Electrocardiographic temporo-spatial assessment of depolarization and repolarization changes after epicardial arrhythmogenic substrate ablation in Brugada syndrome.

Aims: In Brugada syndrome (BrS), with spontaneous or ajmaline-induced coved ST elevation, epicardial electro-anatomic potential duration maps (epi-PDMs) were detected on a right ventricle (RV) outflow tract (RVOT), an arrhythmogenic substrate area (AS area), abolished by epicardial-radiofrequency ablation (EPI-AS-RFA). Novel CineECG, projecting 12-lead electrocardiogram (ECG) waveforms on a 3D heart model, previously localized depolarization forces in RV/RVOT in BrS patients. We evaluate 12-lead ECG and CineECG depolarization/repolarization changes in spontaneous type-1 BrS patients before/after EPI-AS-RFA, compared with normal controls. Methods and results: In 30 high-risk BrS patients (93% males, age 37 + 9 years), 12-lead ECGs and epi-PDMs were obtained at baseline, early after EPI-AS-RFA, and late follow-up (FU) (2.7-16.1 months). CineECG estimates temporo-spatial localization during depolarization (Early-QRS and Terminal-QRS) and repolarization (ST-Tpeak, Tpeak-Tend). Differences within BrS patients (baseline vs. early after EPI-AS-RFA vs. late FU) were analysed by Wilcoxon signed-rank test, while differences between BrS patients and 60 age-sex-matched normal controls were analysed by the Mann-Whitney test. In BrS patients, baseline QRS and QTc durations were longer and normalized after EPI-AS-ATC (151 ± 15 vs. 102 ± 13 ms, P < 0.001; 454 ± 40 vs. 421 ± 27 ms, P < 0.000). Baseline QRS amplitude was lower and increased at late FU (0.63 ± 0.26 vs. 0.84 ± 13 ms, P < 0.000), while Terminal-QRS amplitude decreased (0.24 ± 0.07 vs. 0.08 ± 0.03 ms, P < 0.000). At baseline, CineECG depolarization/repolarization wavefront prevalently localized in RV/RVOT (Terminal-QRS, 57%; ST-Tpeak, 100%; and Tpeak-Tend, 61%), congruent with the AS area on epi-PDM. Early after EPI-AS-RFA, RV/RVOT localization during depolarization disappeared, as Terminal-QRS prevalently localized in the left ventricle (LV, 76%), while repolarization still localized on RV/RVOT [ST-Tpeak (44%) and Tpeak-Tend (98%)]. At late FU, depolarization/repolarization forces prevalently localized in the LV (Terminal-QRS, 94%; ST-Tpeak, 63%; Tpeak-Tend, 86%), like normal controls. Conclusion: CineECG and 12-lead ECG showed a complex temporo-spatial perturbation of both depolarization and repolarization in BrS patients, prevalently localized in RV/RVOT, progressively normalizing after epicardial ablation.

Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes.

Brugada Syndrome (BrS) is a genetic heart condition linked to sudden cardiac death. Though the SCN5A gene is primarily associated with BrS, there is a lack of comprehensive studies exploring the connection between SCN5A mutation locations and the clinical presentations of the syndrome. This study aimed to address this gap and gain further understanding of the syndrome. The investigation classified 36 high-risk BrS patients based on SCN5A mutations within the transmembrane/structured (TD) and intra-domain loops (IDLs) lacking a 3D structure. We characterized the intrinsically disordered regions (IDRs) abundant in IDLs, using bioinformatics tools to predict IDRs and post-translational modifications (PTMs) in NaV1.5. Interestingly, it was found that current predictive tools often underestimate the impacts of mutations in IDLs and disordered regions. Moreover, patients with SCN5A mutations confined to IDL regions-previously deemed 'benign'-displayed clinical symptoms similar to those carrying 'damaging' variants. Our research illuminates the difficulty in stratifying patients based on SCN5A mutation locations, emphasizing the vital role of IDLs in the NaV1.5 channel's functioning and protein interactions. We advocate for caution when using predictive tools for mutation evaluation in these regions and call for the development of improved strategies in accurately assessing BrS risk.

Deep learning unmasks the ECG signature of Brugada syndrome.

