Increased Ca2+ Transient Underlies RyR2-Related Left Ventricular Noncompaction.

BACKGROUND: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M+/-, has recently been linked to a new cardiac disorder termed RyR2 Ca2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M+/- loss-of-function mutation on cardiac structure and function. METHODS: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M+/- mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M+/- mutation. RESULTS: As in humans, RyR2-I4855M+/- mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M+/- mice were highly susceptible to electrical stimulation-induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M+/- mutation increased the peak Ca2+ transient but did not alter the L-type Ca2+ current, suggesting an increase in Ca2+-induced Ca2+ release gain. The RyR2-I4855M+/- mutation abolished sarcoplasmic reticulum store overload-induced Ca2+ release or Ca2+ leak, elevated sarcoplasmic reticulum Ca2+ load, prolonged Ca2+ transient decay, and elevated end-diastolic Ca2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca2+-calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca2+ handling proteins in the RyR2-I4855M+/- mutant compared with wild type. CONCLUSIONS: The RyR2-I4855M+/- mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M+/- mutation increases the peak Ca2+ transient by increasing the Ca2+-induced Ca2+ release gain and the end-diastolic Ca2+ level by prolonging Ca2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca2+ levels may underlie RyR2-associated LVNC.

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.

A Clinical Diagnostic Test for Calcium Release Deficiency Syndrome.

Importance: Sudden death and cardiac arrest frequently occur without explanation, even after a thorough clinical evaluation. Calcium release deficiency syndrome (CRDS), a life-threatening genetic arrhythmia syndrome, is undetectable with standard testing and leads to unexplained cardiac arrest. Objective: To explore the cardiac repolarization response on an electrocardiogram after brief tachycardia and a pause as a clinical diagnostic test for CRDS. Design, Setting, and Participants: An international, multicenter, case-control study including individual cases of CRDS, 3 patient control groups (individuals with suspected supraventricular tachycardia; survivors of unexplained cardiac arrest [UCA]; and individuals with genotype-positive catecholaminergic polymorphic ventricular tachycardia [CPVT]), and genetic mouse models (CRDS, wild type, and CPVT were used to define the cellular mechanism) conducted at 10 centers in 7 countries. Patient tracings were recorded between June 2005 and December 2023, and the analyses were performed from April 2023 to December 2023. Intervention: Brief tachycardia and a subsequent pause (either spontaneous or mediated through cardiac pacing). Main Outcomes and Measures: Change in QT interval and change in T-wave amplitude (defined as the difference between their absolute values on the postpause sinus beat and the last beat prior to tachycardia). Results: Among 10 case patients with CRDS, 45 control patients with suspected supraventricular tachycardia, 10 control patients who experienced UCA, and 3 control patients with genotype-positive CPVT, the median change in T-wave amplitude on the postpause sinus beat (after brief ventricular tachycardia at ≥150 beats/min) was higher in patients with CRDS (P < .001). The smallest change in T-wave amplitude was 0.250 mV for a CRDS case patient compared with the largest change in T-wave amplitude of 0.160 mV for a control patient, indicating 100% discrimination. Although the median change in QT interval was longer in CRDS cases (P = .002), an overlap between the cases and controls was present. The genetic mouse models recapitulated the findings observed in humans and suggested the repolarization response was secondary to a pathologically large systolic release of calcium from the sarcoplasmic reticulum. Conclusions and Relevance: There is a unique repolarization response on an electrocardiogram after provocation with brief tachycardia and a subsequent pause in CRDS cases and mouse models, which is absent from the controls. If these findings are confirmed in larger studies, this easy to perform maneuver may serve as an effective clinical diagnostic test for CRDS and become an important part of the evaluation of cardiac arrest.

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

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

RYR2-ryanodinopathies: from calcium overload to calcium deficiency.

