Selectivity Filter Mutation in Na_V1.5 Promotes Ventricular Tachycardia

Area of Science:

• Cardiovascular Research
• Molecular Cardiology
• Genetics

Background:

• Loss-of-function mutations in the SCN5A gene, encoding cardiac sodium channel Na_V1.5, impair cardiac function.
• These impairments lead to reduced sodium current (I_Na), slowed ventricular conduction, and arrhythmias associated with Brugada syndrome (BrS).
• A novel missense mutation, K1419E (DEEA), in the Na_V1.5 selectivity filter has been identified in BrS patients, but its functional impact is largely unknown.

Purpose of the Study:

• To characterize the functional consequences of the Na_V1.5 DEEA mutation.
• To investigate the impact of this mutation on cardiac electrophysiology and arrhythmia susceptibility in a murine model.

Main Methods:

• Heterologous expression and patch clamp electrophysiology in CHO cells.
• Immunolabeling and voltage optical mapping of DEEA mutant hearts.
• In vivo electrocardiography in a heterozygous DEEA murine model.

Main Results:

• DEEA mutation resulted in lower Na_V1.5 current density but unchanged protein expression.
• Optical mapping revealed slowed conduction velocity in DEEA hearts.
• Flecainide administration exacerbated conduction slowing and induced ventricular arrhythmias in vivo.

Conclusions:

• The DEEA mutation causes a functionally deficient Na_V1.5 channel.
• This functional deficiency mechanistically links the DEEA mutation to slowed cardiac conduction and proarrhythmic events in BrS.
• This study provides the first mechanistic insights into the proarrhythmic consequences of this specific BrS mutation.