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September 16, 1997Circulation

Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome

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Why the study?

Does mexiletine reduce transmural dispersion of repolarization and prevent torsade de pointes in canine models of LQT2 and LQT3?

Population

Arterially perfused wedge of canine left ventricle mimicking LQT2 (using d-sotalol) and LQT3 (using ATX-II)

Comparison

Mexiletine (2 to 20 micromol/L) vs Baseline conditions (d-sotalol or ATX-II alone)

Design

Preclinical

Authors

WSWataru ShimizuCACharles Antzelevitch

Discussion

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Overview

May support human LQT2/LQT3 trials; leaves open clinical efficacy and safety.

Key Points

  • This study aims to investigate the effects of sodium channel block on repolarization and arrhythmogenesis in LQT2 and LQT3.
  • Simultaneously recorded transmural ECG and transmembrane action potentials in canine left ventricle.
  • Used d-sotalol to mimic LQT2 and ATX-II for LQT3 in experiments.
  • Assessed the effects of mexiletine on QT interval and TDR across different concentrations.
  • Mexiletine significantly abbreviated QT intervals and action potential durations across all cell types, more in LQT3.
  • 2 to 5 micromol/L of mexiletine suppressed spontaneous TdP and decreased the vulnerable window for TdP induction.
  • Higher doses (10 to 20 micromol/L) completely suppressed stimulation-induced TdP in both LQT2 and LQT3 models.

Structured PICO

Does mexiletine reduce transmural dispersion of repolarization and prevent torsade de pointes in canine models of LQT2 and LQT3?

P
Population
Arterially perfused wedge of canine left ventricle mimicking LQT2 (using d-sotalol) and LQT3 (using ATX-II)
I
Intervention
Mexiletine (2 to 20 micromol/L)
C
Comparator
Baseline conditions (d-sotalol or ATX-II alone)
O
Outcome
Transmural dispersion of repolarization (TDR), QT interval, APD90, and incidence of torsade de pointes (TdP)surrogate

Mexiletine effectively reduces transmural dispersion of repolarization and prevents torsade de pointes in experimental models of both LQT2 and LQT3, suggesting potential therapeutic value beyond LQT3.

Cite This Study

Shimizu et al. (1997) studied this question.

synapsesocial.com/papers/69f69138e405cc4465bc2ac3https://doi.org/10.1161/01.cir.96.6.2038
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Long QT Syndrome Patients With Mutations of the <i>SCN5A</i> and <i>HERG</i> Genes Have Differential Responses to Na <sup>+</sup> Channel Blockade and to Increases in Heart Rate1995 · 819 citations
  2. 2Efficacy of permanent pacing in the management of high-risk patients with long QT syndrome.1991 · 196 citations
  3. 3TU Alternans, Long QTU, and Torsade de Pointes: Clinical and Experimental Observations1992 · 65 citations
  4. 4Ionic bases for electrophysiological distinctions among epicardial, midmyocardial, and endocardial myocytes from the free wall of the canine left ventricle.1993 · 464 citations
  5. 5Distribution of M Cells in the Canine Ventricle1994 · 135 citations