Cardiac examination method, image generation method, and program

Abstract

The present invention provides a method for easily distinguishing between diseases and pathological conditions in cardiomyocytes, particularly diseases and pathological conditions that exhibit metabolic abnormalities of fatty acids and / or neutral fats. A method for examining the heart, comprising the following steps (1) and (2): Step (1): generating an image G1 in a subject by the image generation method M1 described in the specification. Step (2): A step of comparing the image G1 with a standard that can determine one or more of the following: normal d0 in the heart, and the presence, degree, and site of onset of pathological conditions d1 to d5.

Description

[Technical Field]

[0001] The present invention relates to a cardiac examination method, an image generation method, and a program. [Background technology]

[0002] The heart is an organ that pumps blood throughout the body by repeatedly contracting and expanding, and its activity requires a continuous supply of energy. Cardiomyocytes actively generate energy using fatty acids as the main substrate. Oxygen is essential for this metabolism, and in an environment with a sufficient oxygen supply, fatty acids are efficiently used as the main energy source. However, when the oxygen supply is insufficient, fatty acid utilization is limited, and as a result, fatty acid uptake into cardiomyocytes is also reduced. In addition, the interconversion of fatty acids and triglycerides occurs constantly within cells, and the dynamics of triglyceride synthesis and degradation are also important factors in metabolism. Because fatty acids are potentially cytotoxic due to their acidic nature, they are usually converted to triglycerides, which are then appropriately degraded and utilized to maintain cellular homeostasis. Recently, triglyceride deposit cardiomyovasculopathy (TGCV), a pathology caused by impaired triglyceride metabolism in cells, has been reported, and evaluation of intracellular triglyceride metabolism has become important. Furthermore, CD36 deficiency, which is accompanied by impaired fatty acid uptake, and mitochondrial cardiomyopathy, which shows excessive fatty acid uptake, have also been reported, and it has become clear that abnormalities in fatty acid and / or triglyceride metabolism are deeply involved in the pathogenesis of cardiac conditions.

[0003] Myocardial fatty acid metabolism scintigraphy, a type of cardiac nuclear medicine test, is used to diagnose the above diseases and pathological conditions. Myocardial fatty acid metabolic scintigraphy mainly uses radioactive analogs of fatty acids. 123 I-β-methyl-p-iodophenylpentadecanoic acid ( 123 I-BMIPP) is administered to the subject as a tracer compound. 123The use of I-BMIPP allows accurate tracing of the dynamics of fatty acids and triglycerides and the detection of metabolic abnormalities of fatty acids and / or triglycerides in cardiomyocytes. Myocardial fatty acid metabolism scintigraphy visualizes myocardial damage (ischemic memory) primarily caused by ischemia, and can be used to evaluate ischemic heart diseases such as myocardial infarction and angina pectoris, as well as cardiac hypertrophy.

[0004] In myocardial fatty acid metabolism scintigraphy, the amount of tracer compound taken up into myocardial cells and the rate of washout from myocardial cells are used as indices.

[0005] Patent Document 1 and Non-Patent Document 1 disclose image processing methods that can calculate the washout rate more accurately. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Japanese Patent No. 7284540 [Non-patent literature]

[0007] [Non-Patent Document 1] Miyauchi, H. et al. (2023). Annals of Nuclear Cardiology, 9, 19-25 Summary of the Invention [Problem to be solved by the invention]

[0008] In the differentiation of cardiac pathologies exhibiting abnormalities in fatty acid and / or triglyceride metabolism, when images separately displaying the amount of tracer compound uptake into cardiomyocytes and the washout rate from cardiomyocytes are used, the evaluating physician must cognitively integrate the information to infer the pathology. However, integrating information and making an evaluation requires a high level of proficiency, and physicians may not be familiar with the detailed pathology of rare diseases. Therefore, the inventors believed that further improvements were needed in methods for easily differentiating cardiac pathologies, particularly those exhibiting abnormalities in fatty acid and / or triglyceride metabolism. An object of the present invention is to provide a cardiac examination method, an image generation method, and a program that can solve the above problems. [Means for solving the problem]

[0009] The present invention includes the following aspects [1] to [6]. [1] A method for examining a heart, comprising the following steps (1) and (2): Step (1): generating an image G1 in a subject by an image generation method M1 Step (2): comparing the image G1 with a standard that can determine one or more of the following: normal (d0) in the heart; and the presence, degree, and site of onset of pathological conditions (d1 to d5); The normal state d0 and the pathological states d1 to d5 are the states shown below: Normal d0: No metabolic abnormalities of fatty acids or triglycerides in the myocardium Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium Condition d3: A condition involving necrotic and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the rest of the myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathology d5: Pathology of mitochondrial cardiomyopathy, The image generating method M1 includes the following steps (i) to (ii): Step (i): A step of selecting color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy based on the following two-dimensional color scale. Step (ii): Correlating the color information C with the associated position information to generate an image including the heart in the region of interest; the two-dimensional color scale has continuously changing colors arranged on a two-dimensional plane formed by a first axis and a second axis; The colors are arranged in the first axis direction so as to change continuously from a color indicating an upper threshold value of the washout rate of the tracer compound to a color indicating a lower threshold value, the colors are arranged in the second axis direction so as to change continuously from a color indicating an upper threshold value of the amount of uptake of the tracer compound, via a color indicating a normal range of uptake, to a color indicating a lower threshold value of uptake; At the upper threshold of the washout rate, a color c1 indicating an upper threshold of the uptake amount, a color c2 indicating a value in the normal range of the uptake amount, and a color c3 indicating a lower threshold of the uptake amount are respectively assigned, At the lower limit threshold of the washout rate, a color c4 indicating an upper limit threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating a lower limit threshold of the uptake amount are respectively assigned, A method for examining the heart, wherein the combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any one of combinations 1 to 6 shown in Table A below.

