Results simulated with the final version of the CRLP model were in all cases compared with all available experimental evidence and with the latest human ventricular cell models published in the literature. 7 1.3 Different waveforms for each of the specialized cells found in the heart 8 1.4 Electrode positions in the standard 12-lead ECG.
Motivation
In particular, cardiac in silico modeling and simulation could improve our understanding of the function of the heart, the generation of various pathologies and their associated manifestations. This would enable the simulation of the electrical activity of the heart from the cell to the body surface and reconstruct in silico the most commonly used bioelectrical signal in the clinics, the electrocardiogram (ECG).
Electrical and Mechanical Activity of the Heart
- Excitability of cardiac cells
- Electromechanical coupling
- Propagation of the electrical signal throughout the heart
- The electrocardiogram
- Acute myocardial ischemia
An EKG is a tool commonly used to assess the electrical and muscular activity of the heart. Supraventricular arrhythmias occur in the upper part of the heart (above the ventricles, including the atria).
Modeling the electrical activity of the heart
- First electrophysiological model of an excitable cell
- Evolution of electrophysiological models for cardiac cells
- Human ventricular electrophysiological models: recent devel-
- The Grandi-Pasqualini-Bers model
- Acute ischemia models
Thus, the ionic conductance of each channel was defined as the product between the maximum conductance of the channel (a constant value) and the fraction of particles in the open state. Using the previous equation, the steady-state values for the fraction of particles in the open state and the constant time needed to reach steady-state can be obtained:
Objectives and Outline of the Thesis
Aim of the thesis
An AP model capable of reproducing cardiac electrophysiological behavior during acute myocardial ischemia will be of utmost importance to investigate the vulnerability to ventricular arrhythmias and to elucidate the underlying mechanisms.
Specific objectives
For this reason, one of the objectives of this thesis is the development of techniques that allow the selection of the ionic conductivity values of the heart by simultaneously considering all of them and calculating the cross effects. One of the objectives of this thesis is to compare electrophysiological properties measured in isolated cells and tissues and to propose methods to account for estimated differences during the development and validation of a computational cardiac model.
Outline of the thesis
Based on the results obtained in Chapter 4, in silico simulations of the experimental protocols were used to adapt the new version of the model, instead of directly comparing experimental and model characterizations. Using that methodology, the main limitations of the GPB model were unraveled and imperfections in the definitions of specific ionic current characteristics were identified.
Methods
- Selected markers
- Stimulation Protocols
- The CRLP Model
- Conducted Simulations
In this regard, the development of the CRLP model from the GPB model was done considering only human data [60]. The voltage-dependent inactivation gate f of the GPB model was replaced by the product of a fast, f, and a slow, f2, inactivation gate, as in [51].
Results
Results for Control Conditions
For the S1S2 reversal curves (Figure 2.4.d)), the TP06 model was in better agreement with the experimental data of [94, 97] than the GPB model. A significant difference in the shape of the S1S2 return curve was observed for the CRLP model compared to the GPB model (Figure 2.4.d)).
Results for Hyperkalemic Conditions
Regarding APD90 restitution, both the TP06 and CRLP model present steep restitution curves, with a high slope (close to 1) only for a narrow DI interval in the case of the CRLP model and for a much wider DI series in the case of the TP06 model (with slope values above 1). We tested the same hyperkalemic conditions in simulated TP06 and GPB 1D fibers and we could not observe branching of the ERP or APD90 curves after increasing [K+]o to 15 mM.
Discussion and conclusions
- New model characteristics
- Simulation of hyperkalemic conditions
- Data sources
- Model limitations
The resulting APD90 value for the CRLP model was closer to the APD90 value of the TP06 model, without significantly changing the AP triangulation of the GPB model, which was well within the reported physiological range. In addition, stage 1 of the AP shows an atypical behavior for the CRLP model.
Materials and Methods
Optimization problem
Upgrade of the CRLP model
Frequency-dependence behavior
Simulation of changes in potassium concentration
Implementation
Results
Sensitivity Analysis
The results of the sensitivity analysis applied to the epicardial version of the CRLP model are shown in Figure 3.3. The value of the integral of the total potassium current, IKtot, in one cardiac cycle was strongly dependent on the conductance of the background chloride current, GCl,bk, and the L-type calcium current, GCaL (S30 . values of -412.62% and 396, 83%, respectively).
Non-linear optimization
Model Comparison
Blue lines represent the results of this work including [K+]i dynamics, green lines represent the CRLP model, red lines represent the GPB model, cyan lines represent the TP06 model and purple lines represent the ORd model. The graphics on the right are zoomed versions of the graphics on the left. a) Fast delayed rectifier potassium current; b).
