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

Lowe JS, Stroud DM, Yang T, Hall L, Atack TC, Roden DM
Cardiovasc Res. 2012 95 (3): 300-7

PMID: 22562703 · PMCID: PMC3633400 · DOI:10.1093/cvr/cvs160

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.

MeSH Terms (23)

Acetanilides Action Potentials Animals Cnidarian Venoms Disease Models, Animal Electrocardiography Female Genetic Predisposition to Disease Humans Long QT Syndrome Male Mice Mice, 129 Strain Mice, Inbred C57BL Mice, Knockout Mice, Transgenic NAV1.5 Voltage-Gated Sodium Channel Piperazines Ranolazine Risk Factors Sex Factors Tachycardia, Ventricular Time Factors

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