[0010] [Table 1]

[0011] [2] The tracer compound 123 I-β-methyl-p-iodophenylpentadecanoic acid ( 123 The cardiac examination method according to [1], wherein the cardiac tissue is a fibroblast (F-BMIPP). [3] The cardiac examination method according to [1] or [2], wherein the three-dimensional position information in the heart is position information indicated by a polar coordinate arrangement. [4] An image generating method comprising the following steps (i) to (ii): Step (i): In a subject suspected of having a cardiac pathology, a step of selecting color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy based on the following two-dimensional color scale. Step (ii): Correlating the color information C with the associated position information to generate an image including the heart in the region of interest; the two-dimensional color scale has continuously changing colors arranged on a two-dimensional plane formed by a first axis and a second axis; The colors are arranged in the first axis direction so as to change continuously from a color indicating an upper threshold value of the washout rate of the tracer compound to a color indicating a lower threshold value, the colors are arranged in the second axis direction so as to change continuously from a color indicating an upper threshold value of the amount of uptake of the tracer compound, via a color indicating a normal range of uptake, to a color indicating a lower threshold value of uptake; At the upper threshold of the washout rate, a color c1 indicating an upper threshold of the uptake amount, a color c2 indicating a value in the normal range of the uptake amount, and a color c3 indicating a lower threshold of the uptake amount are respectively assigned, At the lower limit threshold of the washout rate, a color c4 indicating an upper limit threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating a lower limit threshold of the uptake amount are respectively assigned, An image generating method in which the combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any one of combinations 1 to 6 shown in Table A below.

[0012] [Table 2]

[0013] [5] The image generating method according to claim 4, wherein the cardiac pathology is one of pathologies d1 to d5 shown below. Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium Condition d3: A condition involving necrotic and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the rest of the myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathophysiology d5: Pathophysiology of mitochondrial cardiomyopathy [6] A program for causing a computer to execute each step of the image generation method described in [4] or [5]. [Effects of the Invention]

[0014] The present invention provides a cardiac examination method, an image generation method and a program that enable easy differentiation of cardiac pathologies, particularly pathologies exhibiting abnormalities in the metabolism of fatty acids and / or triglycerides. [Brief explanation of the drawings]

[0015] [Figure 1-1] Figure 1-1 shows a color solid. [Figure 1-2] Figure 1-2 shows the RGB channel decomposition image of Figure 1-1. [Figure 2-1] FIG. 2-1 shows the color scale of the present invention. [Figure 2-2] Figure 2-2 shows the RGB channel decomposition image of Figure 2-1. [Figure 3-1] Figure 3-1 shows an example of the criteria to be compared. [Figure 3-2] Figure 3-2 shows the RGB channel decomposition image of Figure 3-1. [Figure 4-1] FIG. 4-1 shows the results of Example 1. [Figure 4-2] Figure 4-2 shows the RGB channel decomposition image of Figure 4-1. [Figure 5-1] Figure 5-1 shows the control color scale. [Figure 5-2] Figure 5-2 shows the RGB channel decomposition image of Figure 5-1. [Figure 6-1] FIG. 6-1 shows the results of Comparative Example 1. [Figure 6-2]Figure 6-2 shows the RGB channel decomposition image of Figure 6-1. DETAILED DESCRIPTION OF THE INVENTION

[0016] [Heart examination method] The method for examining the heart of the present invention includes the following steps (1) and (2). Step (1): generating an image G1 in a subject by an image generation method M1 Step (2): comparing the image G1 with a standard that can determine one or more of the following: normal (d0) in the heart; and the presence, degree, and site of onset of pathological conditions (d1 to d5); The normal state d0 and the pathological states d1 to d5 are the states shown below: Normal d0: No metabolic abnormalities of fatty acids or triglycerides in the myocardium Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium Condition d3: A condition involving necrotic and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the rest of the myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathology d5: Pathology of mitochondrial cardiomyopathy, The image generating method M1 includes the following steps (i) to (ii): Step (i): A step of selecting color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy based on the following two-dimensional color scale. Step (ii): Correlating the color information C with the associated position information to generate an image including the heart in the region of interest; the two-dimensional color scale has continuously changing colors arranged on a two-dimensional plane formed by a first axis and a second axis; The colors are arranged in the first axis direction so as to change continuously from a color indicating an upper threshold value of the washout rate of the tracer compound to a color indicating a lower threshold value, the colors are arranged in the second axis direction so as to change continuously from a color indicating an upper threshold value of the amount of uptake of the tracer compound, via a color indicating a normal range of uptake, to a color indicating a lower threshold value of uptake; At the upper threshold of the washout rate, a color c1 indicating an upper threshold of the uptake amount, a color c2 indicating a value in the normal range of the uptake amount, and a color c3 indicating a lower threshold of the uptake amount are respectively assigned, At the lower limit threshold of the washout rate, a color c4 indicating an upper limit threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating a lower limit threshold of the uptake amount are respectively assigned, The combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any one of combinations 1 to 6 shown in Table A below.

