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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 Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction RESULTS: We studied 1010 patients diagnosed with HCM during childhood ( 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.

Background: Previous studies on lone/unexplained atrial fibrillation and atrial flutter (AF) did not exclude patients with contemporary secondary AF triggers. We characterized unexplained AF using a strict definition, and compared it to secondary AF. Methods: In this population-based study, unexplained AF was defined by the lack of any identifiable triggering medical/surgical diagnosis. Comparisons by AF type (unexplained vs secondary), age-of-onset (≤ / > 65 years), and sex were undertaken. Data were acquired by linking 6 population databases maintained by the Alberta Ministry of Health over a 9-year period (April 2006 to March 2015). The primary composite outcome of stroke, transient ischemic attack, thromboembolism, and/or death was assessed. Results: There were 33,150 incident AF diagnoses identified, including 1145 patients (3.5%) with unexplained AF, 931 (81.2%) of whom were aged ≤ 65 years (2.8% of diagnoses, and 79% male). Patients with unexplained AF less often received rate/rhythm-control drugs (P 65 ans) et par sexe ont été effectuées. Les données ont été acquises en reliant six bases de données de population maintenues par le ministère de la Santé de l’Alberta sur une période de neuf ans (avril 2006 à mars 2015). Le paramètre d’évaluation principal comprenant l’accident vasculaire cérébral (AVC), l’accident ischémique transitoire, la thromboembolie et/ou le décès a été évalué. Résultats: Au total, 33 150 diagnostics de FA ont été recensés, dont 1 145 patients (3,5 %) présentant une FA inexpliquée, parmi lesquels 931 (81,2 %) étaient âgés de ≤ 65 ans (2,8 % des diagnostics, et 79 % d’hommes). Les patients atteints de FA inexpliquée ont moins souvent reçu de médicaments pour contrôler la fréquence ou le rythme cardiaque (p < 0,0001), mais ils ont plus souvent subi une cardioversion électrique (p < 0,0001) par rapport aux patients atteints de FA secondaire. Les hommes étaient plus jeunes au moment du diagnostic d’une FA inexpliquée (45 [intervalle interquartile : 34 à 59] vs 58 [intervalle interquartile : 40 à 69] ans; p < 0,001). Après un ajustement pour l’âge au moment du diagnostic, il n’y avait pas de différence entre les sexes quant au paramètre d’évaluation principal. La survie sans événement chez les patients jeunes ayant présenté une FA inexpliquée (âge ≤ 65 ans) était de 99,4 % à un an, et de 98,3 % à trois ans. À trois ans, une ou plusieurs hospitalisations/consultations à l’urgence pour des raisons non cardiovasculaires et pour une FA sont survenues chez 56,6 % et 23,8 % de ces patients, respectivement. Conclusions: En utilisant une définition contemporaine stricte de la FA inexpliquée, cette étude montre que cette affection est rare, majoritairement masculine, et qu’elle est associée à une excellente survie sans événement. Cependant, le taux élevé d’utilisation de soins actifs dans les hôpitaux après le diagnostic est préoccupant.

Brief Summary Cardiogenic shock (CS) is a high-acuity and time-sensitive condition associated with significant morbidity and mortality that may be best served with centralized care by an experienced multi-disciplinary team. We propose that existing Canadian "hub-and-spoke" systems for timely revascularization in ST-elevation myocardial infarction can be leveraged to expand, and ultimately improve timely referral, transfer, and survival of CS patients.

Women of child-bearing age comprise a large proportion of the patients followed by inherited arrhythmia clinics. Despite being a rare and dangerous diagnosis, cardiac and obstetric care providers should know that catecholaminergic polymorphic ventricular tachycardia (CPVT) is not a contraindication to pregnancy. In fact, pregnancy was not associated with an increased risk of CPVT-associated arrhythmias in a recent large cohort study, and most guideline-based anti-arrhythmic drug treatments are life-saving and carry a low risk of teratogenesis. In principle, the potential for CPVT destabilization may be more likely to occur after anti-arrhythmic drugs are decreased or stopped during pregnancy, when an implantable cardioverter defibrillator (ICD) shock exacerbates catecholamine release, or if adrenaline surges are triggered by labor and delivery. Therefore, all pregnant women should be followed by a cardio-obstetrics team with extensive knowledge of CPVT diagnosis, as well as arrhythmia risk stratification fand management. This multidisciplinary care should begin preconception and involve counseling on preimplantation genetic testing, choosing safe and effective anti-arrhythmic drugs, stopping contraindicated medications, optimal programming of ICDs, and planning for the brief hyper-adrenergic period of labor and delivery. The latest data on pregnancy in CPVT is reviewed here and the optimal care for this rare and complex patient population outlined.

