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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...

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Detalles Bibliográficos
Autores principales: Renard, Estelle, Walton, Richard D., Benoist, David, Brette, Fabien, Bru-Mercier, Gilles, Chaigne, Sébastien, Charron, Sabine, Constantin, Marion, Douard, Matthieu, Dubes, Virginie, Guillot, Bastien, Hof, Thomas, Magat, Julie, Martinez, Marine E., Michel, Cindy, Pallares-Lupon, Néstor, Pasdois, Philippe, Récalde, Alice, Vaillant, Fanny, Sacher, Frédéric, Labrousse, Louis, Rogier, Julien, Kyndt, Florence, Baudic, Manon, Schott, Jean-Jacques, Barc, Julien, Probst, Vincent, Sarlandie, Marine, Marionneau, Céline, Ashton, Jesse L., Hocini, Mélèze, Haïssaguerre, Michel, Bernus, Olivier
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Inc 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10406612/
https://www.ncbi.nlm.nih.gov/pubmed/37227351
http://dx.doi.org/10.1016/j.jacep.2023.03.009
Descripción
Sumario: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.