Point score for predicting development of cardiovascular events in young men

Abstract

FIELD: medicine; cardiology.SUBSTANCE: invention can be used to predict the risk of developing cardiovascular events in young men. The patient's waist circumference is measured, the levels of triglycerides, non-high-density lipoprotein cholesterol and leptin are assessed. If a man has a waist circumference of ≥ 98 cm, 5 points are awarded; if the triglyceride level is ≥1.3 mmol / l, 5 points are awarded; if the non-HDL cholesterol level is ≥ 4.5 mmol / l, 4 points are awarded; if the leptin level is ≥ 4.56 ng / ml, 3 points are awarded. If the total points are less than 8, a low risk is determined, and if the total points are greater than or equal to 8, a high risk of developing cardiovascular events in young men is determined.EFFECT: creating a cost-effective and publicly available method for determining the likelihood of cardiovascular diseases in young men.1 cl, 3 dwg, 4 tbl, 3 ex

Description

[0001] The invention relates to medicine, namely cardiology, and can be used for individual prediction of the risk of developing cardiovascular events in young men.

[0002] According to numerous studies, young men exhibit an increased risk of developing cardiovascular disease compared to women of the same age. This phenomenon is associated with a number of factors, including increased body mass index (BMI), blood pressure (BP), and blood lipid levels in men.

[0003] Cohort studies confirm this pattern. For example, a study involving 14,966 people showed that over a six-year observation period, the incidence of CVD was 6.1% in men and 1.8% in women (p < 0.001). Moreover, an increased risk of developing CVD in healthy middle-aged men was observed regardless of traditional risk factors such as arterial hypertension (HTN), carbohydrate and lipid metabolism disorders, obesity, physical inactivity, and smoking [1]. Data from the ESSE-RF in the Kemerovo region also indicate an association between male gender and smoking, hypertension, and a less favorable metabolic profile in young people. Similar results were obtained with a longer observation period (29.7 years), where age, male gender, smoking, BMI, blood pressure, pulse pressure, and resting heart rate have a significant impact on the development of fatal CVD [2].It is important to note that in studies with older participants (mean age 50.8 years), the association of metabolic syndrome and its components with CVD risk was more pronounced in women than in men [3].

[0004] An analysis of two large studies conducted in Russia - the Lipid Research Clinics (LRC) and the Epidemiology of Cardiovascular Diseases (ESSE-RF-1, ESSERF-2) - showed an association between non-LDL cholesterol levels and all-cause mortality among men aged 35 to 64 years. An increase in non-LDL cholesterol above 4.5 mmol / L was associated with an increased risk of both fatal and non-fatal cardiovascular events [4]. However, when a threshold of lower non-LDL cholesterol values ​​(≥3.7 mmol / L) was set, the authors did not record gender differences in the prevalence of non-LDL hypercholesterolemia. Age-related changes also showed that average non-LDL cholesterol values ​​increased only in women, while in men they decreased after 55 years.Furthermore, the prevalence of elevated non-LDL cholesterol (≥3.7 mmol / L) was higher in young men than in women, while it was higher in older women than in men [5].

[0005] According to the recommendations of the World Health Organization (WHO), the criteria indicating a high risk of cardiovascular events in adults are defined as a waist circumference (WC) over 94 cm for men and over 80 cm for women. At the same time, national clinical guidelines in a number of countries specify risk boundaries taking into account population characteristics. For example, the recommendations of the American College of Cardiology (ACC / AHA) set the following thresholds: for men - 102 cm or more, for women - 88 cm or more. These values ​​​​are considered critical for determining an increased risk of cardiovascular disease [6]. The European Society of Cardiology (ESC / EAS) also recommends taking into account regional characteristics. For example, for Central Europe and Russia, the WC boundaries are 94 cm for men and 80 cm for women. At the same time, in southern Europe, the cutoff points are higher: 98 cm for men and 88 cm for women [7].For Asian populations, the recommended WC values ​​are even lower: less than 90 cm for men and less than 80 cm for women [8]. Given the vast size and diversity of Russia's geographic conditions, it is likely that different regions may have their own criteria for determining waist circumference.

[0006] A study conducted as part of the Framingham Heart Study found that triglyceride (TG) levels above 1.7 mmol / L were associated with an increased risk of cardiovascular disease in participants over 30 years of age [9]. This study highlights the importance of TG as an independent risk factor in cardiovascular disease. A meta-analysis based on various population studies showed that in young men (under 45 years of age), high triglyceride levels predict the risk of fatal and non-fatal cardiovascular events. A study of over 20,000 men aged 20 to 39 years found that an increase in TG levels by 1 mmol / L was associated with a 12% increase in the risk of coronary insufficiency

[10] . These data highlight the importance of monitoring and controlling TG levels in this age group.

[0007] Research suggests that elevated leptin levels may be associated with a higher risk of cardiovascular disease. Leptin promotes inflammation and also plays a role in vascular tone and blood pressure regulation

[11] . Excessive leptin secretion, which is often observed in obesity, may lead to insulin resistance and atherosclerosis

[12] . A meta-analysis including various population-based studies noted that elevated leptin levels correlate with an increased risk of CVD in both men and women, but the results vary depending on age and other metabolic factors

[13] . One study found a direct association between elevated leptin levels and the risk of CVD in men with a mean age of 41.48±8.26, even after adjusting for BMI and other risk factors

[14] .

