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The Role of Late INa in Development of Cardiac Arrhythmias

  • Charles AntzelevitchEmail author
  • Vladislav Nesterenko
  • John C. Shryock
  • Sridharan Rajamani
  • Yejia Song
  • Luiz Belardinelli
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 221)

Abstract

Late I Na is an integral part of the sodium current, which persists long after the fast-inactivating component. The magnitude of the late I Na is relatively small in all species and in all types of cardiomyocytes as compared with the amplitude of the fast sodium current, but it contributes significantly to the shape and duration of the action potential. This late component had been shown to increase in several acquired or congenital conditions, including hypoxia, oxidative stress, and heart failure, or due to mutations in SCN5A, which encodes the α-subunit of the sodium channel, as well as in channel-interacting proteins, including multiple β subunits and anchoring proteins. Patients with enhanced late I Na exhibit the type-3 long QT syndrome (LQT3) characterized by high propensity for the life-threatening ventricular arrhythmias, such as Torsade de Pointes (TdP), as well as for atrial fibrillation. There are several distinct mechanisms of arrhythmogenesis due to abnormal late I Na, including abnormal automaticity, early and delayed afterdepolarization-induced triggered activity, and dramatic increase of ventricular dispersion of repolarization. Many local anesthetic and antiarrhythmic agents have a higher potency to block late I Na as compared with fast I Na. Several novel compounds, including ranolazine, GS-458967, and F15845, appear to be the most selective inhibitors of cardiac late I Na reported to date. Selective inhibition of late I Na is expected to be an effective strategy for correcting these acquired and congenital channelopathies.

Keywords

Ion channel currents Electrophysiology Long QT syndrome Sudden cardiac death Cardiac arrhythmias 

Notes

Support

Supported by grants HL47678 from NHLBI, NIH (CA), C026424 from NYSTEM (CA), Gilead Sciences, Inc. and the Masons of New York State, Florida, Massachusetts Connecticut, Maryland, Rhode Island, and Wisconsin.

Conflicts of Interest

Dr. Antzelevitch is a consultant to Gilead Sciences and Dr. Belardinelli, Shryock, and Rajamani are employed by Gilead Sciences.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Charles Antzelevitch
    • 1
    Email author
  • Vladislav Nesterenko
    • 1
  • John C. Shryock
    • 2
  • Sridharan Rajamani
    • 2
  • Yejia Song
    • 3
  • Luiz Belardinelli
    • 2
  1. 1.Masonic Medical Research LaboratoryUticaUSA
  2. 2.Department of BiologyCardiovascular Therapeutic Area, Gilead SciencesFoster CityUSA
  3. 3.Division of Cardiology, College of MedicineUniversity of FloridaGainesvilleUSA

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