CN109173057A - Biological pacemaker model building method and terminal device - Google Patents
Biological pacemaker model building method and terminal device Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
- A61N1/37512—Pacemakers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
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Abstract
The present invention is suitable for pacemaker modeling technique field, provides a kind of biological pacemaker model building method and terminal device.The described method includes: building inward K~+currents model of ion channel, building pace-making current ion channel pattern, biological pacemaker model is generated according to other model of ion channel reconstruct on inward K~+currents model of ion channel, pacemaker current model of ion channel and the ventricular muscle cell film that prestores, judge whether the electrophysiological characteristics of biological pacemaker model are qualified, if it is determined that electrophysiological characteristics are qualified, then the success of biological pacemaker model construction is determined.After adopting the above scheme, the process that biological pacemaker is applied is accelerated, being applied to clinic to biological pacemaker has important guiding significance.
Description
Technical field
The invention belongs to pacemaker modeling technique field more particularly to a kind of biological pacemaker model building method and terminals
Equipment.
Background technique
In recent years, cardiovascular disease has become the matter of utmost importance for threatening national health, and has the tendency that Continued.Its
In, the sole therapy means of arrhythmia cordis caused by atrioventricular block etc. are electronic pacemakers, and application is being drawn for many years
The life more than millions of patients has been rescued, them is allow to live as normal person.But due to pacemaker fancy price, implantation
The economic problems such as expense, medical insurance covering after preoperative, actually only a few peoples can receive implantable heart pacer treatment.Biology
The appearance of pacemaker related experiment provides new method for treatment arrhythmia cordis, and biological pacemaker is that one kind passes through gene modification
Or stem cell induction differentiation, the cardiac muscle cell with autonomous pacing function for being similar to sinus node cells is obtained, by certain amount
Automatic pacemaker cells be injected into some region of heart, so that heart still is able to spontaneous pace-making in the case where sinoatrial node lesion
Treatment arrhythmia cordis method.Studies have shown that cell therapy or both collective effect can make ventricle by gene therapy,
Atrium, the cardiac muscle cells such as atrioventricular node generate automatic rhythmicity, and entire heart is driven regularly to beat, and then constitute biology pace-making
Device.The biological pacemaker has many advantages, such as that it is convenient to be such as implanted into, and is not necessarily to open chest surgery；Can with the mood mutual response of patient,
It is more in line with psychological need etc..
However, to the experimental study of biological pacemaker, can only be tested at present for animal, there are many limitations,
The process that biological pacemaker is applied is slowed down significantly.
Summary of the invention
In view of this, the embodiment of the invention provides a kind of biological pacemaker model building method and terminal device, with solution
It can only certainly be tested in the prior art for animal, there are many limitations, have slowed down biological pacemaker significantly and have been applied
Process the problem of.
The first aspect of the embodiment of the present invention provides a kind of biological pacemaker model building method, comprising:
Construct inward K~+currents model of ion channel；
Building pace-making current ion channel pattern；
According to the inward K~+currents model of ion channel, the pacemaker current model of ion channel and the heart prestored
Other model of ion channel reconstruct biological pacemaking channels model on the muscle cell membrane of room, and reconstruct is generated biological pacemaker model；
Judge whether the electrophysiological characteristics of the biological pacemaker model are qualified；
If the electrophysiological characteristics of the biological pacemaker model are qualified, determine the biological pacemaker model construction at
Function.
As further technical solution, the method also includes:
The biological pacemaker model integration is formed to biological pacemaker simulation mould into the ventricle single cell model prestored
Type；
Sarcoplasmic reticulum leakage current in the biological pacemaker simulation model, which is obtained, according to the emulation technology prestored flows into cytoplasm
The first interior calcium current and subspace calcium pump electric current flow into intracytoplasmic second calcium current；
Judged according to first calcium current and second calcium current intracellular in the biological pacemaker simulation model
Whether calcium ion concentration reaches default stable state after preset time；
If intracellular calcium concentration reaches default stable state after preset time in the biological pacemaker simulation model,
Determine that the biological pacemaker model paces successfully.
As further technical solution, the method also includes:
According to expression formulaThe inward K~+currents model of ion channel is constructed,
Wherein, IK1For inward K~+currents, GK1For the conductance of inward K~+currents ion channel, Ko is the potassium outside ventricular cells
Ion concentration, K1∞For the inward rectification coefficient of non-temporal dependence, VmFor ventricular cells transmembrane voltage, E is the reversion of potassium channel
Current potential.
As further technical solution, the method also includes:
According to expression formula If=If,Na+If,K；If,Na=Gf,Na*y(Vm-ENa)；If,K=Gf,K*y(Vm-EK) building described
Current ion of fighting channel pattern, wherein IfFor pacemaker current, If,NaFor IfThe electric current ion channel current penetrating to Na, If,KFor
IfThe electric current ion channel current penetrating to K, Gf,NaFor If,NaMaximum conductance value, Gf,KFor If,KMaximum conductance value, ENaFor sodium
The equilibrium potential of ion, EKFor the equilibrium potential of potassium ion, VmFor ventricular cells transmembrane voltage, y is that the activation of pacemaker current becomes
Amount.
