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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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Feedback length effects. Feedback of internal shortening on myoplasmic [Ca2 + ]myo transient. The protocol used comprises of 9 beats of isometric contraction followed by a 0.8 s rest interval and beat 10 (shown above) when the cell is allowed to internally shorten (∙) or held at a fixed sarcomere length of 2.2 μm (∗). (A) The sarcomere length in both the cases shows the degree of contraction when the cell is allowed to internally shorten via a series elastic element (KSE = 2). (B) Isosarcometric case shows enhanced force when compared to the isometric case. The inset shows corresponding steady state F-Ca relationships (C) As seen in experimental studies, the isosarcometric case shows a modest decrease in [Ca2 + ]myo transient. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C.
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Figure 7: Feedback length effects. Feedback of internal shortening on myoplasmic [Ca2 + ]myo transient. The protocol used comprises of 9 beats of isometric contraction followed by a 0.8 s rest interval and beat 10 (shown above) when the cell is allowed to internally shorten (∙) or held at a fixed sarcomere length of 2.2 μm (∗). (A) The sarcomere length in both the cases shows the degree of contraction when the cell is allowed to internally shorten via a series elastic element (KSE = 2). (B) Isosarcometric case shows enhanced force when compared to the isometric case. The inset shows corresponding steady state F-Ca relationships (C) As seen in experimental studies, the isosarcometric case shows a modest decrease in [Ca2 + ]myo transient. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C.

Mentions: Figure 7 shows the three types of simulated twitch responses studied, compared in their force vs. time plots, as well as in their normalized force vs. Ca2 + myo phase diagrams. This plotting format aids in drawing a comparison that highlights the unique characteristics of each loading condition. The protocol used here is a steady state 5 Hz stimulation without a rest interval before the test twitch (unlike Figures 3, 5 and 6). Figure 7A shows that the isosarcometric case results in maximum force development, whereas the unloaded case records the minimum force for identical sarcomere length and initial conditions. Figure 7B shows the phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol constructed from model-generated data captured at steady state (the last in a train of stimuli comprising 100 cycles at 5 Hz stimulation) from a twitch caused by a Ca2 + myo transient resulting from a voltage clamp pulse (amplitude -40 mv to 10 mv and a duration of 50 ms). The initial pre-contraction sarcomere length in the isometric case and the sarcomere length clamp in the isosarcometric case are both set to 2.2 μm whereas the equilibrium length in the unloaded case is chosen as 1.9 μm [13].


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

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

Feedback length effects. Feedback of internal shortening on myoplasmic [Ca2 + ]myo transient. The protocol used comprises of 9 beats of isometric contraction followed by a 0.8 s rest interval and beat 10 (shown above) when the cell is allowed to internally shorten (∙) or held at a fixed sarcomere length of 2.2 μm (∗). (A) The sarcomere length in both the cases shows the degree of contraction when the cell is allowed to internally shorten via a series elastic element (KSE = 2). (B) Isosarcometric case shows enhanced force when compared to the isometric case. The inset shows corresponding steady state F-Ca relationships (C) As seen in experimental studies, the isosarcometric case shows a modest decrease in [Ca2 + ]myo transient. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Feedback length effects. Feedback of internal shortening on myoplasmic [Ca2 + ]myo transient. The protocol used comprises of 9 beats of isometric contraction followed by a 0.8 s rest interval and beat 10 (shown above) when the cell is allowed to internally shorten (∙) or held at a fixed sarcomere length of 2.2 μm (∗). (A) The sarcomere length in both the cases shows the degree of contraction when the cell is allowed to internally shorten via a series elastic element (KSE = 2). (B) Isosarcometric case shows enhanced force when compared to the isometric case. The inset shows corresponding steady state F-Ca relationships (C) As seen in experimental studies, the isosarcometric case shows a modest decrease in [Ca2 + ]myo transient. Model generated data corresponds to an idealized rat ventricular myocyte at 22.5°C.
Mentions: Figure 7 shows the three types of simulated twitch responses studied, compared in their force vs. time plots, as well as in their normalized force vs. Ca2 + myo phase diagrams. This plotting format aids in drawing a comparison that highlights the unique characteristics of each loading condition. The protocol used here is a steady state 5 Hz stimulation without a rest interval before the test twitch (unlike Figures 3, 5 and 6). Figure 7A shows that the isosarcometric case results in maximum force development, whereas the unloaded case records the minimum force for identical sarcomere length and initial conditions. Figure 7B shows the phase plots of normalized force versus the instantaneous Ca2 + concentration in the cytosol constructed from model-generated data captured at steady state (the last in a train of stimuli comprising 100 cycles at 5 Hz stimulation) from a twitch caused by a Ca2 + myo transient resulting from a voltage clamp pulse (amplitude -40 mv to 10 mv and a duration of 50 ms). The initial pre-contraction sarcomere length in the isometric case and the sarcomere length clamp in the isosarcometric case are both set to 2.2 μm whereas the equilibrium length in the unloaded case is chosen as 1.9 μm [13].

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