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Article Dans Une Revue JACC: Clinical Electrophysiology Année : 2023

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

Estelle Renard (1, 2, 3, 4, 5, 6, 7, 8) , Richard D Walton (1, 2, 3, 4, 5, 6, 7, 8) , David Benoist (1, 2, 3, 4, 5, 6, 7, 8) , Fabien Brette (1, 2, 3, 4, 5, 6, 7, 8) , Gilles Bru-Mercier (9, 1, 2, 3, 4, 5, 6, 7, 8) , Sébastien Chaigne (1, 2, 3, 4, 5, 6, 7, 8) , Sabine Charron (1, 2, 3, 4, 5, 6, 7, 8) , Marion Constantin (1, 2, 3, 4, 5, 6, 7, 8) , Matthieu Douard (1, 2, 3, 4, 5, 6, 7, 8) , Virginie Dubes (1, 2, 3, 4, 5, 6, 7, 8) , Bastien Guillot (1, 2, 3, 4, 5, 6, 7, 8) , Thomas Hof (1, 2, 3, 4, 5, 6, 7, 8) , Julie Magat (1, 2, 3, 4, 5, 6, 7, 8) , Marine E Martinez (1, 2, 3, 4, 5, 6, 7, 8) , Cindy Michel (1, 2, 3, 4, 5, 6, 7, 8) , Néstor Pallares-Lupon (1, 2, 3, 4, 5, 6, 7, 8) , Philippe Pasdois (1, 2, 3, 4, 5, 6, 7, 8) , Alice Récalde (1, 2, 3, 4, 5, 6, 7, 8) , Fanny Vaillant (1, 2, 3, 4, 5, 6, 7, 8) , Frédéric Sacher (1, 2, 3, 4, 5, 6, 7, 8) , Louis Labrousse (2) , Julien Rogier (6) , Florence Kyndt (10) , Manon Baudic (11) , Jean-Jacques Schott (10) , Julien Barc (11) , Vincent Probst (12) , Marine Sarlandie (11) , Céline Marionneau (11) , Jesse L Ashton (13) , Mélèze Hocini (6, 8) , Michel Haïssaguerre (14, 6) , Olivier Bernus (2)
Julien Rogier
  • Fonction : Auteur

Résumé

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.
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hal-04297499 , version 1 (21-11-2023)

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Estelle Renard, Richard D Walton, David Benoist, Fabien Brette, Gilles Bru-Mercier, et al.. Functional Epicardial Conduction Disturbances Due to a SCN5A Variant Associated With Brugada Syndrome. JACC: Clinical Electrophysiology, 2023, 9 (8), pp.1248-1261. ⟨10.1016/j.jacep.2023.03.009⟩. ⟨hal-04297499⟩
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