The sarcoplasmatic reticulum (SR) cardiac ryanodine receptor/calcium release channel RyR2 is an essential regulator of cardiac excitation-contraction coupling and intracellular calcium homeostasis. Mutations of the RYR2 are the cause of rare, potentially lethal inherited arrhythmia disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described more than 20 years ago and is the most common and most extensively studied cardiac ryanodinopathy. Over time, other distinct inherited arrhythmia syndromes have been related to abnormal RyR2 function. In addition to CPVT, there are at least two other distinct RYR2-ryanodinopathies that differ mechanistically and phenotypically from CPVT: RYR2 exon-3 deletion syndrome and the recently identified calcium release deficiency syndrome (CRDS). The pathophysiology of the different cardiac ryanodinopathies is characterized by complex mechanisms resulting in excessive spontaneous SR calcium release or SR calcium release deficiency. While the vast majority of CPVT cases are related to gain-of-function variants of the RyR2 protein, the recently identified CRDS is linked to RyR2 loss-of-function variants. The increasing number of these cardiac 'ryanodinopathies' reflects the complexity of RYR2-related cardiogenetic disorders and represents an ongoing challenge for clinicians. This state-of-the-art review summarizes our contemporary understanding of RYR2-related inherited arrhythmia disorders and provides a systematic and comprehensive description of the distinct cardiac ryanodinopathies discussing clinical aspects and molecular insights. Accurate identification of the underlying type of cardiac ryanodinopathy is essential for the clinical management of affected patients and their families.

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.

Current gaps in knowledge in inherited arrhythmia syndromes.

The 3 most common inherited arrhythmia syndromes-Brugada syndrome, congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-were initially described in the previous century. Since then, research has evolved, which has enabled us to identify patients prior to the onset of potentially life-threatening symptoms. However, there are significant gaps in knowledge that complicate clinical management of these patients today. With this review paper, we aim to highlight the most important knowledge gaps in clinical research of these inherited arrhythmia syndromes.

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.

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.

Potential overdiagnosis of long QT syndrome using exercise stress and QT stand testing in children and adolescents with a low probability of disease.

BACKGROUND: Long QT syndrome (LQTS) is a dangerous arrhythmia disorder that often presents in childhood and adolescence. The exercise stress test (EST) and QT-stand test may unmask QT interval prolongation at key heart rate transition points in LQTS, but their utility in children is debated. OBJECTIVE: To determine if the QT-stand test or EST can differentiate children with a low probability of LQTS from those with confirmed LQTS. METHODS: This retrospective study compares the corrected QT intervals (QTc) of children (<19 years) during the QT-stand test and EST. Patients were divided into three groups for comparison: confirmed LQTS (n = 14), low probability of LQTS (n = 14), and a control population (n = 9). RESULTS: Using the Bazett formula, confirmed LQTS patients had longer QTc intervals than controls when supine, standing, and at 3-4 min of recovery (p ≤ .01). Patients with a low probability of LQTS had longer QTc duration upon standing (p = .018) and at 1 min of recovery (p = .016) versus controls. There were no significant QTc differences at any transition point between low probability and confirmed LQTS. Using the Fridericia formula, differences in QTc between low probability and confirmed LQTS were also absent at the transition points examined, except at 1 min into exercise, where low probability patients had shorter QTc intervals (437 vs. 460 ms, p = .029). CONCLUSION: The diagnostic utility of the QT stand test and EST remains unclear in pediatric LQTS. The formula used for heart rate correction may influence accuracy, and dynamic T-U wave morphology changes may confound interpretation in low probability situations.

The Effect of Carbetocin Dose on Transmural Dispersion of Myocardial Repolarization in Healthy Parturients Scheduled for Elective Cesarean Delivery Under Spinal Anesthesia: A Prospective, Randomized Clinical Trial.

BACKGROUND: QT interval prolongation is associated with torsade de pointes but remains a poor predictor of drug torsadogenicity. Increased transmural dispersion of myocardial repolarization (TDR), measured as the time interval between the peak and end of the T wave (Tp-e), is a more reliable predictor. Carbetocin is recommended as an uterotonic in patients undergoing cesarean delivery (CD), but its effect on Tp-e is unknown. We evaluated the effect of carbetocin dose on Tp-e and Bazett-corrected QT intervals (QTc) during elective CD under spinal anesthesia. METHODS: On patient consent, 50 healthy parturients undergoing elective CD with a standardized spinal anesthetic and phenylephrine infusion were randomized to receive an intravenous (IV) bolus of carbetocin 50 µg (C50) or 100 µg (C100) via an infusion pump over 1 minute. A 12-lead electrocardiogram (ECG) was obtained at baseline, 5 minutes after spinal anesthesia, then 5 and 10 minutes after carbetocin administration. A cardiologist blinded to group and timing of ECGs measured QTc and Tp-e using Emori's criteria. Primary outcome was the change in Tp-e at 5 minutes after carbetocin administration between the C50 and C100 groups and within each group compared to baseline values. Secondary outcomes included occurrence of arrhythmias, changes in QTc at 5 and 10 minutes after carbetocin, changes in both QTc and Tp-e after spinal anesthesia compared to baseline between and within groups. RESULTS: Data from 41 parturients with a mean (standard deviation [SD]) age of 39.0 (0.7) years and weight of 75.0 (12.0) kg were analyzed. Between groups, at 5 minutes after carbetocin administration, Tp-e in C100 was 4.1 milliseconds longer compared to C50 (95% confidence interval [CI], 0.8-7.5; P = .01). Within groups, at 5 minutes after carbetocin administration, C50 did not significantly increase Tp-e compared to baseline (mean difference [MD] 1.9 milliseconds; 95% CI, -0.95 to 4.81 milliseconds; P = .42) but C100 did (MD 5.1 milliseconds; 95% CI, 2.1-8.1; P = .003). QTc increased significantly within C50 and C100 groups at 5 and 10 minutes after carbetocin administration (all P < .001), with no between-group differences. There were no arrhythmias. CONCLUSIONS: Tp-e was unaffected by C50 IV given after CD in healthy parturients under spinal anesthesia, but minimally prolonged by C100. The increase in QTc after carbetocin administration was statistically significant, but with no apparent dose-dependent effect. The minimal Tp-e prolongation at the higher dose is unlikely to have any clinically significant impact on TDR and therefore the risk of inducing torsade de pointes is low.