Background: Truncating variants in the desmosomal gene PKP2 (PKP2 tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity. Methods: We identified individuals with PKP2 tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The PKP2 tv 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: PKP2 tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique PKP2 tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with PKP2 tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10 −4 ). The ARVC cohort included 487 ARVC probands with 144 distinct PKP2 tv, with 25 PKP2 tv common to both cohorts. The odds ratio for ARVC for the 25 common PKP2 tv 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 PKP2 tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with PKP2 tv (7.9% versus 4.3%; odds ratio, 2.11; P =0.005). Conclusions: PKP2 tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how PKP2 tv cause ARVC in combination with associated genetic and environmental risk factors.

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.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-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 β-blocker initiation and age at start of β-blocker therapy 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 β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-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: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac arrhythmia condition, triggered by physical or acute emotional stress, that predominantly expresses early in life. Gain-of-function mutations in the cardiac ryanodine receptor gene (RYR2) account for the majority of CPVT cases, causing substantial disruption of intracellular calcium (Ca) homeostasis particularly during the periods of β-adrenergic receptor stimulation. However, the highly variable penetrance, patient outcomes, and drug responses observed in clinical practice remain unexplained, even for patients with well-established founder RyR2 mutations. Therefore, investigation of the electrophysiological consequences of CPVT-causing RyR2 mutations is crucial to better understand the pathophysiology of the disease. The development of strategies for reprogramming human somatic cells to human induced pluripotent stem cells (hiPSCs) has provided a unique opportunity to study inherited arrhythmias, due to the ability of hiPSCs to differentiate down a cardiac lineage. Employment of genome editing enables generation of disease-specific cell lines from healthy and diseased patient-derived hiPSCs, which subsequently can be differentiated into cardiomyocytes. This paper describes the means for establishing an hiPSC-based model of CPVT in order to recapitulate the disease phenotype in vitro and investigate underlying pathophysiological mechanisms. The framework of this approach has the potential to contribute to disease modeling and personalized medicine using hiPSC-derived cardiomyocytes. © 2021 Wiley Periodicals LLC., The authors gratefully acknowledge financial support from the Stem Cell Network(FY21/ACCT2-13 to GFT); the Canadian Institutes of Health Research Institute of Circulatory and Respiratory Health (GR020601 toGFT and FVP); and the Mining for Miraclesfund raising on behalf of the BC Children’s Hospital Foundation (to G.F.T., S.S., and F.L.).

Introduction: Arrhythmogenic cardiomyopathy (ACM) resulting from variants in the desmosomal gene desmoplakin (DSP) is typically an adult onset disorder. Here, we describe penetrance, expression and outcomes of DSP-associated ACM in children. Methods: Patients aged ≤21 years with pathogenic/likely pathogenic variants in DSP were included. Penetrance was defined by:(i) ECG: T-wave inversion V4-V6; mean QRS amplitude 500 VPBs/24 hours, non-sustained or sustained ventricular arrhythmia (VA)(iii) LV dysfunction (EF Results: We identified 24 patients (67% female) inclusive of 8 probands and 16 family members. Variants were truncating in 22 and missense in 2; a second variant occurred in 4. Presenting symptoms were cardiac arrest (1); myocardial inflammation (3) with cardiac arrest (1), sustained VA (1), dyspnea (2), syncope (1), palpitations (1). ACM was penetrant in 17 (71%), with expression first evident at 15.2±3.3 years. The cardiac phenotype was left dominant (12) and biventricular (5). Isolated RV disease was not seen. Penetrant features were:(i) ECG: transient T-wave inversion in 1 (6%) and QRS amplitude Conclusions: DSP-mediated ACM may be fully penetrant in children affecting both probands and family members. VA and subepicardial LGE are prominent early features of disease and pediatric surveillance should reflect these findings.

