Background-Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. Methods and Results-Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. Conclusions-In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low.Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events. (Circulation. 2010;121:635-643.)

BACKGROUND L-type calcium channel (LTCC) mutations have been associated with Brugada syndrome (BrS), short QT (SQT) syndrome, and Timothy syndrome (LQT8). Little is known about the extent to which LTCC mutations contribute to the J-wave syndromes associated with sudden cardiac death. OBJECTIVE The purpose of this study was to identify mutations in the α1, β2, and α2δ subunits of LTCC (Cav1.2) among 205 probands diagnosed with BrS, idiopathic ventricular fibrillation (IVF), and early repolarization syndrome (ERS). CACNA1C, CACNB2b, and CACNA2D1 genes of 162 probands with BrS and BrS+SQT, 19 with IVF, and 24 with ERS were screened by direct sequencing. METHODS/RESULTS Overall, 23 distinct mutations were identified. A total of 12.3%, 5.2%, and 16% of BrS/BrS+SQT, IVF, and ERS probands displayed mutations in α1, β2, and α2δ subunits of LTCC, respectively. When rare polymorphisms were included, the yield increased to 17.9%, 21%, and 29.1% for BrS/BrS+SQT, IVF, and ERS probands, respectively. Functional expression of two CACNA1C mutations associated with BrS and BrS+SQT led to loss of function in calcium channel current. BrS probands displaying a normal QTc had additional variations known to prolong the QT interval. CONCLUSION The study results indicate that mutations in the LTCCs are detected in a high percentage of probands with J-wave syndromes associated with inherited cardiac arrhythmias, suggesting that genetic screening of Cav genes may be a valuable diagnostic tool in identifying individuals at risk. These results are the first to identify CACNA2D1 as a novel BrS susceptibility gene and CACNA1C, CACNB2, and CACNA2D1 as possible novel ERS susceptibility genes.

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Background-Brugada syndrome is an arrhythmogenic disease characterized by an ECG pattern of ST-segment elevation in the right precordial leads and augmented risk of sudden cardiac death. Little is known about the clinical presentation and prognosis of this disease in children. Methods and Results-Thirty children affected by Brugada syndrome who were Ͻ16 years of age (mean, 8Ϯ4 years) were included. All patients displayed a type I ECG pattern before or after drug provocation challenge. Diagnosis of Brugada syndrome was made under the following circumstances: aborted sudden death (nϭ1), syncope of unexplained origin (nϭ10), symptomatic supraventricular tachycardia (nϭ1), suspicious ECG (nϭ1), and family screening for Brugada syndrome (nϭ17). Syncope was precipitated by fever in 5 cases. Ten of 11 symptomatic patients displayed a spontaneous type I ECG. An implantable cardioverter-defibrillator was implanted in 5 children; 4 children were treated with hydroquinidine; and 1 child received a pacemaker because of symptomatic sick sinus syndrome. During a mean follow-up of 37Ϯ23 months, 1 child experienced sudden cardiac death, and 2 children received an appropriate implantable cardioverter-defibrillator shock; all of them were symptomatic and had manifested a type I ECG spontaneously. One child had a cardioverter-defibrillator infection that required explantation of the defibrillator. Conclusions-In the largest population of children affected by Brugada syndrome described to date, fever represented the most important precipitating factor for arrhythmic events, and as in the adult population, the risk of arrhythmic events was higher in previously symptomatic patients and in those displaying a spontaneous type I ECG.

Objectives The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS). Background BrS is an inherited sudden cardiac death syndrome. Fewer than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8 in the electrical function of the heart. Methods Clinical analysis and direct sequencing of BrS-susceptibility genes were performed on 150 probands, family members and >200 healthy controls. Expression and co-immunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations. Results We identified 17 SCN10A mutations in 25 probands (20 M/5 F); 23 of the 25 (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). BrS patients with SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals than SCN10A negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous co-expression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current (INa) compared with WT-SCN5A alone. In contrast, co-expression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in INa, respectively. Co-immunoprecipitation studies performed provide evidence for co-association of Nav1.8 and Nav1.5 in the plasma membrane. Conclusions Our study identifies SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.

