Objective This study evaluated the efficacy and safety of flecainide in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) on top of conventional drug therapy. Background CPVT is an inherited arrhythmia syndrome caused by gene mutations that destabilize cardiac ryanodine receptor Ca2+ release channels. Sudden death is incompletely prevented by conventional drug therapy with β-blockers +/− Ca2+ channel blockers. The anti-arrhythmic agent flecainide directly targets the molecular defect in CPVT by inhibiting premature Ca2+ release and triggered beats in vitro. Methods We collected data from every consecutive genotype-positive CPVT patient started on flecainide at eight international centers before November 13, 2009. The primary outcome measure was the reduction of ventricular arrhythmias during exercise testing. Results Thirty-three patients received flecainide because of exercise-induced ventricular arrhythmias despite conventional, for different reasons not always optimal, therapy (median age of 25 years, range 7 to 68; 70% female). Exercise tests comparing flecainide with conventional therapy alone were available in 29 patients. Twenty-two (76%) patients had either a partial (n=8) or complete (n=14) suppression of exercise-induced ventricular arrhythmias by flecainide (p<0.001). No patient experienced worsening of exercise-induced ventricular arrhythmias. Median daily flecainide dose in responders was 150 mg (range 100 to 300 mg). During a median follow-up of 20 months (range 12 to 40) one patient experienced ICD shocks for polymorphic ventricular arrhythmias, which was associated with low flecainide levels. In one patient, flecainide successfully suppressed exerciseinduced ventricular arrhythmias for 29 years. Conclusions Flecainide reduced exercise-induced ventricular arrhythmias patients with CPVT uncontrolled by conventional drug therapy.

BackgroundSudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.ObjectivesThis study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.MethodsWe evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.ResultsA clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.ConclusionsMolecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Background-Genetic testing can diagnose long-QT syndrome (LQTS) in asymptomatic relatives of patients with an identified mutation; however, it is costly and subject to availability. The accuracy of a simple algorithm that incorporates resting and exercise ECG parameters for screening LQTS in asymptomatic relatives was evaluated, with genetic testing as the gold standard. Methods and Results-Asymptomatic first-degree relatives of genetically characterized probands were recruited from 5 centers.QT intervals were measured at rest, during exercise, and during recovery. Receiver operating characteristics were used to establish optimal cutoffs. An algorithm for identifying LQTS carriers was developed in a derivation cohort and validated in an independent cohort. The derivation cohort consisted of 69 relatives (28 with LQT1, 20 with LQT2, and 21 noncarriers).Mean age was 35Ϯ18 years, and resting corrected QT interval (QTc) was 466Ϯ39 ms. Abnormal resting QTc (females Ն480 ms; males Ն470 ms) was 100% specific for gene carrier status, but was observed in only 48% of patients; however, mutations were observed in 68% and 42% of patients with a borderline or normal resting QTc, respectively. Among these patients, 4-minute recovery QTc Ն445 ms correctly restratified 22 of 25 patients as having LQTS and 19 of 21 patients as being noncarriers. The combination of resting and 4-minute recovery QTc in a screening algorithm yielded a sensitivity of 0.94 and specificity of 0.90 for detecting LQTS carriers. When applied to the validation cohort (nϭ152; 58 with LQT1, 61 with LQT2, and 33 noncarriers; QTcϭ443Ϯ47 ms), sensitivity was 0.92 and specificity was 0.82. Conclusions-A simple algorithm that incorporates resting and exercise-recovery QTc is useful in identifying LQTS in asymptomatic relatives. (Circulation. 2011;124:2187-2194.)