WO2004105597A1

WO2004105597A1 - Diagnosis of fragile plaque by active temperature-measurement

Info

Publication number: WO2004105597A1
Application number: PCT/JP2003/015224
Authority: WO
Inventors: Tsunenori Arai; Takeshi Yanagihara; Sayaka Ohmori
Original assignee: Keio University
Priority date: 2003-05-29
Filing date: 2003-11-28
Publication date: 2004-12-09
Also published as: JPWO2004105597A1; AU2003304154A1

Abstract

It is intended to provide an apparatus for judging the fragility of a plaque in vessel wall with the use of a high-strength pulse beam such as a pulse laser. An active temperature-measurement apparatus for judging the fragility of a plaque at an arteriosclerotic site which has: (1) a balloon catheter to be inserted into a vessel; (2) a high-strength pulse beam irradiation unit for irradiating a plaque at an arteriosclerotic site with a high-strength pulse beam; (3) a temperature-measurement unit for measuring a temperature change on the vessel surface which is caused by the conduction of heat generated at the plaque site due to the high-strength pulse beam irradiation; and (4) a temperature transient response analysis unit for analyzing the fragility of the plaque based on the temperature change on the vessel surface.

Description

Technical Information Diagnosis of vulnerable plaque by active temperature measurement

The present invention relates to an apparatus including a catheter for determining fragility of a plaque in a blood vessel wall, for example, an arteriosclerosis site, by active temperature measurement. Specifically, plaque vulnerability is determined by irradiating high-intensity pulsed light to the atherosclerotic site and analyzing the conduction of heat generated in the plaque by the high-intensity pulsed light through the blood vessel wall Device. Background art

Atherosclerosis in the coronary arteries causes various complications. The site of atherosclerosis is composed of plaque and fibrous cap, and cracking or rupture of the fibrous cap leads to thrombus formation, often leading to major organ infarction such as acute myocardial infarction. It is thought that inflammation is involved in the progression from stable plaques with low risk of complications to vulnerable plaques with high risk of broken complications. Vulnerable plaque is usually covered by a thin fibrous cap within the vessel wall, and its formation is largely dependent on the infiltration of macrophages, smooth muscle cells and T lymphocytes. It has been reported that the progression of inflammation is accompanied by an increase in the temperature of the plaque (VAN DE R WAL, A. shi. Eta 1., Circulation, 89, 36-44, 1994, CAS S CE LLS, W. eta 1., T he Lancet, 347, 144 7—144 9, 199 96 and S TEFANAD IS, G. eta 1., Circulation, 99, 19 6 5—Γ 9 7 1, see '1 9 9 9), It has been suggested that vulnerable plaque can be detected by measuring plaque temperature, and that the risk of complications such as myocardial infarction can be determined.

However, the plaque is covered with a fibrous cap, and with the current catheter system, the temperature can be measured only on the inner surface of the blood vessel wall, and it is difficult to directly measure the plaque temperature. It is also conceivable to measure the temperature rise on the inner surface of the blood vessel wall due to the heat generated and conducted by the plaque.However, since the blood flow partially removes the heat, the temperature rise is 0.1 ° C. It is practically extremely difficult to accurately measure the temperature rise of the blood vessel wall.

The heat generated by the plaque is transmitted through the fibrous cap covering the plaque and transmitted to the inner surface of the blood vessel wall, where the size (width and thickness) of the plaque and the thickness of the fibrous cap affect the heat transfer. It is considered that the temperature rise on the inner surface of the blood vessel wall varies depending on the size of the plaque and the thickness of the fibrous cap. This suggests that the ability to measure the heat transfer pattern generated by the plaque will determine whether the plaque is stable or vulnerable. In fact, using a model simulating an atherosclerotic lesion, a diode laser is applied from the adventitia side to control the irradiation pattern using a shirt to the part corresponding to the plaque simulating a rise in temperature due to inflammation. A heat conduction simulation model for estimating the thickness of the fibrous cap was reported by examining the conduction pattern of the generated heat to the part corresponding to the fibrous cap, by irradiating the heat with a continuous laser. (Takemi Ma tsuieta 1., I EEE TRAN SACT I ONS ON BI OMED I CA L ENG I NEER I NG, V o 1.8, o. 4, A ri 1 200 1 and Tak em i Ma tsuiet 1., J ourna 1 of Me dic a 1 E nineering & Technology, Vol. 25, number 5, 18 1-18 4, September / October 2000). However, in this simulated simulated model, at in vitro 0, indian green (ICG) was injected into the intima of the porcine thoracic descending aorta to enhance the absorption of laser light, mimicking Braak. Then, the ICG absorption site was irradiated with a laser to generate heat, and a temporal change in temperature on the blood vessel wall surface due to the conduction of the heat was measured to simulate thermal conduction (Takemi Matsuieta 1., J. ourna 1 of Medica 1 Engineering & Technology, V o 1 ume 25, number 5, 18 1-18 4, September ZO ctober 200 1). This model experiment shows that the heat transfer pattern changes with the thickness of the fibrous cap covering the plaque. However, we did not use a model that accurately mimics the actual atherosclerotic site, and the heat conduction simulation model is a one-dimensional model that relates the temperature rise of the fibrous cap model due to heat conduction and the thickness of the fibrous cap. It was only a model, far from an accurate simulation of heat transfer in the vasculature. Further, in the heat conduction simulation model, although the temperature change of the blood vessel wall is measured with time, only the temperature rise (ΔΤ) of the blood vessel wall surface is followed, and the transient response to the temperature change with time is measured. Is not analyzed in detail. Furthermore, they did not suggest how to actually irradiate the laser in-vivo and generate heat artificially, and how to measure the heat conducted from there to the inner surface of the blood vessel wall.

The present invention provides an apparatus for determining plaque vulnerability at an atherosclerotic site using high intensity pulsed light such as a pulsed laser. Aim. Specifically, by irradiating high-intensity pulsed light to the atherosclerotic site, generating heat by absorbing the pulsed light with a plaque, and measuring the conduction pattern of the generated heat on the inner surface of the blood vessel wall, An object of the present invention is to calculate the thickness of the fibrous cap covering the plaque and / or the degree of inflammation of the plaque, and to provide an apparatus for determining whether the plaque is stable or vulnerable. Disclosure of the invention

The present inventors have conducted intensive studies to solve the above problems in the conventional technology. In other words, when high-intensity pulsed light is applied to the inside of a blood vessel wall, for example, an arteriosclerosis site, and the plaque generates heat by absorbing the high-intensity pulsed light, how the generated heat is conducted through the blood vessel wall A heat conduction simulation model of the blood vessel wall was created to examine how the temperature on the inner surface of the blood vessel wall changes over time. At this time, in order to create a more accurate heat conduction simulation model for the blood vessel wall, a two-dimensional or two-dimensional transient heat conduction finite element analysis was used. The present inventors actually irradiate high-intensity pulsed light to an atherosclerotic site and actually measure a temperature change pattern of a blood vessel wall due to conduction of heat when plaque generates heat, The pattern is compared with the temperature change pattern calculated by the heat conduction simulator for the blood vessel wall, and fitting is performed by adjusting the parameters to cover the plaque at the atherosclerotic site. The inventors have found that the thickness of the fibrous cap and / or the degree of progression of plaque inflammation can be calculated, and completed the present invention.

That is, the present invention is as follows.

[1] An active temperature measuring device for determining the fragility of a plaque in a blood vessel wall,

(1) a catheter inserted into a blood vessel, (2) high-intensity pulsed light irradiating means for irradiating the blood vessel wall with high-intensity pulsed light, and

(3) Temperature measurement means for measuring the temporal change in temperature on the inner surface of the blood vessel wall due to the conduction of heat generated in the plaque portion due to absorption of the irradiated high-intensity pulsed light into the plaque portion in the blood vessel wall

An arc temperature measuring device.

