Hypertrophic Cardiomyopathy and Ventricular Preexcitation in the Young: Cause and Accessory Pathway Characteristics.

BACKGROUND: The cause of hypertrophic cardiomyopathy (HCM) in the young is highly varied. Ventricular preexcitation (preexcitation) is well recognized, yet little is known about the specificity for any cause and the characteristics of the responsible accessory pathways (AP). METHODS: Retrospective cohort study of patients <21 years of age with HCM/preexcitation from 2000 to 2022. The cause of HCM was defined as isolated HCM, storage disorder, metabolic disease, or genetic syndrome. Atrioventricular AP (true AP) were distinguished from fasciculoventricular fibers (FVF) using standard invasive electrophysiology study criteria. AP were defined as high risk if any of the following were <250 ms: shortest preexcited RR interval in atrial fibrillation, shortest paced preexcited cycle length, or anterograde AP effective refractory period. RESULTS: We identified 345 patients with HCM and 28 (8%) had preexcitation (isolated HCM, 10/220; storage disorder, 8/17; metabolic disease, 5/19; and genetic syndrome, 5/89). Six (21%) patients had clinical atrial fibrillation (1 with shortest preexcited RR interval <250 ms). Twenty-two patients underwent electrophysiology study which identified 23 true AP and 16 FVF. Preexcitation was exclusively FVF mediated in 8 (36%) patients. Five (23%) patients had AP with high-risk conduction properties (including ≥1 patient in each etiologic group). Multiple AP were seen in 8 (36%) and AP plus FVF in 10 (45%) patients. Ablation was acutely successful in 13 of 14 patients with recurrence in 3. One procedure was complicated by complete heart block after ablation of a high-risk midseptal AP. There were significant differences in QRS amplitude and delta wave amplitude between groups. There were no surface ECG features that differentiated AP from FVF. CONCLUSIONS: Young patients with HCM and preexcitation have a high likelihood of underlying storage disease or metabolic disease. Nonisolated HCM should be suspected in young patients with large QRS and delta wave amplitudes. Surface ECG is not adequate to discriminate preexcitation from a benign FVF from that secondary to potentially life-threatening AP.

Left Ventricular Systolic Dysfunction in Patients Diagnosed With Hypertrophic Cardiomyopathy During Childhood: Insights From the SHaRe Registry.

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe (Sarcomeric Human Cardiomyopathy Registry) were analyzed. LVSD was defined as left ventricular ejection fraction <50% on echocardiographic reports. Prognosis was assessed by a composite of death, cardiac transplantation, and left ventricular assist device implantation. Predictors of developing incident LVSD and subsequent prognosis with LVSD were assessed using Cox proportional hazards models. RESULTS: We studied 1010 patients diagnosed with HCM during childhood (<18 years of age) and compared them with 6741 patients with HCM diagnosed as adults. In the pediatric HCM cohort, median age at HCM diagnosis was 12.7 years (interquartile range, 8.0-15.3), and 393 (36%) patients were female. At initial SHaRe site evaluation, 56 (5.5%) patients with childhood-diagnosed HCM had prevalent LVSD, and 92 (9.1%) developed incident LVSD during a median follow-up of 5.5 years. Overall LVSD prevalence was 14.7% compared with 8.7% in patients with adult-diagnosed HCM. Median age at incident LVSD was 32.6 years (interquartile range, 21.3-41.6) for the pediatric cohort and 57.2 years (interquartile range, 47.3-66.5) for the adult cohort. Predictors of developing incident LVSD in childhood-diagnosed HCM included age <12 years at HCM diagnosis (hazard ratio [HR], 1.72 [CI, 1.13-2.62), male sex (HR, 3.1 [CI, 1.88-5.2), carrying a pathogenic sarcomere variant (HR, 2.19 [CI, 1.08-4.4]), previous septal reduction therapy (HR, 2.34 [CI, 1.42-3.9]), and lower initial left ventricular ejection fraction (HR, 1.53 [CI, 1.38-1.69] per 5% decrease). Forty percent of patients with LVSD and HCM diagnosed during childhood met the composite outcome, with higher rates in female participants (HR, 2.60 [CI, 1.41-4.78]) and patients with a left ventricular ejection fraction <35% (HR, 3.76 [2.16-6.52]). CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

Current management of inherited arrhythmia syndromes associated with the cardiac ryanodine receptor.

