WO2012039420A1 - Bionic aortic baroreflex system for treating disease associated with aortic baroreflex dysfunction - Google Patents

Bionic aortic baroreflex system for treating disease associated with aortic baroreflex dysfunction Download PDF

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WO2012039420A1
WO2012039420A1 PCT/JP2011/071470 JP2011071470W WO2012039420A1 WO 2012039420 A1 WO2012039420 A1 WO 2012039420A1 JP 2011071470 W JP2011071470 W JP 2011071470W WO 2012039420 A1 WO2012039420 A1 WO 2012039420A1
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arterial
aortic
bionic
signal
arterial pressure
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PCT/JP2011/071470
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French (fr)
Japanese (ja)
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砂川　賢二
公太 船越
細川　和也
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国立大学法人九州大学
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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
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
    • A61N1/36114—Cardiac control, e.g. by vagal stimulation
    • A61N1/36117—Cardiac control, e.g. by vagal stimulation for treating hypertension
    • 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
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36135—Control systems using physiological parameters
    • A61N1/36139—Control systems using physiological parameters with automatic adjustment
    • 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
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36171—Frequency
    • 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
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/36167—Timing, e.g. stimulation onset
    • A61N1/36175—Pulse width or duty cycle
    • 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
    • A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
    • A61N1/36128—Control systems
    • A61N1/36146—Control systems specified by the stimulation parameters
    • A61N1/3615—Intensity
    • A61N1/36153—Voltage

Definitions

  • the present invention relates to a system for the treatment of diseases or conditions associated with arterial baroreflex dysfunction.
  • HFpEF heart failure
  • Arterial baroreflex is also called baroreceptor reflex, and is a control system for buffering changes in blood pressure and thereby stabilizing blood pressure.
  • Arterial baroreflex controls arterial pressure (AP) mainly by changing vascular resistance and effective circulating blood volume. That is, the arterial baroreflex disorder is a condition in which control of blood volume has been lost, and a hemodynamic buffering mechanism is lacking for changes in blood volume.
  • Non-patent Document 1 a report that the arterial baroreflex can be artificially mimicked regardless of the treatment of heart failure.
  • HFpEF has a 5-year survival rate of 30% and the prognosis is extremely poor, but treatment has not been established.
  • arterial baroreflex dysfunction induced by arteriosclerosis makes hemodynamics sensitive to changes in blood volume. Therefore, it is considered that pulmonary edema is easily induced in such a state regardless of the presence of left ventricular systolic dysfunction, even with a very small increase in blood volume.
  • the present invention provides a bionic arterial baroreflex system that restores normal capacity tolerance in the absence of physiological arterial baroreflex and is therefore useful for the treatment of HFpEF.
  • the system of the present invention for restoring arterial baroreflex function can be used for the treatment of various diseases that can occur with arterial baroreflex dysfunction.
  • Bio for treating heart failure comprising an arterial pressure sensor, a regulator (bionic brain), and an electrical nerve stimulator that generates a rectangular wave train according to instructions from the regulator and stimulates the aortic decompression nerve Nick arterial baroreflex system.
  • Arterial pressure sensing means for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means to perform clinical
  • a calculation means for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means;
  • a bionic arterial baroreflex system comprising: biostimulation means (preferably an electrical nerve stimulator for stimulating the aortic decompression nerve) for stimulating a site capable of regulating blood pressure.
  • Arterial pressure sensing means for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means,
  • a calculation means for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means;
  • a biological stimulation means preferably an electrical nerve stimulating device for stimulating the aortic decompression nerve for stimulating a site where blood pressure can be regulated, and the calculation means receives the input arterial pressure signal.
  • the calculation in the regulator is performed by convolution integration of an impulse response calculated in advance from normal life activity and an arterial pressure signal sensed by the life activity sensing means, or the impulse response is expressed by a delta function.
  • the bionic arterial baroreflex system according to any one of [1] to [3], which is implemented by approximation.
  • the system of the present invention can be used for the treatment of diseases or conditions associated with arterial baroreflex dysfunction. *
  • Arteriosclerosis can cause impairment of arterial baroreflex, but arteriosclerosis-induced arterial baroreflex dysfunction sensitizes hemodynamics to changes in blood volume and therefore increases small blood volume Again, pulmonary edema is easily induced in the absence of left ventricular systolic dysfunction.
  • the bionic arterial baroreflex system of the present invention is a powerful tool in the treatment of heart failure (HFpEF) in which normal capacity tolerance is restored and hence ejection fraction is maintained in the absence of physiological arterial baroreflex.
  • HFpEF heart failure
  • the bionic arterial baroreflex system will also be equally useful in the treatment of heart failure with systolic dysfunction.
  • Orthostatic hypotension is also known as a well-known disease that can be caused by arterial baroreflex dysfunction, but it is considered that orthostatic hypotension can be treated according to the present invention.
  • the critical volume is defined as the injection volume required for the left atrial pressure to reach 20 mmHg. It is the graph which showed the estimated mean blood pressure (mBP) of an arterial baroreflex normal rat and an arterial baroreflex failure rat when a left atrial pressure reached 20 mmHg.
  • mBP mean blood pressure
  • 1 is a schematic diagram of a bionic arterial baroreflex system.
  • FIG. It is a figure regarding the identification of the transfer function of a regulator (bionic brain). It is a graph of a transfer function (left) and an impulse response (right). It is the figure which outlined the experimental system for evaluating the performance of a bionic arterial baroreflex system.
  • CSP carotid sinus pressure
  • AP arterial blood pressure
  • baroreceptors are distributed in the carotid sinus and aortic arch, and when blood pressure rises, impulses are transmitted to the solitary nucleus of the medulla oblong according to the extension of the arterial wall.
  • the solitary nucleus suppresses the sympathetic nerve and stimulates the parasympathetic nerve.
  • the stimulation to the baroreceptor is reduced, the function of the solitary nucleus is attenuated, the parasympathetic nerve is suppressed, and the sympathetic nerve is stimulated.
  • an increase in cardiac contraction force, pulse and contraction of peripheral arteries occur, and blood pressure is maintained.
  • the veins also contract, increasing the amount of blood returned to the heart.
  • the bionic arterial reflex system of the present invention can be used for a patient who cannot maintain normal blood pressure due to some kind of failure in such a blood pressure regulation mechanism.
  • the bionic arterial baroreflex system of the present invention will be described with reference to the drawings.
  • the basic configuration of the bionic arterial baroreflex system is shown in FIG.
  • the bionic arterial baroreflex system of the present invention comprises at least arterial pressure sensing means (2), calculation means (3) and aortic decompression nerve stimulation means (4).
  • Arterial pressure sensing means (2) senses the blood pressure in the artery and outputs the blood pressure.
  • arterial pressure sensing means or “arterial pressure (AP) sensor” means means capable of sensing arterial pressure information from a living body and outputting an arterial pressure signal, unless otherwise specified.
  • the arterial pressure information includes various information correlated with the arterial pressure, and the “arterial pressure sensing means” may include various means as long as it can be continuously detected.
  • the “arterial pressure sensing means” includes means for non-invasive arterial pressure measurement by, for example, oscillometric method, tonometry method, or volume compensation method, in addition to means for invasive blood pressure measurement. .
  • the arterial pressure sensing means (2) is not particularly limited as long as it can sense arterial pressure information from a living body and output an arterial pressure signal.
  • an arterial pressure sensor (narrow sense) is exemplified. Can do.
  • the calculation means (3) receives the arterial pressure signal sensed by the arterial pressure sensing means (2), analyzes and processes the arterial pressure signal, A clinically effective biostimulation signal is calculated and a biostimulation signal is output.
  • the biostimulation signal calculated by the calculation means (3) is output to the biostimulation means (4) described later.
  • an arterial pressure signal sensed by the arterial pressure sensing means is input to calculate a clinically effective biological stimulation signal, Means for outputting a biostimulation signal.
  • the term “clinically effective” as used herein is effective for adjusting the arterial pressure in the same manner as when relying on physiological arterial pressure reflex when stimulating a portion of a living body where the arterial pressure can be adjusted. That means.
  • the arterial pressure signal sensed by the arterial pressure sensing means (2) may be first input to an amplifying device (not shown) and amplified.
  • the amplifying apparatus includes a filter device that can remove a frequency higher than a certain frequency and a frequency lower than a certain frequency to remove a signal derived from a living body and power line noise.
  • the amplified signal may be converted from an analog signal to a digital signal by an A / D conversion device (not shown), and then input to an analysis processing device (not shown).
  • predetermined processing is performed, and a biological stimulus signal is calculated.
  • the calculation means (3) may include an identification means for identifying whether the input arterial pressure signal is due to normal biological activity or abnormal biological activity. When the arterial pressure signal is identified as normal biological activity, the biostimulation signal is not output. When the input biological activity signal is identified as abnormal biological activity, the biostimulation signal is output. You may design as follows.
  • the calculation of the biostimulation signal in the calculation means (3) will be described below, taking as an example the case of controlling the arterial pressure by stimulating the aortic decompression nerve.
  • the blood pressure and the impulse response of the calculation means (3) are convolutionally integrated in order to determine the biological stimulus signal.
  • the impulse response can be calculated by performing a Fourier transform on the arterial pressure signal, obtaining a transfer function based on the Fourier transformed value, and performing an inverse Fourier transform on the transfer function.
