Impact of the method of calculating 30-day readmission rate after hospitalization for heart failure. Data from the VancOuver CoastAL Acute Heart Failure (VOCAL-AHF) registry.

BACKGROUND: Thirty-day readmission rate after heart failure (HF) hospitalization is widely used to evaluate healthcare quality. Methodology may substantially influence estimated rates. We assessed the impact of different definitions on HF and all-cause readmission rates. METHODS: Readmission rates were examined in 1,835 patients discharged following HF hospitalization using 64 unique definitions derived from five methodological factors: (1) ICD-10 codes (broad vs narrow), (2) index admission selection (single admission only first-in-year vs. random sample; or multiple admissions in year with vs. without 30-day blanking period), (3) variable denominator (number alive at discharge vs. number alive at 30-days), (4) follow-up period start (discharge date vs day following discharge), and (5) annual reference-period (calendar vs fiscal). The impact of different factors was assessed using linear-regression. RESULTS: The calculated 30-day readmission rate for HF varied more than 2-fold depending solely on the methodological approach (6.5% to 15.0%). All-cause admission rates exhibited similar variation (18.8% to 29.9%). The highest rates included all consecutive index admissions (HF 11.1-15.0%, all-cause 24.0-29.9%), and lowest only one index admission per patient per year (HF 6.5-11.3%, all-cause 18.8-22.7%). When including multiple index admissions and compared to blanking the 30-days post-discharge, not blanking was associated with 2.3% higher readmission rates. Selecting a single admission per year with a first-in-year approach lowered readmission rates by 1.5%, while random-sampling admissions lowered estimates further by 5.2% (p<0.001). CONCLUSION: Calculated 30-day readmission rates varied more than 2-fold by altering methods. Transparent and consistent methods are needed to ensure reproducible and comparable reporting.

An international multicenter cohort study on implantable cardioverter-defibrillators for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there are limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic patients with CPVT with and without ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with ICD (31.1%) and 162 without ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in the no ICD group and in those not on optimal medical therapy. Patients with ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

Novel Magnetic Resonance Imaging Tools for Hypertrophic Cardiomyopathy Risk Stratification.

Hypertrophic cardiomyopathy (HCM) is a common genetic disorder with a well described risk of sudden cardiac death; however, risk stratification has remained a challenge. Recently, novel parameters in cardiac magnetic resonance imaging (CMR) have shown promise in helping to improve upon current risk stratification paradigms. In this manuscript, we have reviewed novel CMR risk markers and their utility in HCM. The results of the review showed that T1, extracellular volume, CMR feature tracking, and other miscellaneous novel CMR variables have the potential to improve sudden death risk stratification and may have additional roles in diagnosis and prognosis. The strengths and weaknesses of these imaging techniques, and their potential utility and implementation in HCM risk stratification are discussed.

Advances in Hypertrophic Cardiomyopathy Disease Modelling Using hiPSC-Derived Cardiomyocytes.

The advent of human induced pluripotent stem cells (hiPSCs) and their capacity to be differentiated into beating human cardiomyocytes (CMs) in vitro has revolutionized human disease modelling, genotype-phenotype predictions, and therapeutic testing. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiomyopathy and the leading known cause of sudden cardiac arrest in young adults and athletes. On a molecular level, HCM is often driven by single pathogenic genetic variants, usually in sarcomeric proteins, that can alter the mechanical, electrical, signalling, and transcriptional properties of the cell. A deeper knowledge of these alterations is critical to better understanding HCM manifestation, progression, and treatment. Leveraging hiPSC-CMs to investigate the molecular mechanisms driving HCM presents a unique opportunity to dissect the consequences of genetic variants in a sophisticated and controlled manner. In this review, we summarize the molecular underpinnings of HCM and the role of hiPSC-CM studies in advancing our understanding, and we highlight the advances in hiPSC-CM-based modelling of HCM, including maturation, contractility, multiomics, and genome editing, with the notable exception of electrophysiology, which has been previously covered.

