Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart
David Park, Akshay Shekhar, John Santucci, Gabriel Redel‐Traub, Sergio Solinas, Shana Mintz, Xianming Lin, Ernest W. Chang, Deven Narke, Yuhe Xia, Mitchell Goldfarb, Glenn I. Fishman
Abstract
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.