  • the transfer function (frequency domain) incorporated in the calculation means (3) was obtained as a graph on the left of FIG. This graph is the impulse response h (t) on the right side of FIG.
  • the history AP (1), AP (2), ..., AP (49) of blood pressure t 1 to 49 observation points is recorded, and the blood pressure just measured is AP
  • the impulse response is approximated by a delta function when calculating the biological stimulus signal.
  • STM AP (0.01) * h (0.01) + AP (0.02) * h (0.02) +... + AP (99.99) * h (99.99 ) + AP (100) * h (100) is calculated every 0.01 seconds (10 6 product-sum operations per second), whereas in the delta function approximation method, one multiplication per 0.01 seconds (1 100 operations per second) is sufficient, and the computational load on the computer can be reduced to 1/10000 or less.
  • the knowledge that the stimulation frequency can be determined by applying a constant value to the blood pressure value is provided for the first time by the present invention.
  • this method has a practically important meaning that the system development becomes easy because the amount of real-time computation can be greatly saved as compared with the convolution integration method.
  • the present inventors have also confirmed that there is no significant difference in control results between the direct convolution and integration method and the simple proportional calculation method.
  • the biological stimulation means (4) inputs the arterial pressure signal calculated by the calculation means (3) described above, and stimulates a part of the living body that can adjust the arterial pressure based on the stimulation signal to Adjust.
  • the term “biological stimulation means” in the present invention includes various means capable of appropriately stimulating a part of a living body where the arterial pressure can be adjusted, unless otherwise specified.
  • the stimulation may be based on electrical stimulation as well as magnetic stimulation, and the stimulation site may be the aortic decompression nerve, the aortic arch itself, the carotid sinus nerve, or the carotid sinus itself. Direct stimulation or electrical field stimulation can be performed.
  • a typical example of the biological stimulation means (4) is an electrical nerve stimulation device that stimulates the aortic decompression nerve. Examples of the site of nerve stimulation include ganglia, the surface of the spinal cord, and a suitable site in the brain, but are not limited thereto as long as the site can be stimulated effectively.
  • the intensity of biostimulation, the width and frequency of the rectangular wave are based on the target species, weight, age, sex, state, stimulation site, target effect, etc. It can be designed as appropriate. Further, it can be designed with reference to an existing treatment device (for example, Rheos® system® (CVRx)) for example for hypertensives.
  • the stimulation voltage can be in the range of 2.0-6.0 Volts for rats (see FIG. 13), and larger voltages, eg, ⁇ 20 when performed on humans. May be Volts.
  • the above-mentioned Rheos® system does not stimulate nerves directly, but adopts a method in which the entire carotid sinus is stimulated by an electric field, but this device can stimulate at a voltage of 7.0 V or less, and can be referred to in the present invention.
  • ⁇ Electric stimulation can also be performed with constant current stimulation in addition to constant voltage stimulation.
  • constant current stimulation for example, 0.01 to 0.2 ⁇ mA for rats and 0.1 to 2.0 ⁇ mA for humans, for example, sufficient stimulation may be possible.
  • the width of the rectangular wave can be 0.5 to 2.0 ms for humans, and the stimulation frequency can be up to 100 Hz for humans. .
  • the bionic arterial baroreflex system is based on blood pressure, and does not use blood pressure as it is as an aortic decompression nerve stimulation signal, but performs an appropriate calculation, and is a therapeutically effective aorta. Since a decompressed nerve stimulation signal is output, stable blood pressure control can be performed in the same manner as a living body.
  • the aortic decompression nerve was cut bilaterally. Normal arterial baroreflex was mimicked by matching CSP to arterial pressure (normal), and arterial baroreflex imperfection was mimicked by maintaining CSP at a steady value regardless of arterial pressure (failure).
  • Dextran was injected stepwise at a rate of 1 to 4 ml / kg / min until the LAP reached 14 to 16 mmHg ( Figure 1).
  • LAP left atrial pressure
  • ⁇ V injection volume
  • Fig. 3 shows typical LAP- ⁇ V and AP- ⁇ V relationships.
  • Arterial baroreflex acts to buffer a critical amount.
  • the critical amount here is ⁇ V required to raise LAP to 20 mmHg.
  • the critical amount was 17.22 ⁇ 1.91 ml / kg under normal conditions, while it significantly decreased to 11.16 ⁇ 1.58 ml / kg under arterial baroreflex failure (p ⁇ 0.01).
  • the difference was 6.05 ml / kg (ie, 25% of the effective circulating blood volume, Ogilivie, Circulation 1992), and the amount corresponding to 420 ml in the 70 kg patient (FIG. 4). Since the carotid sinus is injured by a surgical procedure for experimental convenience, the simulated normal arterial baroreflex function is impaired as compared with the original normal arterial baroreflex function. Therefore, the difference in patients may be even greater than this calculation. Arterial baroreflex failure, on the other hand, increases blood pressure (mBP) at a critical amount ( Figure 5).
  • mBP blood pressure
  • Arterial baroreflex failure makes hemodynamics sensitive to changes in blood volume and makes patients more prone to pulmonary edema regardless of LV function.
  • the HFpEF patient has arteriosclerosis at the base, the patient will be prone to pulmonary edema.
  • Surgical procedure Baroreceptor region was separated from systemic circulation. The carotid sinus pressure was adjusted with a servo-driven piston pump. Bilateral aortic decompression nerve was cut. An electrode pair was attached to the proximal end of any one aortic decompression nerve.
  • Fig. 6 shows a schematic diagram of the bionic arterial baroreflex system.
  • the bionic arterial baroreflex system consists of an arterial pressure (AP) sensor, a regulator (bionic brain) and an electrical nerve stimulator.
  • the stimulator generates a rectangular wave train according to a command from the regulator to stimulate the aortic decompression nerve.
  • the regulator automatically calculates the instantaneous stimulation frequency of the aortic decompression nerve according to the convolution algorithm.
  • the bionic arterial baroreflex system used digitized arterial pressure (BP) at 200 Hz (or higher frequency), averaged over 0.5 seconds (mean blood pressure, mBP), and resampled at 2 Hz.
  • the length of time for averaging blood pressure can vary from the moment (5 ms) to 30 seconds, depending on the purpose of the system.
  • the resampling frequency may be matched to the average time length (Nyquist frequency).
  • the cut-off frequency of the body-specific arterial baroreflex is about 0.1 Hz, and the bionic arterial baroreflex system using a resampling frequency lower than 0.2 Hz cannot reproduce the physiological arterial baroreflex.
  • even such a system can reduce the computational complexity and reproduce the arterial baroreflex in the range below the physiological cutoff frequency.
  • the mBP was converted to the stimulation frequency of the aortic decompression nerve by the controller. Although less accurate, it is possible to make the convolution integration period shorter than 60 seconds (10-60 seconds).
  • the impulse response of the regulator approximated a delta function.
  • the scaling factor is approximated by the time integration of the impulse response.
  • the aortic decompression nerve was stimulated according to the stimulation frequency obtained by the control device.
  • the aortic decompression nerve may be left, right or both.
  • the stimulation frequency was updated with the resampling frequency.
  • the stimulation pulse width could be 0.1-2.0 ms and the stimulation voltage could be in the range of 2.0-6.0 volts.
  • the hypotensive effect of aortic decompression nerve stimulation was saturated above 80 Hz. Therefore, the stimulation frequency was limited to zero to 80 Hz (FIG. 13).
  • Bionic arterial baroreflex system restores normal arterial baroreflex function, which is indistinguishable from physiological arterial baroreflex in the absence of physiological arterial baroreflex.
  • the simplified algorithm of the bionic arterial baroreflex system reduces the computational complexity resulting from real-time convolution and does not degrade performance.
  • Bionic arterial baroreflex system may be a powerful tool in preventing pulmonary edema episodes in heart failure with preserved ejection fraction.

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Abstract

The present invention provides a bionic aortic baroreflex system which restores normal volume tolerance in the absence of physiological aortic baroreflex and, therefore, is useful in treating HFpEF. More specifically, the invention provides a bionic aortic baroreflex system comprising: an aortic pressure sensing means (aortic pressure (AP) sensor) for sensing aortic pressure data from a living organism and outputting an aortic pressure signal; a calculation means (regulator) for inputting the aortic pressure signal, which is sensed by the aortic pressure sensing means, calculating a clinically effective aortic depressor nerve stimulation signal and outputting the aortic depressor nerve stimulation signal; and an aortic depressor nerve stimulation means (electrical nerve stimulator) for inputting the aortic depressor nerve stimulation signal, which is calculated by the calculation means, and stimulating the aortic depressor nerve of the living organism on the basis of the aortic depressor nerve stimulation signal.

Description

動脈圧反射機能障害に関連した疾患を治療するためのバイオニック動脈圧反射システムBionic arterial baroreflex system for treating diseases associated with arterial baroreflex dysfunction
　本発明は、動脈圧反射機能障害に関連した疾患又は状態の処置のためのシステムに関する。 The present invention relates to a system for the treatment of diseases or conditions associated with arterial baroreflex dysfunction.
