CN109173057B - Biological pacemaker model construction method and terminal equipment - Google Patents
Biological pacemaker model construction method and terminal equipment Download PDFInfo
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- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
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- A61N1/37512—Pacemakers
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Abstract
The invention is suitable for the technical field of pacemaker modeling, and provides a method for constructing a biological pacemaker model and terminal equipment. The method comprises the following steps: the method comprises the steps of constructing an inward rectification potassium current ion channel model, constructing a pacing current ion channel model, reconstructing according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes to generate a biological pacemaker model, judging whether the electrophysiological characteristics of the biological pacemaker model are qualified, and judging that the biological pacemaker model is successfully constructed if the electrophysiological characteristics are judged to be qualified. After the scheme is adopted, the application process of the biological pacemaker is accelerated, and the method has important instructive significance for the application of the biological pacemaker to clinic.
Description
Technical Field
The invention belongs to the technical field of pacemaker modeling, and particularly relates to a biological pacemaker model construction method and terminal equipment.
Background
In recent years, cardiovascular diseases have become a primary problem threatening the health of people and have a continuous trend toward high levels. Among them, the only treatment of arrhythmia caused by atrioventricular block and the like is electronic pacemaker, which has been used for many years to save the lives of more than several million patients so that they can live as normal. However, due to the high price of pacemakers, the cost before and after implantation, and economic problems of medical insurance coverage, only a few people can actually receive the treatment of the implanted cardiac pacemakers. The biological pacemaker is a method for treating arrhythmia, which obtains myocardial cells with an autonomous pacing function similar to sinus node cells by gene modification or stem cell induced differentiation, injects a certain amount of automatic pacing cells into a certain region of the heart and enables the heart to perform spontaneous pacing under the condition of sinus node lesion. Research shows that the gene therapy, cell therapy or both can make the heart muscle cells of ventricle, atrium and atrioventricular node produce automatic rhythm and drive the whole heart to beat regularly to form biological pacemaker. The biological pacemaker has the advantages of convenient implantation and no need of open chest operation; can respond to the emotion of the patient, and better meets the physiological requirements and the like.
However, experimental research on biological pacemakers can only be performed on animals, and has many limitations, which greatly slows down the application process of biological pacemakers.
Disclosure of Invention
In view of this, embodiments of the present invention provide a method for constructing a biological pacemaker model and a terminal device, so as to solve the problems that in the prior art, experiments can only be performed on animals, a plurality of limitations exist, and the process of application of a biological pacemaker is greatly slowed down.
The first aspect of the embodiments of the present invention provides a method for constructing a biological pacemaker model, including:
constructing an inward rectification potassium current ion channel model;
constructing a pacing current ion channel model;
reconstructing a biological pacing channel model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other prestored ion channel models on ventricular muscle cell membranes, and generating a biological pacemaker model through reconstruction;
judging whether the electrophysiological characteristics of the biological pacemaker model are qualified or not;
and if the electrophysiological characteristics of the biological pacemaker model are qualified, judging that the construction of the biological pacemaker model is successful.
As a further technical solution, the method further comprises:
Integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model;
acquiring a first calcium current of leakage current of a sarcoplasmic reticulum in the biological pacemaker simulation model flowing into cytoplasm and a second calcium current of subspace calcium pump current flowing into cytoplasm according to a prestored simulation technology;
judging whether the concentration of calcium ions in a cell in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current;
and if the concentration of the calcium ions in the cells in the biological pacemaker simulation model reaches a preset steady state after a preset time, judging that the biological pacemaker model successfully paces.
As a further technical solution, the method further comprises:
according to the expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of the inward rectifying potassium current ion channel, Ko is the concentration of ventricular extracellular potassium ions, K1∞Is a time-independent inward rectification coefficient, VmIs the transmembrane voltage of ventricular cells, and E is the inverse potential of potassium channels.
As a further technical solution, the method further comprises:
According to the expression If＝If,Na+If,K；If,Na＝Gf,Na*y(Vm-ENa)；If,K＝Gf,K*y(Vm-EK) Constructing the pacing current ion channel model, wherein IfFor pacing current, If,NaIs shown as IfCurrent to Na-permeable ion channel current, If,KIs shown as IfCurrent to K-permeable ion channel current, Gf,NaIs If,NaMaximum value of conductance, Gf,KIs If,KMaximum value of conductance of, ENaIs the equilibrium potential of sodium ions, EKIs the equilibrium potential of potassium ions, VmIs the ventricular cell transmembrane voltage and y is the activation variable for the pacing current.
