Figure 1.
Effects of sex-steroid hormones E2, progesterone, and testosterone on cardiac ion channels.
(A) Dose-dependence curves are shown for experimental (left traces) and simulated (right traces) inhibition of IKr current by E2. The simulated IKr tail currents (right) compared to experimentally measured IKr (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) IKs 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) IKs 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) IKs (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 ICa,L (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.
Figure 2.
Simulated effects of sex hormones on cardiac action potentials.
The APD for each concentration of sex-steroid hormone is indicated for the 50th 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 (APD90) is shown in horizontal bar graphs (right panels).
Figure 3.
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.
Figure 4.
Simulated combined effects of female hormones during the menstrual cycle and male hormones on cardiac action potentials.
Shown is the 50th 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).
Figure 5.
Estrogen and testosterone differentially affect sensitivity of IKr to drugs.
(A) Experimental (top) and simulated (bottom) dose-dependence curves for inhibition of hERG current by E4031 (control — black line), an IKr 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 (50th 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).
Figure 6.
Pause-induced EAD susceptibility is increased in the late follicular phase of the menstrual cycle.
(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.
Figure 7.
Estrogen increases vulnerability to reentry during short-long-short pacing protocols.
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.
Figure 8.
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.