Sodium Channel Isoform Diversity Underlies Chamber-Specific Cardiac Excitability

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Voltage-gated sodium (Na_V) channels are essential for cardiac excitability.
• While Na_V1.5 is the predominant cardiac isoform, the roles of other Na_V isoforms in the heart are not fully understood.

Purpose of the Study:

• To investigate the functional contributions of non-Na_V1.5 isoforms in the heart.
• To characterize the chamber-specific distribution and impact of Na_V isoforms on cardiac function.

Main Methods:

• Development of a chemical-genetic mouse model (Na_V1.5^GX/GX) for selective Na_V1.5 inhibition.
• In vivo electrocardiography and ex vivo optical mapping of cardiac activity.
• Whole-cell voltage-clamp recordings and use of isoform-selective inhibitors to analyze sodium current composition.

Main Results:

• Acute inhibition of Na_V1.5 in Na_V1.5^GX/GX mice led to significant conduction defects and arrhythmias.
• Optical mapping demonstrated dose-dependent, chamber-specific sensitivity to Na_V1.5 inhibition, with the right ventricle being most affected.
• Patch-clamp analysis revealed differential expression of non-Na_V1.5 isoforms (e.g., Na_V1.8, Na_V1.1/1.3) across cardiac chambers.

Conclusions:

• Cardiac sodium currents exhibit a chamber-specific isoform landscape, potentially explaining the right ventricular predilection in Brugada syndrome.
• Non-Na_V1.5 isoforms are critical mediators of chamber-specific cardiac pathologies.
• These non-Na_V1.5 isoforms represent potential novel pharmacological targets for cardiac diseases.