Fibroblast growth factor homologous factors serve as a molecular rheostat in tuning arrhythmogenic cardiac late sodium current

Voltage-gated sodium (Nav1.5) channels support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of Na(V)1.5 inactivation results in a small persistent Na influx known as late Na current (I(Na,L)), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. Here, using low-noise multi-channel recordings in heterologous systems, LQTS3 patient-derived iPSCs cardiomyocytes, and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1–4) tune pathogenic I(Na,L) in an isoform-specific manner. This scheme suggests a complex orchestration of I(Na,L) in cardiomyocytes that may contribute to variable disease expressivity of Na(V)1.5 channelopathies. We further leverage these observations to engineer a peptide-inhibitor of I(Na,L) with a higher efficacy as compared to a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of I(Na,L) in pathophysiology and outline potential therapeutic avenues.