PURPOSE OF REVIEW: Gain-of-function variants in the gene encoding the cardiac ryanodine receptor ( RYR2 ) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). The exercise stress test (EST) has long been fundamental in diagnosis and management, but recent work has further explored its role. A new entity termed calcium release deficiency syndrome (CRDS) has been associated with loss-of-function RYR2 variants and a different arrhythmic phenotype. RECENT FINDINGS: Standard EST is not perfectly reproducible with regards to provocation of arrhythmia in CPVT. A newly described burst EST protocol may be more sensitive in this regard. Nadolol is the most effective beta blocker in CPVT, though arrhythmic events remain frequent and dual therapy with flecainide and/or left cardiac sympathetic denervation may add protection. A recent report renews debate regarding the use of implantable defibrillator therapy in CPVT. CRDS is characterized by later age of presentation, normal/near normal EST, and ventricular arrhythmia induced by a novel ventricular stimulation protocol. SUMMARY: Burst EST may aid in the diagnosis and management of CPVT. Nadolol is the preferred beta blocker in CPVT, and consideration should be given to early dual therapy. CRDS should be suspected in patients with arrhythmic events, rare RYR2 variants, and a phenotype inconsistent with CPVT.

Gene Therapy for Catecholaminergic Polymorphic Ventricular Tachycardia.

Over the last three decades, the genetic basis of various inherited arrhythmia syndromes has been elucidated, providing key insights into cardiomyocyte biology and various regulatory pathways associated with cellular excitation, contraction, and repolarisation. As varying techniques to manipulate genetic sequence, gene expression, and different cellular pathways have become increasingly defined and understood, the potential to apply various gene-based therapies to inherited arrhythmia has been explored. The promise of gene therapy has generated significant interest in the medical and lay press, providing hope for sufferers of seemingly incurable disorders to imagine a future without repeated medical intervention, and, in the case of various cardiac disorders, without the risk of sudden death. In this review, we focus on catecholaminergic polymorphic ventricular tachycardia (CPVT), discussing the clinical manifestations, genetic basis, and molecular biology, together with current avenues of research related to gene therapy.

Radiofrequency Catheter Ablation for Pediatric Atrioventricular Nodal Reentrant Tachycardia: Impact of Age on Procedural Methods and Durable Success.

Background Catheter-based slow-pathway modification (SPM) is the treatment of choice for symptomatic atrioventricular nodal reentrant tachycardia (AVNRT). We sought to investigate the interactions between patient age and procedural outcomes in pediatric patients undergoing catheter-based SPM for AVNRT. Methods and Results A retrospective cohort study was performed, including consecutive patients undergoing acutely successful SPM for AVNRT from 2008 to 2017. Those with congenital heart disease, cardiomyopathy, and accessory pathways were excluded. Patients were stratified by age quartile at time of SPM. The primary outcome was AVNRT recurrence. A total of 512 patients underwent successful SPM for AVNRT. Age quartile 1 had 129 patients with a median age and weight of 8.9 years and 30.6 kg, respectively. Radiofrequency energy was used in 98% of cases. Follow-up was available in 447 (87%) patients with a median duration of 0.8 years (interquartile range, 0.2-2.5 years). AVNRT recurred in 22 patients. Multivariable Cox proportional hazard modeling identified atypical AVNRT (hazard ratio [HR], 5.83; 95% CI, 2.01-16.96; P=0.001), dual atrioventricular nodal only (HR, 4.09; 95% CI, 1.39-12.02; P=0.011), total radiofrequency lesions (HR, 1.06 per lesion; 95% CI, 1.01-1.12; P=0.032), and the use of a long sheath (HR, 3.52; 95% CI, 1.23-10.03; P=0.010) as predictors of AVNRT recurrence; quartile 1 patients were not at higher risk of recurrence (HR, 0.45; 95% CI, 0.10-1.97; P=0.29). Complete heart block requiring permanent pacing occurred in one quartile 2 patient at 14.9 years of age. Conclusions Pediatric AVNRT can be treated with radiofrequency-SPM with high procedural efficacy and minimal risk of complications, including heart block. Atypical AVNRT and dual atrioventricular nodal physiology without inducible tachycardia remain challenging substrates.

