Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

Abstract

Arrhythmias arise from breakdown of orderly action potential (AP) activation, propagation and recovery driven by interactive opening and closing of successive voltage-gated ion channels, in which one or more Na$^{+}$ current components play critical parts. Early peak, Na$^{+}$ currents (I${Na}$) reflecting channel activation drive the AP upstroke central to cellular activation and its propagation. Sustained late Na$^{+}$ currents (I${Na-L}$) include contributions from a component with a delayed inactivation timecourse influencing AP duration (APD) and refractoriness, potentially causing pro-arrhythmic phenotypes. The magnitude of I${Na-L}$ can be analysed through overlaps or otherwise in the overall voltage dependences of the steady-state properties and kinetics of activation and inactivation of the Na$^{+}$ conductance. This was useful in analysing repetitive firing associated with paramyotonia congenita in skeletal muscle. Similarly, genetic cardiac Na$^{+}$ channel abnormalities increasing I${Na-L}$ are implicated in triggering phenomena of automaticity, early and delayed afterdepolarisations and arrhythmic substrate. This review illustrates a wide range of situations that may accentuate I${Na-L}$. These include (1) overlaps between steady-state activation and inactivation increasing $\textit{window current}$, (2) kinetic deficiencies in Na$^{+}$ channel inactivation leading to $\textit{bursting phenomena}$ associated with repetitive channel openings and (3) $\textit{non-equilibrium gating}$ processes causing channel re-opening due to more rapid recoveries from inactivation. All these biophysical possibilities were identified in a selection of abnormal human SCN5A genotypes. The latter presented as a broad range of clinical arrhythmic phenotypes, for which effective therapeutic intervention would require specific identification and targeting of the diverse electrophysiological abnormalities underlying their increased I${Na-L}$.