Introduction: Pressure overload from hypertension (HTN) is an important cause of left ventricular hypertrophy (LVH) in the general population, however its impact on disease expression in hypertrophic cardiomyopathy (HCM), and differences based on the presence/absence of a sarcomeric gene variant are not well characterized. Hypothesis: HTN is associated with more prominent manifestations of HCM. Methods: Genotyped HCM patients in the Sarcomeric Human Cardiomyopathy Registry were designated SARC+ ((likely) pathogenic sarcomeric variant present) or SARC- and categorized as having HTN (≥140/90 mmHg) or normal blood pressure (nonHTN; Results: Of 1706 patients (62% male), 445 (26%) had HTN. Median follow up was 4.2 years. SARC+ nonHTN patients were youngest and SARC- HTN patients oldest (p Conclusions: HTN is associated with worse HF outcomes in HCM, especially among SARC+ patients, but has minimal impact on the degree of cardiac remodeling.

Background Broad genomic screening including whole exome sequencing (ES) is increasingly used in clinical care. Families may elect to receive pathogenic and likely pathogenic genetic variants in 30 genes associated with inherited cardiac disorders recommended as reportable by the ACMG, termed cardiac secondary findings (CSF). Most families (91%) opt to receive CSF for the proband, and 73% of parents opt to receive CSF for themselves1. Our initial experience of 33 patients with 22 different CSF identified a low diagnostic yield and high proportion of patients referred for evaluation with non-reportable findings, with only 4 CSF classified as P/LP (4/22; 18%). Three patients (9%) had concordant clinical findings but none met diagnostic criteria2. Purpose The purpose of this analysis was to evaluate the genetic and clinical findings in a secondary cohort. Methods All patients who presented to a joint familial cardiogenetic clinic were included. Identified CSF were categorized by 2015 ACMG criteria for variant classification. Clinical evaluation was performed using contemporaneous diagnostic criteria based on potential phenotypes associated with identified CSF. Variant classification and clinical findings were compared in the initial and secondary cohorts. The study was approved by the Institutional Review Board. Results Forty patients (20 male; age 19.5±15.9 years) from 20 families were evaluated with 19 different CSF. The variant consequence was missense (12), frameshift (6) and premature stop codon (1), and ACMG classification was pathogenic/likely pathogenic in 15/19 (79%) (p Complete clinical evaluation was performed in 35 (88%) individuals and is ongoing in 5. Concordant findings were identified in 12/35 (34%) (p Two patients were symptomatic prior to diagnosis; a 16-year-old female with palpitations and ventricular ectopy considered benign (DSP), and a 41-year-old female with syncope and documented torsade de pointes experienced before cascade screening (KCNQ1). Three patients received defibrillators on primary (ACM) or secondary (LQTS) prevention indications and 2 received ILRs (ACM). Beta-blockers were prescribed for 5 with LQTS (3), CPVT (1) and KCNQ1 CSF but no phenotype (2). Avoidance of provocative medication was recommended for 11. Ten patients with pathogenic CSF (MYBPC3 (2), RYR2 (1), SCN5A (4), KCNH2 (3)) had no discernable phenotype. Conclusions In this secondary analysis there was a marked increase in the proportion of pathogenic/likely pathogenic CSF and associated clinical findings, including those necessitating significant management strategies. This data may help inform results disclosure and referral streams for patients with CSF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Mannion and Roberts Families Table 1

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.

β-Blockers are a cornerstone of therapy for cardiovascular disease, but their clinical benefits are not consistent across the class and specific agents are preferred for certain indications. Further, when prescribed, a patient's clinical status might change, requiring the cardiologist to switch to an alternate agent. Examples of such scenarios include the development or a worsening of chronic noncardiac diseases (eg, hyperthyroidism, renal failure), new cardiac-related disease (eg, heart failure, atrial fibrillation), or practical/safety issues (eg, pregnancy, cost, side effects). However, guidelines on how to best switch to a different β-blocker are lacking. Additionally, most hospital-based formularies and guidelines do not provide recommendations around common challenges, like medication intolerance or adjustments for acute illness. We present a practical approach to switching between commonly prescribed β-blockers, which considers drug interchangeability for various indications, rationale for switching, necessary initial adjustments to dose/frequency, and differences in target/maximal doses.