Frequency response
Response to changes in extracellular potassium
Time to reach 90% of steady-state membrane potential (t90%). modified CRLP model compared to 14% for the original CRLP model, both of which are values within experimentally defined limits [53]. a) b). In table 3.2, the steady-state value of [K+]i in the optimized CRLP model is shown for each simulated [K+]o value.
Computational Cost
Discussion
- Response surface optimization
- Database generation
- Computational cost
- Definition of the optimization problem
- Model comparison
- Response to potassium concentration changes
In this chapter, the confidence region ratio is used to independently validate the RSA for the objective function and constraints instead of considering the augmented Lagrangian of the problem. In this chapter, the integral of the total potassium current (IKtot) during a cardiac cycle was chosen as the objective function for minimization.
Conclusions
In the Courtemanche-Ramirez-Nattel (CRN) model [47], the ionic conductances GNa, GK1, Gto, GKr and GKs were fitted to obtain an accurate input resistance, AP morphology, AP amplitude (APA) and firing rate in increase (dV /dtmax). In the updated version of the LR model [106], the theoretical APD return curve was compared.
Materials and Methods
- L-type calcium channel gating
- Characterization of L-type calcium voltage-dependent inac-
- Steady-state AP markers
- Ionic contributors to AP markers
- Computational simulations
In the CRLP model, the formulation of voltage-dependent ICaL inactivation is similar to that of the TP06 model. The authors propose to replace the INacurrent formulation of the original ORd model with the formulation proposed in the TP06 model.
Results
Characterization of L-type calcium voltage-dependent inac-
The evolution of the voltage-dependent ICaLgate variables during the pre-impulse potential is shown in figure 4.3.c). However, the difference between the results of the CRLP model and the experiments from [1] was smaller than for the TP06 model (see Figure 4.2.d)).
Ionic contributors to AP markers
For Vmax, when INa was replaced with that defined in the TP06 model (Figure 4.7), the different behavior between cell and tissue simulations was reversed. Similarly, the role of the ICaL current was very similar to that of the GPB model.
Discussion
Effect of submodel variable interactions in the evaluation of
One of the most important differences between the model output (multiplication of the steady-state gate value) and the result of the in silico simulations is that the curves representing the voltage-dependent inactivation were steady-state (Figure 4.2.a)). moved. Nevertheless, the in silico simulation results with this model reproduced the experimental observations slightly better than the TP06 model.
Effect of cell-to-cell interactions in the evaluation of ionic
Conclusions
As a first step, the time constants of the ICaL voltage-dependent inactivation gates were modified to give a more realistic shape of the AP. Due to the implications that a partial modification of an ion model can have on model performance, as noted in Chapter 4, the steady-state value of the voltage-dependent turn-off gates ICaL was adjusted to better reproduce the data available experimental current. from three different studies [1-3] using the algorithm proposed in chapter 3 and the in silico simulation of these experimental protocols described in chapter 4.
Methods
Modification of I CaL voltage-dependent inactivation time con-
Adjustment of I CaL voltage-dependent inactivation steady-state100
A minimization problem was defined in which the value of the parameters fss,∞, f2,ss,∞, qf, qf 2, Vf,1/2, Vf 2,1/2 is sought to best fit experimental steady-state state ICaL voltage dependent inactivation data. Each marker was calculated for varying ICaL conductance ranging from -30% to +30% of the original value in the CRLP model.
Results
Solution to the minimization problem
This MatLab-based software uses the ode15s solver with a maximum step of 0.1 ms to solve the model's ODEs.
New definition of I CaL current
In tissue, the obtained resolution provided values of APD, triangulation, and APD fitting to sudden cycle length changes within the physiological range, although the systolic and diastolic [Ca2+] values were somewhat further away from the physiological range than for the original CRLP model ( see table 5.2). . After the readjustment proposed in this chapter, AP presents a physiological form at the end of phase 1. JesúsCarro.
Discussion
Development and validation of a new ionic current formulation107
A minimization problem is mathematically defined to adapt the formulation of the ICaL stream in the CRLP model. Replication of the experimental data in [1] and [3] with the optimized ICaL model resulted in differences between in silico and experimental results being remarkably smaller than for the initial CRLP model.
Conclusions
When updating the ICaL current expression (chapter 5), the methodologies described in chapter 4 and parameters related to the steady state were used. Specifically, the upper and lower limits of the physiological range of a given electrophysiological property were determined from the maximum and minimum value of that property found in the literature.
