RU2843249C1 - Method for non-invasive diagnosis of severity of atherosclerotic lesions of coronary arteries - Google Patents

Abstract

FIELD: medical science.

SUBSTANCE: invention relates to medicine, specifically to cardiology, and can be used for non-invasive diagnosis of severity of atherosclerotic lesions of coronary arteries. Patients’ blood is sampled; blood serum is examined for the concentration of growth differentiation factor-15 (GDF-15) and endocan (ESM-1) by enzyme immunoassay. Obtained values are substituted into formula to calculate degree of manifestation of coronary atherosclerosis F=-2.355+0.024*GDF-15+0.171*ESM-1, where F is severity of coronary atherosclerosis in points; GDF-15 is concentration of GDF-15 in blood, pg/ml; ESM-1 is blood ESM-1 concentration, ng/ml. If F is 22 points or less, moderate severity of coronary atherosclerosis is diagnosed. If F falls within range of 23-32 points, a manifested degree of atherosclerotic coronary artery disease is diagnosed. If F is more than 33 points, extremely severe coronary atherosclerosis is diagnosed.

EFFECT: method provides an opportunity to increase the accuracy and information value of the early non-invasive diagnosis of coronary microvascular bed damage in the examination of patients with cardiovascular diseases with atherosclerotic coronary artery disease by determining in blood serum concentrations of two prognostic biomarkers: growth differentiation factor-15 and endocan.

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Description

The invention relates to medicine, namely to cardiology, and can be used for non-invasive diagnostics of the degree of atherosclerotic lesions of the coronary arteries.

According to modern data, coronary heart disease (CHD) occupies a leading position in the list of the most significant social problems in terms of prevalence and risk of complications. In this regard, effective prevention of this nosology and its timely diagnosis have been recognized as the most important state task. It is known that the main cause of CHD is atherosclerotic lesions of the coronary bed: hemodynamically pronounced stenosis of the coronary arteries is the cause of impaired myocardial perfusion and is a substrate for the development of acute coronary events. Therefore, the detection of coronary artery disease, as well as the assessment of its severity, is of unconditional clinical interest (E.I. Usova, A.S. Aliyeva, A.N. Yakovlev et al. The role of multi-omics technologies and genetic analysis in the diagnosis and prognosis of cardiovascular diseases. Russian journal of personalized medicine. 2022; 2 (2): 6-16).

There is a known method for diagnosing atherosclerotic changes in the coronary arteries (A.A. Obedinsky, N.R. Obedinskaya, N.A. Nikitin, et al. Multivessel coronary disease in patients with stable coronary heart disease: current state of the problem and gaps in evidence. Siberian Journal of Clinical and Experimental Medicine. 2022; 37 (2): 28-34), which includes catheterization of the coronary artery followed by the introduction of a radiopaque substance and measurement of the internal diameter of the artery, while coronary angiography (CAG) allows visualization of atherosclerotic plaques that change the internal diameter of the vessel, and is considered the "gold standard" for identifying stenotic atherosclerotic lesions of the arteries.

However, this method has significant drawbacks, which include the invasive nature of the study, which can lead to serious complications: bleeding, development of vascular aneurysms, acute blood flow disorders in the coronary arteries, life-threatening arrhythmias; there are certain indications and contraindications for this study, it can only be used in a specialized center, which requires high qualifications of the doctor conducting the study, which makes it impossible to use this method as a screening method for detecting coronary atherosclerosis in the general population.

A method is known for diagnosing atherosclerotic changes in the coronary arteries by examining the anatomy of the vascular wall and the morphology of the atherosclerotic plaque using intravascular ultrasound (A. Ya. Novak, N. N. Meleshenko, L. G. Geletsyan et al. Endovascular surgery. 2022; 9 (3): 252-259).

However, intravascular ultrasound is performed during coronary angiography and is an invasive and unsafe examination for the patient, requiring hospitalization of the patient.

The search for screening methods for non-invasive outpatient diagnostics of the severity of coronary atherosclerosis in patients with coronary heart disease is currently relevant.

Currently, the search for new laboratory biomarkers is ongoing, which is necessary for a better understanding of the pathogenetic basis of cardiovascular diseases, their prevention and prognosis. A valid biomarker should be specific, representative of the underlying disease, reproducible, understandable for clinical judgment and quantifiable by simple and inexpensive methods.

