Construction method and system of mouse ventricular myoelectricity physiological model containing M layers

Abstract

The invention discloses a construction method and system of a mouse ventricular myoelectricity physiological model containing M layers, and belongs to the technical field of ventricular myoelectricity physiological simulation, the method comprises the following steps: collecting experimental data of mouse ventricular muscles, including platform phase current data, cell action potential time history obtained by patch clamp experiments and the like; screening heterogeneous current; adjusting the current coefficient of the heterogeneous current in the basic model according to the platform phase current data to obtain a second model; determining the arrangement sequence of each layer in the myocardial tissue; setting the number of myocardial cells according to the QRS time history of the experimental data, and adjusting the proportion of the number of cells in each layer to obtain a third model; and after electrical coupling, obtaining the mouse ventricular myoelectricity physiological model. Based on experimental data, a second model capable of representing the electrophysiological characteristics of M-layer myocardial cells of a mouse is constructed, action potential is simulated and coupled to a third model for adjusting the number and proportion of cells of a transmural layer, and a mouse electrocardiogram meeting experimental observation can be accurately simulated.

Description

Technical Field

[0001] This invention relates to the field of ventricular myophysiological simulation technology, specifically to a method and system for constructing a mouse ventricular myophysiological model containing the M layer. Background Technology

[0002] The ventricular wall contains four different types of cardiomyocytes: endocardial cells, epicardial cells, M cells, and Purkinje cells. These different types of cardiomyocytes have different functions and electrophysiological characteristics.

[0003] Patch-clamp technique is a common technique for studying the electrophysiological characteristics of mouse cardiomyocytes. In patch-clamp experiments, mouse ventricular myocardial tissue is enzymatically digested, and ventricular myocardial cells are selected under a microscope based on the morphological differences between atrial and ventricular myocardial cells. However, the mouse heart is very small, and the ventricular myocardium is very thin. In practice, it is difficult to directly detect and verify the electrical properties of mouse M-layer cardiomyocytes in patch-clamp experiments. The related experimental procedures are difficult to perform and have poor reproducibility, making it difficult to establish unified conclusions regarding the electrophysiological characteristics of mouse M-layer cardiomyocytes.

[0004] Cardiac electrophysiological modeling can supplement the deficiencies of current electrophysiological experimental techniques. Cardiac modeling and simulation technology, as an essential supplementary means for studying the electrophysiological characteristics of the myocardium, avoids cumbersome and complex experimental operations and has been widely validated in the study of ion channel mechanisms and in guiding the implementation of clinical diagnosis and treatment strategies. At the cellular level, modeling and simulation are used to explore the gating characteristics of ion channels; at the tissue level, electrophysiological models are used to explore the laws of electrical conduction, simulate electrocardiograms, and study the ion mechanisms behind electrophysiological characteristics under physiological and pathological conditions.

[0005] Existing mouse heart tissue models only contain two transmural layers: the inner and outer layers, which cannot accurately simulate mouse electrocardiograms in practical applications. Therefore, a mouse ventricular electrophysiological model including the mouse M layer needs to be constructed based on the two-layer model. Summary of the Invention

[0006] To address the aforementioned technical problems in the existing technology, this invention provides a method and system for constructing a mouse ventricular myocardial electrophysiological model containing an M-layer. This method constructs a mouse ventricular myocardial electrophysiological model containing an M-layer of cardiomyocytes, providing a more reliable and accurate technical guarantee for studying the current heterogeneity of mouse transmural ventricular myocytes.

[0007] This invention discloses a method for constructing a mouse ventricular myocardial electrophysiological model comprising an M-layer, including the following steps: collecting experimental data of mouse ventricular myocardium, the experimental data including plateau current data, cell action potential time series obtained from patch-clamp experiments, etc.; screening for heterogeneous currents based on the characteristics of M-layer cardiomyocytes; adjusting the current coefficient of heterogeneous currents in the basic model based on the plateau current data of the experimental data to obtain a second model, the second model being used to simulate the action potential of M-layer cardiomyocytes; determining the arrangement order of the endocardium, M-layer cardiomyocytes, and epicardium of the myocardial tissue; setting the number of cardiomyocytes and the proportion of cells in each layer based on the QRS time series of the experimental data to obtain a third model; and electrically coupling the second model and the third model to obtain a mouse ventricular myocardial electrophysiological model.

[0008] Preferably, the heterogeneous current includes any one of the following currents or a combination thereof: ultrafast rectified potassium current I Kur Slow-delay rectified potassium current I ks Fast rectified potassium current I kr Inward rectified potassium current I K1 and sodium ion channel current I Na .

