Method and system for constructing a mouse ventricular myocardial electrophysiological model containing an M layer
By constructing a ventricular myocardial electrophysiological model including the M layer, the difficulty in simulating the electrophysiological characteristics of mouse ventricular M layer cardiomyocytes was solved, accurate simulation of mouse electrocardiograms was achieved, and the reliability and repeatability of the experiment were improved.
Patent Information
- Application Number
- CN202411842200.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-09-30
- Estimated Expiration
- 2044-12-13
AI Technical Summary
Existing technologies make it difficult to accurately simulate the electrophysiological characteristics of mouse ventricular M-layer cardiomyocytes, resulting in difficult experimental operations, poor repeatability, and the inability to establish unified conclusions.
A ventricular myocardial electrophysiological model including the M layer was constructed. By collecting experimental data, screening heterogeneous currents, adjusting current coefficients, determining cell arrangement order, and performing electrical coupling, an electrophysiological model of mouse ventricular myocardium was established.
The reliable and accurate simulation of the electrophysiological characteristics of mouse M-layer cardiomyocytes was achieved, the accuracy of electrocardiogram simulation was improved, and the problems of difficult experimental operation and poor repeatability were solved.
Smart Images
Figure CN119761017B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of ventricular myoelectrical physiology simulation, and in particular to a method and system for constructing a mouse ventricular myoelectrical physiology model comprising an M layer. Background Art
[0002] The ventricular wall contains four different types of cardiomyocytes: endocardial cells, epicardial cells, M cells and Purkinje cells. Different types of cardiomyocytes have different functions and electrophysiological characteristics.
[0003] Patch clamping is a common technique for studying the electrophysiological properties of mouse cardiomyocytes. During patch clamp experiments, mouse ventricular myocardial tissue is enzymatically dissociated, and ventricular myocytes are selected under a microscope based on the different morphologies of atrial and ventricular myocytes. However, the mouse heart is very small and the ventricular myocardium is very thin. Directly detecting and verifying the electrical properties of mouse M-layer cardiomyocytes during patch clamp experiments is difficult. The associated experimental procedures are difficult and reproducible, making it difficult to establish consistent conclusions about the electrophysiological properties of mouse M-layer cardiomyocytes.
[0004] Cardiac electrophysiological modeling can complement the shortcomings of current electrophysiological experimental techniques. As a necessary supplement to studying myocardial electrophysiological properties, cardiac modeling and simulation technology circumvents tedious and complex experimental procedures and has been widely validated in ion channel mechanism research 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 electrical conduction patterns, simulate electrocardiograms, and study the ionic mechanisms underlying electrophysiological properties under physiological and pathological conditions.
[0005] Existing mouse heart tissue models only contain two transmural layers: the endocardium and the epicardium, which cannot accurately simulate mouse electrocardiograms in practical applications. Therefore, it is necessary to construct a mouse ventricular electrophysiological model that includes the mouse M layer based on the two-layer model. Summary of the Invention
[0006] In response to the above-mentioned technical problems existing in the prior art, the present invention provides a method and system for constructing a mouse ventricular myoelectrical physiological model comprising an M layer, thereby constructing a mouse ventricular myoelectrical physiological model comprising M layer cardiomyocytes, providing a more reliable and accurate technical guarantee for studying the heterogeneity of mouse transmural ventricular myocyte currents.
[0007] The present invention discloses a method for constructing a mouse ventricular myocardial electrophysiological model comprising an M layer, comprising the following steps: collecting experimental data of the mouse ventricular myocardium, the experimental data comprising plateau current data, cell action potential duration obtained by a patch clamp experiment, etc.; screening heterogeneous currents according to the characteristics of the M layer myocardial cells; adjusting the current coefficient of the heterogeneous current in a basic model according to the plateau current data of the experimental data to obtain a second model, wherein the second model is used to simulate the action potential of the M layer myocardial cells; determining the arrangement order of the endocardium, the M layer myocardial cells, and the epicardium of the myocardial tissue; setting the number of myocardial cells and the ratio of the number of cells in each layer according to the QRS duration 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 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 .
[0009] Preferably, the 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;
[0010] The basic model is the Bondarenko mouse ventricular myocyte model.
