Pathophysiology of the cardiac late Na current and its potential as a drug target

Jonathan D. Moreno, Colleen E Clancy

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

A pathological increase in the late component of the cardiac Na + current, I NaL, has been linked to disease manifestation in inherited and acquired cardiac diseases including the long QT variant 3 (LQT3) syndrome and heart failure. Disruption in I NaL leads to action potential prolongation, disruption of normal cellular repolarization, development of arrhythmia triggers, and propensity to ventricular arrhythmia. Attempts to treat arrhythmogenic sequelae from inherited and acquired syndromes pharmacologically with common Na + channel blockers (e.g. flecainide, lidocaine, and amiodarone) have been largely unsuccessful. This is due to drug toxicity and the failure of most current drugs to discriminate between the peak current component, chiefly responsible for single cell excitability and propagation in coupled tissue, and the late component (I NaL) of the Na + current. Although small in magnitude as compared to the peak Na + current (~1-3%), I NaL alters action potential properties and increases Na + loading in cardiac cells. With the increasing recognition that multiple cardiac pathological conditions share phenotypic manifestations of I NaL upregulation, there has been renewed interest in specific pharmacological inhibition of I Na. The novel antianginal agent ranolazine, which shows a marked selectivity for late versus peak Na + current, may represent a novel drug archetype for targeted reduction of I NaL. This article aims to review common pathophysiological mechanisms leading to enhanced I NaL in LQT3 and heart failure as prototypical disease conditions. Also reviewed are promising therapeutic strategies tailored to alter the molecular mechanisms underlying I Na mediated arrhythmia triggers.

Original languageEnglish (US)
Pages (from-to)608-619
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume52
Issue number3
DOIs
StatePublished - Mar 2012

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Keywords

  • Amiodarone
  • CAMKII
  • Late Na current
  • Long-QT
  • LQT3
  • Na overload
  • NAV1.5
  • Ranolazine
  • SCN5A

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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