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

backgroundBrugada syndrome is a significant cause of sudden cardiac death (SCD), but the underlying mechanisms remain hypothetical.

objectivesThis study aimed to elucidate this knowledge gap through detailed ex vivo human heart studies.

methodsA 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

resultsA 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

conclusionsThis study demonstrates for the first time that SCD associated with a Brugada-SCN5A variant can be caused by localized functionally, not structurally, impaired conduction.