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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

Predicted effects of sex hormones on cardiac tissue and QT-intervals.Action potential (50th paced beat at 1000 ms pacing frequency) propagation from top (cell# 1) to bottom (cell# 100) in a 1 cm cardiac fiber is shown. Time is on the x-axis and voltage on the z-axis. (A) Application of E2 and progesterone (i): control case (no E2), (ii): 0.1 nM E2, (iii): 1 nM E2, (iv): 2.5 nM progesterone, and (v): 40.6 nM progesterone. (B) Comparison of QT intervals is shown in top panel. Lower panels are pseudo ECGs showing the effect of hormones on QT intervals for different cases. The corresponding T-waves are indicated.
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pcbi-1000658-g003: Predicted effects of sex hormones on cardiac tissue and QT-intervals.Action potential (50th paced beat at 1000 ms pacing frequency) propagation from top (cell# 1) to bottom (cell# 100) in a 1 cm cardiac fiber is shown. Time is on the x-axis and voltage on the z-axis. (A) Application of E2 and progesterone (i): control case (no E2), (ii): 0.1 nM E2, (iii): 1 nM E2, (iv): 2.5 nM progesterone, and (v): 40.6 nM progesterone. (B) Comparison of QT intervals is shown in top panel. Lower panels are pseudo ECGs showing the effect of hormones on QT intervals for different cases. The corresponding T-waves are indicated.

Mentions: We next computed the effects of sex-steroid hormones in a one-dimensional strand of coupled M cells (results from other cell types are shown in Supplemental Figure S2) to determine the effects of hormones in an electrotonically coupled system (Figure 3). We also computed spatial gradients of depolarization and repolarization to generate a pseudo ECG electrogram (Figure 3B). APs were initiated via a stimulus applied to the first cell and then propagated from top to bottom along the 1 cm fiber. Figure 3A show that the first cell fired first and then repolarized first.


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)

Predicted effects of sex hormones on cardiac tissue and QT-intervals.Action potential (50th paced beat at 1000 ms pacing frequency) propagation from top (cell# 1) to bottom (cell# 100) in a 1 cm cardiac fiber is shown. Time is on the x-axis and voltage on the z-axis. (A) Application of E2 and progesterone (i): control case (no E2), (ii): 0.1 nM E2, (iii): 1 nM E2, (iv): 2.5 nM progesterone, and (v): 40.6 nM progesterone. (B) Comparison of QT intervals is shown in top panel. Lower panels are pseudo ECGs showing the effect of hormones on QT intervals for different cases. The corresponding T-waves are indicated.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000658-g003: Predicted effects of sex hormones on cardiac tissue and QT-intervals.Action potential (50th paced beat at 1000 ms pacing frequency) propagation from top (cell# 1) to bottom (cell# 100) in a 1 cm cardiac fiber is shown. Time is on the x-axis and voltage on the z-axis. (A) Application of E2 and progesterone (i): control case (no E2), (ii): 0.1 nM E2, (iii): 1 nM E2, (iv): 2.5 nM progesterone, and (v): 40.6 nM progesterone. (B) Comparison of QT intervals is shown in top panel. Lower panels are pseudo ECGs showing the effect of hormones on QT intervals for different cases. The corresponding T-waves are indicated.
Mentions: We next computed the effects of sex-steroid hormones in a one-dimensional strand of coupled M cells (results from other cell types are shown in Supplemental Figure S2) to determine the effects of hormones in an electrotonically coupled system (Figure 3). We also computed spatial gradients of depolarization and repolarization to generate a pseudo ECG electrogram (Figure 3B). APs were initiated via a stimulus applied to the first cell and then propagated from top to bottom along the 1 cm fiber. Figure 3A show that the first cell fired first and then repolarized first.

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