Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients

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Abstract

BACKGROUND - Mexiletine (Mex) has been proposed as a gene-specific therapy for patients with long-QT syndrome type 3 (LQT3) caused by mutations in the cardiac sodium channel gene (SCN5A). The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations. We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations. METHODS AND RESULTS - We identified 4 SCN5A mutations in 5 symptomatic LQT3 patients with different responses to Mex (6 to 8 mg·kg·d). We classified the mutations as sensitive to Mex (P1332L, R1626P; ≥10% of QTc shortening and QTc S941N=WT>M1652R, suggesting that Mex-sensitive mutants present prolonged recovery from Mex block. CONCLUSIONS - We propose that voltage dependence of channel availability and shifts of V1/2 of steady-state inactivation correlate with the clinical response observed in LQT3 patients. This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3.

Original languageEnglish
Pages (from-to)1137-1144
Number of pages8
JournalCirculation
Volume116
Issue number10
DOIs
Publication statusPublished - Sep 2007

Keywords

  • Electrophysiology
  • Genetics
  • Ion channels
  • Long-QT syndrome
  • Pharmacology
  • Sodium

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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