What is the clinical evidence from this study?

Study design: Other. Population: Catecholaminergic polymorphic ventricular tachycardia (CPVT)-like phenotype (n=2). Intervention: SCN5A T1857I mutation vs. Wild-type Nav1.5. Primary outcome: Biophysical properties of Nav1.5 and simulated cardiac action potentials.

December 22, 2020Open Access

Biophysical Characterization of a Novel SCN5A Mutation Associated With an Atypical Phenotype of Atrial and Ventricular Arrhythmias and Sudden Death

Key Result

The novel SCN5A T1857I mutation causes a net gain-of-function in Nav1.5 gating, leading to increased window currents and simulated ventricular afterdepolarizations that predispose carriers to tachy-arrhythmias.

Structured PICO

Population

Two teenage sisters with a novel SCN5A mutation (T1857I) presenting with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy, followed for 5 years.

Exposure

T1857I variant in the C-terminus of Nav1.5 (SCN5A)

Comparator

Wild-type (WT) Nav1.5

Outcome

Channel gating properties (voltage-dependence of activation and inactivation, recovery from fast inactivation, late currents, window currents) and simulated cardiac excitability (action potential duration and after depolarizations)surrogate

The novel T1857I mutation in SCN5A causes a net gain-of-function in Nav1.5 gating, increasing window currents and predisposing carriers to ventricular after depolarizations and atypical CPVT-like arrhythmias.

Limitations

Action potential modeling did not account for recovery from inactivation.
Experiments were performed using CHOK1 cells, a heterologous expression system that may lack various critical structures or accessory subunits present in intact human cells.

Abstract

Background Sudden cardiac death (SCD) is an unexpected death that occurs within an hour of the onset of symptoms. Hereditary primary electrical disorders account for up to 1/3 of all SCD cases in younger individuals and include conditions such as catecholaminergic polymorphic ventricular tachycardia (CPVT). These disorders are caused by mutations in the genes encoding cardiac ion channels, hence they are known as cardiac channelopathies. We identified a novel variant, T1857I, in the C-terminus of Nav1.5 ( SCN5A ) linked to a family with a CPVT-like phenotype characterized by atrial tachy-arrhythmias and polymorphic ventricular ectopy occurring at rest and with adrenergic stimulation, and a strong family history of SCD. Objective Our goal was to functionally characterize the novel Nav1.5 variant and determine a possible link between channel gating and clinical phenotype. Methods We first used electrocardiogram recordings to visualize the patient cardiac electrical properties. Then, we performed voltage-clamp of transiently transfected CHO cells. Lastly, we used the ventricular/atrial models to visualize gating defects on cardiac excitability. Results Voltage-dependences of both activation and inactivation were right-shifted, the overlap between activation and inactivation predicted increased window currents, the recovery from fast inactivation was slowed, there was no significant difference in late currents, and there was no difference in use-dependent inactivation. The O’Hara-Rudy model suggests ventricular after depolarizations and atrial Grandi-based model suggests a slight prolongation of atrial action potential duration. Conclusion We conclude that T1857I likely causes a net gain-of-function in Nav1.5 gating, which may in turn lead to ventricular after depolarization, predisposing carriers to tachy-arrhythmias.

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