Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study
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{"title"=>"Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study", "type"=>"journal", "authors"=>[{"first_name"=>"Pei-Chi", "last_name"=>"Yang"}, {"first_name"=>"Junko", "last_name"=>"Kurokawa"}, {"first_name"=>"Tetsushi", "last_name"=>"Furukawa"}, {"first_name"=>"Colleen E.", "last_name"=>"Clancy"}], "year"=>2010, "source"=>"PLoS Computational Biology", "identifiers"=>{"pmid"=>"20126530", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "issn"=>"1553-7358", "doi"=>"10.1371/journal.pcbi.1000658"}, "id"=>"9ed8d9df-aef1-38ba-8c25-fbf314ef8bdd", "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.", "link"=>"http://www.mendeley.com/research/acute-effects-sex-steroid-hormones-susceptibility-cardiac-arrhythmias-simulation-study-5", "reader_count"=>9, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Librarian"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Agricultural and Biological Sciences"=>3, "Medicine and Dentistry"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>3}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Chile"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/429550", "https://ndownloader.figshare.com/files/429560", "https://ndownloader.figshare.com/files/429577", "https://ndownloader.figshare.com/files/429584", "https://ndownloader.figshare.com/files/429600", "https://ndownloader.figshare.com/files/429616", "https://ndownloader.figshare.com/files/429630"], "description"=>"<div><p>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.</p></div>", "links"=>[], "tags"=>["acute", "effects", "steroid", "hormones", "susceptibility", "cardiac", "simulation"], "article_id"=>144805, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1000658.s001", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s002", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s003", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s004", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s005", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s006", "https://dx.doi.org/10.1371/journal.pcbi.1000658.s007"], "stats"=>{"downloads"=>31, "page_views"=>13, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Acute_Effects_of_Sex_Steroid_Hormones_on_Susceptibility_to_Cardiac_Arrhythmias_A_Simulation_Study/144805", "title"=>"Acute Effects of Sex Steroid Hormones on Susceptibility to Cardiac Arrhythmias: A Simulation Study", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-01-29 01:20:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/865491"], "description"=>"<p>Four snapshots following application of hormones and/or drug at indicated time points. Tissues were stimulated along one edge and propagated from endocardial to epicardial region followed by a point stimulus applied in the right corner of the endocardial region. Voltages are indicated by color gradient.</p>", "links"=>[], "tags"=>["increases", "vulnerability", "reentry", "short-long-short", "pacing"], "article_id"=>535944, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g007", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estrogen_increases_vulnerability_to_reentry_during_short_long_short_pacing_protocols_/535944", "title"=>"Estrogen increases vulnerability to reentry during short-long-short pacing protocols.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:39:04"}
  • {"files"=>["https://ndownloader.figshare.com/files/865008"], "description"=>"<p>The APD for each concentration of sex-steroid hormone is indicated for the 50<sup>th</sup> paced beat at a cycle length of 1000 ms in single M-cells. (A)–(B) Simulated APD in the presence of E2 (0.1 and 1 nM) and progesterone (2.5 and 40.6 nM) compared to control condition (0 nM). (C) Simulated APD with combined effects of E2 and progesterone at three physiological concentrations corresponding to different stages of the menstrual cycle: early follicular phase (estrogen: 0.1 nM and progesterone: 2.5 nM), late follicular phase (estrogen: 1 nM and progesterone: 2.5 nM) and luteal phase (estrogen: 0.7 nM and progesterone: 40.6 nM). (D) Simulated effects of two physiological concentrations of testosterone (10 and 35 nM) on APD. The corresponding APD at 90% repolarization (APD<sub>90</sub>) is shown in horizontal bar graphs (right panels).</p>", "links"=>[], "tags"=>["hormones", "cardiac"], "article_id"=>535465, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulated_effects_of_sex_hormones_on_cardiac_action_potentials_/535465", "title"=>"Simulated effects of sex hormones on cardiac action potentials.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:31:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/864885"], "description"=>"<p>(A) Dose-dependence curves are shown for experimental (left traces) and simulated (right traces) inhibition of I<sub>Kr</sub> current by E2. The simulated I<sub>Kr</sub> tail currents (right) compared to experimentally measured I<sub>Kr</sub> (left) at −40 mV following depolarization to a test potential = +20 mV in the absence (control) or presence of E2 (1 and 10 nM). (B) I<sub>Ks</sub> was experimentally recorded at a test potential of +50 mV from a holding potential of −40 mV with 0 nM and 100 nM progesterone (top traces). Simulated (lower races) I<sub>Ks</sub> are shown in the presence of 0 nM (control case), 2.5 nM (follicular phase), 40.6 nM (luteal phase) and 100 nM progesterone during a voltage pulse from −40 mV to +50 mV. (C) I<sub>Ks</sub> (left panels) were elicited by 3.5-s test pulses to +50 mV from a holding potential of −40 mV (experiment — top traces and simulation — lower traces) in the absence and presence of testosterone (10 nM and 300 nM). The effect on I<sub>Ca,L</sub> (right panels) from experimental data (top traces) and simulated results (lower traces) during a voltage step from −40 mV to 0 mV under control condition (0 nM), 10 nM and 300 nM testosterone.