After the most common causes of sudden cardiac death including ischemic and structural heart disease have been ruled out, clinicians on the front lines of emergent medical care can be faced with unexplained and recurrent life-threatening arrhythmia episodes in children and adults. In these cases, an inherited arrhythmia syndrome should be suspected, and a departure from conventional advanced cardiac life support algorithms may be required. This review focuses on the electrocardiographic clues of an inherited arrhythmia syndrome that can be uncovered through a careful analysis of the baseline electrocardiogram (ECG) and classification of the presenting ventricular arrhythmia and its mode of onset. After presenting an informed working diagnosis and an explanation of the implied electrophysiologic mechanisms, discussion provides a protocol approach to acute and subacute management decisions. Careful attention to a patient's response to treatment and its ECG surrogates have the potential to facilitate tailored therapy based on the underlying arrhythmogenic substrate and pathophysiology.

Objectives This investigation was a retrospective study of catecholaminergic polymorphic ventricular tachycardia (CPVT) patients in Canada and the Netherlands to compare pregnancy, postpartum, and nonpregnant event rates. Background CPVT is characterized by life-threatening arrhythmias during exertion or emotional stress. The arrhythmic risk in CPVT patients during pregnancy is unknown. Methods Baseline demographics, genetics, treatment, and pregnancy complications were reviewed. Event rate calculations assumed a 40-week pregnancy and 24-week postpartum period. Results Ninety-six CPVT patients had 228 pregnancies (median 2 pregnancies per patient; range: 1 to 10; total: 175.4 pregnant patient-years). The median age of CPVT diagnosis was 40.7 years (range: 12 to 84 years), with a median follow-up of 2.9 years (range: 0 to 20 years; total 448.1 patient-years). Most patients had pregnancies before CPVT diagnosis (82%). Pregnancy and postpartum cardiac events included syncope (5%) and an aborted cardiac arrest (1%), which occurred in patients who were not taking beta-blockers. Other complications included miscarriages (13%) and intrauterine growth restriction (1 case). There were 6 cardiac events (6%) during the nonpregnant period. The pregnancy and postpartum event rates were 1.71 and 2.85 events per 100 patient-years, respectively, and the combined event rate during the pregnancy and postpartum period was 2.14 events per 100 patient-years. These rates were not different from the nonpregnant event rate (1.46 events per 100 patient-years). Conclusions The combined pregnancy and postpartum arrhythmic risk in CPVT patients was not elevated compared with the nonpregnant period. Most patients had pregnancies before diagnosis, and all patients with events were not taking beta-blockers at the time of the event.

Patients with inherited arrhythmia syndromes (IASs) and inherited cardiomyopathies (ICs) are periodically encountered in both general and specialist practices. These syndromes include long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, early repolarisation syndrome, and hypertrophic and arrhythmogenic cardiomyopathies. In general, the presence of an IAS or IC is not a contraindication to pregnancy, but does require additional expertise and patient engagement. In this review, we summarise the various pregnancy-related considerations in patients with IAS and IC, including the impact of physiologic/hemodynamic changes on heart failure progression or arrhythmia propensity, maternal and fetal pregnancy risk stratification, prenatal genetic testing, and the specialised care and monitoring required through pregnancy, labour, and delivery and into the postpartum period. Management of patients with IASs and IC during pregnancy and the postpartum period requires collaboration between patient and provider, with a shared understanding of the general safety and potential risks during the pregnancy and postpartum periods. Patients should be aware of the safety of various medications throughout pregnancy, and those with implantable cardioverter-defibrillators should be managed according to device guidelines. A peripartum care and delivery plan should be established, with multidisciplinary input from various specialists including obstetrics, cardiac obstetrics, and inherited arrhythmia specialists wherever appropriate.