[0017] [Table 3]

[0018] The examination method of the present invention is directed to the heart, and preferably to the left ventricle of the heart.

[0019] <Process (1)> In step (1), an image G1 is generated in a subject by an image generation method M1. (Subjects) The subject is not particularly limited as long as it is a subject requiring a cardiac examination. Subject species include mammals, including humans, and non-human mammals include monkeys, mice, rats, rabbits, dogs, cats, cows, sheep, horses, pigs, etc. When the subject is a human, there are no limitations on sex, race, or age.

[0020] Subjects who require cardiac examination include, for example, subjects suspected of having any of the following cardiac pathologies d1 to d5, and subjects who need to be differentiated from the following pathologies. Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium Condition d3: A condition involving necrotic and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the rest of the myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathology d5: Pathology of mitochondrial cardiomyopathy.

[0021] The normal and pathological conditions are explained below.

[0022] ·Normal d0 Normal d0 is a state in which there are no metabolic abnormalities of fatty acids and triglycerides in the myocardium. It is synonymous with "healthy individuals."

[0023] Pathophysiology d1: Triglyceride deposit cardiomyovasculopathy (TGCV) In triglyceride-accumulating cardiomyovasculation disease, impaired triglyceride breakdown in myocardial cells leads to intracellular accumulation of triglycerides and impaired fatty acid utilization for energy. Reflecting this, the uptake of tracer compounds is normal, but the washout rate is significantly reduced.

[0024] Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium In this condition, there is myocardium with triglyceride-accumulating myocardial vasculopathy and necrotic and / or damaged myocardium. Triglyceride accumulation myocardial vasculopathy is as described above. In necrotic and / or injured myocardium, fatty acid uptake is reduced or, if uptake occurs, back-diffuses very early, resulting in significantly reduced tracer compound uptake and washout at the time of early imaging. A typical example of necrosis and injury is old myocardial infarction (OMI), which is a type of necrosis. Myocardial infarction is the necrosis of myocardial cells caused by a decrease or interruption of blood flow. A decrease or interruption of blood flow is also called ischemia. In the case of injury, myocardial cells do not die, but the amount of tracer compound taken up and its washout itself decreases depending on the degree of injury.

[0025] Condition D3: A condition involving necrotic and / or damaged myocardium, but without any abnormalities in the metabolism of fats and triglycerides in the myocardium. In this pathological condition, there are necrotic and / or damaged myocardium and myocardium in which triglyceride-accumulating myocardial vasculopathy has not occurred and in which there are no abnormalities in the metabolism of fat and triglycerides. Areas without necrosis and / or injury are essentially normal myocardium, with tracer compound uptake and washout rates within normal ranges.

[0026] Pathological condition d4: Pathological condition of CD36 deficiency CD36 deficiency is a genetic defect in the CD36 (Cluster of Differentiation 36) protein, a fatty acid transporter, that prevents fatty acids from being taken up into cells. This results in significantly reduced uptake of tracer compounds throughout the heart, resulting in a significantly reduced washout rate.

[0027] Pathophysiology d5: Pathophysiology of mitochondrial cardiomyopathy Mitochondrial cardiomyopathy is one of the clinical phenotypes of genetic mitochondrial diseases, which are caused by pathogenic mutations in nuclear DNA or mitochondrial DNA, resulting in abnormalities in mitochondrial function, particularly oxidative phosphorylation. In mitochondrial cardiomyopathy, mitochondrial energy production using fatty acids as a substrate is impaired, resulting in excessive fatty acid uptake. This leads to a marked increase in the uptake of tracer compounds. It is speculated that the increased fatty acid uptake is due to a positive feedback loop.

[0028] {Image generation method M1} The image generating method M1 includes the following steps (i) to (ii). Step (i): A step of selecting color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy based on the following two-dimensional color scale. Step (ii): Correlating the color information C with the associated position information to generate an image including the heart in the region of interest;

[0029] (Myocardial fatty acid metabolism scintigraphy) Myocardial fatty acid metabolism scintigraphy is a technique for visualizing the state of fatty acid metabolism by tracing the dynamics of fatty acids and triglycerides in the myocardium using a tracer compound labeled with a radioisotope. Myocardial fatty acid metabolism scintigraphy itself is known, and can be performed, for example, by administering a tracer compound to a subject and using, for example, single photon emission computed tomography (SPECT).

[0030] (tracer compound) As a tracer compound used in myocardial fatty acid metabolism scintigraphy, a labeled analog compound of a fatty acid that is taken up into myocardial cells via a fatty acid transporter and metabolized is preferably used. As the label, labeling with a radioisotope is preferred, for example, radioactive iodine 123 Among them, the tracer compounds used in myocardial fatty acid metabolism scintigraphy include: 123 I-β-methyl-p-iodophenylpentadecanoic acid ( 123 I-BMIPP) is widely used and is preferred. Other tracer compounds include 11 C-palmitic acid. The method of administering the tracer compound to the subject is not particularly limited and can be appropriately determined by a person skilled in the art. 123 In the case of I-BMIPP, intravenous administration is preferred. The dose of the tracer compound to be administered to a subject is not particularly limited and can be determined appropriately by a person skilled in the art. For example, the dose can be determined based on age, body weight, etc.