Cascade testing for inherited cardiac conditions: Risk perception and screening after a negative genetic test result.

First-degree relatives of a proband with an inherited cardiac condition (ICC) are offered predictive genetic testing for the pathogenic or likely pathogenic (P/LP) cardiac gene variant (CGV) to clarify their risk for the familial condition. Relatives who test negative for a familial P/LP CGV typically do not require longitudinal cardiac surveillance. To our knowledge, no previous study has investigated adjustment to risk reduction and subsequent screening practices in genotype-negative relatives from an ICC population. We thus investigated risk perception and ongoing screening practices in genotype-negative adults who received cardiac genetic counseling. Correlations between clinical and demographic variables and risk perception and screening practices were also investigated. On average, participants (n = 71) reported a perceived 19.5% lifetime risk of developing the ICC in their family, despite their negative genetic test result. The majority (54%) of participants reported having undergone cardiac screening after disclosure of their negative result. There were no significant correlations between clinical and demographic variables and risk perception or screening practices. Furthermore, risk perception was not found to impact the likelihood of cardiac screening. These findings suggest that even with comprehensive cardiac genetic counseling, a proportion of this population did not accurately comprehend or recall their cardiac disease risk. Additional interventions beyond traditional result disclosure should be explored to help genotype-negative individuals adjust to their reduction in risk for a familial ICC.

Population Prevalence of Premature Truncating Variants in Plakophilin-2 and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: A UK Biobank Analysis.

BACKGROUND: Truncating variants in the desmosomal gene PKP2 (PKP2tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity. METHODS: We identified individuals with PKP2tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed. RESULTS: PKP2tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10-4). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2tv, with 25 PKP2tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2tv was 0.047 (95% CI, 0.001-0.268; P=2.43×10-6), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate PKP2tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2tv (7.9% versus 4.3%; odds ratio, 2.11; P=0.005). CONCLUSIONS: PKP2tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2tv cause ARVC in combination with associated genetic and environmental risk factors.

Sudden Cardiac Arrest in the Paediatric Population.

Sudden cardiac arrest in the young is a rare event with a range of potential causes including cardiomyopathies, ion channelopathies, and autonomic nervous system dysfunction. Investigations into the cause involve a multidisciplinary team, including cardiologists, geneticists, and psychologists. In addition to a detailed medical history, family history and circumstances surrounding the event are important in determining the cause. Clinical investigations including an electrocardiogram are fundamental in diagnosis and should be interpreted cautiously because some children may have atypical presentations and an evolving phenotype. The potential for misdiagnosis exists that could lead to incorrect long-term management strategies. If an inherited condition is suspected, genetic testing of the patient and cascade screening of family members is recommended with genetic counselling and psychological support. Medical management is left to the treating physician acknowledging that a clear diagnosis cannot be made in approximately half of cases. Secondary prevention implantable defibrillators are widely deployed but can be associated with complications in young patients. A plan for safe return to activity is recommended along with a proper transition of care into adulthood. Broad screening of the general population for arrhythmia syndromes is not recommended; preventative measures include screening paediatric patients for risk factors by their primary care physician. Several milestone events or activities that take place in youth could be used as opportunities to promote safety. Further work into risk stratification of this paediatric population through patient registries and greater awareness of cardiopulmonary resuscitation and automated external defibrillator use in saving lives is warranted.

