Brugada syndrome (BrS) is a rare autosomal dominant inherited channel disorder characterized by a specific electrocardiographic pattern of right precordial ST-segment elevation. Clinically, patients may experience polymorphic ventricular tachycardia and ventricular fibrillation, leading to recurrent syncope and sudden cardiac death (SCD) in the absence of structural cardiomyopathy. The A-kinase anchor protein 9 (AKAP9) gene, located on chromosome 7, encodes the AKAP9 protein, which plays a crucial role in regulating the phosphorylation of slowly activating delayed rectifier potassium channels (IKs). Here, we present a rare case of BrS associated with an insertion mutation in AKAP9, resulting in a frameshift mutation.

Brugada syndrome (BrS) is an inherited disease characterized by right precordial ST-segment elevation in the right precordial leads on electrocardiograms (ECG), and high risk of life-threatening ventricular arrhythmia and sudden cardiac death (SCD). Mutations in the responsible genes have not been fully characterized in the BrS patients, except for the SCN5A gene. We identified a new genetic variant, c.1189C>T (p.R397C), in the KCNH2 gene in the asymptomatic male proband diagnosed with BrS and mild QTc shortening. We hypothesize that this variant could alter IKr-current and may be causative for the rare non-SCN5A-related form of BrS. To assess its pathogenicity, we performed patch-clamp analysis on IKr reconstituted with this KCNH2 mutation in the Chinese hamster ovary cells and compared the phenotype with the wild type. It appeared that the R397C mutation does not affect the IKr density, but facilitates activation, hampers inactivation of the hERG channels, and increases magnitude of the window current suggesting that the p.R397C is a gain-of-function mutation. In silico modeling demonstrated that this missense mutation potentially leads to the shortening of action potential in the heart.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 μM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Pathogenic mutations in SCN5A could result in dysfunctions of Nav1.5 and consequently lead to a wide range of inherited cardiac diseases. However, the presence of numerous SCN5A-related variants with unknown significance (VUS) and the comprehensive genotype-phenotype relationship pose challenges to precise diagnosis and genetic counseling for affected families. Here, we functionally identified two novel compound heterozygous variants (L256del and L1621F) in SCN5A in a Chinese family exhibiting complex congenital cardiac phenotypes from sudden cardiac death to overlapping syndromes including sick sinus syndrome and dilated cardiomyopathy in an autosomal recessive pattern. In silico tools predicted decreased stability and hydrophobicity of the two mutated proteins due to conformational changes. Patch-clamp electrophysiology revealed slightly decreased sodium currents, accelerated inactivation, and reduced sodium window current in the Nav1.5-L1621F channels as well as no sodium currents in the Nav1.5-L256del channels. Western blotting analysis demonstrated decreased expression levels of mutated Nav1.5 on the plasma membrane, despite enhanced compensatory expression of the total Nav1.5 expression levels. Immunofluorescence imaging showed abnormal condensed spots of the mutated channels within the cytoplasm instead of normal membrane distribution, indicating impaired trafficking. Overall, we identified the loss-of-function characteristics exhibited by the two variants, thereby providing further evidence for their pathogenic nature. Our findings not only extended the variation and phenotype spectrums of SCN5A, but also shed light on the crucial role of patch-clamp electrophysiology in the functional analysis of VUS in SCN5A, which have significant implications for the clinical diagnosis, management, and genetic counseling in affected individuals with complex cardiac phenotypes.

The aim of this study was to investigate the outcomes of catheter ablation (CA) in preventing arrhythmic events among patients with symptomatic Brugada syndrome (BrS) who declined implantable cardioverter defibrillator (ICD) implantation.
A total of 40 patients with symptomatic BrS were included in the study, of which 18 refused ICD implantation and underwent CA, while 22 patients received ICD implantation. The study employed substrate modification (including endocardial and epicardial approaches) and ventricular fibrillation (VF)-triggering pre-mature ventricular contraction (PVC) ablation strategies. The primary outcomes were a composite endpoint consisting of episodes of VF and sudden cardiac death during the follow-up period. The study population had a mean age of 43.8 ± 9.6 years, with 36 (90.0%) of them being male. All patients exhibited the typical Type 1 BrS electrocardiogram pattern, and 16 (40.0%) were carriers of an SCN5A mutation. The Shanghai risk scores were comparable between the CA and the ICD groups (7.05 ± 0.80 vs. 6.71 ± 0.86, P = 0.351). Ventricular fibrillation-triggering PVCs were ablated in 3 patients (16.7%), while VF substrates were ablated in 15 patients (83.3%). Epicardial ablation was performed in 12 patients (66.7%). During a median follow-up of 46.2 (17.5-73.7) months, the primary outcomes occurred more frequently in the ICD group than in the CA group (5.6 vs. 54.5%, Log-rank P = 0.012).
Catheter ablation is an effective alternative therapy for improving arrhythmic outcomes in patients with symptomatic BrS who decline ICD implantation. Our findings support the consideration of CA as an alternative treatment option in this population.

