Fibrosis, Connexin-43, and Conduction Abnormalities in the Brugada Syndrome

Abstract

BackgroundThe right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial.ObjectivesThis study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation.MethodsSix whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation.ResultsCollagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p = 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p = 0.003) and the epicardium (OR: 2.00; p = 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p = 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 ± 9.7 months.ConclusionsBrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS.

SCN5A Genetic Polymorphisms Associated With Increased Defibrillator Shocks in Brugada Syndrome

“…Ohkubo et al also reported prolonged QRS duration of more than 120 ms, as measured on a standard ECG, that is associated with life‐threatening ventricular arrhythmia in BrS 9. These findings occur because of abnormal slow and fragmented epicardial electrograms from reduction in gap junction expression at right ventricular outflow tract evidenced by autopsies 11. These abnormal electrograms caused by cardiac conduction delay may lead to generate reentry of ventricular arrhythmia, as shown in this study, by appropriate ICD therapy in BrS patients (Table 1).…”

“…These SCN5A polymorphisms could decrease expression of sodium‐channel proteins and alter gating properties resulting in prolongation of the QRS duration and slow conduction in the heart 7, 9. The SCN5A mutations may be associated with early and frequent VF recurrence or SCA in BrS patients, which may be related to fibrosis in the right ventricular outflow tract epicardial surface 10, 11. Most studies on SCN5A mutations included both asymptomatic and symptomatic BrS patients 8, 9, 10, 11.…”

Development of a Patient-Derived Induced Pluripotent Stem Cell Model for the Investigation of <i>SCN5A</i>-D1275N-Related Cardiac Sodium Channelopathy

“…35 Consistent with this, tissue samples from the right ventricular outflow tract of patients with Brugada syndrome carrying SCN5A mutations, exhibited epicardial and myocardial fibrosis. 36 In our hiPSC model, we found no significant difference in Ca 2+ transient measurements between the D1275N and Control cells. Further investigations are needed to elucidate the causing mechanism of SCN5A-related DCM.…”

The Brugada Syndrome ― From Gene to Therapy ―

“…23 Postmortem analyses of unexplained sudden death victims in different series were all concordant in describing peculiar tissue abnormalities at the RVOT, 24 characterized by reduced connexin-43 expression, interstitial fibrosis, 25 and activation slowing that conditions an absent transmural repolarization gradient, and abnormal conduction restitution. 26 To date, both theories are believed to be involved in the etiopathogenesis of BrS as demonstrated by an elegant study of ECG imaging on 25 BrS and 6 RBBB patients; unlike BrS, RBBB showed delayed activation in the entire RV, without ST-segment elevation, fractionation, or repolarization abnormalities. 27 penetrance 8,12 (i.e., the abnormal gene is inherited by 50% of the offspring, and both males and females equally inherit the defective gene, but not all will develop the disease).…”