　駆出率（ejection fraction, EF）が保たれた心不全（HFpEF）の有病率が増加してきている。HFpEFは急性心不全の約50％を占めるにもかかわらず、病因は未知のままである。疫学的研究によって、HFpEF患者の大部分は高齢女性（閉経後）であり、しばしば高血圧、腎不全及び肥満を伴うことが示されている。これらのすべての要因は動脈硬化の原因であることが知られている。動脈硬化は、動脈圧反射領域における動脈壁を硬化し、それによって動脈圧反射機能を悪化させる。 The prevalence of heart failure (HFpEF) in which the ejection fraction (ejection) is maintained is increasing. Although HFpEF accounts for about 50% of acute heart failure, the etiology remains unknown. Epidemiological studies have shown that the majority of HFpEF patients are elderly women (postmenopausal), often with hypertension, renal failure and obesity. All these factors are known to be responsible for arteriosclerosis. Atherosclerosis stiffens the arterial wall in the arterial baroreflex area, thereby deteriorating the arterial baroreflex function.
　動脈圧反射は、圧受容器反射とも呼ばれ、血圧の変化を緩衝し、それにより血圧を安定させるための制御システムである。動脈圧反射は、主に血管抵抗及び有効循環血液量を変化させることによって、動脈圧（AP）を制御している。すなわち動脈圧反射障害は、血液容量の制御を失った状態であり血液容量の変化に対して血行動態の緩衝機構を欠いている病態である。 Arterial baroreflex is also called baroreceptor reflex, and is a control system for buffering changes in blood pressure and thereby stabilizing blood pressure. Arterial baroreflex controls arterial pressure (AP) mainly by changing vascular resistance and effective circulating blood volume. That is, the arterial baroreflex disorder is a condition in which control of blood volume has been lost, and a hemodynamic buffering mechanism is lacking for changes in blood volume.
　動脈圧反射システムに関しては、犬で作成した報告がある。しかし、これは心不全の治療などとは無関係に動脈圧反射を人工的に模倣できたことの報告に留まる（非特許文献1）。 Regarding the arterial baroreflex system, there are reports made by dogs. However, this is only a report that the arterial baroreflex can be artificially mimicked regardless of the treatment of heart failure (Non-patent Document 1).
　一方、様々な要因によって正常な生体調節機能を果たすことができない中枢器官に変わって、その中枢器官があたかも正常に機能しているかのように各器官を調節することができる生体調節機能代替を用いた治療用システム並びに該システムに基づく心臓ペーシングシステム、血圧調節システム及び心疾患治療用システム（特許文献1）が検討されてきた。 On the other hand, instead of a central organ that cannot perform normal bioregulatory functions due to various factors, a bioregulatory function alternative that can regulate each organ as if the central organ is functioning normally is used. A therapeutic system that has been used, a cardiac pacing system based on the system, a blood pressure regulation system, and a cardiac disease treatment system (Patent Document 1) have been studied.
WO2004／012814（特許第4189448号）WO2004 / 012814 (Patent No. 4189448)
　HFpEFの5年生存率は30％であり、予後は極端に悪いが、治療は確立されていない。一方、動脈硬化が誘導する動脈圧反射機能障害は、血行動態を血液量変化に対して敏感にする。そのため、左心室収縮機能障害の存在に関わらずこのような状態では、ごく少量の血液量増加に対しても、肺水腫が容易に誘導されると考えられる。 HFpEF has a 5-year survival rate of 30% and the prognosis is extremely poor, but treatment has not been established. On the other hand, arterial baroreflex dysfunction induced by arteriosclerosis makes hemodynamics sensitive to changes in blood volume. Therefore, it is considered that pulmonary edema is easily induced in such a state regardless of the presence of left ventricular systolic dysfunction, even with a very small increase in blood volume.
　本発明は、生理的動脈圧反射の非存在下で、正常な容量耐性を回復し、そのためHFpEFの治療に有用な、バイオニック動脈圧反射システムを提供する。動脈圧反射機能を回復させる本発明のシステムは、動脈圧反射機能障害で起こり得る種々の疾患の治療のために、用いることができる。 The present invention provides a bionic arterial baroreflex system that restores normal capacity tolerance in the absence of physiological arterial baroreflex and is therefore useful for the treatment of HFpEF. The system of the present invention for restoring arterial baroreflex function can be used for the treatment of various diseases that can occur with arterial baroreflex dysfunction.
　本発明は以下を提供する。
 [1］動脈圧センサ、レギュレータ（バイオニックブレイン）、及びレギュレータからの命令にしたがって矩形波列を生成して、大動脈減圧神経を刺激する電気的神経刺激装置からなる、心不全を治療するためのバイオニック動脈圧反射システム。 
［2］生体からの動脈圧情報を感知して動脈圧信号を出力するための動脈圧感知手段（動脈圧センサ）と；該動脈圧感知手段により感知された動脈圧信号を入力して、臨床上有効な生体刺激信号を算出し、該生体刺激信号を出力するための算出手段（レギュレータ）と；該算出手段によって算出された生体刺激信号を入力して、該生体刺激信号に基づいて、生体の、血圧を調節することができる部位を刺激するための生体刺激手段（好ましくは、大動脈減圧神経を刺激する電気的神経刺激装置）と、からなる、バイオニック動脈圧反射システム。 
［3］生体からの動脈圧情報を感知して動脈圧信号を出力するための動脈圧感知手段（動脈圧センサ）と；該動脈圧感知手段により感知された動脈圧信号を入力して、臨床上有効な生体刺激信号を算出し、該生体刺激信号を出力するための算出手段（レギュレータ）と；該算出手段によって算出された生体刺激信号を入力して、該生体刺激信号に基づいて、生体の、血圧を調節することができる部位を刺激するための生体刺激手段（好ましくは、大動脈減圧神経を刺激する電気的神経刺激装置）と、からなり、該算出手段が、入力された動脈圧信号が正常な生体活動によるものであるか、異常な生体活動によるものであるかを識別する識別手段を備え、入力された生体活動信号が正常な生体活動であると識別された場合、生体刺激信号の出力は行わず、入力された生体活動信号が異常な生体活動であると識別された場合、生体刺激信号を出力する、バイオニック動脈圧反射システム。 
［4］該レギュレータにおける算出が、正常時の生体活動から予め算出したインパルス応答と該生体活動感知手段により感知された動脈圧信号の畳み込み積分により実施されるか、又は該インパルス応答をデルタ関数で近似することにより実施される、［1］～［3］のいずれか一に記載のバイオニック動脈圧反射システム。 
［5］駆出率が保たれた心不全（HFpEF）の治療、収縮期機能障害を伴う心不全の治療、又は起立性低血圧の治療のための、［1］～［4］のいずれか一に記載のバイオニック動脈圧反射システム。 
［6］刺激される血圧を調節することができる部位が、左、右又は両方の大動脈減圧神経である、1～5のいずれか一に記載のバイオニック動脈圧反射システム。 
［7］刺激パルス幅期間が、0.1～2.0m秒である、［1］～［6］のいずれか一に記載の、バイオニック動脈圧反射システム。 
［8］刺激周波数が、100 Hz以下である、［1］～［7］のいずれか一に記載の、バイオニック動脈圧反射システム。 The present invention provides the following.
[1] Bio for treating heart failure, comprising an arterial pressure sensor, a regulator (bionic brain), and an electrical nerve stimulator that generates a rectangular wave train according to instructions from the regulator and stimulates the aortic decompression nerve Nick arterial baroreflex system.
[2] Arterial pressure sensing means (arterial pressure sensor) for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means to perform clinical A calculation means (regulator) for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means; A bionic arterial baroreflex system comprising: biostimulation means (preferably an electrical nerve stimulator for stimulating the aortic decompression nerve) for stimulating a site capable of regulating blood pressure.
[3] Arterial pressure sensing means (arterial pressure sensor) for sensing arterial pressure information from a living body and outputting an arterial pressure signal; and inputting an arterial pressure signal sensed by the arterial pressure sensing means, A calculation means (regulator) for calculating a biostimulation signal that is effective and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means; And a biological stimulation means (preferably an electrical nerve stimulating device for stimulating the aortic decompression nerve) for stimulating a site where blood pressure can be regulated, and the calculation means receives the input arterial pressure signal. Is provided with an identification means for identifying whether the signal is due to normal biological activity or abnormal biological activity, and if the input biological activity signal is identified as normal biological activity, Output of A bionic arterial baroreflex system that outputs a biostimulation signal when the input bioactivity signal is identified as an abnormal bioactivity without being performed.
[4] The calculation in the regulator is performed by convolution integration of an impulse response calculated in advance from normal life activity and an arterial pressure signal sensed by the life activity sensing means, or the impulse response is expressed by a delta function. The bionic arterial baroreflex system according to any one of [1] to [3], which is implemented by approximation.
[5] Any one of [1] to [4] for treating heart failure with sustained ejection fraction (HFpEF), treating heart failure with systolic dysfunction, or treating orthostatic hypotension The bionic arterial baroreflex system described.
[6] The bionic arterial baroreflex system according to any one of 1 to 5, wherein the site capable of regulating the stimulated blood pressure is the left, right or both aortic decompression nerves.
[7] The bionic arterial baroreflex system according to any one of [1] to [6], wherein the stimulation pulse width period is 0.1 to 2.0 milliseconds.
[8] The bionic arterial baroreflex system according to any one of [1] to [7], wherein the stimulation frequency is 100 Hz or less.
