JPWO2004105597A1 - Diagnosis of vulnerable plaque by active temperature measurement - Google Patents

Abstract

An apparatus for determining the vulnerability of plaque in a blood vessel wall using high-intensity pulsed light such as a pulsed laser. An active temperature measuring device for determining the fragility of plaque at an arteriosclerosis site, comprising: (1) a balloon catheter inserted into a blood vessel; High intensity pulsed light irradiation means for irradiating, (3) Temperature measuring means for measuring temperature change of blood vessel wall surface due to conduction of heat generated in plaque portion by high intensity pulsed light irradiation, and (4) Temperature change of blood vessel wall surface Active temperature measuring device with temperature transient response analysis means to analyze plaque vulnerability.

Description

  The present invention relates to an apparatus including a catheter for determining plaque fragility in a blood vessel wall, for example, atherosclerotic site, by active temperature measurement. More specifically, the present invention relates to an apparatus for determining the vulnerability of a plaque by irradiating an arteriosclerotic site with high-intensity pulsed light and analyzing conduction in the blood vessel wall of heat generated in the plaque portion by the high-intensity pulsed light irradiation.

Atherosclerosis in coronary arteries causes various complications. The arteriosclerotic site is composed of plaque and fibrous capsule, and the fissure or rupture of the fibrous capsule leads to thrombus formation, often leading to major organ infarction such as acute myocardial infarction. Inflammation is considered to be involved in the progression from stable plaques with a low risk of complications to vulnerable plaques that are prone to failure and have a high risk of complications. Vulnerable plaques are usually covered with a thin fibrous cap in the blood vessel wall, and the formation of macrophages, smooth muscle cells, and T lymphocytes is largely involved in the formation. It has been reported that the progression of inflammation is accompanied by an increase in plaque temperature (VAN DER WAL, AC et al., Circulation, 89, 36-44, 1994, CASSCELLS, W. et al., The Lancet. 347, 1447-1449, 1996 and STEFANADIS, G. et al., Circulation, 99, 1965-1971, 1999), vulnerable plaque can be detected by measuring plaque temperature, myocardial infarction, etc. It has been suggested that it is possible to determine the risk of complications.
However, the plaque is covered with a fibrous capsule, and with the current catheter system, only the inner surface of the blood vessel wall can be measured, and it is difficult to directly measure the plaque temperature. It is also conceivable to measure the temperature rise of the inner wall of the blood vessel due to the heat generated and conducted in the plaque, but usually a part of the heat is taken away by the blood flow, so the temperature rise is as low as about 0.1 ° C, In practice, it is extremely difficult to accurately measure the temperature rise of the blood vessel wall.
The heat generated in the plaque is conducted through the fibrous capsule covering the plaque and is 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 capsule affect the heat conduction, 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 capsule. This suggests that if the conduction pattern of the heat generated in the plaque can be measured, it can be determined whether the plaque is stable or fragile. Actually, using a model simulating atherosclerotic lesions, a diode laser was irradiated from the outer membrane side, and the irradiation pattern was controlled using a shutter on the part corresponding to the plaque simulating the temperature rise due to inflammation. There has been a report on a heat conduction simulation model for generating heat by irradiating a laser, examining the conduction pattern of the heat generated to the part corresponding to the fibrous coating, and estimating the thickness of the fibrous coating (Takemi). Matsui et al., IEEE TRANSACTIONS ON BIOMDICAL ENGINEERING, Vol. 48, No. 4, April 2001, and Takemi Matsui et al., Journal of Medical Engineering & Engineering Engineering. 25, number 5,181-184, September / October 2001). However, in this simulation model, indocyanine green (ICG) is injected in vitro in the porcine thoracic descending aortic vascular wall intima to inject plaque into the ICG absorption site. The laser was irradiated to generate heat, and the temperature change over time on the blood vessel wall surface due to the heat conduction was measured to simulate the heat conduction (Takemi Matsui et al., Journal of Medical Engineering & Technology, Volume 25, number 5,181-184, September / October 2001). This model experiment shows that the heat conduction pattern changes with the thickness of the fibrous cap covering the plaque. However, a model that accurately mimics the actual arteriosclerosis site was not used, and the heat conduction simulation model was also a one-dimensional model that related the increase in temperature of the fibrous capsule model due to heat conduction and the thickness of the fibrous capsule. It was far from accurate heat conduction simulation in the vascular system. Furthermore, in the heat conduction simulation model, although the temperature change of the blood vessel wall is measured over time, only the temperature rise (ΔT) of the blood vessel wall surface is followed, and the transient response in the temperature change over time is detailed. Has not been analyzed. Furthermore, there was no suggestion of how to actually measure the heat conducted to the plaque in vivo in order to irradiate the plaque with a laser, artificially generate heat, and conduct from there to the inner surface of the blood vessel wall.
An object of the present invention is to provide an apparatus for determining plaque vulnerability at an atherosclerotic site using high-intensity pulsed light such as a pulsed laser. Specifically, high-intensity pulsed light is irradiated to the arteriosclerotic site, heat is generated by the absorption of pulsed light by the plaque, and the conduction pattern of the generated heat on the inner surface of the blood vessel wall is measured, thereby fibrosis covering the plaque An object of the present invention is to provide an apparatus for calculating the thickness of a coating and / or the degree of inflammation of plaque and determining whether the plaque is stable or fragile.

The inventors of the present invention have intensively studied to solve the above problems in the prior art. That is, when high intensity pulsed light is irradiated in the blood vessel wall, for example, atherosclerosis site, and heat is generated by absorption of the high intensity pulsed light by the plaque, how the generated heat is conducted in the blood vessel wall and the blood vessel In order to investigate what temporal change pattern of the temperature of the wall inner surface, a heat conduction simulation model of the blood vessel wall was created. At this time, in order to create a more accurate heat conduction simulation model for the blood vessel wall, it was created by two-dimensional or three-dimensional unsteady heat conduction finite element analysis. The present inventors actually irradiate the atherosclerosis site with high-intensity pulsed light, actually measure the temperature change pattern of the blood vessel wall due to the heat conduction when heat is generated in the plaque, The thickness of the fibrous cap covering the plaque at the atherosclerotic site and / or the progression of plaque inflammation by adjusting the parameters compared with the temperature change pattern calculated by the heat conduction simulator for the blood vessel wall It was found that the degree could be calculated, and the present invention was completed.
That is, the present invention is as follows.
[1] An active temperature measuring device for determining the vulnerability of plaque in a blood vessel wall,
(1) a catheter inserted into a blood vessel,
(2) High-intensity pulsed light irradiation means for irradiating the blood vessel wall with high-intensity pulsed light, and (3) Heat generated in the plaque part due to absorption of the irradiated high-intensity pulsed light into the plaque part in the blood vessel wall An active temperature measuring device having temperature measuring means for measuring a temperature change with time of an inner surface of a blood vessel wall due to conduction.
[2] An active temperature measuring device for determining the vulnerability of plaque in a blood vessel wall,
(1) a catheter inserted into a blood vessel,
(2) High-intensity pulsed light irradiation means for irradiating the blood vessel wall with high-intensity pulsed light,
(3) a temperature measuring means for measuring a temporal temperature change of the inner surface of the blood vessel wall due to conduction of heat generated in the plaque portion by absorption of the irradiated high-intensity pulsed light into the plaque portion in the blood vessel wall; and (4) the blood vessel An active temperature measuring device having a temperature transient response analyzing means for analyzing the vulnerability of a plaque from a change in temperature of a wall inner surface over time.
[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 carotene deposited on the plaque.
