JP6967857B2 - How to assist in determining the risk of cardiovascular disease, etc. - Google Patents

Description

The present invention relates to a method of assisting in determining the risk of cardiovascular disease, coronary heart disease or stroke, and a method of assisting in the diagnosis of stroke.

The main components of lipids in serum / plasma are cholesterol, triglycerides, phospholipids, etc., and these blood lipids bind to apoproteins and circulate in the blood as lipoproteins. Depending on the difference in density, these lipoproteins are chylomicrons (CM), ultra-low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (hereinafter sometimes referred to as LDL), and high density lipo. It is classified into proteins (hereinafter sometimes referred to as HDL) and the like. Of these lipoproteins, LDL is the main carrier of cholesterol from the liver to each tissue, and it is said that an increase in LDL cholesterol (hereinafter referred to as LDL-C) is closely related to the development of arteriosclerosis. ing. From this, LDL-C is considered to be a risk factor for arteriosclerosis, ischemic heart disease (coronary artery disease), etc., and it is important to know the content of LDL-C in the diagnosis, treatment and prevention of these diseases. It is regarded as an index. On the other hand, many cases of ischemic heart disease and the like have been observed even if LDL-C in the blood is in the normal range, and recently, attention has been paid to changes in the quality of LDL particles.

LDL containing a large amount of triglyceride (hereinafter, may be referred to as TG-rich LDL) is a lipoprotein having different properties from normal LDL having a high cholesterol content. It has been reported that the blood concentration increases with the progress of liver disease, and it accounts for most of the lipoproteins present in the blood at the end stage of liver disease. In addition, TG-rich LDL foams macrophages, and the rate of macrophage foaming by this TG-rich LDL is directly proportional to the serum concentration of malondialdehyde-modified LDL, which is a type of oxidized LDL, in the blood of healthy subjects. Although triglyceride peroxide is hardly detected in, triglyceride in LDL is considered to be closely related to oxidized LDL, based on reports that a significant increase in triglyceride peroxide is observed in the blood of patients with liver disease. Has been done. When comparing triglycerides in LDL of healthy subjects (hereinafter referred to as LDL-TG) with patients with coronary heart disease (CHD), LDL- in blood in patients with coronary heart disease It has been reported that TG increases (Non-Patent Document 1). However, there is no evidence that those with high LDL-TG are at increased risk of developing coronary heart disease in the future among healthy individuals who do not currently develop coronary artery disease.

On the other hand, there is no evidence of an association with LDL-TG for stroke, and whether it can be used to diagnose patients with stroke, or subjects with high LDL-TG are at increased risk of developing stroke in the future. It is not clear if this is the case.

As a method for quantifying LDL-TG, there is a method for obtaining a combination of two-step operations of fraction separation and triglyceride quantification. Fraction separation operations include ultracentrifugation methods, electrophoresis methods, methods using high performance liquid chromatography, etc., and as quantitative methods, for example, for triglyceride measurement using an automatic analyzer used in clinical examinations. There is a method of performing quantification using a reagent. LDL-TG can be quantified by combining these two, but since these are performed in two steps, a pretreatment step that completely separates LDL and lipoproteins other than LDL, and a measurement step. The operation is complicated and time-consuming. In addition, depending on the separation method, it may be difficult to recover the separated sample itself, it may be difficult to recover it quantitatively, or even a method that can recover it quantitatively requires skill in the work. Special equipment may be required. These are expensive methods and are difficult to spread in terms of convenience and economy.

As a method for solving these problems, which can be measured by an automatic analyzer or the like without performing a fractionation operation, the second step is to remove triglyceride in all lipoproteins other than LDL in the first step. A method for measuring triglyceride in LDL remaining in the step (Patent Documents 1 and 2), and after removing triglyceride in HDL (free glycerol and) in the first step, only triglyceride in LDL is removed in the second step. A measuring method (Patent Document 3) is known.

Japanese Unexamined Patent Publication No. 2006-180707 WO2013 / 157642 Republished No. 2000-043537

Circulation 2004; 109, 2844-2849

It is an object of the present invention to provide a method for assisting in determining the risk of cardiovascular disease, coronary heart disease or stroke. Further, an object of the present invention is to provide a method for assisting the diagnosis of stroke.

As a result of diligent research, the inventors of the present application have found that in healthy subjects who have not developed cardiovascular disease, coronary heart disease or stroke, if the blood LDL-TG level is high, cardiovascular disease or coronary heart disease will occur in the future. Alternatively, they have found that the possibility of developing a stroke is high, and that the blood LDL-TG level is high in a patient who has a stroke, and completed the present invention.

That is, the present invention provides the following.
(1) Including measuring the LDL-TG level in blood isolated from healthy subjects, the high LDL-TG level measured indicates that the risk of cardiovascular disease, coronary heart disease or stroke is high. A method of assisting in determining the risk of cardiovascular disease, coronary heart disease or stroke.

