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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) In the basal condition, progesterone (P4) enhances IKs. a, Representative superimposed IKs current traces in the control and after treatment with 100 nM P4. IKs was elicited by depolarization to +50 mV from a holding potential of -40 mV at 0.1 Hz. b, Concentration-response curve for IKs enhancement by progesterone. EC50 was 2.6 nM.B) In the SNS-stimulation-mimicked condition, progesterone suppressed ICa,L. a, Representative superimposed ICa,L current traces in the control, during intracellular dialysis of cAMP and OA, and after treatment with 100 nM P4 in the continued presence of cAMP and OA. ICa,L was elicited by depolarization from a holding potential of -40 mV to 0 mV at 0.1 Hz. b, Concentration-response curve for ICa,L suppression by progesterone. IC50 was 29.9 nM.
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Figure 3: A) In the basal condition, progesterone (P4) enhances IKs. a, Representative superimposed IKs current traces in the control and after treatment with 100 nM P4. IKs was elicited by depolarization to +50 mV from a holding potential of -40 mV at 0.1 Hz. b, Concentration-response curve for IKs enhancement by progesterone. EC50 was 2.6 nM.B) In the SNS-stimulation-mimicked condition, progesterone suppressed ICa,L. a, Representative superimposed ICa,L current traces in the control, during intracellular dialysis of cAMP and OA, and after treatment with 100 nM P4 in the continued presence of cAMP and OA. ICa,L was elicited by depolarization from a holding potential of -40 mV to 0 mV at 0.1 Hz. b, Concentration-response curve for ICa,L suppression by progesterone. IC50 was 29.9 nM.

Mentions: Despite distinct biophysical mechanism for IKs and ICa,L regulation, the principal mediator for both IKs enhancement in the basal condition and ICa,L suppression in the SNS-stimulated condition appears to be nitric oxide (NO), since both were abolished by nitric oxide (NO) trappers and eNOS inhibitors [31, 32]. However, the mechanism by which NO modulates IKs and ICa,L appears to be different. ICa,L suppression by progesterone was abolished by an inhibitor of soluble guanylyl cyclase (sGC), indicating that ICa,L is regulated by progesterone via a NO/sGC/cGMP axis (Fig. 3) [33]. Antagonistic action of cAMP and cGMP for ICa,L has been demonstrated, which appears to vary among species [34]. In rabbit and frog ventricular myocytes, cGMP antagonizes cAMP effects by promoting cAMP breakdown by activating cGMP-dependent phosphodiesterase (PDE2) [34]. In guinea-pig and rat ventricular myocytes, cAMP-dependent protein kinase (PKA) phosphorylates the α-subunit of ICa,L and enhances ICa,L only in the presence of A-kinase anchoring protein (AKAP) [34]. cGMP-dependent protein kinase (PKG) phosphorylates both the α-subunit and the β-subunit of ICa,L [35]. Phosphorylation of the α-subunit by PKG does not affect ICa,L, likely due to the absence of AKAP, while phosphorylation of the β-subunit antagonizes the effect of the α-subunit phosphorylation by PKA [35]. In addition, the inhibition of PDE3 by cGMP to enhance the cAMP-induced activation and facilitation of ICa,L, and activation of protein phosphatase via cGMP-PKG signaling pathway to suppress the cAMP-mediated facilitation may contribute to the complicated interaction of cAMP and cGMP in the heart.


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) In the basal condition, progesterone (P4) enhances IKs. a, Representative superimposed IKs current traces in the control and after treatment with 100 nM P4. IKs was elicited by depolarization to +50 mV from a holding potential of -40 mV at 0.1 Hz. b, Concentration-response curve for IKs enhancement by progesterone. EC50 was 2.6 nM.B) In the SNS-stimulation-mimicked condition, progesterone suppressed ICa,L. a, Representative superimposed ICa,L current traces in the control, during intracellular dialysis of cAMP and OA, and after treatment with 100 nM P4 in the continued presence of cAMP and OA. ICa,L was elicited by depolarization from a holding potential of -40 mV to 0 mV at 0.1 Hz. b, Concentration-response curve for ICa,L suppression by progesterone. IC50 was 29.9 nM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: A) In the basal condition, progesterone (P4) enhances IKs. a, Representative superimposed IKs current traces in the control and after treatment with 100 nM P4. IKs was elicited by depolarization to +50 mV from a holding potential of -40 mV at 0.1 Hz. b, Concentration-response curve for IKs enhancement by progesterone. EC50 was 2.6 nM.B) In the SNS-stimulation-mimicked condition, progesterone suppressed ICa,L. a, Representative superimposed ICa,L current traces in the control, during intracellular dialysis of cAMP and OA, and after treatment with 100 nM P4 in the continued presence of cAMP and OA. ICa,L was elicited by depolarization from a holding potential of -40 mV to 0 mV at 0.1 Hz. b, Concentration-response curve for ICa,L suppression by progesterone. IC50 was 29.9 nM.
Mentions: Despite distinct biophysical mechanism for IKs and ICa,L regulation, the principal mediator for both IKs enhancement in the basal condition and ICa,L suppression in the SNS-stimulated condition appears to be nitric oxide (NO), since both were abolished by nitric oxide (NO) trappers and eNOS inhibitors [31, 32]. However, the mechanism by which NO modulates IKs and ICa,L appears to be different. ICa,L suppression by progesterone was abolished by an inhibitor of soluble guanylyl cyclase (sGC), indicating that ICa,L is regulated by progesterone via a NO/sGC/cGMP axis (Fig. 3) [33]. Antagonistic action of cAMP and cGMP for ICa,L has been demonstrated, which appears to vary among species [34]. In rabbit and frog ventricular myocytes, cGMP antagonizes cAMP effects by promoting cAMP breakdown by activating cGMP-dependent phosphodiesterase (PDE2) [34]. In guinea-pig and rat ventricular myocytes, cAMP-dependent protein kinase (PKA) phosphorylates the α-subunit of ICa,L and enhances ICa,L only in the presence of A-kinase anchoring protein (AKAP) [34]. cGMP-dependent protein kinase (PKG) phosphorylates both the α-subunit and the β-subunit of ICa,L [35]. Phosphorylation of the α-subunit by PKG does not affect ICa,L, likely due to the absence of AKAP, while phosphorylation of the β-subunit antagonizes the effect of the α-subunit phosphorylation by PKA [35]. In addition, the inhibition of PDE3 by cGMP to enhance the cAMP-induced activation and facilitation of ICa,L, and activation of protein phosphatase via cGMP-PKG signaling pathway to suppress the cAMP-mediated facilitation may contribute to the complicated interaction of cAMP and cGMP in the heart.

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