[0031] (Single Photon Emission Computed Tomography (SPECT)) Single Photon Emission Computed Tomography (SPECT) itself is a well-known imaging method. Typically, a SPECT device equipped with a gamma camera is used to detect gamma rays emitted from a tracer compound administered to a subject and measure the radiation count value. The measurement data is then reconstructed and converted into three-dimensional information. The resulting three-dimensional information is then divided into any number of three-dimensional information-holding fractions, and a representative count value for each fraction is determined. In conventional SPECT, the representative values ​​for each fraction are converted to create an image that can be visually compared. In SPECT, two-dimensional information is acquired from multiple directions for a three-dimensional object, and three-dimensional information is reconstructed based on this information. Therefore, unlike planar images, which are taken from one direction, it is possible to acquire information that excludes the distribution of tracer compounds in other organs, tissues, etc. that overlap the region of interest in three dimensions.

[0032] Specific methods for reconstructing measurement data and converting it into three-dimensional information include the well-known filtered back projection (FBP) method and the ordered subset expectation maximization (OSEM) method. The three-dimensional information includes three-dimensional position information and a count value.

[0033] The three-dimensional information is divided into any number of three-dimensional information-retaining fractions. The number of three-dimensional information-retaining fractions is not particularly limited as long as the acquired information can be processed in a state suitable for the purpose, but examples include 500 to 10,000 fractions, and preferably 1,000 to 5,000 fractions. Specific examples include, but are not limited to, approximately 1,500 fractions, 2,048 fractions (16 x 128), and 2,400 fractions (20 x 120). Specific examples of methods for dividing into any number of fractions include SPECT analysis software provided by various manufacturers.

[0034] Hereinafter, an embodiment will be described in which the SPECT analysis software Heart Risk View-S (HRV-S) manufactured by Nippon Medi-Physics Co., Ltd. divides the cardiac region into an arbitrary number of three-dimensional information-holding fractions. First, the cardiac region is divided into 20 donut-shaped sections of different sizes perpendicular to the longitudinal centerline. However, the apex of the heart is subjected to a separate special process. More specifically, the cardiac region is divided into 20 sections along the longitudinal axis. Next, each doughnut-shaped portion is subjected to circumferential profile analysis, in which lines are drawn radially from the long axis center line to divide it. More specifically, it can be divided into 120 3-degree increments or 60 6-degree increments, for example. When the circumferential profile analysis is divided into 120 sections, the cardiac region is divided into 2400 sections.

[0035] (Tracer compound uptake and washout rate) In the image generation method M1, the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy are used. Tracer compound uptake The amount of tracer compound uptake is an index that reflects the amount of local distribution of the tracer compound in myocardial cells. Preferably, it is expressed by the count value of radiation incident on an imaging device. As the imaging device, a camera such as a gamma camera is preferably used. The radiation is preferably collimated through a collimator.

[0036] Washout rate of tracer compounds The washout rate (WR) is a quantification of the time-dependent distribution of a tracer compound within myocardial cells. The tracer compound first accumulates within myocardial cells and is then washed out of the myocardial cells over time. It is an index of the degree of intracellular retention. Specifically, it is the percentage of the tracer compound released outside the cells within a certain period of time.

[0037] (Calculation method of uptake amount and washout rate) The uptake and washout rates of the tracer compound are calculated based on the data obtained by SPECT imaging of the subject. Specifically, the SPECT data is reconstructed and converted into three-dimensional information, and the resulting three-dimensional information is divided into any number of three-dimensional information-holding fractions, and the representative count value for each fraction is determined. Each fraction consists of multiple VOIs (Volumes of Interest). The SPECT device acquires the number of incident gamma rays emitted from the radiopharmaceutical per unit time in each VOI as a count value. The representative count value for each fraction is selected based on the count values ​​of multiple VOIs belonging to that fraction. For example, the maximum, mode, median, minimum, or average of the count values ​​of multiple VOIs belonging to that fraction can be used as the representative count value for that fraction. The maximum count value is preferred.

[0038] The uptake amount is calculated based on the first imaging data acquired by imaging a predetermined time after administration of the tracer compound to the subject. The first imaging data is also called an early image. Typically, the uptake amount of each fraction is a representative count value of each fraction in the first imaging data. The predetermined time after administration can be appropriately set depending on the type of tracer compound. 123In the case of I-BMIPP, the predetermined time is preferably 5 to 60 minutes, more preferably 10 to 40 minutes, and even more preferably 15 to 30 minutes after administration of the tracer compound.

[0039] The washout rate is calculated based on the first imaging data and second imaging data obtained by imaging the subject at a time after the first imaging data is acquired. The second imaging data is also called a later image. The time after the acquisition of the first imaging data can be appropriately set depending on the type of tracer compound. 123 In the case of I-BMIPP, the time is preferably 1 to 6 hours after the first imaging, more preferably 2 to 5 hours, and even more preferably 3 to 4 hours. The radioactivity of the tracer compound decreases over time between the acquisition of the first imaging data and the acquisition of the second imaging data. Therefore, it is preferable to correct the count value acquired in the second imaging data to a decay-corrected value. The decay correction can be performed based on the tracer compound used and the interval between the acquisition of the first imaging data and the acquisition of the second imaging data.

