A secondgeneration computational modeling of cardiac electrophysiology: response of action potential to ionic concentration changes and metabolic inhibition
 Nour Eddine Alaa†^{1}Email author,
 Hamid Lefraich†^{1} and
 Imane El Malki^{1}
https://doi.org/10.1186/174246821146
© Alaa et al.; licensee BioMed Central Ltd. 2014
Received: 16 July 2014
Accepted: 28 September 2014
Published: 21 October 2014
Abstract
Background
Cardiac arrhythmias are becoming one of the major health care problem in the world, causing numerous serious disease conditions including stroke and sudden cardiac death. Furthermore, cardiac arrhythmias are intimately related to the signaling ability of cardiac cells, and are caused by signaling defects. Consequently, modeling the electrical activity of the heart, and the complex signaling models that subtend dangerous arrhythmias such as tachycardia and fibrillation, necessitates a quantitative model of action potential (AP) propagation. Yet, many electrophysiological models, which accurately reproduce dynamical characteristic of the action potential in cells, have been introduced. However, these models are very complex and are very time consuming computationally. Consequently, a large amount of research is consecrated to design models with less computational complexity.
Results
This paper is presenting a new model for analyzing the propagation of ionic concentrations and electrical potential in space and time. In this model, the transport of ions is governed by NernstPlanck flux equation (NP), and the electrical interaction of the species is described by a new cable equation. These set of equations form a system of coupled partial nonlinear differential equations that is solved numerically. In the first we describe the mathematical model. To realize the numerical simulation of our model, we proceed by a finite element discretization and then we choose an appropriate resolution algorithm.
Conclusions
We give numerical simulations obtained for different input scenarios in the case of suicide substrate reaction which were compared to those obtained in literature. These input scenarios have been chosen so as to provide an intuitive understanding of dynamics of the model. By accessing time and space domains, it is shown that interpreting the electrical potential of cell membrane at steady state is incorrect. This model is general and applies to ions of any charge in space and time domains. The results obtained show a complete agreement with literature findings and also with the physical interpretation of the phenomenon. Furthermore, various numerical experiments are presented to confirm the accuracy, efficiency and stability of the proposed method. In particular, we show that the scheme is secondorder accurate in space.
Keywords
Background
Cardiac disease is the leading cause of deaths worldwide. A proportion of them is caused by rhythm irregularities of the heart, such as atrial fibrillation. In the healthy heart, the cardiac contraction is produced by softly propagating nonlinear electrical waves of excitation. Any disturbance in conduction or coordination of electrical signals can result in abnormal heart rhythms, so called arrhythmias. Bradycardia, tachycardia, heart block, and atrial and ventricular fibrillation are examples of arrhythmias. The stimulation of cardiac cells is instigated by a sudden change in the electrical potential across the cell membrane due to the transmembrane flux of charged ions. The release and propagation of an electrical signal, which is ensured by controlled opening and closing of ions channels, is one of the most important functions of the cell. About fiftytwo years ago, the first continuous mathematical model of cardiac cell designed to reproduce cell membrane action potentials is presented by Hodgkin and Huxley[1]. Ever since, many complex models have been developed for cardiac cells inspired by their approach. Most of these models can be classified in three sets. 1) “First generation” of ionic models which are able to reproduce basic ionic currents such as the BeelerRuter (BR)[2] and LuoRudyI (LRI)[3] models. 2) “Second generation” of models, which in addition to a biophysically detailed description of ion channel, pump and exchanger currents, also contain the intracellular ionic concentrations such as the DiFrancescoNoble[4]. 3) simplified models that only contain the minimum set of phenomenological currents necessary to reproduce mesoescopic features of cell dynamics, e.g., conduction velocity (CV) restitution and action potential (AP) restitution[5, 6]. Generally, simulations based on first and second generation models are computationally demanding, however it is often desirable to designate the minimum key characteristics necessary to characterize a specific phenomenon and then proceed by using simplified models.
The purpose of this paper is to design a new computer model of cardiac action potential, which can be classified in the set of second generation models as in addition to a detailed description of ion channels, it also includes detailed description of intracellular concentrations. However, given the trend of researchers in the field, which aims to offer models with less computational complexity, we made a further simplification in the ions representation, the so called meanfield approximation of ionic solution, in which ions are not considered as microscopic discrete entities but as continuous charge densities. This leads us to a fully continuous model, Nernstplanck equations for the species concentrations and a modified cable equation for the electrical potential. This model has the advantage of besides containing a detailed biophysical description of the cardiac activity is less computationally demanding because of the simplification we made. This model is more general than those in literature of membrane transport as it extends them in three topics: 1) it’s a multidimensional model, 2) it allow accessing both time and space domains for the transport equation and also for the electrical potential equation, 3) it includes different reaction kinetics terms.