In recent years, the strategy of a multimarker approach has become popular: studies confirm that the simultaneous quantification of several laboratory parameters can be a more powerful tool for stratifying the risk of cardiovascular diseases and monitoring the effectiveness of therapy, since it allows for a more accurate assessment of multiple aspects of pathogenesis, which is invaluable for basic and clinical research.

A method for non-invasive diagnostics of atherosclerotic lesions of the coronary arteries is known (RU Patent No. 2553942), which consists in the fact that an echocardiographic examination is carried out to identify signs of sclerogenic changes in the aorta, then using the echocardiographic data, the value of the function F is first calculated using the formula developed by the authors, taking into account two demographic parameters - gender and age, one clinical parameter - arterial hypertension and one echocardiographic parameter - the presence of sclerogenic lesions of the aorta, then the value of the probability level P is calculated, and if the value of P is less than or equal to 0.204, belonging to the subgroup of patients with unchanged coronary arteries is determined, if P is greater than 0.204, belonging to the subgroup of patients with non-obstructive coronary sclerosis is determined.

The disadvantages of the method are low accuracy and information content, since it only predicts non-obstructive atherosclerosis, while the greatest risk of acute coronary syndromes is associated with hemodynamically significant stenoses.

A method for non-invasive diagnostics of coronary atherosclerosis is known (RU Patent No. 2372026), including determination of the stiffness index (SI) based on the characteristics of the average volume pulse curve recorded on the finger of the upper limb using the photoplethysmographic method, wherein the average SI value of 4 pulse curves recorded 2, 3, 4 and 5 minutes after taking nitroglycerin (81 ng) is taken as the arterial stiffness indicator, the probability of coronary artery atherosclerosis is calculated using the original formula, the probability of coronary artery atherosclerosis is taken as very low at test values less than or equal to 0.07, low - at values from 0.08 to 0.35, relatively low - at values from 0.36 to 0.50, relatively high - at values from 0.51 to 0.75, high - at values from 0.76 to 0.92 and very high - with values greater than or equal to 0.93.

The disadvantages of this method are that it is labor-intensive to perform, is not very suitable for outpatient and polyclinic medical care, and is not very accurate.

A method for non-invasive diagnostics of coronary atherosclerosis is known (V.A. Metelskaya, N.E. Gavrilova, E.A. Yarovaya, S.A. Boytsov Integrated biomarker: possibilities of non-invasive diagnostics of coronary atherosclerosis. Russian journal of cardiology. 2017; 6 (146): 132-138), including the use of the integrated biomarker i-BIO to assess the severity of coronary atherosclerosis according to the Gensini index, using a number of parameters - gender, intima-media thickness, the number of atherosclerotic plaques, the degree of damage to the carotid arteries, as well as biochemical indicators - triglycerides, glucose, fibrinogen, highly specific C-reactive protein, adiponectin, with subsequent allocation of three intervals of i-BIO values, correlated with the Gensini index.

The disadvantages of this method are as follows: the use of the intima-media thickness indicator determined during standard ultrasound examination of the carotid arteries, namely, the obtained values of this indicator are highly variable due to the technique of performing the study, as a result of which this technique is excluded from modern recommendations for the diagnosis of atherosclerosis (Diagnostics and correction of lipid metabolism disorders for the prevention and treatment of atherosclerosis. Russian recommendations, VII revision. Atherosclerosis and dyslipidemia. 2020; 1 (38): 7-42).

A method for non-invasive diagnostics of coronary atherosclerosis is known (RU Patent No. 2760539) using the biomarker-CA, calculated based on the following parameters: gender, intima-media thickness (IMT), β stiffness index, L-/CAVI ₁ cardio-ankle vascular index, total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL), the values of which are used by scaling, and with a CA biomarker value, which is the sum of points, of at least 5 points, a high probability of coronary atherosclerosis is established, with a CA biomarker value of less than 5 points, coronary artery atherosclerosis is unlikely.

The disadvantages of the method are insufficient information content and low accuracy of assessing the individual risk of developing coronary heart disease, the labor intensity of performing the diagnostic algorithm, as well as the use of the IMT indicator, the values of which have high variability due to the performance of the study, which is inappropriate for use in diagnostics.