The 2023 Canadian Cardiovascular Society Clinical Practice Update on Management of the Patient With a Prolonged QT Interval.

A prolonged QT interval on the electrocardiogram is associated with an increased risk of the torsades de pointes form of ventricular arrhythmia resulting in syncope, sudden cardiac arrest or death, or misdiagnosis as a seizure disorder. The cause of QT prolongation can be congenital and inherited as an autosomal dominant variant, or it can be transient and acquired, often because of QT-prolonging drugs or electrolyte abnormalities. Automated measurement of the QT interval can be inaccurate, especially when the baseline electrocardiogram is abnormal, and manual verification is recommended. In this clinical practice update we provide practical tips about measurement of the QT interval, diagnosis, and management of congenital long QT syndrome and acquired prolongation of the QT interval. For congenital long QT syndrome, certain ß-adrenergic-blocking drugs are highly effective, and implantable defibrillators are infrequently required. Many commonly prescribed drugs such as antidepressants and antibiotics can prolong the QT interval, and recommendations are provided on their safe use.

Calcium Release Deficiency Syndrome: A New Inherited Arrhythmia Syndrome.

Calcium release deficiency syndrome (CRDS) is a newly described form of inherited arrhythmia caused by damaging loss-of-function variants in the cardiac ryanodine receptor (RyR2). Unlike the prototypical RyR2 gain-of-function channelopathy, known as catecholaminergic polymorphic ventricular tachycardia, patients with CRDS are predisposed to sudden death usually in the absence of any electrical abnormalities at rest or during stress electrocardiography. This makes diagnosis incredibly challenging, however, an invasive electrophysiologic test appears to be effective in unmasking the phenotype, called the long-burst, long-pause, short-coupled ventricular extra-stimulus protocol. Optimal therapies for patients with CRDS remain unestablished, although flecainide appears to be a promising candidate drug.

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.

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.

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.

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.

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.

A Population-Based Study of Unexplained/Lone Atrial Fibrillation: Temporal Trends, Management, and Outcomes.

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 < 0.0001), but they more often underwent electrical cardioversion (P < 0.0001) vs secondary AF patients. Men were younger at unexplained AF diagnosis (45 [interquartile range: 34-59] vs 58 [interquartile range: 40-69] years; P < 0.001). After adjusting for age at diagnosis, there were no sex-based differences in the primary outcome. Event-free survival in young unexplained AF (age ≤ 65 years) was 99.4% at 1 year and 98.3% at 3 years. At 3 years, hospitalization(s)/emergency visit(s) for noncardiovascular reasons and for AF occurred in 56.6% and 23.8% of these patients, respectively. CONCLUSIONS: Using a strict contemporary definition of unexplained AF, this study shows that the condition is rare, predominantly male, and has excellent event-free survival. However, the high rate of acute hospital utilization after diagnosis is concerning.

CONTEXTE: Les études précédentes sur le flutter auriculaire et la fibrillation auriculaire (FA) idiopathiques/inexpliqués n'excluaient pas les patients présentant des déclencheurs contemporains de FA secondaire. Nous avons caractérisé la FA inexpliquée en utilisant une définition stricte, et l'avons comparée à la FA secondaire. MÉTHODOLOGIE: Dans cette étude basée sur une population, la FA inexpliquée a été définie par l'absence de tout diagnostic médical/chirurgical de déclencheur identifiable. Des comparaisons par type de FA (inexpliquée vs secondaire), par âge d'apparition (≤ / > 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.

Clinical and Functional Characterization of Ryanodine Receptor 2 Variants Implicated in Calcium-Release Deficiency Syndrome.

