title: Increased late sodium current contributes to long QT-related arrhythmia susceptibility in female mice.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  These data identify variable late I(Na) as a modulator of gender-dependent arrhythmia susceptibility.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, 2215B Garland Avenue, Nashville, TN 37232-0575, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Lowe
authors.forename: Dina Myers
authors.initials: DM
authors.lastname: Stroud
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Lynn
authors.initials: L
authors.lastname: Hall
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Atack
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D003064:Cnidarian Venoms; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008133:Long QT Syndrome / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D012307:Risk Factors; D012737:Sex Factors; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000083:Acetanilides; D003064:Cnidarian Venoms; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; C028800:toxin II (Anemonia sulcata); D000069458:Ranolazine