[5] A photodynamic drug (PDT drug) for Photodynamic Therapy is preliminarily accumulated in the plaque to be determined for vulnerability, and the wavelength of the high-intensity pulsed light in (2) is close to the absorption wavelength of the PDT drug. The active temperature measuring device according to any one of [1] to [3], which is characterized.
[6] The catheter of (1), wherein the temperature measuring unit of the temperature measuring means of (3) comes into contact with the inner surface of the blood vessel wall by expanding the balloon and measures the temperature, [1] to [5] The active temperature measuring device according to any one of the above.
[7] The high-intensity pulsed light is irradiated into the blood vessel wall by the high-intensity pulsed light irradiating means of (2), and the high-intensity pulsed light is absorbed into the plaque to generate heat, and the blood vessel wall is generated by the temperature measuring means of (3). The temperature change over time of the inner surface of the blood vessel wall due to the generated heat conducted through the inside is measured, and the actual temperature change transient response curve and the temperature transient response analysis means of the inner surface of the blood vessel wall are measured by the temperature transient response analysis means of (4). In any one of [1] to [6], the time-dependent temperature change simulation model curves created by using the heat conduction simulator for the blood vessel wall including are compared, and the vulnerability of the plaque in the blood vessel wall is determined. The active temperature measuring device described.
[8] A heat conduction simulator for a blood vessel wall in which a time-dependent temperature change simulation model curve on the inner surface of the blood vessel wall is adjusted for physical parameters of the blood vessel wall, parameters relating to the structure of the blood vessel wall, and parameters relating to heat generation by irradiation with high-intensity pulsed light. The active temperature measuring device according to [7], which is created by using.
[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 time-dependent temperature change simulation model curve calculated by the heat conduction simulator for the blood vessel wall and the actual temperature change of the inner surface of the blood vessel wall after irradiation of the high-intensity pulsed light to the blood vessel are analyzed by the analysis means of (4). By comparing the transient response curve and changing the parameter related to the thickness of the fibrous capsule in the vessel wall, the actual temperature change transient response curve and the calculated temperature change simulation model curve are fitted to the plaque. The active temperature measuring device according to any one of [1] to [9], wherein the thickness of the covering fibrous coating is calculated to determine plaque vulnerability.
[11] Further, by changing a parameter related to the degree of inflammation of the plaque, the actual temperature change transient response curve and the calculated temperature change simulation model curve are fitted to estimate the degree of inflammation of the plaque. The active temperature measuring device according to [10], wherein the vulnerability of the plaque is determined.
[12] The beam thickness can be changed in the high-intensity pulsed light irradiating means of (2), and the transient response curve of the temperature change over time of the inner surface of the blood vessel wall when the thick beam is irradiated indicates the blood flow direction of the plaque. The active temperature measuring device according to any one of [1] to [11], which reflects a size.
[13] The active temperature measuring device according to any one of [1] to [12], wherein the temperature measuring means of (3) is capable of simultaneously measuring a plurality of points over time.
[14] In the temperature transient response analyzing means of (4), the thickness of the fibrous coating covering the plaque is calculated by fitting the first half of the peak of the temperature change transient response curve of the blood vessel wall inner surface over time due to heat conduction. The active temperature measuring device according to any one of [1] to [13].
[15] In the temperature transient response analyzing means of (4), the thickness (volume, depth) of the plaque is calculated by fitting the latter half of the peak of the temperature change transient response curve of the blood vessel wall inner surface due to heat conduction over time. The active temperature measuring device according to any one of [1] to [13].
[16] A plaque vulnerability determination system in a blood vessel wall,
(1) Transfer data to the temperature transient response analysis means with respect to the temperature response transient response curve of the inner wall of the blood vessel due to heat generated by irradiation of the high intensity pulsed light to the plaque portion in the blood vessel wall and conducted to the inner surface of the blood vessel wall. means,
(2) Temperature transient response analysis means for analyzing the thickness of the fibrous coating covering the plaque based on the transferred data relating to the temperature change transient response curve,
(A) storage means for storing data relating to heat conduction parameters to the blood vessel wall and heat conduction simulation model curve data; and (b) a time-dependent temperature change simulation model at a temperature measurement point obtained by a heat conduction simulator for the blood vessel wall. A temperature transient response analyzing means having a computing means for comparing a curve and a temperature change transient response curve measured at a temperature measuring point, changing a parameter in a heat conduction simulation, and matching the simulation result with the actual result, And (3) a plaque vulnerability determination system having output means for outputting information on the thickness of the fibrous coating covering the analyzed plaque.
[17] (6) In the calculation means of (a), an actual time-dependent temperature change transient response curve and a calculated time-dependent temperature change simulation model curve are further obtained by changing parameters related to the degree of inflammation of plaque. The plaque vulnerability determination system according to [16], wherein fitting is performed to estimate the degree of progression of plaque inflammation, and information relating to the degree of progression of plaque inflammation is output in the output unit (3).
[18] A method for determining plaque vulnerability in an arteriosclerotic site,
(1) a step in which the temperature transient response analysis means receives data relating to a temperature change transient response curve of the inner surface of the blood vessel wall due to heat generated by irradiation of the high-intensity pulse light to the plaque portion of the arteriosclerosis site and conducted to the inner surface of the blood vessel wall;
(2) The temperature change simulation model curve over time calculated by the heat conduction simulator for the blood vessel wall stored in the transient response analysis means is compared with the actually measured temperature change transient response curve over time to cover the plaque. Fitting the actual temporal temperature change transient response curve and the calculated temporal temperature change simulation model curve by changing a parameter related to the thickness of the fibrous cap, and calculating the thickness of the fibrous cap covering the plaque; And (3) a plaque vulnerability determination method including a step of outputting the calculated thickness of the fibrous coating covering the plaque.
[19] Further, in the step (2), an actual time-dependent temperature change transient response curve and a calculated time-dependent temperature change simulation model curve are fitted by changing a parameter relating to the degree of inflammation of the plaque, and the plaque The plaque vulnerability determination method according to [18], wherein the degree of inflammation progression is estimated, and the calculated degree of plaque inflammation progression is output in step (3).

FIG. 1 is a diagram showing an apparatus of the present invention.
FIG. 2 is a diagram showing a heat conduction simulation model for the blood vessel wall.
FIG. 3 is a conceptual diagram of the system of the present invention.
FIG. 4 is a flow of processing executed by the system of the present invention.
FIG. 5 is a diagram showing the results of measuring the temperature history of three points of the intima / media / outer membrane when the blood vessel piece is heated.
FIG. 6 is a diagram showing the results of measuring the heat capacities of freshly isolated porcine aorta and porcine dry descending aorta using a differential scanning calorimeter (DSC).
FIG. 7 is a diagram showing the result of heat conduction calculation performed so as to match the result of the temperature measurement experiment on the blood vessel wall.
FIG. 8 is a diagram showing the specific heat adjusted to match the temperature measurement experiment using the specific heat value using the result of the heat capacity measurement by DSC.
FIG. 9 is a diagram showing a result of comparison between heat conduction calculation using the obtained specific heat value and a corresponding temperature measurement experiment.