[0011] Preferably, the 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.
[0012] Preferably, the arrangement order from inside to outside is: endocardium, M layer myocardial cells and epicardium;
[0013] 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.
[0014] Preferably, the calculation formula for electrical coupling is:
[0015] C m * dV m / dt = -I ion + I stim(1)
[0016] Among them, C m is the membrane capacitance, V m is the membrane potential, I stim is the stimulation current, I ion is the membrane current, which includes the heterogeneous current.
[0017] Preferably,
[0018] 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 myocardium, from the endocardium to the epicardium.
[0019] Preferably, a one-dimensional electrocardiogram is simulated by a mouse ventricular myocardial electrophysiological model.
[0020] The present invention also provides a system for implementing the above construction method, comprising an acquisition module, an action potential simulation module, a tissue simulation module and a coupling module;
[0021] The acquisition module is used to collect experimental data of mouse ventricular myocardium;
[0022] The action potential simulation module is used to screen heterogeneous currents based on 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 matches the experimental data to obtain a second model; and simulate the action potential 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; set the number of myocardial cells according to the QRS duration, and adjust the cell number ratio of the endocardium, M layer myocardial cells and epicardium to obtain a third model;
[0024] The coupling module is used to electrically couple the second model and the third model to obtain a mouse ventricular myoelectrical physiological model.
[0025] Preferably, the system further comprises an electrocardiogram simulation module, which is used to simulate a one-dimensional electrocardiogram using a mouse ventricular myocardial electrophysiological model.
[0026] Compared with the existing technology, the beneficial effects of the present invention are: based on the experimental data of mouse ventricular muscle, 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 it is 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 is consistent with experimental observations. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 is the ultrafast rectifier potassium current IKur Current coefficient adjustment simulation diagram;
[0028] Figure 2 is the inward rectifier potassium current I K1 Current coefficient adjustment simulation diagram;
[0029] Figure 3 is the sodium channel current I Na Current coefficient adjustment simulation diagram;
[0030] Figure 4 It is a simulation diagram of the action potential of the epicardium, M layer and endocardium;
[0031] Figure 5 It is a simulated electrocardiogram of the mouse ventricular myocardial electrophysiological model and the comparison model;
[0032] Figure 6A This is a simulation diagram of electrical conduction containing the M layer;
[0033] Figure 6B This is the electrical conduction simulation diagram without the M layer;
[0034] Figure 7 This is a flow chart of the method for constructing a mouse ventricular myocardial electrophysiological model of the present invention;
[0035] Figure 8 It is a system logic block diagram of the present invention. DETAILED DESCRIPTION
[0036] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts shall fall within the scope of protection of the present invention.
[0037] The present invention is described in further detail below 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 is the end of rapid repolarization, and phase 4 resting potential. Phase 2 is also called the plateau phase, which is slow repolarization and is determined by Ca 2+ and a small amount of Na + Inflow and K + 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 low reliability. Specifically, the plateau phase of mouse M-layer cardiomyocytes is long, and experimental studies have failed to yield valid data on the ionic mechanisms underlying this characteristic. Establishing a mouse M-layer cardiomyocyte electrophysiological model could circumvent these challenges in experimental research, providing a powerful tool for studying current heterogeneity in mouse transmural ventricular myocytes and, consequently, facilitating the study of mouse cardiac electrophysiological properties under physiological and pathological conditions.
[0040] like Figure 7 Specifically, the method for constructing a mouse ventricular myocardial electrophysiological model comprising M-layer cardiomyocytes comprises the following steps:
[0041] Step 101: collecting experimental data of mouse ventricular myocardium, wherein the experimental data includes plateau current data, cell action potential duration obtained from patch clamp experiment, and the like.
[0042] Step 102: Screening heterogeneous currents based on the characteristics of the M-layer cardiomyocytes.
[0043] The plateau phase of M-layer myocardial cells is longer than that of the endocardium and epicardium, so the plateau current is heterogeneous. The plateau current mainly consists of ultrafast rectifier potassium current I Kur , slow delayed rectifier potassium current I ks , fast rectifier potassium current I kr and inward rectifier potassium current I K1 .
[0044] Step 103: 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, so that the heterogeneous current in the plateau period of the second model is consistent with the experimental data.