As further technical solution, the whether qualified packet of the electrophysiological characteristics for judging the biological pacemaker model
It includes:
According to expression formulaDetermine the electrophysiological characteristics of pacemaker cells in the biological pacemaker simulation model,
Wherein, V is film potential, and t is the time, and dV is the integral to ventricular cells transmembrane voltage V, and dt is the integral to time t, CmIt is thin
The capacitor of after birth per unit area, IionFor all transmembrane current summations；
Iion=INa+Ito+IKr+IKs+ICaL+INaCa
IionExpression formula are as follows:+INaK+IpCa+IpK+IbCa+IbNa+IX, wherein INaFor quick sodium current, ItoIt is instantaneous export-oriented
Electric current, IKrFor ultrarapid delayed rectifier electric current, IKsFor slow delayed rectifier current, ICaLFor L-type calcium current, INaCaFor sodium Calcium exchanger electricity
Stream, INaKFor sodium potassium pump electric current, IpCaFor calcium pump electric current, IpKFor potassium pump electric current, IbCaFor background calcium current, IbNaFor background sodium electricity
Stream, IXElectric current is targeted for pace-making,
IXExpression formula are as follows:Wherein, α, β are modification IK1With IfThe parameter of electric current；
The value of α and β judges whether to induce spontaneous pace-making behavior in ventricular muscle cell in adjustment model；
If it is determined that then the electrophysiological characteristics of the biological pacemaker model are qualified induction of spontaneous pace-making behavior.
The second aspect of the embodiment of the present invention provides a kind of biological pacemaker model construction device, comprising:
Potassium current model of ion channel constructs module, for constructing inward K~+currents model of ion channel；
Pacemaker current model of ion channel constructs module, for constructing pace-making current ion channel pattern；
Biological pacemaker model generation module, for according to the inward K~+currents model of ion channel, described
The reconstruct of other model of ion channel generates biological pacemaker mould on current ion of fighting channel pattern and the ventricular muscle cell film prestored
Type；
Whether electrophysiological characteristics judgment module, the electrophysiological characteristics for judging the biological pacemaker model are qualified；
Electrophysiological characteristics determine qualified module, if the electrophysiological characteristics for the biological pacemaker model are qualified, sentence
The fixed biological pacemaker model construction success.
As further technical solution, described device further include:
Biological pacemaker simulation model generation module, for by the biological pacemaker model integration to the ventricle list prestored
Biological pacemaker simulation model is formed in cell model；
Calcium current obtains module, for obtaining sarcoplasm in the biological pacemaker simulation model according to the emulation technology prestored
Net leakage current flows into intracytoplasmic first calcium current and subspace calcium pump electric current flows into intracytoplasmic second calcium current；
Calcium ion concentration judgment module, for judging the biology according to first calcium current and second calcium current
Whether intracellular calcium concentration reaches default stable state after preset time in pacemaker simulation model；
Model, which paces, successfully assert module, for intracellular calcium concentration in biological pacemaker simulation model when default
Between after reach default stable state, then determine that the biological pacemaker model paces successfully.
As further technical solution, described device further include:
Pacemaker current model of ion channel constructs submodule, for according to expression formula
Construct the inward K~+currents model of ion channel, wherein IK1For inward K~+currents, GK1For inward rectification potassium electricity
It wanders about as a refugee the conductance of subchannel, KoPotassium concentration outside for ventricular cells, K1∞For the inward rectification coefficient of non-temporal dependence, Vm
For ventricular cells transmembrane voltage, E is the reversal potential of potassium channel.
The third aspect of the embodiment of the present invention provides a kind of biological pacemaker model construction terminal device, including storage
Device, processor and storage in the memory and the computer program that can run on the processor, the processor
The method as described in above-mentioned first aspect is realized when executing the computer program.
The fourth aspect of the embodiment of the present invention provides a kind of computer readable storage medium, the computer-readable storage
Media storage has computer program, and the side as described in above-mentioned first aspect is realized when the computer program is executed by processor
Method.
Existing beneficial effect is the embodiment of the present invention compared with prior art: after adopting the above scheme, by that will construct
Other ions on successful inward K~+currents model of ion channel, pacemaker current model of ion channel and ventricular muscle cell film
Channel pattern reconstructs to form biological pacemaking channels model, then by biological pacemaking channels model integration into ventricle single cell model shape
At biological pacemaker model, judge whether the biological pacemaker model to be formed constructs success further according to electrophysiological characteristics, if success,
It then can direct quantitatively react after carrying out biological pacemaker treatment, the action potential situation of change of ventricular muscle cell, from cell
The reason of biological pacemaker therapy can cause ventricular muscle cell to generate automatic rhythmicity is explained in film ionic current level, and is ground
Study carefully influence of the different kinds of ions channel to ventricular muscle cell pacing capabili ties, the process that biological pacemaker is applied is accelerated, to life
Object pacemaker, which is applied to clinic, important guiding significance.
Detailed description of the invention
It to describe the technical solutions in the embodiments of the present invention more clearly, below will be to embodiment or description of the prior art
Needed in attached drawing be briefly described, it should be apparent that, the accompanying drawings in the following description is only of the invention some
Embodiment for those of ordinary skill in the art without any creative labor, can also be according to these
Attached drawing obtains other attached drawings.
Fig. 1 is a kind of step flow chart of biological pacemaker model building method provided in an embodiment of the present invention；
Fig. 2 be another embodiment of the present invention provides a kind of biological pacemaker model building method step flow chart；
Fig. 3 be another embodiment of the present invention provides a kind of biological pacemaker model construction device structural schematic diagram；
Fig. 4 is a kind of schematic diagram of biological pacemaker model construction terminal device provided in an embodiment of the present invention；
Fig. 5 is ventricular muscle cell reconstruct G provided in an embodiment of the present inventionK1In the case of the pacing cycle time schematic diagram；
Fig. 6 is ventricular muscle cell reconstruct G provided in an embodiment of the present inventionK1In the case of pacing cycle process schematic diagram；
Fig. 7 is ventricular muscle cell reconstruct G provided in an embodiment of the present inventionfIn the case of the pacing cycle time schematic diagram；
Fig. 8 is ventricular muscle cell reconstruct G provided in an embodiment of the present inventionfIn the case of pacing cycle Action Potential Duration.
