Faculty Bibliography

BACKGROUND:Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS/RESULTS:=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS:SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE.

PURPOSE OF REVIEW/OBJECTIVE:In this chapter we will discuss the most recent and relevant evidences published in the field of inherited arrhythmogenic disorders, focusing on the so called 'channelopathies' that are associated with sudden cardiac death (SCD) in children: long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), and catecholaminergic polymorphic ventricular tachycardia (CPVT). RECENT FINDINGS/RESULTS:We will discuss the latest diagnostic criteria for channelopathies released by the European Society of Cardiology, the new data on BrS in children and the recent evidence supporting a genotype-specific therapy for LQTS type 3. Moreover, we will present further insights into the risk stratification of the children affected by LQTS, analyzing the role of imaging for the prediction of life-threatening arrhythmias. In addition, we will offer a perspective on how to deal with genetic results in families affected by SCD at very young ages. SUMMARY/CONCLUSIONS:The selected publications will aid pediatricians in their clinical work when managing little patients with inherited arrhythmias, providing the most recent information for diagnosis, risk stratification, and management.

Short QT syndrome (SQTS) is one of the rarest inheritable cardiac channelopathies, characterized by an accelerated cardiac repolarization, which is also the substrate for the development of life-threatening ventricular arrhythmias. Up to this date, fewer than 200 SQTS cases have been reported in the literature worldwide. Patients with SQTS may experience a cardiac arrest as early as in the neonatal period or as late as 80 years old. The cumulative probability of experiencing a cardiac arrest by the fifth decade of life approaches 40%, highlighting the importance of early recognition and management. SQTS is an autosomal dominant disease with five identified causative genes, including three that encode for potassium channels (KCNH2, KCNQ1, and KCNJ2) and two that encode for subunits of the L-type calcium channels (CACNA1C and CACNB2). The term "early repolarization" (ER) has long been used to refer to a heterogeneous group of specific QRS-T junction patterns that are commonly found on the electrocardiograms of young healthy subjects. In the last decade, it has been suggested that in some individuals, the presence of ER may be associated with an increased risk of sudden cardiac death, and thus the term "early repolarization syndrome" (ERS) has progressively entered into use. Up to this point, however, whether ER constitutes a true primary arrhythmic disorder or whether it is simply a predisposing substrate that facilitates arrhythmias in the presence of other triggers remains an unresolved issue. In this review paper, we aim to integrate the current literature on SQTS and ERS. For each, we will describe the key steps that first led to the identification of the syndrome before moving into a discussion of our current understanding of each entity, including the epidemiology, genetics, diagnosis, clinical manifestations, and management.

RATIONALE/BACKGROUND:) cause dominant catecholaminergic polymorphic ventricular tachycardia (CPVT), a leading cause of sudden death in apparently healthy individuals exposed to emotions or physical exercise. OBJECTIVE:. METHODS AND RESULTS/RESULTS:-R4496C mRNA, whereas protein quantification showed that total RyR2 was reduced by 15% in the heart of treated mice. Furthermore, AAV9-miRYR2-U10 effectively (1) reduced isoproterenol-induced delayed afterdepolarizations and triggered activity in infected cells, (2) reduced adrenergically mediated ventricular tachycardia in treated mice, (3) reverted ultrastructural abnormalities of junctional sarcoplasmic reticulum and transverse tubules, and (4) attenuated mitochondrial abnormalities. CONCLUSIONS:The study demonstrates that allele-specific silencing with miRYR2-U10 prevents life-threatening arrhythmias in CPVT mice, suggesting that the reduction of mutant RyR2 may be a novel therapeutic approach for CPVT.

Importance: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with beta-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively. Objective: To determine whether flecainide dosed to therapeutic levels and added to beta-blocker therapy is superior to beta-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT. Design, Setting, and Participants: This investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated beta-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing. Interventions: Patients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels. Main Outcomes and Measures: The primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia). Results: Of 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms. Conclusions and Relevance: In this randomized clinical trial of patients with CPVT, flecainide plus beta-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus beta-blocker and beta-blocker alone. Trial Registration: clinicaltrials.gov Identifier: NCT01117454.

OBJECTIVES/OBJECTIVE:This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND:SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS:Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS:was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS:We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.

PURPOSE OF REVIEW/OBJECTIVE:In this article, we discuss the most recent and relevant studies published in the field of inherited arrhythmogenic disorders, focusing in particular on channelopathies (Long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia) and arrhythmogenic right ventricular cardiomyopathy (ARVC). RECENT FINDINGS/RESULTS:We discuss the updated diagnostic criteria for channelopathies released by the European Society of Cardiology, the new results on the value of programmed electrical stimulation in patients with Brugada syndrome, and the recent evidences supporting a genotype-specific therapy for Long QT syndrome type 3. Moreover, we will present further insights into the clinical course and risk stratification of patients affected by ARVC, analyzing in particular the role of antiarrhythmic drugs for the prevention of life-threatening arrhythmias. Finally, we will explore the innovative therapeutic approaches that may be available in the future for patients with inherited arrhythmogenic disorders, such as the gene therapy. SUMMARY/CONCLUSIONS:The review will aid physicians in their clinical work when managing patients with inherited arrhythmias and ARVC, providing the most recent information for diagnosis, risk stratification, and management.