[0045] In a specific implementation, the Bondarenko mouse ventricular myocyte model is used as a basic model, and the value of the heterogeneous current coefficient is set to be greater than 1 or less than 1.
[0046] More specifically, change I kr and I ks When simulating the current coefficient of the action potential, the plateau period has almost no effect, so the coefficients of both are set to 1. Kur The change in the plateau phase is most obvious, and I Kur Decrease, the plateau period is extended, here set I Kur The coefficient is less than 1. Only change I Kur The current coefficient of the action potential is shown in Table 1 and Figure 1 As the current coefficient decreases, APD90 gradually increases. 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 current heterogeneity of the three layers of canine ventricular myocardium, the inward delayed rectifier potassium current I K1 Minimum, and I K1 To reduce the repolarization process, set the current coefficient to less than 1. Only the IK1 current coefficient is changed. The change of action potential parameters can be seen in Table 2 and 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, so the sodium ion channel current (I Na ) coefficient is greater than 1. Only change I Na Current coefficient, the change of action potential parameters is 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 relationship between each current coefficient and APD90 is not linear. In the experimental recording of the action potential of a single mouse ventricular myocyte, the APD90 time to complete 90% repolarization ranges from about 12 to 54 milliseconds, and the APD90 of the M layer is the longest. In order to make the simulation results consistent with the experimental records, I Kur , I K1 and I Na The current coefficients are set to 0.55, 0.8 and 1.2 respectively, and the APD90 generated by the M layer is 54.6 milliseconds.
[0056] Step 104: Simulate action potentials 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 show a significant plateau prolongation, which is 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 the adjacent cell 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 equivalent conductance values. Therefore, the potential difference between the inside and outside sides generates current through the gap junctions.
[0059] Step 105: Determine the arrangement order of the endocardium, M layer, and epicardium of the myocardial tissue: from inside to outside, the order is: endocardium, M layer, and epicardium.
[0060] Step 106: The number of myocardial cells is set according to the QRS duration, and the ratio of the number of myocardial cells in the endocardium, M layer, and epicardium is adjusted to obtain a third model.
[0061] The QRS duration, also known as the QRS complex duration, represents the time it takes for an electrical stimulus to propagate from the endocardium to the epicardium. In specific tests, the QRS duration in mice was approximately 10 milliseconds. It should be noted that QRS duration varies slightly between species and testing methods. When the cell length was set to 0.01 cm and the number of one-dimensional cardiomyocytes, N, was set to 32, the simulated QRS duration was 10 milliseconds.
[0062] Step 107: electrically coupling the second model and the third model to obtain a mouse ventricular myocardial electrophysiological model.
[0063] The second model is used to simulate the action potential, and the third model is a ventricular muscle tissue structure model. The action potential can be coupled to the third model through electrical coupling. Specifically, the method of first differentiation and then difference is used to calculate the electrical coupling between cells. The formula is as follows:
[0064] C m * dV m / dt = -I ion + I stim (1)
[0065] Among them, C m is the membrane capacitance, V m is the membrane potential, I stim is the stimulation current, I ion is the membrane current, which contains three currents adjusted in 103 steps: I Kur , I K1 and I Na Formula 1 is a differential operation of the change in membrane current per unit time.
[0066]
[0067] Among them, I tot is the sum of the membrane current and the stimulus current, is the gradient of the membrane potential along the one-dimensional ventricular muscle direction, and Formula 2 is the difference operation of the change of membrane potential per unit time.
[0068] Step 108: Simulate a one-dimensional electrocardiogram using the mouse ventricular myocardial electrophysiological model.
[0069] Step 109: Remove the M layer in the mouse ventricular electrophysiological model and set the cell number of the endocardium and epicardium to 16:16 as a comparison model. The main parameters of the two models are compared in Table 4 and Figure 5 It can be seen that M-layer cells play a key role in the electrocardiogram. The T wave indicates the repolarization difference of the transmural ventricular myocardium. The key to this difference is that M-layer cells produce a longer plateau period, which is more consistent with experimental observations.
