Gating-dependent mechanisms for flecainide action in SCN5A-linked arrhythmia syndromes

Prakash C. Viswanathan, Connie R. Bezzina, Alfred L. George, Dan M. Roden, Arthur A M Wilde, Jeffrey R. Balser*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Background - Mutations in the cardiac sodium (Na) channel gene (SCN5A) give rise to the congenital long-QT syndrome (LQT3) and the Brugada syndrome. Na channel blockade by antiarrhythmic drugs improves the QT interval prolongation in LQT3 but worsens the Brugada syndrome ST-segment elevation. Although Na channel blockade has been proposed as a treatment for LQT3, flecainide also evokes "Brugada-like" ST-segment elevation in LQT3 patients. Here, we examine how Na channel inactivation gating defects in LQT3 and Brugada syndrome elicit proarrhythmic sensitivity to flecainide. Methods and Results - We measured whole-cell Na current (INa) from tsA-201 cells transfected with ΔKPQ, a LQT3 mutation, and 1795insD, a mutation that provokes both the LQT3 and Brugada syndromes. The 1795insD and ΔKPQ channels both exhibited modified inactivation gating (from the closed state), thus potentiating tonic INa block. Flecainide (1 μmol/L) tonic block was only 16.8 ± 3.0% for wild type but was 58.0±6.0% for 1795insD (P<0.01) and 39.4±8.0% (P<0.05) for ΔKPQ. In addition, the 1795insD mutation delayed recovery from inactivation by enhancing intermediate inactivation, with a 4-fold delay in recovery from use-dependent flecainide block. Conclusions - We have linked 2 inactivation gating defects ("closed-state" fast inactivation and intermediate inactivation) to flecainide sensitivity in patients carrying LQT3 and Brugada syndrome mutations. These results provide a mechanistic rationale for predicting proarrhythmic sensitivity to flecainide based on the identification of specific SCN5A inactivation gating defects.

Original languageEnglish (US)
Pages (from-to)1200-1205
Number of pages6
JournalCirculation
Volume104
Issue number10
DOIs
StatePublished - Sep 4 2001

Keywords

  • Flecainide
  • Ion channels
  • Long-QT syndrome
  • Pharmacology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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