Increased late sodium current contributes to long QT-related arrhythmia susceptibility in female mice

Cardiovasc Res. 2012 Aug 1;95(3):300-7. doi: 10.1093/cvr/cvs160. Epub 2012 May 4.

Abstract

Aims: Female gender is a risk factor for long QT-related arrhythmias, but the underlying mechanisms remain uncertain. Here, we tested the hypothesis that gender-dependent function of the post-depolarization 'late' sodium current (I(Na-L)) contributes.

Methods and results: Studies were conducted in mice in which the canonical cardiac sodium channel Scn5a locus was disrupted, and expression of human wild-type SCN5A cDNA substituted. Baseline QT intervals were similar in male and female mice, but exposure to the sodium channel opener anemone toxin ATX-II elicited polymorphic ventricular tachycardia in 0/9 males vs. 6/9 females. Ventricular I(Na-L) and action potential durations were increased in myocytes isolated from female mice compared with those from males before and especially after treatment with ATX-II. Further, ATX-II elicited potentially arrhythmogenic early afterdepolarizations in myocytes from 0/5 male mice and 3/5 female mice.

Conclusion: These data identify variable late I(Na) as a modulator of gender-dependent arrhythmia susceptibility.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetanilides / pharmacology
  • Action Potentials
  • Animals
  • Cnidarian Venoms
  • Disease Models, Animal
  • Electrocardiography
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Long QT Syndrome / etiology*
  • Long QT Syndrome / genetics
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • NAV1.5 Voltage-Gated Sodium Channel / deficiency*
  • NAV1.5 Voltage-Gated Sodium Channel / drug effects
  • NAV1.5 Voltage-Gated Sodium Channel / genetics
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism*
  • Piperazines / pharmacology
  • Ranolazine
  • Risk Factors
  • Sex Factors
  • Tachycardia, Ventricular / chemically induced
  • Tachycardia, Ventricular / etiology*
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Time Factors

Substances

  • Acetanilides
  • Cnidarian Venoms
  • NAV1.5 Voltage-Gated Sodium Channel
  • Piperazines
  • SCN5A protein, human
  • Scn5a protein, mouse
  • toxin II (Anemonia sulcata)
  • Ranolazine