Cardiac ryanodine receptor (RyR2) gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia, a condition characterized by prominent ventricular ectopy in response to catecholamine stress, which can be reproduced on exercise stress testing (EST). However, reports of sudden cardiac death (SCD) have emerged in EST-negative individuals who have loss-of-function (LOF) RyR2 mutations. The clinical relevance of RyR2 LOF mutations including their pathogenic mechanism, diagnosis, and treatment are all unknowns. Here, we performed clinical and genetic evaluations of individuals who suffered from SCD and harbored an LOF RyR2 mutation. We carried out electrophysiological studies using a programed electrical stimulation protocol consisting of a long-burst, long-pause, and short-coupled (LBLPS) ventricular extra-stimulus. Linkage analysis of RyR2 LOF mutations in six families revealed a combined logarithm of the odds ratio for linkage score of 11.479 for a condition associated with SCD with negative EST. A RyR2 LOF mouse model exhibited no catecholamine-provoked ventricular arrhythmias as in humans but did have substantial cardiac electrophysiological remodeling and an increased propensity for early afterdepolarizations. The LBLPS pacing protocol reliably induced ventricular arrhythmias in mice and humans having RyR2 LOF mutations, whose phenotype is otherwise concealed before SCD. Furthermore, treatment with quinidine and flecainide abolished LBLPS-induced ventricular arrhythmias in model mice. Thus, RyR2 LOF mutations underlie a previously unknown disease entity characterized by SCD with normal EST that we have termed RyR2 Ca2+ release deficiency syndrome (CRDS). Our study provides insights into the mechanism of CRDS, reports a specific CRDS diagnostic test, and identifies potentially efficacious anti-CRDS therapies., This work was supported by research grants from the Canadian Institutes of Health Research (PJT-155940) to S.R.W.C. and (PJT 166105 and MOP 142486) to R.A.R.; the National Natural Science Foundation of China (81903611) to B.S.; the Spanish Ministry of Science Innovation and Universities SAF2017-88019-C3-R to L.H.-M. and R.B. and Marato-2015-20-30 to L.H.-M.; the Royal Netherlands Academy of Sciences (CVON 2012-10 PREDICT) to A.A.M.W.; the E-Rare Joint Transnational Call for Proposals 2015 “Improving Diagnosis and Treatment of Catecholaminergic Polymorphic Ventricular Tachycardia: Integrating Clinical and Basic Science” to S.R.W.C., S.S., and A.A.M.W.; the European Research Council Grant “EU-rhythmy” ERC-ADG-2014 (ID: 669387) to S.G.P.; the Novo Nordisk Foundation, Denmark (NNF18OC0031258) to H.K.J.; and the NIH (R01HL057832) to M.F. B.S. and J.Y. are recipients of the Alberta Innovates-Health Solutions (AIHS) Fellowship Award. J.W. is a recipient of the Libin Cardiovascular Institute of Alberta and Cumming School of Medicine Postdoctoral Fellowship Award. X.Z. and W.G. are recipients of the AIHS Studentship Award. S.R.W.C. holds the Heart and Stroke Foundation Chair in Cardiovascular Research.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by cardiac arrest during sudden exertion. However, standard exercise stress testing (EST) lacks sensitivity, leading to misdiagnosis and undertreatment. After a nondiagnostic standard gradual EST, we report 6 patients who underwent a novel burst exercise test characterized by sudden high workload at the outset of testing. In 5 of 6 patients, the burst EST induced new and more complex arrhythmias versus standard EST, which compelled medication initiation in 3 patients. We postulate that this simple EST modification better mimics a typical CPVT triggering event and could improve diagnostic sensitivity and therapeutic decision making.

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 ofCASQ2-CPVT was sought through an international multicenter collaboration.Methods:Genotype-phenotype segregation inCASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominantCASQ2missense 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 pathogenicCASQ2variant, were identified. AmongCASQ2homozygotes 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 66CASQ2heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative toCASQ2heterozygotes,CASQ2homozygote/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;PCASQ2missense 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 ofCASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygousCASQ2variants 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.

