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Multiphysics model of a rat ventricular myocyte: a voltage-clamp study.

Krishna A, Valderrábano M, Palade PT, Clark WJ - Theor Biol Med Model (2012)

Bottom Line: We also study the impact of temperature (22 to 38°C) on myofilament contractile response.The critical role of myofilament Ca2 + sensitivity in modulating developed force is likewise studied, as is the indirect coupling of intracellular contractile mechanism with the plasma membrane via the Na + /Ca2 + exchanger (NCX).Thus, the model provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility that have appeared in the literature over the past several decades.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Electrical and Computer Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

ABSTRACT

Background: The objective of this study is to develop a comprehensive model of the electromechanical behavior of the rat ventricular myocyte to investigate the various factors influencing its contractile response.

Methods: Here, we couple a model of Ca2 + dynamics described in our previous work, with a well-known model of contractile mechanics developed by Rice, Wang, Bers and de Tombe to develop a composite multiphysics model of excitation-contraction coupling. This comprehensive cell model is studied under voltage clamp (VC) conditions, since it allows to focus our study on the elaborate Ca2 + signaling system that controls the contractile mechanism.

Results: We examine the role of various factors influencing cellular contractile response. In particular, direct factors such as the amount of activator Ca2 + available to trigger contraction and the type of mechanical load applied (resulting in isosarcometric, isometric or unloaded contraction) are investigated. We also study the impact of temperature (22 to 38°C) on myofilament contractile response. The critical role of myofilament Ca2 + sensitivity in modulating developed force is likewise studied, as is the indirect coupling of intracellular contractile mechanism with the plasma membrane via the Na + /Ca2 + exchanger (NCX). Finally, we demonstrate a key linear relationship between the rate of contraction and relaxation, which is shown here to be intrinsically coupled over the full range of physiological perturbations.

Conclusions: Extensive testing of the composite model elucidates the importance of various direct and indirect modulatory influences on cellular twitch response with wide agreement with measured data on all accounts. Thus, the model provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility that have appeared in the literature over the past several decades.

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Role of myofilament Ca2 + sensitivity. Dependence of isometric contraction on myofilament Ca2 + sensitivity (MCS). (A) The steady state normalized force versus [Ca2 + ]myo relationship shows a rightward shift with decreasing myofilament Ca2 + sensitivity. (B) Traces for normalized force recorded at steady state with an overlay of the [Ca2 + ]myo transient. The inset shows MCS dependent changes in TD50 (time taken from 50% activation to 50% relaxation). (C) Phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol. (D) Traces for sarcomere length indicating increased shortening with temperature. (E) Degree of sarcomere shortening and peak shortening velocity as a function of MCS. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C driven by standard 50 ms voltage pulses at a repetition frequency of 5 Hz.
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Figure 10: Role of myofilament Ca2 + sensitivity. Dependence of isometric contraction on myofilament Ca2 + sensitivity (MCS). (A) The steady state normalized force versus [Ca2 + ]myo relationship shows a rightward shift with decreasing myofilament Ca2 + sensitivity. (B) Traces for normalized force recorded at steady state with an overlay of the [Ca2 + ]myo transient. The inset shows MCS dependent changes in TD50 (time taken from 50% activation to 50% relaxation). (C) Phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol. (D) Traces for sarcomere length indicating increased shortening with temperature. (E) Degree of sarcomere shortening and peak shortening velocity as a function of MCS. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C driven by standard 50 ms voltage pulses at a repetition frequency of 5 Hz.

Mentions: Temperature is known to have a strong effect on the L-type Ca2 + current (ICa,L), the Ca2 + -transient and the contractile mechanics. One very significant effect of temperature on whole-cell ICa,L is the pronounced increase in its rate of decline with an increase in temperature [31,32]. Thus, with an increase from room to body temperature, peak inward trigger current increases but the waveform becomes much narrower. Figure 10A shows model-generated ICa,Lwaveforms at temperatures between 22°C (+) and 38°C (∗) in steps of 4°C, where one can observe the increase in peak current but also the increased rate of decline in the trigger current waveform with an increase in temperature. Specifically, peak ICa,L at 22°C was 8.31 pA/pF compared with 15.05 pA/pF at 38°C, whereas time taken for 50% 50% ICa,L inactivation (RT50,I) decreased from 10.75 ms at 22°C to 2.95 ms 38°C (inset in Figure 10A). These indices are in general agreement with measured voltage clamp data [32,33] obtained from rat ventricular trabeculae.


Multiphysics model of a rat ventricular myocyte: a voltage-clamp study.