（Ａ）Ｔ＞４５℃の場合の比熱値は１２Ｊ／ｇＫで固定して、Ｔ＜４５℃の比熱値のみを変化させて血管片に対する測温実験の結果と合わせるように熱伝導計算を行った。
（Ｂ）ＤＳＣによる熱容量測定の結果を元に比熱の値を入力した熱伝導計算を行った。
比熱以外のパラメータは上記と同じものを使った。ＤＳＣによる熱容量測定の結果をそのまま用いた場合では計算結果があわせるべき測温実験の結果とかけ離れたため、ＤＳＣで測定した熱容量の値を定数倍した値を入力した後に微調整を行い、測温実験の結果と合わせるようにした。
以下の結果が得られた。
（Ａ）血管壁に対する測温実験の結果と合うように行った熱伝導計算を行った結果の一例を図７に示す。この場合は、比熱を５．８Ｊ／ｇＫ（Ｔ＜４５℃）、１２Ｊ／ｇＫ（Ｔ＞４５℃）、熱伝導率を０．４２Ｗｍ−１Ｋ−１とすることで精度の高い熱伝導計算を行うことができた。同様の検討を繰り返すと、４５℃以下の比熱値を５〜８Ｊ／ｇＫと設定した時に測温実験と熱伝導シミュレーションの結果が合うことが判明した。
（Ｂ）ＤＳＣによる熱容量測定の結果を利用した比熱値を用いて測温実験と合うように比熱を調整したものを図８に示す。この比熱値を使った熱伝導計算と該当する測温実験の比較を図９に示す。外膜側で約３℃ほどの誤差があるものの、ほぼ正確に熱伝導計算を行えている。
その他２０サンプルについて測温実験結果についてもこの比熱値１を用いた熱伝導計算を行ったが、ほぼ全ての場合で±５℃以内での熱伝導計算を行うことができている。
このように、熱伝導計算で用いた比熱値（Ｔ＞４５℃）は、心筋に関して調整された値が０．４２Ｊｇ−１Ｋ−１であるのと比較すると数割大きい値である。心筋のコラーゲンの含有量は乾燥重量で５．０〜７．０（ｇ／１００ｇ）であるのに対して、下行大動脈では１８．７（ｇ／１００ｇ）と多い。一般に、タンパク質の方が水よりも比熱が大きいことが知られているので、比熱値の違いはこの組成の違いにより生じたと考えられる。あくまでも熱伝導計算に用いた比熱の値は見かけの比熱値であるが、概ね真値に近いのではないかと考えられた。また、ＤＳＣによる熱容量の測定値を２倍にした後、微調整した比熱値を用いた場合には大きい誤差の無い熱伝導計算が行えた。ただし、ＤＳＣによる熱容量測定の結果から得られたように、タンパクの熱変性による吸熱よりも水分の蒸発に伴う吸熱の寄与の方が比熱の温度変化に与える影響の割合が大きいとすると、この比熱値を用いた方法は妥当であるといえる。
このような検討により、血管壁に対する熱伝導シミュレータを構築した。Hereinafter, the present invention will be described in detail.
The device of the present invention is an active temperature measuring device that detects the presence of vulnerable plaque that induces thrombus formation and causes acute myocardial infarction. The thickness of the coating and / or the progression of inflammation is known. Based on these pieces of information, it is possible to determine whether the plaque is stable or vulnerable, that is, the plaque vulnerability. Knowing the fragility of plaques can assess the risk of suffering from myocardial infarction. In the present invention, active temperature measurement means that artificial heat is generated by plaque by irradiating a high-intensity pulsed light within a blood vessel wall, for example, an arteriosclerosis site, and the artificially generated heat is measured on the inner surface of the blood vessel wall. It is a term for passive temperature measurement in which naturally generated heat is measured on the inner surface of a blood vessel wall.
The apparatus of the present invention is an apparatus having a catheter, and includes a high-intensity pulsed light irradiation means, a temperature measurement means on the inner surface of the blood vessel wall, a balloon, and a temperature transient response analysis means.
By making the pulsed light to be irradiated with high intensity and easily absorbed by the pigment deposited on the plaque, the high-intensity pulsed light passes through the fibrous capsule covering the plaque and is present in the plaque when it reaches the plaque. It is absorbed by the dye and generates heat in that area. The generated heat is immediately conducted from the place of occurrence to the surroundings, and part of it 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, so the amount of heat generated in the plaque changes, and the thickness of the fibrous coating covering the plaque heats the vessel wall The time required for the heat transfer to reach the inner surface and the temperature of the inner surface of the blood vessel wall rising due to heat conduction are different. Therefore, the thickness of the fibrous coating covering the plaque and / or the degree of inflammation of the plaque can be determined by monitoring the temperature change on the inner surface of the blood vessel wall after irradiation with the high-intensity pulsed light. At this time, by creating a simulation model of heat conduction in the blood vessel wall (heat conduction simulator for the blood vessel wall) and comparing the change pattern of the model with the actually measured temperature change pattern of the blood vessel wall, Can know the thickness of the skin and the degree of inflammation of the plaque. The inflammation of the plaque is mainly determined by the number of macrophages that are inflammatory cells infiltrating the plaque. It can be said that the inflammation of the plaque progresses as the number of macrophages increases. Macrophages in the plaque phagocytose cholesterol lipids, and carotene is deposited accordingly. As will be described later, in one embodiment of the present invention, high-intensity pulsed light having a wavelength absorbed by carotene is irradiated, and the energy of the high-intensity pulsed light is absorbed by carotene and generates heat. In addition, the number of macrophages in the plaque and the size of the plaque do not completely correspond to each other, but the plaque size generally reflects the number of accumulated macrophages. The determination of the degree of progression mainly means determination 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 making the beam of high-intensity pulsed light to be irradiated thick as described later.
As the catheter of the apparatus of the present invention, those normally used in blood vessel endoscopes and the like can be used, and the diameter and the like are not limited. High-intensity pulsed light transmission means for the catheter, means for laterally emitting high-intensity pulsed light, balloons for closing the blood flow during high-intensity pulsed light irradiation and temperature measurement, and liquid feeding / suction means for dilating / deflating the balloon Alternatively, air intake / intake means, temperature measurement means, and the like are provided.
As the high-intensity pulsed light generation means, a normal therapeutic high-intensity pulsed light generator can be used. In the device of the present invention, the high-intensity pulsed light passes through the fibrous capsule portion at the arteriosclerotic site, and when it reaches the plaque portion, it is absorbed by the plaque and generates heat there.
This is because, as described above, carotene is deposited on the plaque, and the carotene absorbs high-intensity pulsed light energy. Therefore, high-intensity pulsed light having a wavelength in the vicinity of 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 the absorption of the high-intensity pulsed light with the same intensity is different, so the area of the plaque where the temperature is generated is different. For this reason, since the obtained temperature change curves with time are different, a lot of information can be obtained by using high-intensity pulsed light having a plurality of wavelengths. Further, the thickness of the beam of high-intensity pulsed light is not limited. By expanding the beam thickness, a region where heat is generated in the plaque is widened, and heat conduction from the entire large region can be measured. As a result, by increasing the beam thickness, it is possible to determine the size of the plaque, particularly the width in the blood flow direction. At this time, high-intensity pulsed light having different thicknesses can be irradiated by disposing high-intensity pulsed light transmission fibers having different thicknesses in the catheter.