[2] Anactipometer for determining the fragility of the plaque in the blood vessel wall,

(1) a catheter inserted into a blood vessel,

(2) high-intensity pulsed light irradiating means for irradiating the blood vessel wall with high-intensity pulsed light,

(3) a temperature measuring means for measuring a temporal change in temperature on the inner surface of the blood vessel wall due to conduction of heat generated in the plaque portion due to absorption of the irradiated high-intensity pulsed light into the plaque portion in the blood vessel wall; and

() Temperature transient response analysis means for analyzing plaque vulnerability from temporal changes in the inner surface of the blood vessel wall

An active temperature measuring device having:

[3] The active temperature measuring device according to [1] or [2], wherein the high-intensity pulsed light is a laser.

[4] The active temperature measuring device according to any one of [1] to [3], wherein the wavelength of the high-intensity pulsed light is equal to the absorption wavelength of the force rotin deposited on the plaque. ,

[5] A photosensitizing agent (PDT agent) for Ph todinemic Therapy is preliminarily accumulated in plaques for which vulnerability is to be determined, and the wavelength of the high-intensity pulsed light in (2) is equal to that of the PDΤ. The active thermometer according to any one of [1] to [3], which is close to an absorption wavelength of a drug. [6] The catheter-palm catheter of (1), wherein the temperature measurement section of the temperature measurement means of (3) contacts the inner surface of the blood vessel wall by expanding the balloon, and measures the temperature. [1] The active temperature measuring device according to any one of claims 1 to 5.

[7] The blood vessel wall is irradiated with the high intensity pulsed light by the high intensity pulsed light irradiating means of (2), and the high intensity pulsed light is absorbed by the black to generate heat. The time-dependent temperature change of the inner surface of the blood vessel wall due to the generated heat conducted through the blood vessel wall is measured by the measuring means, and the actual time-dependent temperature change of the inner surface of the blood vessel wall is measured by the temperature transient response analyzing means (4). Transient response curve and temperature transient response analysis A temporal temperature change simulation model curve created using a heat conduction simulator for the vessel wall including the means is compared to determine the vulnerability of the plaque in the vessel wall The active temperature measuring device according to any one of [1] to [6].

[8] The time-varying temperature change simulation model curve on the inner surface of the blood vessel wall adjusts the parameters of the physical properties of the blood vessel wall, the parameters of the structure of the blood vessel wall, and the parameters of the heat generation due to high-intensity pulsed light irradiation. The active temperature measuring device according to [7], which is created using a heat conduction simulator for a wall.

[9] The active temperature measuring device according to [8], wherein the parameter relating to the structure of the blood vessel wall is obtained by intravascular ultrasound imaging (IVUS).

[10] The analysis means of (4) uses the simulation model curve of the temperature change over time calculated by the heat conduction simulator for the blood vessel wall and the actual time-lapse temperature of the inner surface of the blood vessel wall after irradiating the blood vessel with high-intensity pulsed light. By comparing the change transient response curve and the parameter concerning the thickness of the fibrous cap in the blood vessel wall, the actual time-dependent temperature change transient curve and the calculated time-dependent temperature change simulation are calculated. Fit the model curve to cover the plaque The active thermometer according to any one of [1] to [9], wherein the thickness of the fibrous cap is calculated to determine plaque vulnerability.

[11] Furthermore, by changing the parameters related to the degree of plaque inflammation progression, the actual time-dependent temperature change transient response curve and the calculated time-dependent temperature change simulation model curve are fitted to fit the plaque. The active thermometer according to [10], which estimates the degree of inflammation and determines the plaque vulnerability.

[1 2] The beam thickness can be changed by the high-intensity pulsed light irradiation means of (2), and the transient response curve of temperature change over time on the inner surface of the blood vessel wall when a thick beam is irradiated shows the plaque blood flow. The active temperature measuring device according to any one of [1] to [1 1], which reflects the size of the direction.

[1 3] The active temperature measuring device according to any one of [1] to [1 2], wherein the temperature measuring means of (3) is capable of simultaneously measuring a plurality of points over time.

[14] In the temperature transient response analysis method of (4), the fibrous cap covering the plaque by fitting the first half of the peak of the transient response curve of temperature change over time on the inner surface of the blood vessel wall due to heat conduction. The active temperature measuring device according to any one of [1] to [1 3], wherein a thickness of the temperature measuring device is calculated.

[15] In the temperature transient response analysis method of (4), the plaque thickness (volume, volume, The active temperature measuring device according to any one of [1] to [1 3], wherein depth is calculated.

[16] A system for determining plaque vulnerability in a blood vessel wall, comprising: (1) the inner surface of a blood vessel wall generated by irradiation of high intensity pulsed light to a plaque portion in the blood vessel wall and transmitted to the inner surface of the blood vessel wall; Means for transferring data relating to the temperature transient response curve over time to the temperature transient response analysis means, (2) Temperature transient response analysis means for analyzing the thickness of the fibrous cap covering the black based on the data on the transferred temperature change transient response curve,

(a) storage means for storing data relating to parameters related to heat conduction to a blood vessel wall and data of a heat conduction simulation model curve; and

(b) Comparison of the temperature change simulation model curve over time at the temperature measurement point obtained by the heat conduction simulator for the blood vessel wall with the transient response curve of the temperature change over time actually measured at the temperature measurement point Calculation means for adjusting the simulation results to the actual results by changing the parameters in the heat conduction simulation

Temperature transient response analysis means having:

(3) Output means for outputting information on the thickness of the fibrous cap covering the analyzed plaque

Plaque vulnerability determination system having

[17] (6) In the calculation means of (a), further, by changing a parameter relating to the degree of progression of plaque inflammation, the actual time-dependent temperature change transient response curve and the calculated time-dependent transient curve are calculated. The temperature change simulation model is fitted with a curve to estimate the degree of progression of plaque inflammation, and the output means of (3) outputs information on the degree of progression of inflammation of the plaque. Vulnerability judgment system.

[18] A method for determining plaque vulnerability at a site of atherosclerosis,

(1) The temperature transient response analysis means obtains data on the temperature change transient response curve of the inner wall of the blood vessel wall due to the heat generated by irradiating the plaque part of the atherosclerotic site with high-intensity pulsed light and conducted to the inner wall of the blood vessel wall. Receiving,

(2) Heat conduction stain on the blood vessel wall stored in the transient response analysis means To compare the simulated temperature change simulation model curve calculated over time with the actual temperature change transient response curve measured over time to change the parameter related to the thickness of the fibrous cap covering the plaque. Fitting the actual temporal temperature change transient response curve and the calculated temporal temperature change simulation model curve to calculate the thickness of the fibrous cap covering the plaque; and

(3) Outputting the calculated thickness of the fibrous cap covering the plaque

Method for determining plaque vulnerability.

[19] Further, in the step (2), by changing a parameter relating to the degree of progression of plaque inflammation, an actual time-dependent temperature change transient response curve and a calculated time-dependent temperature change simulation are obtained. The plaque vulnerability determination according to [18], in which the plaque inflammation progress is estimated by fitting the plaque model curve and the plaque inflammation progress is estimated in the step (3). Method. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing an apparatus of the present invention.

FIG. 2 is a diagram showing a heat conduction simulation model for a blood vessel wall.

FIG. 3 is a conceptual diagram of the system of the present invention.