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.

Implantable cardioverter-defibrillators in previously undiagnosed patients with catecholaminergic polymorphic ventricular tachycardia resuscitated from sudden cardiac arrest.

AIMS: In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), implantable cardioverter-defibrillator (ICD) shocks are sometimes ineffective and may even trigger fatal electrical storms. We assessed the efficacy and complications of ICDs placed in patients with CPVT who presented with a sentinel event of sudden cardiac arrest (SCA) while undiagnosed and therefore untreated. METHODS AND RESULTS: We analysed 136 patients who presented with SCA and in whom CPVT was diagnosed subsequently, leading to the initiation of guideline-directed therapy, including ß-blockers, flecainide, and/or left cardiac sympathetic denervation. An ICD was implanted in 79 patients (58.1%). The primary outcome of the study was sudden cardiac death (SCD). The secondary outcomes were composite outcomes of SCD, SCA, appropriate ICD shocks, and syncope. After a median follow-up of 4.8 years, SCD had occurred in three patients (3.8%) with an ICD and none of the patients without an ICD (P = 0.1). SCD, SCA, or appropriate ICD shocks occurred in 37 patients (46.8%) with an ICD and 9 patients (15.8%) without an ICD (P < 0.0001). Inappropriate ICD shocks occurred in 19 patients (24.7%) and other device-related complications in 22 patients (28.9%). CONCLUSION: In previously undiagnosed patients with CPVT who presented with SCA, an ICD was not associated with improved survival. Instead, the ICD was associated with both a high rate of appropriate ICD shocks and inappropriate ICD shocks along with other device-related complications. Strict adherence to guideline-directed therapy without an ICD may provide adequate protection in these patients without all the potential disadvantages of an ICD.

Chronotropic incompetence as a risk predictor in children and young adults with catecholaminergic polymorphic ventricular tachycardia.

INTRODUCTION: Risk stratification tools for catecholaminergic polymorphic ventricular tachycardia (CPVT) are limited. The exercise stress test (EST) is the most important diagnostic and prognostic test. We aimed to determine whether heart rate (HR) and blood pressure (BP) response during EST were associated with the risk of arrhythmias. MATERIALS AND METHODS: We studied the association between HR and BP response and ventricular arrhythmia burden on EST in 20 CPVT patients. HR reserve values <80% and ≤62% were used to define chronotropic incompetence (CI) off and on therapy, respectively. Symptoms and ventricular arrhythmia score (VAS) in all patients with respect to CI and BP during index EST off therapy and on maximal therapy were compared. RESULTS: CI in CPVT patients off therapy was associated with a worse VAS during EST (P = .046). Patients with CI also more frequently presented with syncope and/or cardiac arrest compared to patients with a normal chronotropic response (P = .008). Once on therapy, patients with CI had similar VAS compared to patients without CI (P = .50), suggesting that treatment attenuates risk related to CI. Patients with CI also had a lower peak systolic BP (P = .041) which persisted on maximal therapy (P = .033). CONCLUSION: Untreated CPVT patients with CI have more ventricular arrhythmias than those without CI. This may serve as a simple disease prognosticator that can be modified by antiarrhythmic therapy. A mechanistic link between CI and arrhythmia susceptibility remains unknown. Larger studies are needed to confirm and establish the mechanism of these findings.