Specific embodiment
In being described below, for illustration and not for limitation, the tool of such as particular system structure, technology etc is proposed
Body details, to understand thoroughly the embodiment of the present invention.However, it will be clear to one skilled in the art that there is no these specific
The present invention also may be implemented in the other embodiments of details.In other situations, it omits to well-known system, device, electricity
The detailed description of road and method, in case unnecessary details interferes description of the invention.
In order to illustrate technical solutions according to the invention, the following is a description of specific embodiments.
As shown in Figure 1, be a kind of step flow chart of biological pacemaker model building method provided in an embodiment of the present invention,
Include:
Step S101 constructs inward K~+currents model of ion channel.
Specifically, inward K~+currents (inward rectifier current, I in sinus node cellsK1) with weak
The characteristic of expression, and IK1Electric current be promote cell repolarization critical current, it is meant that in sinus node cells, repolarization currents compared with
It is small, so that the diastolic potential of cell is in the value of a calibration, with Cardiac myocytesK1The associated gene hypotype of ion channel includes
Kir2.1, Kir2.2 and Kir2.3, experimental study are shown, in ventricular muscle cell, knock out the base of any one or several Kir2.x
Because of expression, IK1 electric current in excitatory cells can be made to generate different degrees of reduction, go to pole automatically so as to cause action potentials of cells
Change.This programme is according to the fact to the electric conductivity value (G of inward K~+currents model of ion channelK1) modify, it is preferred that recognize
For GK1Initial value is the G of former ventricular modelK1(5.405nS/pF) is adjusted in the range of 0 to 1 times, is simulated in ventricular cells
The effect of weak expression IK1.
Step S102, building pace-making current ion channel pattern.
Specifically, having the hyperpolarization-activated current pacemaker current (funny of height expression in sinus node cells
current,If), IfElectric current is nature pacemaker current, it is the decisive electricity for making the resting potential of cell generate spontaneous depolarization
Stream, however in ventricular cells, the expressing gene of the ion channel is not present or low expression, influences sinus node cells If ammeter
The gene hypotype reached includes HCN1, HCN2 and HCN4, and HCN gene is added or over-expressed in experiment display in ventricular muscle cell,
It can make expression in ventricular myocytes of congestive If electric current, to induce the automatic pace-making behavior of ventricular muscle cell, this programme is based on HCN genome
The fact that overexpression generation If electric current, models the dynamic process in the channel, modifies preset If current ion channel
Electric conductivity value (the G of modelf), it is preferred that think GfInitial value is the G of Sinus Node Modelf(0.027nS/pF), in 0 to 8 times of model
Interior adjustment is enclosed, the effect that If electric current is expressed and be overexpressed in ventricular cells is simulated.
Step S103, according to the inward K~+currents model of ion channel, the pacemaker current model of ion channel
Biological pacemaker model is generated with other model of ion channel reconstruct on the ventricular muscle cell film that prestores.
Specifically, there are many types of ion channel, corresponding ion stream and Various Functions on ventricular muscle cell film, in order to lure
The automatic pace-making behavior for leading ventricular muscle cell, to the G in Models of ventricular cellK1And GfTwo important parameters are adjusted, with
Simulate weak expression I shown in BioexperimentK1Electric current is overexpressed IfThe ventricular muscle cell that electric current is led to paces behavior automatically.Especially
, the present invention utilizes computer model, and G is arrangedK1Ratio be α, GfRatio be β, pass through the adjustment to α and β value, quantify GK1
And GfRatio to pace-making stability and robustness influence.
Step S104 judges whether the electrophysiological characteristics of the biological pacemaker model are qualified.
Specifically, by the biological pacemaker model integration of reconstruct into ventricle single cell model, it is preferred that this programme is made
Ventricle single cell model is Ten Tusscher building for describing the computation model of human cardiac ventricle's cellular physiological events,
By after analytical integration in ventricle single cell model action potentials of cells intrinsic indication, such as pacing cycle time, action potential
Whether time-histories is qualified come the electrophysiological characteristics of evaluating constructed biological pacemaker model.
Step S105 determines the biological pacemaker mould if the electrophysiological characteristics of the biological pacemaker model are qualified
Type constructs successfully.
Specifically, electrophysiological characteristics include action potential, pacing cycle time, Action Potential Duration, action potential diastole
Interphase and amplitude of action etc. quantitatively evaluate the electrophysiological characteristics of constructed biological pacemaker model.Preferably, it says
It crosses applicant and repeatedly measures and obtain, the pacing cycle time of human cardiac ventricle's cell is 800-1000ms, and Action Potential Duration is
300-400ms, action potential diastolic interval are 500-600ms, show that biology rises when amplitude of action is between -80-40mV
Fight device model electrophysiological characteristics it is qualified, if there is one not to be inconsistent standardization, show the electrophysiological characteristics of biological pacemaker model not
It is qualified.For the characteristic of calculating action current potential, the period of action potential is divided first, it is preferred that most by action potential
For dot as starting point, the smallest point of next action potential divides the action potential of a cycle as terminal, meanwhile, voltage
It depolarizes to a positive current potential and just thinks that it is a cycle.Pacing cycle time (cycle length, CL) calculation method
For the time difference in two periods.Action Potential Duration (action potential duration, APD) is Depolarization rate
The difference of highest time and 90% time of voltage repolarization to amplitude.
The experimental results showed that if only considering IK1Influence to pace-making can be thin in ventricular muscles when α ∈ [0,0.08]
Automatic pace-making behavior is induced in born of the same parents.
If only considering IfInfluence to pace-making can induce automatic rise when β ∈ [3.4,8] in ventricular muscle cell
It fights behavior.
