[HTML][HTML] Sodium channel biophysics, late sodium current and genetic arrhythmic syndromes

KR Chadda, K Jeevaratnam, M Lei… - Pflügers Archiv-European …, 2017 - Springer
Pflügers Archiv-European Journal of Physiology, 2017Springer
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 …
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 window current, (2) kinetic deficiencies in Na+ channel inactivation leading to bursting phenomena associated with repetitive channel openings and (3) 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.
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