Furthermore, a photodynamic therapy (PDT drug) photosensitive drug (PDT drug) may be previously accumulated in the plaque. PDT is a combination treatment using a photosensitizing agent such as a certain porphyrin derivative and a light beam such as a laser beam, and the photosensitizing agent selectively accumulates in a lesion such as a cancer tissue to be treated. This is a treatment method that destroys the tissue mainly by photochemical reaction by irradiating the lesion with a light beam such as laser light after administering a photosensitive drug by a method such as intravenous injection. . By selectively accumulating the PDT drug in the plaque, the high-intensity pulsed light to be irradiated is absorbed by the PDT drug accumulated in the plaque more efficiently than carotene, and the calorific value in the plaque becomes larger than that in the case of carotene. For this reason, since the fitting between the calculation result calculated by the heat conduction simulator for the blood vessel wall and the actual measurement result can be performed using a higher numerical value, a more accurate result can be derived. Various PDT drugs are known. For example, Photofrin II (PHE) (630 nm) (polyhemophorphyrin ether / ester), ATX-S10 (670 nm) (gallium porphyrin complex), 5-ALA (630 nm) (5- aminolevuric acid hydrochloride), NPe6 (664 nm) (mono-L-aspartyl chlorine 6), m-THPC (652 nm) (tetra (m-hydroxyphenyl) chlorin), SnET2 (637 nm-Pin) 690 nm) (benzoporphyrin derivative mon oacid ring A), Lu-tex (732 nm) (Lutetium Texaphyrin), etc. (common names, absorption wavelengths are shown, and general names are shown). Any known PDT drug containing these can be used. Since each PDT drug has a specific absorption wavelength, it is necessary to use high-intensity pulsed light that is close to the absorption wavelength of the PDT drug. A PDT drug accumulates in a plaque by being administered by intravenous injection or the like. This is considered to be due to phagocytosis by macrophages accumulated in plaques. Although the administration timing of the PDT drug varies depending on the type of drug, it is administered several hours to several days before temperature measurement by the apparatus of the present invention. This is because the PDT drug is sufficiently accumulated in the plaque by allowing sufficient time. The PDT drug is administered by dissolving the drug in a suitable buffer solution such as a phosphate buffered salt solution and adding a pharmaceutically acceptable additive as necessary. Examples of additives include solubilizing agents such as organic solvents, pH adjusters such as acids and bases, stabilizers such as ascorbic acid, excipients such as glucose, and isotonic agents such as sodium chloride. The administration method is not limited, and may be administered by intravenous injection, intramuscular injection, subcutaneous injection, oral administration or the like. The dose of the PDT drug is not limited, and is 0.01 to 100 mg / kg body weight, preferably 1 to 5 mg / kg body weight when systemically administered by intravenous injection or the like.
Examples of the high-intensity pulse light to be used include a second harmonic of a pulse laser and a titanium sapphire laser, and a light beam generated by a wavelength-tunable optical parametric oscillator (OPO; Optical Parametric Oscillator). Examples of the laser include pulsed dye lasers such as flash lamp excitation and XeCl excimer laser excitation, and semiconductor lasers such as GaAlAs. Among these, OPO having high wavelength tunability is desirable. Examples of OPO include Coherent's Mira-OPO.
When the PDT agent is not used, the wavelength of the high-intensity pulsed light used is the absorption wavelength of carotene, which is 450 to 500 nm, preferably 450 to 480 nm. When the PDT agent is preliminarily accumulated in the plaque, the absorption of the PDT agent is performed. High-intensity pulsed light having a wavelength close to the wavelength is used.
The intensity of the high-intensity pulsed light to be irradiated is not limited, but it is necessary to be an intensity that does not destroy the fibrous coating covering the plaque, and the temperature rise of the blood vessel wall is 30 ° C. in order to prevent temperature degeneration due to the heat of the blood vessel wall. It is necessary to have the following strength.
The irradiation time of the high-intensity pulsed light is not limited, but is preferably about 1 millisecond.
The means for transmitting the high-intensity pulsed light to the blood vessel wall of the artery includes means for side-emitting high-intensity pulsed light located near the distal end of the catheter and high-intensity pulsed light from the high-intensity pulsed light generator. A quartz fiber (optical fiber) that is transmitted to the high-intensity pulsed light side emitting means is included. As used herein, “near the distal end” means a portion close to the end opposite to the end (proximal end) connected to the high-intensity pulsed light generator, It refers to a portion about several tens of centimeters from the distal end.
The quartz fiber is contained in the catheter, and one end thereof is connected to the high-intensity pulsed light generator, and the other end is connected to the high-intensity pulsed light side emitting means. The quartz fiber used in the present invention can be widely used from a very thin fiber having a diameter of about 0.05 to 0.3 mm to a visible one as long as it can be accommodated in a catheter and transmit high-intensity pulsed light energy. Can be used.
The high-intensity pulsed light side emitting means is a means for irradiating the arterial blood vessel wall with high-intensity pulsed light. The high-intensity pulsed light transmitted along the blood vessel through the quartz fiber enters the blood vessel wall and enters the artery. It is necessary to irradiate the side to reach the plaque of the sclerotic lesion. Side irradiation of high-intensity pulsed light can be achieved by refracting or scattering high-intensity pulsed light. Examples of the side-emission means include prisms and scattering materials. For example, a prism may be provided so that high-intensity pulsed light is irradiated laterally near the distal end of the quartz fiber, or high-intensity pulsed light is irradiated laterally near the distal end of the quartz fiber. The surface may be roughened as described above. In addition, a scattering material such as alumina or silica that scatters high-intensity pulsed light may be applied near the distal end of the quartz fiber, and these scattering materials may be included in the balloon. Also good. The area range where the high-intensity pulsed light emitted from the vicinity of the distal end of the quartz fiber irradiates the artery is 0.5 cm. ² ~ 3cm ² Is preferred. The irradiation area range can be set as appropriate by changing the thickness of the high-intensity pulse light beam. The thickness of the high-intensity pulse light beam can be changed by changing the thickness of the fiber transmitting the high-intensity pulse light. That's fine.
Also, the number of high-intensity pulsed light irradiation is not limited to one, and a plurality of locations may be irradiated simultaneously. By irradiating multiple locations at the same time, heat is generated at multiple locations in the plaque, and heat conduction from these locations can be measured, thus obtaining more diverse information about the status of the plaque and the state of the fibrous cap be able to. In this case, a plurality of high-intensity pulsed light transmission fibers may be disposed in the catheter, and a means for irradiating the plurality of high-intensity pulsed light at the distal end of the catheter may be disposed.
As the balloon, a coronary balloon used for an ordinary balloon catheter can be used. The balloon is attached near the distal end of the catheter. The balloon is provided with temperature measuring means described later. By expanding the balloon, the temperature measurement part (temperature measurement probe) of the temperature measurement means and the blood vessel wall come into contact with each other, and the temperature of the inner surface of the blood vessel wall can be measured. The means for expanding the balloon is not particularly limited, but can be achieved by supplying an appropriate liquid or gas into the balloon. In this case, a liquid / gas supply / discharge tube is also provided in the catheter. The pressure when the balloon during expansion presses against the blood vessel wall is 0.2-1 kg / cm ² Between is desirable. As described above, the balloon may include a high-intensity pulsed light side emitting means.
The temperature measuring means of the apparatus of the present invention is a means that can measure the temperature of the inner surface of the blood vessel wall.
A temperature measuring probe such as a contact thermometer or a thermocouple can be used as the temperature measuring unit of the temperature measuring means. When using a contact-type thermometer or thermocouple as a probe for temperature measurement, as described above, these must be in contact with the blood vessel wall, so install them outside the balloon or embedded in the balloon. The temperature measuring probe is brought into contact with the blood vessel wall when the balloon is expanded. The temperature measurement probe and the temperature display means are connected by a line disposed in the catheter, and temperature information is transmitted to the temperature display means. The temperature display means also includes a processor, and the transmitted temperature information is processed by the processor, and the processing data is transferred to the temperature transient response analysis means.
FIG. 1 shows a configuration diagram of an active temperature measuring device of the present invention.