As a further technical solution, the determining whether the electrophysiological property of the biological pacemaker model is qualified includes:
according to the expression
Determining the electrophysiological properties of the paced cells in the biological pacemaker simulation model, wherein V is membrane potential, t is time, dV is the integral of transmembrane voltage V of the ventricular cells, dt is the integral of time t, CmCapacitance per unit area of cell membrane, IionIs the sum of all transmembrane currents;
Iion＝INa+Ito+IKr+IKs+ICaL+INaCa
Iionthe expression is as follows: + INaK+IpCa+IpK+IbCa+IbNa+IXWherein, INaFor rapid sodium current, ItoFor instantaneous outward current, IKrFor rapidly delaying the rectified current, IKsFor slow delay of the rectified current, ICaLIs a type L calcium current, INaCaIs sodium calcium exchange current, INaKIs a sodium potassium pump current, IpCaIs a calcium pump current, IpKIs a potassium pump current, IbCaAs background calcium current, I bNaFor background sodium current, IXThe current is targeted for the purpose of pacing,
IXthe expression is as follows:
wherein α, β are modifications IK1And IfA parameter of the current;
adjusting the values of alpha and beta in the model to judge whether spontaneous pacing behaviors are induced in ventricular myocytes;
and if the spontaneous pacing behavior is judged to be induced, the electrophysiological characteristics of the biological pacemaker model are qualified.
A second aspect of an embodiment of the present invention provides a biological pacemaker model constructing apparatus, including:
the potassium current ion channel model building module is used for building an inward rectification potassium current ion channel model;
the pacing current ion channel model building module is used for building a pacing current ion channel model;
the biological pacemaker model generating module is used for reconstructing and generating a biological pacemaker model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes;
the electrophysiological characteristic judgment module is used for judging whether the electrophysiological characteristics of the biological pacemaker model are qualified or not;
and the electrophysiological characteristic determination qualified module is used for determining that the biological pacemaker model is successfully constructed if the electrophysiological characteristics of the biological pacemaker model are qualified.
As a further technical solution, the apparatus further comprises:
the biological pacemaker simulation model generation module is used for integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model;
the calcium current acquisition module is used for acquiring a first calcium current of the leakage current of the sarcoplasmic reticulum in the simulation model of the biological pacemaker, which flows into cytoplasm, and a second calcium current of the subspace calcium pump, which flows into cytoplasm, according to a prestored simulation technology;
the calcium ion concentration judgment module is used for judging whether the calcium ion concentration in the cell in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current;
and the model pacing success identification module is used for judging that the pacing of the biological pacemaker model is successful when the concentration of calcium ions in cells in the biological pacemaker simulation model reaches a preset steady state after a preset time.
As a further technical solution, the apparatus further includes:
a pacing current ion channel model construction submodule for constructing a model according to an expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, G K1Conductance of the inwardly rectifying potassium current ion channel, KoIs the extracellular potassium ion concentration of the ventricle, K1∞Is a time-independent inward rectification coefficient, VmIs the voltage across the ventricular cell membrane, and E is the inverse potential of the potassium channel.
A third aspect of embodiments of the present invention provides a biological pacemaker model constructing terminal apparatus comprising a memory, a processor and a computer program stored in the memory and executable on the processor, the processor implementing the method according to the first aspect when executing the computer program.
A fourth aspect of embodiments of the present invention provides a computer-readable storage medium having stored thereon a computer program which, when executed by a processor, performs the method according to the first aspect.
Compared with the prior art, the embodiment of the invention has the following beneficial effects: after the scheme is adopted, the successfully constructed inward rectification potassium current ion channel model, the pacing current ion channel model and other ion channel models on ventricular muscle cell membranes are reconstructed to form a biological pacing channel model, the biological pacing channel model is integrated into the ventricular unicellular model to form a biological pacemaker model, whether the formed biological pacemaker model is successfully constructed or not is judged according to the electrophysiological characteristics, if the model is successfully constructed, the change of the action potential of the ventricular myocyte can be directly and quantitatively reflected after the biological pacemaker treatment, explaining the reason that the biological pacemaker therapy can cause ventricular myocytes to generate automatic rhythms from the level of cell membrane ion current, and the influence of various ion channels on the pacing capacity of ventricular myocytes is researched, the application process of the biological pacemaker is accelerated, and the biological pacemaker has important instructive significance for the application of the biological pacemaker in clinic.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments or the prior art descriptions will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without inventive exercise.
FIG. 1 is a flow chart of steps of a method for constructing a model of a biological pacemaker according to an embodiment of the present invention;
FIG. 2 is a flow chart illustrating steps of a method for constructing a model of a biological pacemaker according to another embodiment of the present invention;
FIG. 3 is a schematic structural diagram of a biological pacemaker model constructing apparatus according to another embodiment of the present invention;
FIG. 4 is a schematic diagram of a biological pacemaker model building terminal device according to an embodiment of the present invention;
FIG. 5 shows ventricular myocyte remodeling G according to embodiments of the present inventionK1A schematic of pacing cycle times in the case;
FIG. 6 shows ventricular myocyte remodeling G according to embodiments of the present inventionK1A schematic diagram of the pacing cycle process in case;
FIG. 7 shows ventricular myocyte remodeling G provided by embodiments of the present invention fA schematic of pacing cycle times in the case;
FIG. 8 shows ventricular myocyte remodeling G provided by embodiments of the present inventionfIn the case of a pacing cycle action potential interval.
Detailed Description
In the following description, for purposes of explanation and not limitation, specific details are set forth, such as particular system structures, techniques, etc. in order to provide a thorough understanding of the embodiments of the invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced in other embodiments that depart from these specific details. In other instances, detailed descriptions of well-known systems, devices, circuits, and methods are omitted so as not to obscure the description of the present invention with unnecessary detail.