L'arrêt cardiaque subit chez les enfants est un événement rare dont les causes possibles comprennent la cardiomyopathie, la maladie des canaux ioniques ou une dysfonction du système nerveux autonome. Pour cerner la cause exacte, on fait appel à une équipe multidisciplinaire composée notamment de cardiologues, de généticiens et de psychologues. En plus de recueillir les antécédents médicaux complets du patient, il est également important de s'enquérir des antécédents familiaux ainsi que des circonstances entourant l'événement. Les examens cliniques comme un électrocardiogramme sont par ailleurs essentiels pour établir le diagnostic, mais doivent être interprétés avec prudence, car chez certains enfants, le tableau peut être atypique et le phénotype peut évoluer. Une erreur de diagnostic pourrait fausser la stratégie de prise en charge à long terme. Si l'on soupçonne une cause héréditaire, un dépistage génétique est recommandé pour le patient et pour chacun des membres de sa famille de même qu'une consultation génétique et un soutien psychologique. Il revient au médecin traitant de déterminer la conduite à suivre et de ne pas perdre de vue que, dans environ la moitié des cas, il n'est pas possible de poser un diagnostic avec certitude. Les défibrillateurs implantables sont largement employés en prophylaxie secondaire, mais s'accompagnent d'un risque de complications chez les jeunes patients. Un plan de retour prudent à l'activité physique est recommandé, et le jeune patient devra être suivi jusqu'à l'âge adulte. Le dépistage systématique des symptômes de l'arythmie dans la population générale n'est pas recommandé. En revanche, le médecin de première ligne peut, à titre préventif, évaluer les facteurs de risque chez les patients pédiatriques. Plusieurs événements marquants ou étapes clés dans la vie de l'enfant pourraient être l'occasion de promouvoir les mesures de sécurité à cet égard. Enfin, il est nécessaire d'effectuer d'autres études sur la stratification des risques dans la population pédiatrique à l'aide des registres de patients et de promouvoir les manœuvres de réanimation cardiorespiratoire ainsi que le recours aux défibrillateurs externes automatisés pour sauver des vies.

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.

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

Accessory pathway ablation in Ebstein anomaly: A challenging substrate.

BACKGROUND: Catheter ablation of accessory pathways (APs) in Ebstein anomaly (EA) has been associated with a high recurrence risk. OBJECTIVE: The purpose of this study was to compare outcomes of AP ablation in EA in an early (1990-2004) vs a recent (2005-2019) era and identify variables associated with recurrence. METHODS: A retrospective review of all catheter ablations for supraventricular tachycardia in EA at our institution was performed. RESULTS: We identified 76 patients with median (25th-75th quartiles) age 9 (2.6-13.3) years. Of these patients, 52 had AP alone, 12 had atrial flutter, 3 had atrioventricular nodal reentrant tachycardia, and 9 had AP plus at least 1 additional arrhythmia. Of the 61 patients with APs, a total of 78 separate APs were identified: 40 right-sided, 37 septal, and 1 left-sided. Acute success for AP first procedure was 89% and did not differ between early and recent eras (89% vs 88%; P = .48). However, 19 patients (31%) required repeat procedures (average 1.4 per patient) due to AP recurrence or ablation failure at first attempt. In comparison to early era, recent era ablations had significantly lower recurrence rates at 1 year (62% vs 19%; P = .005). At median follow-up of 2.5 (0.2-7) years, ultimate AP elimination after all procedures was 93%. Younger age at time of electrophysiological study (<2 vs 12-47 years: hazard ratio [HR] 7.3; P = .003) and ablation era (early era vs recent era: HR 3.65; P = .009) predicted recurrence. CONCLUSION: Outcomes for AP ablation in patients with EA have improved, but there is still a relatedly high recurrence risk requiring repeat procedures.

Lead age as a predictor for failure in pediatrics and congenital heart disease.

