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bioRxiv · 10.1101/805986

Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

Tsumoto, K.·Ashihara, T.·Naito, N.·Shimamoto, T.·Amano, A.·Kurata, Y.·Kurachi, Y.
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Abstract

One phenotypic feature of Brugada syndrome (BrS) is slowed conduction due to the reduction (loss-of-function) of Na+ channels. In contrast, recent clinical observations in BrS patients highlighted the poor correlation between the phenotype (typical ECG change or lethal arrhythmia) and the genotype (SCN5A mutation). Inspired by our previous theoretical study which showed that reduced Na+ channels in the lateral membrane (LM) of ventricular myocytes caused the slowing of conduction under myocardial ischemia, we hypothesized that a loss-of-function of Na+ channels caused by the decreases in Na+ channel expression within myocytes leads to phase-2 reentry (P2R), the major triggering mechanism of lethal arrhythmias in BrS. We constructed an in silico human ventricular myocardial strand and ring models, and investigated the relationship between the subcellular Na+ channel distribution and P2R. Reducing Na+ channel expression in the LM of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, we showed that both the reduction in Na+ channels on the LM of each myocyte and tissue-level heterogeneity of Na+ channel expression were essential for P2R as well as P2R-mediated reentrant excitation. Our data suggest that the alteration in subcellular Na+ channel distribution together with a tissue-level heterogeneity of Na+ channels can cause arrhythmogenesis in BrS.

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Tsumoto, K., Ashihara, T., Naito, N., Shimamoto, T., Amano, A., Kurata, Y., Kurachi, Y.. 2019-10-16. Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome. https://doi.org/10.1101/805986

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