　本発明のシステムは、動脈圧反射機能障害に関連した疾患又は状態の処置のために用いることができる。　 The system of the present invention can be used for the treatment of diseases or conditions associated with arterial baroreflex dysfunction. *
　動脈硬化は、動脈圧反射機能を障害する原因となりうるが、動脈硬化が誘導する動脈圧反射機能障害は、血行動態を血液量の変化に対して敏感にし、そしてそのため、少量の血液量の増加に対しても、左心室収縮機能障害の非存在下で、肺水腫が容易に誘導される。本発明のバイオニック動脈圧反射システムは、生理的動脈圧反射の非存在下で、正常な容量耐性を回復し、それゆえ駆出率が保たれた心不全（HFpEF）の治療において強力なツールとなりえる。バイオニック動脈圧反射システムはまた、収縮期機能障害を伴う心不全の治療において、同等に有用であろう。 Arteriosclerosis can cause impairment of arterial baroreflex, but arteriosclerosis-induced arterial baroreflex dysfunction sensitizes hemodynamics to changes in blood volume and therefore increases small blood volume Again, pulmonary edema is easily induced in the absence of left ventricular systolic dysfunction. The bionic arterial baroreflex system of the present invention is a powerful tool in the treatment of heart failure (HFpEF) in which normal capacity tolerance is restored and hence ejection fraction is maintained in the absence of physiological arterial baroreflex. Yeah. The bionic arterial baroreflex system will also be equally useful in the treatment of heart failure with systolic dysfunction.
　動脈圧反射機能障害で起こり得る疾患としてよく知られているものに起立性低血圧も挙げられるが、本発明により、起立性低血圧も治療可能であると考えられる。 Orthostatic hypotension is also known as a well-known disease that can be caused by arterial baroreflex dysfunction, but it is considered that orthostatic hypotension can be treated according to the present invention.
ラットにおいて、大動脈減圧神経を両側性に切断し、頸動脈洞を体循環から分離した。頸動脈洞内圧（CSP）を動脈圧に一致させることによって正常動脈圧反射を模倣し（正常）、そして動脈圧に関わらずCSPを定常値に維持することによって動脈圧反射不全を模倣した（不全）。In rats, the aortic decompression nerve was cut bilaterally and the carotid sinus was separated from systemic circulation. Mimics normal arterial baroreflex by matching carotid sinus pressure (CSP) to arterial pressure (normal), and mimics arterial baroreflex failure by maintaining CSP at a steady value regardless of arterial pressure (failure) ). 代表的な時系列データのグラフである。It is a graph of typical time series data. 代表例における左心房圧（LAP）-注入容量（ΔV）関係、及び動脈圧（AP）-注入容量（ΔV）関係図である。It is a left atrial pressure (LAP) -injection volume (ΔV) relationship and an arterial pressure (AP) -injection volume (ΔV) relationship diagram in a representative example. 動脈圧反射正常ラット及び動脈圧反射不全ラットの臨界量を示したグラフである。臨界量とは左心房圧が20mmHgに達するのに要する注入容量と定義している。It is the graph which showed the critical amount of the arterial baroreflex normal rat and the arterial baroreflex failure rat. The critical volume is defined as the injection volume required for the left atrial pressure to reach 20 mmHg. 左心房圧が20mmHgに達したときの動脈圧反射正常ラット及び動脈圧反射不全ラットの推定平均血圧（mBP）を示したグラフである。It is the graph which showed the estimated mean blood pressure (mBP) of an arterial baroreflex normal rat and an arterial baroreflex failure rat when a left atrial pressure reached 20 mmHg. バイオニック動脈圧反射システムの概略図である。1 is a schematic diagram of a bionic arterial baroreflex system. FIG. レギュレータ（バイオニックブレイン）の伝達関数の同定に関する図である。It is a figure regarding the identification of the transfer function of a regulator (bionic brain). 伝達関数（左）及びインパルス応答（右）のグラフである。It is a graph of a transfer function (left) and an impulse response (right). バイオニック動脈圧反射システムの性能を評価するための実験系を概要した図である。It is the figure which outlined the experimental system for evaluating the performance of a bionic arterial baroreflex system. バイオニック動脈圧反射システムを用いた場合の頸動脈洞内圧（CSP）-動脈圧(AP)関係と生理的CSP－AP関係を比較したグラフである。FIG. 6 is a graph comparing the carotid sinus pressure (CSP) -arterial pressure (AP) relationship and the physiological CSP-AP relationship when using the bionic arterial baroreflex system. 左心房圧(LAP)、注入容量の時系列（左）とLAP-注入容量関係（右）についてのグラフである。It is a graph about the time series (left) and LAP-injection volume relationship (right) of left atrial pressure (LAP) and an injection volume. バイオニック動脈圧反射システム（BBS）と生理的動脈圧反射の左心房圧(LAP)-注入容量関係を比較したグラフである。バイオニック動脈圧反射システム（BBS）の有効循環血液量の調節は生理的動脈圧反射のそれと同等である。It is the graph which compared the left atrial pressure (LAP) -injection volume relationship of a bionic arterial baroreflex system (BBS) and physiological arterial baroreflex. The regulation of the effective circulating blood volume of the bionic arterial baroreflex system (BBS) is equivalent to that of the physiological arterial baroreflex. レギュレータからの命令にしたがって生成された矩形波列の例を示した図である。It is the figure which showed the example of the rectangular wave train produced | generated according to the command from a regulator.
　通常、圧受容器は頚動脈洞と大動脈弓に分布し、血圧が上昇すると動脈壁の伸展に応じて延髄の孤束核にインパルスが伝達される。孤束核は交感神経を抑制して副交感神経を刺激する。逆に、血圧が低下すると圧受容器への刺激が減少して孤束核の働きは減弱し、副交感神経が抑制され交感神経が刺激される。これにより、心収縮力、脈拍の増加と末梢動脈の収縮が生じ、血圧が維持される。また静脈も収縮し、血液の心臓への還流量が増加する。本発明のバイオニック動脈反射システムは、このような血圧調節機構に何らかの障害が生じて、血圧を正常に維持することができない患者に用いることができる。以下、本発明のバイオニック動脈圧反射システムについて、図面を引用しつつ説明する。 Normally, baroreceptors are distributed in the carotid sinus and aortic arch, and when blood pressure rises, impulses are transmitted to the solitary nucleus of the medulla oblong according to the extension of the arterial wall. The solitary nucleus suppresses the sympathetic nerve and stimulates the parasympathetic nerve. Conversely, when the blood pressure is lowered, the stimulation to the baroreceptor is reduced, the function of the solitary nucleus is attenuated, the parasympathetic nerve is suppressed, and the sympathetic nerve is stimulated. Thereby, an increase in cardiac contraction force, pulse and contraction of peripheral arteries occur, and blood pressure is maintained. The veins also contract, increasing the amount of blood returned to the heart. The bionic arterial reflex system of the present invention can be used for a patient who cannot maintain normal blood pressure due to some kind of failure in such a blood pressure regulation mechanism. Hereinafter, the bionic arterial baroreflex system of the present invention will be described with reference to the drawings.
　バイオニック動脈圧反射システムの基本構成は図6に示される。本発明のバイオニック動脈圧反射システムは、少なくとも、動脈圧感知手段（2）、算出手段（3）及び大動脈減圧神経刺激手段（4）とから構成される。 The basic configuration of the bionic arterial baroreflex system is shown in FIG. The bionic arterial baroreflex system of the present invention comprises at least arterial pressure sensing means (2), calculation means (3) and aortic decompression nerve stimulation means (4).
　動脈圧感知手段（2）（本発明では、「動脈圧センサ」ということもある。）は、動脈内の血圧を感知して血圧を出力する。 Arterial pressure sensing means (2) (also referred to as “arterial pressure sensor” in the present invention) senses the blood pressure in the artery and outputs the blood pressure.
　本発明で「動脈圧感知手段」又は「動脈圧（AP）センサ」というときは、特に記載した場合を除き、生体からの動脈圧情報を感知して動脈圧信号を出力することができる手段をいう。動脈圧情報には、動脈圧に相関する種々の情報が含まれ、また連続的に感知することができる限り、「動脈圧感知手段」には種々の手段が含まれうる。「動脈圧感知手段」には、観血式血圧測定のための手段のほか、例えば、オシロメトリック法、トノメトリー法、又は容積補償法による非観血的な動脈圧測定のための手段が含まれる。 In the present invention, the term “arterial pressure sensing means” or “arterial pressure (AP) sensor” means means capable of sensing arterial pressure information from a living body and outputting an arterial pressure signal, unless otherwise specified. Say. The arterial pressure information includes various information correlated with the arterial pressure, and the “arterial pressure sensing means” may include various means as long as it can be continuously detected. The “arterial pressure sensing means” includes means for non-invasive arterial pressure measurement by, for example, oscillometric method, tonometry method, or volume compensation method, in addition to means for invasive blood pressure measurement. .
　動脈圧感知手段（2）としては、生体からの動脈圧情報を感知して動脈圧信号を出力することができるものであれば特に限定されないが、例えば、動脈圧センサ（狭義）を例示することができる。 The arterial pressure sensing means (2) is not particularly limited as long as it can sense arterial pressure information from a living body and output an arterial pressure signal. For example, an arterial pressure sensor (narrow sense) is exemplified. Can do.