Temperature transient response analysis means
When the thickness of the fibrous coating 2 covering the plaque 1 and / or the progress of inflammation of the plaque 1 is determined using the apparatus of the present invention, a heat conduction simulator for the blood vessel wall 3 is first constructed. The heat conduction simulator for the blood vessel wall can be constructed by two-dimensional or three-dimensional unsteady heat conduction finite element analysis. The heat conduction calculation by the finite element method is based on the heat transport equation at the nodes of the divided elements, assuming that heat transfer occurs only between adjacent elements by dividing the object whose heat conduction is to be calculated into fine elements. This is a method for calculating heat conduction. At this time, a heat conduction simulator for the blood vessel wall 3 can be constructed by deriving parameters specific to the blood vessel wall 3 using a commercially available heat conduction calculation program. An example of such a program is Quick Therm BIO (Computational Mechanics Laboratory) created based on heat conduction to the myocardium. By inputting physical property parameters of the blood vessel wall 3 into the program, A conduction simulator can be constructed.
Specifically, for example, the porcine aorta is heated, the temperature history (temperature change over time) of the intima, media and adventitia of the aorta is measured using a thermocouple, and the program is used. Then, the heat conduction calculation simulating the experimental system can be performed, and various parameters can be adjusted to match the results of the temperature measurement experiment. Various parameters can be selected. For example, the calculation may be performed by changing the specific heat value. In this case, calorimetry is performed using a differential scanning calorimeter in order to finely observe the specific heat change of the blood vessel wall. Finally, a heat conduction simulator reflecting the physical properties of the blood vessel wall 3 can be constructed by adjusting the parameters so as to match the physical properties of the blood vessel wall 3 based on the calculation result.
Next, parameters related to the actual structure of the blood vessel wall and 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 is analyzed by angiography or intravascular ultrasound imaging (IVUS) for the subject blood vessel to be evaluated for plaque vulnerability, and information such as the thickness of the blood vessel and the thickness of the blood vessel wall 3 is obtained. To get. A commercially available system may be used for angiography and IVUS. These pieces of information are input to the heat conduction simulator for the constructed blood vessel wall 3. However, in IVUS and angiography, the presence of plaque 1 can be estimated, but the degree of inflammation of plaque 1 (the state of plaque 1) and the plaque 1 reflected by the thermal conductivity coefficient of plaque 1, the size of plaque 1, etc. It is not possible to obtain accurate information about the internal structure of the blood vessel wall 3 such as the thickness of the fibrous coating 2 covering the skin. Therefore, the structure information of the actual blood vessel wall 3 obtained by angiography and IVUS is further added to the degree of inflammation of the plaque 1 such as the thermal conductivity coefficient of the plaque and the size of the plaque 1 and the fibrous coating 2 covering the plaque 1. Enter parameters for thickness. By inputting information related to the structure of the blood vessel wall 3, a finite element method model in which parameters related to the structure of the blood vessel wall 3 of the test blood vessel including the state of the plaque 1 are adjusted is created. It is possible to construct a heat conduction simulator for a blood vessel wall that also reflects physical property values. Among the parameters related to the structure of the blood vessel wall 3, the parameters relating to the degree of inflammation of the plaque 1 such as the thermal conductivity coefficient of the plaque 1 and the size of the plaque 1 and the thickness of the fibrous capsule 2 covering the plaque 1 are as follows: When comparing the actual temporal temperature change transient response curve of the inner surface and the temporal temperature change simulation model curve created using the heat conduction simulator for the blood vessel wall including the temperature transient response analyzing means, adjustment and fitting are performed.
Furthermore, the heating term by irradiation of the high intensity pulse 4 light of the blood vessel is input to the simulator. The term for heating the blood vessel by irradiation with high-intensity pulsed light refers to a parameter relating to heat that can be generated by irradiation with high-intensity pulsed light. At this time, the heating term can be set in accordance with the actual method of irradiation with high-intensity pulsed light. For example, when the high-intensity pulsed light beam is thin when actually performing active temperature measurement, the range in which heat is generated in the plaque is narrow, and heat is conducted from a narrow heat generation site to the blood vessel wall. On the other hand, if the beam of high-intensity pulsed light is thick, the range in which heat is generated in the plaque is widened, and is conducted from a wide heat generation site to the vessel wall. When the thickness of the high-intensity pulsed light beam is changed as described above, the heating term is changed corresponding to each beam having a different thickness. The change in temperature when the beam of high-intensity pulsed light is thick reflects the size of the plaque in the bloodstream direction. Here, the size of the plaque in the blood flow direction means parallel to the blood flow, and means the size in both the forward and reverse directions of the blood. In actual active temperature measurement, the side temperature point is not limited to one point, and a plurality of points may be set. In this case, a parameter relating to the position of the temperature measuring point may be changed in the simulator.
As described above, the blood vessel wall heat conduction simulation model including the parameters of the physical properties of the blood vessel wall, the blood vessel structure, and the heat generated in the active temperature measurement is completed.
Using such a simulator with adjusted parameters, it is possible to calculate the temperature change with time at the temperature measuring point on the inner surface of the blood vessel wall. In this case, the simulator simulates heat conduction using the finite element method model of the blood vessel from which the structural information is obtained, and calculates the temperature change with time at the temperature measuring point.
Since the blood vessel wall heat conduction simulator of the present invention performs heat conduction calculation using a multi-dimensional finite element method, the size of the heat generation site, the amount of heat generated, the temperature measurement point, etc. can be set arbitrarily. Even if any parameters are set, the temperature change with time at the temperature measuring point can be calculated and obtained as a temperature change simulation model curve. FIG. 2 shows a schematic diagram of a temperature change simulation model curve at a certain temperature measurement point obtained by calculation of a heat conduction simulator for a blood vessel wall.
Next, active temperature measurement is actually performed on the blood vessel wall, and the temperature change over time at the temperature measurement point is actually measured. At this time, the temperature change with time at the temperature measuring point is a transient response, and the temperature transient response can be analyzed by the temperature transient response analyzing means of the present invention. The transient response means that when a transfer function H (f) is given to the control system S, when an input signal u (t) is given, it causes an output x (t), and this x This is a transitional process shown until (t) reaches a new steady state. 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, the temperature change can be analyzed as a transient response, not merely the temperature rise, so that it is much more accurate than simply measuring the temperature rise value (ΔT) at the temperature measuring point. You can know the state.
The physical parameter of the blood vessel wall input to the heat conduction simulator for the blood vessel wall does not change as long as the object of 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 measurement is performed on a blood vessel in which no plaque is present, the blood vessel structure is accurately analyzed by the above IVUS, and thus the actually measured temperature change transient response curve and the temperature change simulation model curve calculated by the simulator are substantially the same. However, when plaque is present on the blood vessel wall, the IVUS cannot accurately measure the thickness of the fibrous coating covering the plaque. Therefore, the temperature over time calculated by the simulator according to the thickness of the fibrous coating. There is a discrepancy between the change simulation model curve and the actually measured temperature transient response curve. Therefore, both curves are fitted by changing the thickness of the fibrous coating as a parameter. The thickness of the fibrous cap when both curves fit represents the actual thickness. Further, since the size of the region where heat is generated and the amount of heat generated vary depending on the degree of inflammation of the plaque, the degree of inflammation of the plaque which cannot be measured by IVUS also causes a shift. Furthermore, since the thermal conductivity coefficient in the plaque is different from that of the normal blood vessel wall, this difference also causes a deviation. The deviation mainly reflects the thickness of the fibrous capsule, and also reflects the degree of inflammation of the plaque indicated by the thermal conductivity coefficient and size (width and thickness) of the plaque.
