Clinical InvestigationElectrophysiologyMechanisms of sex and age differences in ventricular repolarization in humans
Section snippets
Methods
This study was approved by the Research Involving Human Subjects Committee of the US FDA. For each of the individual clinical studies included in this analysis, the studies were approved by the local institutional review boards; and all subjects gave informed consent. This project was supported in part by FDA’s Critical Path Initiative, FDA’s Office of Women’s Health, and appointments to the Research Participation Program at the Center for Devices and Radiological Health administered by the Oak
Results
Women represented 41% of the 2,235 subjects in the study population. The Table summarizes the population characteristics and the ECG measurements by sex for the whole population as well as for different age groups by decade.
In the overall population, QTc was shorter in men than in women (QTcF: [mean ± SD] 394 ± 16 vs 408 ± 15 milliseconds, P < .001). QTc increased more with age in men (QTcF: 2.7 milliseconds per decade, 95% CI 1.8-3.6 milliseconds per decade, P < .001) than in women (QTcF: 1.1
Discussion
This study demonstrated that, in healthy adult subjects at rest, shorter QTc in men than in women is entirely explained by shorter early repolarization and that this difference diminishes with increasing age. Simulations of testosterone’s effects on ICaL and IKs confirmed this finding and revealed that testosterone’s effects on ICaL play a larger role than its effects on IKs in shortening early repolarization. In the context of drug-induced arrhythmias, the decreased ICaL from testosterone may
Limitations
This was a cross-sectional study, which included same-day baseline ECG recordings per subject; thus, within-subject changes over time could not be assessed. However, it represents a clear snapshot of the sex and age normal limits of the studied ECG intervals. In addition, children were not included in this study and the number of subjects ≥60 years old is limited. There is high variability (ie, >10% within each age group) in the average testosterone levels in men reported in the literature.17,
Conclusions
In healthy adult subjects at rest, shorter QTc in men than women is due to shorter early repolarization (J-Tpeakc); and these differences diminish with increasing age because of a greater increase in early repolarization in men. Simulations suggested that the primary reason for lengthening QTc as men age (and testosterone levels decrease) is due to testosterone’s effects on ICaL. With the larger difference in testosterone levels between women and men, testosterone’s effects on IKs also
Disclosures
The authors have no conflicts of interest to report.
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