Hybrid-Approach Ablation in Drug-Refractory Arrhythmogenic Right Ventricular Cardiomyopathy.

Management of ventricular arrhythmias (VAs) beyond implantable cardioverter-defibrillator positioning in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) is challenging. Catheter ablation of the ventricular substrate often requires a combination of endocardial and epicardial approaches, with disappointing outcomes due to the progressive nature of the disease. We report the Universitair Ziekenhuis Brussel experience through a case series of 16 patients with drug-refractory ARVC, who have undergone endocardial and/or epicardial catheter ablation of VAs with a thoracoscopic hybrid-approach. After a mean follow-up time of 5.16 years (SD 2.9 years) from the first hybrid-approach ablation, VA recurrence was observed in 5 patients (31.25%): among these, patients 4 patients (80%) received a previous ablation and 1 of 11 patients (9.09%) who had a hybrid ablation as first approach had a VA recurrence (80% vs 9.09%; log-rank p = 0.04). Despite the recurrence rate of arrhythmic events, all patients had a significant reduction in the arrhythmic burden after ablation, with a mean of 4.65 years (SD 2.9 years) of freedom from clinically significant arrhythmias, defined as symptomatic VAs or implantable cardioverter-defibrillator-delivered therapies. In conclusion, our case series confirms that management of VAs in patients with ARVC is difficult because patients do not always respond to antiarrhythmic medications and can require multiple invasive procedures. A multidisciplinary approach involving cardiologists, cardiac surgeons, and cardiac electrophysiologists, together with recent cardiac mapping techniques and ablation tools, might mitigate these difficulties and improve outcomes.

Role of Electrocardiographic Tpeak-Tend for the Prediction of Ventricular Arrhythmic Events in the Brugada Syndrome.

Some previous studies have proposed the electrocardiographic Tpeak-Tend (TpTe) as a possible predictor of ventricular arrhythmic events in patients with Brugada syndrome (BrS). We sought to analyze the association between the parameters of repolarization dispersion (TpTe, TpTe/QT, TpTe dispersion, QTc, and QTd) and ventricular fibrillation/sudden cardiac death in a large cohort of patients with type 1 BrS. A total of 448 consecutive patients with BrS (men 61%, age 45 ± 16 years) with spontaneous (n = 96, 21%) or drug-induced (n = 352, 79%) type 1 electrocardiogram were retrospectively included. At the time of the diagnosis or during a mean follow-up of 93 ± 47 months (median 88 months), 43 patients (9%) documented ventricular arrhythmias. No significant difference was observed in TpTe, TpTe/QT, maximum TpTe, and TpTe dispersion between asymptomatic patients and those with syncope and malignant arrhythmias. TpTe/QT ratio did not also significantly differ between patients with ventricular fibrillation/sudden cardiac death and those asymptomatic ones. In conclusion, TpTe was not significantly prolonged in those patients with type 1 BrS presenting with unexplained syncope or malignant arrhythmic events during follow-up.

Long-Term Follow-Up of Probands With Brugada Syndrome.

This study analyzes the natural history of a large cohort of probands with Brugada syndrome (BrS) to assess the predictive value of different clinical and electrocardiographic parameters for the development of ventricular fibrillation (VF) or sudden cardiac death (SCD) during a long-term follow-up. Baseline characteristics of 289 consecutive probands (203 men; mean age 45 ± 16 years) with a Brugada type 1 electrocardiogram were analyzed. After a mean follow-up of 10.1 ± 4.6 years, 29 malignant arrhythmias occurred. On multivariate analysis, a history of VF and syncopal episodes, fragmented QRS (f-QRS), spontaneous type 1 electrocardiogram, and early repolarization pattern were significantly associated with later occurrence of VF/SCD. In patients with drug-induced BrS, the accentuation or de novo appearance of f-QRS in other leads was always associated with VF/SCD. Cerebrovascular events occurred in 8 patients with atrial fibrillation (15.1%), most of them (75%) presenting as the first clinical manifestation. The time-to-diagnosis was found to be significantly shorter in those patients who directly came to our center than in those who referred to our center for a second opinion. In conclusion, systematic use of the pharmacologic challenge in patients with unexplained cardiovascular symptoms and/or atrial fibrillation might significantly improve the identification of BrS with a shortening of the time-to-diagnosis. The CHA2DS2VASc score might be inappropriate for predicting transient ischemic attack or stroke in BrS. This study confirms the independent predictive value of previous VF and syncopal episodes, f-QRS, type 1 electrocardiogram, and early repolarization pattern. In BrS a sufficiently long follow-up is necessary before conclusions on prognosis are apparent.