Introduction
In this paper we present a numerical simulation of such systems, for a large class of reaction kinetics, however, for the applications we considered a suicide substrate reaction. This article is organized in the following way. The next section is devoted to the modeling of the problem. Then, we did a finite element discretization of the mathematical model. After that we present applications, results and numerical experiments showing the accuracy, efficiency and stability of the proposed method. Finally, conclusions are drawn in the last section.
Governing equations
Modeling the electromigration of ions
Modeling the electrical potential
Variational formulation of the problem
where${C}_{i,0}^{h},{\varphi}_{0}^{h}$ are the projections of C_{i,0},ϕ_{0} on W_{ h }.
Channel blockers in the treatment of cardiac arrhythmias
Channel blockers (CB’s) are a type of drugs which binds to the enzyme inside the pore of a specific type of ion channel and blocks the flux of ions through it. Channel blockers are useful agents in antiarrhythmic drug therapy, especially supraventricular tachyarrhythmias[8–10]. Furthermore, there is many genetic diseases that modify and block cardiac ion channels, causing cardiac channelopathies[11]. Consequently, to model such a channel inhibition, we need to establish the transport system for suicide substrate reaction.
Suicide substrate kinetics
where E, S and P stand for enzyme, substrate, and product, respectively; X and Y, enzymesubstrate intermediates; E_{ i }, inactivated enzyme; and the k’s are positive rate constants.
Numerical scheme
In this section, we present the numerical scheme for solving the problem, we used for the time marching scheme an implicit scheme for the transport equations and an explicit second order RungeKutta[17] scheme for the potential equation.
Time marching scheme
Our method is based on an explicit second order RungeKutta scheme for the potential equation and an implicit scheme for the transport equations. To this end, let us denote by$\left({C}_{1,h}^{n+1},{C}_{2,h}^{n+1},\dots ,{C}_{6,h}^{n+1},{\varphi}_{h}^{n+1}\right)$ and$\left({C}_{1,h}^{n},{C}_{2,h}^{n},\dots ,{C}_{6,h}^{n},{\varphi}_{h}^{n}\right)$ the approximate value at time t=t^{n+1} and t=t^{ n }, respectively and by δ t the time step size. Then by using (7) and the following algorithm, we determine the unknown fields.
Algorithm of resolution
We used the following algorithm to calculate ϕ_{ h } and C_{i,h}.

Initialize for i=1,…,6${C}_{i,h}^{0}={C}_{i,0}^{h}\left(x\right),$${\varphi}_{h}^{0}={\varphi}_{0}^{h}\left(x\right)\phantom{\rule{1em}{0ex}}\phantom{\rule{1em}{0ex}}\phantom{\rule{2em}{0ex}}$

Loop over n
At step n:

Calculate${\varphi}_{h}^{n+1}$ solution of${\int}_{\Omega}{\varphi}_{h}^{n+1}{v}_{h}={\int}_{\Omega}\phantom{\rule{0.3em}{0ex}}\left({\varphi}_{h}^{n}+\frac{{\varphi}_{h}^{{k}_{1}}+{\varphi}_{h}^{{k}_{2}}}{2}\right){v}_{h}.$where:${\int}_{\Omega}{\varphi}_{h}^{{k}_{1}}{v}_{h}=\mathrm{\delta t}\xb7{H}^{{v}_{h}}\left({C}_{1,h}^{n},{C}_{2,h}^{n},\dots ,{C}_{6,h}^{n},{\varphi}_{h}^{n}\right);$and${\int}_{\Omega}{\varphi}_{h}^{{k}_{2}}{v}_{h}=\mathrm{\delta t}\xb7{H}^{{v}_{h}}\left({C}_{1,h}^{n}+{C}_{1,h}^{{k}_{1}},{C}_{2,h}^{n}+{C}_{2,h}^{{k}_{1}},\dots ,{C}_{6,h}^{n}+{C}_{6,h}^{{k}_{1}},{\varphi}_{h}^{n}+{\varphi}_{h}^{{k}_{1}}\right);$where:${\int}_{\Omega}{C}_{i,h}^{{k}_{1}}{w}_{h}=\mathrm{\delta t}\xb7{G}_{i}^{{w}_{h}}\left({C}_{1,h}^{n},{C}_{2,h}^{n},\dots ,{C}_{6,h}^{n},{\varphi}_{h}^{n}\right)\phantom{\rule{1em}{0ex}}\phantom{\rule{1em}{0ex}}\forall i=1,\dots 6.$

Calculate${C}_{1,h}^{n+1},{C}_{2,h}^{n+1},{C}_{3,h}^{n+1},{C}_{4,h}^{n+1},{C}_{5,h}^{n+1},{C}_{6,h}^{n+1}$ solutions of:
initialize
${C}_{i,h}^{n+1,0}={C}_{i,h}^{n}$ for i=1,…,6,