FIG. 4 is a flowchart of a process executed by the system of the present invention. FIG. 5 is a diagram showing the results of measuring the temperature histories at three points of the intima, the media and the adventitia when heating the vascular segment.

Fig. 6 shows the differential movement of a pitta freshly extracted with a differential scanning calorimeter (DS). FIG. 6 is a view showing the results of measuring the heat capacity of the vein and the porcine dry descending aorta. 'FIG. 7 is a diagram showing the results of a heat conduction calculation performed to match the results of the temperature measurement experiment on the blood vessel wall.

FIG. 8 is a diagram showing a specific heat adjusted to match a temperature measurement experiment using a specific heat value based on a heat capacity measurement result by DSC.

Figure 9 shows the results of a comparison between the heat transfer calculation using the obtained specific heat value and the corresponding temperature measurement experiment. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The device of the present invention is an active temperature measuring device for detecting the presence of a vulnerable plaque that induces thrombus formation and causes acute myocardial infarction. The thickness of the fibrous cap covering the plaque and the degree of inflammation or inflammation are known. With this information, it is possible to determine whether the plaque is stable or vulnerable, that is, the vulnerability of the plaque. Once the plaque vulnerability is known, the risk of developing myocardial non-mammary obstruction can be assessed. In the present invention, the actuated temperature measurement means that heat is artificially generated in a plaque by irradiating high-intensity pulsed light to the inside of a blood vessel wall, for example, an arteriosclerosis site, and the artificially generated heat is converted into a blood vessel. It refers to measuring on the inner surface of the wall, and is a term for passive temperature measurement in which naturally generated heat is measured on the inner surface of the blood vessel wall.

The device of the present invention is a device having a catheter, and includes high-intensity pulsed light irradiation means, temperature measurement means for the inner surface of a blood vessel wall, pallets, and temperature transient response analysis means.

High-intensity pulsed light covers the plaque by irradiating the pulsed light with high intensity and easily absorbed by the pigment deposited on the plaque After passing through the fibrous cap and reaching the plaque, it is absorbed by pigment present in the plaque and generates heat there. ， The generated heat is immediately conducted to the surrounding area from the point of generation, and partly passes through the fibrous cap and reaches the inner surface of the blood vessel wall. The amount of pigment that absorbs high-intensity pulsed light deposited in the plaque varies depending on the degree of inflammation of the plaque, which changes the amount of heat generated in the plaque, and the thickness of the fibrous cap covering the plaque. As a result, the time required for heat to reach the inner surface of the blood vessel wall and the temperature of the inner wall of the blood vessel rising due to heat conduction are different. Therefore, by monitoring the temperature change on the inner surface of the blood vessel wall after irradiation with the high-intensity pulsed light, the thickness of the fibrous cap covering the plaque and / or the degree of progression of the plaque inflammation can be determined. At this time, a simulation model of heat conduction in the blood vessel wall (a heat conduction simulator for the blood vessel wall) was created, and the change pattern of the model was compared with the actually measured temperature change pattern of the blood vessel wall. Thus, the degree of inflammation of the plaque can be determined by the thickness of the fibrous cap. The inflammatory nature of the plaque is mainly determined by the number of macrophages, which are inflammatory cells infiltrating the plaque. It can be said that the greater the number of macrophages, the more plaque inflammation progresses. Macrophages in the plaques phagocytose cholesterol lipids, resulting in the deposition of carotene. As described below, in one embodiment of the present invention, high-intensity pulsed light having a wavelength that is absorbed by carotene is irradiated, and the energy of the high-intensity pulsed light is absorbed by carotene to generate heat. . In addition, although the number of macrophages and the size of the plaque in the plaque do not completely correspond to each other, the size of the plaque generally reflects the number of accumulated macrophages. Judgment of the degree of progression of inflammation of the plaque mainly means judgment of the size (width and thickness) of the plaque. In particular, the size of the plaque in the blood flow direction can be determined by thickening the beam of the high-intensity pulsed light to be irradiated as described later. Can be.

As the catheter of the device of the present invention, a catheter usually used in a blood vessel endoscope or the like can be used, and the diameter and the like are not limited. High-intensity pulsed light transmission means, high-intensity pulsed light side emission means, balloon for closing high-intensity pulsed light and blood flow during temperature measurement, and liquid supply / drainage means for expanding and contracting the balloon Or, air supply / intake means, temperature measurement means, etc. are provided.

As the high-intensity pulsed light generating means, a normal high-intensity pulsed light generator for treatment can be used. In the device of the present invention, the high-intensity pulsed light penetrates the fibrous cap portion of the arterial sclerosis site, and when it reaches the plaque portion, is absorbed by the plaque and generates heat there.

This is because carotene is deposited on the plaque as described above, and the carotene absorbs high-intensity pulsed light energy. Therefore, high-intensity pulsed light having a wavelength near 450 nm to 500 nm, which is the absorption wavelength of carotene, is used. If the wavelength of the high-intensity pulsed light is different, the efficiency of absorbing the same intensity of the high-intensity pulsed light is different, so that the area of the plaque where the temperature is generated differs. For this reason, the obtained time-dependent temperature change curve also differs, so that more information can be obtained by using high-intensity pulsed light having a plurality of wavelengths. The thickness of the high intensity pulsed light beam is not limited. As the beam thickness increases, the area in the plaque where heat is generated increases, and the heat transfer from the entire large area can be measured. As a result, it is possible to determine the size of the plaque, particularly the width in the blood flow direction, by increasing the thickness of the beam. At this time, by arranging high-intensity pulsed light transmission fibers having different diameters in the catheter, it is possible to irradiate high-intensity pulsed light having different beam thicknesses. In addition, a photosensitizing drug (PDT drug) for photodynamic therapy (PDT) may be accumulated in the plaque in advance. PDT is a combination therapy using a photosensitizing drug such as a certain porphyrin derivative and a light beam such as laser light, and is selectively applied to a lesion such as cancer tissue to be treated by the photosensitizing drug. It utilizes the property of accumulating in the skin, and after the photosensitizing drug is administered by intravenous injection or other method, the lesion is irradiated with a light beam such as a laser beam to mainly cause photochemical reactions. Is a treatment for destroying the tissue. By selectively accumulating the PDT drug on the plaque, the irradiating high-intensity pulsed light is absorbed by the PDT drug accumulated on the plaque more efficiently than carotene, and the calorific value of the plaque is larger than that of carotene It becomes bad. For this reason, the fitting between the calculation result calculated by the heat conduction simulator for the blood vessel wall and the actually measured result can be performed using a higher numerical value, so that a more accurate result can be derived. is there. Various PDT drugs are known, for example, P hotofrinll (PHE) (630 nm) (po 1 yhematoporphyrine the τ / ester), ATX—S 10 (670 nm) (gal 1 iumporphyrincomple), 5-ALA (630 nm) (5-amino 1 evurinicacidhydrochlo ride) ^ NP e 6 (664 nm) (mono-L-aspartylchlorine 6), m-THPC (652 nm) To tetra (m-hydroxyphenyl) chlorin), SnET2 (637 nm) (tinethyletio-urpurin), BPD-MA (690 nm) (benzoporphyrinderivat ivemonoacidring A ') Lu-tex (732 nm) ) (Lutetium Texaphyrin) 'etc. It shows the name of the product, the absorption wavelength, and the generic name.) Any of the known PDT agents, including these, can be used. Since each PDT drug has its own absorption wavelength, it is necessary to use high-intensity pulsed light that is close to the absorption wavelength of the PDT drug. The PDT drug accumulates in plaques when administered, for example, by intravenous injection. This is considered to be due to phagocytosis by macrophages accumulated in the plaque. The administration timing of the PDT drug varies depending on the type of the drug, but is administered several hours to several days before the temperature is measured by the device of the present invention. This is to allow sufficient time for the PDT drug to accumulate on the plaques. The PDT drug is administered by dissolving the drug in an appropriate buffer such as a phosphate buffer solution, and adding a pharmaceutically acceptable additive as necessary. Additives include solubilizers such as organic solvents, IDH regulators such as acids and bases, stabilizers such as ascorbic acid, excipients such as glucose, and isotonic agents such as sodium chloride. No. The method of administration is not limited, and administration may be by intravenous injection, intramuscular injection, subcutaneous injection, oral administration, or the like. The dose of the PDT drug is not limited either, and when administered systemically by intravenous injection or the like, the weight is 0.01 to 10 OmgZkg, preferably 1 to 5 mg / kg body weight.