　算出手段（3）（本発明では、「レギュレータ」ということもある。）は、動脈圧感知手段（2）により感知された動脈圧信号を入力して、この動脈圧信号を解析、処理し、臨床上有効な生体刺激信号を算出し、生体刺激信号を出力する。算出手段（3）により算出された生体刺激信号は、後述する生体刺激手段（4）に出力される。 The calculation means (3) (also referred to as “regulator” in the present invention) receives the arterial pressure signal sensed by the arterial pressure sensing means (2), analyzes and processes the arterial pressure signal, A clinically effective biostimulation signal is calculated and a biostimulation signal is output. The biostimulation signal calculated by the calculation means (3) is output to the biostimulation means (4) described later.
　本発明で「算出手段」又は「レギュレータ」というときは、特に記載した場合を除き、動脈圧感知手段により感知された動脈圧信号を入力して、臨床上有効な生体刺激信号を算出し、該生体刺激信号を出力するための手段をいう。ここでいう「臨床上有効」とは、生体の、動脈圧を調整することができる部位を刺激した場合に、生理的動脈圧反射に拠る場合と同様に動脈圧を調節するのに有効であることをいう。 When referred to as “calculation means” or “regulator” in the present invention, unless otherwise specified, an arterial pressure signal sensed by the arterial pressure sensing means is input to calculate a clinically effective biological stimulation signal, Means for outputting a biostimulation signal. The term “clinically effective” as used herein is effective for adjusting the arterial pressure in the same manner as when relying on physiological arterial pressure reflex when stimulating a portion of a living body where the arterial pressure can be adjusted. That means.
　算出手段（3）においては、動脈圧感知手段（2）によって感知された動脈圧信号は、まず増幅装置（図示せず）に入力し、増幅してもよい。尚、増幅装置は、ある一定周波数以上の周波数及びある一定周波数以下の周波数を除去して生体に由来する信号及び電力線雑音を除去することができるフィルタ装置を備えていることが好ましい。増幅された信号はA／D変換装置（図示せず）によりアナログ信号からデジタル信号に変換されてもよく、その後に、解析処理装置（図示せず）に入力されてもよい。解析処理装置において、所定の処理が行われ、生体刺激信号が算出される。　なお、算出手段（3）は、入力された動脈圧信号が正常な生体活動によるものであるか、異常な生体活動によるものであるかを識別する識別手段を備えていてもよく、入力された動脈圧信号が正常な生体活動であると識別された場合、生体刺激信号の出力は行わず、入力された生体活動信号が異常な生体活動であると識別された場合、生体刺激信号を出力するように設計してもよい。 In the calculating means (3), the arterial pressure signal sensed by the arterial pressure sensing means (2) may be first input to an amplifying device (not shown) and amplified. In addition, it is preferable that the amplifying apparatus includes a filter device that can remove a frequency higher than a certain frequency and a frequency lower than a certain frequency to remove a signal derived from a living body and power line noise. The amplified signal may be converted from an analog signal to a digital signal by an A / D conversion device (not shown), and then input to an analysis processing device (not shown). In the analysis processing apparatus, predetermined processing is performed, and a biological stimulus signal is calculated. The calculation means (3) may include an identification means for identifying whether the input arterial pressure signal is due to normal biological activity or abnormal biological activity. When the arterial pressure signal is identified as normal biological activity, the biostimulation signal is not output. When the input biological activity signal is identified as abnormal biological activity, the biostimulation signal is output. You may design as follows.
　算出手段（3）における、生体刺激信号の算出について、大動脈減圧神経を刺激して動脈圧を制御する場合を例に、以下で説明する。 The calculation of the biostimulation signal in the calculation means (3) will be described below, taking as an example the case of controlling the arterial pressure by stimulating the aortic decompression nerve.
　本発明のシステムの一態様においては、生体刺激信号を確定するために、血圧と算出手段（3）のインパルス応答の畳み込み積分を行う。 In one aspect of the system of the present invention, the blood pressure and the impulse response of the calculation means (3) are convolutionally integrated in order to determine the biological stimulus signal.
　インパルス応答は、動脈圧信号をフーリエ変換し、該フーリエ変換した値をもとに伝達関数を求め、該伝達関数を逆フーリエ変換することで算出できる。具体的には、本発明者らの実験では、算出手段（3）に組み込む伝達関数（周波数領域）が、図8の左にあるグラフとして得られたが、これを逆フーリエ変換して時間領域のグラフにしたものが図8右のインパルス応答h(t)である。 The impulse response can be calculated by performing a Fourier transform on the arterial pressure signal, obtaining a transfer function based on the Fourier transformed value, and performing an inverse Fourier transform on the transfer function. Specifically, in the experiments of the present inventors, the transfer function (frequency domain) incorporated in the calculation means (3) was obtained as a graph on the left of FIG. This graph is the impulse response h (t) on the right side of FIG.
　そして畳み込み積分を用いる態様においては、例えば血圧のt=1～49観測点の履歴AP(1), AP(2), …, AP(49)が記録されているとして、たった今測定した血圧がAP(0)の時に、更新すべき大動脈減圧神経刺激の周波数STMはSTM=AP(0)*h(0) + AP(1)*h(1)+ AP(2)*h(2)+ AP(3)*h(3)+ AP(4)*h(4)+ … + AP(49)*h(49)で与えられる。 In the embodiment using the convolution integral, for example, the history AP (1), AP (2), ..., AP (49) of blood pressure t = 1 to 49 observation points is recorded, and the blood pressure just measured is AP The frequency STM of the aortic decompression nerve stimulation to be updated at (0) is STM = AP (0) * h (0) + AP (1) * h (1) + AP (2) * h (2) + AP (3) * h (3) + AP (4) * h (4) +… + AP (49) * h (49).
　本発明のシステムの別の一態様においては、生体刺激信号を算出する際に、インパルス応答をデルタ関数で近似する。具体的には、本発明者らの実験では、図8の右のグラフに示されるように、インパルス応答はh(0)を除いてh(1)～h(49)までがほぼ0となった。そこでh(0)以外はすべて0と近似すると（インパルス応答をデルタ関数で近似することに相当）、STM=AP(0)*h(0)の簡単な演算（血圧値に比例した刺激周波数）でSTMが求められる。すなわち、本発明者らの検討によると、神経刺激に対する血圧応答の動的な特性は、比較的単純であった。そのため、図13に示したように、血圧値に一定値（スケーラー：インパルス応答の時間積分）を掛けた周波数で矩形波列を生成し、大動脈減圧神経を刺激するだけの単純な計算で代用可能である。 In another aspect of the system of the present invention, the impulse response is approximated by a delta function when calculating the biological stimulus signal. Specifically, in our experiment, as shown in the right graph of FIG. 8, the impulse response is almost zero from h (1) to h (49) except for h (0). It was. Therefore, if all except h (0) are approximated to 0 (equivalent to approximating the impulse response with a delta function), simple calculation of STM = AP (0) * h (0) (stimulation frequency proportional to blood pressure value) STM is required. That is, according to the study by the present inventors, the dynamic characteristic of the blood pressure response to nerve stimulation was relatively simple. Therefore, as shown in Fig. 13, a simple calculation that generates a rectangular wave train at a frequency obtained by multiplying the blood pressure value by a constant value (scaler: time integration of impulse response) and stimulates the aortic decompression nerve can be substituted. It is.
　この単純化がもたらすメリットは、計算量の節約である。畳み込み積分方式で0.01秒ごとに100秒間の履歴を畳み込み積分する場合、STM=AP(0.01)*h(0.01) + AP(0.02)*h(0.02) + … +AP(99.99)*h(99.99) + AP(100)*h(100)を0.01秒毎に演算する（1秒間に106個の積和演算量）のに対して、デルタ関数近似方式では0.01秒に1個の掛け算（1秒間で100個の演算）でよく、1／10000以下にコンピュータの計算負荷を軽減しうる。この血圧値に一定値をかけて刺激周波数が確定できるという知見は、本発明によって初めて提供される。その上この方式に拠れば、畳み込み積分方式に比して実時間演算量を大幅に節約できるため、システム開発が容易になるという実用上重要な意義がある。なお本発明者らにより、直接の畳み込み積分方式と単純な比例計算方式とでは、制御の結果に有意な差がないことも確認された。 The benefit of this simplification is the savings in computational complexity. When convolving and integrating 100 seconds of history every 0.01 seconds with the convolution integration method, STM = AP (0.01) * h (0.01) + AP (0.02) * h (0.02) +… + AP (99.99) * h (99.99 ) + AP (100) * h (100) is calculated every 0.01 seconds (10 6 product-sum operations per second), whereas in the delta function approximation method, one multiplication per 0.01 seconds (1 100 operations per second) is sufficient, and the computational load on the computer can be reduced to 1/10000 or less. The knowledge that the stimulation frequency can be determined by applying a constant value to the blood pressure value is provided for the first time by the present invention. In addition, this method has a practically important meaning that the system development becomes easy because the amount of real-time computation can be greatly saved as compared with the convolution integration method. The present inventors have also confirmed that there is no significant difference in control results between the direct convolution and integration method and the simple proportional calculation method.