Routinely collected electronic health records (EHRs) data contain a vast amount of valuable information for conducting epidemiological studies. With the right tools, we can gain insights into disease processes and development, identify the best treatment and develop accurate models for predicting outcomes. Our recent systematic review has found that the number of big data studies from Hong Kong has rapidly increased since 2015, with an increasingly common application of artificial intelligence (AI). The advantages of big data are that i) the models developed are highly generalisable to the population, ii) multiple outcomes can be determined simultaneously, iii) ease of cross-validation by for model training, development and calibration, iv) huge numbers of useful variables can be analyzed, v) static and dynamic variables can be analyzed, vi) non-linear and latent interactions between variables can be captured, vii) artificial intelligence approaches can enhance the performance of prediction models. In this paper, we will provide several examples (cardiovascular disease, diabetes mellitus, Brugada syndrome, long QT syndrome) to illustrate efforts from a multi-disciplinary team to identify data from different modalities to develop models using territory-wide datasets, with the possibility of real-time risk updates by using new data captured from patients. The benefit is that only routinely collected data are required for developing highly accurate and high-performance models. AI-driven models outperform traditional models in terms of sensitivity, specificity, accuracy, area under the receiver operating characteristic and precision-recall curve, and F1 score. Web and/or mobile versions of the risk models allow clinicians to risk stratify patients quickly in clinical settings, thereby enabling clinical decision-making. Efforts are required to identify the best ways of implementing AI algorithms on the web and mobile apps.

In Brugada syndrome (BrS), phase 2 re-excitation/re-entry (P2R) induced by the transient outward potassium current (Ito) is a proposed arrhythmia mechanism; yet, the most common genetic defects are loss-of-function sodium channel mutations.
The authors used computer simulations to investigate how sodium channel dysfunction affects P2R-mediated arrhythmogenesis in the presence and absence of Ito.
Computer simulations were carried out in 1-dimensional cables and 2-dimensional tissue using guinea pig and human ventricular action potential models.
In the presence of Ito sufficient to generate robust P2R, reducing sodium current (INa) peak amplitude alone only slightly potentiated P2R. When INa inactivation kinetics were also altered to simulate reported effects of BrS mutations and sodium channel blockers, however, P2R occurred even in the absence of Ito. These effects could be potentiated by delaying L-type calcium channel activation or increasing ATP-sensitive potassium current, consistent with experimental and clinical findings. INa-mediated P2R also accounted for sex-related, day and night-related, and fever-related differences in arrhythmia risk in BrS patients.
Altered INa kinetics synergize powerfully with reduced INa amplitude to promote P2R-induced arrhythmias in BrS in the absence of Ito, establishing a robust mechanistic link between altered INa kinetics and the P2R-mediated arrhythmia mechanism.

Ventricular fibrillation (VF) is a life-threatening arrhythmia that usually happens in patients with structural heart diseases. However, fever-induced ventricular fibrillation in structurally normal hearts was reported, and the four main diseases associated with these cases were Brugada syndrome, long QT syndrome, idiopathic ventricular fibrillation, and non-cardiovascular diseases. In this review, we analyzed this phenomenon and its clinical characteristics.

Risk stratification of patients with Brugada syndrome (BrS) remains challenging. Signal-averaged electrocardiogram (SAECG) is a noninvasive tool that can be used to identify the electrophysiologic substrate potentially underlying fatal ventricular arrhythmias. The aim of this meta-analysis is to summarize the existing evidence about the role of late potentials (LP) as a predictor for arrhythmic events in patients with BrS. A systematic search in the MedLine database through to June 2022 without any limitations was performed. Ten studies were included in the quantitative synthesis (1431 patients with BrS, mean age 47.4 years, males 86%). Of these, 1220 patients underwent SAECG evaluation (53.2% had positive LP, and 20.6% had a fatal arrhythmic event). There was a nonsignificant association between positive LPs and fatal arrhythmic events [RR: 2.06 (0.98-4.36), P = 0.06, I 2 = 82%]. By including only studies with patients without a history of fatal arrhythmia, the association between LP with arrhythmic events remained nonsignificant [RR: 1.29 (0.67-2.48), P = 0.44, I 2 = 54%]. In conclusion, there is a possible association between LP and fatal arrhythmic events in patients with BrS, but the literature remains inconclusive. Large cohort studies using a multiparametric approach for risk stratification purposes are needed to improve the risk stratification of BrS and to optimize the selection of BrS patients that should be referred for implantable cardioverter-defibrillator.

Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/β-catenin signaling has been recently established. However, the role of Wnt/β-catenin signaling in BrS and underlying mechanisms remains unknown.
Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp.
BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/β-catenin signaling. Notably, inhibition of Wnt/β-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with β-catenin, and reduced expression of Nav1.5 leads to re-localization of β-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/β-catenin signaling to suppress SCN5A transcription.
Our findings suggest that aberrant activation of Wnt/β-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/β-catenin as a potential therapeutic target.