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

Research output: Contribution to journalArticle

143 Citations (Scopus)

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

Fingerprint

Mexiletine
Mutation
Sodium Channels
Long QT syndrome type 3
Genetic Therapy
Cardiac Arrhythmias

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients. / Ruan, Yanfei; Liu, Nian; Bloise, Raffaella; Napolitano, Carlo; Priori, Silvia G.

In: Circulation, Vol. 116, No. 10, 09.2007, p. 1137-1144.

Research output: Contribution to journalArticle

@article{b355dee0f6404afc8a8c7cce86a9da22,
title = "Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients",
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.",
keywords = "Electrophysiology, Genetics, Ion channels, Long-QT syndrome, Pharmacology, Sodium",
author = "Yanfei Ruan and Nian Liu and Raffaella Bloise and Carlo Napolitano and Priori, {Silvia G.}",
year = "2007",
month = "9",
doi = "10.1161/CIRCULATIONAHA.107.707877",
language = "English",
volume = "116",
pages = "1137--1144",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "10",

}

TY - JOUR

T1 - Gating properties of SCN5A mutations and the response to mexiletine in long-QT syndrome type 3 patients

AU - Ruan, Yanfei

AU - Liu, Nian

AU - Bloise, Raffaella

AU - Napolitano, Carlo

AU - Priori, Silvia G.

PY - 2007/9

Y1 - 2007/9

N2 - 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.

AB - 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.

KW - Electrophysiology

KW - Genetics

KW - Ion channels

KW - Long-QT syndrome

KW - Pharmacology

KW - Sodium

UR - http://www.scopus.com/inward/record.url?scp=34548378735&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548378735&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.107.707877

DO - 10.1161/CIRCULATIONAHA.107.707877

M3 - Article

C2 - 17698727

AN - SCOPUS:34548378735

VL - 116

SP - 1137

EP - 1144

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 10

ER -