# Hypokalaemia and bradycardia unmask the loss-of-function phenotype of a Brugada Syndrome SCN5A mutation

## TL;DR

This study shows how hypokalaemia and bradycardia can trigger dangerous heart rhythms in a person with a specific Brugada Syndrome mutation.

## Contribution

The study identifies hypokalaemia and bradycardia as critical factors unmasking a loss-of-function phenotype in a specific SCN5A mutation.

## Key findings

- WT/S805L channels show either normal or loss-of-function behavior depending on membrane potential.
- Hypokalaemia and bradycardia induce diastolic hyperpolarization, promoting loss-of-function in Na+ channels.
- Computational and structural modeling confirm the mechanism linking hyperpolarization to arrhythmia risk.

## Abstract

Loss-of-function (LOF) mutations of the cardiac Na+ channel (SCN5A) are causatively associated with the Brugada Syndrome (BrS). However, the onset of Ventricular Fibrillation (VF) is a rare event, and critical factors favouring the pathological phenotype remain often elusive. This study explores how concomitant triggering conditions may impact on VF onset in a symptomatic proband carrying the S805L/SCN5A BrS mutation.

Clinical, in-vitro, numerical, and structural analyses were performed. A 67-year-old male was resuscitated after cardiac arrest, and clinical analysis upon hospitalisation revealed severe hypokalaemia (2.5 mEq/L). The ECG showed a coved type-I BrS pattern and the SCN5A mutation (S805L) was identified. Patch-clamp studies carried out in a heterologous expression system (HEK293 cells) revealed that WT/S805L channels exhibit two different phenotypes (normal and LOF); the main parameter controlling this distribution is the cell membrane potential. A protected/normal behaviour was observed at −80 mV; conversely, LOF occurred at more negative potentials (−100/−120 mV). Further analyses in isolated outflow tract ventricular cardiomyocytes showed that hypokalaemia (and bradycardia) induced diastolic potential hyperpolarisation, thus favouring the Na+ current LOF. Computational and molecular modelling confirmed our findings and revealed the structural determinant of this alteration.

WT/S805L Na+ channels exhibit either a LOF or a wild-type-like behaviour depending on the membrane potential. Since hypokalaemia and slow pacing rate induce cell hyperpolarisation and the associated LOF, they represent concurrent elements creating the scenario responsible for the VF and cardiac arrest. These results may represent an interpretative paradigm applicable to other BrS mutations.

Graphical Abstract