Brugada syndrome in the young: an assessment of risk factors predicting future events.

AIMS: To investigate the clinical characteristics, prognoses, and presence of risk factors in young patients with Brugada syndrome (BS). METHODS AND RESULTS: A consecutive cohort of 128 young BS patients (≤25 years old at diagnosis) was analysed. Eighty-eight patients (69%) were asymptomatic, whereas 40 (31%) presented with clinical manifestations of BS. Markers of prognosis and risk were identified upon comparison of these two groups. A history of malignant syncope was strong predictors of ventricular arrhythmic events. Family history of sudden cardiac death (SCD) and mutations in the SCN5A gene did not associate with increased risk. Symptomatic patients presented with significantly abnormal baseline electrical characteristics when compared with the asymptomatic cohort, including spontaneous type I electrocardiograph (ECG) patterns, sinus node dysfunction (SND), first-degree atrioventricular (AV) block, and intra-ventricular conduction delay. The symptomatic group more frequently exhibited atrial arrhythmias. Electrophysiological studies resulted positive more frequently in symptomatic patients, but no risk association for future events could be determined. During the follow-up period (mean: 65 months), 10 arrhythmic events occurred in nine symptomatic patients (event rate: 4.5% per year). No events occurred in the asymptomatic group. Variables significantly associated with arrhythmic events during follow-up were presence of symptoms at diagnosis and spontaneous type I ECG. The presence of atrial arrhythmias and conduction abnormalities was also associated with the risk of arrhythmic events during follow-up. CONCLUSION: Symptomatic BS in the young age is a rare but malignant condition that can manifest with a spectrum of electrical abnormalities (i.e. SND, atrial tachycardias, AV block, and infra-nodal conduction delay) and result in the extreme cases in lethal arrhythmic events and SCD.

SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.

SCN5A mutations involving the α-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the α-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non-dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non-dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome.

Contribution of Cardiac Sodium Channel ß-Subunit Variants to Brugada Syndrome.

BACKGROUND: Brugada syndrome (BrS) is an inheritable cardiac disease associated with syncope, malignant ventricular arrhythmias and sudden cardiac death. The largest proportion of mutations in BrS is found in the SCN5A gene encoding the α-subunit of cardiac sodium channels (Nav1.5). Causal SCN5A mutations are present in 18-30% of BrS patients. The additional genetic diagnostic yield of variants in cardiac sodium channel ß-subunits in BrS patients was explored and functional studies on 3 novel candidate variants were performed. METHODS AND RESULTS: TheSCN1B-SCN4B genes were screened, which encode the 5 sodium channel ß-subunits, in a SCN5A negative BrS population (n=74). Five novel variants were detected; in silico pathogenicity prediction classified 4 variants as possibly disease causing. Three variants were selected for functional study. These variants caused only limited alterations of Nav1.5 function. Next generation sequencing of a panel of 88 arrhythmia genes could not identify other major causal mutations. CONCLUSIONS: It was hypothesized that the studied variants are not the primary cause of BrS in these patients. However, because small functional effects of these ß-subunit variants can be discriminated, they might contribute to the BrS phenotype and be considered a risk factor. The existence of these risk factors can give an explanation to the reduced penetrance and variable expressivity seen in this syndrome. We therefore recommend including the SCN1-4B genes in a next generation sequencing-based gene panel.