The high-intensity pulsed light used is a pulse laser, a second harmonic of a titanium sapphire laser, or a tunable optical parametric oscillator (OPO). Generated light. Examples of the laser include a pulsed dye laser such as flash lamp pumping and XeC1 excimer laser pumping, and a semiconductor laser such as GaA1As. Of these, 0 P0 having a high wavelength tunable performance is desirable. New As an example of 0P0, there is MiRa-0P0 of Cohrent.

If no PDT agent is used, the wavelength of the high intensity pulsed light used is 450 nm to 500 nm, preferably 450 nm to 480 nm, which is the absorption wavelength of the PDT drug. High intensity pulsed light is used.

The intensity of the high-intensity pulsed light to be applied is not limited, but it must be high enough not to destroy the fibrous cap covering the plaque.In addition, the temperature of the blood vessel wall rises to prevent thermal denaturation of the blood vessel wall due to heat. Must be less than 30 ° C.

The irradiation time of the high-intensity pulsed light is not limited, but is preferably about 1 ms. Means for transmitting high-intensity pulsed light to the vascular wall of the artery include a means for emitting high-intensity pulsed light near the distal end of the catheter and high-intensity pulsed light for generating high-intensity pulsed light A quartz fiber (optical fiber) transmitted from the device to the high-intensity pulsed light emitting means is included. As used herein, the term “near the distal end” means a portion near the end opposite to the end (proximal end) connected to the high-intensity pulsed light generator, and includes the distal end and the distal end. Refers to the part about 10 cm from the distal end.

The quartz fiber is included in the catheter, and is connected at one end to the high-intensity pulsed light generator and at the other end to the high-intensity pulsed light emitting means. The suidou fiber used in the present invention fits inside a catheter, ranging from a very thin diameter of about 0.05 to 0.3 mm to a visible one, and transmits high-intensity pulsed light energy. As far as possible, a wide variety of diameters can be used.

The high-intensity pulsed light radiating means is a means for irradiating the arterial blood vessel wall with high-intensity pulsed light, and the high-intensity pulsed light transmitted along the blood vessel in the quartz fiber enters the blood vessel wall. Side irradiation must be performed to reach the plaque of the atherosclerotic lesion. Side irradiation of high intensity pulsed light can be achieved by refracting or scattering high intensity pulsed light. The side radiating means includes a prism, a scattering material, and the like. For example, a prism may be provided so that high-intensity pulsed light is laterally irradiated near the distal end of quartz fiber, or high-intensity pulsed light is laterally irradiated near the distal end of quartz fiber. The surface may be roughened as described above. In addition, a scattering substance such as alumina-silica force for scattering high-intensity pulsed light may be applied to the vicinity of the distal end of the quartz fiber, or these scattering substances may be contained in the balloon. You may leave. The area range in which the high-intensity pulsed light emitted laterally from the vicinity of the distal end of the quartz fiber irradiates the artery is preferably 0.5 cm ² to 3 cm ² . The irradiation area range can be appropriately set by changing the beam width of the high-intensity pulsed light, and the beam width of the high-intensity pulsed light can be adjusted to the thickness of the fiber transmitting the high-intensity pulsed light. You can change it.

The high intensity pulsed light irradiation is not limited to one location, and a plurality of locations may be irradiated simultaneously. Simultaneous irradiation of multiple locations generates heat at multiple locations within the plaque, and the conduction of heat from those locations can be measured. A variety of information can be obtained. In this case, a plurality of high-intensity pulsed light transmitting fibers may be provided in the catheter, and a means for irradiating a plurality of high-intensity pulsed lights may be provided at the distal end of the catheter.

As the balloon, a balloon for coronary artery used in a normal balloon catheter can be used. The balloon is attached near the distal end of the catheter. The temperature measurement unit (described later) is installed on the puloon by expanding the balloon. The contact between the probe and the blood vessel wall makes it possible to measure the temperature inside the blood vessel wall The means for expanding the balloon is not particularly limited, but by supplying an appropriate liquid or gas into the balloon. In this case, Katate, Liquid and gas supply and discharge pipes are also provided in the tank. The pressure at which the balloon presses against the vessel wall during inflation is preferably between 0.2 and 1 kg Z cm ² . As described above, the balloon may include high-intensity pulsed light emitting means. The temperature measuring means of the device of the present invention is a means capable of measuring the temperature of the inner surface of the blood vessel wall.

A temperature measuring probe such as a contact thermometer and a thermocouple can be used as a temperature measuring part of the temperature measuring means. If contact thermometers or thermocouples are used as temperature measuring probes, they must be placed outside the balloon or buried in the balloon, as described above, because they need to contact the vessel wall. The temperature probe should be in contact with the vessel wall when the pallet expands. The probe for temperature measurement and the temperature display means are connected by a line provided in the catheter, and the temperature information is transmitted to the temperature display means. The temperature display means also includes a processor, which processes the transmitted temperature information, and transfers the processed data to the temperature transient response analysis means.

FIG. 1 shows a configuration diagram of the active temperature measuring device of the present invention.

Temperature transient response analysis means

When using the apparatus of the present invention to determine the thickness of the fibrous cap 2 covering the plaque 1 or the degree of inflammation of the plaque 1, first construct a heat conduction simulator for the vascular wall 3 I do. A heat transfer simulator for the vessel wall can be constructed by two- or three-dimensional transient heat transfer finite element analysis. The heat conduction calculation by the finite element method is based on the assumption that the object for which the heat conduction is to be calculated is divided into small elements, and that heat transfer occurs only between adjacent elements, and the heat transport equation at the nodes of the divided elements This is a method of calculating heat conduction by At this time, the parameters specific to the blood vessel wall 3 are derived by using a commercially available heat conduction calculation program, and You can build a 'heat conduction' simulator. An example of such a program is the QUICK Therm BIO (Computational Mechanics Laboratory) created based on heat conduction to the myocardium.Entering the physical property parameters of the vascular wall 3 into the program Thus, a heat conduction simulator for the blood vessel wall 3 can be constructed.

Specifically, for example, heating the aorta of the septum, measuring the temperature history (temporal temperature change) of the intima, media and adventitia of the aorta using a thermocouple, and using the program Then, heat conduction calculation simulating the experimental system is performed, and various parameters may be adjusted to match the results of the temperature measurement experiment. Various parameters can be selected, for example, by calculating by changing the value of specific heat. In this case, calorimetry is performed using a differential scanning calorimeter to observe the specific heat change of the blood vessel wall in detail. Finally, by adjusting the parameters based on the calculation results so as to match the physical properties of the blood vessel wall 3, a heat conduction simulator that reflects the physical properties of the blood vessel wall '3 can be constructed. .

Next, the parameters relating to the actual structure of the blood vessel wall and the generated heat are input to the heat conduction simulator for the blood vessel wall 3 constructed by adjusting the physical property parameters. .

