Presence of symptoms and documented AFL/AF are the best predictors of SD in TGA patients. Patients with these findings should be further evaluated for risk of SD.

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.

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 β-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.

Epicardial pacemaker implantation is the most common approach for small children requiring pacemaker implantation, though it is not free from complications. This article reviews the experience with endocardial pacemaker implantation, as an alternative approach, in children < or =10 kg at two centers. Thirty-nine children, median age 3.8 months (2 days-35 months), weight 4.6 kg (2.3-10 kg) underwent endocardial permanent pacing (VVI/R in 38, DDDR in 1). Indications for pacing were complete heart block (CHB) in 34 (congenital in 21, postsurgical in 12, congenitally corrected transposition of the great arteries 1), long QT syndrome in 3, and sinus bradycardia in 2 children. Two children with postsurgical CHB died 7 days and 3 weeks after implantation, respectively, due to heart failure and septicemia, despite appropriate pacemaker therapy. Over a median follow-up of 4.3 years (9 months-15.3 years), 12 patients underwent 18 generator replacements. Five patients were upgraded to physiological pacing. Ten patients underwent 12 ventricular lead advancements. Ventricular lead extraction was attempted 11 times in nine patients and succeeded 10 times. Two patients were converted to epicardial dual chamber systems. Two prepectorally placed generators required resiting due to threatened skin necrosis. Infective endocarditis on the lead, 9 months postimplant required removal of the system in one patient. The subclavian vein was found to be asymptomatically thrombosed in four patients. Endocardial permanent pacing is feasible and effective in children < or = 10 kg and an acceptable alternative to epicardial pacing.

Aims  Sudden death and aborted sudden death have been observed in patients with biallelic variants in TECRL. However, phenotypes have only begun to be described and no data are available on medical therapy after long-term follow-up. Methods and results  An international, multi-centre retrospective review was conducted. We report new cases associated with TECRL variants and long-term follow-up from previously published cases. We present 10 cases and 37 asymptomatic heterozygous carriers. Median age at onset of cardiac symptoms was 8 years (range 1–22 years) and cases were followed for an average of 10.3 years (standard deviation 8.3), right censored by death in three cases. All patients on metoprolol, bisoprolol, or atenolol were transitioned to nadolol or propranolol due to failure of therapy. Phenotypes typical of both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT) were observed. We also observed divergent phenotypes in some cases despite identical homozygous variants. None of 37 heterozygous family members had a cardiac phenotype. Conclusion  Patients with biallelic pathogenic TECRL variants present with variable cardiac arrhythmia phenotypes, including those typical of long QT syndrome and CPVT. Nadolol and propranolol may be superior beta-blockers in this setting. No cardiac disease or sudden death was present in patients with a heterozygous genotype.