Mechanisms of sex and age differences in ventricular repolarization in humans

doi:10.1016/j.ahj.2014.07.010

American Heart Journal

Volume 168, Issue 5, November 2014, Pages 749-756.e3

https://doi.org/10.1016/j.ahj.2014.07.010 Get rights and content

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.

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 I_CaL and I_Ks confirmed this finding and revealed that testosterone’s effects on I_CaL play a larger role than its effects on I_Ks in shortening early repolarization. In the context of drug-induced arrhythmias, the decreased I_CaL 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-T_peakc); 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 I_CaL. With the larger difference in testosterone levels between women and men, testosterone’s effects on I_Ks also

Disclosures

The authors have no conflicts of interest to report.

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Clinical InvestigationElectrophysiologyMechanisms of sex and age differences in ventricular repolarization in humans

Introduction

Methods

Results

Conclusion

Section snippets

Methods

Results

Discussion

Limitations

Conclusions

Disclosures

Am Heart J

Pharmacol Ther

J Electrocardiol

J Am Coll Cardiol

J Am Coll Cardiol

Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs

JAMA

Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades—1969-1998

Pharmacoepidemiol Drug Saf

An analysis of the time-relations of electrocardiograms

Heart

Sex differences in the evolution of the electrocardiographic QT interval with age

Can J Cardiol

Nontranscriptional regulation of cardiac repolarization currents by testosterone

Circulation

Differential distribution of cardiac ion channel expression as a basis for regional specialization in electrical function

Circ Res

Guidance for industry E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs

Improving the assessment of heart toxicity for all new drugs through translational regulatory science

Clin Pharmacol Ther

Electrocardiographic data quality in thorough QT/QTc studies

Drug Saf

Transformation of the Mason-Likar 12-lead electrocardiogram to the Frank vectorcardiogram

Die Systolendauer im Elektrokardiogramm bei normalen Menschen und bei Herzkranken

Acta Med Scand

Sex differences in the rate dependence of the T wave descending limb

Cardiovasc Res

Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation

PLoS Comput Biol

ECGSIM: an interactive tool for studying the genesis of QRST waveforms

Heart

Clinical Investigation
Electrophysiology
Mechanisms of sex and age differences in ventricular repolarization in humans