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Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.

Yang PC, Kurokawa J, Furukawa T, Clancy CE - PLoS Comput. Biol. (2010)

Bottom Line: We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models.Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval.Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California, Davis, Davis, California, United States of America.

ABSTRACT
Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The "female" model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The "male" model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

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Related in: MedlinePlus

Simulated drug-induced arrhythmias during short-long-short pacing protocols.(A) Comparison of 2D heterogeneous tissue dynamics in the absence or presence of E-4031 during the late follicular phase, and application of testosterone 3 nM with E-4031. (B) The same protocol as above was used, but the premature stimulus was applied during the vulnerable window in the middle of endocardial near the boundary between endocardial region and M cells. The late follicular phase with E-4031 is shown.
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pcbi-1000658-g008: Simulated drug-induced arrhythmias during short-long-short pacing protocols.(A) Comparison of 2D heterogeneous tissue dynamics in the absence or presence of E-4031 during the late follicular phase, and application of testosterone 3 nM with E-4031. (B) The same protocol as above was used, but the premature stimulus was applied during the vulnerable window in the middle of endocardial near the boundary between endocardial region and M cells. The late follicular phase with E-4031 is shown.

Mentions: In Figure 8A (top), the simulations suggest no reentrant activity during the late follicular phase of the menstrual cycle (progesterone 2.5 nM and 1 nM E2). However, when 10 nM E-4031 is applied during the late follicular phase, a spiral wave is readily induced (Figure 8A – middle). We also tested the effects of male hormone (testosterone) in the presence of E-4031. Figure 8A (bottom) shows that testosterone 3nM with 10 nM E-4031 did not trigger reentry activity.


Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study.

Yang PC, Kurokawa J, Furukawa T, Clancy CE - PLoS Comput. Biol. (2010)

Simulated drug-induced arrhythmias during short-long-short pacing protocols.(A) Comparison of 2D heterogeneous tissue dynamics in the absence or presence of E-4031 during the late follicular phase, and application of testosterone 3 nM with E-4031. (B) The same protocol as above was used, but the premature stimulus was applied during the vulnerable window in the middle of endocardial near the boundary between endocardial region and M cells. The late follicular phase with E-4031 is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2813260&req=5

pcbi-1000658-g008: Simulated drug-induced arrhythmias during short-long-short pacing protocols.(A) Comparison of 2D heterogeneous tissue dynamics in the absence or presence of E-4031 during the late follicular phase, and application of testosterone 3 nM with E-4031. (B) The same protocol as above was used, but the premature stimulus was applied during the vulnerable window in the middle of endocardial near the boundary between endocardial region and M cells. The late follicular phase with E-4031 is shown.
Mentions: In Figure 8A (top), the simulations suggest no reentrant activity during the late follicular phase of the menstrual cycle (progesterone 2.5 nM and 1 nM E2). However, when 10 nM E-4031 is applied during the late follicular phase, a spiral wave is readily induced (Figure 8A – middle). We also tested the effects of male hormone (testosterone) in the presence of E-4031. Figure 8A (bottom) shows that testosterone 3nM with 10 nM E-4031 did not trigger reentry activity.

Bottom Line: We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models.Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval.Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of California, Davis, Davis, California, United States of America.

ABSTRACT
Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The "female" model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The "male" model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

Show MeSH
Related in: MedlinePlus