Krishna A, Valderrábano M, Palade PT, Clark WJ - Theor Biol Med Model (2012)

Role of myofilament Ca2 + sensitivity. Dependence of isometric contraction on myofilament Ca2 + sensitivity (MCS). (A) The steady state normalized force versus [Ca2 + ]myo relationship shows a rightward shift with decreasing myofilament Ca2 + sensitivity. (B) Traces for normalized force recorded at steady state with an overlay of the [Ca2 + ]myo transient. The inset shows MCS dependent changes in TD50 (time taken from 50% activation to 50% relaxation). (C) Phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol. (D) Traces for sarcomere length indicating increased shortening with temperature. (E) Degree of sarcomere shortening and peak shortening velocity as a function of MCS. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C driven by standard 50 ms voltage pulses at a repetition frequency of 5 Hz.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3585474&req=5

Figure 10: Role of myofilament Ca2 + sensitivity. Dependence of isometric contraction on myofilament Ca2 + sensitivity (MCS). (A) The steady state normalized force versus [Ca2 + ]myo relationship shows a rightward shift with decreasing myofilament Ca2 + sensitivity. (B) Traces for normalized force recorded at steady state with an overlay of the [Ca2 + ]myo transient. The inset shows MCS dependent changes in TD50 (time taken from 50% activation to 50% relaxation). (C) Phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol. (D) Traces for sarcomere length indicating increased shortening with temperature. (E) Degree of sarcomere shortening and peak shortening velocity as a function of MCS. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C driven by standard 50 ms voltage pulses at a repetition frequency of 5 Hz.
Mentions: Temperature is known to have a strong effect on the L-type Ca2 + current (ICa,L), the Ca2 + -transient and the contractile mechanics. One very significant effect of temperature on whole-cell ICa,L is the pronounced increase in its rate of decline with an increase in temperature [31,32]. Thus, with an increase from room to body temperature, peak inward trigger current increases but the waveform becomes much narrower. Figure 10A shows model-generated ICa,Lwaveforms at temperatures between 22°C (+) and 38°C (∗) in steps of 4°C, where one can observe the increase in peak current but also the increased rate of decline in the trigger current waveform with an increase in temperature. Specifically, peak ICa,L at 22°C was 8.31 pA/pF compared with 15.05 pA/pF at 38°C, whereas time taken for 50% 50% ICa,L inactivation (RT50,I) decreased from 10.75 ms at 22°C to 2.95 ms 38°C (inset in Figure 10A). These indices are in general agreement with measured voltage clamp data [32,33] obtained from rat ventricular trabeculae.

Bottom Line: We also study the impact of temperature (22 to 38°C) on myofilament contractile response.The critical role of myofilament Ca2 + sensitivity in modulating developed force is likewise studied, as is the indirect coupling of intracellular contractile mechanism with the plasma membrane via the Na + /Ca2 + exchanger (NCX).Thus, the model provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility that have appeared in the literature over the past several decades.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Electrical and Computer Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.

ABSTRACT

Background: The objective of this study is to develop a comprehensive model of the electromechanical behavior of the rat ventricular myocyte to investigate the various factors influencing its contractile response.

Methods: Here, we couple a model of Ca2 + dynamics described in our previous work, with a well-known model of contractile mechanics developed by Rice, Wang, Bers and de Tombe to develop a composite multiphysics model of excitation-contraction coupling. This comprehensive cell model is studied under voltage clamp (VC) conditions, since it allows to focus our study on the elaborate Ca2 + signaling system that controls the contractile mechanism.

Results: We examine the role of various factors influencing cellular contractile response. In particular, direct factors such as the amount of activator Ca2 + available to trigger contraction and the type of mechanical load applied (resulting in isosarcometric, isometric or unloaded contraction) are investigated. We also study the impact of temperature (22 to 38°C) on myofilament contractile response. The critical role of myofilament Ca2 + sensitivity in modulating developed force is likewise studied, as is the indirect coupling of intracellular contractile mechanism with the plasma membrane via the Na + /Ca2 + exchanger (NCX). Finally, we demonstrate a key linear relationship between the rate of contraction and relaxation, which is shown here to be intrinsically coupled over the full range of physiological perturbations.

Conclusions: Extensive testing of the composite model elucidates the importance of various direct and indirect modulatory influences on cellular twitch response with wide agreement with measured data on all accounts. Thus, the model provides mechanistic insights into whole-cell responses to a wide variety of testing approaches used in studies of cardiac myofilament contractility that have appeared in the literature over the past several decades.

Show MeSH
Related in: MedlinePlus