When trying to obtain information on the thickness of the fibrous coating by analysis, the thickness of the fibrous coating is set as a parameter of the blood vessel structure in the heat conduction simulator for the blood vessel wall. While changing this parameter, the temperature change at the temperature measurement point is simulated and the temperature change transient response curve actually measured is compared with the temperature change simulation model curve calculated by the simulator. By repeating this operation, two curves are fitted. In this case, it can be said that the parameters are fitted so that the two curves overlap. The comparison / fitting of curves may be performed by calculating approximate equations of both curves and calculating based on the equations, or using all or part of the coordinate (time, temperature) data of each point of the curve as a data set. You may compare. The thickness value of the fibrous coating as a parameter when the fitting is completed becomes the actual thickness of the fibrous coating. As described above, the temperature change at the temperature measuring point reflects not only the thickness of the fibrous capsule but also the degree of inflammation of the plaque, so there is also an item indicating the degree of inflammation of the plaque as a structural parameter of the blood vessel wall. By adopting, it is possible to estimate and determine the degree of plaque inflammation by fitting. As described above, the plaque thermal conductivity coefficient and the plaque size reflect the degree of inflammation of the plaque, and therefore, the plaque thermal conductivity coefficient and the plaque size may be employed as parameters.
When high-intensity pulsed light is irradiated to the arteriosclerotic region of the blood vessel, heat is generated in a certain region in the plaque according to the thickness of the beam, and heat is conducted from the entire region where the heat is generated to the surroundings. At this time, the heat generated in the portion close to the temperature measurement point arrives at the temperature measurement point first, and the temperature at the temperature measurement point rises rapidly after irradiation with the high-intensity pulsed light. Next, the heat that has reached the temperature measurement point is taken away by the blood flow, or is conducted and diffused from the temperature measurement point to other parts, so that the temperature at the temperature measurement point decreases after showing a peak. At this time, since the heat conducted from a portion far from the temperature measurement point reaches the temperature measurement point with a delay, the temperature drop 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 thinner the fibrous coating covering the plaque, the faster the generated heat reaches the temperature measuring point without attenuation, so that the peak temperature is reached earlier and the peak temperature value is higher. In addition, the wider the heat generation area in the plaque, the slower the temperature drop after the peak since heat is conducted to the temperature measuring point for a long time after the peak temperature at the temperature measuring point. In other words, the pattern of temperature change before the temperature at the temperature measurement point reaches the peak reflects the thickness of the fibrous coating, and the pattern of temperature change after the temperature at the temperature measurement point reaches the peak indicates the thermal conductivity coefficient and large value. It reflects the degree of plaque inflammation, particularly the plaque thickness, as indicated by thickness (width and thickness) and the like. Here, the thickness of the plaque means the size of the plaque in the blood flow direction and the vertical direction, and is also referred to as the depth of the plaque. In addition, 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 measurement point has reached its peak, especially the plaque state, especially the plaque blood flow direction And the plaque thickness (plaque volume).
Therefore, when trying to determine the vulnerability of the plaque only by the thickness of the fibrous capsule, it is only necessary to fit the temperature change curve over time before the peak, and to estimate the degree of inflammation of the plaque. In this case, the temperature change curve over time may be fitted after the peak. In reality, the vulnerability of the plaque is mainly determined by the thickness of the fibrous coating covering the plaque. Therefore, it is possible to determine the vulnerability of the plaque with considerable accuracy by simply comparing the first half.
In actual active temperature measurement, if the PDT drug is accumulated in advance in the plaque, and the high-intensity pulsed light to be irradiated is close to the absorption wavelength of the PDT drug, the energy of the high-intensity pulsed light is efficiently converted to PDT. Absorbed by drugs. Therefore, the heat generation at the plaque is increased, and a large amount of heat is conducted, so that the temperature at the temperature measuring point is also increased. For this reason, fitting can be performed using a larger temperature measurement value. Therefore, by using the PDT drug, transient response analysis can be performed with higher accuracy, and more accurate determination can be performed.
The transient response analyzing means of the present invention includes a heat conduction simulator for the blood vessel wall and means for inputting the actually measured temperature change.
As described above, the heat conduction simulator for the blood vessel wall includes the storage means storing the data on the heat conduction parameters for the blood vessel wall and the data of the heat conduction simulation model curve, and the temperature measurement obtained by the heat conduction simulation for the blood vessel wall. Temporal temperature change simulation model curve at the point is calculated, the model curve is compared with the actual temperature change transient response curve measured at the temperature measurement point, and the parameters are changed to fit the two temperature change curves Including calculation means. Here, the data of the heat conduction simulation model curve refers to data related to the approximate equation of the curve, a data set representing the coordinates of points on the curve, and the like.
The temperature change input unit may be a device that manually inputs the actual measurement value using a keyboard or the like, or the temperature measurement means and the transient response analysis means are electronically connected, and data related to the temperature change at the same time as the temperature measurement is a transient response. It may be transferred to the analysis means.
Plaque vulnerability assessment system in arteriosclerotic sites
The present invention also includes a plaque vulnerability determination system in a blood vessel wall, for example, at a site of arteriosclerosis. The system
(1) Means for transferring data related to a temperature change transient response curve over time of a blood vessel wall inner surface due to heat generated in plaque caused by irradiation of high intensity pulsed light into the blood vessel wall and conducted to the blood vessel wall inner surface to a temperature transient response analyzing means ,
(2) A temperature transient response analyzing means for analyzing the thickness of the fibrous cap covering the plaque and / or the progress of inflammation of the plaque based on the transferred data on the temperature change transient response curve,
(A) storage means for storing data on parameters for heat conduction to the blood vessel wall and heat conduction simulation model curve data; and
(B) Compare 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 temperature response transient response curve measured over time at the temperature measurement point, and change the parameters in the heat conduction simulation. Calculation means to fit two temperature change curves and match the simulation result with the actual result
A temperature transient response analysis means comprising:
(3) A plaque vulnerability determination system having an output means for outputting information on the thickness of the fibrous coating covering the analyzed plaque and / or the degree of progression of inflammation of the plaque. Here, the means for transferring the data related to the temperature change transient response curve over time to the temperature transient response analyzing means may be means for directly transferring data electronically 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 an input means such as a keyboard. The heat conduction simulator for the blood vessel wall included in the temperature transient response analysis means is a simulator constructed as described above. The output unit includes a printing unit, a display unit on a display, and the like. When output by the output means, it may be a specific numerical value indicating the thickness of the fibrous coating or the like, or may be a determination regarding the vulnerability of the graded plaque. FIG. 3 shows a schematic diagram of the system of the present invention.
Furthermore, the present invention also includes a method for determining plaque vulnerability in a blood vessel wall, for example, at the arteriosclerosis site, using the system. The method includes a step in which the temperature transient response analysis means receives data relating to a temperature change transient response curve of the inner surface of the blood vessel wall due to heat generated in the plaque and conducted to the inner surface of the blood vessel wall by irradiation of high-intensity pulsed light to the arteriosclerosis site Compare the temperature change simulation model curve over time calculated by the heat conduction simulator for the vessel wall stored in the transient response analysis means with the actually measured temperature change transient response curve over time, and check the fibrous coating covering the plaque. Fitting the actual time-dependent temperature change transient response curve and the calculated time-dependent temperature change simulation model curve by changing the parameters related to the thickness and / or plaque inflammation progression, the simulation results into the actual results Combine, calculate the thickness of the fibrous cap covering the plaque, and / or Comprising the step guess progression of inflammation plaque, as well as the thickness of the fibrous cap that covers the calculated plaque, and / or inferred plaque step for outputting the progress of inflammation. FIG. 4 shows a process flow of the method executed by the system of the present invention.
Hereinafter, the present invention will be described in detail based on examples. However, the present invention is not limited to the following examples.
