Affiliations 

  • 1 Faculty of Health and Medical Sciences, University of Surrey, VSM Building, Guildford, GU2 7AL, UK
  • 2 Department of Pharmacology, University of Oxford, Oxford, OX1 3QT, UK
  • 3 Physiological Laboratory, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK. clh11@cam.ac.uk
Pflugers Arch., 2017 06;469(5-6):629-641.
PMID: 28265756 DOI: 10.1007/s00424-017-1959-1

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.