Search

Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, SCN5A , but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.

Background: Treatment options for high-risk Brugada syndrome (BrS) with recurrent ventricular fibrillation (VF) are limited. Catheter ablation is increasingly performed but a large study with long-term outcome data is lacking. We report the results of the multicenter, international BRAVO (Brugada Ablation of VF Substrate Ongoing Registry) for treatment of high-risk symptomatic BrS. Methods: We enrolled 159 patients (median age 42 years; 156 male) with BrS and spontaneous VF in BRAVO; 43 (27%) of them had BrS and early repolarization pattern. All but 5 had an implantable cardioverter-defibrillator for cardiac arrest (n=125) or syncope (n=34). A total of 140 (88%) had experienced numerous implantable cardioverter-defibrillator shocks for spontaneous VF before ablation. All patients underwent a percutaneous epicardial substrate ablation with electroanatomical mapping except for 8 who underwent open-thoracotomy ablation. Results: In all patients, VF/BrS substrates were recorded in the epicardial surface of the right ventricular outflow tract; 45 (29%) patients also had an arrhythmic substrate in the inferior right ventricular epicardium and 3 in the posterior left ventricular epicardium. After a single ablation procedure, 128 of 159 (81%) patients remained free of VF recurrence; this number increased to 153 (96%) after a repeated procedure (mean 1.2±0.5 procedures; median=1), with a mean follow-up period of 48±29 months from the last ablation. VF burden and frequency of shocks decreased significantly from 1.1±2.1 per month before ablation to 0.003±0.14 per month after the last ablation ( P P =0.0274). There were no arrhythmic or cardiac deaths. Complications included hemopericardium in 4 (2.5%) patients. Conclusions: Ablation treatment is safe and highly effective in preventing VF recurrence in high-risk BrS. Prospective studies are needed to determine whether it can be an alternative treatment to implantable cardioverter-defibrillator implantation for selected patients with BrS. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04420078.

Three decades have passed since the Brugada syndrome (BrS) clinical entity was introduced in the early 1990s. During the first 2 decades, treatment of patients with BrS was challenging because there were limited treatment options, and an implantable cardioverter-defibrillator was the only choice for high-risk patients with BrS, that is, those who had aborted sudden cardiac death or had previous ventricular fibrillation episodes. In this article, the authors focus on these advances and how to treat patients with BrS with catheter ablation.

Our group began investigating the cause of sudden unexplained death syndrome in Thailand in 1994 and found that among sudden unexplained death syndrome patients, the Brugada phenotype was ubiquitous. Following this important observation, Brugada syndrome (BrS) became our main research focus and has galvanized our collaboration with several global prominent scientists over the past 30 years. Through this collaborative research, we made major progress toward better understanding of the syndrome and gained knowledge in genetic background, pathophysiology, and new management. Two consensus reports were published to help define diagnostic criteria, risk stratification, and management of BrS patients. In this review, we share our experiences and progress of our research and development of our program that was designed to identify the cause of sudden death, understand pathophysiology of the syndrome, and develop effective and safe management and therapy of BrS patients. Although our work in Thailand was challenging at the beginning, it later blossomed into a multicollaborative research enterprise that has produced several important findings that have shed light on the pathophysiology of BrS and development of a new effective treatment modality, catheter ablation.