The prototype chosen is a method for non-invasive diagnostics of atherosclerotic lesions of the coronary arteries (RU Patent No. 2781411, published on 11.10.2022), which includes determining the concentration of soluble ST2 in the blood serum of patients after detection of non-obstructive atherosclerotic lesions of the coronary arteries by means of an enzyme-linked immunosorbent assay, and when the soluble ST2 level is 31.304 ng/ml or more, coronary microvascular lesions are diagnosed.

The disadvantages of this method include low accuracy and insufficient information content, since it claims to be able to diagnose damage to the microcirculatory bed only, while there is no data on the relationship between the laboratory marker and the severity of damage to the coronary arteries.

The conducted patent information search did not reveal any methods for non-invasive diagnostics of the severity of atherosclerotic lesions of the coronary arteries with the essential features of the claimed method.

The above-described level of technology indicates that in non-invasive diagnostics of the degree of severity of coronary artery disease, the problem is low accuracy and insufficient information content in assessing the individual risk of developing coronary heart disease, as well as the impossibility of using it in outpatient settings, which does not allow for the provision of personalized assistance in the early stages of the disease and thereby effectively preventing the risk of developing and progressing clinical forms of coronary artery atherosclerosis.

The technical result achieved by the invention is an increase in the accuracy and information content of early non-invasive diagnostics of the degree of damage to the coronary microvascular bed when examining patients with cardiovascular diseases with atherosclerotic damage to the coronary arteries.

The development of a method for non-invasive diagnostics of the severity of atherosclerotic lesions of the coronary arteries by determining the values of serum concentrations of growth differentiation factor-15 (GDF-15) and endocan (ESM-1) using enzyme immunoassay and subsequent calculation of the severity of coronary atherosclerosis using a formula in points, which are used to assess three degrees of severity, will improve the accuracy of diagnostics without hospitalizing the patient, and provide personalized care in the early stages of the disease, which will significantly reduce the risk of development and progression of clinical forms of atherosclerosis of the coronary arteries.

It is proposed, as in the prototype, to determine the concentration of prognostic biomarkers in the patient’s blood serum using enzyme immunoassay, followed by an assessment of the severity of coronary atherosclerosis.

The essence of the claimed invention lies in the fact that in the method for non-invasive diagnostics of the severity of atherosclerotic lesions of the coronary arteries, including taking blood from patients, determining the concentration of growth differentiation factor-15 (GDF-15) and endocan (ESM-1) in the blood serum using enzyme immunoassay, the obtained values of GDF-15 and ESM-1 are substituted into the formula for calculating the severity of coronary atherosclerosis F = - 2.355 + 0.024 * GDF-15 + 0.171 * ESM-1, where F is the severity of coronary atherosclerosis, in points; GDF-15 is the concentration of GDF-15 in the blood, pg / ml; ESM-1 is the concentration of ESM-1 in the blood, ng / ml; and with an F value equal to or less than 22 points, a moderate degree of coronary atherosclerosis is diagnosed, with an F value within 23-32 points, a severe degree of atherosclerotic damage to the coronary arteries is diagnosed, with an F value greater than 33 points, an extremely severe degree of coronary atherosclerosis is diagnosed.

The cause-and-effect relationship between the set of essential features and the technical result provided by the invention is as follows: determining the levels of concentration of growth differentiation factor-15 and endocan in blood serum using enzyme immunoassay and subsequent calculation according to the formula of the severity of coronary atherosclerosis in points for assessing the degree of damage to the coronary arteries as moderate, severe or extremely severe, allows for non-invasive screening diagnostics at the early stages of the disease with subsequent determination of indications for treatment, and also ensures the prevention of complications due to the use of available clinical and instrumental methods, taking into account the most significant clinical signs in calculations, and using a method for determining the probability of the presence of coronary sclerosis.

Growth differentiation factor-15 (GDF-15), a member of the transforming growth factor beta superfamily, is a marker of inflammation and apoptosis of cells, primarily atypical ones. GDF-15 expression is induced in macrophages under the influence of interleukin-1 and TNF-α, leading to inhibition of both their activation and the inflammatory response itself (May V.M., Pimentel M., Zimerman L.I., Rohde L.E. GDF-15 as a Biomarker in Cardiovascular Disease. Arq Bras Cardiol. 2021; 116 (3): 494-500. DOI: 10.36660/abc.20200426). When assessing the intima-media thickness and plaque height in the carotid arteries using ultrasound, it was found that the proportion of thickened atherosclerotic plaques increased with increasing GDF-15 levels (Lind L., Wallentin L., Kempf T. et al. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. Eur Heart J. 2009; 30 (19): 2346-53). The use of growth-differentiation factor-15 for diagnostics is associated with the ability of cardiomyocytes to produce GDF-15 in response to stress, which underlies the prognostic value of this marker.