[0070] Table 4
[0071] QRS (ms) T wave amplitude (mv) Mouse ventricular myocardial electrophysiological model 10 0.053 Comparison Model 13 0.026
[0072] Figure 6A and Figure 6B The figure shows the electrical conduction of the ventricular myocardium in one dimension, which reflects the difference in membrane potential of each layer of cells during repolarization at the same time T. Figure 6A The repolarization dispersion (RDD) of the epicardium, M layer, and endocardium differed significantly. RDD refers to the differences in the repolarization time course of cells in each ventricular layer during repolarization; the greater the difference in time course, the greater the RDD. Figure 6B In the second epicardium, the M layer is replaced by epicardial cells, and the repolarization dispersion of each layer is small.
[0073] Based on experimental data from mouse ventricular myocardium, the present invention constructs a second model that can characterize the electrophysiological characteristics of mouse M-layer cardiomyocytes, which is used to simulate action potentials and couple them to one-dimensional transmural ventricular muscle tissue. By adjusting the number and proportion of cells in the transmural layer, the mouse electrocardiogram is accurately simulated to be consistent with experimental observations.
[0074] This specification also provides a system for implementing the above method, such as Figure 8 , including an 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 collect experimental data of mouse ventricular myocardium;
[0076] The action potential simulation module 2 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 a second model; and simulate the action potential using the second model;
[0077] The tissue simulation module 3 is used to determine the arrangement order of the endocardium, M layer and epicardium of the myocardial tissue; set the number of myocardial cells according to the QRS duration, adjust the cell number ratio of the endocardium, M layer myocardial cells and epicardium, and obtain a 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 further comprises an electrocardiogram (ECG) simulation module, which is used to simulate a one-dimensional electrocardiogram (ECG) using a mouse ventricular myocardial electrophysiological model.
[0080] Existing electrophysiological models of mouse ventricular myocardium do not include M-layer cardiomyocytes. This manual adds an M-layer cardiomyocyte model to the open-source endocardial-epicardial two-layer transmural ventricular myocardium electrophysiological model, thereby constructing an endocardial-M-layer-epicardial three-layer model, improving the mouse ventricular myocardial electrophysiological model and enhancing the accuracy of one-dimensional mouse myocardial tissue electrocardiogram simulation.
[0081] In a specific application, a mouse model of acute kidney injury was simulated using a mouse ventricular myocardial electrophysiological model: serum K + , Ca 2+ 、Na + The plasma concentration was input into the mouse ventricular myoelectric electrophysiological model and a simulated one-dimensional electrocardiogram was output. After testing, the simulated one-dimensional electrocardiogram was 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. Those skilled in the art will readily appreciate that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention shall be included within the scope of protection of the present invention.
Claims
1. A method for constructing a mouse ventricular myocardial electrophysiological model comprising an M layer, characterized in that: The following steps are involved: collecting experimental data of mouse ventricular myocardium, wherein the experimental data includes plateau current data; Based on 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 arrangement of the endocardium, M-layer myocardial cells, and epicardium in myocardial tissue; The number of myocardial cells was set according to the QRS duration of the experimental data, and the cell number ratios of the endocardium, M layer myocardial cells, and epicardium were adjusted to obtain the third model; The second model and the third model are electrically coupled to obtain a mouse ventricular myocardial electrophysiological model; The heterogeneous current includes any one of the following currents or their combination: 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 ; 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.
2. The construction method according to claim 1, 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.
3. 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.
4. 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 membrane capacitance, V m is the membrane potential, I stim is the stimulation current, I ion is the membrane current, which includes the heterogeneous current.
5. The construction method according to claim 4, 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 myocardium, from the endocardium to the epicardium.
6. The construction method according to claim 1, characterized in that Simulate one-dimensional electrocardiogram using a mouse ventricular myocardial electrophysiological model.
7. A system, characterized in that: Used to implement the construction method according to any one of claims 1 to 6, 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 based on 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 matches the experimental data to obtain a second model; and simulate the action potential using 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 was set according to the QRS duration, and the ratio of the number of endocardial, M-layer myocardial cells and epicardial cells was 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 myoelectrical physiological model.
8. The system according to claim 7, characterized in that It also includes an electrocardiogram simulation module, which is used to simulate a one-dimensional electrocardiogram through a mouse ventricular myoelectric electrophysiological model.