Selectivity filter mutation in Na _V 1.5 promotes ventricular tachycardia.

Area of Science:

• Cardiovascular Research
• Molecular Cardiology
• Genetics

Background:

• Loss-of-function mutations in the SCN5A gene impair cardiac sodium channel Na_V1.5 function, leading to Brugada syndrome (BrS).
• A novel selectivity filter mutation, K1419E (DEKA→DEEA), has been identified in BrS patients, but its functional impact on Na_V1.5 and arrhythmogenesis remains unclear.

Purpose of the Study:

• To investigate the functional consequences of the Na_V1.5 DEEA mutation on cardiac electrophysiology and arrhythmogenesis.
• To establish a murine model for studying the proarrhythmic mechanisms of this BrS-associated mutation.

Main Methods:

• Generated heterozygous Na_V1.5 DEEA knock-in mice.
• Utilized heterologous expression systems and isolated cardiomyocytes to assess Na_V1.5 channel function.
• Performed optical mapping in isolated hearts and in vivo electrophysiological studies.

Main Results:

• DEEA mutation resulted in reduced Na_V1.5 current density in cardiomyocytes.
• Na_V1.5 DEEA hearts exhibited slowed ventricular conduction velocity.
• Flecainide unmasked a susceptibility to ventricular arrhythmias in vivo in DEEA mice.

Conclusions:

• The Na_V1.5 DEEA mutation causes a functional deficiency in Na_V1.5, leading to slowed cardiac conduction.
• This functional deficit predisposes the heart to arrhythmias, providing mechanistic insight into Brugada syndrome.
• The DEEA murine model serves as a valuable tool for understanding BrS pathophysiology.