Importance: Calcium-release deficiency syndrome (CRDS), which is caused by loss-of-function variants in cardiac ryanodine receptor 2 (RyR2), is an emerging cause of ventricular fibrillation. However, the lack of complex polymorphic/bidirectional ventricular tachyarrhythmias during exercise stress testing (EST) may distinguish it from catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, in the first clinical series describing the condition, mouse and human studies showed that the long-burst, long-pause, short-coupled ventricular extra stimulus (LBLPS) electrophysiology protocol reliably induced CRDS ventricular arrhythmias. Data from larger populations with CRDS and its associated spectrum of disease are lacking. Objective: To further insight into CRDS through international collaboration. Design, Setting, and Participants: In this multicenter observational cohort study, probands with unexplained life-threatening arrhythmic events and an ultrarare RyR2 variant were identified. Variants were expressed in HEK293 cells and subjected to caffeine stimulation to determine their functional impact. Data were collected from September 1, 2012, to March 6, 2021, and analyzed from August 9, 2015, to March 6, 2021. Main Outcomes and Measures: The functional association of RyR2 variants found in putative cases of CRDS and the associated clinical phenotype(s). Results: Of 10 RyR2 variants found in 10 probands, 6 were loss-of-function, consistent with CRDS (p.E4451del, p.F4499C, p.V4606E, p.R4608Q, p.R4608W, and p.Q2275H) (in 4 [67%] male and 2 [33%] female probands; median age at presentation, 22 [IQR, 8-34] years). In 5 probands with a documented trigger, 3 were catecholamine driven. During EST, 3 probands with CRDS had no arrhythmias, 1 had a monomorphic couplet, and 2 could not undergo EST (deceased). Relatives of the decedents carrying the RyR2 variant did not have EST results consistent with CPVT. After screening 3 families, 13 relatives were diagnosed with CRDS, including 3 with previous arrhythmic events (23%). None had complex ventricular tachyarrhythmias during EST. Among the 19 confirmed cases with CRDS, 10 had at least 1 life-threatening event at presentation and/or during a median follow-up of 7 (IQR, 6-18) years. Two of the 3 device-detected ventricular fibrillation episodes were induced by a spontaneous LBLPS-like sequence. ß-Blockers were used in 16 of 17 surviving patients (94%). Three of 16 individuals who were reportedly adherent to ß-blocker therapy (19%) had breakthrough events. Conclusions and Relevance: The results of this study suggest that calcium-release deficiency syndrome due to RyR2 loss-of-function variants mechanistically and phenotypically differs from CPVT. Ventricular fibrillation may be precipitated by a spontaneous LBLPS-like sequence of ectopy; however, CRDS remains difficult to recognize clinically. These data highlight the need for better diagnostic tools and treatments for this emerging condition.

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.

The design and rationale of the Advancing Cardiac Care Unit-based Rapid Assessment and Treatment of hypErcholesterolemia (ACCURATE) study.

Familial hypercholesterolemia (FH) is an inherited condition characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD). Despite being the most common inherited cardiovascular disorder, it is still highly underdiagnosed and undertreated worldwide. We designed the Advancing Cardiac Care Unit-based Rapid Assessment and Treatment of hypErcholesterolemia (ACCURATE) study to test the hypothesis that opportunistic genetic testing for FH among patients hospitalized for acute coronary syndrome (ACS) will increase the diagnosis of FH and improve patient outcomes. ACCURATE is a non-randomized, controlled trial of patients <60 years old admitted to an acute cardiac unit with ACS and elevated LDL-C levels. The first cohort will consist of a control group of patients presenting with ACS who will be treated according to usual standard-of-care. The second cohort will consist of patients presenting with ACS in whom research-based genetic testing for FH will be performed during hospitalization and the results returned to the treating physicians. The primary endpoint will be the number of patients with a new diagnosis of FH. The secondary endpoints will be the proportion of patients who undergo intensification of lipid-lowering therapy, the lowest LDL-C level achieved, and the proportion of patients reaching guideline recommended lipid targets in the 12 months after the index ACS. To our knowledge, ACCURATE represents the first clinical trial of genetic testing for FH in the acute cardiac care setting and is expected to help identify optimal approaches to increase the diagnosis and treatment of FH.