Contrasting Ionic Mechanisms of Impaired Conduction in FHF1- and FHF2-Deficient Hearts

摘要

Proper function of the cardiac sodium channel is essential for normal membrane excitability and conduction in the heart. FHFs (fibroblast growth factor homologous factors) 1–4 bind to the C-terminal domains of voltage-gated sodium channels, regulating channel trafficking and gating properties.1 FHF2 is the predominant family member expressed in the mouse ventricle, with knockout mice displaying cardiac conduction disease.2 In contrast, FHF1 is the predominant family member expressed in mouse atria (Figure [A through D]) and human atrial and ventricular myocardium3 (Figure [E]). Clinically, mutations in FHF1 have been linked to both idiopathic ventricular tachycardia4 and Brugada syndrome.5 Furthermore, reductions in FHF1 expression have been observed in diseased left atrial and left ventricular tissue,3 while FHF2–4 levels are not significantly changed (Figure [E]). Thus, dysregulated FHF1 activity may play a mechanistic role in both heritable and acquired arrhythmic disorders. Accordingly, using complementary in vivo murine models and human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs), we sought to determine the distinct consequences of FHF1 deficiency on cardiac electrophysiology.