[0009] Preferably, the ultrafast rectified potassium current I Kur The current coefficient is 0.5-0.6; the inward rectified potassium current I K1 The current coefficient is 0.7-0.9; the sodium ion channel current I... Na The current coefficient is 1.0-1.4;

[0010] The basic model is the Bondarenko mouse ventricular myocyte model.

[0011] Preferably, the ultrafast rectified potassium current I Kur The current coefficient is 0.55; the inward rectified potassium current I K1 The current coefficient is 0.8; the sodium ion channel current I... Na The current coefficient is 1.2.

[0012] Preferably, the arrangement order from the inside out is: endocardium, M layer of myocardial cells, and epicardium;

[0013] The QRS duration was 9-10 milliseconds, the cell length was set to 0.01 cm, and the number of one-dimensional cardiomyocytes N was set to 32.

[0014] Preferably, the formula for calculating electrical coupling is:

[0015] C m * dV m / dt = -I ion + I stim(1)

[0016] Among them, C m It is a film capacitor, V m It is the membrane potential, I stim It is the stimulation current, I ion It is the membrane current, which includes heterogeneous current.

[0017] Preferred,

[0018] Among them, I tot It is the sum of membrane current and stimulation current. This represents the membrane potential gradient along the one-dimensional ventricular myocardium, from the endocardium to the epicardium.

[0019] Preferably, a one-dimensional electrocardiogram is simulated using a mouse ventricular electrophysiological model.

[0020] The present invention also provides a system for implementing the above-described construction method, comprising an acquisition module, an action potential simulation module, an tissue simulation module, and a coupling module;

[0021] The acquisition module is used to collect experimental data from mouse ventricular myocardium;

[0022] The action potential simulation module is used to screen heterogeneous currents based on the characteristics of M-layer cardiomyocytes; adjust the current coefficient of heterogeneous currents in the basic model to make the plateau phase consistent with experimental data to obtain a second model; and simulate action potentials using the second model.

[0023] The tissue simulation module is used to determine the arrangement order of the endocardium, M layer, and epicardium of the myocardial tissue; the number of cardiomyocytes is set according to the QRS time history, and the cell ratio of the endocardium, M layer cardiomyocytes, and epicardium is adjusted to obtain the third model;

[0024] The coupling module is used to electrically couple the second model and the third model to obtain a mouse ventricular electrophysiological model.

[0025] Preferably, the system further includes an electrocardiogram (ECG) simulation module, which is used to simulate a one-dimensional electrocardiogram using a mouse ventricular electromyography model.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows: Based on experimental data of mouse ventricular myocardium, a second model that can characterize the electrophysiological characteristics of mouse M-layer cardiomyocytes is constructed to simulate the action potential of M-layer cardiomyocytes, and coupled to a third model that adjusts the number and proportion of cells in the transmural layer, which can accurately simulate the mouse electrocardiogram that conforms to experimental observation. Attached Figure Description

[0027] Figure 1 It is an ultra-fast rectified potassium current IKur Simulation diagram of current coefficient adjustment;

[0028] Figure 2 It is the inward rectified potassium current I K1 Simulation diagram of current coefficient adjustment;

[0029] Figure 3 It is the sodium ion channel current I Na Simulation diagram of current coefficient adjustment;

[0030] Figure 4 It is a simulation diagram of the action potentials of the epicardium, M layer, and endocardium;

[0031] Figure 5 It is a simulated electrocardiogram of a mouse ventricular electromyography model and a comparative model;

[0032] Figure 6A This is a simulation diagram of electrical conduction containing the M-layer;

[0033] Figure 6B This is a simulation diagram of electrical conduction without the M layer;

[0034] Figure 7 This is a flowchart of the method for constructing the mouse ventricular myocardial electrophysiological model of the present invention;

[0035] Figure 8 This is the system logic block diagram of the present invention. Detailed Implementation

[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] The present invention will now be described in further detail with reference to the accompanying drawings:

[0038] Overview: Myocardial electrophysiology is a method of examining cardiac conduction, which can be divided into four phases: Phase 0 depolarization, Phase 1 rapid repolarization, Phase 2 plateau, Phase 3 the end of rapid repolarization, and Phase 4 resting potential. Phase 2, also known as the plateau phase, is a slow repolarization phase caused by Ca2+. 2+ and a small amount of Na + Inflow and K + This is due to outflow.

