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

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.

• Authors: John S Lowe, Dina Myers Stroud, Tao Yang, Lynn Hall, Thomas C Atack, Dan M Roden
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 95 Issue 3 Pg. 300-7 (Aug 01 2012) ISSN: 1755-3245 [Electronic] England
• PMID: 22562703 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

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

Topics

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