In addition, as shown in Fig. 2, in a specific example, the method also includes:
The biological pacemaker model integration is formed biology pace-making by step S201 into the ventricle single cell model prestored
Device simulation model.
Step S202 obtains sarcoplasmic reticulum leakage current stream in the biological pacemaker simulation model according to the emulation technology prestored
Enter intracytoplasmic first calcium current and subspace calcium pump electric current flows into intracytoplasmic second calcium current.
Step S203 judges the biological pacemaker simulation model according to first calcium current and second calcium current
Whether middle intracellular calcium concentration reaches default stable state after preset time.
Step S204, if intracellular calcium concentration reaches pre- after preset time in the biological pacemaker simulation model
If stable state, then determine that the biological pacemaker model paces successfully.
Specifically, judging pace-making by the way that whether analysis action potential and intracellular Ca2+ transition are in stable cyclically-varying
Stability, in IfUnder the action of, there are tranquillization phenomenons at pace-making initial stage for ventricular muscle cell calcium transient, but pace-making the later period by
It gradually tends towards stability, shows good pacing capabili ties, wherein sarcoplasmic reticulum leakage current flows into intracytoplasmic first calcium current and son
It is to flow into intracytoplasmic calcium current that space calcium pump electric current, which flows into intracytoplasmic second calcium current, and the increase of the two causes jointly
The accumulation of intracellular calcium concentration, intracellular calcium concentration have reached preset stable state after preset time, illustrate that biology rises
Device of fighting pace-making model paces successfully, and has stability.Preferably, stable state is preset as intracellular calcium in one cycle
First accumulation is then exhausted from, and the final beginning and end for keeping intracellular calcium total amount in each period reaches balance.
In addition, in a specific example, the method also includes:
According to expression formulaThe inward K~+currents model of ion channel is constructed,
Wherein, IK1For inward K~+currents, GK1For the conductance of inward K~+currents ion channel, Ko is the potassium outside ventricular cells
Ion concentration, K1∞For the inward rectification coefficient of non-temporal dependence, VmFor ventricular cells transmembrane voltage, E is the reversion of potassium channel
Current potential, by adjusting GK1Value adjust inward K~+currents model of ion channel.
In addition, in a specific example, the method also includes:
According to expression formula If=If,Na+If,K；If,Na=Gf,Na*y(Vm-ENa)；If,K=Gf,K*y(Vm-EK) building described
Current ion of fighting channel pattern, wherein IfFor pacemaker current, If,NaFor IfThe electric current ion channel current penetrating to Na, If,KFor
IfThe electric current ion channel current penetrating to K, Gf,NaFor If,NaMaximum conductance value, Gf,KFor If,KMaximum conductance value, Gf,NaWith
Gf,KValue it is identical, be referred to as Gf, ENaFor the equilibrium potential of sodium ion, EKFor the equilibrium potential of potassium ion, VmFor ventricular cells across
Membrane voltage, y are the activation variable of pacemaker current, so that model and biological pacemaker test the ion channel voltage and current number measured
According to the different current strength of conductance simulation for being mutually fitted, and passing through change pacemaker current ion channel.
In addition, judging the electrophysiological characteristics of the biological pacemaker model described in the method in a specific example
Whether qualification includes:
According to expression formulaDetermine the electrophysiological characteristics of pacemaker cells in the biological pacemaker simulation model,
Wherein, V is film potential, and t is the time, and dV is the integral to ventricular cells transmembrane voltage V, and dt is the integral to time t, CmIt is thin
The capacitor of after birth per unit area, IionFor all transmembrane current summations；
Iion=INa+Ito+IKr+IKs+ICaL+INaCa
IionExpression formula are as follows:+INaK+IpCa+IpK+IbCa+IbNa+IX, wherein INaFor quick sodium current, ItoIt is instantaneous export-oriented
Electric current, IKrFor ultrarapid delayed rectifier electric current, IKsFor slow delayed rectifier current, ICaLFor L-type calcium current, INaCaFor sodium Calcium exchanger electricity
Stream, INaKFor sodium potassium pump electric current, IpCaFor calcium pump electric current, IpKFor potassium pump electric current, IbCaFor background calcium current, IbNaFor background sodium electricity
Stream, IXElectric current is targeted for pace-making,
IXExpression formula are as follows:Wherein, α, β are modification IK1With IfThe parameter of electric current；
The value of α and β judges whether to induce spontaneous pace-making behavior in ventricular muscle cell in adjustment model；
If it is determined that then the electrophysiological characteristics of the biological pacemaker model are qualified induction of spontaneous pace-making behavior.Specifically,
It is ventricular muscle cell in reconstruct G as shown in Fig. 5, Fig. 6, Fig. 7 and Fig. 8K1In the case of pacing cycle time and Action Potential Duration and
Ventricular muscle cell reconstructs GfIn the case of pacing cycle time and Action Potential Duration, pacing cycle time and Action Potential Duration
Unit is millisecond (millisecond, ms), GK1And GfConcentration unit be nanosecond/pico farad (nanoSecond/
PicoFarad, nS/pF), biological pacemaker model is based on human cardiac ventricle's myocyte model, by weakening or blocking IK1Electric current
Expression, increase IfPacemaker current expresses to realize, in human cardiac ventricle's cell model, GK1For 5.405nS/pF；In sinus
In room nodal cell model, GfFor 0.027nS/pF.In order to study different GK1And GfIt is worth the influence to biological pacemaker pacing capabili ties,
G is setK1Ratio α be [0,1], GfRatio beta be [0,8], this programme constructs biological pacemaker model in a manner of three kinds, point
It Wei not only IK1The biological pacemaker model of induction, only IfThe biological pacemaker model and I of inductionK1And IfCommon induction
Biological pacemaker model simulate Bioexperiment and induced in ventricular muscle cell by adjusting the value and ratio of α in model and β
Spontaneous pace-making behavior, if only considering IK1Influence to pace-making can be lured when α ∈ [0,0.08] in ventricular muscle cell
From dynamic pace-making behavior.If only considering IfInfluence to pace-making can be induced when β ∈ [3.4,8] in ventricular muscle cell
Automatic pace-making behavior.In IK1And IfUnder collective effect, when α ∈ [0,0.2], [0,3] β ∈, it can be lured in ventricular muscle cell
From dynamic pace-making behavior.
