Rationale:
FHFs (fibroblast growth factor homologous factors) are key regulators of sodium channel (Na
V
) 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 Na
v
availability in
Fhf2
knockout (
Fhf2
KO
) 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 (gCa
V
) using verapamil or by reducing gap junctional conductance (Gj) using carbenoxolone or by backcrossing into a cardiomyocyte-specific Cx43 (connexin 43) heterozygous background. All conditions produced conduction block in
Fhf2
KO
mice, with
Fhf2
wild-type (
Fhf2
WT
) mice showing normal impulse propagation. To explore the ionic mechanisms of block in
Fhf2
KO
hearts, multicellular linear strand models incorporating FHF2-deficient Na
v
inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced gCa
V
or diminished Gj are very different. Enhanced Na
v
inactivation due to FHF2 deficiency shifts dependence onto calcium current (I
Ca
) to sustain electrotonic driving force, axial current flow, and action potential (AP) generation from cell-to-cell. In the setting of diminished Gj, slower charging time from upstream cells conspires with accelerated Na
v
inactivation in mutant strands to prevent sufficient downstream cell charging for AP propagation.
Conclusions:
FHF2-dependent effects on Na
v
inactivation ensure adequate sodium current (I
Na
) reserve to safeguard against numerous threats to reliable cardiac impulse propagation.