[0040] The washout rate of each fraction is calculated by the following formula (I). Formula (I): Washout rate (WR) (%) = {(representative count value of the relevant fraction in the first photographed data) - (representative count value of the relevant fraction in the second photographed data)} / (representative count value of the relevant fraction in the first photographed data) × 100

[0041] (2D color scale) The two-dimensional color scale has continuously changing colors arranged on a two-dimensional plane formed by a first axis and a second axis, The colors are arranged in the first axis direction so as to change continuously from a color indicating an upper threshold value of the washout rate of the tracer compound to a color indicating a lower threshold value, the colors are arranged in the second axis direction so as to change continuously from a color indicating an upper threshold value of the amount of uptake of the tracer compound, via a color indicating a normal range of uptake, to a color indicating a lower threshold value of uptake; At the upper threshold of the washout rate, a color c1 indicating an upper threshold of the uptake amount, a color c2 indicating a value in the normal range of the uptake amount, and a color c3 indicating a lower threshold of the uptake amount are respectively assigned, At the lower limit threshold of the washout rate, a color c4 indicating an upper limit threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating a lower limit threshold of the uptake amount are respectively assigned, The combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any one of combinations 1 to 6 shown in Table A above.

[0042] In the color scale, continuously varying colors are arranged on a two-dimensional plane formed by a first axis and a second axis, which are preferably orthogonal to each other, i.e., the two-dimensional plane is quadrangular, preferably rectangular or square. The first axis corresponds to the washout rate (WR) of the tracer compound. The first axis corresponds to an increase in WR from a first end corresponding to a lower washout rate threshold to a second end corresponding to an upper washout rate threshold. Preferably, the first end of the first axis corresponds to the right end and the second end of the first axis corresponds to the left end, and the first axis corresponds to an increase in WR from right to left. The second axis corresponds to the amount of tracer compound uptake. The second axis corresponds to increasing uptake from a first end corresponding to a lower threshold uptake to a second end corresponding to an upper threshold uptake. Preferably, the first end of the second axis corresponds to the bottom end and the second end of the second axis corresponds to the top end, and the second axis corresponds to increasing uptake from bottom to top.

[0043] In the two-dimensional color scale according to the present invention, designated colors are assigned and arranged at the four corners of the two-dimensional plane and the midpoints of the two sides parallel to the second axis direction. Specifically, for the upper threshold of the washout rate, a color c1 indicating the upper threshold of the uptake amount, a color c2 indicating the value of the normal range of the uptake amount, and a color c3 indicating the lower threshold of the uptake amount are assigned, At the lower threshold of the washout rate, a color c4 indicating the upper threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating the lower threshold of the uptake amount are assigned.

[0044] Generally, colors can be expressed by the RGB color system, which expresses colors by combining three primary colors, for example, red, green, and blue. In the RGB color system, the content of each of the three primary colors, red, green, and blue, is expressed in 8 bits, that is, 256 gradations from 0 to 255. In the RGB color system, the colors white, black, red, green, blue, yellow, cyan, and magenta are expressed as shown in Table B below. Figure 1 shows a color cube formed by arranging colors expressed by the RGB color system in a three-dimensional space.

[0045] [Table 4]

[0046] In the two-dimensional color scale of the present invention, the combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any of combinations 1 to 6 shown in Table A. However, the white, red, green, blue, yellow, cyan, and magenta assigned to color c1, color c2, color c3, color c4, color c5, and color c6 may be analogous colors thereof.

[0047] In the two-dimensional color scale of the present invention, the colors are arranged so as to change continuously except for the points where the above colors are specified. The mode in which the colors change continuously is also called gradation. The continuous change in color is preferably a linear change. The color arrangement in the two-dimensional color scale of the present invention can be easily created by a person skilled in the art. For example, in the color solid shown in Figure 1, the color arrangement in the two-dimensional color scale of the present invention is formed on the corresponding surface. Specifically, the color arrangements in the above combinations 1 to 6 correspond to the faces in FIG. 1 shown in Table C below.

[0048] [Table 5]

[0049] The upper and lower thresholds for the washout rate of the tracer compound on the first axis can be set, for example, based on previously measured data from a group of healthy individuals and a group of patients diagnosed with each pathology. The reference data are values ​​for each three-dimensional information-retaining fraction, which will be described later. Examples of previously measured data include literature values ​​and cohort data from the facility where the cardiac examination method of the present invention is performed or from other facilities. The upper threshold of the washout rate can be set based on data from a group of healthy individuals measured in advance. For example, the 95% prediction interval of the washout rate from a group of healthy individuals measured in advance can be calculated, and the upper threshold can be set to a value near the upper limit of the prediction interval. This interval differs depending on the equipment, testing protocol, etc. at each facility, so is not limited, but can be set, for example, between 15% and 40%. The lower threshold of the washout rate can be set based on data on the pathology of triglyceride-accumulating cardiomyosurgery (pathology d1), the necrotic myocardium in the pathology of triglyceride-accumulating cardiomyosurgery accompanied by necrotic and / or damaged myocardium (pathology d2), the necrotic myocardium in the pathology of necrotic and / or damaged myocardium but without fatty acid and triglyceride metabolic abnormalities in the remaining myocardium (pathology d3), and the pathology of CD36 deficiency (pathology d4). For example, the 95% prediction intervals of these washout rates can be calculated, and the lower threshold can be set to a value near the lower limit of the prediction interval.

