title: Mechanisms of sex and age differences in ventricular repolarization in humans.
abstract: BACKGROUND
  Corrected QT interval (QTc) is shorter in postpubertal men than in women; however, QTc lengthens as men age and testosterone levels decrease. Animal studies have demonstrated that testosterone decreases L-type calcium current and increases slow delayed rectifier potassium current; however, it is not known how these contribute to QTc differences by sex and age in humans. We separately analyzed early versus late repolarization duration and performed simulations of the effect of testosterone on the electrocardiogram (ECG) to examine the mechanism of sex and age differences in QTc in humans.
  
  
  METHODS
  Twelve-lead ECGs from 2,235 healthy subjects (41% women) in Thorough QT studies were analyzed to characterize sex- and age-dependent differences in depolarization (QRS), early repolarization (J-T(peak)), and late repolarization (T(peak)-T(end)). In addition, we simulated the effects of testosterone on calcium current, slow delayed rectifier potassium current, and surface ECG intervals.
  
  
  RESULTS
  QTc was shorter in men than in women (394 ± 16 vs 408 ± 15 milliseconds, P < .001), which was due to shorter early repolarization (213 ± 16 vs 242 ± 16 milliseconds, P < .001), as men had longer depolarization (94 ± 7 vs 89 ± 7 milliseconds, P < .001) and longer late repolarization (87 ± 10 vs 78 ± 9 milliseconds, P < .001). Sex difference in QTc decreased with age and was due to changes in early repolarization. Simulations showed that the early repolarization changes were most influenced by testosterone's effect on calcium current.
  
  
  CONCLUSIONS
  Shorter QTc in men compared to women is explained by shorter early repolarization, and this difference decreases with age. These sex and age differences in repolarization appear to be caused by testosterone effects on calcium current.
authors.affiliation: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD; BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Aragón, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vicente
authors.affiliation: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD; Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Loriano
authors.initials: L
authors.lastname: Galeotti
authors.affiliation: Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD. Electronic address: david.strauss@fda.hhs.gov.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D004562:Electrocardiography; D055724:Electrophysiological Phenomena / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012737:Sex Factors; D013739:Testosterone / Q000502:physiology; D016276:Ventricular Function / Q000502:physiology*; D055815:Young Adult
chemical_list: D013739:Testosterone