　なお本明細書の実施例では、ラットを用いた実験結果が示されているが、ラット以外にも犬、ウサギでデルタ関数に近いインパルス応答になっていることが分かっており、ヒトでもこの性質は保存されていると考えられる（Kubota T. The American journal of physiology. 1992、　Sato T. The American journal of physiology. 1998）。すなわち、上述のデルタ関数近似方式は、ヒトに対しても有効である。考慮すべきは、インパルス応答の絶対値がラットとヒトでは異なる可能性がある点である。この点については、ヒトに適用する際には比較的小さい値から滴定し、漸増することにより、解決可能である。 In the examples of the present specification, experimental results using rats are shown, but it is known that the impulse response is similar to the delta function in dogs and rabbits other than rats, and this property is also observed in humans. Are conserved (KubotaKT. American journal of physiology. 1992, Sato T. The American journal of physiology. 1998). That is, the above-described delta function approximation method is also effective for humans. It should be considered that the absolute value of the impulse response may be different between rats and humans. This can be solved by titrating from a relatively small value and gradually increasing it when applied to humans.
　生体刺激手段（4）は、上述した算出手段（3）によって算出された動脈圧信号を入力して、刺激信号に基づいて、生体の、動脈圧を調整することができる部位を刺激して血圧を調節する。本発明で「生体刺激手段」というときは、特に記載した場合を除き、生体の、動脈圧を調整することができる部位を適切に刺激することができる種々の手段が含まれる。刺激は、電気刺激のほか、磁気刺激に拠ってもよく、また刺激部位は、大動脈減圧神経のほか、大動脈弓そのもの、頸動脈洞神経、又は頸動脈洞そのものでありうる。直接刺激することもでき、また電気フィールド刺激することもできる。生体刺激手段（4）の典型的な例は、大動脈減圧神経を刺激する電気的神経刺激装置である。神経刺激の部位としては、神経節、脊髄表面や脳内の好適な部位などを例示することができるが、有効に刺激できる部位であればこれに限定されない。 The biological stimulation means (4) inputs the arterial pressure signal calculated by the calculation means (3) described above, and stimulates a part of the living body that can adjust the arterial pressure based on the stimulation signal to Adjust. The term “biological stimulation means” in the present invention includes various means capable of appropriately stimulating a part of a living body where the arterial pressure can be adjusted, unless otherwise specified. The stimulation may be based on electrical stimulation as well as magnetic stimulation, and the stimulation site may be the aortic decompression nerve, the aortic arch itself, the carotid sinus nerve, or the carotid sinus itself. Direct stimulation or electrical field stimulation can be performed. A typical example of the biological stimulation means (4) is an electrical nerve stimulation device that stimulates the aortic decompression nerve. Examples of the site of nerve stimulation include ganglia, the surface of the spinal cord, and a suitable site in the brain, but are not limited thereto as long as the site can be stimulated effectively.
　本発明のバイオニック動脈圧反射システムにおいては、生体刺激の強度、矩形波の幅及び周波数は、対象の生物種、体重、年齢、性別、状態、刺激部位、及び目標とする効果等に基づき、適宜設計することができる。また、既存の、例えば高血圧者を対象とした治療装置（例えば、Rheos system （CVRx社））等を参考に、設計することができる。例えば、電気刺激に拠る場合、刺激電圧は、ラットに対しては、2.0～6.0 Voltsの範囲とすることができ（図13参照）、ヒトに対して行う場合は、より大きな電圧、例えば～20 Volts程度となる可能性がある。前掲Rheos systemは神経を直接刺激するのではなく、頸動脈洞全体を電気フィールド刺激する方式を採るが、この装置では7.0V以下で刺激できており、本発明においても参考にすることができる。 In the bionic arterial baroreflex system of the present invention, the intensity of biostimulation, the width and frequency of the rectangular wave are based on the target species, weight, age, sex, state, stimulation site, target effect, etc. It can be designed as appropriate. Further, it can be designed with reference to an existing treatment device (for example, Rheos® system® (CVRx)) for example for hypertensives. For example, when relying on electrical stimulation, the stimulation voltage can be in the range of 2.0-6.0 Volts for rats (see FIG. 13), and larger voltages, eg, ˜20 when performed on humans. May be Volts. The above-mentioned Rheos® system does not stimulate nerves directly, but adopts a method in which the entire carotid sinus is stimulated by an electric field, but this device can stimulate at a voltage of 7.0 V or less, and can be referred to in the present invention.
　電気刺激はまた、定電圧刺激以外に、定電流刺激でも実施可能と考えられる。その際には、ラットに対しては、例えば0.01～0.2 mA、ヒトに対しては、例えば0.1～2.0 mAで、十分な刺激が可能であろう。 ¡Electric stimulation can also be performed with constant current stimulation in addition to constant voltage stimulation. In that case, for example, 0.01 to 0.2 μmA for rats and 0.1 to 2.0 μmA for humans, for example, sufficient stimulation may be possible.
　本発明のバイオニック動脈圧反射システムにおいては、矩形波の幅は、ヒトに対して0.5～2.0msとすることができ、また刺激周波数は、ヒトに対して100Hzまでとしても問題ないと考えられる。 In the bionic arterial baroreflex system of the present invention, the width of the rectangular wave can be 0.5 to 2.0 ms for humans, and the stimulation frequency can be up to 100 Hz for humans. .
　以上詳述したように、本発明に係るバイオニック動脈圧反射システムは、血圧に基づき、しかも血圧をそのまま大動脈減圧神経刺激信号として使用するのではなく、適切な演算を行い、治療上有効な大動脈減圧神経刺激信号を出力するので、生体と同じように安定した血圧制御を行うことができる。 As described above in detail, the bionic arterial baroreflex system according to the present invention is based on blood pressure, and does not use blood pressure as it is as an aortic decompression nerve stimulation signal, but performs an appropriate calculation, and is a therapeutically effective aorta. Since a decompressed nerve stimulation signal is output, stable blood pressure control can be performed in the same manner as a living body.
　[1.　動脈圧反射不全］
　1-1.　方法
　正常左心室（LV）機能を有する5匹の麻酔したスプレーグ・ドーリー・ラットにおいて、両側頸動脈洞を体循環から分離し、サーボ駆動ピストンポンプによって頸動脈洞圧（CSP）を調節した。左心房圧（LAP）及び動脈圧（AP）を測定した。 [1. Arterial baroreflex insufficiency]
1-1. Methods In 5 anesthetized Sprague-Dawley rats with normal left ventricular (LV) function, the bilateral carotid sinus is separated from the systemic circulation and the carotid sinus pressure (CSP) is measured by a servo-driven piston pump. Adjusted. Left atrial pressure (LAP) and arterial pressure (AP) were measured.
　大動脈減圧神経を両側性に切断した。CSPを動脈圧に一致させることによって正常動脈圧反射を模倣し（正常）、そして動脈圧に関わらずCSPを定常値に維持することによって動脈圧反射不全を模倣した（不全）。 The aortic decompression nerve was cut bilaterally. Normal arterial baroreflex was mimicked by matching CSP to arterial pressure (normal), and arterial baroreflex imperfection was mimicked by maintaining CSP at a steady value regardless of arterial pressure (failure).
　LAPが14～16mmHgに達するまで、毎分1～4ml／kgの割合でデキストランを段階的に注入した（図1）。 Dextran was injected stepwise at a rate of 1 to 4 ml / kg / min until the LAP reached 14 to 16 mmHg (Figure 1).
　左心房圧（LAP）及び注入容量（ΔV）の関係を単一指数関数曲線に適合させた。LAPが20mmHg（肺水腫）に到達する臨界量を算出した。 The relationship between left atrial pressure (LAP) and injection volume (ΔV) was fitted to a single exponential curve. The critical amount for LAP to reach 20 mmHg (pulmonary edema) was calculated.
Figure JPOXMLDOC01-appb-M000001
 　LAP及び平均血圧（mBP）関係を対数曲線に適合させ、LAP＝20mmHgでのmBPを算出した。
Figure JPOXMLDOC01-appb-M000001
 The LAP and mean blood pressure (mBP) relationship was fitted to a logarithmic curve, and mBP at LAP = 20 mmHg was calculated.