Endocan (ESM-1), being a surrogate marker of inflammation and endothelial dysfunction, plays a crucial role in the processes of angiogenesis, inflammation and vascular permeability (Bessa J., Albino-Teixeira A., Reina-Couto M., Sousa T. Endocan: A novel biomarker for risk stratification, prognosis and therapeutic monitoring in human cardiovascular and renal diseases. Clin Chim Acta. 2020; 509: 310-335). Endocan expression in endothelial cells is increased in response to inflammatory triggers such as lipopolysaccharides and cytokines (TNF-α, transforming growth factor β1, fibroblast growth factor 2, interleukin-1β, hypoxia-inducible factor 1α), and is decreased by interferon γ (Chen J., Jiang L., Yu X.H. et al. Endocan: A Key Player of Cardiovascular Disease. Front Cardiovasc Med. 2022; 5; 8: 798699). Endocan also enhances the production of proinflammatory cytokines by endothelial cells, the expression of adhesion molecules, and the adhesion between monocytes and endothelial cells. In addition, ESM-1-activated adhesion molecules can secrete potent chemokines such as IL-8 and monocyte chemotactic protein-1, which are essential for the inflammatory response and promote the progression of atherosclerosis (Li C, Geng H, Ji L, Ma X, Yin Q, Xiong H. ESM-1: A Novel Tumor Biomaker and its Research Advances. Anticancer Agents Med Chem. 2019; 19 (14): 1687-1694).

The use of the two most significant interrelated prognostic biomarkers, the concentration of which is determined in the blood serum, for early diagnostics of atherosclerotic lesions of the coronary arteries allows, using a mathematical equation, to quantitatively determine the degree of severity of atherosclerotic lesions of the coronary arteries in points, which is consistent with the points that could previously only be determined using the Syntax scale during coronary angiography, while increasing the reliability of the results obtained, the informativeness of the assessment, which allows for accelerated diagnostics and monitoring of therapy for its timely correction.

The claimed diagnostic algorithm can be an early criterion for assessing damage to the coronary microvascular bed in patients with cardiovascular diseases against the background of non-obstructive atherosclerosis of the coronary arteries, which is associated with an increased risk of development and progression of heart failure, and also provides for an expansion of functional capabilities for the early detection of coronary heart disease.

The claimed method has been developed for the first time.

The method is as follows.

The patient is given a venous blood sample on an empty stomach. The blood in a vacuum tube is kept at room temperature for 30 minutes, then centrifuged for 15 minutes at 2500 rpm and the blood serum is aliquoted for subsequent freezing at -70°C.

Commercial test systems are used for enzyme immunoassay to determine serum GDF-15 and ESM-1 concentration levels.

Quantitative assessment of GDF-15 and ESM-1 concentrations in blood serum is carried out in accordance with the manufacturer's instructions. A microplate photometer, an automatic microplate washer, and a thermoshaker for plates are used in the determination process.

The obtained values of GDF-15 and ESM-1 concentration levels are inserted into the formula for calculating the degree of coronary atherosclerosis F:

F=-2.355+0.024*GDF-15+0.171*ESM-1, where

F - the degree of severity of coronary atherosclerosis, in points;

GDF-15 - concentration of GDF-15 in blood, pg/ml;

ESM-1 - concentration of ESM-1 in blood, ng/ml;

If the F value is equal to or less than 22 points, a moderate degree of coronary atherosclerosis is diagnosed.

If the F value is within 23-32 points, a pronounced degree of atherosclerotic damage to the coronary arteries is diagnosed.

If the F value is more than 33 points, an extremely severe degree of coronary atherosclerosis is diagnosed.

The method was developed based on the results of examination of 220 patients with established diagnosis of coronary heart disease. The diagnosis of coronary heart disease was proven clinically and confirmed angiographically (coronary angiography) in accordance with the criteria of the European Society of Cardiology and the European Association of Cardiothoracic Surgeons of 2014. A study was conducted of the relationship between serum concentrations of GDF-15 and ESM-1 with the severity of atherosclerotic processes in the coronary bed in patients with coronary heart disease.