BACKGROUND: Pediatric and congenital heart disease (CHD) patients have a high rate of transvenous (TV) lead failure. OBJECTIVE: To determine whether TV lead age can aid risk assessment for lead failure to guide the decision of whether a lead should be replaced or reused at the time of a generator change. METHODS: Retrospective cohort study of patients <21 years old undergoing TV device implant from 2000 to 2014 at our institution. Patient, device, and lead variables were collected. Leads were compared in groups based on how many generator changes were completed. RESULTS: A total of 393 leads in 257 patients met inclusion criteria, 60 leads failed (15%). Failed leads were more likely to have not yet undergone generator change (p = .048). CHD (p = .045), Tendril lead type (p = .02) and silicone insulation (p = .02) were associated with failure. In multivariate analysis, younger leads (p = .022), number of generator changes (p = .003), CHD (p = .005) and silicone insulation (p = .004) remained significant while Tendril lead type did not (p = .052). Survival curves show an early decline around 4 years. CONCLUSIONS: Lead failure rate in pediatric and CHD patients is high. Leads that have not yet undergone a generator change were more likely to fail in this cohort. The strategy of serial replacement based on lead age needs further research to justify in this population.

2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

Risk Factors for Early Recurrence Following Ablation for Accessory Pathways: The Role of Consolidation Lesions.

BACKGROUND: Atrioventricular reentrant tachycardia is common in children. Catheter ablation is increasingly used as a first-line therapy with a high acute success rate, but recurrence during follow-up remains a concern. The aim of this study was to identify risk factors for recurrence after accessory pathway (AP) ablation. METHODS: Retrospective cohort study including patients who underwent AP ablation between 2013 and 2018. Cox proportional hazards model was used to examine the association between patient and procedural characteristics and recurrence during follow-up. RESULTS: From 558 AP ablation procedure, 542 (97%) were acutely successful. During a median follow-up of 0.4 (interquartile range, 0.1-1.4) years, there were 42 (8%) patients with documented recurrence. On univariate analysis, early recurrence was associated with younger age, congenital heart disease, multiple AP, AP location (right sided and posteroseptal versus left sided), cryoablation (versus radiofrequency), empirical ablation, the lack of full power radiofrequency lesions (<50 W), radiofrequency consolidation time <90 seconds and the use of fluoroscopy without a 3-dimensional electroanatomic mapping system. On multivariable analysis, only multiple AP (hazard ratio, 2.78 [95% CI, 1.063-4.74]) and radiofrequency consolidation time < 90 seconds (hazard ratio, 4.38 [95% CI, 1.92-9.51]) remained significantly associated with early recurrence; this association remained true when analyzed in subgroups by pathway location for right and left free wall AP. CONCLUSIONS: In our institutional experience, radiofrequency consolidation time <90 seconds after ablation of AP was associated with an increased risk of early recurrence.

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.

Value of provocative electrophysiology testing in the management of pediatric patients after congenital heart surgery.

OBJECTIVE: To determine the impact of provocative electrophysiology testing in postoperative congenital heart disease (CHD) patients on the management of supraventricular tachycardia (SVT) and clinical outcomes. METHODS: This is a retrospective study including patients <18 years of age with surgery for CHD who had postoperative SVT between 2006 and 2017. Postoperative outcomes were compared between patients with and without postoperative electrophysiology testing using the Wilcoxon rank sum test, Fisher's exact test, Kaplan-Meier method with the log-rank test, and Cox proportional hazard model. RESULTS: From 341 patients who had SVT after surgery for CHD, 65 (19%) had postoperative electrophysiology testing. There was no significant difference in baseline patient characteristics or surgical complexity between patients with and without electrophysiology testing. Patients with inducible SVT on electrophysiology testing were more likely to have recurrence of SVT prior to hospital discharge with an odds ratio 4.0 (95% confidence interval 1.3, 12.0). Patients who underwent postoperative electrophysiology testing had shorter intensive care unit (12 [6, 20] vs 16 [9, 32] days, HR 2.1 [95% CI 1.6, 2.8], P < .001) and hospital (25 [13, 38] vs 31 [18, 54] days, HR 1.8 [95% CI 1.4, 2.4], P < .001) length of stay. CONCLUSION: Postoperative electrophysiology testing was associated with improved postoperative outcomes, likely related to the ability to predict recurrence of arrhythmia and tailored antiarrhythmic management.