title: The arrhythmogenic consequences of increasing late INa in the cardiomyocyte.
abstract: This review presents the roles of cardiac sodium channel NaV1.5 late current (late INa) in generation of arrhythmic activity. The assumption of the authors is that proper Na(+) channel function is necessary to the maintenance of the transmembrane electrochemical gradient of Na(+) and regulation of cardiac electrical activity. Myocyte Na(+) channels' openings during the brief action potential upstroke contribute to peak INa and initiate excitation-contraction coupling. Openings of Na(+) channels outside the upstroke contribute to late INa, a depolarizing current that persists throughout the action potential plateau. The small, physiological late INa does not appear to be critical for normal electrical or contractile function in the heart. Late INa does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na(+) loading. An increase of late INa, due to acquired conditions (e.g. heart failure) or inherited Na(+) channelopathies, facilitates the formation of early and delayed afterpolarizations and triggered arrhythmias, spontaneous diastolic depolarization, and cellular Ca(2+) loading. These in turn increase the spatial and temporal dispersion of repolarization time and may lead to reentrant arrhythmias.
authors.affiliation: Department of Biology, Cardiovascular Therapeutic Area, Gilead Sciences, Foster City, CA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
authors.forename: Yejia
authors.initials: Y
authors.lastname: Song
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D013779:Tetrodotoxin; D012964:Sodium; D002118:Calcium
keywords: Afterpotential; Arrhythmia; Heart; Late INa; Reentry