Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms

Abstract

<jats:title>Abstract</jats:title> <jats:p>The cardiac sodium channel NaV1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some NaV1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective NaV1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the NaV1.5 complex. In this alternative view, alterations in NaV1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of NaV1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through NaV1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of NaV1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of NaV1.5 is essential for the development of novel preventive and therapeutic strategies.</jats:p>

Mechanisms of Arrhythmias in the Brugada Syndrome

“…The origin of interstitial fibrosis in Brugada syndrome patients is unclear. The sodium channel Na V 1.5 may, next to its electrogenic role, be involved in the formation of fibrosis [ 122 , 123 ]. It is also thought that RAD affects the attachment of cardiomyocytes to the extracellular matrix resulting in gaps between myocytes and space for fibrosis to form [ 65 ].…”

Inhibitory effect of eslicarbazepine acetate and S-licarbazepine on Nav1.5 channels

“…Further work is required to establish whether the basis for this PR prolongation is indeed via Na v 1.5 inhibition. In addition, it would be of interest to investigate the efficacy of ESL and S-Lic in the context of heritable arrhythmogenic mutations in SCN5A, as well as the possible involvement of the β subunits (24,26,52,53). The findings presented here are also relevant in the context of Na v 1.5 expression in carcinoma cells (54).…”

Inhibitory Effect of Eslicarbazepine Acetate and S-Licarbazepine on Nav1.5 Channels

“…Further work is required to establish whether the basis for this PR prolongation is indeed via Na v 1.5 inhibition. In addition, it would be of interest to investigate the efficacy of ESL and S-Lic in the context of heritable arrhythmogenic mutations in SCN5A , as well as the possible involvement of the β subunits ( Brackenbury and Isom, 2008 ; Uebachs et al, 2010 ; Doeser et al, 2014 ; Rivaud et al, 2020 ). The findings presented here are also relevant in the context of Na v 1.5 expression in carcinoma cells ( Fraser et al, 2014 ).…”