Figure JPOXMLDOC01-appb-M000002
Figure JPOXMLDOC01-appb-M000002
　1-2.　結果及び考察
　図2に、代表的な時系列データを示した。図1の正常ラットへの外科処置では、頸動脈洞は血管を結紮又は塞栓させることで体循環から分離独立させ、なおかつサーボ調節ピストンポンプによって頸動脈洞内圧を自在に操ることができるようにしている一方で、大動脈弓からの動脈圧反射は大動脈減圧神経を切断することで神経的に分離されている。すなわちこの手技によって、1匹のラットで頸動脈洞内圧（carotid sinus pressure）を体血圧（systemic blood pressure）に一致させると生理的動脈圧反射を再現することができ、頸動脈洞内圧を体血圧とは無関係に一定値にすることによって動脈圧反射不全を再現することができる。図2から、2段目の頸動脈洞内圧が1段目の体血圧と一致しているときと、それとは無関係に一定値をとっているときがあるのが一見して分かるが、このように1匹のラットで頸動脈洞内圧を切り替えるだけで2つの状態を模倣することができた。詳細には、生理的動脈圧反射(図2の1段目と2段目が同様の値の区間)においては注入容量（infused volume、4段目）が多いにもかかわらず、左心房圧（left atrial pressure、5段目)がそれほど高くならず、他方動脈圧反射不全（2段目が、1段目の値に関わらず一定値である区間）では、より少ない注入容量にもかかわらず左心房圧はより高くなった。なお、図2の3段目の腎交感神経活動（renal sympathetic nerve activity）は、生理的動脈圧反射では血圧上昇とともに漸減し、動脈圧反射不全では変化しないことを示す。 1-2. Results and discussion Figure 2 shows typical time-series data. In the surgical procedure for normal rats in FIG. 1, the carotid sinus is separated from the systemic circulation by ligating or embolizing blood vessels, and the internal pressure of the carotid sinus can be manipulated freely by a servo-regulating piston pump. On the other hand, the arterial baroreflex from the aortic arch is separated neurologically by cutting the aortic decompression nerve. In other words, this technique can reproduce the physiological arterial pressure reflex by matching the carotid sinus pressure to the systemic blood pressure in one rat, The arterial baroreflex insufficiency can be reproduced by setting it to a constant value regardless of the above. From Fig. 2, it can be seen at a glance that the second-stage carotid sinus pressure is consistent with the first-stage body blood pressure, and sometimes has a constant value regardless of this. In one rat, it was possible to mimic two states by simply switching the carotid sinus pressure. Specifically, in the physiological arterial baroreflex (the interval where the first and second stages in FIG. 2 have similar values), the left atrial pressure ( left atrial pressure (5th stage) is not so high, while in arterial baroreflex failure (section where 2nd stage is constant regardless of 1st stage value) Atrial pressure was higher. In addition, the renal sympathetic nerve activity (renal sympathetic nerve activity) of the 3rd step | paragraph of FIG. 2 shows that it decreases gradually with the blood pressure rise in the physiological arterial baroreflex, and does not change by arterial baroreflex failure.
　また、図3に、代表的なLAP-ΔV関係及びAP-ΔV関係を示した。 Fig. 3 shows typical LAP-ΔV and AP-ΔV relationships.
　動脈圧反射は臨界量を緩衝する働きがある。ここでいう臨界量とはLAPを20mmHgにまで上昇させるのに要したΔVのことである。臨界量は正常下では17.22±1.91ml／kgであり、一方、動脈圧反射不全下では、11.16±1.58ml／kgに顕著に減少した（p＜0.01）。相違は、6.05ml／kg（すなわち、有効循環血液量の25％、Ogilivie、Circulation　1992）であり、70kg患者では420mlに相当する量であった（図4）。実験都合上の外科処置により頸動脈洞の傷害がおこるため、模倣した正常動脈圧反射機能は本来の正常動脈圧反射機能より損なわれている。そのため患者における相違は、この算出よりもさらに大きい可能性がある。一方、動脈圧反射不全は、臨界量での血圧（mBP）を増加させる（図5）。 Arterial baroreflex acts to buffer a critical amount. The critical amount here is ΔV required to raise LAP to 20 mmHg. The critical amount was 17.22 ± 1.91 ml / kg under normal conditions, while it significantly decreased to 11.16 ± 1.58 ml / kg under arterial baroreflex failure (p <0.01). The difference was 6.05 ml / kg (ie, 25% of the effective circulating blood volume, Ogilivie, Circulation 1992), and the amount corresponding to 420 ml in the 70 kg patient (FIG. 4). Since the carotid sinus is injured by a surgical procedure for experimental convenience, the simulated normal arterial baroreflex function is impaired as compared with the original normal arterial baroreflex function. Therefore, the difference in patients may be even greater than this calculation. Arterial baroreflex failure, on the other hand, increases blood pressure (mBP) at a critical amount (Figure 5).
　本実験により、下記が明らかになった。 This experiment revealed the following.
　正常動脈圧反射の非存在下で、正常LV機能を持つラットモデルにおいて、容量注入によって左心房圧ならびに血圧が容易に増加する。 In the absence of the normal arterial baroreflex, in the rat model with normal LV function, left atrial pressure and blood pressure are easily increased by volume injection.
　動脈圧反射不全は、血行動態を血液量の変化に対して敏感にし、そしてLV機能に関わらず患者を肺水腫になりやすくする。 Arterial baroreflex failure makes hemodynamics sensitive to changes in blood volume and makes patients more prone to pulmonary edema regardless of LV function.
　HFpEF患者の根底に動脈硬化がある場合、患者は肺水腫になりやすくなるであろう。 If the HFpEF patient has arteriosclerosis at the base, the patient will be prone to pulmonary edema.
　［2.　バイオニック動脈圧反射システム］
　2-1.　方法
　動物：13匹のスプレーグ・ドーリー・ラット
　麻酔：すべての動物をα－クロラロース及びウレタンの混合物で麻酔した。 [2. Bionic arterial baroreflex system]
2-1. Method Animals: 13 Sprague Dawley Rats Anesthesia: All animals were anesthetized with a mixture of α-chloralose and urethane.
　外科処置：圧受容器領域を体循環から分離した。頸動脈洞内圧をサーボ駆動ピストンポンプで調節した。両側大動脈減圧神経を切断した。いずれか1本の大動脈減圧神経の近位端に電極対を取り付けた。 Surgical procedure: Baroreceptor region was separated from systemic circulation. The carotid sinus pressure was adjusted with a servo-driven piston pump. Bilateral aortic decompression nerve was cut. An electrode pair was attached to the proximal end of any one aortic decompression nerve.
　図6に、バイオニック動脈圧反射システムの略図を示した。バイオニック動脈圧反射システムは、動脈圧（AP）センサ、レギュレータ（バイオニックブレイン）及び電気的神経刺激装置からなる。刺激装置は、レギュレータからの命令にしたがって矩形波列を生成して、大動脈減圧神経を刺激する。 Fig. 6 shows a schematic diagram of the bionic arterial baroreflex system. The bionic arterial baroreflex system consists of an arterial pressure (AP) sensor, a regulator (bionic brain) and an electrical nerve stimulator. The stimulator generates a rectangular wave train according to a command from the regulator to stimulate the aortic decompression nerve.
　2-2.　レギュレータ（バイオニックブレイン）の伝達関数の同定
　レギュレータの伝達関数（Hバイオニック）はHCSP－AP／HSTM－APによって与えられた。 2-2. Identification of the transfer function of the regulator (bionic brain) The transfer function of the regulator (H bionic ) was given by H CSP-AP / H STM-AP .
　レギュレータは畳み込みアルゴリズムにしたがって、大動脈減圧神経の瞬間刺激周波数を自動的に計算する。 The regulator automatically calculates the instantaneous stimulation frequency of the aortic decompression nerve according to the convolution algorithm.
　2-3.　レギュレータの伝達関数の算出（バイオニックブレイン、H バイオニック ）
　Hバイオニックはデルタ関数に似ているため、以後、デルタ関数で近似する（図8）。 2-3. Calculation of regulator transfer function (bionic brain, H bionic )
Since H bionic is similar to the delta function, it is approximated by the delta function (Fig. 8).
　2-4.　バイオニック動脈圧反射システムの実行
　Hバイオニックをレギュレータ（バイオニックブレイン）内に実装した。生体固有の動脈圧反射及びバイオニック動脈圧反射システムにおけるCSP（carotid sinus pressure、頸動脈洞圧）－AP関係を比較した（図10）。 2-4. Implementation of the bionic arterial baroreflex system The H bionic was implemented in a regulator (bionic brain). We compared the CSP (carotid sinus pressure) -AP relationship in the native arterial baroreflex and the bionic arterial baroreflex system (Figure 10).
　2-5.　結果及び考察
　結果を、図11～13に示した。バイオニック動脈圧反射システムは、正常血液量耐性を回復した（図11）。また、有効循環血液量の調節は、バイオニック動脈圧反射システム（BBS）と生理学的動脈圧反射システムとの間で異ならなかった（図12）。 2-5. Results and discussion results are shown in Figs . 11-13 . The bionic arterial baroreflex system restored normal blood volume tolerance (Figure 11). Also, the regulation of effective circulating blood volume did not differ between the bionic arterial baroreflex system (BBS) and the physiological arterial baroreflex system (Figure 12).
　用いたバイオニック動脈圧反射システムは、動脈圧（BP）を200Hz（又はより高い周波数）でデジタル化し、そして0.5秒にわたって平均し（平均血圧、mBP）、そして2Hzでリサンプリングした。血圧を平均する時間長は、システムの目的に応じて、瞬間（5m秒）～30秒まで、多様とすることができる。リサンプリング周波数は、当然、平均した時間長にマッチ（ナイキスト周波数）させてもよい。生体固有の動脈圧反射の遮断周波数は、約0.1Hzであり、0.2Hzより低いリサンプリング周波数を用いたバイオニック動脈圧反射システムでは、生理的動脈圧反射を再現することができない。しかし、そのようなシステムであっても、計算の複雑度を減少させ、なおかつ生理的遮断周波数以下の範囲の動脈圧反射を再現することはできる。 The bionic arterial baroreflex system used digitized arterial pressure (BP) at 200 Hz (or higher frequency), averaged over 0.5 seconds (mean blood pressure, mBP), and resampled at 2 Hz. The length of time for averaging blood pressure can vary from the moment (5 ms) to 30 seconds, depending on the purpose of the system. Naturally, the resampling frequency may be matched to the average time length (Nyquist frequency). The cut-off frequency of the body-specific arterial baroreflex is about 0.1 Hz, and the bionic arterial baroreflex system using a resampling frequency lower than 0.2 Hz cannot reproduce the physiological arterial baroreflex. However, even such a system can reduce the computational complexity and reproduce the arterial baroreflex in the range below the physiological cutoff frequency.