One in 10 cases of sudden cardiac death strikes without warning as the result of an inherited arrhythmic cardiomyopathy, such as Brugada Syndrome (BrS). Normal physiological variations often obscure visible signs of this and related life-threatening channelopathies in conventional electrocardiograms (ECGs). Sodium channel blockers can reveal previously hidden diagnostic ECG features, however, their use carries the risk of life-threatening proarrhythmic side effects. The absence of a nonintrusive test places a grossly underestimated fraction of the population at risk of SCD. Here, we present a machine-learning algorithm that extracts, aligns, and classifies ECG waveforms for the presence of BrS. This protocol, which succeeds without the use of a sodium channel blocker (88.4% accuracy, 0.934 AUC in validation), can aid clinicians in identifying the presence of this potentially life-threatening heart disease.

Right ventricular epicardial arrhythmogenic substrate in long-QT syndrome patients at risk of sudden death.

AIMS: The long-QT syndrome (LQTS) represents a leading cause of sudden cardiac death (SCD). The aim of this study was to assess the presence of an underlying electroanatomical arrhythmogenic substrate in high-risk LQTS patients. METHODS AND RESULTS: The present study enrolled 11 consecutive LQTS patients who had experienced frequent implantable cardioverter-defibrillator (ICD discharges triggered by ventricular fibrillation (VF). We acquired electroanatomical biventricular maps of both endo and epicardial regions for all patients and analyzed electrograms sampled from several myocardial regions. Abnormal electrical activities were targeted and eliminated by the means of radiofrequency catheter ablation. VF episodes caused a median of four ICD discharges in eleven patients (6 male, 54.5%; mean age 44.0 ± 7.8 years, range 22-53) prior to our mapping and ablation procedures. The average QTc interval was 500.0 ± 30.2 ms. Endo-epicardial biventricular maps displayed abnormally fragmented, low-voltage (0.9 ± 0.2 mV) and prolonged electrograms (89.9 ± 24.1 ms) exclusively localized in the right ventricular epicardium. We found electrical abnormalities extending over a mean epicardial area of 15.7 ± 3.1 cm2. Catheter ablation of the abnormal epicardial area completely suppressed malignant arrhythmias over a mean 12 months of follow-up (median VF episodes before vs. after ablation, 4 vs. 0; P = 0.003). After the procedure, the QTc interval measured in a 12-lead ECG analysis shortened to a mean of 461.8 ± 23.6 ms (P = 0.004). CONCLUSION: This study reveals that, among high-risk LQTS patients, regions localized in the epicardium of the right ventricle harbour structural electrophysiological abnormalities. Elimination of these abnormal electrical activities successfully prevented malignant ventricular arrhythmia recurrences.

High-risk Brugada syndrome: factors associated with arrhythmia recurrence and benefits of epicardial ablation in addition to implantable cardioverter defibrillator implantation.

AIMS: This study aims to evaluate the prognostic impact of the arrhythmogenic substrate size in symptomatic Brugada syndrome (BrS) as well as to validate the long-term safety and effectiveness of epicardial radiofrequency ablation (RFA) compared with no-RFA group. METHODS AND RESULTS: In this prospective investigational long-term registry study, 257 selected symptomatic BrS patients with implantable cardioverter defibrillator (ICD) implantation were included. Among them, 206 patients underwent epicardial RFA and were monitored for over 5 years post-ablation (RFA group), while 51 patients received only ICD implantation declining RFA. Primary endpoints included risk factors for ventricular fibrillation (VF) events pre-ablation and freedom from VF events post-ablation. In the RFA group, BrS substrates were identified in the epicardial surface of the right ventricle. During the pre-RFA follow-up period (median 27 months), VF episodes and VF storms were experienced by 53 patients. Independent risk factors included substrate size [hazard ratio (HR), 1.13; 95% confidence interval (CI), 1.08-1.18; P < 0.001], aborted cardiac arrest (HR, 2.98; 95% CI, 1.68-5.28; P < 0.001), and SCN5A variants (HR, 2.22; 95% CI, 1.15-4.27; P = 0.017). In the post-RFA follow-up (median 40 months), the RFA group demonstrated superior outcomes compared with no-RFA (P < 0.001) without major procedure-related complications. CONCLUSION: Our study underscores the role of BrS substrate extent as a crucial prognostic factor for recurrent VF and validates the safety and efficacy of RFA when compared with a no-RFA group. Our findings highlight the importance of ajmaline in guiding epicardial mapping/ablation in symptomatic BrS patients, laying the groundwork for further exploration of non-invasive methods to guide informed clinical decision-making.

