Non-canonical Sodium Channel Isoforms Underlie Chamber Specific Cardiac Excitability

Voltage-gated sodium (Na _V ) channels drive cardiac excitability. While Na _V 1.5 is the primary cardiac isoform, the composition and functional contributions of non-Na _V 1.5 isoforms in the heart remain unclear. Here, we developed a chemical-genetic mouse model (Na _V 1.5-GX) in which Na _V 1.5 can be selectively and reversibly inhibited by acyl- and aryl-sulfonamide compounds (GX drugs). Na _V 1.5-GX mice exhibited normal cardiac function at baseline, but acute GX drug administration caused profound conduction defects and arrhythmias. Whole-heart optical mapping revealed dose-dependent chamber-specific sensitivity to Na _V 1.5 inhibition, with the right ventricle (RV) being the most sensitive, followed by the left ventricle (LV), left atrium (LA), and right atrium (RA). Patch-clamp recordings of isolated cardiomyocytes with application of Na _V isoform-selective inhibitors showed that Na _V 1.5 contributed 93% of sodium current in the LV, 81% in the RV and 78% in the LA. Non-Na _V 1.5 isoforms were differentially enriched across chambers: Na _V 1.8 in the LV, Na _V 1.1/1.3 in the RV, and Na _V 1.2/1.6/1.7 in the atria. These results reveal a surprising chamber-specific isoform landscape of cardiac sodium currents which may underlie the right ventricular predominant phenotype of Brugada syndrome and highlight non-Na _V 1.5 isoforms as potential mediators of chamber-specific cardiac pathologies and as pharmacological targets.