONCLUSION: Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.

Impact of Obesity on Left Ventricular Thickness in Children with Hypertrophic Cardiomyopathy.

Obesity is associated with additional left ventricular hypertrophy (LVH) in adults with hypertrophic cardiomyopathy (HCM). It is not known whether obesity can lead to further LVH in children with HCM. Echocardiographic LV dimensions were determined in 504 children with HCM. Measurements of interventricular septal thickness (IVST) and posterior wall thickness (PWT), and patients' weight and height were recorded. Obesity was defined as a body mass index (BMI) ≥ 99th percentile for age and sex. IVST data was available for 498 and PWT data for 484 patients. Patient age ranged from 2 to 20 years (mean ± SD, 12.5 ± 3.9) and 340 (68%) were males. Overall, patient BMI ranged from 7 to 50 (22.7 ± 6.1). Obesity (BMI 18-50, mean 29.1) was present in 140 children aged 2-19.6 (11.3 ± 4.1). The overall mean IVST was 20.5 ± 9.6 mm and the overall mean PWT was 11.0 ± 8.4 mm. The mean IVST in the obese patients was 21.6 ± 10.0 mm and mean PWT was 13.3 ± 14.7 mm. The mean IVST in the non-obese patients was 20.1 ± 9.5 mm and mean PWT was 10.4 ± 4.3 mm. Obesity was not significantly associated with IVST (p = 0.12), but was associated with increased PWT (0.0011). Obesity is associated with increased PWT but not IVST in children with HCM. Whether obesity and its impact on LVH influences clinical outcomes in children with HCM needs to be studied.

The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry.

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.