Alterations of the Sialylation Machinery in Brugada Syndrome.

Brugada Syndrome (BrS) is an inherited arrhythmogenic disorder with an increased risk of sudden cardiac death. Recent evidence suggests that BrS should be considered as an oligogenic or polygenic condition. Mutations in genes associated with BrS are found in about one-third of patients and they mainly disrupt the cardiac sodium channel NaV1.5, which is considered the main cause of the disease. However, voltage-gated channel's activity could be impacted by post-translational modifications such as sialylation, but their role in BrS remains unknown. Thus, we analyzed high risk BrS patients (n = 42) and healthy controls (n = 42) to assess an involvement of sialylation in BrS. Significant alterations in gene expression and protein sialylation were detected in Peripheral Blood Mononuclear Cells (PBMCs) from BrS patients. These changes were significantly associated with the phenotypic expression of the disease, as the size of the arrhythmogenic substrate and the duration of epicardial electrical abnormalities. Moreover, protein desialylation caused a reduction in the sodium current in an in vitro NaV1.5-overexpressing model. Dysregulation of the sialylation machinery provides definitive evidence that BrS affects extracardiac tissues, suggesting an underlying cause of the disease. Moreover, detection of these changes at the systemic level and their correlation with the clinical phenotype hint at the existence of a biomarker signature for BrS.

Brugada Syndrome: New Insights From Cardiac Magnetic Resonance and Electroanatomical Imaging.

BACKGROUND: Brugada syndrome (BrS) is considered a purely electrical disease with variable electrical substrates. Variable rates of mechanical abnormalities have been also reported. Whether exists a link between electrical and mechanical abnormalities has never been previously explored. This investigational physiopathological study aimed to determine the relationship between the substrate size/location, as exposed by ajmaline provocation, and the severity of mechanical abnormalities, as assessed by cardiac magnetic resonance in patients with BrS. METHODS: Twenty-four consecutive high-risk patients with BrS (mean age, 38±11 years, 17 males), presenting with malignant syncope and documented polymorphic ventricular tachycardia/ventricular fibrillation, and candidate to implantable cardioverter defibrillator implantation, underwent cardiac magnetic resonance and electroanatomic maps. During each examination, ajmaline test (1 mg/kg over 5 minutes) was performed. Cardiac magnetic resonance findings were compared with 24 age, sex, and body surface area-matched controls. In patients with BrS, the correlation between the electrical substrate extent and right ventricular regional mechanical abnormalities before/after ajmaline challenge was analyzed. RESULTS: After ajmaline, patients with BrS showed a reduction of right ventricular (RV) ejection fraction (P<0.001), associated with decreased transversal displacement (U, P<0.001) and longitudinal strain (ε, P<0.001) localized at RV outflow tract. In patients with BrS significant preajmaline/postajmaline changes of transversal displacement (ΔU, P<0.001) and longitudinal strain (Δε, P<0.001) were found. In the control group, no mechanical changes were observed after ajmaline. The electrical substrate consistently increased after ajmaline from 1.7±2.8 cm2 to 14.2±7.3 cm2 (P<0.001), extending from the RV outflow tract to the neighboring segments of the RV anterior wall. Postajmaline RV ejection fraction inversely correlated with postajmaline substrate extent (r=-0.830, P<0.001). In patients with BrS and normal controls, cardiac magnetic resonance detected neither myocardial fibrosis nor RV outflow tract morphological abnormalities. CONCLUSIONS: BrS is a dynamic RV electromechanical disease, where functional abnormalities correlate with the maximal extent of the substrate size. These findings open new lights on the physiopathology of the disease. Registration: URL: https://clinicaltrial.gov; Unique identifier: NCT03524079.

Second-generation laser balloon ablation for the treatment of atrial fibrillation assessed by continuous rhythm monitoring: the LIGHT-AF study.