</p>", "links"=>[], "tags"=>["sex-steroid", "hormones", "testosterone", "cardiac", "ion"], "article_id"=>535338, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g001", "stats"=>{"downloads"=>1, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_sex_steroid_hormones_E2_progesterone_and_testosterone_on_cardiac_ion_channels_/535338", "title"=>"Effects of sex-steroid hormones E2, progesterone, and testosterone on cardiac ion channels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:28:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/865203"], "description"=>"<p>Shown is the 50<sup>th</sup> paced beat at a cycle length of 1000 ms in 1D cables. (A) (i): Early follicular phase (ii): Late follicular phase (iii): Luteal phase. Simulated APD in the presence of two physiological concentrations (iv and v) of testosterone. (B) The computed virtual electrograms show QT intervals change during various stages of menstrual cycle and at two concentrations of testosterone (lower panels). The vertical bar graph shows the QT intervals under different circumstances (top panel).</p>", "links"=>[], "tags"=>["hormones", "menstrual", "cardiac"], "article_id"=>535662, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g004", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulated_combined_effects_of_female_hormones_during_the_menstrual_cycle_and_male_hormones_on_cardiac_action_potentials_/535662", "title"=>"Simulated combined effects of female hormones during the menstrual cycle and male hormones on cardiac action potentials.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:34:22"}
  • {"files"=>["https://ndownloader.figshare.com/files/865551"], "description"=>"<p>(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.</p>", "links"=>[], "tags"=>["drug-induced", "arrhythmias", "short-long-short", "pacing"], "article_id"=>536008, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g008", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Simulated_drug_induced_arrhythmias_during_short_long_short_pacing_protocols_/536008", "title"=>"Simulated drug-induced arrhythmias during short-long-short pacing protocols.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:40:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/865115"], "description"=>"<p>Action potential (50<sup>th</sup> 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.</p>", "links"=>[], "tags"=>["hormones", "cardiac"], "article_id"=>535574, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g003", "stats"=>{"downloads"=>0, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Predicted_effects_of_sex_hormones_on_cardiac_tissue_and_QT_intervals_/535574", "title"=>"Predicted effects of sex hormones on cardiac tissue and QT-intervals.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:32:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/865305"], "description"=>"<p>(A) Experimental (top) and simulated (bottom) dose-dependence curves for inhibition of hERG current by E4031 (control — black line), an I<sub>Kr</sub> blocker, and after addition of estrogen (E2 — light gray line) and DHT (dark gray line). The curves for each concentration of E2 and DHT are indicated. (B) Simulated APD (50<sup>th</sup> beat at a pacing rate of 1000 ms) with 10 nM E4031 in the presence of both E2 and progesterone (late follicular phase — i). (ii) Simulated effects of testosterone (3 nM) on APD with E4031 application. The computed ECG (low traces) shows that QT interval is substantially longer in case (i) than in case (ii).</p>", "links"=>[], "tags"=>["testosterone", "differentially"], "article_id"=>535769, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estrogen_and_testosterone_differentially_affect_sensitivity_of_I_Kr_to_drugs_/535769", "title"=>"Estrogen and testosterone differentially affect sensitivity of I<sub>Kr</sub> to drugs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:36:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/865409"], "description"=>"<p>(A) The simulated cell was paced for 10 beats at BCL = 1000 ms (s1) followed by varying s1–s2 intervals and long pause intervals. The intervals between s1 and s2 are shown on the x-axis, pause intervals on y-axis and APD are indicated by color gradient. Simulated EAD formations under three conditions, late follicular phase (left panel), in the presence (middle) of testosterone 3 nM and E-4031 10 nM, and addition of E4031 in the absence of sex-steroid hormones (right). (B) Simulated APDs during the late follicular phase with E-4031 (10 nM) application at three basic cycle lengths (500 ms, 750 ms, and 1000 ms). The point indicated by an arrow (right panel) corresponding fiber and pseudo ECG (lower panels) under same conditions.</p>", "links"=>[], "tags"=>["ead", "susceptibility", "follicular", "menstrual"], "article_id"=>535867, "categories"=>["Medicine", "Physiology"], "users"=>["Pei-Chi Yang", "Junko Kurokawa", "Tetsushi Furukawa", "Colleen E. Clancy"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000658.g006", "stats"=>{"downloads"=>2, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pause_induced_EAD_susceptibility_is_increased_in_the_late_follicular_phase_of_the_menstrual_cycle_/535867", "title"=>"Pause-induced EAD susceptibility is increased in the late follicular phase of the menstrual cycle.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-29 01:37:47"}

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