Methods
Adjustment of ionic conductances
After reaching steady state after each of the above drug actions, 10 pulses were recorded at a pacing CL of 1000 ms. Table 6.1 summarizes the evaluation of these two markers in the TESZT data set, both at baseline and after each of the described pharmacologic inhibitions of potassium.
Model comparison
The original code of the DENIS application can be found here: https://bitbucket.org/usj_bsicos/denis-myocyte/src/beta_v1. The equations of the model were solved using Fordward-Euler integrator with a time step of 0.002 ms.
Model validation
For the simulations, the model was exported to C++ and included in the application of the DENIS project (http://denis.usj.es). The same evaluation described for the optimized CRLP model was performed for the initial CRLP model to evaluate the effect of the model optimization presented in this chapter.
Results
Model optimization
AP of a single epicardial cell simulated under control conditions with the optimized CRLP model and with other published human ventricular cell models. Nevertheless, other commonly used human ventricular AP models present systolic [Ca2+]i levels similar to those of the optimized CRLP model.
Model validation
The optimized CRLP model, despite being closer to the experimental limits than the initial CRLP model, only provided physiological results for CL increases but not decreases, as with all other models except for the GPB model happened.
Discussion
Model performance
One of the limitations of the original CRLP model was related to the prolongation of APD after inhibition of potassium current. Large differences were found between the simulated results with the initial CRLP model and the experimental range.
Optimization algorithm
Although the optimized CRLP model made the results still outside the experimental limits, the optimization algorithm allowed to reduce the difference between the model and the average experimental value by more than 27%. The difference between simulated and maximum experimental value of the adaptation time was reduced by as much as 40.3% compared to the original CRLP model.
Validation
In the optimization algorithm used in chapter 3 for the incorporation of [K+]idynamics in the original CRLP model, the objective function was only defined by the integral of the total potassium current during a cardiac cycle. In that study, the authors defined the objective function to be zero when the distance between the marker and the mean value is lower than the experimental standard error of the mean and to increase linearly from this region.
Conclusions
Identification of major issues in electrophysiological model
In this thesis, a number of techniques were proposed to minimize the impact of the issues described above and, when possible, to integrate them into the process of developing and validating the model. As it is sometimes not possible to consider all model components at the same time due to computational limitations, in this thesis the focus has been on showing when specific elements must necessarily be considered, when it is possible to simplify the model and when it can be practical to consider only part of the available information.
New techniques for improved model development and validation138
Based on the above, one of the main conclusions of the diploma thesis is the need to take into account as many elements of the model as possible in the process of development and validation. Furthermore, the influence of different ionic currents on electrical wave propagation must be taken into account when defining these stimulation protocols.
Publications in Conference Proceedings
XXXVI Annual International Conference of the IEEE Engineering in Medicine and Biology Society, Chicago (USA), p. Pueyo, A Methodology to Improve Human Ventricular Models for the Investigation of Cardiac Arrhythmias, at the 61st Annual Meeting of the Biophysical Society, New Orleans, USA, 2017.
Other Conferences
Physical Constants
Enviromental Parameters
Fractional Currents
Ion Concentrations
Sodium Transport
Potassium Currents
Chlorine currents
Calcium Transport
SR Calcium Fluxes
Buffering
Model Equations
Nerst Potentials
I Na :Fast Sodium Current
I Na,bk : Background Sodium Current
I NaK : Na-K Pump Current
I Kr : Rapidly Activating Potassium Current
I Ks : Slowly Activating Potassium Current
I Kp : Plateau Potassium Current
I to : Transient Outward Potassium Current
I K1 :Inward Rectifier Potassium Current
I ClCa : Calcium-Activated Chlorine Current
I Cl,bk : Background Chlorine Current
I CaL : L-type Calcium Current
I ncx : Na-Ca Exchanger Current
I pCa : Sarcolemmal Calcium Pump Current
I Ca,bk : Background Calcium Current
SR Fluxes: Calcium Release, SR Calcium Pump, SR Calcium
Ion Homeostasis
Membrane Potential
Enviromental Parameters
Fractional Currents
Sodium Transport
Potassium Currents
Chlorine currents
Calcium Transport
SR Calcium Fluxes
Model Equations
- I to : Transient Outward Potassium Current
- I CaL : L-type Calcium Current
- SR Fluxes: Calcium Release, SR Calcium Pump, SR Calcium
- Ion Homeostasis
- Membrane Potential
Properties of calcium current in isolated human ventricular myocytes from patients with terminal heart failure. Negative displacement of the rs-t segment in the electrocardiogram and its relationships to positive displacement; an experimental study.