Functional Epicardial Conduction Disturbances Due to a SCN5A Variant Associated With Brugada Syndrome.

Background: Brugada syndrome is a significant cause of sudden cardiac death (SCD), but the underlying mechanisms remain hypothetical.
Objectives: This study aimed to elucidate this knowledge gap through detailed ex vivo human heart studies.
Methods: A heart was obtained from a 15-year-old adolescent boy with normal electrocardiogram who experienced SCD. Postmortem genotyping was performed, and clinical examinations were done on first-degree relatives. The right ventricle was optically mapped, followed by high-field magnetic resonance imaging and histology. Connexin-43 and Na _V 1.5 were localized by immunofluorescence, and RNA and protein expression levels were studied. HEK-293 cell surface biotinylation assays were performed to examine Na _V 1.5 trafficking.
Results: A Brugada-related SCD diagnosis was established for the donor because of a SCN5A Brugada-related variant (p.D356N) inherited from his mother, together with a concomitant NKX2.5 variant of unknown significance. Optical mapping demonstrated a localized epicardial region of impaired conduction near the outflow tract, in the absence of repolarization alterations and microstructural defects, leading to conduction blocks and figure-of-8 patterns. Na _V 1.5 and connexin-43 localizations were normal in this region, consistent with the finding that the p.D356N variant does not affect the trafficking, nor the expression of Na _V 1.5. Trends of decreased Na _V 1.5, connexin-43, and desmoglein-2 protein levels were noted; however, the RT-qPCR results suggested that the NKX2-5 variant was unlikely to be involved.
Conclusions: This study demonstrates for the first time that SCD associated with a Brugada-SCN5A variant can be caused by localized functionally, not structurally, impaired conduction.
Competing Interests: Funding Support and Author Disclosures This work received financial support from the French Government as part of the “Investments of the Future” program managed by the National Research Agency (ANR-10-IAHU04-LIRYC), the Leducq-Foundation (RHYTHM network, 16CVD02), and the Fondation Coeur et Artères (FC17T2). Dr Barc is supported by the ANR JCJC LEARN (R21006NN, RPV21014NNA). Dr Schott is supported by IRP-, an I-SITE NExT health and engineering initiative (Ecole Centrale & Nantes University) and by the IRP- GAINES funded by INSERM and CNRS. Dr Marionneau is supported by the ANR-16-CE92-0013-01 and the National Institutes of Health (R01-HL148803). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)