All patients underwent selective coronary angiography using the General Electric Optima IGS 330 angiographic unit. The standard examination technique began with a puncture of the femoral or radial artery under local infiltration anesthesia using the Seldinger method with the installation of a 6-7 French introducer. A standard Judkins left catheter (JL 4.0) was used for selective catheterization of the left coronary artery (LCA). A standard Judkins right catheter (JR 4.0) was used for catheterization of the right coronary artery (RCA). Before performing CAG, the patient was asked about intolerance to novocaine and iodine-containing drugs. The contrast agent was administered in a volume of 5-8 milliliters per shooting. Six projections were used to visualize all segments of the LCA, and at least three for the RCA. Hemodynamic parameters were assessed and electrocardiographic monitoring was performed using the Solar physiological station (General).

For an objective quantitative assessment of the severity of atherosclerotic lesions of the coronary arteries, taking into account the localization of the lesion and a number of morphological indicators of stenosis - vessel occlusion, bifurcation lesion, ostial stenosis, longitudinal atherosclerotic lesion, calcification, intracoronary thrombus and others, the SYNTAX scale is used in the form of an online calculator. This scale is a tool for determining the severity of coronary artery atherosclerosis: it is generally accepted that coronary artery disease is moderate with a SYNTAX score of less than or equal to 22 points, severe with a score of 23-32 points, and extremely severe with a score of more than 33 points (B.S. Grigoriev, K.V. Petrosyan, A.V. Abrosimov. Anatomical risk assessment scale SYNTAX Score - a tool for determining the severity of coronary artery disease and predicting the outcomes of endovascular interventions. Creative cardiology. 2019; 13 (2): 159-172).

To study the concentration of GDF-15 and ESM-1 in blood serum, commercial test systems manufactured by Cloud Clone, USA (GDF-15, pg/ml) and Aviscera, USA (ESM-1, ng/ml) were used. Quantitative assessment of biomarkers in blood serum was performed by enzyme immunoassay using specific antibodies labeled with peroxidase. Blood in a vacuum tube was kept at room temperature for 30 minutes, after centrifugation for 15 minutes at 2500 rpm, the blood serum was aliquoted for further freezing at -70°C. Enzyme immunoassay was performed according to the manufacturer's instructions. In the process of determination, a Multiskan FC microplate photometer (Thermo Fisher Scientific (USA); automatic microplate washer W600 Sinnowa (China); thermoshaker for plates PST-60HL Biosan (Latvia) were used.

The obtained values of GDF-15 and ESM-1 concentrations were inserted into the formula for calculating the degree of coronary atherosclerosis F:

F=-2.355+0.024*GDF-15+0.171*ESM-1.

The degree of severity F was considered moderate with a value equal to or less than 22 points, severe with 23-32 points, and extremely severe with a score greater than 33.

Multivariate linear regression analysis was used to assess the independent relationship of continuous variables with a quantitative factor. For multiple comparisons of central tendencies in independent samples in cases of quantitative or ordinal data, the Kruskal-Wallis test was used; the Mann-Whitney test with Bonferroni correction was used as a posteriori criterion for subsequent pairwise comparisons. Statistical comparisons of the proportions of nominal features were performed using the Pearson chi-square test. The critical region was assumed to be two-sided in all cases.

To test the mathematical model for assessing the relationship between atherosclerotic coronary artery disease according to SYNTAX scores and laboratory indices of subclinical inflammation GDF-15 and ESM-1, a linear multivariate regression analysis was performed.

This model is acceptable for forecasting. This is evidenced by: highly significant value of Fisher criterion F=126.30, p<0.00001, multiple correlation coefficient 0.7358, adjusted determination coefficient 0.5371, Durbin-Watson coefficient was 1.9605.

Table 1 shows the results of multivariate linear regression analysis of the relationship between GDF-15 and ESM-1 indicators and SYNTAX scale scores.

Table 1 demonstrates a statistically significant relationship between the patient's SYNTAX score as a result of CAG and the concentration of GDF-15 and ESM-1.

Based on the results of the regression analysis with the inclusion of the two most significant indicators, a formula for calculating the degree of expression F was obtained:

F=-2.355+0.024*GDF-15, pg/ml+0.171*ESM-1, ng/ml.