[0050] The upper and lower thresholds and normal range of the tracer compound uptake amount on the second axis can be set, for example, based on previously measured data of a group of healthy individuals and a group of patients diagnosed with each pathology. The reference data are values ​​for each three-dimensional information-retaining fraction described below. Examples of previously measured data include literature values ​​and cohort data from the facility where the cardiac examination method of the present invention is performed or from other facilities. The normal range of uptake can be set based on data from a group of healthy individuals measured in advance. The normal range of uptake values ​​assigned to colors c2 and c5 are preferably values ​​near the upper limit of the normal range of uptake of the tracer compound. The lower limit threshold of the uptake amount can be set based on data on the necrotic myocardium in a condition of triglyceride-accumulating myocardial vasculopathy accompanied by necrosis and / or injury of the myocardium (condition d2), the necrotic myocardium in a condition accompanied by necrosis and / or injury of the myocardium but without metabolic abnormalities of fatty acids and triglycerides in the remaining myocardium (condition d3), and the condition of CD36 deficiency (condition d4). Preferably, the lower limit threshold is close to the upper limit for the above conditions. The upper threshold of the uptake amount is set, for example, so that the normal range of the uptake amount is the median value between the upper threshold and the lower threshold.

[0051] Figure 2 shows the two-dimensional color scale when the color combination is Combination 1. In the figure, "Count" indicates the amount of tracer compound taken up, "WR" indicates the washout rate, "High" indicates the upper threshold, "Normal" indicates normality, and "Low" indicates the lower threshold.

[0052] (Step (i)) In step (i), color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy is selected based on the above two-dimensional color scale. The selected color information C uniquely corresponds to the amount of tracer compound taken up and the washout rate of the tracer compound in each three-dimensional information-retaining fraction in the heart.

[0053] (Step (ii)) In step (ii), the color information C is associated with the associated position information to generate an image including the heart in the region of interest. The image can be created, for example, as a polar map, which is a display using a polar coordinate arrangement. For example, when displaying the left ventricle on a polar map using polar coordinates, multiple cross sections perpendicular to the centerline of the left ventricle's long axis are set, and lines are drawn radially from the centerline on each cross section, dividing the entire left ventricle into wedge-shaped sections. The heart has a three-dimensional, sac-like structure made up of myocardium, and the part corresponding to the myocardium is shaped like a distorted truncated pyramid. Each section is a panel (pixel) that makes up the left ventricle, and is arranged in polar coordinates along the long axis. The center of the circle is located at the tip of the heart (apex), and the base of the left ventricle is located on the periphery.

[0054] Thus, an image G1 is generated for the test subject. Figure 4 shows examples of images generated using the two-dimensional color scale shown in Figure 2 for a healthy subject and a patient with each pathology.

[0055] A characteristic pattern of image G1 is shown for each subject. Each will be explained below.

[0056] Normal d0: No abnormalities in the metabolism of fatty acids and triglycerides in the myocardium Both the amount of tracer compound taken up and the washout rate of the tracer compound are within the normal range, and the entire image G1 exhibits a color in the region near color c2 or slightly closer to color c3.

[0057] Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy The amount of tracer compound taken up is normal, but the washout rate of the tracer compound is reduced. The entire image G1 shows a color in the area close to color c5 or slightly closer to color c6.

[0058] Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium In myocardium with triglyceride-accumulating cardiomyovasculature, which is not necrotic or damaged, the amount of tracer compound uptake is normal and the washout rate of the tracer compound is reduced, resulting in a color in the region near color c5 or slightly closer to color c6. In necrotic and / or damaged myocardium, both the amount of tracer compound uptake and the washout rate of the tracer compound are reduced, resulting in a color center in the region closer to color c6, with a mixture of colors closer to color c5 or color c3. The above colors are mixed throughout image G1.

[0059] Condition D3: A condition involving necrotic and / or damaged myocardium, but without any abnormalities in the metabolism of fatty acids and triglycerides in the rest of the myocardium. In myocardium without metabolic abnormalities of fatty acids and triglycerides, the amount of tracer compound taken up is normal, but the color is in the region near color c2 or closer to color c3. In necrotic and / or damaged myocardium, both the amount of tracer compound taken up and the washout rate of the tracer compound are reduced, and colors closer to color c5 or color c3 are mixed in the color center of the region closer to color c6. The above colors are mixed throughout image G1.

[0060] Pathological condition d4: Myocardium with CD36 deficiency Throughout the heart, both the amount of tracer compound taken up and the rate of washout of the tracer compound decrease. Throughout image G1, colors closer to color c5 or color c3 are mixed in the color center of areas closer to color c6.

[0061] Pathological condition d5: Myocardium of mitochondrial cardiomyopathy, Throughout the heart, the amount of tracer compound taken up is significantly increased, and the washout rate of the tracer compound is normal or slightly decreased. Throughout image G1, colors closer to color c4 or color c2 are mixed in the color center of areas closer to color c1.

[0062] <Process (2)> In step (2), the image G1 is compared with a standard that can determine one or more of the following: normality in the heart, and the presence, degree, and site of onset of pathological conditions d1 to d5. As described above, image G1 shows characteristic patterns in healthy individuals and patients with various pathologies. Therefore, image G1 in a subject serves as an indicator of one or more of the presence, severity, and onset site of pathologies d1 to d5. The presence of a pathological condition can be determined, for example, by evaluating the color of the entire or a portion of image G1 and determining the characteristics of the myocardium that make up the entire image in terms of uptake and washout rate. The degree of the pathological condition can be evaluated, for example, by the range of the diseased myocardium in image G1. The site of the pathological condition can be determined, for example, by determining which part of the heart the abnormal part corresponds to in image G1. Specifically, the correspondence between each part in the left ventricle polar coordinate display and parts of the left ventricle is publicly known. Medical professionals such as doctors can use it to assist in diagnosis or for definitive diagnosis.

