Na_V1.8 as Proarrhythmic Target in a Ventricular Cardiac Stem Cell Model

Area of Science:

• Cardiovascular Electrophysiology
• Ion Channel Function
• Cardiac Arrhythmia Mechanisms

Background:

• The sodium channel Na_V1.8, encoded by the SCN10A gene, is implicated in cardiac electrophysiology.
• Previous research linked Na_V1.8 to arrhythmogenesis via persistent sodium current (I_NaL) in human cardiomyocytes.
• The specific role of Na_V1.8 in ventricular arrhythmogenesis requires further investigation at the cellular level.

Purpose of the Study:

• To investigate the contribution of Na_V1.8 to human ventricular arrhythmogenesis.
• To assess the effects of Na_V1.8 inhibition and SCN10A gene knockout on cardiac cellular electrophysiology.
• To identify Na_V1.8 as a potential anti-arrhythmic therapeutic target.

Main Methods:

• Utilized induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) from SCN10A knockout models.
• Employed pharmacological inhibition of Na_V1.8 in control and knockout cardiomyocytes.
• Conducted functional voltage-clamp experiments to measure ionic currents and action potentials.
• Analyzed sarcoplasmic reticulum Ca²⁺ sparks, waves, and delayed afterdepolarizations (DAD).

Main Results:

• Na_V1.8 inhibition and SCN10A knockout significantly reduced the persistent sodium current (I_NaL) in ventricular iPSC-CM.
• No significant effects on ventricular action potential duration at 90% repolarization (APD₉₀) were observed.
• Reduced frequency of spontaneous Ca²⁺ sparks and waves, and fewer delayed afterdepolarizations (DAD) were noted in Na_V1.8 inhibited/knockout cells.
• Na_V1.8 primarily impacts arrhythmogenesis at a subcellular level, with minimal effect on systolic Ca²⁺ release.

Conclusions:

• Na_V1.8-induced I_NaL contributes to proarrhythmic triggers in human ventricular cardiomyocytes.
• Pharmacological inhibition or genetic knockout of Na_V1.8 effectively diminishes these proarrhythmic triggers.
• Na_V1.8 represents a promising therapeutic target for anti-arrhythmic strategies.