Late sodium current associated cardiac electrophysiological and mechanical dysfunction

Pflugers Arch. 2018 Mar;470(3):461-469. doi: 10.1007/s00424-017-2079-7. Epub 2017 Nov 10.


Late sodium current (INaL) is a small sustained inward current observed during the cardiac action potential plateau phase following decay of the early peak INa. The endogenous INaL is relatively small in normal hearts but exerts functionally significant effects on cardiomyocyte repolarization with potentially pro-arrhythmic effects in hearts with reduced repolarization reserve. Enhanced INa,L occurs in long QT syndrome 3 (LQTS 3) patients, and under a number of pathological and pharmacological cardiovascular conditions, including bradycardia, myocardial ischemia, reperfusion injury, and heart failure. It may there play important roles in arrhythmogenesis and mechanical dysfunction. Experimental and clinical research suggests that INaL inhibition may prevent and treat cardiac arrhythmias and improve ventricular pump function. Selective INa,L inhibitors, exemplified by ranolazine, GS-967 and GS-458967 have little or no effect on peak sodium current and/or IKr, and carry no or minimal pro-arrhythmic risk compared to those associated with administration of classical class I or III antiarrhythmic drugs, particularly in patients with ischemic heart disease. This increased understanding of INaL may be encouraging to clinicians in use of INaL inhibitors to treat cardiac arrhythmias and mechanical dysfunction directly associated with enhanced INaL such as LQTS type 3, and myocardial ischemia. This review discusses the roles of endogenous and enhanced INaL in arrhythmogenesis and mechanical dysfunction, and the basic and clinical research of INaL inhibitors.

Keywords: Cardiac arrhythmias; INaL; Late sodium current; Mechanical dysfunction antiarrhythmic drugs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Action Potentials
  • Animals
  • Anti-Arrhythmia Agents / pharmacology
  • Anti-Arrhythmia Agents / therapeutic use*
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / metabolism*
  • Arrhythmias, Cardiac / physiopathology
  • Humans
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Sodium Channel Blockers / pharmacology
  • Sodium Channel Blockers / therapeutic use*
  • Sodium Channels / metabolism*


  • Anti-Arrhythmia Agents
  • Sodium Channel Blockers
  • Sodium Channels