AIMS: Balloon-based technologies have been developed to simplify catheter ablation of atrial fibrillation (AF), to improve the clinical outcome of the procedure and to achieve durable pulmonary vein isolation (PVI). The objective of this study is to evaluate the safety and efficacy of second-generation laser balloon (LB2) ablation in the treatment of AF using a continuous cardiac rhythm monitoring strategy. Atrial tachyarrhythmias (ATas) recurrences were assessed with implantable cardiac monitors (ICMs) or devices. METHODS AND RESULTS: All patients underwent LB2 ablation procedure. The primary endpoint was the first recurrence of any, >5.5 and >24 h duration ATas after the blanking period (90 days). In-hospital visits were performed at 3, 6, and 12 months. Seventy-three patients (68% male, mean age 59.8 ± 11.3) were included in the study. The average procedure, fluoroscopy, and laser ablation times were 81.5 ± 30.1, 21.5 ± 12.4, and 33.8 ± 9.7, respectively. All PVs were isolated using the LB2 with no need of touch-up using focal catheters. No major complications occurred during or after the procedures. The one-year freedom from recurrences was 66.9% (95% CI: 57.0-76.7%), 81.0% (69.5-88.5%), and 86.8% (76.1-92.9%) considering any, 5.5-h and 24-h cut-off duration, respectively. At 3, 6, and 12 months, any ATas was recorded in 22%, 32%, and 25% of patients, with a ≥5% arrhythmic burden documented in 4%, 5%, and 3%, respectively. Few patients reported AF-related symptoms (7%, 8%, and 5%). CONCLUSION: LB2 ablation is a safe and effective procedure, showing a high freedom from recurrences and low arrhythmic burden as documented by a continuous rhythm monitoring strategy.

Assessing QT interval in COVID-19 patients:safety of hydroxychloroquine-azithromycin combination regimen.

BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population. METHOD: A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT). RESULTS: A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3 452 ± 26.4 vs Group 2 436.3 ± 28.4 vs Group 1 424.4 ± 24.3 ms, respectively; p < 0.001). Multivariate analysis demonstrated that HCQ/AZT combination (OR 9.02, p = 0.001) and older age (OR 1.04, p = 0.031) were independent predictors of QTc prolongation. The risk increased with age (incremental utility analysis p = 0.02). Twenty patients (18%) died, and no cardiac arrest neither arrhythmic fatalities were documented. CONCLUSIONS: The HCQ/AZT combination therapy causes a significantly increase of QT interval compared to HCQ alone. Older patients under such regimen are at higher risk of experiencing QT prolongation. The use of such drugs may be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients as no arrhythmic fatalities occurred.

Brugada syndrome genetics is associated with phenotype severity.

AIMS: Brugada syndrome (BrS) is associated with an increased risk of sudden cardiac death due to ventricular tachycardia/fibrillation (VT/VF) in young, otherwise healthy individuals. Despite SCN5A being the most commonly known mutated gene to date, the genotype-phenotype relationship is poorly understood and remains uncertain. This study aimed to elucidate the genotype-phenotype correlation in BrS. METHODS AND RESULTS: Brugada syndrome probands deemed at high risk of future arrhythmic events underwent genetic testing and phenotype characterization by the means of epicardial arrhythmogenic substrate (AS) mapping, and were divided into two groups according to the presence or absence of SCN5A mutation. Two-hundred probands (160 males, 80%; mean age 42.6 ± 12.2 years) were included in this study. Patients harbouring SCN5A mutations exhibited a spontaneous type 1 pattern and experienced aborted cardiac arrest or spontaneous VT/VF more frequently than the other subjects. SCN5A-positive patients exhibited a larger epicardial AS area, more prolonged electrograms and more frequently observed non-invasive late potentials. The presence of an SCN5A mutation explained >26% of the variation in the epicardial AS area and was the strongest predictor of a large epicardial area. CONCLUSION: In BrS, the genetic background is the main determinant for the extent of the electrophysiological abnormalities. SCN5A mutation carriers exhibit more pronounced epicardial electrical abnormalities and a more aggressive clinical presentation. These results contribute to the understanding of the genetic determinants of the BrS phenotypic expression and provide possible explanations for the varying degrees of disease expression.

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome.

Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the SCN5A gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS.

Novel CineECG Derived From Standard 12-Lead ECG Enables Right Ventricle Outflow Tract Localization of Electrical Substrate in Patients With Brugada Syndrome.

