Nav1.5 Beyond Genetics: Loss of Cardiac Sodium-Channel Function in Brugada Syndrome

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ID: 329044
2026
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Abstract
Abstract Brugada syndrome is usually interpreted through SCN5A genetics, yet many patients with a Brugada phenotype carry no clearly pathogenic SCN5A variant and penetrance among carriers is incomplete. Cardiac sodium-channel function is therefore not a direct readout of coding sequence but an integrated property shaped by the channelosome, transcriptional and epigenetic control, post-translational modification, metabolic state, and inflammatory signaling. Through these routes, oxidative stress, altered glycosylation, and Nedd4-2-dependent ubiquitination can reduce peak sodium current in experimental systems, potentially lowering conduction reserve; inflammatory mediators may additionally modify the regional substrate through other ionic pathways without altering the SCN5A coding sequence in the experimental system, converging on the loss-of-function phenotype that characterizes Brugada syndrome, in contrast to the late-current gain of function of long QT syndrome type 3. Epicardial adipose tissue may provide a regional context for such signals at the right ventricular outflow tract, where conduction reserve is low and the substrate preferentially localizes, and anti-Nav1.5 autoantibodies provide a humoral route to reduced channel availability. We examine sequence-independent modifiers that may dynamically reduce Nav1.5 function and define the experimental framework needed to establish their clinical weight.
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Authors Luigi Anastasia, Giuseppe Ciconte, Alessandro Fuga, Dudie Gjeci, Tiziano Dallavilla, Marco Piccoli, Federica Cirillo, Alessia Vuturo, Raffaele Salerno, Davide Antonio Morciano, Antonio Izzo, Marcello Manfredi, Carlo Pappone
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Journal EP Europace
Year 2026
DOI
10.1093/europace/euag261
URL
https://doi.org/10.1093/europace/euag261
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