[0039] Due to the small size and thin transmural layer of the mouse heart, patch-clamp electrophysiological experiments are challenging and yield unreliable results. Furthermore, the long plateau phase in mouse M-layer cardiomyocytes has prevented the acquisition of reliable data regarding the ionic mechanisms underlying this characteristic. Constructing a mouse M-layer cardiomyocyte electrophysiological model can circumvent these difficulties in experimental research, providing a powerful tool for studying the current heterogeneity of mouse transmural ventricular myocytes, and thus promoting the study of the electrophysiological characteristics of the mouse heart under physiological and pathological conditions.

[0040] like Figure 7 The specific implementation of the mouse ventricular electrophysiological model containing M-layer cardiomyocytes includes the following steps:

[0041] Step 101: Collect experimental data from mouse ventricular myocardium, including plateau current data and cell action potential duration obtained from patch-clamp experiments.

[0042] Step 102: Screen for heterogeneous currents based on the characteristics of M layer cardiomyocytes.

[0043] The plateau phase of M-layer cardiomyocytes is longer than that of the endocardium and epicardium, therefore the plateau current exhibits heterogeneity. The plateau current mainly consists of the ultrafast rectified potassium current I. Kur Slow-delay rectified potassium current I ks Fast rectified potassium current I kr and inward rectified potassium current I K1 .

[0044] Step 103: Based on the plateau current data from the experiment, adjust the current coefficient of the heterogeneous current in the basic model to obtain the second model, so that the heterogeneous current during the plateau period of the second model matches the experimental data.

[0045] In practice, the Bondarenko mouse ventricular myocyte model was used as the basic model, and the value of the heterogeneous current coefficient was set to be greater than 1 or less than 1.

[0046] More specifically, change I kr and I ks When simulating the current coefficient and action potential, the plateau period is almost unaffected; therefore, the coefficients for both are set to 1. Kur The changes are most noticeable during the plateau phase, and I Kur Decrease, plateau period prolonged, here set I Kur The coefficient is less than 1. Only I is changed. Kur The current coefficient was used to obtain the parameter changes of the action potential, as shown in Table 1 and... Figure 1 As the current coefficient decreases, APD90 gradually increases. Here, APD90 represents the time required to complete 90% repolarization.

[0047] Table 1

[0048] <![CDATA[I Kur Current coefficient 0.9 0.8 0.7 0.6 0.5 APD90 34 38.9 46 50.2 54

[0049] Drawing on the heterogeneity of ventricular currents in canine three-layer ventricular myocardium, in which the inward delayed rectifier potassium current I in the M-layer cells... K1 Minimum, and I K1 Reduce and prolong the repolarization process by setting the current coefficient to less than 1. See Table 2 for the changes in the action potential parameters by only changing the IK1 current coefficient. Figure 2 As the current coefficient decreases, APD90 gradually increases.

[0050] Table 2

[0051] <![CDATA[I K1 Current coefficient 0.8 0.6 0.4 0.2 0 APD90 31.3 32.2 33.1 34.1 34.8

[0052] The density of sodium ion channels in mouse M-layer cells is greater than that in epicardial cells; therefore, the sodium ion channel current (I0.05) in M-layer cells is higher. Na The coefficient is greater than 1. Only change I. Na The changes in the parameters of the current coefficient and the resulting action potential are shown in Table 3 and... Figure 3 As the current coefficient decreases, APD90 gradually decreases.

[0053] Table 3

[0054] <![CDATA[I Na Current coefficient 2 1.8 1.6 1.4 1.2 APD90 39.1 36.4 34.4 32.9 31.6

[0055] The current coefficients and APD90 are not linearly related. In experimental recordings of action potentials in single mouse ventricular myocytes, the APD90 time to complete 90% repolarization ranged from approximately 12 to 54 milliseconds, with the longest APD90 observed in the M layer. To ensure consistency between the simulation results and experimental records, I... Kur I K1 and I Na The current coefficients were set to 0.55, 0.8 and 1.2 respectively, and the APD90 generated by the M layer was 54.6 milliseconds.

[0056] Step 104: Simulate action potential using the second model.

[0057] Figure 4 The simulation of action potentials in the epicardium, M layer, and endocardium is shown. The M layer cells exhibit a significant plateau phase prolongation, consistent with experimental observations.

[0058] Under electrical stimulation, the cell membrane potential changes from positive inside and negative outside to negative inside and positive outside. After the cell receives electrical stimulation, the membrane potential changes, while the membrane potential of adjacent cells remains unchanged. At this time, a potential difference is generated on the surface of the cell membranes of the two cells. The cells are connected by gap junctions, which have an equivalent conductance value. Therefore, the potential difference between the inside and outside of the gap junctions generates a current.