[0063] The standard to be compared is, for example, a control image created in advance by the image generating method M1 using healthy subjects and patients with each of the pathological conditions d1 to d5 as subjects. In another embodiment, the two-dimensional color scale itself can be used as a standard for comparison. The color of the image G1 of the subject can be used as an index to determine each pathological condition. For convenience, the two-dimensional color scale can be configured such that the name of the disease indicating each pathological condition is written in the area of ​​the characteristic color that appears in that condition. An example of such a standard is shown in Figure 3-1. This makes it possible to determine the pathological condition even if one is not familiar with pathological conditions indicating abnormalities in fatty acid and / or triglyceride metabolism.

[0064] In the image G1 obtained by the present invention, it becomes possible to distinguish between pathological conditions that were previously difficult to distinguish. For example, when using images that separately display the washout rate and uptake amount of a tracer compound, it is difficult to distinguish between triglyceride-accumulating myocardial vasculopathy, in which the washout rate is reduced (pathology d1), and CD36 deficiency (pathology d4), because the uptake amount is a relative display of data obtained from a single scan. It is also difficult to distinguish between triglyceride-accumulating myocardial vasculopathy, in which the washout rate is reduced and accompanied by necrotic and / or damaged myocardium (pathology d2), and a condition in which necrotic and / or damaged myocardium is present but the rest of the myocardium does not have abnormalities in fatty acid and triglyceride metabolism (pathology d3). Furthermore, unless an upper threshold value above the normal range was set for the amount of tracer compound uptake, it was difficult to distinguish the pathological state of mitochondrial cardiomyopathy (pathological state d5) in which the amount of uptake is significantly increased.

[0065] [Image generation method] The present invention also relates to the image generating method M1 described above, in which a subject suspected of having a heart disease is used as a test subject. The image obtained by the image generating method of the present invention can be used as an index for determining one or more selected from the group consisting of normal d0 and the presence, degree, and site of onset of pathological conditions d1 to d5 in the heart. Pathophysiology d1: Pathophysiology of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid-depleting myocardial vasculopathy accompanied by necrotic and / or damaged myocardium Condition d3: A condition involving necrotic and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the rest of the myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathophysiology d5: Pathophysiology of mitochondrial cardiomyopathy

[0066] [program] The program of the present invention is a program for causing a computer to execute each step of the image processing method. Examples of the computer include a desktop or portable personal computer (PC) or a workstation. The computer may be constructed by combining multiple computers of any type connected via a communication network such as the Internet or an intranet. The computer is a data processing device and may further include input means such as a keyboard, a mouse, a touch panel, etc.; and output devices such as a display, a printer, etc.

[0067] The program may be provided by being recorded on a recording medium such as a CD-ROM, a DVD-ROM, a semiconductor memory, etc. Alternatively, the program may be provided as a data signal via a communication network. The program is executed, for example, by a workstation of the SPECT system. [Example]

[0068] The present invention will be described in more detail below with reference to examples.

[0069] (patient) The following patients were selected as study subjects with the approval of the Chiba University Ethics Committee. Healthy individuals without cardiovascular disease (Normal) Patients with triglyceride-accumulating cardiomyovasculopathy (TGCV) TGCV patients with previous myocardial infarction (OMI) (TGCV+OMI) Non-TGCV patients with extensive OMI (non-TGCV+OMI) CD36 deficiency patients Patients with mitochondrial cardiomyopathy

[0070] (Myocardial fatty acid metabolism scintigraphy) According to the protocol recommended by the Japanese Society of Nuclear Cardiology, the subjects were placed at rest after fasting for at least 12 hours. 123 111 MBq of I-BMIPP (trade name: Cardiodyne; manufactured by Nippon Medi-Physics Co., Ltd.) was administered intravenously. Early and delayed images were acquired 20 and 210 minutes later, respectively. The SPECT system used was a NM / CT 870 DR (GE Healthcare Japan) equipped with an extended low-energy general-purpose collimator.

[0071] The shooting conditions are as follows: 64x64 matrix 180°step and shoot mode Sampling angle 6° 60 seconds / view Pixel size: 5.89mm Slice width: 5.89 mm

[0072] 123 The energy window for I was set to 159 keV ± 10% (main) and 130 keV ± 10% (sub).

[0073] Image reconstruction was performed by filtered back projection using a ramp filter. Scatter correction was performed using a 10th-order Butterworth filter (cutoff frequency 0.4 cycles / cm).

[0074] (SPECT analysis) SPECT analysis software used was Heart Risk View-S (HRV-S, manufactured by Nippon Medi-Physics Co., Ltd.). Using this software, the following data was collected for each of the 2400 segments (20 rows and 120 columns) of the left ventricle of the heart: 123 The I uptake counts and washout rates (WR) were analyzed semi-automatically, and files containing the data were exported in Comma-Separated Values ​​(CSV) format.

[0075] Example 1 (2D color scale) A two-dimensional color scale was created using a Cartesian coordinate system in which the horizontal axis represents the washout rate and the vertical axis represents the uptake counts. The horizontal axis moves from right to left, corresponding to an increase in the washout rate, and the vertical axis moves from bottom to top, corresponding to an increase in the uptake counts.