Background-Cryoablation has emerged as an alternative to radiofrequency catheter ablation (RFCA) for the treatment of atrioventricular (AV) nodal reentrant tachycardia (AVNRT). The purpose of this prospective randomized study was to test whether cryoablation is as effective as RFCA during both short-term and long-term follow-up with a lower risk of permanent AV block. Methods and Results-A total of 509 patients underwent slow pathway cryoablation (nϭ251) or RFCA (nϭ258). The primary end point was immediate ablation failure, permanent AV block, and AVNRT recurrence during a 6-month follow-up. Secondary end points included procedural parameters, device functionality, and pain perception. Significantly more patients in the cryoablation group than the RFCA group reached the primary end point (12.6% versus 6.3%; Pϭ0.018). Whereas immediate ablation success (96.8% versus 98.4%) and occurrence of permanent AV block (0% versus 0.4%) did not differ, AVNRT recurrence was significantly more frequent in the cryoablation group (9.4% versus 4.4%; Pϭ0.029). In the cryoablation group, procedure duration was longer (138Ϯ54 versus 123Ϯ48 minutes; Pϭ0.0012) and more device problems occurred (13 versus 2 patients; Pϭ0.033). Pain perception was lower in the cryoablation group (PϽ0.001). Conclusions-Cryoablation for AVNRT is as effective as RFCA over the short term but is associated with a higher recurrence rate at the 6-month follow-up. The risk of permanent AV block does not differ significantly between cryoablation and RFCA. The potential benefits of cryoenergy relative to ablation safety and pain perception are counterbalanced by longer procedure times, more device problems, and a high recurrence rate. Clinical Trial Registration-URL: http://www.clinicaltrials.gov.

Aims The true incidence of life‐threatening ventricular tachyarrhythmic events and the risk of sudden cardiac death in the early stage of peripartum cardiomyopathy (PPCM) are still unknown. We aimed to assess the usefulness of the wearable cardioverter/defibrillator (WCD) to bridge a potential risk for life‐threatening arrhythmic events in patients with early PPCM, severely reduced left ventricular ejection fraction (LVEF) and symptoms of heart failure. Methods and results Twelve consecutively admitted women with PPCM were included in this single‐centre, prospective observational study between September 2012 and September 2013. Patients with LVEF ≤35% were considered to use the WCD for 3 months or even 6 months when considered necessary for LVEF recovery. Nine of the 12 women had a severely reduced LVEF (mean 18.3%) at the time of study enrolment; seven women received a WCD, while two patients refused to wear a WCD. During a median WCD follow‐up of 81 days (range 25–345 days), we observed a total of four events of ventricular fibrillation with appropriate and successful WCD shocks in three of the seven women receiving a WCD. No syncope or sudden arrhythmic deaths occurred in women not using the WCD during a median follow‐up of 12 months (range 5–15 months). All women showed impressive improvement of LVEF during follow‐up. Conclusion PPCM patients with severely reduced LVEF have an elevated risk for ventricular tachyarrhythmias early after diagnosis. Therefore, use of the WCD should be considered in all women with early‐stage PPCM and severely reduced LVEF during the first 6 months after initiation of heart failure therapy.

OBJECTIVES-The purpose of this study was to compare the effect of intravenous flecainide and ajmaline with respect to their ability to induce or accentuate the typical ECG pattern of Brugada syndrome.BACKGROUND-Brugada syndrome is associated with a high incidence of sudden cardiac death. The typical ECG pattern of ST-segment elevation in the right precordial leads often is concealed, but it can be unmasked with sodium channel blockers such as flecainide and ajmaline. Little is known about the relative effectiveness of these provocative agents in unmasking Brugada syndrome.