[0059] Step 105: Determine the order of the endocardium, M layer and epicardium of the myocardial tissue: from the inside to the outside, they are: endocardium, M layer and epicardium.

[0060] Step 106: Set the number of cardiomyocytes according to the QRS time history, and adjust the ratio of the number of endocardial, M-layer cardiomyocytes and epicardial cells to obtain the third model.

[0061] The QRS duration, also known as the QRS complex duration, represents the time it takes for electrical stimulation to travel from the endocardium to the epicardium. In specific tests, the QRS duration in mice is approximately 10 milliseconds. It should be noted that the QRS duration varies slightly between different species and testing methods. When the cell length is set to 0.01 cm and the number of one-dimensional cardiomyocytes N is set to 32, the simulated QRS duration is 10 milliseconds.

[0062] Step 107: Electrically couple the second and third models to obtain a mouse ventricular electrophysiological model.

[0063] The second model is used for action potential simulation, and the third model is a ventricular myocardial tissue structure model. Action potentials can be coupled into the third model through electrical coupling. Specifically, a method of differentiation followed by difference is used to calculate the electrical coupling between cells, as shown in the following formula:

[0064] C m * dV m / dt = -I ion + I stim (1)

[0065] Among them, C m It is a film capacitor, V m It is the membrane potential, I stim It is the stimulation current, I ion It is the membrane current, which includes the three currents adjusted in step 103: I Kur I K1 and I Na Formula 1 is a differential calculation of the change in membrane current per unit time.

[0066]

[0067] Among them, I tot It is the sum of membrane current and stimulation current. Equation 2 represents the gradient of membrane potential along the one-dimensional ventricular myocardial direction, and it is a differential calculation of the change in membrane potential per unit time.

[0068] Step 108: Simulate a one-dimensional electrocardiogram using a mouse ventricular electrophysiological model.

[0069] Step 109: Remove the M layer from the mouse ventricular electrophysiological model and set the cell ratio of the endocardium and epicardium to 16:16 as a control model. See Table 4 for a comparison of the main parameters of the two models. Figure 5 It is evident that M-layer cells play a crucial role in electrocardiograms. The T wave indicates the repolarization differences in transmural ventricular myocardium, and the key to these differences lies in the longer plateau phase produced by M-layer cells, which is more consistent with experimental observations.

[0070] Table 4

[0071] QRS(ms) T-wave amplitude (mV) Mouse ventricular electrophysiological model 10 0.053 Contrast Model 13 0.026

[0072] Figure 6A and Figure 6B This illustrates the electrical conduction of one-dimensional transmural ventricular myocardium, reflecting the differences in membrane potential among different cell layers during repolarization at the same time point T. Figure 6A The repolarization dispersion differs significantly among the epicardium, M layer, and endocardium. Repolarization dispersion refers to the difference in repolarization time duration among cells in different ventricular layers during repolarization; the greater the time duration difference, the greater the repolarization dispersion. Figure 6B In the second epicardium, the position of layer M is replaced by epicardial cells, and the repolarization dispersion of each layer is small.

[0073] Based on experimental data of mouse ventricular myocardium, this invention constructs a second model that can characterize the electrophysiological characteristics of mouse M-layer cardiomyocytes to simulate action potentials. This model is then coupled into one-dimensional transmural ventricular myocardium tissue. By adjusting the number and proportion of cells in the transmural layer, the electrocardiogram of mice that matches experimental observations can be accurately simulated.

[0074] This specification also provides a system for implementing the above methods, such as... Figure 8 It includes a data acquisition module 1, an action potential simulation module 2, a tissue simulation module 3, and a coupling module 4;

[0075] The acquisition module 1 is used to acquire experimental data of mouse ventricular myocardium;

[0076] Action potential simulation module 2 is used to screen heterogeneous currents based on the characteristics of M-layer cardiomyocytes; adjust the current coefficient of heterogeneous currents in the basic model to make the plateau phase consistent with the experimental data to obtain the second model; and simulate action potentials using the second model.

[0077] The tissue simulation module 3 is used to determine the arrangement order of the central endocardium, M layer and epicardium of the myocardial tissue; the number of cardiomyocytes is set according to the QRS time history, and the cell ratio of the endocardium, M layer cardiomyocytes and epicardium is adjusted to obtain the third model;

[0078] The coupling module 4 is used to electrically couple the second model and the third model to obtain a mouse ventricular myocardial electrophysiological model.

[0079] The system also includes an electrocardiogram (ECG) simulation module, which is used to simulate a one-dimensional electrocardiogram using a mouse ventricular electromyography model.