In order to explain the technical means of the present invention, the following description will be given by way of specific examples.
As shown in fig. 1, a flowchart of steps of a method for constructing a biological pacemaker model according to an embodiment of the present invention includes:
and S101, constructing an inward rectification potassium current ion channel model.
In particular, an inward rectifier potassium current (I) in the sinoatrial node cellK1) Has the property of weak expression, and IK1The current is the key current for promoting cell repolarization, which means that in the sinoatrial node cell, the repolarization current is small, so that the diastolic potential of the cell is at a positive value, corresponding to the myocardial cell I K1The ion channel associated gene subtypes include Kir2.1, Kir2.2 and Kir2.3, and experimental studies show that knocking out the gene expression of any one or several Kir2.x in ventricular myocytes can reduce IK1 current in excitatory cells to different degrees, thereby causing automatic depolarization of cell action potential. The scheme is based on the fact that the electric conductance value (G) of the inward rectification potassium current ion channel modelK1) Making modifications, preferably, consider GK1Initial value is G of the original ventricle modelK1(5.405nS/pF), adjusted in the 0 to 1 fold range, mimicking the effect of weakly expressing IK1 in ventricular cells.
And step S102, constructing a pacing current ion channel model.
In particular, hyperpolarized activation current pacing currents (I) with high expression in sinoatrial node cellsf)，IfThe current is the natural pacing current which is the decisive current for causing the resting potential of the cell to generate automatic depolarization, however, in the ventricular cell, the expression gene of the ion channel is absent or low expressed, and the gene subtypes influencing the expression of the If current of the sinoatrial node cell comprise HCN1, HCN2 and HCN4The cell expresses If current so as to induce the automatic pacing behavior of ventricular myocytes, the scheme models the dynamic process of the channel based on the fact that HCN genome is overexpressed to generate If current, and modifies the conductance value (G) of a preset If current ion channel model f) Preferably, G is considered to befInitial value is G of the sinoatrial node modelf(0.027nS/pF), adjusted in the range of 0 to 8 fold, mimicking the effect of expressing and overexpressing If current in ventricular cells.
And S103, reconstructing according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes to generate a biological pacemaker model.
Specifically, there are several ion channels on ventricular myocyte membrane with different ion flow and function, and in order to induce the automatic pacing of ventricular myocyte, G in ventricular myocyte modelK1And GfTwo important parameters were adjusted to simulate the weak expression I shown in biological experimentsK1Current, over-expression of IfCurrent-induced ventricular myocyte autoregulation behavior. In particular, the invention utilizes a computer model to set GK1In the ratio of alpha, GfIs beta, and G is quantified by adjusting the values of alpha and betaK1And GfThe effect of ratio (c) on pacing stability and robustness.
And step S104, judging whether the electrophysiological characteristics of the biological pacemaker model are qualified.
Specifically, the reconstructed biological pacemaker model is integrated into a ventricular single cell model, preferably, the ventricular single cell model used in the scheme is a calculation model which is constructed by Ten Tusscher and used for describing the physiological activity of human ventricular cells, and whether the electrophysiological characteristics of the constructed biological pacemaker model are qualified or not is evaluated by analyzing inherent indications of cell action potentials in the integrated ventricular single cell model, such as pacing cycle time and action potential time course.
And S105, if the electrophysiological characteristics of the biological pacemaker model are qualified, judging that the biological pacemaker model is successfully constructed.
Specifically, the electrophysiological characteristics include an action potential, a pacing cycle time, an action potential time interval, an action potential diastolic interval, an action potential amplitude, and the like to quantitatively evaluate the electrophysiological characteristics of the constructed biological pacemaker model. Preferably, the multiple measurements of the applicant show that the pacing cycle time of the human ventricular cell is 800-1000ms, the action potential time interval is 300-400ms, the action potential diastolic interval is 500-600ms, the electrophysiological characteristics of the biological pacemaker model are qualified when the action potential amplitude is between-80 mV and 40mV, and the electrophysiological characteristics of the biological pacemaker model are unqualified if one is not qualified. In order to calculate the characteristics of the action potential, the cycle of the action potential is first divided, and it is preferable that the action potential of one cycle is divided with the minimum point of the action potential as a start point and the minimum point of the next action potential as an end point, and that the one cycle is considered to be when the voltage is depolarized to a positive potential. The pacing Cycle Length (CL) is calculated as the difference between the two cycles. The Action Potential Duration (APD) is the difference between the time at which the depolarization rate is highest and the time at which the voltage repolarizes to 90% of the amplitude.
The experimental results show that if only I is consideredK1The effect on pacing is that when α ∈ [0,0.08 ]]When this happens, automatic pacing behavior can be induced in ventricular myocytes.
If only consider IfThe effect on pacing is when [ beta ] [3.4,8 ]]When activated, can induce automated pacing behavior in ventricular myocytes.
Further, as shown in fig. 2, in a specific example, the method further comprises:
step S201, integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model.
