Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart

Abstract

Rationale: Fibroblast growth factor homologous factors (FHFs) are key regulators of sodium channel inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced sodium channel availability in Fhf2 knockout mice predisposes to abnormal excitability at the tissue level are not well defined. Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Methods and Results: Fhf2 KO mice were challenged by reducing calcium conductance using verapamil or by reducing gap junctional conductance using carbenoxolone or by backcrossing into a connexin 43 heterozygous (Cx43 +/- ) background. All conditions produced conduction block in Fhf2 KO mice, with Fhf2 WT showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2 KO hearts, multicellular linear strand models incorporating FHF2-deficient sodium channel inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced calcium conductance or gap junction uncoupling are very different. Enhanced sodium channel inactivation due to FHF2 deficiency shifts dependence onto calcium current to sustain electrotonic driving force, axial current flow, and action potential generation from cell-to-cell. In the setting of gap junction uncoupling, slower charging time from upstream cells conspires with accelerated sodium channel inactivation in mutant strands to prevent sufficient downstream cell charging for action potential propagation. Conclusions: FHF2-dependent effects on sodium channel inactivation ensure adequate sodium current reserve to safeguard against numerous threats to reliable cardiac impulse propagation.

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

“…The four FHF isoforms (FHF1–4) have emerged as versatile Na V modulators in neurons 52 , 61 , 62 and cardiomyocytes 34 , 36 , 43 , 51 . Structurally, the primary FHF binding site resides in the CTD 49 , in close proximity to the CaM binding IQ domain 63 .…”

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

“…Besides the role of the sodium channel ancillary subunits, additional SCN5A/Na v 1.5 interacting proteins have been reported in BrS. Mutations in Plakophilin (PKP2) [260,371] MOG1 [9,201,[372][373][374][375], FGF13 [376], syntrophin (SNTA1) [377], NEDD4 [378,379], Tmem168 [379] and telethonin [285,286] are identified in BrS patients and their implication to sodium channel function has been reported. Distinct Na v 1.5 interacting protein mutants lead to I Na deficit [261,286,375,377] while others influence Na v trafficking and thus subcellular localization [201,379].…”

Enhanced sodium channel inactivation by temperature and FHF2 deficiency blocks heat nociception

“…Most FHF isoforms induce a depolarizing shift in voltage dependence of Na v inactivation without altering the voltage for activation 9,19,33 . This voltage shift increases sodium current generated by Na v s in three ways: 1) by reducing the fraction of channels rendered inactive at steady state resting potential, 2) by reducing the rate of closed-state Na v inactivation during membrane depolarization, and 3) by slowing rate of Na v inactivation from the open state 21,22 .…”

“…Naturally occurring or engineered mutations in FHF genes result in disorders of excitable tissues, including ataxia 14,34 , epilepsies 11,24,27,31 , hypothalamus-induced obesity 29 , hypoalgesia 35 , and cardiac conduction block 21,22 . Fhf2 null mice are sensitive to ventricular cardiac conduction block when exposed to various stressors, including sodium or calcium channel blockers, uncoupling agents, or hyperthermia 21,22 . FHF2 deficiency and elevated core body temperature collaborate to reduce availability and speed inactivation of cardiac Na v 1.5 leading to failure of action potential conduction through myocardium 21 .…”

“…Most FHF isoforms induce a depolarizing shift in voltage dependence of Na v inactivation without altering the voltage for activation 9,19,33 , thereby increasing sodium current generated by Na v s. Mutations in FHF genes result in various disorders of excitable tissues 11,14,21,22,24,27,29,31,34,35 . Fhf2 null mice are sensitive to ventricular cardiac conduction block when exposed to various stressors, including sodium or calcium channel blockers, uncoupling agents, or hyperthermia 21,22 . FHF2 deficiency and elevated core body temperature collaborate to reduce availability and speed inactivation of cardiac Na v 1.5 leading to failure of action potential conduction through myocardium 21 .…”