Background Common and rare variants, including those in the gene for the cardiac structural protein titin (TTN), have been implicated in the risk of developing atrial fibrillation (AF). However, the effect of genetic variants on risk of AF compared with established modifiable risk factors is unclear. The objective of this study was to evaluate the risk of AF and associated cardiovascular complications in TTN variant carriers and examine interactions between TTN variants or common variants and modifiable AF risk factors. Methods We used whole exome sequencing data of 49,881 individuals and genotyping data of 408,572 individuals from the UK Biobank to examine the associations of TTN variants, polygenic risk, and 4 risk factors (hypertension, diabetes, obesity, and smoking) with AF. Adjusted hazard ratios (aHRs) were calculated with the use of Cox proportional hazards models. Results TTN variant carrier status was associated with a higher risk of AF (aHR 2.10, 95% CI 1.59-2.79; P = 2.54 × 10−7) and higher risk of dilated cardiomyopathy in AF patients (aHR 10.39, 95% CI 5.31-20.33; P = 8.37 × 10−12). We identified additive effects between TTN variants and polygenic risk with hypertension, diabetes, obesity, and smoking on the risk of AF. Conclusions Genetic and modifiable cardiovascular risk factors contribute to the probability of developing AF. Our findings highlight the potential utility of incorporating data from targeted sequencing or genotyping of common variants to further inform AF risk stratification and aggressive management of modifiable cardiovascular risk factors.

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 (

Pregnancy is a period of increased cardiovascular risk in a woman's life. In the setting of an inherited arrhythmia syndrome (IAS), cardiologists and obstetricians may be unfamiliar with cardiovascular optimization and risk stratification in pregnancy. Historically, there were little data addressing the safety of pregnancy in these rare disorders. Recent advances suggest that no type of IAS represents an absolute contraindication to pregnancy. However, it is imperative that obstetric and cardiovascular clinicians understand the major forms of IAS and how they affect the risks and course of pregnancy. This includes any disease-specific proarrhythmic triggers unique to pregnancy, such as the postpartum period in long QT syndrome (especially type 2), which poses the greatest risk of arrhythmias, and the adrenergic nature of labor and delivery, which is relevant to catecholaminergic polymorphic ventricular tachycardia. Fortunately, several effective antiarrhythmic options exist that pose little fetal risk. IAS-specific optimization of implantable cardioverter-defibrillator algorithms, drug therapy, and a maternal cardiac plan addressing the antepartum, labor, and delivery and postpartum periods reduces the risk. Where evidence does not exist, there are plausible mechanistic considerations to guide clinicians. To achieve optimal outcomes, early involvement of an expert pregnancy heart team comprising obstetrics, genetics, cardiology, and anesthesiology team members and a shared decision-making approach to IAS issues in pregnancy are needed.

Sudden cardiac death (SCD) is a leading cause of death in sport. Inherited heart rhythm disorders that cause SCD in young individuals include, but are not limited to, long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome, arrhythmogenic cardiomyopathy and hypertrophic cardiomyopathy (HCM). The 2005 American College of Cardiology and the European Society of Cardiology consensus statements recommended uniform and mandatory disqualification of athletes with inherited heart rhythm disorders from competitive sports due to the potential risk of fatal arrhythmias precipitated by adrenergic stress.1 2 This broad, universal mandate for exclusion is an antiquated practice from a time where risk was mostly unpredictable and risk reduction strategies poorly defined. The discovery of many evidence-based markers of risk can facilitate a precision medicine approach to exercise prescription in patients with inherited heart rhythm disorders. The risk of recurrent cardiac events is lower than previously thought for primary electrical diseases such as LQTS and CPVT. Young athletes, those aged 21 years or younger, receiving the recommended treatment for LQTS and CPVT (eg, beta blockers and avoidance of QT prolonging medications at a minimum) are not at an increased risk for SCD during competitive sports.3 4 For the other major channelopathy, Brugada syndrome, …

The majority of episodes of syncope are innocent and will not occur again. However, in certain instances, in particular when associated with brady- or tachyarrhythmias, syncope is more likely to be recurrent or predict risk of sudden death. A comprehensive evaluation including patient history, physical examination, and directed investigations allows the clinician to discriminate between innocent and sinister syncope. Arrhythmic syncope is typically associated with minimal prodrome or postdrome, and a higher risk of injury. Identification of the key presenting features is the first step in risk stratification and directs the clinician to an optimal investigation strategy and, as such, timely diagnosis and treatment.