[0080] Existing mouse ventricular myocardial electrophysiological models do not include the M-layer cardiomyocytes. This manual adds an M-layer cardiomyocyte model to the open-source intracardiac-extracardiac two-transmural-layer ventricular myocardial electrophysiological model, thereby constructing a three-layer model of intracardiac-M-extracardiac, which improves the mouse ventricular myocardial electrophysiological model and enhances the accuracy of one-dimensional myocardial electrocardiogram simulation in mice.

[0081] In a specific application, a mouse model of acute kidney injury was simulated using a mouse ventricular electrophysiological model: serum potassium was collected from the mouse model. + Ca 2+ Na + The plasma concentration was calculated and input into a mouse ventricular electromyography model, and a simulated one-dimensional electrocardiogram was output. After testing, the simulated one-dimensional electrocardiogram was found to be consistent with the experimental data.

[0082] The above are merely preferred embodiments of the present invention and are not intended to limit the present invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for constructing a mouse ventricular myoelectric electrophysiological model comprising an M layer, characterized in that: The following steps are involved: Collecting experimental data of mouse ventricular muscle, wherein the experimental data includes plateau current data; According to the characteristics of M-layer cardiomyocytes, heterogeneous currents were screened; According to the plateau current data of the experimental data, the current coefficient of the heterogeneous current in the basic model is adjusted to obtain a second model, wherein the second model is used to simulate the action potential; Determine the order of the endocardium, M-layer myocardial cells, and epicardium in myocardial tissue; The number of myocardial cells is set according to the QRS duration of the experimental data, and the ratio of the number of endocardial, M-layer myocardial cells and epicardial cells is adjusted to obtain the third model; The second model and the third model are electrically coupled to obtain a mouse ventricular myoelectric electrophysiological model.

2. The construction method according to claim 1, characterized in that: The heterogeneous current includes any one of the following currents or a combination thereof: ultrafast rectifier potassium current I Kur , slow delayed rectifier potassium current I ks , fast rectifier potassium current I kr , inward rectifier potassium current I K1 and sodium channel current I Na .

3. The construction method according to claim 2, characterized in that: Ultrafast rectifier potassium current I Kur The current coefficient is 0.5-0.6; the inward rectifier potassium current I K1 The current coefficient is: 0.7-0.9; the sodium ion channel current I Na The current coefficient is 1.0-1.4; The basic model is the Bondarenko mouse ventricular myocyte model.

4. The construction method according to claim 3, characterized in that: Ultrafast rectifier potassium current I Kur The current coefficient is 0.55; the inward rectifier potassium current I K1 The current coefficient is: 0.8; the sodium ion channel current I Na The current coefficient is 1.

2.

5. The construction method according to claim 1, characterized in that: The arrangement order from inside to outside is: endocardium, M layer myocardial cells and epicardium; The QRS duration was 9–10 ms, the cell length was set to 0.01 cm, and the number of one-dimensional myocardial cells N was set to 32.

6. The construction method according to claim 1, characterized in that: The calculation formula for electrical coupling is: C m * dV m / dt = -I ion + I stim (1) Among them, C m is the film capacitance, V m is the membrane potential, I stim is the stimulus current, I ion is the membrane current, and the membrane current includes the heterogeneous current.

7. The construction method according to claim 6, characterized in that: Among them, I tot is the sum of the membrane current and the stimulus current, It is the membrane potential gradient along the one-dimensional ventricular muscle, from the endocardium to the epicardium.

8. The construction method according to claim 1, characterized in that: Simulate one-dimensional electrocardiogram using a mouse ventricular myocardial electrophysiological model.

9. A system, characterized in that: Used to implement the construction method according to any one of claims 1 to 8, comprising an acquisition module, an action potential simulation module, a tissue simulation module and a coupling module; The acquisition module is used to collect experimental data of mouse ventricular myocardium; The action potential simulation module is used to screen heterogeneous currents according to the characteristics of the M-layer myocardial cells; adjust the current coefficient of the heterogeneous current in the basic model so that the plateau phase is consistent with the experimental data to obtain the second model; and simulate the action potential through the second model; The tissue simulation module is used to determine the arrangement order of the endocardium, M layer and epicardium of the myocardial tissue; The number of myocardial cells is set according to the QRS duration, and the ratio of the number of endocardial, M-layer myocardial cells and epicardial cells is adjusted to obtain the third model; The coupling module is used to electrically couple the second model and the third model to obtain a mouse ventricular myoelectric electrophysiological model.

10. The system according to claim 9, characterized in that It also includes an ECG simulation module, which is used to simulate a one-dimensional electrocardiogram through a mouse ventricular myoelectric electrophysiological model.

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