First, the blood vessel structure of a test blood vessel for which plaque vulnerability is to be determined is analyzed by angiography or intravascular ultrasound imaging (IVUS) to determine the thickness of the blood vessel and the thickness of the blood vessel wall 3. Get information such as Commercially available systems may be used for angiography and IVUS. These pieces of information are input to the constructed heat conduction simulator for the blood vessel wall 3. However, in IVUS and angiography, although the presence of plaque 1 can be inferred, the degree of inflammation of plaque 1 (state of plaque 1) reflected by the heat transfer coefficient of plaque 1 and the size of plaque 1 It is possible to obtain accurate information about the internal structure of the blood vessel wall 3, such as the thickness of the fibrous cap 2 covering the plaque 1 and I can't. Therefore, based on the actual structural information of the vascular wall 3 obtained by angiography and IVUS, the degree of inflammation of the plaque 1 such as the heat transfer coefficient of the plaque and the size of the plaque 1 and the fiber covering the plaque 1 Enter the parameter about the thickness of the functional coating 2. By inputting the information on the structure of the vascular wall 3, a finite element method model in which the parameters of the structure of the vascular wall 3 of the test vessel including the state of the plaque 1 are adjusted is created. A heat conduction simulator for the blood vessel wall that reflects not only the structure but also the physical properties can be constructed. Among the parameters relating to the structure of the blood vessel wall 3, the parameters relating to the degree of inflammation of the plaque 1 such as the heat transfer coefficient of the black 1 and the size of the plaque 1 and the thickness of the fibrous cap 2 covering the plaque 1 are described above. The comparison between the actual time-dependent temperature change transient response curve of the inner surface of the blood vessel wall and the time-dependent temperature change simulation model curve created using the heat conduction simulator for the blood vessel wall including the temperature transient response analysis means was performed. Is adjusted and fitting is performed.

In addition, the heating term of the blood vessel by high-intensity pulse 4 light irradiation is input to the simulator. The term of heating of a blood vessel by high-intensity pulsed light irradiation refers to a parameter relating to heat that can be generated by high-intensity pulsed light irradiation or the like. At this time, the heating term can be set in accordance with the actual method of irradiating the high intensity pulsed light. For example, when a high-intensity pulsed light beam is actually thin when performing actual temperature measurement, the range in which heat is generated in the plaque is narrow, and heat is transmitted to the blood vessel wall from a narrow heat generating site. On the other hand, if the beam of the high-intensity pulsed light is too thick, the area of heat generated in the black area will be wide, and the heat will be transmitted to the blood vessel wall from a wide heat generation site. When the thickness of the high-intensity pulsed light beam is changed in this way, the heating term is changed corresponding to the beam of each thickness. Temperature changes when the beam of high-intensity pulsed light is large reflect, in particular, the size of the plaque in the blood flow direction. Here, the size of the plaque in the blood flow direction is Parallel means the size of the blood in both the forward and reverse directions. Also, in actual actual temperature measurement, 'The temperature measurement point is not limited to one point, but may be set at multiple points. In this case, the parameter relating to the position of the temperature measuring point in the simulator may be changed.

As described above, a vascular wall heat conduction simulation model including parameters on physical properties of the vascular wall, vascular structure, and heat generated in active temperature measurement is completed.

Using a simulator in which such parameters are adjusted, it is possible to calculate a temporal change in temperature at a temperature measuring point on the inner surface of the blood vessel wall. In this case, the simulator simulates the heat conduction by the finite element method model of the blood vessel that has obtained the structural information, and calculates the temperature change over time at the temperature measurement point. Since the heat conduction simulator of the blood vessel wall of the present invention performs heat conduction calculation using a multi-dimensional finite element method, the size of a generated portion of the conducted heat, the amount of generated heat, a temperature measuring point, and the like can be arbitrarily set. No matter what parameters are set, it is possible to calculate the temperature change over time at the temperature measurement point and obtain a temperature change simulation model curve. Figure 2 shows a schematic diagram of the temperature change simulation model curve at the temperature measurement point obtained by the calculation of the heat conduction simulator for the blood vessel wall.

Next, an actual temperature measurement is performed on the blood vessel wall, and a temporal temperature change at the temperature measurement point is actually measured. At this time, the temporal change in temperature at the temperature measurement point is a transient response, and the temperature transient response can be analyzed by the temperature transient response analysis means of the present invention. The transient response is defined as the transfer function H (f

), When an input signal u (t) is given, it causes an output X (t), which is shown by the time X (t) reaches a new steady state. Refers to a transient process. In the present invention, the temperature change (X (t)) at the temperature measuring point shows a transient response, and finally reaches a steady state. In the present invention, since the temperature change can be analyzed as a transient response, not merely as a matter of temperature rise, it is far more than simply measuring the temperature rise value (Δ Τ) at the temperature measuring point. The state of the plaque can be accurately known, and the physical property parameters of the blood vessel wall input to the heat conduction simulator for the blood vessel wall do not change as long as the target of the active temperature measurement is the blood vessel wall. The parameters related to the heating term are also adjusted according to the actual active temperature measurement conditions. When the measurement is performed on a blood vessel without plaque, since the structure of the blood vessel is accurately analyzed by the IVUS, the measured temperature change transient response curve and the temperature change simulation model curve calculated by the simulator are almost the same. However, when plaque is present on the blood vessel wall, the IVUS cannot accurately measure the thickness of the fibrous cap covering the plaque, and the time calculated by the simulator according to the thickness of the fibrous cap Temperature variation There is a deviation between the simulation model curve and the actually measured temperature transient response curve. Therefore, both curves are fitted by changing the thickness of the fibrous cap as a parameter. The thickness of the fibrous cap when both curves are fitted represents the actual thickness. In addition, since the size of the heat-generating region and the amount of heat generated vary depending on the degree of plaque inflammation, the degree of black inflammation, which cannot be measured by IVUS, also causes a shift. Furthermore, the difference in heat transfer coefficient in the plaque is different from that of the normal blood vessel wall, and this difference also causes a shift. The deviation mainly reflects the thickness of the fibrous cap, and also reflects the degree of progression of plaque inflammation as indicated by the plaque's coefficient of thermal conductivity and size ('width and thickness).

When trying to obtain information on the thickness of the fibrous cap by analysis, the thickness of the fibrous cap is set as a parameter of the vascular structure in the heat conduction simulator for the blood vessel wall. Changing this parameter to the temperature measurement point The temperature change in the simulation is calculated by simulation, and the temperature change transient response curve measured each time is compared with the temperature change simulation model curve calculated by the simulator. By repeating this process, the two curves are fitted. In this case, it can also be said that the illuminants are fitted so that the two curves overlap. In addition, the comparison of the curves. The fitting may be performed by calculating an approximate equation of the two curves and calculating based on the equations, or may be performed on all or a part of the coordinate (time, temperature) data of each point of the curve. May be compared as a data set. The value of the fibrous cap thickness as a parameter when the fitting is completed is the actual fibrous cap thickness. As described above, the change in temperature at the temperature measurement point reflects not only the thickness of the fibrous cap but also the degree of plaque inflammation, so that the plaque inflammation progresses as a structural parameter of the vascular wall. By adopting an item indicating the degree, the degree of progression of plaque inflammation can be estimated and determined by fitting. As described above, the plaque coefficient of thermal conductivity and plaque size reflect the degree of progression of inflammation of the plaque, so the plaque coefficient of thermal conductivity and the size of the plaque are used as parameters. It is good to adopt.

