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

• Published in: Cardiovascular research 2012-08, Vol.95 (3), p.300-307
• Main Authors: LOWE, John S, MYERS STROUD, Dina, TAO YANG, HALL, Lynn, ATACK, Thomas C, RODEN, Dan M
• Format: Article
• Language: English
• Subjects: Acetanilides - pharmacology; Action Potentials; Animals; Biological and medical sciences; Cardiac dysrhythmias; Cardiology. Vascular system; Cnidarian Venoms; Disease Models, Animal; Electrocardiography; Female; Genetic Predisposition to Disease; Heart; Humans; Long QT Syndrome - etiology; Long QT Syndrome - genetics; Long QT Syndrome - metabolism; Long QT Syndrome - physiopathology; Male; Medical sciences; 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; Original; 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
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvs160

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