[Example 1] Construction of heat conduction simulator for blood vessel wall
Combined with blood vessel wall temperature measurement experiment for stepped intimal surface temperature change using porcine abdominal aorta and heat conduction simulation using heat transfer calculation software "Quick Therm BIO" (Computational Mechanics Research Center) using finite element method And compared. The above software was developed by examining myocardial conduction. In this example, the specific heat value with the largest change in thermophysical properties was adjusted as the only parameter so as to be compatible with the blood vessel wall temperature measurement experiment.
A freshly isolated porcine descending aorta was used as an experimental sample. The porcine descending aorta is similar in composition to human coronary arteries, such as collagen, and is suitable for experimental samples because it has a larger wall thickness than the coronary arteries. This was cut into a length (blood flow direction) of 25 mm and a width of 20 mm to obtain a blood vessel piece. Later, the media was torn to install a thermocouple for measuring the temperature change of the media. The total thickness of the blood vessel wall was 1.4 to 2.5 mm, and the thickness from the intimal surface to the torn surface was 0.6 to 1.2 mm.
In order to perform heating and cooling, a method of alternately contacting aluminum blocks (40 mm cube) heated to a high temperature or 37 ° C. was adopted. Aluminum has a large thermal conductivity of 237 W / mK and a heat capacity of 0.901 J / Kg, so that the temperature change of the contact surface is small even after contact with the blood vessel piece, and it is suitable for heating and cooling. The blood vessel piece was placed on expanded polystyrene. This is because the heat conductivity is sufficiently small as 0.05 W / mK, so that the heat in and out of the outer film can be suppressed to a small value. For temperature history, T-type thermocouples (T / TT-30-1, Ishikawa Sangyo, Tokyo) are installed at three points of the inner membrane, middle membrane, and outer membrane, and a digital recorder (DL708E, Yokogawa Electric, Tokyo) is installed. Recorded.
FIG. 5 shows the results of measuring the temperature history of three points of the intima / media / outer membrane when the blood vessel piece is heated. Since the heat was transmitted with a slight delay from the temperature history of the inner and outer membranes, and the peak temperature gradually decreased from the inner membrane side, reasonable measurement results were obtained.
Next, in order to determine the physical property parameters for the blood vessel wall, heat capacity measurement was performed using a differential scanning calorimeter (DSC).
Two types of samples were used: freshly isolated porcine aorta, and porcine isolated descending aorta placed in an environment where the humidity was 20% or less for 24 hours and dried. After opening the blood vessel, it was chopped 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 weighed 3.3 to 5.8 mg and the dried one was 2.4 to 6.7 mg.
The DSCs used were DSC20 (Seiko Electronics Industry, Tokyo), SSC / 580 thermal controller (Seiko Electronics Industry, Tokyo). A sample enclosed in an aluminum container was placed in the DSC 20 and measurement was started. The measurement start temperature was 22 ° C., the measurement end temperature was 100 ° C., the temperature increase rate was 10 ° C./min, and the sampling interval was 0.4 s. The temperature was set to be 0 to 2O <0> C and the DSC was output as a voltage signal of 0 to 2 V in the range of -0.5 to 9.5 mJ / s.
The results of measuring the heat capacities of the freshly isolated porcine aorta and the porcine dry descending aorta by DSC are shown in FIG. In the dried product, the specific heat continues to increase almost linearly, whereas in the fresh product, the heat capacity increases exponentially as it approaches 100 ° C. Therefore, it is considered that the difference in heat capacity generated between the two was caused by the endotherm accompanying the evaporation of water. It is suggested that the temperature change of the heat capacity of the blood vessel wall accounts for a larger proportion of the endotherm accompanying the evaporation of water than the endotherm accompanying the heat denaturation of the protein.
Next, heat conduction calculation by the finite element method was performed.
Heat conduction calculation simulating an experimental system was performed using a heat conduction calculation program, Quick Therm bio (registered trademark) (Computational Mechanics Laboratory, Tokyo). The finite element was separated from the blood vessel wall by dividing it into 32 equal parts to the right. 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 50 μm in the thickness direction, which can be said to be sufficiently small. Each parameter for the blood vessel wall has not been studied 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 at 45 ° C. as a result of considering the endothermic effect due to heat denaturation of the protein. Only the specific heat value was changed as a change parameter, and adjustment was made so that the error from the experimental result was about ± 2 ° C. or less. Strictly speaking, changes in physical property values may appear not only in specific heat but also in thermal conductivity and density, but here, only the specific heat that seems to have the largest change is changed, and all other parameter changes are also specific heat values. Adjusted to include changes in Table 1 shows the main physical property values used in the heat conduction calculation.

(A) The specific heat value when T> 45 ° C. is fixed at 12 J / gK, and only the specific heat value at T <45 ° C. is changed, and the heat conduction calculation is performed so as to match the result of the temperature measurement experiment on the blood vessel piece. It was.
(B) Based on the result of the heat capacity measurement by DSC, a heat conduction calculation was performed by inputting a specific heat value.
The same parameters as above were used except for the specific heat. When the results of heat capacity measurement by DSC are used as they are, the calculation results are far from the results of temperature measurement experiments that should be matched. Therefore, fine adjustment is made after inputting a value obtained by multiplying the heat capacity value measured by DSC by a constant number, and temperature measurement experiments are performed. Matched with the result of.
The following results were obtained.
(A) An example of the result of the heat conduction calculation performed so as to match the result of the temperature measurement experiment on the blood vessel wall is shown in FIG. In this case, accurate heat conduction calculation can be performed by setting the specific heat to 5.8 J / gK (T <45 ° C.), 12 J / gK (T> 45 ° C.), and the thermal conductivity to 0.42 Wm−1K−1. Could be done. When the same examination was repeated, it was found that when the specific heat value of 45 ° C. or less was set to 5 to 8 J / gK, the results of the temperature measurement experiment and the heat conduction simulation matched.
(B) FIG. 8 shows the specific heat adjusted to match the temperature measurement experiment using the specific heat value using the heat capacity measurement result by DSC. A comparison between the heat conduction calculation using this specific heat value and the corresponding temperature measurement experiment is shown in FIG. Although there is an error of about 3 ° C. on the outer membrane side, the heat conduction calculation can be performed almost accurately.
For the other 20 samples, the heat conduction calculation using the specific heat value 1 was performed for the temperature measurement experiment result, but the heat conduction calculation within ± 5 ° C. could be performed in almost all cases.
Thus, the specific heat value (T> 45 ° C.) used in the heat conduction calculation is a value that is several percent higher than the value adjusted for the myocardium is 0.42 Jg-1K-1. Myocardial collagen content is 5.0 to 7.0 (g / 100 g) in dry weight, whereas the descending aorta is 18.7 (g / 100 g). In general, it is known that the specific heat of protein is larger than that of water, so it is considered that the difference in specific heat value is caused by the 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. In addition, after doubling the measured value of the heat capacity by DSC and using the finely adjusted specific heat value, the heat conduction calculation without a large error could be performed. However, as can be seen from the results of heat capacity measurement by DSC, if the contribution of endotherm accompanying the evaporation of moisture has a greater effect on the temperature change of the specific heat than the endotherm by heat denaturation of protein, this specific heat It can be said that the method using values is appropriate.
Based on these studies, a heat conduction simulator for the vascular wall was constructed.

By using the apparatus of the present invention, it is possible to forcibly heat the plaque at the arteriosclerotic site by irradiation with high-intensity pulsed light, and analyze the conduction pattern of the generated heat.
The heat conduction pattern reflects the thickness of the fibrous capsule covering the plaque and the degree of inflammation of the plaque. Therefore, using the heat conduction simulator for the blood vessel wall that has been constructed in advance, the heat conduction pattern calculated by the simulator and the actually measured heat using the thickness and / or plaque state of the fibrous coating covering the plaque as parameters. By fitting the conduction pattern, the fibrous coating covering the plaque and the state of the plaque can be known. As a result, plaque vulnerability can be determined, and the risk of suffering from myocardial infarction can be evaluated.