As shown in figure 3, be a kind of structural schematic diagram of biological pacemaker model construction device provided in an embodiment of the present invention,
Include:
Potassium current model of ion channel constructs module 301, for constructing inward K~+currents model of ion channel.
Pacemaker current model of ion channel constructs module 302, for constructing pace-making current ion channel pattern.
Biological pacemaker model generation module 303, for according to the inward K~+currents model of ion channel, described
The reconstruct of other model of ion channel generates biological pacemaker in pacemaker current model of ion channel and the ventricular muscle cell film prestored
Model.
Whether electrophysiological characteristics judgment module 304, the electrophysiological characteristics for judging the biological pacemaker model are qualified.
Electrophysiological characteristics determine qualified module 305, if the electrophysiological characteristics for the biological pacemaker model are qualified,
Determine the biological pacemaker model construction success.
In addition, in a specific example, described device further include:
Biological pacemaker simulation model generation module, for by the biological pacemaker model integration to the ventricle list prestored
Biological pacemaker simulation model is formed in cell model.
Calcium current obtains module, for obtaining sarcoplasm in the biological pacemaker simulation model according to the emulation technology prestored
Net leakage current flows into intracytoplasmic first calcium current and subspace calcium pump electric current flows into intracytoplasmic second calcium current.
Calcium ion concentration judgment module, for judging the biology according to first calcium current and second calcium current
Whether intracellular calcium concentration reaches default stable state after preset time in pacemaker simulation model.
Model, which paces, successfully assert module, if existing for intracellular calcium concentration in the biological pacemaker simulation model
Reach default stable state after preset time, then determines that the biological pacemaker model paces successfully.
In addition, in a specific example, described device further include:
Pacemaker current model of ion channel constructs submodule, for according to expression formula
Construct the inward K~+currents model of ion channel, wherein IK1For inward K~+currents, GK1For inward rectification potassium electricity
It wanders about as a refugee the conductance of subchannel, KoPotassium concentration outside for ventricular cells, K1∞For the inward rectification coefficient of non-temporal dependence, Vm
For ventricular cells transmembrane voltage, E is the reversal potential of potassium channel.
In addition, in a specific example, described device further include:
Pacemaker current model of ion channel constructs submodule, using according to expression formula If=If,Na+If,K；If,Na=Gf,Na*y
(Vm-ENa)；If,K=Gf,K*y(Vm-EK) the building pacemaker current model of ion channel, wherein IfFor pacemaker current, If,NaFor
IfThe electric current ion channel current penetrating to Na, If,KFor IfThe electric current ion channel current penetrating to K, Gf,NaFor If,NaMaximum
Electric conductivity value, Gf,KFor If, the maximum conductance value of K, ENaFor the equilibrium potential of sodium ion, EKFor the equilibrium potential of potassium ion, VmFor the heart
Ventricular cell transmembrane voltage, y are the activation variable of pacemaker current.
In addition, the electrophysiological characteristics judgment module is also used in a specific example:
According to expression formulaDetermine that the electro physiology of pacemaker cells in the biological pacemaker simulation model is special
Property, wherein V is film potential, and t is the time, and dV is the integral to ventricular cells transmembrane voltage V, and dt is the integral to time t, Cm
For the capacitor of cell membrane per unit area, IionFor all transmembrane current summations.
Iion=INa+Ito+IKr+IKs+ICaL+INaCa
IionExpression formula are as follows:+INaK+IpCa+IpK+IbCa+IbNa+IX, wherein INaFor quick sodium current, ItoIt is instantaneous export-oriented
Electric current, IKrFor ultrarapid delayed rectifier electric current, IKsFor slow delayed rectifier current, ICaLFor L-type calcium current, INaCaFor sodium Calcium exchanger electricity
Stream, INaKFor sodium potassium pump electric current, IpCaFor calcium pump electric current, IpKFor potassium pump electric current, IbCaFor background calcium current, IbNaFor background sodium electricity
Stream, IXElectric current is targeted for pace-making,
IXExpression formula are as follows:Wherein, α, β are modification IK1With IfThe parameter of electric current.
The value of α and β judges whether to induce spontaneous pace-making behavior in ventricular muscle cell in adjustment model.
If it is determined that then the electrophysiological characteristics of the biological pacemaker model are qualified induction of spontaneous pace-making behavior.
It should be understood that the size of the serial number of each step is not meant that the order of the execution order in above-described embodiment, each process
Execution sequence should be determined by its function and internal logic, the implementation process without coping with the embodiment of the present invention constitutes any limit
It is fixed.
Fig. 4 is a kind of schematic diagram of biological pacemaker model construction terminal device provided in an embodiment of the present invention, the implementation
The biological pacemaker model construction terminal device 4 of example includes: processor 40, memory 41 and is stored in the memory 41
And the computer program 42 that can be run on the processor 40, such as biological pacemaker model construction program.The processor
The step in above-mentioned each biological pacemaker model building method embodiment is realized when the 40 execution computer program 42, such as
Step 101 shown in FIG. 1 is to 105.Alternatively, the processor 40 realizes that above-mentioned each device is real when executing the computer program 42
Apply the function of each module/unit in example, such as the function of module 301 to 305 shown in Fig. 2.