Consequently, the degree of expression of coronary atherosclerosis is considered moderate when the values obtained as a result of using the formula are equal to or less than 22 points, severe when the values are within 23-32 points, and extremely severe when the number of points on the scale is more than 33.

The method is confirmed by the following clinical examples.

Example 1

Patient M., 72 years old. Diagnosis: IHD: atherosclerotic heart disease. Atherosclerosis of the coronary arteries (CAG 12/24/21). Hypertension stage III, degree 3, risk 4. Persistent form of typical atrial flutter with variable AV conduction. CHADS-VASc 2 points, HAS-BLED 1 point. Heart failure IIA with preserved left ventricular ejection fraction (EF 61%), FC II.

According to CAG, the patient had 15 points on the SYNTAX scale. The concentration of GDF-15 was 650 pg/ml, ESM-1 - 5.15 ng/ml.

The obtained values were substituted into the formula for calculating F:

F=-2.355+0.024*650+0.171*5.15=14.13

The obtained value of the degree of expression equal to 14.3 points is consistent with the SYNTAX points and corresponds to moderate expression of atherosclerotic lesions of the coronary bed - less than 22.

Example 2

Patient Shch., 70 years old. Diagnosis: IHD: post-infarction (2010) cardiosclerosis. Atherosclerosis of the coronary arteries (CAG 17.01.22). Hypertension stage III, degree 2, risk 4. Frequent polyfocal ventricular extrasystole, including paired, allorhythmia of the bigeminy type; unstable paroxysm of monomorphic ventricular tachycardia. Lown GUB. HF PA with preserved left ventricular ejection fraction (EF 53%), FC III.

According to CAG, the patient had 26.5 points on the SYNTAX scale. The concentration of GDF-15 was 980 pg/ml, ESM-1 - 20.67 ng/ml.

The obtained values were substituted into the formula for calculating the degree of expression F:

F=-2.355+0.024*980+0.171*20.67=24.52

The obtained result was 24.52 points, which is consistent with the points on the SYNTAX scale and corresponds to pronounced atherosclerotic lesions of the coronary arteries - 23-32 points.

Example 3

Patient N., 62 years old. Diagnosis: IHD: post-infarction (2019) cardiosclerosis. Atherosclerosis of the coronary arteries (CAG 04.03.22). Hypertension stage III, degree 2, risk 4. Heart failure IIB with reduced left ventricular ejection fraction (EF 39%), FC III. Chronic post-infarction aneurysm of the septal-apical zone of the left ventricle.

According to CAG, the patient had 46.5 points on the SYNTAX scale. The concentration of GDF-15 was 1795 pg/ml, ESM-1 - 32.71 ng/ml.

The obtained values were substituted into the formula for calculating F:

F=-2.355+0.024*1795+0.171*32.71=46.32

The obtained result was 46.32 points, which is consistent with the points on the SYNTAX scale and corresponds to extremely severe atherosclerotic lesions of the coronary arteries - more than 33 points.

The proposed method allows to assess the severity of early atherosclerotic lesions of the coronary arteries in patients with coronary artery disease, which creates the prerequisites for dispensary observation and the appointment of optimally personalized treatment aimed at restoring coronary blood flow and myocardial metabolism.

The method allows for non-invasive, accurate and informative assessment of the severity of atherosclerotic lesions of the coronary arteries without hospitalization of the patient, is available in outpatient settings, and allows for a reduction in the time required to conduct research.

Claims (1)

A method for non-invasive diagnostics of the severity of atherosclerotic lesions of the coronary arteries, including blood sampling from patients, determination of the concentration of growth differentiation factor-15 (GDF-15) and endocan (ESM-1) in the blood serum using enzyme-linked immunosorbent assay, characterized in that the obtained values are substituted into the formula for calculating the severity of coronary atherosclerosis F = -2.355 + 0.024 * GDF-15 + 0.171 * ESM-1, where F is the severity of coronary atherosclerosis in points; GDF-15 is the concentration of GDF-15 in the blood, pg / ml; ESM-1 is the concentration of ESM-1 in the blood, ng / ml; and with an F value equal to or less than 22 points, a moderate degree of coronary atherosclerosis is diagnosed, with an F value within 23-32 points, a severe degree of atherosclerotic damage to the coronary arteries is diagnosed, with an F value greater than 33 points, an extremely severe degree of coronary atherosclerosis is diagnosed.