Step S202, a first calcium current of the sarcoplasmic reticulum leakage current flowing into cytoplasm and a second calcium current of the subspace calcium pump current flowing into cytoplasm in the biological pacemaker simulation model are obtained according to a prestored simulation technology.
Step S203, judging whether the concentration of the calcium ions in the cell in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current.
And S204, if the concentration of the calcium ions in the cells in the biological pacemaker simulation model reaches a preset steady state after a preset time, judging that the biological pacemaker model is successful in pacing.
Specifically, pacing stability is assessed by analyzing whether the action potential and intracellular calcium transients exhibit stable periodic changes, at I fUnder the action of the voltage regulator, the ventricular myocyte calcium transient has a resting phenomenon in the initial stage of pacing, but gradually becomes stable in the later stage of pacing, and the good pacing capability is displayed, wherein a first calcium current flowing into cytoplasm through a sarcoplasmic reticulum leakage current and a second calcium current flowing into cytoplasm through a subspace calcium pump current are calcium currents flowing into the cytoplasm, the calcium currents increase together to cause the accumulation of the intracellular calcium concentration, and the intracellular calcium ion concentration reaches a preset steady state after a preset time, so that the success of pacing of a biological pacemaker pacing model is demonstrated, and the stability is realized. Preferably, the steady state is preset such that intracellular calcium ions are accumulated and then discharged within a cycle, and finally the total amount of intracellular calcium ions is kept in equilibrium at the beginning and end of each cycle.
Further, in one particular example, the method further comprises:
according to the expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of the inward rectifying potassium current ion channel, Ko is the concentration of ventricular extracellular potassium ions, K1∞Is a time-independent inward rectification coefficient, VmIs transmembrane voltage of ventricular cell, E is reversal potential of potassium channel, and G is regulated K1To adjust the inward rectifying potassium current ion channel model.
Further, in one particular example, the method further comprises:
according to the expression If＝If,Na+If,K；If,Na＝Gf,Na*y(Vm-ENa)；If,K＝Gf,K*y(Vm-EK) Constructing the pacing current ion channel model, wherein IfFor pacing current, If,NaIs shown as IfCurrent to Na-permeable ion channel current, If,KIs IfCurrent to K-permeable ion channel current, Gf,NaIs If,NaMaximum value of conductance, Gf,KIs If,KMaximum value of conductance, Gf,NaAnd Gf,KAre the same and are collectively referred to as Gf，ENaIs the equilibrium potential of sodium ions, EKIs the equilibrium potential of potassium ions, VmIs the transmembrane voltage of ventricular cells, and y is the activation variable of pacing current, so that the model is fitted with the voltage and current data of the ion channel measured by the biological pacemaker experiment, and different current intensities are simulated by changing the conductance of the pacing current ion channel.
Further, in one particular example, the method of determining whether the electrophysiological properties of the biological pacemaker model qualify comprises:
according to the expression
Determining the electrophysiological properties of the paced cells in the biological pacemaker simulation model, wherein V is membrane potential, t is time, dV is the integral of transmembrane voltage V of the ventricular cells, dt is the integral of time t, CmCapacitance per unit area of cell membrane, I ionIs the sum of all transmembrane currents;
Iion＝INa+Ito+IKr+IKs+ICaL+INaCa
Iionthe expression is as follows: + INaK+IpCa+IpK+IbCa+IbNa+IXWherein, INaFor rapid sodium current, ItoFor instantaneous outward current, IKrFor rapidly delaying the rectified current, IKsFor slow delay of the rectified current, ICaLIs a type L calcium current, INaCaIs sodium calcium exchange current, INaKIs a sodium potassium pump current, IpCaIs a calcium pump current, IpKIs a potassium pump current, IbCaAs background calcium current, IbNaFor background sodium current, IXThe current is targeted for pacing purposes,
IXthe expression is as follows:
wherein α, β are modifications IK1And IfA parameter of the current;
adjusting the values of alpha and beta in the model to judge whether spontaneous pacing behaviors are induced in ventricular myocytes;
and if the spontaneous pacing behavior is judged to be induced, the electrophysiological characteristics of the biological pacemaker model are qualified. Specifically, as shown in FIGS. 5, 6, 7 and 8, the ventricular myocytes are in the reconstructed GK1Pacing cycle time and action potential time course and ventricular myocyte remodeling in cases GfIn the case of a pacing cycle time and an action potential time interval, the units of the pacing cycle time and the action potential time interval are milliseconds (ms), GK1And GfThe concentration unit of (1) is nanoSecond/picoFarad (nS/pF), and the biological pacemaker model is based on a human ventricular myocyte model by weakening or blocking I K1Expression of electric current, increase of IfExpression of pacing Current, in the human ventricular cell model, GK15.405 nS/pF; in the sinoatrial node cell model, GfAnd is 0.027 nS/pF. To study the different GK1And GfEffect of value on the pacing ability of a biological pacemaker, setting GK1Has a ratio alpha of [0,1]，GfHas a ratio beta of [0,8 ]]In the scheme, the biological pacemaker model is constructed in three ways, namely IK1Induced biological pacemaker model, Only IfInduced biological pacemaker model, andK1and IfA co-induced biological pacemaker model simulates spontaneous pacing behavior induced in ventricular myocytes by a biological experiment by adjusting the values and ratios of alpha and beta in the model if only I is consideredK1The effect on pacing is determined when alpha is equal to 0,0.08]When the temperature of the water is higher than the set temperature,automatic pacing behavior can be induced in ventricular myocytes. If only consider IfThe effect on pacing is determined when beta e [3.4,8 ]]When activated, can induce automated pacing behavior in ventricular myocytes. In IK1And IfUnder the combined action, when alpha is equal to 0,0.2]，β∈[0,3]When activated, can induce automated pacing behavior in ventricular myocytes.