Illustratively, the computer program 42 can be divided into one or more module/units, it is one or
Multiple module/units are stored in the memory 41, and are executed by the processor 40, to complete the present invention.Described one
A or multiple module/units can be the series of computation machine program instruction section that can complete specific function, which is used for
Implementation procedure of the computer program 42 in the biological pacemaker model construction terminal device 4 is described.For example, the meter
Calculation machine program 42 can be divided into synchronization module, summarizing module, obtain module, return module (module in virtual bench),
Each module concrete function is as follows:
Construct inward K~+currents model of ion channel.
Building pace-making current ion channel pattern.
According to the inward K~+currents model of ion channel, the pacemaker current model of ion channel and the heart prestored
The reconstruct of other model of ion channel generates biological pacemaker model on the muscle cell membrane of room.
Judge whether the electrophysiological characteristics of the biological pacemaker model are qualified.
If the electrophysiological characteristics of the biological pacemaker model are qualified, then it is assumed that the biological pacemaker model construction at
Function.
The biological pacemaker model integration is formed to biological pacemaker simulation mould into the ventricle single cell model prestored
Type.
Sarcoplasmic reticulum leakage current in the biological pacemaker simulation model, which is obtained, according to the emulation technology prestored flows into cytoplasm
The first interior calcium current and subspace calcium pump electric current flow into intracytoplasmic second calcium current.According to first calcium current and institute
It states the second calcium current and judges whether intracellular calcium concentration reaches after preset time in the biological pacemaker simulation model
Default stable state.
If intracellular calcium concentration reaches default stable state after preset time in the biological pacemaker simulation model,
Determine that the biological pacemaker model paces successfully.
According to expression formulaThe inward K~+currents model of ion channel is constructed,
Wherein, IK1For inward K~+currents, GK1For the conductance of inward K~+currents ion channel, KoPotassium outside for ventricular cells from
Sub- concentration, K1∞For the inward rectification coefficient of non-temporal dependence, VmFor ventricular cells transmembrane voltage, E is the reversion electricity of potassium channel
Position.
According to expression formula If=If,Na+If,K；If,Na=Gf,Na*y(Vm-ENa)；If,K=Gf,K*y(Vm-EK) building described
Current ion of fighting channel pattern, wherein IfFor pacemaker current, If,NaFor IfThe electric current ion channel current penetrating to Na, If,KFor
IfThe electric current ion channel current penetrating to K, Gf,NaFor If,NaMaximum conductance value, Gf,KFor If,KMaximum conductance value, ENaFor sodium
The equilibrium potential of ion, EKFor the equilibrium potential of potassium ion, VmFor ventricular cells transmembrane voltage, y is that the activation of pacemaker current becomes
Amount.
According to expression formulaDetermine the electrophysiological characteristics of pacemaker cells in the biological pacemaker simulation model,
Wherein, V is film potential, and t is the time, and dV is the integral to ventricular cells transmembrane voltage V, and dt is the integral to time t, CmIt is thin
The capacitor of after birth per unit area, IionFor all transmembrane current summations.
Iion=INa+Ito+IKr+IKs+ICaL+INaCa
IionExpression formula are as follows:+INaK+IpCa+IpK+IbCa+IbNa+IX, wherein INaFor quick sodium current, ItoIt is instantaneous export-oriented
Electric current, IKrFor ultrarapid delayed rectifier electric current, IKsFor slow delayed rectifier current, ICaLFor L-type calcium current, INaCaFor sodium Calcium exchanger electricity
Stream, INaKFor sodium potassium pump electric current, IpCaFor calcium pump electric current, IpKFor potassium pump electric current, IbCaFor background calcium current, IbNaFor background sodium electricity
Stream, IXElectric current is targeted for pace-making.
IXExpression formula are as follows:Wherein, α, β are modification IK1With IfThe parameter of electric current.
The value of α and β judges whether to induce spontaneous pace-making behavior in ventricular muscle cell in adjustment model.
If it is determined that then the electrophysiological characteristics of the biological pacemaker model are qualified induction of spontaneous pace-making behavior.
The biological pacemaker model construction terminal device 4 can be desktop PC, notebook, palm PC and cloud
Server etc. is held to calculate equipment.The biological pacemaker model construction terminal device may include, but be not limited only to, processor 40,
Memory 41.It will be understood by those skilled in the art that Fig. 4 is only the example of biological pacemaker model construction terminal device 4, and
The restriction to biological pacemaker model construction terminal device 4 is not constituted, may include components more more or fewer than diagram, or
Certain components or different components are combined, such as the biological pacemaker model construction terminal device can also include input
Output equipment, network access equipment, bus etc..
Alleged processor 40 can be central processing unit (Central Processing Unit, CPU), can also be
Other general processors, digital signal processor (Digital Signal Processor, DSP), specific integrated circuit
(Application Specific Integrated Circuit, ASIC), ready-made programmable gate array (Field-
Programmable Gate Array, FPGA) either other programmable logic device, discrete gate or transistor logic,
Discrete hardware components etc..General processor can be microprocessor or the processor is also possible to any conventional processor
Deng.