Background: Risk stratification in catecholaminergic polymorphic ventricular tachycardia remains ill defined. Heart rate recovery (HRR) immediately after exercise is regulated by autonomic reflexes, particularly vagal tone, and may be associated with symptoms and ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Our objective was to evaluate whether HRR after maximal exercise on the exercise stress test (EST) is associated with symptoms and ventricular arrhythmias. Methods: In this retrospective observational study, we included patients ≤65 years of age with an EST without antiarrhythmic drugs who attained at least 80% of their age- and sex-predicted maximal HR. HRR in the recovery phase was calculated as the difference in heart rate (HR) at maximal exercise and at 1 minute in the recovery phase (ΔHRR1′). Results: We included 187 patients (median age, 36 years; 68 [36%] symptomatic before diagnosis). Pre-EST HR and maximal HR were equal among symptomatic and asymptomatic patients. Patients who were symptomatic before diagnosis had a greater ΔHRR1′ after maximal exercise (43 [interquartile range, 25–58] versus 25 [interquartile range, 19–34] beats/min; P P P =0.01). After diagnosis, patients with a ΔHRR1′ in the upper tertile of its distribution had significantly more arrhythmic events as compared with patients in the other tertiles ( P =0.045). Conclusions: Catecholaminergic polymorphic ventricular tachycardia patients with a larger HRR following exercise are more likely to be symptomatic and have complex ventricular arrhythmias during the first EST off antiarrhythmic drug.

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 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.

Background The implantable cardioverter-defibrillator (ICD) may be associated with a high risk of complications in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT). However, ICDs in this population have not been systematically evaluated. Objective The purpose of this study was to characterize the use and outcomes of ICDs in CPVT. Methods We conducted a systematic review using Embase, MEDLINE, PubMed, and Google Scholar to identify studies that included patients with CPVT who had an ICD. Results Fifty-three studies describing 1429 patients with CPVT were included. In total, 503 patients (35.2%) had an ICD (median age 15.0 years; interquartile range 11.0–21.0 years). Among ICD recipients with a reported medication status, 96.7% were prescribed β-blockers and 13.2% flecainide. Sympathetic denervation was performed in 23.2%. Nearly half of patients received an ICD for primary prevention (47.3%), and 12.8% were prescribed optimal antiarrhythmic therapy. During follow-up, 40.1% had ≥1 appropriate shock, 20.8% experienced ≥1 inappropriate shock, 19.6% had electrical storm, and 7 patients (1.4%) died. An ICD-associated electrical storm was implicated in 4 deaths. Additional complications such as lead failure, endocarditis, or surgical revisions were observed in 96 of 296 patients (32.4%). A subanalysis of the 10 studies encompassing 330 patients with the most detailed ICD-related data showed similar trends. Conclusion In this population with CPVT, ICDs were common and associated with a high burden of shocks and complications. The reliance on primary prevention ICDs, and poor uptake of adjuvant antiarrhythmic therapies, suggests that improved adherence to guideline-directed management could reduce ICD use and harm.

The autonomic nervous system (ANS) is complex and plays an important role in cardiac arrhythmia pathogenesis. A deeper understanding of the anatomy and development of the ANS has shed light on its involvement in cardiac arrhythmias. Alterations in levels of Sema-3a and NGF, both growth factors involved in innervation patterning during development of the ANS, leads to cardiac arrhythmias. Dysregulation of the ANS, including polymorphisms in genes involved in ANS development, have been implicated in sudden infant death syndrome. Disruptions in the sympathetic and/or parasympathetic systems of the ANS can lead to cardiac arrhythmias and can vary depending on the type of arrhythmia. Simultaneous stimulation of both the sympathetic and parasympathetic systems is thought to lead to atrial fibrillation whereas increased sympathetic stimulation is thought to lead to ventricular fibrillation or ventricular tachycardia. In inherited arrhythmia syndromes, such as Long QT and Catecholaminergic Polymorphic Ventricular Tachycardia, sympathetic system stimulation is thought to lead to ventricular tachycardia, subsequent arrhythmias, and in severe cases, cardiac death. On the other hand, arrhythmic events in Brugada Syndrome have been associated with periods of high parasympathetic tone. Increasing evidence suggests that modulation of the ANS as a therapeutic strategy in the treatment of cardiac arrhythmias is safe and effective. Further studies investigating the involvement of the ANS in arrhythmia pathogenesis and its modulation for the treatment of cardiac arrhythmias is warranted.

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