As shown in fig. 3, a schematic structural diagram of a biological pacemaker model constructing apparatus according to an embodiment of the present invention includes:
A potassium current ion channel model building module 301, configured to build an inward rectification potassium current ion channel model.
A pacing current ion channel model building module 302, configured to build a pacing current ion channel model.
And the biological pacemaker model generating module 303 is configured to reconstruct and generate a biological pacemaker model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and a pre-stored other ion channel model on a ventricular muscle cell membrane.
An electrophysiological characteristic determination module 304, configured to determine whether the electrophysiological characteristic of the biological pacemaker model is qualified.
An electrophysiological characteristic determination eligibility module 305, configured to determine that the biological pacemaker model is successfully constructed if the electrophysiological characteristic of the biological pacemaker model is eligible.
Further, in one particular example, the apparatus further comprises:
and the biological pacemaker simulation model generation module is used for integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model.
And the calcium current acquisition module is used for acquiring a first calcium current of the sarcoplasmic reticulum leakage current flowing into cytoplasm and a second calcium current of the subspace calcium pump current flowing into cytoplasm in the biological pacemaker simulation model according to a prestored simulation technology.
And the calcium ion concentration judgment module is used for judging whether the calcium ion concentration in the cell in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current.
And the model pacing success identification module is used for judging that the pacing of the biological pacemaker model is successful if the concentration of calcium ions in cells in the biological pacemaker simulation model reaches a preset steady state after preset time.
Further, in one particular example, the apparatus further comprises:
a pacing current ion channel model construction submodule for constructing a model according to an expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of an inward rectifying potassium current ion channel, KoIs the concentration of potassium ions outside the ventricle1∞Is a time-independent inward rectification coefficient, VmIs the transmembrane voltage of ventricular cells, and E is the inverse potential of potassium channels.
Further, in one particular example, the apparatus further comprises:
constructing a submodule of a pacing current ion channel model according to an expression If＝If,Na+If,K；If,Na＝Gf,Na*y(Vm-ENa)；If,K＝Gf,K*y(Vm-EK) Constructing the pacing current ion channel model, wherein IfFor pacing current, I f,NaIs shown as IfCurrent to Na-permeable ion channel current, If,KIs shown as IfIon channel current, G, with current permeable to Kf,NaIs shown as If,NaMaximum conductance value of (1), Gf,KMaximum conductance of If, K, ENaIs the equilibrium potential of sodium ions, EKIs the equilibrium potential of potassium ions, VmIs the ventricular cell transmembrane voltage and y is the activation variable for the pacing current.
In addition, in a specific example, the electrophysiological property determination module is further configured to:
according to the expression
Determining the electrophysiological properties of the paced cells in the biological pacemaker simulation model, wherein V is membrane potential, t is time, dV is the integral of transmembrane voltage V of the ventricular cells, dt is the integral of time t, CmCapacitance per unit area of cell membrane, IionIs the sum of all transmembrane currents.
Iion＝INa+Ito+IKr+IKs+ICaL+INaCa
IionThe expression is as follows: + INaK+IpCa+IpK+IbCa+IbNa+IXWherein, INaFor rapid sodium current, ItoFor instantaneous outward current, IKrFor rapidly delaying the rectified current, IKsFor slow delay of the rectified current, ICaLIs a type L calcium current, INaCaIs sodium calcium exchange current, INaKIs a sodium potassium pump current, IpCaIs a calcium pump current, IpKIs a potassium pump current, IbCaAs background calcium current, IbNaFor background sodium current, IXThe current is targeted for pacing purposes,
IXthe expression is as follows:
wherein α, β are modifications IK1And IfA parameter of the current.
The values of α and β in the model are adjusted to determine whether spontaneous pacing behavior is induced in ventricular myocytes.
And if the spontaneous pacing behavior is judged to be induced, the electrophysiological characteristics of the biological pacemaker model are qualified.
It should be understood that, the sequence numbers of the steps in the foregoing embodiments do not imply an execution sequence, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present invention.
Fig. 4 is a schematic diagram of a biological pacemaker model constructing terminal device according to an embodiment of the present invention, where the biological pacemaker model constructing terminal device 4 of the embodiment includes: a processor 40, a memory 41, and a computer program 42, such as a biological pacemaker model building program, stored in the memory 41 and executable on the processor 40. The processor 40, when executing the computer program 42, implements the steps in the various embodiments of the biological pacemaker model construction method described above, such as steps 101 to 105 shown in fig. 1. Alternatively, the processor 40, when executing the computer program 42, implements the functions of each module/unit in the above-mentioned device embodiments, for example, the functions of the modules 301 to 305 shown in fig. 2.
