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Voltage Gated Sodium Channels pp 137–168Cite as

The Role of Late I Na in Development of Cardiac Arrhythmias

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Part of the book series: Handbook of Experimental Pharmacology ((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.

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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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Authors and Affiliations

  1. Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, NY, 13501, USA

    Charles Antzelevitch & Vladislav Nesterenko

  2. Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Foster City, CA, USA

    John C. Shryock, Sridharan Rajamani & Luiz Belardinelli

  3. Division of Cardiology, College of Medicine, University of Florida, Gainesville, FL, USA

    Yejia Song

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  1. Charles Antzelevitch
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  2. Vladislav Nesterenko
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  3. John C. Shryock
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  4. Sridharan Rajamani
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  5. Yejia Song
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  6. Luiz Belardinelli
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Correspondence to Charles Antzelevitch .

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  1. Biomedical Physiology & Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada

    Peter C. Ruben

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Antzelevitch, C., Nesterenko, V., Shryock, J.C., Rajamani, S., Song, Y., Belardinelli, L. (2014). The Role of Late I Na in Development of Cardiac Arrhythmias. In: Ruben, P. (eds) Voltage Gated Sodium Channels. Handbook of Experimental Pharmacology, vol 221. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41588-3_7

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