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.

Catecholaminergic polymorphic ventricular tachycardia: a model for genotype-specific therapy.

PURPOSE OF REVIEW: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening syndrome defined by exercise-induced or emotion-induced ventricular arrhythmias, typically caused by gain-of-function mutations in RYR2-encoded ryanodine receptor-2 (RyR2). This review will discuss recent advances and ongoing challenges in devising genotype-specific CPVT therapies. RECENT FINDINGS: CPVT patients were once universally thought to be at high risk of sudden death; however, as more cases emerge, CPVT is being re-defined as a complex syndrome of variable expressivity. Treatment was traditionally limited to ß-blockers and implantable cardioverter defibrillators, and although ß-blockers remain a mainstay of treatment, implantable cardioverter defibrillator use is associated with adverse events and should be limited. New applications for older therapies, like flecainide and cardiac denervation, appear to better target the mechanistic basis of CPVT arrhythmias. Recent advances in our understanding of RyR2 structure and function can help in identifying novel therapeutic targets. SUMMARY: CPVT is usually related to RyR2 or associated proteins. Emerging studies reveal several genotype-phenotype correlations, which may eventually influence therapeutic decision-making. Flecainide has improved CPVT outcomes and will likely have broader clinical indications in the near future. Gene therapy has shown promise in animal models but has yet to be studied in humans. Sudden death can occur as a sentinel symptom, making preventive therapy that targets molecular mechanism(s) of arrhythmia a key area of ongoing investigation. VIDEO ABSTRACT.

A novel RYR2 loss-of-function mutation (I4855M) is associated with left ventricular non-compaction and atypical catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy usually caused by gain-of-function mutations ryanodine receptor type-2 (RyR2). Left ventricular non-compaction (LVNC) is an often genetic cardiomyopathy. A rare LVNC-CPVT overlap syndrome may be caused by exon 3 deletion in RyR2. We sought to characterize the phenotypic spectrum and molecular basis of a novel RyR2 mutation identified in a family with both conditions. METHODS: Several members of an affected family underwent clinical and genetic assessments. A homology model of the RyR2 pore-region was generated to predict the location and potential impact of their RyR2 mutation. Ca2+-release assays were performed to characterize the functional impact of the RyR2 mutant expressed in HEK293 cells. RESULTS: A multigenerational family presented with a history of sudden death and a phenotype of atypical CPVT and LVNC. Genetic testing revealed a RYR2 mutation (I4855M) in two affected individuals. A homology model of the RyR2 pore-region showed that the I4855M mutant reside is located in the highly conserved 'inner vestibule', a water-filled cavity. I4855M may interfere with Ca2+ permeation and affect interactions between RyR2 pore subunits, and is thus predicted in silico to be damaging. Expression and functional studies in HEK293 cells revealed that I4855M inhibited caffeine-induced Ca2+ release and exerted a dominant-negative impact on wild type RyR2. CONCLUSIONS: This study identifies a potentially lethal overlapping syndrome of LVNC and atypical CPVT related to a novel RYR2 variant. Structural and functional studies suggest that this is a loss-of-function mutation, which exerts a dominant-negative effect on wild type RyR2.

Advances in the diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia.

Since the sentinel description of exercise-triggered ventricular arrhythmias in 21 children, our recognition and understanding of catecholaminergic polymorphic ventricular tachycardia has improved substantially. A variety of treatments are now available, but reaching a diagnosis before cardiac arrest remains a challenge. Most cases are related to variants in the gene encoding for ryanodine receptor-2 (RyR2), which mediates calcium-induced calcium release. Up to half of cases remain genetically elusive. The condition is presently incurable, but one basic intervention, the universal administration of ß-blockers, has improved survival. In the past, implantable cardioverter-defibrillators (ICDs) were frequently implanted, especially in those with a history of cardiac arrest. Treatment limitations include under-dosing and poor compliance with ß-blockers, and potentially lethal ICD-related electrical storm. Newer therapies include flecainide and sympathetic ganglionectomy. Limited data have suggested that genotype may predict phenotype in catecholaminergic polymorphic ventricular tachycardia, including a higher risk of life-threatening cardiac events in subjects with variants in the C-terminus of ryanodine receptor-2 (RyR2). At present, international efforts are underway to better understand this condition through large prospective registries. The recent publication of gene therapy in an animal model of the recessive form of the disease highlights the importance of improving our understanding of the genetic underpinnings of the disease.