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

• DOI: 10.1016/j.jacep.2023.03.009
• Publication Date: 2023-05-24T18:45:24Z
• Authors: Estelle Renard; Richard D. Walton; David Benoist; Fabien Brette; Gilles Bru-Mercier; Sébastien Chaigne; Sabine Charron; Marion Constantin; Matthieu Douard; Virginie Dubes; Bastien Guillot; Thomas Hof; Julie Magat; Marine E. Martinez; Cindy Michel; Néstor Pallares-L...; Philippe Pasdois; Alice Récalde; Fanny Vaillant; Frédéric Sacher; Louis Labrousse; Julien Rogier; Florence Kyndt; Manon Baudic; Jean-Jacques Schott; Julien Barc; Vincent Probst; Marine Sarlandie; Céline Marionneau; Jesse L. Ashton; Mélèze Hocini; Michel Haïssaguerre; Olivier Bernus
• Keywords: Sudden Death; Nav1.5

Brugada syndrome is a significant cause of sudden cardiac death (SCD), but the underlying mechanisms remain hypothetical. This study aimed to elucidate this knowledge gap through detailed ex vivo human heart studies. A was obtained from 15-year-old adolescent boy with normal electrocardiogram who experienced SCD. Postmortem genotyping performed, and clinical examinations were done on first-degree relatives. The right ventricle optically mapped, followed by high-field magnetic resonance imaging histology. Connexin-43 NaV1.5 localized immunofluorescence, RNA protein expression levels studied. HEK-293 cell surface biotinylation assays performed examine trafficking. Brugada-related SCD diagnosis established for donor because SCN5A variant (p.D356N) inherited his mother, together concomitant NKX2.5 unknown significance. Optical mapping demonstrated epicardial region impaired conduction near outflow tract, in absence repolarization alterations microstructural defects, leading blocks figure-of-8 patterns. connexin-43 localizations region, consistent finding that p.D356N does not affect trafficking, nor NaV1.5. Trends decreased NaV1.5, connexin-43, desmoglein-2 noted; however, RT-qPCR results suggested NKX2-5 unlikely be involved. demonstrates first time associated Brugada-SCN5A can caused functionally, structurally, conduction.