The memory 41 can be the internal storage unit of the biological pacemaker model construction terminal device 4, such as
The hard disk or memory of biological pacemaker model construction terminal device 4.The memory 41 is also possible to the biological pacemaker mould
Type constructs the External memory equipment of terminal device 4, such as the grafting being equipped on the biological pacemaker model construction terminal device 4
Formula hard disk, intelligent memory card (Smart Media Card, SMC), secure digital (Secure Digital, SD) card, flash card
(Flash Card) etc..Further, the memory 41 can also both include that the biological pacemaker model construction terminal is set
Standby 4 internal storage unit also includes External memory equipment.The memory 41 is for storing the computer program and institute
Other programs and data needed for stating biological pacemaker model construction terminal device.The memory 41 can be also used for temporarily
Store the data that has exported or will export.
It is apparent to those skilled in the art that for convenience of description and succinctly, only with above-mentioned each function
Can unit, module division progress for example, in practical application, can according to need and by above-mentioned function distribution by different
Functional unit, module are completed, i.e., the internal structure of described device is divided into different functional unit or module, more than completing
The all or part of function of description.Each functional unit in embodiment, module can integrate in one processing unit, can also
To be that each unit physically exists alone, can also be integrated in one unit with two or more units, it is above-mentioned integrated
Unit both can take the form of hardware realization, can also realize in the form of software functional units.In addition, each function list
Member, the specific name of module are also only for convenience of distinguishing each other, the protection scope being not intended to limit this application.Above system
The specific work process of middle unit, module, can refer to corresponding processes in the foregoing method embodiment, and details are not described herein.
In the above-described embodiments, it all emphasizes particularly on different fields to the description of each embodiment, is not described in detail or remembers in some embodiment
The part of load may refer to the associated description of other embodiments.
Those of ordinary skill in the art may be aware that list described in conjunction with the examples disclosed in the embodiments of the present disclosure
Member and algorithm steps can be realized with the combination of electronic hardware or computer software and electronic hardware.These functions are actually
It is implemented in hardware or software, the specific application and design constraint depending on technical solution.Professional technician
Each specific application can be used different methods to achieve the described function, but this realization is it is not considered that exceed
The scope of the present invention.
In embodiment provided by the present invention, it should be understood that disclosed device/terminal device and method, it can be with
It realizes by another way.For example, device described above/terminal device embodiment is only schematical, for example, institute
The division of module or unit is stated, only a kind of logical function partition, there may be another division manner in actual implementation, such as
Multiple units or components can be combined or can be integrated into another system, or some features can be ignored or not executed.Separately
A bit, shown or discussed mutual coupling or direct-coupling or communication connection can be through some interfaces, device
Or the INDIRECT COUPLING or communication connection of unit, it can be electrical property, mechanical or other forms.
The unit as illustrated by the separation member may or may not be physically separated, aobvious as unit
The component shown may or may not be physical unit, it can and it is in one place, or may be distributed over multiple
In network unit.It can select some or all of unit therein according to the actual needs to realize the mesh of this embodiment scheme
's.
It, can also be in addition, the functional units in various embodiments of the present invention may be integrated into one processing unit
It is that each unit physically exists alone, can also be integrated in one unit with two or more units.Above-mentioned integrated list
Member both can take the form of hardware realization, can also realize in the form of software functional units.
If the integrated module/unit be realized in the form of SFU software functional unit and as independent product sale or
In use, can store in a computer readable storage medium.Based on this understanding, the present invention realizes above-mentioned implementation
All or part of the process in example method, can also instruct relevant hardware to complete, the meter by computer program
Calculation machine program can be stored in a computer readable storage medium, the computer program when being executed by processor, it can be achieved that on
The step of stating each embodiment of the method.Wherein, the computer program includes computer program code, the computer program generation
Code can be source code form, object identification code form, executable file or certain intermediate forms etc..The computer-readable medium
It may include: any entity or device, recording medium, USB flash disk, mobile hard disk, magnetic that can carry the computer program code
Dish, CD, computer storage, read-only memory (ROM, Read-Only Memory), random access memory (RAM,
Random Access Memory), electric carrier signal, telecommunication signal and software distribution medium etc..It should be noted that described
The content that computer-readable medium includes can carry out increasing appropriate according to the requirement made laws in jurisdiction with patent practice
Subtract, such as in certain jurisdictions, according to legislation and patent practice, computer-readable medium do not include be electric carrier signal and
Telecommunication signal.
Embodiment described above is merely illustrative of the technical solution of the present invention, rather than its limitations；Although referring to aforementioned reality
Applying example, invention is explained in detail, those skilled in the art should understand that: it still can be to aforementioned each
Technical solution documented by embodiment is modified or equivalent replacement of some of the technical features；And these are modified
Or replacement, the spirit and scope for technical solution of various embodiments of the present invention that it does not separate the essence of the corresponding technical solution should all
It is included within protection scope of the present invention.
Claims (10)
1. a kind of biological pacemaker model building method characterized by comprising
Construct inward K~+currents model of ion channel；
Building pace-making current ion channel pattern；
According to the inward K~+currents model of ion channel, the pacemaker current model of ion channel and the ventricular muscles prestored
The reconstruct of other model of ion channel generates biological pacemaker model on cell membrane；
Judge whether the electrophysiological characteristics of the biological pacemaker model are qualified；
If the electrophysiological characteristics of the biological pacemaker model are qualified, the biological pacemaker model construction success is determined.
2. biological pacemaker model building method as described in claim 1, which is characterized in that further include:
The biological pacemaker model integration is formed into biological pacemaker simulation model into the ventricle single cell model prestored；
It is intracytoplasmic that sarcoplasmic reticulum leakage current inflow in the biological pacemaker simulation model is obtained according to the emulation technology prestored
First calcium current and subspace calcium pump electric current flow into intracytoplasmic second calcium current；
According to first calcium current and second calcium current judge in the biological pacemaker simulation model intracellular Ca2+ from
Whether sub- concentration reaches default stable state after preset time；
If intracellular calcium concentration reaches default stable state after preset time in the biological pacemaker simulation model, determine
The biological pacemaker model paces successfully.