Claims (19)

An active temperature measuring device for determining the vulnerability of plaque in a blood vessel wall,
(1) a catheter inserted into a blood vessel,
(2) High-intensity pulsed light irradiation means for irradiating the blood vessel wall with high-intensity pulsed light, and (3) Conduction of heat generated in the plaque by absorption of the irradiated high-intensity pulsed light into the plaque in the blood vessel wall An active temperature measuring device having a temperature measuring means for measuring a temperature change of a blood vessel wall with time. An active temperature measuring device for determining the vulnerability of plaque in a blood vessel wall,
(1) a catheter inserted into a blood vessel,
(2) High-intensity pulsed light irradiation means for irradiating the blood vessel wall with high-intensity pulsed light,
(3) a temperature measuring means for measuring a temporal temperature change of the inner surface of the blood vessel wall due to conduction of heat generated in the plaque by absorption of the irradiated high-intensity pulsed light into the plaque in the blood vessel wall; and (4) the blood vessel wall An active temperature measuring device having a temperature transient response analyzing means for analyzing the vulnerability of a plaque from the temperature change of the inner surface over time. The active temperature measuring device according to claim 1 or 2, wherein the high-intensity pulsed light is a laser. The active temperature measuring device according to any one of claims 1 to 3, wherein the wavelength of the high-intensity pulsed light is equivalent to the absorption wavelength of carotene deposited on the plaque. A photodynamic drug (PDT drug) for photodynamic therapy is pre-integrated on the plaque to be determined for vulnerability, and the wavelength of the high-intensity pulsed light in (2) is close to the absorption wavelength of the PDT drug. The active temperature measuring device according to any one of claims 1 to 3. The catheter balloon catheter according to (1), wherein the temperature measuring unit of the temperature measuring means (3) comes into contact with the inner surface of the blood vessel wall by expanding the balloon and measures the temperature. The active temperature measuring device according to claim 1. The high-intensity pulsed light irradiation means (2) irradiates the blood vessel wall with high-intensity pulsed light, and the plaque absorbs the high-intensity pulsed light to generate heat, and the temperature measurement means (3) conducts the blood vessel wall. The time-dependent temperature change of the inner surface of the blood vessel wall due to the generated heat is measured, and the blood vessel wall including the actual time-dependent temperature change transient response curve of the inner surface of the blood vessel wall and the temperature transient response analyzing means by the temperature transient response analyzing means of (4) The temperature change simulation model curve calculated over time using a heat conduction simulator is compared to determine the vulnerability of the plaque in the blood vessel wall according to any one of claims 1 to 6. Active temperature measuring device. Simulation model curve of temperature change over time on the inner surface of the blood vessel wall is calculated using a heat conduction simulator for the blood vessel wall in which the physical property parameters of the blood vessel wall, the parameters related to the structure of the blood vessel wall, and the parameters related to heat generation by irradiation with high-intensity pulsed light are adjusted. The active temperature measuring device according to claim 7. The active temperature measuring device according to claim 8, wherein the parameter relating to the structure of the blood vessel wall is obtained by intravascular ultrasound imaging (IVUS). The analysis means of (4) is a temperature change simulation model curve over time calculated by the heat conduction simulator for the blood vessel wall, and an actual temperature change transient response curve of the blood vessel wall inner surface after high intensity pulse light irradiation to the blood vessel. The thickness of the fibrous capsule covering the plaque is changed by changing the parameter related to the thickness of the fibrous coating on the blood vessel wall and fitting the temperature change simulation model curve to the actual temperature change transient response curve. The active temperature measuring device according to any one of claims 1 to 9, wherein the temperature is calculated and the vulnerability of the plaque is determined. Furthermore, by changing the parameters related to the degree of inflammation of the plaque, the actual temperature change transient response curve and the calculated temperature change simulation model curve were fitted to estimate the degree of plaque inflammation. The active temperature measuring device according to claim 10, wherein vulnerability is determined. The beam thickness can be changed in the high-intensity pulsed light irradiating means of (2), and the time-dependent temperature change transient response curve of the blood vessel wall inner surface when the thick beam is irradiated indicates the magnitude of the plaque blood flow direction. The active temperature measuring device according to any one of claims 1 to 11, which is reflected. The active temperature measuring device according to any one of claims 1 to 12, wherein the temperature measuring means (3) is capable of simultaneously measuring a plurality of points over time. In the temperature transient response analysis means of (4), the thickness of the fibrous coating covering the plaque is calculated by fitting the first half of the peak of the temperature change transient response curve of the blood vessel wall inner surface over time due to heat conduction. The active temperature measuring device according to any one of claims 1 to 13, In the temperature transient response analyzing means of (4), the thickness (volume, depth) of the plaque is calculated by fitting the latter half of the peak of the temperature response transient response curve of the blood vessel wall inner surface due to heat conduction over time. The active temperature measuring device according to any one of claims 1 to 13, A plaque vulnerability determination system in a blood vessel wall,
(1) Means for transferring data related to a temperature change transient response curve over time of a blood vessel wall inner surface by heat generated by irradiation of a high intensity pulsed light to a plaque portion of the blood vessel wall and conducted to the blood vessel wall inner surface to a temperature transient response analyzing means ,
(2) Temperature transient response analysis means for analyzing the thickness of the fibrous coating covering the plaque based on the transferred data relating to the temperature change transient response curve,
(A) storage means for storing data relating to parameters for heat conduction to the blood vessel wall and data of heat conduction simulation model curves; and (b) a temperature change simulation model over time at a temperature measuring point calculated by a heat conduction simulator for the blood vessel wall. Temperature transient response analysis means that has a computing means that compares the curve and the transient temperature change curve over time measured at the temperature measurement point, changes the parameters in the heat conduction simulation, and fits the simulation results to the actual results And (3) a plaque vulnerability determination system having an output means for outputting information on the thickness of the fibrous coating covering the analyzed plaque. (6) In the calculation means of (a), an actual time-dependent temperature change transient response curve and a calculated time-dependent temperature change simulation model curve are fitted to the plaque by changing a parameter relating to the degree of inflammation of the plaque. 17. The plaque vulnerability determination system according to claim 16, wherein the degree of inflammation progression is estimated and information on the degree of plaque inflammation progression is output in the output means of (3). A method for determining plaque vulnerability in a blood vessel wall,
(1) a step in which the temperature transient response analysis means receives data relating to a temperature change transient response curve of the inner surface of the blood vessel wall due to heat generated by irradiation of the plaque on the blood vessel wall with high-intensity pulsed light and conducted to the inner surface of the blood vessel wall;
(2) The temperature change simulation model curve over time calculated by the heat conduction simulator for the blood vessel wall stored in the transient response analysis means is compared with the actually measured temperature change transient response curve over time to cover the plaque. Fitting the actual temporal temperature change transient response curve and the calculated temporal temperature change simulation model curve by changing a parameter related to the thickness of the fibrous cap, and calculating the thickness of the fibrous cap covering the plaque; And (3) a plaque vulnerability determination method including a step of outputting the calculated thickness of the fibrous coating covering the plaque. Further, in the step (2), the actual temperature change transient response curve and the calculated temperature change simulation model curve are fitted by changing a parameter related to the degree of inflammation of the plaque, and the progression of the inflammation of the plaque. The plaque vulnerability determination method according to claim 18, wherein the degree of inflammation is estimated, and the calculated degree of progression of inflammation of the plaque is output in step (3).

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