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A Combined Approach Using Patch-Clamp Study and Computer Simulation Study for Understanding Long QT Syndrome and TdP in Women.

Furukawa T, Kurokawa J, Clancy CE - Curr Cardiol Rev (2008)

Bottom Line: Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner.Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy.A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-Informational Pharmacology, Madical Research Institute, Tokyo Medical and Dental University.

ABSTRACT
Female sex is an independent risk factor for development of torsade de pointes (TdP)-type arrhythmias in both congenital and acquired long QT syndrome (LQTS). In females, QT(c) interval and TdP risk vary during the menstrual cycle and around delivery. Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner. Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy. Based on this model, progesterone is predicted to have protective effects against sympathetic nervous system-induced arrhythmias in congenital LQTS and drug-induced TdP in acquired LQTS. A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

No MeSH data available.


Related in: MedlinePlus

A) Simulated action potentials in the absence (a) and presence (b) of simulated SNS stimulation under baseline conditions (dashed line) and with 2.5 nM (solid line) and 40.6 nM (dashed-dot-dot line) progesterone. The 10th paced beat at a pacing interval of 400 ms is shown.B) Left panel: Simulated action potentials (10th paced beat at a 400 ms pacing interval) in a 1 cm cardiac fiber (cell number=100; top is cell #1, and bottom is cell #100). An action potential was elicited at cell #1, and propagated from top to bottom. a, Baseline (no SNS stimulation and no progesterone). b, With 40.6 nM progesterone. c, With 40.6 nM progesterone in the presence of SNS stimulation. Right panel: Computed virtual electrograms under the three conditions. The corresponding T-waves are indicated with arrows.
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Figure 4: A) Simulated action potentials in the absence (a) and presence (b) of simulated SNS stimulation under baseline conditions (dashed line) and with 2.5 nM (solid line) and 40.6 nM (dashed-dot-dot line) progesterone. The 10th paced beat at a pacing interval of 400 ms is shown.B) Left panel: Simulated action potentials (10th paced beat at a 400 ms pacing interval) in a 1 cm cardiac fiber (cell number=100; top is cell #1, and bottom is cell #100). An action potential was elicited at cell #1, and propagated from top to bottom. a, Baseline (no SNS stimulation and no progesterone). b, With 40.6 nM progesterone. c, With 40.6 nM progesterone in the presence of SNS stimulation. Right panel: Computed virtual electrograms under the three conditions. The corresponding T-waves are indicated with arrows.

Mentions: We incorporated effects of progesterone obtained in our biological experiments in the Faber-Rudy model of the guinea pig myocyte [38]. Since reported progesterone level in women is ~2.5 nM in the follicular phase and ~40.6 nM in the luteal phase [39], we incorporated effects of progesterone at 2.5 nM and at 40.6 nM. The model predicts that progesterone at 40.6 nM shortens APD by 3.7 % under basal conditions and 4.6 % under SNS-stimulated conditions compared to APD at 2.5 nM progesterone (Fig. 4) [30]. Clinically observed QT intervals are shorter by about 2.4%-2.8 % in the luteal phase than in follicular phase [5], and so the APD shortening predicted in the model (3.7-4.6 %) fits well with the observed fluctuation in QT interval during the menstrual cycle in women.


A Combined Approach Using Patch-Clamp Study and Computer Simulation Study for Understanding Long QT Syndrome and TdP in Women.

Furukawa T, Kurokawa J, Clancy CE - Curr Cardiol Rev (2008)

A) Simulated action potentials in the absence (a) and presence (b) of simulated SNS stimulation under baseline conditions (dashed line) and with 2.5 nM (solid line) and 40.6 nM (dashed-dot-dot line) progesterone. The 10th paced beat at a pacing interval of 400 ms is shown.B) Left panel: Simulated action potentials (10th paced beat at a 400 ms pacing interval) in a 1 cm cardiac fiber (cell number=100; top is cell #1, and bottom is cell #100). An action potential was elicited at cell #1, and propagated from top to bottom. a, Baseline (no SNS stimulation and no progesterone). b, With 40.6 nM progesterone. c, With 40.6 nM progesterone in the presence of SNS stimulation. Right panel: Computed virtual electrograms under the three conditions. The corresponding T-waves are indicated with arrows.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2801855&req=5

Figure 4: A) Simulated action potentials in the absence (a) and presence (b) of simulated SNS stimulation under baseline conditions (dashed line) and with 2.5 nM (solid line) and 40.6 nM (dashed-dot-dot line) progesterone. The 10th paced beat at a pacing interval of 400 ms is shown.B) Left panel: Simulated action potentials (10th paced beat at a 400 ms pacing interval) in a 1 cm cardiac fiber (cell number=100; top is cell #1, and bottom is cell #100). An action potential was elicited at cell #1, and propagated from top to bottom. a, Baseline (no SNS stimulation and no progesterone). b, With 40.6 nM progesterone. c, With 40.6 nM progesterone in the presence of SNS stimulation. Right panel: Computed virtual electrograms under the three conditions. The corresponding T-waves are indicated with arrows.
Mentions: We incorporated effects of progesterone obtained in our biological experiments in the Faber-Rudy model of the guinea pig myocyte [38]. Since reported progesterone level in women is ~2.5 nM in the follicular phase and ~40.6 nM in the luteal phase [39], we incorporated effects of progesterone at 2.5 nM and at 40.6 nM. The model predicts that progesterone at 40.6 nM shortens APD by 3.7 % under basal conditions and 4.6 % under SNS-stimulated conditions compared to APD at 2.5 nM progesterone (Fig. 4) [30]. Clinically observed QT intervals are shorter by about 2.4%-2.8 % in the luteal phase than in follicular phase [5], and so the APD shortening predicted in the model (3.7-4.6 %) fits well with the observed fluctuation in QT interval during the menstrual cycle in women.

Bottom Line: Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner.Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy.A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

View Article: PubMed Central - PubMed

Affiliation: Department of Bio-Informational Pharmacology, Madical Research Institute, Tokyo Medical and Dental University.

ABSTRACT
Female sex is an independent risk factor for development of torsade de pointes (TdP)-type arrhythmias in both congenital and acquired long QT syndrome (LQTS). In females, QT(c) interval and TdP risk vary during the menstrual cycle and around delivery. Biological experiments including single-cell current recordings with the patch-clamp technique and biochemical experiments show that progesterone modulates cardiac K(+) current and Ca(2+) current via the non-genomic pathway of the progesterone receptor, and thus the cardiac repolarization duration, in a concentration-dependent manner. Incorporation of these biological findings into a computer model of single-cell and coupled-cell cardiomyocytes simulates fluctuations in QT(c) interval during the menstrual cycle with reasonable accuracy. Based on this model, progesterone is predicted to have protective effects against sympathetic nervous system-induced arrhythmias in congenital LQTS and drug-induced TdP in acquired LQTS. A combined biological and computational approach may provide a powerful means to risk stratify TdP risk in women.

No MeSH data available.


Related in: MedlinePlus