Loop over k untill$\sum _{i=1}^{6}{\u2225{C}_{i,h}^{n+1,k+1}{C}_{i,h}^{n+1,k}\u2225}_{{L}_{2}\left(\Omega \right)}<\mathit{\text{eps}}$$\begin{array}{l}\phantom{\rule{15.0pt}{0ex}}{\int}_{\Omega}\frac{{C}_{1,h}^{n+1,k+1}{C}_{1,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{1}{\int}_{\Omega}\nabla {C}_{1,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{1}{\int}_{\Omega}{C}_{1,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}\\ \phantom{\rule{8em}{0ex}}\phantom{\rule{5em}{0ex}}={\int}_{\Omega}\left({k}_{1}{C}_{2,h}^{n+1,k}{C}_{1,h}^{n+1,k+1}+{k}_{1}{C}_{3,h}^{n+1,k}+{k}_{3}{C}_{4,h}^{n+1,k}\right){w}_{h}\end{array}$$\phantom{\rule{15.0pt}{0ex}}\begin{array}{l}{\int}_{\Omega}\frac{{C}_{2,h}^{n+1,k+1}{C}_{2,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{2}{\int}_{\Omega}\nabla {C}_{2,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{2}{\int}_{\Omega}{C}_{2,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}\\ \phantom{\rule{8em}{0ex}}\phantom{\rule{5em}{0ex}}={\int}_{\Omega}\left({k}_{1}{C}_{2,h}^{n+1,k+1}{C}_{1,h}^{n+1,k+1}+{k}_{1}{C}_{3,h}^{n+1,k}\right){w}_{h}\end{array}$$\phantom{\rule{15.0pt}{0ex}}\begin{array}{l}\phantom{\rule{1em}{0ex}}{\int}_{\Omega}\frac{{C}_{3,h}^{n+1,k+1}{C}_{3,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{3}{\int}_{\Omega}\nabla {C}_{3,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{3}{\int}_{\Omega}{C}_{3,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}\\ \phantom{\rule{8em}{0ex}}\phantom{\rule{5em}{0ex}}={\int}_{\Omega}\left({k}_{1}{C}_{2,h}^{n+1,k+1}{C}_{1,h}^{n+1,k+1}\left({k}_{1}+{k}_{2}\right){C}_{3,h}^{n+1,k+1}\right){w}_{h}\end{array}$$\phantom{\rule{15.0pt}{0ex}}\begin{array}{l}{\int}_{\Omega}\frac{{C}_{4,h}^{n+1,k+1}{C}_{4,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{4}{\int}_{\Omega}\nabla {C}_{4,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{4}{\int}_{\Omega}{C}_{4,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}\\ \phantom{\rule{8em}{0ex}}\phantom{\rule{5em}{0ex}}={\int}_{\Omega}\left({k}_{2}{C}_{3,h}^{n+1,k+1}\left({k}_{3}+{k}_{4}\right){C}_{4,h}^{n+1,k+1}\phantom{\rule{1em}{0ex}}\right){w}_{h}\phantom{\rule{1em}{0ex}}\end{array}$$\phantom{\rule{15.0pt}{0ex}}{\int}_{\Omega}\frac{{C}_{5,h}^{n+1,k+1}{C}_{5,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{5}{\int}_{\Omega}\nabla {C}_{5,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{5}{\int}_{\Omega}{C}_{5,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}={\int}_{\Omega}{k}_{4}{C}_{4,h}^{n+1,k+1}{w}_{h}$$\phantom{\rule{15.0pt}{0ex}}{\int}_{\Omega}\frac{{C}_{6,h}^{n+1,k+1}{C}_{6,h}^{n}}{\mathrm{\delta t}}{w}_{h}+{d}_{6}{\int}_{\Omega}\nabla {C}_{6,h}^{n+1,k+1}\nabla {w}_{h}+{m}_{6}{\int}_{\Omega}{C}_{6,h}^{n+1,k+1}\nabla {\varphi}_{h}^{n+1}\nabla {w}_{h}={\int}_{\Omega}{k}_{3}{C}_{4,h}^{n+1,k+1}{w}_{h}$
Results and discussion
In this section, aiming to understand how an action potential emerges from the mathematical structure that we have developed we study the dynamics of the model for different types of input. Pulse input, timedependent input, and sinusoidally varying amplitude input are considered in turn. These input scenarios have been chosen so as to provide an intuitive understanding of dynamics of the model. We present the behavior of the Voltage in response to a short current input, a time dependent input, and a sinusoidal current input. To describe signaling in a cell body, this one can be assumed to be an ellipse. For all the results of this section, we considered the following parameters:
For the computations cell capacitance per unit surface area is taken as C_{ m }=2.0 μ F/c m^{2} and surface to volume ratio is set to S=0.2 μ m^{1}, following Bernus et al.[18]. Taggart et al.[19] found the velocity for conductance along the fiber direction in human myocardium 70 c m/s, which required a cellular resistivity ρ=162Ω c m for Tusscher et al.[20]. This is of the same magnitude of ρ=180Ω c m used by Bernus et al.[18] and the ρ=181Ω c m used by Jongsma and Wilders[21], and it leads to a diffusion coefficient D=1/(ρ S C_{ m }) of 0.00154 c m^{2}/m s. The cell is represented by an ellipse with semimajor axis a = 2 and semiminor axis b = 1. The diffusion coefficients of the ions are d_{1}=10^{3}m^{2}.s^{1}, d_{2}=2.10^{3}m^{2}.s^{1}, d_{3}=5.10^{3}m^{2}.s^{1}, d_{4}=10^{3}m^{2}.s^{1}, d_{5}=2.10^{3}m^{2}.s^{1}, d_{6}=4.10^{6}m^{2}.s^{1}, the reaction parameters are k_{1}=2 s^{1}, k_{1}=4 s^{1}, k_{2}=12 s^{1}, k_{3}=10 s^{1} and k_{4}=2 s^{1}. The charge number of the ions are z_{1}=1, z_{2}=1,z_{3}=1, z_{4}=1, z_{5}=1 and z_{6}=1. The initial concentrations are e_{0}=0.5 μ M and s_{0}=0.5 μ M;ϕ_{ rest }=0 and ϕ_{0}=80 m V. The data employed for the reaction parameters and initial concentrations were taken from Burke et al.[22]. The time step of the simulation is d t=10^{5}s, and T=0.006 s. The stimulus current I_{ stim }, is the key to stimulate the system. In the heart, the excitation is ensured by the SinoAtrial Node. Here we applied a single stimulus, which delivers a short current pulse of 1 m s and strength 200 μ A/c m^{2}, beginning at t=120×10^{5}s at the center of the cell. Let’s mention that the Dirac at (0.0) can be approached by f= exp(1000(x^{2}+y^{2})).
Numerical result 1: electrophysiological validation of the model
To validate the model three criterion are considered 1) excitability 2) All or none 3) action potential morphology.
Excitability
All or none
Action potential morphology
This model has characteristics of cardiac cell as it reproduces the triangular AP morphology (see Figure1) with no sustained plateaus, which is similar to the AP shape obtained with more complex models Nygren et al.[23] and cherry et al.[24]. Furthermore, the figure is similar to the action potential block by saxitoxin in the book[25].
Numerical result 2: response to a time dependent current input
Numerical result 3: visualizing current spread and its impact on the product and substrate concentrations
The convergence test
The rate of convergence of the scheme is difficult to prove analytically. However, numerical experimentation suggests that the scheme is secondorder accurate in space. A quantitative estimate of the convergence error was obtained by performing a number of simulations for the same initial condition on a set of increasingly finer space meshes and time steps. The initial conditions are constants. Let T_{ h } the mesh generation of Ω, and h(T_{ h })=m a x{d i a m(e_{ k })e_{ k }∈T_{ h }}, we take h=0.1,h=0.15 and h=0.2. For each mesh we integrate to time T with$\mathit{\text{dt}}=\frac{\mathit{\text{hT}}}{16}$. Note that as we refine the space step we also refine the time step. The error of the numerical solution was defined as$E\left(h\right)=\mathit{\text{dt}}\times \stackrel{{N}_{s}}{\sum _{i=1}}\stackrel{{N}_{t}}{\sum _{n=0}}\underset{k}{max}{\u2225{C}_{i,h}^{n,k+1}{C}_{i,h}^{n,k}\u2225}_{{L}^{2}\left(\Omega \right)}$.
Error of convergence for different mesh sizes
Mesh size  h1 =0.2  h2 =0.15  h3 =0.1 

Error  19.10^{5}  14.10^{5}  95.10^{6} 
Stability and accuracy tests
Conclusion
In this paper, a new secondgeneration model of the set simulating cardiac action potential is proposed by using a more general mathematical model and a numerical technique based on the finite element method. The electrophysiological validation of the problem shows that the model has all characteristics of cardiac cells: excitability, all or none, and the triangular AP morphology which is similar to those obtained with more complex models Nygren et al.[23] and Cherry et al.[24]. Moreover, after comparison we can observe a complete consistency with literature findings[25]. A variety of numerical experiments were presented to confirm the accuracy, efficiency, and stability of the proposed method.
Notes
Declarations
Acknowledgements
We are grateful to the anonymous referee for the corrections and useful suggestions that have improved this article.
Authors’ Affiliations
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