Illustratively, the computer program 42 may be partitioned into one or more modules/units that are stored in the memory 41 and executed by the processor 40 to implement the present invention. The one or more modules/units may be a series of computer program instruction segments capable of performing specific functions for describing the execution process of the computer program 42 in the biological pacemaker model constructing terminal apparatus 4. For example, the computer program 42 may be divided into a synchronization module, a summary module, an acquisition module, and a return module (a module in a virtual device), and each module has the following specific functions:
and constructing an inward rectification potassium current ion channel model.
And constructing a pacing current ion channel model.
And reconstructing to generate a biological pacemaker model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes.
And judging whether the electrophysiological characteristics of the biological pacemaker model are qualified.
And if the electrophysiological characteristics of the biological pacemaker model are qualified, the biological pacemaker model is successfully constructed.
And integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model.
And acquiring a first calcium current of the leakage current of the sarcoplasmic reticulum flowing into cytoplasm and a second calcium current of the subspace calcium pump current flowing into the cytoplasm in the biological pacemaker simulation model according to a prestored simulation technology. And judging whether the intracellular calcium ion concentration in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current.
And if the concentration of the calcium ions in the cells in the biological pacemaker simulation model reaches a preset steady state after a preset time, judging that the biological pacemaker model paces successfully.
According to the expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of an inward rectifying potassium current ion channel, KoIs the concentration of potassium ions outside the ventricle1∞Is a time-independent inward rectification coefficient, VmIs the transmembrane voltage of ventricular cells, and E is the inverse potential of potassium channels.
According to the expression If＝If,Na+If,K；If,Na＝Gf,Na*y(Vm-ENa)；If,K＝Gf,K*y(Vm-EK) Constructing the pacing current ion channel model, wherein IfFor pacing current, If,NaIs IfCurrent to Na-permeable ion channel current, I f,KIs shown as IfCurrent to K-permeable ion channel current, Gf,NaIs If,NaMaximum value of conductance, Gf,KIs If,KMaximum value of conductance of, ENaIs the equilibrium potential of sodium ions, EKIs the equilibrium potential of potassium ions, VmIs the ventricular cell transmembrane voltage and y is the activation variable for the pacing current.
According to the expression
Determining electrophysiological properties of paced cells in the biological pacemaker simulation model, wherein V is membrane potential and t is timedV is the integral of the transmembrane voltage V of the ventricular cell, dt is the integral of the time t, CmCapacitance per unit area of cell membrane, IionIs the sum of all transmembrane currents.
Iion＝INa+Ito+IKr+IKs+ICaL+INaCa
IionThe expression is as follows: + INaK+IpCa+IpK+IbCa+IbNa+IXWherein, INaFor rapid sodium current, ItoFor instantaneous outward current, IKrFor rapidly delaying the rectified current, IKsFor slow delay of the rectified current, ICaLIs a type L calcium current, INaCaIs sodium calcium exchange current, INaKIs a sodium potassium pump current, IpCaAs a calcium pump current, IpKIs a potassium pump current, IbCaAs background calcium current, IbNaFor background sodium current, IXTargeting the current for pacing.
IXThe expression is as follows:
wherein α, β are modifications IK1And IfA parameter of the current.
The values of α and β in the model are adjusted to determine whether spontaneous pacing behavior is induced in ventricular myocytes.
And if the spontaneous pacing behavior is judged to be induced, the electrophysiological characteristics of the biological pacemaker model are qualified.
The biological pacemaker model building terminal device 4 may be a desktop computer, a notebook, a palm computer, a cloud server and other computing devices. The biological pacemaker model building terminal device may include, but is not limited to, a processor 40 and a memory 41. Those skilled in the art will appreciate that fig. 4 is merely an example of a biological pacemaker model constructing terminal apparatus 4 and does not constitute a limitation of biological pacemaker model constructing terminal apparatus 4, and may include more or fewer components than those shown, or some components may be combined, or different components, e.g., the biological pacemaker model constructing terminal apparatus may further include an input-output device, a network access device, a bus, etc.
The Processor 40 may be a Central Processing Unit (CPU), other general purpose Processor, a Digital Signal Processor (DSP), an Application Specific Integrated Circuit (ASIC), an off-the-shelf Programmable Gate Array (FPGA) or other Programmable logic device, discrete Gate or transistor logic, discrete hardware components, etc. A general purpose processor may be a microprocessor or the processor may be any conventional processor or the like.
The memory 41 may be an internal storage unit of the biological pacemaker model construction terminal apparatus 4, such as a hard disk or a memory of the biological pacemaker model construction terminal apparatus 4. The memory 41 may also be an external storage device of the biological pacemaker model constructing terminal apparatus 4, such as a plug-in hard disk, a Smart Media Card (SMC), a Secure Digital (SD) Card, a Flash memory Card (Flash Card), or the like provided on the biological pacemaker model constructing terminal apparatus 4. Further, the memory 41 may also include both an internal storage unit and an external storage device of the biological pacemaker model constructing terminal apparatus 4. The memory 41 is used to store the computer program and other programs and data required by the biological pacemaker model to construct a terminal device. The memory 41 may also be used to temporarily store data that has been output or is to be output.