[0076] On the horizontal axis, the upper threshold of the washout rate was set to 30%, which is near the upper limit of the prediction interval for the washout rate for normal d0 at the inventor's facility. The lower threshold of the washout rate was set to -20%, which is near the lower limit of the data for pathological condition d1, necrotic myocardial areas in pathological condition d2, necrotic myocardial areas in pathological condition d3, and pathological condition d4 at the inventor's facility. On the vertical axis, the lower threshold of the uptake count was set to a value near the upper limit of the measurement results in the pathology of CD36 deficiency and the pathology of necrotic and / or damaged myocardium. The midpoint of the vertical axis was set to a value near the upper limit of the measurement results in the pathology of other than mitochondrial cardiomyopathy. The upper threshold of the uptake count was determined based on the previously set lower threshold and midpoint.

[0077] The following colors were assigned on the two-dimensional color scale: Upper threshold for washout rate and upper threshold for uptake count: Yellow Upper threshold of washout rate and uptake count value close to the upper limit of measurement results in pathologies other than mitochondrial cardiomyopathy: White Upper threshold for washout rate and lower threshold for uptake count: Cyan Lower threshold for washout rate and upper threshold for uptake count: Red Magenta: Lower threshold of washout rate and close to the upper limit of uptake counts measured in pathologies other than mitochondrial cardiomyopathy Lower threshold for washout rate and lower threshold for uptake count: Blue

[0078] The colors were assigned using a gradation that continuously changes between the assigned colors, and the two-dimensional color scale created is shown in Figure 2-1.

[0079] Based on the SPECT analysis data of the subject, a two-dimensional color scale was applied to the washout rate and uptake amount of each segment, and the corresponding color was selected. An image displayed in a polar coordinate system was created using Heart Risk View-S software. The created image is shown in Figure 4-1.

[0080] Comparative Example 1 The color assignments were changed as follows to create a contrasting two-dimensional color scale: Upper threshold of washout rate and upper threshold of uptake amount: White Upper threshold of washout rate and lower threshold of uptake: Blue Lower threshold of washout rate and upper threshold of uptake: Orange Lower threshold of washout rate and lower threshold of uptake: black

[0081] The control two-dimensional color scale created is shown in Figure 5-1. A controlled two-dimensional color scale was applied to the test subjects, and the resulting image is shown in Figure 6-1.

[0082] In the control 2D color scale, both TGCV and CD36 deficiency exhibit colors that indicate normal counts and low WR values ​​throughout the heart, making it impossible to distinguish between these pathologies. In contrast, when using the 2D color scale of the present invention, CD36 deficiency exhibits colors that indicate low counts and low WR values ​​throughout the heart, making it possible to distinguish between TGCV and CD36 deficiency. Furthermore, in the control two-dimensional color scale, both normal cases and mitochondrial cardiomyopathy show colors that indicate normal ranges for counts and WR throughout the heart, making it impossible to distinguish between the two. However, in the two-dimensional color scale of the present invention, mitochondrial cardiomyopathy shows colors that indicate high counts and normal or slightly reduced WR throughout the heart, making it possible to distinguish between normal cases and mitochondrial cardiomyopathy.

Claims

1. An imaging method comprising the steps of: Step (i): In a subject suspected of having a cardiac pathology, a step of selecting color information C corresponding to the amount of tracer compound uptake and the washout rate of the tracer compound obtained in association with three-dimensional position information in the heart by myocardial fatty acid metabolism scintigraphy based on the following two-dimensional color scale. Step (ii): Correlating the color information C with the associated position information to generate an image including the heart in the region of interest; the two-dimensional color scale has continuously changing colors arranged on a two-dimensional plane formed by a first axis and a second axis; The colors are arranged in the first axis direction so as to change continuously from a color indicating an upper threshold value of the washout rate of the tracer compound to a color indicating a lower threshold value, the colors are arranged in the second axis direction so as to change continuously from a color indicating an upper threshold value of the amount of uptake of the tracer compound, via a color indicating a normal range of uptake, to a color indicating a lower threshold value of uptake; In the upper threshold of the washout rate, a color c1 indicating an upper threshold of the uptake amount, a color c2 indicating a value in the normal range of the uptake amount, and a color c3 indicating a lower threshold of the uptake amount are respectively assigned, At the lower limit threshold of the washout rate, a color c4 indicating an upper limit threshold of the uptake amount, a color c5 indicating a value in the normal range of the uptake amount, and a color c6 indicating a lower limit threshold of the uptake amount are respectively assigned, An image generating method in which the combination of color c1, color c2, color c3, color c4, color c5, and color c6 is any one of combinations 1 to 6 shown in Table A below. Table 1 2. The imaging method of claim 1, wherein the tracer compound is 123 I-β-methyl-p-iodophenylpentadecanoic acid ( 123 I-BMIPP).

3. An image generation method as described in claim 1, wherein the three-dimensional position information in the heart is position information represented by a polar coordinate arrangement.

4. 2. The image generating method according to claim 1, wherein the cardiac pathology is one of pathologies d1 to d5 shown below. Pathological condition d1: Pathological condition of triglyceride accumulation myocardial vasculopathy Condition d2: Neutral lipid accumulation myocardial vasculopathy accompanied by necrosis and / or damaged myocardium Condition d3: A condition accompanied by necrosis and / or damaged myocardium, but without metabolic abnormalities of fatty acids and triglycerides in the other myocardium. Pathological condition d4: Pathological condition of CD36 deficiency Pathological condition d5: Pathological condition of mitochondrial cardiomyopathy

5. A program for causing a computer to execute each step of the image generating method according to any one of claims 1 to 4.

Images