INDUSTRIAL APPLICABILITY The present invention provides for the first time a method for accurately determining the high or low risk of developing these diseases in the future at the stage where cardiovascular disease, coronary heart disease or stroke has not occurred. If it is determined that the risk is high, it is possible to try to reduce the risk by changing the lifestyle or taking medicine, and it is possible to prevent the onset of these diseases.

In addition, the present invention has made it possible to assist in the rapid and accurate diagnosis of stroke. Therefore, in the early stage of the onset of stroke, prompt treatment can be performed and death caused by stroke can be prevented.

In the method of the present invention, the LDL-TG value in blood is measured. As the blood sample, it is preferable to use serum or plasma because it is easy to measure.

The method itself for measuring the LDL-TG value in blood is well known (for example, Patent Documents 1 to 3 above), and reagents for that purpose are also commercially available. Therefore, it is easy to obtain blood LDL-TG using a commercially available reagent. Can be quantified.

In healthy individuals who have not developed cardiovascular disease, coronary heart disease or stroke, the higher the blood LDL-TG level, the higher the likelihood of developing these diseases in the future. Therefore, it is possible to assist in determining the risk of developing these diseases in the future based on the measured blood LDL-TG level. The higher the blood LDL-TG level, the higher the possibility of developing these diseases in the future. Therefore, specific criteria can be set as appropriate. For example, in the example below, the subjects were divided into four equal parts based on the blood LDL-TG value, and the incidence rate within 15.6 years in each group was investigated. As a result, the first quartile with the lowest LDL-TG value. The incidence in the 2nd, 3rd, and 4th quartiles was statistically significantly increased with a high statistically significant difference. .. Since the lower limit of the second quartile at this time is 17.1 mg / dL, for example, the threshold value is set to 17 mg / dL, and if it exceeds 17 mg / dL, it can be determined that the risk is high. Alternatively, when a higher risk is regarded as a high risk, for example, an intermediate value of 22.7 mg / dL or more can be determined as a high risk. In this way, the threshold value can be arbitrarily set in consideration of the high risk to be detected. For example, any value in the range of 17 mg / dL to 40 mg / dL, particularly any value in the range of 25 mg / dL to 35 mg / dL, can be set as the threshold value. Since the LDL-TG value may differ depending on the group such as ethnic group, the intermediate value or average value in the group, the value at the boundary between the first quartile and the second quartile, etc. may be used as the threshold value. , A value in the vicinity of these (for example, an arbitrary value within ± 20%) can be determined as a threshold value. Furthermore, the higher the threshold value is, the higher the risk is. Therefore, the risk can be determined based on a specific measured value, and the probability can be determined by associating the measured value with the frequency of occurrence of an event. Can also be indicated numerically.

Similarly, based on the blood LDL-TG level, it is possible to assist in the diagnosis of stroke during onset, and to evaluate and determine whether Stroke is severe or not. For example, if the quantitative value of LDL-TG exceeds 20 to 40 mg / dL, preferably 30 mg / dL, it is judged that the risk of developing CVD or CHD or Stroke in the future is high. However, this does not apply because the standard value for FCHL diagnosis may differ depending on the ethnic group. In addition, it can be determined that the risk of developing CHD or Stroke increases as the LDL-TG level increases to 40 mg / dL and 50 mg / dL among humans diagnosed with a high risk of developing CHD or Stroke.

Hereinafter, the present invention will be specifically described based on examples. However, the present invention is not limited to the following examples.

Example 1
LDL-TG concentrations were measured using stored samples (serum) from a cohort study in the United States. Specifically, LDL-TG concentrations were measured in 9,334 patients who did not develop CHD or stroke at baseline blood sampling. Then, from the results of 15.6 years of follow-up of the subjects of the cohort study, CHD and stroke onset (and CVD combined with these) during that period were investigated, and the relationship with the measurement items was verified.

For the measurement of LDL-TG, LDL-TG "Seiken" (manufactured by Denka Seiken Co., Ltd.) was used.

The LDL-TG values were divided into quartiles and the hazard ratios to the first quartile were compared using the COX proportional regression model model.

The results are shown in Table 1.

As shown in Table 1, the hazard ratios of CHD, stroke, and CVD increase in the 2nd, 3rd, and 4th quartiles with respect to the 1st quartile, and the risk Was observed to increase. The above results indicate that the degree of risk of developing CHD, stroke (and CVD in combination) in the future can be determined by determining the LDL-TG value.

Claims (1)

Circulation, including measuring LDL-TG levels in blood isolated from healthy individuals, high LDL-TG levels measured indicate a high risk of cardiovascular disease, coronary heart disease or stroke A method to assist in determining the risk of organ disease, coronary heart disease or stroke.