It will be apparent to those skilled in the art that, for convenience and brevity of description, only the above-mentioned division of the functional units and modules is illustrated, and in practical applications, the above-mentioned function distribution may be performed by different functional units and modules according to needs, that is, the internal structure of the apparatus is divided into different functional units or modules to perform all or part of the above-mentioned functions. Each functional unit and module in the embodiments may be integrated in one processing unit, or each unit may exist alone physically, or two or more units are integrated in one unit, and the integrated unit may be implemented in a form of hardware, or in a form of software functional unit. In addition, specific names of the functional units and modules are only used for distinguishing one functional unit from another, and are not used for limiting the protection scope of the present application. The specific working processes of the units and modules in the system may refer to the corresponding processes in the foregoing method embodiments, and are not described herein again.
In the above embodiments, the description of each embodiment has its own emphasis, and reference may be made to the related description of other embodiments for parts that are not described or recited in any embodiment.
Those of ordinary skill in the art will appreciate that the various illustrative elements and algorithm steps described in connection with the embodiments disclosed herein may be implemented as electronic hardware, or combinations of computer software and electronic hardware. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the technical solution. Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the present invention.
In the embodiments provided in the present invention, it should be understood that the disclosed apparatus/terminal device and method may be implemented in other ways. For example, the above-described embodiments of the apparatus/terminal device are merely illustrative, and for example, the division of the modules or units is only one logical division, and there may be other divisions when actually implemented, for example, a plurality of units or components may be combined or integrated into another system, or some features may be omitted, or not executed. In addition, the shown or discussed mutual coupling or direct coupling or communication connection may be through some interfaces, indirect coupling or communication connection of devices or units, and may be in an electrical, mechanical or other form.
The units described as separate parts may or may not be physically separate, and parts displayed as units may or may not be physical units, may be located in one place, or may be distributed on a plurality of network units. Some or all of the units can be selected according to actual needs to achieve the purpose of the solution of the embodiment.
In addition, functional units in the embodiments of the present invention may be integrated into one processing unit, or each unit may exist alone physically, or two or more units are integrated into one unit. The integrated unit may be implemented in the form of hardware, or may also be implemented in the form of a software functional unit.
The integrated modules/units, if implemented in the form of software functional units and sold or used as separate products, may be stored in a computer readable storage medium. Based on such understanding, all or part of the flow of the method according to the embodiments of the present invention may also be implemented by a computer program, which may be stored in a computer-readable storage medium, and when the computer program is executed by a processor, the steps of the method embodiments may be implemented. Wherein the computer program comprises computer program code, which may be in the form of source code, object code, an executable file or some intermediate form, etc. The computer-readable medium may include: any entity or device capable of carrying the computer program code, recording medium, usb disk, removable hard disk, magnetic disk, optical disk, computer Memory, Read-Only Memory (ROM), Random Access Memory (RAM), electrical carrier wave signals, telecommunications signals, software distribution medium, and the like. It should be noted that the computer readable medium may contain other components which may be suitably increased or decreased as required by legislation and patent practice in jurisdictions, for example, in some jurisdictions, computer readable media which may not include electrical carrier signals and telecommunications signals in accordance with legislation and patent practice.
The above-mentioned embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; such modifications and substitutions do not substantially depart from the spirit and scope of the embodiments of the present invention, and are intended to be included within the scope of the present invention.
Claims (10)
1. A method for constructing a biological pacemaker model is characterized by comprising the following steps:
constructing an inward rectification potassium current ion channel model;
constructing a pacing current ion channel model;
reconstructing to generate a biological pacemaker model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes;
judging whether the electrophysiological characteristics of the biological pacemaker model are qualified, specifically, integrating the reconstructed biological pacemaker model into the ventricular single cell model, and evaluating whether the electrophysiological characteristics of the constructed biological pacemaker model are qualified by analyzing inherent indications of cell action potentials in the integrated ventricular single cell model;
And if the electrophysiological characteristics of the biological pacemaker model are qualified, determining that the biological pacemaker model is successfully constructed, specifically, when each item of the action potential, the pacing cycle time, the action potential time interval, the action potential diastolic interval and the action potential amplitude of the biological pacemaker model is qualified, the electrophysiological characteristics of the biological pacemaker model are qualified.
2. The method of constructing a biological pacemaker model according to claim 1, further comprising:
integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model;
acquiring a first calcium current of leakage current of a sarcoplasmic reticulum in the biological pacemaker simulation model flowing into cytoplasm and a second calcium current of subspace calcium pump current flowing into cytoplasm according to a prestored simulation technology;
judging whether the intracellular calcium ion concentration in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current;
and if the concentration of the calcium ions in the cells in the biological pacemaker simulation model reaches a preset steady state after a preset time, judging that the biological pacemaker model paces successfully.