　60秒間に渡るHバイオニック（レギュレータ又はバイオニックブレイン）のインパルス応答を用いたmBPの実時間畳み込みを適用することによって、mBPを制御装置によって大動脈減圧神経の刺激周波数に変換した。正確さは劣るが、畳み込み積分の期間を60秒間より短くする（10～60秒間）ことも可能である。 By applying real-time convolution of mBP with the impulse response of H bionic (regulator or bionic brain) over 60 seconds, the mBP was converted to the stimulation frequency of the aortic decompression nerve by the controller. Although less accurate, it is possible to make the convolution integration period shorter than 60 seconds (10-60 seconds).
　レギュレータのインパルス応答は、デルタ関数に近似した。それにより、正確さを損なうことなく、畳み込み積分をmBPに単純なスケーリング係数を掛ける操作のみで代用することができた。これによって、煩雑な畳み込み操作が排除される。スケーリング係数は、インパルス応答の時間積分によって概算される。 The impulse response of the regulator approximated a delta function. As a result, it was possible to substitute the convolution integral only by multiplying mBP by a simple scaling factor without losing accuracy. This eliminates complicated convolution operations. The scaling factor is approximated by the time integration of the impulse response.
　制御装置によって得られる刺激周波数にしたがって、大動脈減圧神経が刺激された。大動脈減圧神経は、左、右または両方であってもよい。刺激周波数はリサンプリング周波数で更新された。刺激パルス幅は0.1～2.0m秒とすることができ、刺激電圧は2.0～6.0ボルトの範囲とすることができた。大動脈減圧神経刺激の降圧効果は80Hzより上で飽和した。したがって、刺激周波数をゼロ～80Hzに制限した（図13）。 The aortic decompression nerve was stimulated according to the stimulation frequency obtained by the control device. The aortic decompression nerve may be left, right or both. The stimulation frequency was updated with the resampling frequency. The stimulation pulse width could be 0.1-2.0 ms and the stimulation voltage could be in the range of 2.0-6.0 volts. The hypotensive effect of aortic decompression nerve stimulation was saturated above 80 Hz. Therefore, the stimulation frequency was limited to zero to 80 Hz (FIG. 13).
　本実験により、下記が明らかになった。 This experiment revealed the following.
　バイオニック動脈圧反射システムは、正常動脈圧反射機能を回復し、これは生理的動脈圧反射の非存在下で、生理的動脈圧反射と見分けが付かない。 Bionic arterial baroreflex system restores normal arterial baroreflex function, which is indistinguishable from physiological arterial baroreflex in the absence of physiological arterial baroreflex.
　バイオニック動脈圧反射システムの単純化されたアルゴリズムによって、実時間畳み込みから生じる計算複雑度が減少し、かつ性能は落ちない。 The simplified algorithm of the bionic arterial baroreflex system reduces the computational complexity resulting from real-time convolution and does not degrade performance.
　刺激条件の詳細が確立されている。 Details of stimulation conditions have been established.
　動脈圧反射不全によって誘導される容量不耐性は、バイオニック動脈圧反射システムによって完全に防止される。 Volume intolerance induced by arterial baroreflex failure is completely prevented by the bionic arterial baroreflex system.
　バイオニック動脈圧反射システムは、駆出率が保たれた心不全において、肺水腫のエピソードを防止する際に強力なツールであろう。 Bionic arterial baroreflex system may be a powerful tool in preventing pulmonary edema episodes in heart failure with preserved ejection fraction.

Claims (8)

  1. 動脈圧センサ、レギュレータ（バイオニックブレイン）、及びレギュレータからの命令にしたがって矩形波列を生成して、大動脈減圧神経を刺激する電気的神経刺激装置からなる、心不全を治療するためのバイオニック動脈圧反射システム。 Bionic arterial pressure for treating heart failure, comprising an arterial pressure sensor, a regulator (bionic brain), and an electrical nerve stimulator that generates a square wave train in accordance with instructions from the regulator to stimulate the aortic decompression nerve Reflection system.
  2. 生体からの動脈圧情報を感知して動脈圧信号を出力するための動脈圧感知手段（動脈圧センサ）と；該動脈圧感知手段により感知された動脈圧信号を入力して、臨床上有効な生体刺激信号を算出し、該生体刺激信号を出力するための算出手段（レギュレータ）と；該算出手段によって算出された生体刺激信号を入力して、該生体刺激信号に基づいて、生体の、血圧を調節することができる部位を刺激するための生体刺激手段（好ましくは、大動脈減圧神経を刺激する電気的神経刺激装置）と、からなる、バイオニック動脈圧反射システム。 Arterial pressure sensing means (arterial pressure sensor) for sensing arterial pressure information from a living body and outputting an arterial pressure signal; inputting an arterial pressure signal sensed by the arterial pressure sensing means, A calculation means (regulator) for calculating a biostimulation signal and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means, and based on the biostimulation signal, A bionic arterial baroreflex system, comprising biological stimulation means (preferably, an electrical nerve stimulator for stimulating the aortic decompression nerve) for stimulating a region capable of adjusting the aorta.
  3. 生体からの動脈圧情報を感知して動脈圧信号を出力するための動脈圧感知手段（動脈圧センサ）と；該動脈圧感知手段により感知された動脈圧信号を入力して、臨床上有効な生体刺激信号を算出し、該生体刺激信号を出力するための算出手段（レギュレータ）と；該算出手段によって算出された生体刺激信号を入力して、該生体刺激信号に基づいて、生体の、血圧を調節することができる部位を刺激するための生体刺激手段（好ましくは、大動脈減圧神経を刺激する電気的神経刺激装置）と、からなり、
    該算出手段が、入力された動脈圧信号が正常な生体活動によるものであるか、異常な生体活動によるものであるかを識別する識別手段を備え、入力された生体活動信号が正常な生体活動であると識別された場合、生体刺激信号の出力は行わず、入力された生体活動信号が異常な生体活動であると識別された場合、生体刺激信号を出力する、バイオニック動脈圧反射システム。     Arterial pressure sensing means (arterial pressure sensor) for sensing arterial pressure information from a living body and outputting an arterial pressure signal; inputting an arterial pressure signal sensed by the arterial pressure sensing means, A calculation means (regulator) for calculating a biostimulation signal and outputting the biostimulation signal; inputting the biostimulation signal calculated by the calculation means, and based on the biostimulation signal, A biological stimulation means (preferably an electrical nerve stimulation device for stimulating the aortic decompression nerve)
    The calculation means includes identification means for identifying whether the input arterial pressure signal is due to normal biological activity or abnormal biological activity, and the input biological activity signal is normal biological activity In the bionic arterial baroreflex system, the biostimulation signal is not output when the biostimulation signal is identified, and the biostimulation signal is output when the biostimulation signal is identified as an abnormal bioactivity.
  4. 該レギュレータにおける算出が、正常時の生体活動から予め算出したインパルス応答と該生体活動感知手段により感知された動脈圧信号の畳み込み積分により実施されるか、又は該インパルス応答をデルタ関数で近似することにより実施される、請求項1～3のいずれか1項記載のバイオニック動脈圧反射システム。 The calculation in the regulator is performed by convolution integration of an impulse response calculated in advance from normal life activity and an arterial pressure signal sensed by the life activity sensing means, or the impulse response is approximated by a delta function. The bionic arterial baroreflex system according to any one of claims 1 to 3, which is implemented by:
  5. 　駆出率が保たれた心不全（HFpEF）の治療、収縮期機能障害を伴う心不全の治療、又は起立性低血圧の治療のための、請求項1～4のいずれか1項に記載のバイオニック動脈圧反射システム。 The bionic according to any one of claims 1 to 4, for the treatment of heart failure with sustained ejection fraction (HFpEF), heart failure with systolic dysfunction, or orthostatic hypotension Arterial baroreflex system.
  6. 　刺激される血圧を調節することができる部位が、左、右又は両方の大動脈減圧神経である、請求項1～5のいずれか1項に記載のバイオニック動脈圧反射システム。 6. The bionic arterial baroreflex system according to any one of claims 1 to 5, wherein the site capable of regulating the stimulated blood pressure is the left, right or both aortic decompression nerves.
  7. 　刺激パルス幅期間が、0.1～2.0m秒である、請求項1～6 のいずれか1項に記載の、バイオニック動脈圧反射システム。 The bionic arterial baroreflex system according to any one of claims 1 to 6, wherein the stimulation pulse width period is 0.1 to 2.0 milliseconds.
  8. 　刺激周波数が、100 Hz以下である、請求項1～7のいずれか1項に記載の、バイオニック動脈圧反射システム。 The bionic arterial baroreflex system according to any one of claims 1 to 7, wherein the stimulation frequency is 100 Hz or less.
PCT/JP2011/071470 2010-09-21 2011-09-21 Bionic aortic baroreflex system for treating disease associated with aortic baroreflex dysfunction WO2012039420A1 (en)

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