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

Voltage-gated sodium channels (Nav channels) support the genesis and brisk spatial propagation of action potentials in the heart. Disruption of NaV1.5 inactivation results in a small persistent sodium influx known as late sodium current (INa,L), which has emerged as a common pathogenic mechanism in both congenital and acquired cardiac arrhythmogenic syndromes. In the present study, using low-noise multichannel recordings in heterologous systems, LQTS3 patient-derived induced pluripotent stem cell cardiomyocytes and mouse ventricular myocytes, we demonstrate that the intracellular fibroblast growth factor homologous factors (FHF1-4) tune pathogenic INa,L in an isoform-specific manner. This scheme suggests a complex orchestration of INa,L in cardiomyocytes that may contribute to variable disease expressivity of NaV1.5 channelopathies. We further leverage these observations to engineer a peptide inhibitor of INa,L with a higher efficacy compared with a well-established small-molecule inhibitor. Overall, these findings lend insights into molecular mechanisms underlying FHF regulation of INa,L in pathophysiology and outline potential therapeutic avenues. Increased late sodium current due to the disruption of voltage-gated sodium channel inactivation is a common pathogenic mechanism in different arrhythmogenic syndromes. Chakouri et al. show that fibroblast growth factor homologous factors (FHFs) modulate pathogenic late sodium current in an isoform-specific way, and leverage this observation to design and test a prototype of inhibitor peptide based on a protein domain from an inhibitory FHF isoform.