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A MODIFIED MATHEMATICAL MODEL OF HUMAN VENTRICULAR CARDIOMYOCYTE INCORPORATING SEPARATE T-TUBULAR AND SURFACE DYADS AND SUBMEMBRANE SPACES
Pásek, Michal ; Bébarová, M. ; Christé, G.
Intracellular Ca2+ load and Ca2+ transient are considerably dependent on distribution of sarcolemmal Ca2+ pump and Na+-Ca2+ exchanger between the t-tubular and surface membranes in the presence of separate dyadic and subsarcolemmal spaces in rat ventricular cell model. To explore analogical phenomenon in human, we modified our previously published model of human ventricular myocyte. When the t-tubular fractions of Na+-Ca2+ exchanger and of sarcolemmal Ca2+ pump were increased to the newly proposed value of 0.95 in the modified model, the following changes were observed at 1 Hz steady-state stimulation: a shortening of the action potential duration at 90% repolarisation by 6% and an increase of the cytosolic Ca2+ transient by 22%. Further analysis revealed a critical role of Ca2+ concentration changes in the subsarcolemmal spaces and consequent change in cellular Ca2+ cycling in this effect.
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Sensitivity of action potential to changes of inward rectifier potassium current IK1 is different in recent models of human ventricular cardiomyocytes
Pásek, Michal ; Šimurda, J. ; Christé, G.
The inwardly rectifying potassium current IK1 is one of the principle ionic currents responsible for repolarization phase of mammalian action potentials (APs). To estimate the impact of individual ionic currents on AP configuration, mathematical models have been widely used. In this study, we compared the effects of alcohol-induced changes of IK1 on AP duration (APD) as simulated in four recently published computer models of human ventricular cells. As expected, increasing or decreasing IK1 conductance by 20% respectively caused a shortening or a lengthening of APD. However, the effect was largely model-dependent, ranging from 1% to about 15% change of APD. Given the conflicting available experimental data on the features of IK1 in human ventricular myocytes there is a need for a set of well-established end-point constraints for a reliable human ventricular myocyte model to be generated.
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Physiological consequences of ion concentration changes in transverse-axial tubular system in a model of human ventricular cardiomyocyte
Ohlidalova, D. ; Pásek, Michal ; Šimurda, J. ; Christé, G.
A mathematical model of human ventricular cell incorporating the transverse axial tubular system (TATS) was designed and used to explore the role of TATS in human ventricular cell electrophysiological activity. The model is based on the latest quantitative description of guinea pig ventricular cell electrophysiology and modified to respect the published data obtained from human cardiac preparations. Computer simulations suggest that significant transient depletions of Ca2+ ions and accumulation of K+ ions may occur in the human TATS. The preliminary analysis of the effects of tubular Ca2+depletions on the activity of the model cell indicates their role in limitation of intracellular Ca2+ overload at higher frequencies of stimulation.
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Quantitative modelling of effect of transverse - axial tubular system on electrical activity of cardiac cells: Development of model II
Pásek, Michal ; Christé, G. ; Šimurda, J.
In this work, we present a new version of cardiac ventricular cell model incorporating the transverse - axial tubular system. The improvements include reformulated description of L-type Ca2+ channel, of Ca2+ induced Ca2+ release from sarcoplasmic reticulum, of intracellular Ca2+ buffering and incorporation of potassium currents Ito, IK(Na) and IK(ATP). In comparison with the previous model (Pásek et al., 2002), the steady state simulations revealed more profound changes of tubular ionic concentration (12.8 % for Ca2+ and 4.7 % for K+ at 1 Hz). The refined model will be used for more exact quantitative exploration of the effect of transverse - axial tubular system on cellular electrical activity and excitation - contraction coupling.
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Quantitative modelling of effect of transverse-axial tubular system on electrical activity of cardiac cells under low [K+]e
Pásek, Michal ; Christé, G. ; Šimurda, J.
In this work, we explored quantitatively the effect of ion concentration changes in the restricted space of transverse-axial tubular system (TAT-system) on ventricular cell arrhythmogenesis under the conditions of low extracellular potassium concentration ([K+]e). The simulations were performed on a model that integrates the quantitative description of electrical activity of surface and tubular membrane with the quantitative description of dynamic changes of intracellular ion concentrations. The results predict that the TAT-system plays a significant protecting role in cellular arrhythmogenesis that arises from the enhancement of potassium concentration gradient between tubular and extracellular spaces at low level of [K+]e.
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Quantitative modelling of effect of transverse-axial tubular system on electrical activity of cardiac cells: development of model
Pásek, Michal ; Christé, G. ; Šimurda, J.
The transverse-axial tubular system (TAT-system) of cardiac muscle is a structure that allows rapid propagation of excitation into the cell interior. As suggested in many recent experimental works, it could have a significant effect on cardiac cell function induced by the accumulation or the depletion of ions in restricted tubular space. In our previous work [27], the basic properties of TAT-system were formulated and preliminary simulations characterizing its effect on cellular electrical activity realised. In this article, we describe the design of a more complex model of ventricular myocyte based mostly on data from guinea pig. The model integrates the description of electrical activity of surface and tubular membranes with the detailed description of mechanisms controlling the intracellular and tubular ion concentrations.
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