3. The method of constructing a biological pacemaker model according to claim 1, further comprising:
according to the expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of an inward rectifying potassium current ion channel, KoIs the concentration of potassium ions outside the ventricle1∞Is a time-independent inward rectification coefficient, VmIs the transmembrane voltage of ventricular cells, and E is the inverse potential of potassium channels.
4. The method of constructing a biological pacemaker model according to claim 3, further comprising:
according to the expression If＝If,Na+If,K；If,Na＝Gf,Na*y(Vm-ENa)；If,K＝Gf,K*y(Vm-EK) Constructing the pacing current ion channel model, wherein IfFor pacing current, If,NaIs IfCurrent to Na-permeable ion channel current, If,KIs IfCurrent to K-permeable ion channel current, Gf,NaIs If,NaMaximum value of conductance, Gf,KIs If,KMaximum value of conductance of, ENaIs the equilibrium potential of sodium ions, EKIs the equilibrium potential of potassium ions, VmIs the ventricular cell transmembrane voltage and y is the activation variable for the pacing current.
5. The method of constructing a biological pacemaker model according to claim 4, wherein said determining whether the electrophysiological properties of the biological pacemaker model are acceptable comprises:
According to the expression
Determining the electrophysiological properties of the paced cells in the biological pacemaker simulation model, wherein V is membrane potential, t is time, dV is the integral of transmembrane voltage V of the ventricular cells, dt is the integral of time t, CmCapacitance per unit area of cell membrane, IionIs the sum of all transmembrane currents;
Iionthe expression is as follows:
wherein, INaFor rapid sodium current, ItoFor instantaneous outward current, IKrFor rapidly delaying the rectified current, IKsFor slow delay of the rectified current, ICaLIs a type L calcium current, INaCaIs sodium calcium exchange current, INaKIs a sodium potassium pump current, IpCaIs a calcium pump current, IpKIs a potassium pump current, IbCaAs background calcium current, IbNaFor background sodium current, IXThe current is targeted for pacing purposes,
IXthe expression is as follows:
wherein α, β are modifications IK1And IfA parameter of the current;
adjusting the values of alpha and beta in the model to judge whether spontaneous pacing behaviors are induced in ventricular myocytes;
and if the spontaneous pacing behavior is judged to be induced, the electrophysiological characteristics of the biological pacemaker model are qualified.
6. A biological pacemaker model constructing apparatus, comprising:
the potassium current ion channel model building module is used for building an inward rectification potassium current ion channel model;
the pacing current ion channel model building module is used for building a pacing current ion channel model;
The biological pacemaker model generating module is used for reconstructing and generating a biological pacemaker model according to the inward rectification potassium current ion channel model, the pacing current ion channel model and other pre-stored ion channel models on ventricular muscle cell membranes;
the electrophysiological characteristic judgment module is used for judging whether the electrophysiological characteristics of the biological pacemaker model are qualified, specifically, integrating the reconstructed biological pacemaker model into the ventricular single cell model, and evaluating whether the electrophysiological characteristics of the constructed biological pacemaker model are qualified by analyzing inherent indications of cell action potentials in the integrated ventricular single cell model;
and the electrophysiological characteristic determination qualified module is used for determining that the biological pacemaker model is successfully constructed if the electrophysiological characteristics of the biological pacemaker model are qualified, and specifically, when each item of the action potential, the pacing cycle time, the action potential time interval, the action potential diastolic interval and the action potential amplitude of the biological pacemaker model is qualified, the electrophysiological characteristics of the biological pacemaker model are qualified.
7. The biological pacemaker model constructing apparatus as recited in claim 6, further comprising:
The biological pacemaker simulation model generation module is used for integrating the biological pacemaker model into a pre-stored ventricular single cell model to form a biological pacemaker simulation model;
the calcium current acquisition module is used for acquiring a first calcium current of a sarcoplasmic reticulum leakage current flowing into cytoplasm and a second calcium current of a subspace calcium pump current flowing into cytoplasm in the biological pacemaker simulation model according to a prestored simulation technology;
the calcium ion concentration judgment module is used for judging whether the calcium ion concentration in the cell in the biological pacemaker simulation model reaches a preset steady state after a preset time according to the first calcium current and the second calcium current;
and the model pacing success identification module is used for judging that the pacing of the biological pacemaker model is successful if the concentration of calcium ions in cells in the biological pacemaker simulation model reaches a preset steady state after preset time.
8. The biological pacemaker model constructing apparatus according to claim 6, further comprising:
a pacing current ion channel model construction submodule for constructing a model according to an expression
Constructing the inward rectification potassium current ion channel model, wherein IK1For inward rectification of potassium current, GK1For conductance of an inward rectifying potassium current ion channel, K oIs the extracellular potassium ion concentration of the ventricle, K1∞Is a time-independent inward rectification coefficient, VmIs the voltage across the ventricular cell membrane, and E is the inverse potential of the potassium channel.
9. A biological pacemaker model constructing terminal device comprising a memory, a processor and a computer program stored in the memory and executable on the processor, wherein the processor implements the steps of the method according to any one of claims 1 to 5 when executing the computer program.
10. A computer-readable storage medium, in which a computer program is stored which, when being executed by a processor, carries out the steps of the method according to any one of claims 1 to 5.
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