Biventricular Myocardial Fibrosis and Sudden Death in Patients With Brugada Syndrome

Abstract

Background Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited. Objectives This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS. Methods The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis. Results Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A -positive cases (n = 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P = 0.27). Conclusions Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.

Structural Heart Alterations in Brugada Syndrome: Is it Really a Channelopathy? A Systematic Review

“…Together, these data suggested that in BrS, at the epicardial surface, interstitial fibrosis and reduced gap junction expression in the RVOT could lead to electrical anomalies. In further support of this finding, in 28 hearts from SCD cases with a non-confirmed diagnosis of BrS, the ventricular myocardium exhibited a higher proportion of collagen, irrespective of sampling location or myocardial layer (the highest proportion was found in the RVOT epicardium in individuals with suspected BrS) ( Table 1 ) [ 22 ]. There was no statistically significant association reported between SCN5A genotype and histotype.…”

“…Other cases diagnosed with BrS but without a positive SCN5A genetic diagnosis could be due to other genetic alterations in this gene [ 35 ] or in other genes [ 36 ]. However, it is also important to remark that only in 57 cases reported in the three most recent studies [ 22 , 25 , 26 ], a comprehensive genetic analysis including gene encoding cardiomyopathies were performed.…”

“…However, no conclusive studies have been published to date specifically examining this association, and the cause of myocardial inflammation remains undetermined. Increased collagen inside the myocardium represents a frequent feature of BrS and is predominant in the RV in both autopsy and endocardial biopsy samples [ 22 ]. However, this evidence is limited, as many of the patients studied did not have a confirmed clinical diagnosis of BrS.…”

Pathogenesis and Management of Brugada Syndrome: Recent Advances and Protocol for Umbrella Reviews of Meta-Analyses in Major Arrhythmic Events Risk Stratification

“…The pathomechanism observed in BrS patients involves depolarization and repolarization abnormalities, inflammation of myocytes, and fibrosis in RVOT and/or RV [ 9 , 12 ]. A recent study performed on whole hearts from deceased patients, whose SCD was accounted to BrS, showed biventricular myocardial fibrosis, especially in the epicardium of the RVOT [ 17 ]. RV myocardium in a number of patients with BrS type 1 ECG pattern have showed histological changes comparable to arrhythmogenic RV cardiomyopathy (ARVC), and indicate possible autoimmune causes of myocardial inflammation in BrS patients [ 9 ].…”

Concealed Substrates in Brugada Syndrome: Isolated Channelopathy or Associated Cardiomyopathy?

“…There was a correlation between structural abnormalities and abnormal potentials, and their ablation abolished the BrS phenotype and malignant arrhythmias [ 9 ]. Another group confirmed that BrS is associated with increased collagen content throughout the RV and the LV, but irrespective of sampling location or myocardial layer in patients experiencing sudden cardiac death [ 61 ]. Based on the data provided above, an endomyocardial biopsy could become a new diagnostic tool for the research of concealed morphological abnormalities in BrS, as well as for the identification of dynamic arrhythmogenic substrates [ 75 , 81 , 82 ].…”