The Brugada pattern manifests as a spontaneous variability of the electrocardiographic marker, suggesting a variability of the underlying electrical substrate.The purpose of this study was to investigate the response of the epicardial substrate of Brugada syndrome (BrS) to programmed ventricular stimulation and to Na blocker infusion.We investigated 6 patients (all male; mean age 54 ± 14 years) with BrS and recurrent ventricular fibrillation. Five had no type 1 BrS electrocardiogram pattern at admission. They underwent combined epicardial-endocardial mapping using multielectrode catheters. Changes in epicardial electrograms were evaluated during single endocardial extrastimulation and after low-dose ajmaline infusion (0.5 mg/kg in 5 minutes).All patients had a region in the anterior epicardial right ventricle with prolonged multicomponent electrograms. Single extrastimulation prolonged late epicardial components by 59 ± 31 ms and in 4 patients abolished epicardial components at some sites, without reactivation by surrounding activated sites. These localized blocks occurred at an initial coupling interval of 335 ± 58 ms and then expanded to other sites, being observed in up to 40% of epicardial sites. Ajmaline infusion prolonged electrogram duration in all and produced localized blocks in 62% of sites in the same patients as during extrastimulation. Epicardial conduction recovery after ajmaline occurred intermittently and at discontinuous sites and produced beat-to-beat changes in local repolarization, resulting in an area of marked electrical disparity. These changes were consistent with models based on microstructural alterations under critical propagation conditions.In BrS, localized functional conduction blocks occur at multiple epicardial sites and with variable patterns, without being reactivated from the surrounding sites.

BACKGROUND: The mechanisms by which sodium channel blockade and high-rate pacing modify electrogram (EGM) substrates of Brugada syndrome (BrS) have not been elucidated. OBJECTIVE: The purpose of this study was to determine the effect of ajmaline and high pacing rate on the BrS substrates. METHODS: Thirty-two patients with BrS (mean age 40 ± 12 years) and frequent ventricular fibrillation episodes underwent right ventricular outflow tract substrate electroanatomical and electrocardiographic imaging (ECGI) mapping before and after ajmaline administration and during high-rate atrial pacing. In 4 patients, epicardial mapping was performed using open thoracotomy with targeted biopsies. RESULTS: Ajmaline increased the activation time delay in the substrate (33%; P = .002), ST-segment elevation in the right precordial leads (74%; P < .0001), and the area of delayed activation (170%; P < .0001), coinciding with the increased substrate size (75%; P < .0001). High atrial pacing rate increased the abnormal EGM duration at the right ventricular outflow tract areas from 112 ± 48 to 143 ± 66 ms (P = .003) and produced intermittent conduction block and/or excitation failure at the substrate sites, especially after ajmaline administration. Biopsies from the 4 patients with thoracotomy showed epicardial fibrosis where EGMs were normal at baseline but became fractionated after ajmaline administration. In some areas, local activation was absent and unipolar EGMs had a monophasic morphology resembling the shape of the action potential. CONCLUSION: Sodium current reduction with ajmaline severely compromises impulse conduction at the BrS fibrotic substrates by producing fractionated EGMs, conduction block, or excitation failure, leading to the Brugada ECG pattern and favoring ventricular fibrillation genesis.

Brugada syndrome (BS) is an autosomal dominant inheritance cardiac arrhythmia disorder associated with sudden death in young adults. Thailand has the highest prevalence of BS worldwide, and over 60% of patients with BS still have unclear disease etiology. Here, we performed a new viral metagenome analysis pipeline called VIRIN and validated it with whole genome sequencing (WGS) data of HeLa cell lines and hepatocellular carcinoma. Then the VIRIN pipeline was applied to identify viral integration positions from unmapped WGS data of Thai males, including 100 BS patients (case) and 100 controls. Even though the sample preparation had no viral enrichment step, we can identify several virus genes from our analysis pipeline. The predominance of human endogenous retrovirus K (HERV-K) viruses was found in both cases and controls by blastn and blastx analysis. This study is the first report on the full-length HERV-K assembled genomes in the Thai population. Furthermore, the HERV-K integration breakpoint positions were validated and compared between the case and control datasets. Interestingly, Brugada cases contained HERV-K integration breakpoints at promoters five times more often than controls. Overall, the highlight of this study is the BS-specific HERV-K breakpoint positions that were found at the gene coding region "NBPF11" (n = 9), "NBPF12" (n = 8) and long non-coding RNA (lncRNA) "PCAT14" (n = 4) region. The genes and the lncRNA have been reported to be associated with congenital heart and arterial diseases. These findings provide another aspect of the BS etiology associated with viral genome integrations within the human genome.