Mechanisms of sex and age differences in ventricular repolarization in humans

Introduction 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. Conclusion 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.