BACKGROUND: In Brugada syndrome (BrS), diagnosed in presence of a spontaneous or ajmaline-induced type-1 pattern, ventricular arrhythmias originate from the right ventricle outflow tract (RVOT). We developed a novel CineECG method, obtained by inverse electrocardiogram (ECG) from standard 12-lead ECG, to localize the electrical activity pathway in patients with BrS. METHODS: The CineECG enabled the temporospatial localization of the ECG waveforms, deriving the mean temporospatial isochrone from standard 12-lead ECG. The study sample included (1) 15 patients with spontaneous type-1 Brugada pattern, and (2) 18 patients with ajmaline-induced BrS (at baseline and after ajmaline), in whom epicardial potential duration maps were available; (3) 17 type-3 BrS pattern patients not showing type-1 BrS pattern after ajmaline (ajmaline-negative); (4) 47 normal subjects; (5) 18 patients with right bundle branch block (RBBB). According to CineECG algorithm, each ECG was classified as Normal, Brugada, RBBB, or Undetermined. RESULTS: In patients with spontaneous or ajmaline-induced BrS, CineECG localized the terminal mean temporospatial isochrone forces in the RVOT, congruent with the arrhythmogenic substrate location detected by epicardial potential duration maps. The RVOT location was never observed in normal, RBBB, or ajmaline-negative patients. In most patients with ajmaline-induced BrS (78%), the RVOT location was already evident at baseline. The CineECG classified all normal subjects and ajmaline-negative patients at baseline as Normal or Undetermined, all patients with RBBB as RBBB, whereas all patients with spontaneous and ajmaline-induced BrS as Brugada. Compared with standard 12-lead ECG, CineECG at baseline had a 100% positive predictive value and 81% negative predictive value in predicting ajmaline test results. CONCLUSIONS: In patients with spontaneous and ajmaline-induced BrS, the CineECG localized the late QRS activity in the RVOT, a phenomenon never observed in normal, RBBB, or ajmaline-negative patients. The possibility to identify the RVOT as the location of the arrhythmogenic substrate by the noninvasive CineECG, based on the standard 12-lead ECG, opens new prospective for diagnosing patients with BrS.

New electromechanical substrate abnormalities in high-risk patients with Brugada syndrome.

BACKGROUND: The relationship between the typical electrocardiographic pattern and electromechanical abnormalities has never been systematically explored in Brugada syndrome (BrS). OBJECTIVES: The aims of this study were to characterize the electromechanical substrate in patients with BrS and to evaluate the relationship between electrical and mechanical abnormalities. METHODS: We enrolled 50 consecutive high-risk patients with BrS (mean age 42 ± 7.2 years), with implantable cardioverter-defibrillator implantation for primary or secondary prevention of ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation [VT/VF]), undergoing substrate mapping and ablation. Patients underwent 3-dimensional (3D) echocardiography with 3D wall motion/deformation quantification and electroanatomic mapping before and after ajmaline administration (1 mg/kg in 5 minutes); 3D mechanical changes were compared with 50 age- and sex-matched controls. The effect of substrate ablation on electromechanical abnormalities was also assessed. RESULTS: In all patients, ajmaline administration induced Brugada type 1 pattern, with a significant increase in the electrical substrate (P < .001), particularly in patients with previous spontaneous VT/VF (P = .007). Induction of Brugada pattern was associated with lowering of right ventricular (RV) ejection fraction (P < .001) and worsening of 3D RV mechanical function (P < .001), particularly in the anterior free wall of the RV outflow tract, without changes in controls. RV electrical and mechanical abnormalities were highly correlated (r = 0.728, P < .001). By multivariate analysis, only the area of RV dysfunction was an independent predictor of spontaneous VT/VF (odds ratio 1.480; 95% confidence interval 1.159-1.889; P = .002). Substrate ablation abolished both BrS-electrocardiographic pattern and mechanical abnormalities, despite ajmaline rechallenge. CONCLUSION: BrS is an electromechanical disease affecting the RV. The typical BrS pattern reflects an extensive RV arrhythmic substrate, driving consistent RV mechanical abnormalities. Substrate ablation abolished both Brugada pattern and mechanical abnormalities.

Genotype-Phenotype Correlation in a Family with Brugada Syndrome Harboring the Novel p.Gln371* Nonsense Variant in the SCN5A Gene.

Brugada syndrome (BrS) is marked by coved ST-segment elevation and increased risk of sudden cardiac death. The genetics of this syndrome are elusive in over half of the cases. Variants in the SCN5A gene are the single most common known genetic unifier, accounting for about a third of cases. Research models, such as animal models and cell lines, are limited. In the present study, we report the novel NM_198056.2:c.1111C>T (p.Gln371*) heterozygous variant in the SCN5A gene, as well as its segregation with BrS in a large family. The results herein suggest a pathogenic effect of this variant. Functional studies are certainly warranted to characterize the molecular effects of this variant.