When high-intensity pulsed light is applied to the atherosclerotic site of a blood vessel, heat is generated in a certain area within the Braak according to the beam thickness, and heat is transmitted from the entire area where the heat is generated to the surroundings. At this time, the heat generated near the temperature measurement point arrives at the temperature measurement point in advance, and the temperature at the temperature measurement point rapidly rises after irradiation with the high-intensity pulsed light. The temperature at the temperature measurement point then peaks and then declines as the heat that reaches the temperature measurement point is lost to the bloodstream, or conducts and diffuses from the temperature measurement point to other parts. At this time, the heat conducted from the part far from the temperature measuring point arrives at the temperature measuring point with a delay, so the temperature decrease after the peak is affected by the heat conducted thereafter. The temperature change pattern shown in Fig. 2 shows such a temperature change. At this time, the fibrous cap covering the plaque is thin, The thinner, the faster the heat generated reaches the temperature measuring point without decay, so the peak temperature is reached earlier and the peak temperature value is higher. In addition, the wider the heat generation area in the black, the longer the heat conducts to the temperature measuring point after the peak temperature at the temperature measuring point, so the temperature decrease after the peak becomes slower. That is, the pattern of temperature change before the temperature at the measuring point reaches the peak reflects the thickness of the fibrous cap, and the pattern of temperature change after the temperature at the measuring point reaches the peak is It reflects the degree of inflammation of the plaque, as indicated by its thickness (width and thickness), etc., especially the thickness of the plaque. Here, the plaque thickness means the size of the plaque in the blood flow direction and the vertical direction, and is also referred to as the plaque depth. Also, when the beam thickness is changed, the heat generation area in the plaque becomes wider, so the pattern of temperature change after the temperature at the temperature measuring point reaches the peak is the state of the plaque, especially the blood flow of the plaque. Reflects directional size and plaque thickness (plaque volume).

Therefore, in order to determine the fragility of the plaque due to the thickness of the fibrous cap alone, the temperature change curve over time should be fitted before the peak, and the progress of the plaque inflammation can be determined. When trying to make a guess judgment, the temperature change curve over time may be fitted after the peak. In practice, the plaque vulnerability is mainly determined by the thickness of the fibrous cap covering the plaque, so it is possible to determine the plaque vulnerability with considerable accuracy by comparing only the first half. is there.

In addition, in the actual active temperature measurement, if the PDT drug is accumulated on the plaque in advance and the high-intensity pulsed light used is close to the absorption wavelength of the PDT drug, the energy of the high-intensity pulsed light can be efficiently used. It is well absorbed by PDT drugs. Therefore, the plaque generates a large amount of heat and conducts a large amount of heat, so that the temperature at the measuring point also increases. For this reason, The fitting can be performed using a larger temperature measurement value. Therefore, by using the PDT agent, the transient response analysis can be performed with higher accuracy, and more accurate judgment can be made.

The transient response analysis means of the present invention includes a heat conduction simulator for a blood vessel wall, and a means for inputting an actually measured temperature change.

As described above, the heat conduction simulator for the blood vessel wall is a storage means for storing data relating to the parameters of the heat conduction to the blood vessel wall and the data of the heat conduction simulation model curve, and for the blood vessel wall. A time-dependent temperature change simulation model curve at a temperature measurement point obtained by a heat conduction simulation is obtained by calculation, and the model curve and a time-dependent temperature change transient response curve actually measured at the temperature measurement point are obtained. And calculating means for comparing two temperature change curves by changing the parameters. Here, the data of the heat conduction simulation model curve refers to data relating to an approximate equation of the curve, a dataset representing coordinates of a point on the curve, and the like.

The temperature change input unit may be a device for manually inputting an actual measurement value using a keyboard or the like, or a temperature measurement unit and a transient response analysis unit may be electronically connected to each other, and the temperature change unit may be connected to the temperature change unit. The data may be transferred to the transient response analysis means.

Vulnerability assessment system for plaque at arteriosclerosis site

The present invention also includes a plaque vulnerability determination system in a blood vessel wall, for example, in a site of atherosclerosis. The system is

(1) Transferring the data on the transient response curve of temperature change on the inner surface of the blood vessel wall due to the heat generated by the plaque due to the irradiation of the high intensity pulsed light into the blood vessel wall and transmitted to the inner surface of the blood vessel wall, to the temperature transient response analysis means Means to do

(2) Based on the data on the transferred temperature change transient response curve, Temperature transient response analysis means for analyzing the thickness of the fibrous cap covering the plaque and / or the degree of inflammation of the black,

(a) Data relating to parameters related to heat conduction to a blood vessel wall; storage means for storing data of a heat conduction simulation model curve; and

(b) Temporal temperature change simulation model curve at the temperature measuring point obtained by a heat conduction simulator for the blood vessel wall and temporal temperature change transient response curve actually measured at the temperature measuring point Computing means for comparing two temperature change curves by changing the parameters in heat conduction simulation and comparing the simulation results with the actual results

Temperature transient response analysis means having:

(3) A black vulnerability determination system having an output means for outputting information on the thickness of the fibrous cap covering the analyzed plaque and / or the degree of progression of plaque inflammation. Here, the means for transferring the data relating to the time-dependent temperature change transient response curve to the temperature transient response analysis means is means for electronically transferring data directly from the temperature measuring means of the active temperature measuring device of the present invention. Alternatively, it may be a means for inputting data once output by printing or display on a display, for example, by input means such as a keyboard. The heat transfer simulator for the blood vessel wall included in the temperature transient response analysis means is a simulator constructed as described above. The output means includes printing means, display means on a display, and the like. When output by a step, it may be a specific numerical value indicating the thickness of the fibrous cap, etc., or may be a judgment on the vulnerability of the graded plaque. 1 shows a schematic diagram of the system of the invention.

Further, the present invention also includes a method for determining plaque vulnerability in a blood vessel wall, for example, at an atherosclerotic site using the system. The method comprises overheating, A step of receiving data on a transient response curve of a temperature change on the inner surface of the blood vessel wall due to heat generated by the black light generated by the irradiation of the high-intensity pulsed light to the atherosclerotic site and transmitted to the inner surface of the blood vessel wall; Covers the plaque by comparing the temporal temperature change simulation model curve calculated by the heat conduction simulator for the blood vessel wall stored in the response analysis means with the actually measured temperature change transient response curve measured over time. By changing the parameters of fibrous cap thickness and plaque inflammation progression, the actual temporal temperature change transient response curve and the calculated temporal temperature change simulation model curve are fitted. Calculate the thickness of the fibrous cap over the plaque to match the simulation results to the actual results, Step guess progress of Lark inflammation, such Rapi thickness of fibrous cap that covers the calculated issued plaques in of, and a step for outputting the progress of inflammation Z or inferred Braak. FIG. 4 shows the flow of the processing of the method executed by the system of the present invention.

Hereinafter, a specific description will be given based on examples of the present invention. Furthermore, the present invention is not limited to the following examples.

[Example 1] Construction of heat conduction simulator for blood vessel wall

Vascular wall temperature measurement for the step-like intimal surface temperature change using the abdominal aorta of the septum and heat using the heat transfer calculation software “Quick Therm BIO” (Computational Mechanics Research Center 1) using the finite element method Conducted simulations were also performed and compared. The above software was developed after studying myocardial conduction.In this example, the specific heat value with the largest change in thermophysical properties was used as the only parameter in order to match the blood vessel wall temperature measurement experiment. It was adjusted.

The porcine freshly removed thoracic descending aorta was used as an experimental sample. The descending aorta of pigs has a similar composition to human coronary arteries, such as collagen, and is more wally than coronary arteries. Suitable for experimental samples due to its large thickness. This was cut into a length (blood flow direction) of 25 mm and a width of 20 mm to obtain a vascular piece. Later, the media was torn to install a thermocouple for measuring the temperature change of the media. The thickness of the entire vessel wall is 1.4 to 2.5 mm, and the thickness from the intima to the torn surface is 0.6 to 1.2 mm.