3. biological pacemaker model building method as described in claim 1, which is characterized in that further include:
According to expression formulaConstruct the inward K~+currents model of ion channel, wherein
IK1For inward K~+currents, GK1For the conductance of inward K~+currents ion channel, KoPotassium ion outside for ventricular cells is dense
Degree, K1∞For the inward rectification coefficient of non-temporal dependence, VmFor ventricular cells transmembrane voltage, E is the reversal potential of potassium channel.
4. biological pacemaker model building method as claimed in claim 3, which is characterized in that further include:
According to expression formula If=If,Na+If,K；If,Na=Gf,Na*y(Vm-ENa)；If,K=Gf,K*y(Vm-EK) the building pace-making electricity
It wanders about as a refugee Sub-channel mode, wherein IfFor pacemaker current, If,NaFor IfThe electric current ion channel current penetrating to Na, If,KFor IfElectricity
Flow the ion channel current penetrating to K, Gf,NaFor If,NaMaximum conductance value, Gf,KFor If,KMaximum conductance value, ENaFor sodium from
The equilibrium potential of son, EKFor the equilibrium potential of potassium ion, VmFor ventricular cells transmembrane voltage, y is the activation variable of pacemaker current.
5. biological pacemaker model building method as claimed in claim 4, which is characterized in that the judgement biology pace-making
Whether qualification includes: the electrophysiological characteristics of device model
According to expression formulaDetermine the electrophysiological characteristics of pacemaker cells in the biological pacemaker simulation model,
In, V is film potential, and t is the time, and dV is the integral to ventricular cells transmembrane voltage V, and dt is the integral to time t, CmFor cell
The capacitor of film per unit area, IionFor all transmembrane current summations；
IionExpression formula are as follows:Wherein, INaFor quick sodium current,
ItoFor instantaneous outward current, IKrFor ultrarapid delayed rectifier electric current, IKsFor slow delayed rectifier current, ICaLFor L-type calcium current, INaCa
For I_ NCX, INaKFor sodium potassium pump electric current, IpCaFor calcium pump electric current, IpKFor potassium pump electric current, IbCaFor background calcium current, IbNa
For background sodium current, IXElectric current is targeted for pace-making,
IXExpression formula are as follows:Wherein, α, β are modification IK1With IfThe parameter of electric current；
The value of α and β judges whether to induce spontaneous pace-making behavior in ventricular muscle cell in adjustment model；
If it is determined that then the electrophysiological characteristics of the biological pacemaker model are qualified induction of spontaneous pace-making behavior.
6. a kind of biological pacemaker model construction device characterized by comprising
Potassium current model of ion channel constructs module, for constructing inward K~+currents model of ion channel；
Pacemaker current model of ion channel constructs module, for constructing pace-making current ion channel pattern；
Biological pacemaker model generation module, for according to the inward K~+currents model of ion channel, pace-making electricity
Other model of ion channel reconstruct on Sub-channel mode and the ventricular muscle cell film that prestores of wandering about as a refugee generates biological pacemaker model；
Whether electrophysiological characteristics judgment module, the electrophysiological characteristics for judging the biological pacemaker model are qualified；
Electrophysiological characteristics determine qualified module, if the electrophysiological characteristics for the biological pacemaker model are qualified, determine institute
State the success of biological pacemaker model construction.
7. biological pacemaker model construction device as claimed in claim 6, which is characterized in that further include:
Biological pacemaker simulation model generation module, for the biological pacemaker model integration is unicellular to the ventricle prestored
Biological pacemaker simulation model is formed in model；
Calcium current obtains module, for obtaining sarcoplasmic reticulum leakage in the biological pacemaker simulation model according to the emulation technology prestored
Electric current flows into intracytoplasmic first calcium current and subspace calcium pump electric current flows into intracytoplasmic second calcium current；
Calcium ion concentration judgment module, for judging that the biology paces according to first calcium current and second calcium current
Whether intracellular calcium concentration reaches default stable state after preset time in device simulation model；
Model, which paces, successfully assert module, if for intracellular calcium concentration in the biological pacemaker simulation model default
Reach default stable state after time, then determines that the biological pacemaker model paces successfully.
8. biological pacemaker model construction device as claimed in claim 6, which is characterized in that further include:
Pacemaker current model of ion channel constructs submodule, for according to expression formulaBuilding
The inward K~+currents model of ion channel, wherein IK1For inward K~+currents, GK1For inward K~+currents from
The conductance of subchannel, KoPotassium concentration outside for ventricular cells, K1∞For the inward rectification coefficient of non-temporal dependence, VmFor the heart
Ventricular cell transmembrane voltage, E are the reversal potential of potassium channel.
9. a kind of biological pacemaker model construction terminal device, including memory, processor and storage are in the memory
And the computer program that can be run on the processor, which is characterized in that when the processor executes the computer program
It realizes such as the step of any one of claim 1 to 5 the method.
10. a kind of computer readable storage medium, the computer-readable recording medium storage has computer program, and feature exists
In when the computer program is executed by processor the step of any one of such as claim 1 to 5 of realization the method.
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| CN110310744A (en) * | 2019-06-10 | 2019-10-08 | 暨南大学 | Construction method, storage medium and the calculating equipment of sinoatrial node virtual physiological tissue |
| CN110459262A (en) * | 2019-07-05 | 2019-11-15 | 暨南大学 | A kind of construction method of human atria mathematical model |
| CN115197903A (en) * | 2022-07-19 | 2022-10-18 | 北京智源人工智能研究院 | Cardiac biological pacemaker, calculation model construction method, simulation method and device |
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