Non-invasive assessment of the arrhythmogenic substrate in Brugada syndrome using signal-averaged electrocardiogram: clinical implications from a prospective clinical trial.

AIMS: Brugada syndrome (BrS) represents a major cause of sudden cardiac death in young individuals. The risk stratification to forecast future life-threatening events is still controversial. Non-invasive assessment of late potentials (LPs) has been proposed as a risk stratification tool. However, their nature in BrS is still undetermined. The purpose of this study is to assess the electrophysiological determinants of non-invasive LPs. METHODS AND RESULTS: Two hundred and fifty consecutive patients with (Group 1, n = 96) and without (Group 2, n = 154) BrS-related symptoms were prospectively enrolled in the registry. Signal-averaged electrocardiogram (SAECG) was performed in all subjects before undergoing epicardial mapping. Group 1 patients exhibited larger arrhythmogenic substrates (AS; 5.8 ± 2.8 vs. 2.6 ± 2.1 cm2, P < 0.001) with more delayed potentials (220.4 ± 46.0 vs. 186.7 ± 42.3 ms, P < 0.001). Late potentials were present in 82/96 (85.4%) Group 1 and in 31/154 (20.1%) Group 2 individuals (P < 0.001). Patients exhibiting LPs had more frequently a spontaneous Type 1 pattern (30.1% vs. 10.9%, P < 0.001), SCN5A mutation (34.5% vs. 21.2%, P = 0.02), and exhibited a larger AS with longer potentials (5.8 ± 2.7 vs. 2.2 ± 1.7 cm2; 231.2 ± 37.3 vs. 213.8 ± 39.0 ms; P < 0.001, respectively). Arrhythmogenic substrate dimension was the strongest predictor of the presence of LPs (odds ratio 1.9; P < 0.001). An AS area of at least 3.5 cm2 identified patients with LPs (area under the curve 0.88, 95% confidence interval 0.843-0.931; P < 0.001) with a sensitivity of 86%, specificity 88%, positive predictive value 85%, and negative predictive value 89%. CONCLUSION: The results of this study support the role of the epicardial AS as an electrophysiological determinant of non-invasive LPs, which may serve as a tool in the non-invasive assessment of the BrS substrate, as SAECG-LPs could be considered an expression of the abnormal epicardial electrical activity.ClinicalTrials.gov number (NCT02641431; NCT03106701).

Novel SCN5A p.W697X Nonsense Mutation Segregation in a Family with Brugada Syndrome.

Brugada syndrome (BrS) is marked by an elevated ST-segment elevation and increased risk of sudden cardiac death. Variants in the SCN5A gene are considered to be molecular confirmation of the syndrome in about one third of cases, while the genetics remain a mystery in about half of the cases, with the remaining cases being attributed to variants in any of a number of genes. Before research models can be developed, it is imperative to understand the genetics in patients. Even data from humans is complicated, since variants in the most common gene in BrS, SCN5A, are associated with a number of pathologies, or could even be considered benign, depending on the variant. Here, we provide crucial human data on a novel NM_198056.2:c.2091G>A (p.Trp697X) point-nonsense heterozygous variant in the SCN5A gene, as well as its segregation with BrS. The results herein suggest a pathogenic effect of this variant. These results could be used as a stepping stone for functional studies to better understand the molecular effects of this variant in BrS.

Comparable clinical characteristics in Brugada syndrome patients harboring SCN5A or novel SCN10A variants.

AIMS: The Brugada syndrome (BrS) is an inherited disease associated with an increased risk of sudden cardiac death. Often, the genetic cause remains undetected. Perhaps due at least in part because the NaV1.8 protein is expressed more in both the central and peripheral nervous systems than in the heart, the SCN10A gene is not included in diagnostic arrhythmia/sudden death panels in the vast majority of cardiogenetics centres. METHODS AND RESULTS: Clinical characteristics were assessed in patients harboring either SCN5A or novel SCN10A variants. Genetic testing was performed using Next Generation Sequencing on genomic DNA. Clinical characteristics, including the arrhythmogenic substrate, in BrS patients harboring novel SCN10A variants and SCN5A variants are comparable. Clinical characteristics, including gender, age, personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate are not significantly different between probands harboring SCN10A or SCN5A variants. CONCLUSION: Future studies are warranted to further characterize the role of these specific SCN10A variants.