In order to perform heating and cooling, a method of alternately contacting a high-temperature or 37-mm heated aluminum mass (40 mm cubic) was adopted. Aluminum has a large thermal conductivity of 237 W / m K and a large heat capacity of 0.901 JZK g, so it has a small temperature change at the contact surface even after contact with a vascular piece, making it suitable for heating and cooling. . The vessel pieces were placed on Styrofoam. This is because the thermal conductivity is sufficiently small, 0.05 W / m K, so that the flow of heat into and out of the outer membrane can be suppressed. For temperature history, T-type thermocouples (T / TT-30-1, Ishikawa Sangyo, Tokyo) were installed at the three points of the inner membrane, middle membrane and outer membrane, and digital recorders (DL 708E, Yokogawa) Denki, Tokyo).

Figure 5 shows the results of measuring the temperature histories at three points of the intima, media and adventitia when heating the vascular segment. From the temperature histories of the media and the epicardium, heat was transmitted with a slight delay, and the peak temperature decreased gradually from the inner membrane side, indicating that appropriate measurement results were obtained.

Then, in order to determine the physical property parameters for the blood vessel wall, the heat capacity was measured by a differential scanning calorimeter (differenttialscaanningca1orimeter; DSC).

Two types of samples were used: a freshly isolated porcine descending aorta, and a porcine isolated descending aorta that was placed in an environment with a humidity of 20% or less for 2 hours and dried. After the vessel was cut open, it was cut into small pieces so that it could be placed in an aluminum container. After measuring the mass, it was sealed in an aluminum container. The fresh one weighs 3.3 to 5.8 mg, the dried one weighs 2.4 to 6.7 mg, Met.

The DSCs used were DSC20 (Seiko I-Digital, Tokyo) and SS CZ580 thermal controller (Seiko Denko, Tokyo). The measurement was started by placing the sample sealed in an aluminum container in DSC20. The measurement start temperature was 22 ° C, the measurement end temperature was 100 ° C, the heating rate was 10 Zmin, and the sampling interval was 0.4 s. The temperature was set to be 0 to 200 ° (DSC is 0 to 2 V in the range of 0.5 to 9.5 mJZs and output as a voltage signal of 0 to 2 V.

FIG. 6 shows the results of measuring the heat capacity of the freshly isolated porcine aorta and the porcine dry descending aorta by DSC. While the heat capacity of the dried product increases almost linearly, the heat capacity of the fresh product increases exponentially as it approaches 100 ° C. Therefore, it is considered that the difference in heat capacity between the two occurred due to the endothermic effect of water evaporation. It is suggested that the temperature change of the heat capacity of the blood vessel wall is larger in the heat absorption due to the evaporation of water than in the heat denaturation of the protein.

Next, the heat conduction was calculated by the finite element method.

Using a heat conduction calculation program, Quick Thermbio (registered trademark) (Institute for Computational Mechanics, Tokyo), heat conduction calculations simulating the experimental system were performed. The division of the finite element with respect to the blood vessel wall was the one divided into 32 equal parts in the right direction. Since the thickness of the blood vessel wall was 1.4 to 2.5 mm, the calculation was performed by cutting a mesh of about 5 O ^ m in the thickness direction, which is sufficiently small. There have been no reports on the parameters of the vessel wall that have been examined in the past, and the values adjusted for the myocardium differ greatly from the experimental results. This value is set so that the specific heat increases stepwise around 45 ° C as a result of considering the effect of endothermic effect due to thermal denaturation of the protein. By changing only the value of the specific heat as a change parameter, the error from the experimental result is about ± 2 ° or less. Adjusted to be below. Strictly speaking, changes in physical properties appear not only in specific heat, but also in thermal conductivity and density, but here, only the specific heat, which is considered to have the largest change, is changed, and all other parameter changes are also changed. Adjustments were made to include changes in the specific heat value. Table 1 shows the main physical properties used in the heat conduction calculation.

(A) The specific heat value for T> 45 ° C is fixed at 12 J / gK, and only the specific heat value for Τ <45 ° C is changed to match the results of the temperature measurement experiments on the vascular pieces. The heat conduction was calculated as follows.

(B) Based on the results of the heat capacity measurement by DSC, the heat conduction was calculated by inputting the value of the specific heat.

The parameters other than the specific heat were the same as above. If the results of the heat capacity measurement by DSC were used as they were, the calculation results would be far from the results of the temperature measurement experiment to be matched.Therefore, after inputting a value obtained by multiplying the value of the heat capacity measured by DSC by a constant, fine-tuning was performed. To match the results. The following results were obtained.

(A) Figure 7 shows an example of the results of a heat conduction calculation performed to match the results of the temperature measurement experiment on the blood vessel wall. In this case, the specific heat is 5.8 J / g K (T <45 ° C), 12 J / g (T> 45 ° C), and the thermal conductivity is 0.42 Wm-1 K _ 1 By doing so, accurate heat conduction calculations could be performed. Repeating the same study, it was found that the results of the temperature measurement experiment and the heat conduction simulation match when the specific heat value at 45 ° C or lower is set to 5 to 8 JZgK.c

(B) Temperature measurement using specific heat value based on heat capacity measurement result by DSC Figure 8 shows the specific heat adjusted to match the test. Figure 9 shows a comparison between the heat transfer calculation using the specific heat value and the corresponding temperature measurement experiment. Although there is an error of about 3 ° C on the outer membrane side, the heat transfer calculation can be performed almost accurately.

For other 20 samples, thermal conductivity was calculated using the specific heat value of 1 for the results of temperature measurement experiments, but in almost all cases, the thermal conductivity was calculated within ± 5 ° C.

Thus, the specific heat value (T> 45 ° C) used in the heat conduction calculation is several times greater than the value adjusted for myocardium of 0.42 Jg-1K-1. This is a relatively large value. Myocardial collagen content is between 5.0 and 7.0 (g / 100 g) by dry weight, whereas the descending aorta is as high as 18.7 (g / 100 g). . In general, it is known that protein has a higher specific heat than water, so it is considered that the difference in specific heat value was caused by this difference in composition. The specific heat value used in the heat conduction calculation is an apparent specific heat value, but it was thought that it was almost close to the true value. Also, after doubling the measured value of the heat capacity by DSC, the heat conduction calculation without large errors could be performed using the finely adjusted specific heat value. However, as can be seen from the results of the heat capacity measurement by DSC, assuming that the contribution of the endothermic effect due to the evaporation of water has a greater effect on the temperature change of the specific heat than the endothermic effect of the thermal denaturation of the protein, It can be said that the method using this specific heat value is appropriate.

Based on these studies, a heat conduction simulator for the blood vessel wall was constructed. Industrial applicability

By using the apparatus of the present invention, the plaque at the atherosclerotic site is forcibly heated by high-intensity pulsed light irradiation, and the conduction pattern of the generated heat can be analyzed. ' The heat conduction pattern reflects the thickness of the fibrous cap covering the plaque and the degree of inflammation of the plaque. Therefore, using the heat conduction simulator for the blood vessel wall constructed in advance, the heat conduction pattern calculated by Shimiyura and the actual condition using the thickness of the fibrous cap covering the plaque or the state of the plaque as a parameter The state of the fibrous cap and the plaque covering the plaque can be determined by fitting the measured heat conduction pattern to the plaque. As a result, the plaque vulnerability can be determined, and the risk of developing myocardial infarction can be evaluated.

Claims

1. An active temperature measuring device for judging the vulnerability of a plaque in a blood vessel wall,-(1) a catheter inserted into a blood vessel,

(2) High-intensity pulsed light irradiating means for irradiating high-intensity pulsed light into the blood vessel wall; and

Request

(3) Absorption of the irradiated high-intensity pulsed light into the plaque in the vessel wall

The temperature change over time on the inner surface of the blood vessel wall due to the conduction of heat generated by the black spot was measured.

Temperature measurement means

An active temperature measuring device having:

2. An active thermometer for determining the fragility of the plaque in the vessel wall,

(1) a catheter inserted into a blood vessel,

(2) High-intensity pulsed light irradiating means for irradiating high-intensity pulsed light into blood vessel wall

(3) a temperature measuring means for measuring a temporal change in temperature on the inner surface of the blood vessel wall due to conduction of heat generated by the plaque due to absorption of the irradiated high-intensity pulsed light into the plaque in the blood vessel wall; and

(4) Temperature transient response analysis means for analyzing plaque vulnerability from temporal changes in temperature on the inner surface of the blood vessel wall

An active temperature measuring device having:

3. The active temperature measuring device according to claim 1 or 2, wherein the high intensity pulsed light is a laser.

4. The active temperature measuring device according to any one of claims 1 to 3, wherein the wavelength of the high-intensity pulsed light is equal to the absorption wavelength of carotene deposited on the plaque. '

5. The photosensitizer (PDT drug) for Ph0 todynamic thyrapy is pre-loaded on the plaque to determine the vulnerability, and the wavelength of the high-intensity pulsed light in (2) is absorbed by the PD Τ drug. The active temperature measurement device according to any one of claims 1 to 3, wherein the active temperature measurement device is close to a wavelength.

6. The catheter balloon according to (1), wherein the temperature measurement part of the temperature measurement means (3) comes into contact with the inner surface of the blood vessel wall by expanding the balloon to measure the temperature. 6. The active temperature measuring device according to any one of items 1 to 5.

7. The high-intensity pulsed light irradiating means of (2) irradiates the blood vessel wall with high-intensity pulsed light, and the high-intensity pulsed light is absorbed by the brake to generate heat. The temporal temperature change of the inner surface of the blood vessel wall due to the generated heat conducted in the blood vessel wall is measured, and the temperature transient response curve of the actual internal surface of the blood vessel wall is obtained by the temperature transient response analysis means (4). A method for comparing a temporal temperature change simulation model curve calculated using a heat conduction simulator with respect to a blood vessel wall including a temperature transient response analysis means to determine the vulnerability of black in the blood vessel wall; 7. The active temperature measuring device according to any one of items 1 to 6.

8. The model curve of the time-dependent temperature change on the inner surface of the blood vessel wall adjusts the parameters of the physical properties of the blood vessel wall, the parameters of the structure of the blood vessel wall, and the parameters of the heat generation due to high-intensity pulsed light irradiation. 8. The active temperature measuring device according to claim 7, wherein the temperature is calculated using a heat conduction simulator.

9. The active measurement according to claim 8, wherein the parameter relating to the structure of the blood vessel wall is obtained by intravascular ultrasound imaging (IVUS).

10.The analysis method in (4) uses the time-lapse simulation model curve calculated by the heat conduction simulator for the blood vessel wall and the actual inner surface of the blood vessel wall after high-intensity pulsed light irradiation. By comparing the temperature change transient response curve with time and changing the parameter relating to the thickness of the fibrous cap of the blood vessel wall, the temperature change simulation model curve is fitted to the actual temperature change transient response curve. 10. The active temperature measuring device according to any one of claims 1 to 9, wherein the thickness of the fibrous cap covering the plaque is calculated by performing blasting, and the plaque vulnerability is determined.

1 1. In addition, the parameters of the degree of plaque inflammation progression are varied to fit the actual temporal temperature change transient response curve and the calculated temporal temperature change simulation model curve to fit the plaque. 10. The active temperature measuring device according to claim 10, wherein the degree of inflammation is estimated to determine plaque vulnerability. '

-1 2. The beam thickness can be changed by the high-robbing pulse light irradiation method described in (2), and the transient response curve of temperature change over time on the inner surface of the blood vessel wall when a thick beam is irradiated shows the plaque blood 12. The active temperature measuring device according to any one of claims 1 to 11, which reflects a magnitude in a flow direction.

13. The active temperature measuring device according to any one of claims 1 to 12, wherein the temperature measuring means of (3) can simultaneously measure the temperature of a plurality of points over time. .

1 In the temperature transient response analysis method of (4), the fibrous cap covering the black by fitting the first half of the peak of the transient response curve of the temperature change over time on the inner surface of the blood vessel wall due to heat conduction The active temperature measuring device according to any one of claims 1 to 13, wherein a thickness of the active temperature measuring device is calculated. 1 5. In the temperature transient response analysis method of (4), fitting the latter half of the peak of the transient response curve of temperature change over time on the inner surface of the blood vessel wall due to heat conduction. The active temperature measurement device according to any one of claims 1 to 13, wherein the thickness (volume, depth) of the plaque is calculated by performing the calculation.

1 6. A system for determining plaque vulnerability in a blood vessel wall,

(1) Transient response of temperature change over time on the inner surface of blood vessel wall due to heat generated by irradiating high intensity pulsed light to the plaque portion of the blood vessel wall and transferred to the inner surface of blood vessel wall Means for transferring to analysis means,

(2) Temperature transient response analysis means for analyzing the thickness of the fibrous cap covering the plaque based on the transferred data on the temperature change transient response curve,

(a) storage means for storing data on parameters related to heat conduction to a blood vessel wall and data of a heat conduction simulation model curve; and

(b) Comparison of the simulation model curve with temperature change over time at the temperature measurement point calculated by the heat conduction simulator for the blood vessel wall and the transient response curve over time with the temperature change actually measured at the temperature measurement point. A calculation method that fits the simulation results to the actual results by changing the parameters in the conduction simulation

Temperature transient response analysis means having:

Plaque vulnerability determination system having

17. In the calculation means of (6) (a), the actual time-dependent temperature change transient response curve and the calculated time-dependent temperature change stain were calculated by changing a parameter relating to the degree of plaque inflammation progression. Fitting the simulation model curve to estimate the degree of plaque inflammation progression, and output information on the progression of plaque inflammation ^ by the output means of (3). Item 16. The Braak vulnerability determination system according to Item 16 above.

1 8. A method for determining vulnerability of plaque in a blood vessel wall,

(1) a step in which the temperature transient response analysis means receives data on a transient response curve of a temperature change on the inner surface of the blood vessel wall due to heat generated by irradiating the plaque of the blood vessel wall with high-intensity pulsed light and conducted to the inner surface of the blood vessel wall;

(2) Compare the temperature change transient response curve calculated over time with the temperature change transient response curve calculated by the heat conduction simulation for the blood vessel wall stored in the transient response analysis means. By changing the parameters of the thickness of the fibrous cap covering the plaque, the actual time-dependent temperature change transient response curve and the calculated time-dependent temperature change simulation model curve are fitted. Calculating the thickness of the fibrous cap covering the plaque; and

(3) Step to output the calculated thickness of the fibrous cap covering the plaque

Method for determining plaque vulnerability.

19. In step (2), the actual time-dependent temperature change transient response curve and the calculated time-dependent temperature change simulation model curve are calculated by changing the parameter relating to the degree of plaque inflammation progression. 19. The plaque vulnerability determination according to claim 18, wherein the plaque is inferred to estimate the degree of plaque inflammation, and the calculated degree of plaque inflammation is output in step (3). Method.