[0008] A known method is “Predicting the risk of a cardiovascular event and its application” patent RU No. 2651708 (G01N 33 / 48, C12Q 1 / 68) including determining the values ​​of biomarkers in an individual’s biological sample, which include the following biomarkers: MMP-12, complement C7, CCL18, α-1-antichymotrypsin complex, GDF-11, α-2-antiplasmin and angiopoietin-2, where the individual has an increased risk of a cardiovascular event if MMP-12, complement C7, CCL18, α-1-antichymotrypsin complex and angiopoietin-2 have an increased level, and GDF-11 and α-2-antiplasmin have a reduced level relative to the control; the in vitro assay comprises at least one capture reagent corresponding to each of said biomarkers, and further comprises selecting said at least one capture reagent from the group consisting of aptamers, antibodies, and a nucleic acid-based probe;the risk of a cardiovascular event is assessed in said individual based on said biomarker values ​​and at least one item of additional biomedical information corresponding to said individual, where said at least one item of additional biomedical information is independently selected from the group consisting of: information corresponding to the presence of cardiovascular risk factors selected from the group consisting of a previous myocardial infarction, angiographic data on stenosis in one or more coronary vessels of more than 50% caused by ischemia load during a treadmill or nuclear stress test or previous coronary revascularization; information corresponding to the physical characteristics of said individual; information corresponding to a change in the weight of said individual; information corresponding to the ethnicity of said individual; information corresponding to the gender of said individual;information consistent with the smoking history of the said individual; information consistent with the alcohol consumption history of the said individual; information consistent with the occupational history of the said individual; information consistent with the family history of cardiovascular disease or other cardiovascular conditions of the said individual; information consistent with the presence or absence in the said individual of at least one genetic marker that correlates with an increased risk of cardiovascular disease in the said individual or a family member of the said individual; information consistent with the clinical symptoms of the said individual; information consistent with other laboratory tests; information consistent with the gene expression values ​​of the said individual;information consistent with the individual's consumption of known cardiovascular risk factors such as a high-saturated fat diet, a high-salt diet, or a high-cholesterol diet; information consistent with the individual's imaging results obtained using techniques selected from the group consisting of electrocardiogram, electrocardiography, carotid ultrasound for intima-media thickness, flow-mediated dilation, pulse wave velocity, ankle-brachial index, stress echocardiography, myocardial perfusion imaging, CT coronary calcification imaging, high-resolution CT angiography, magnetic resonance imaging, and other medical imaging techniques; information regarding the individual's drug treatment.

[0009] The disadvantages of this method are the complexity and duration associated with the collection of a large amount of anamnestic and instrumental data, the need for special equipment for the study of these biomarkers and their processing

[0010] The goal of the proposed development is to create a cost-effective and accessible method for determining the risk of cardiovascular disease in young men. This will enable timely preventive measures aimed at preventing the development of serious cardiovascular diseases and reducing disability among the working-age population.

[0011] This method involves measuring the patient's waist circumference (WC), assessing triglyceride (TG), non-high-density lipoprotein cholesterol (non-HDL-C), and leptin levels. If a man's WC exceeds 98 cm, 5 points are awarded; if the TG level is ≥1.3 mmol / L, 5 points are awarded; if the non-HDL-C level is ≥4.5 mmol / L, 4 points are awarded; and if the leptin level is ≥4.56 ng / ml, 3 points are awarded. A score greater than or equal to 8 indicates a high risk of developing cardiovascular events in young men.

[0012] The claimed method is carried out as follows.

[0013] To construct the population sample, the database of the Territorial Fund for Compulsory Medical Insurance of Persons Aged 25-44 was used for a district in Novosibirsk, typical in terms of industrial, social, population-demographic, and transportation structures, as well as the level of population migration. A random number generator was used to create a representative sample. A total of 528 men were screened.

[0014] The follow-up period of the cohort was 10.0 [8.9; 10.9] years (maximum 11.6 years). The endpoint of cardiovascular events was composite and included: death from cardiovascular disease, myocardial infarction, probable myocardial infarction, revascularization, acute cerebrovascular accident, cerebrovascular disease. Cases of cardiovascular events in the study cohort were identified by comparing the Acute Myocardial Infarction Registry (the WHO Acute Myocardial Infarction Registry Program has been maintained at the Research Institute of Therapeutic, Preventive and Microbiological Medicine, Branch of the Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, from 1982 to the present), data from the automated medical information system (MIAS), and the database of examined individuals. Fatal cases in the study cohort were identified by copying data from “Medical Death Certificates” for the period from 01.02.2014 to 31.12.2023, obtained from the Department of Civil Registration of Death Acts in the city of Novosibirsk.

[0015] The waist circumference was measured using a tape measure, placing it horizontally in the middle between the lower edge of the costal arch and the sacral part of the ilium.

[0016] A single blood sample was drawn from the cubital vein in the fasting state, 12 hours after a meal. Blood lipid profile, glucose, and creatinine were measured enzymatically using standard ThermoFisher reagents on a Konelab 30i automated biochemistry analyzer (Finland).

[0017] At the initial stage, more than 17 adipocytokines were analyzed and one was selected that was the most statistically significant and easiest to determine at the outpatient stage.

[0018] The levels of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), glucagon, interleukin 6 (IL-6), insulin, leptin, monocyte chemotactic factor 1 (MCP-1), pancreatic polypeptide (PP), and tumor necrosis factor alpha (TNF-α) were determined using the multiplex analysis method using the Human Metabolic Hormone V3 panel (MILLIPLEX).

[0019] Statistical processing of the obtained results was carried out using the SPSS software package (version 13.0). Normal distribution was tested using the Kolmogorov-Smirnov test. Due to the non-normal distribution of most of the studied indicators, the data are presented for categorical variables as absolute and relative values ​​- n (%), and for continuous variables as Me [25;75], where Me is the median, 25 and 75 are the 1st and 3rd quartiles. To compare two independent samples, the non-parametric Mann-Whitney U-test was used. To compare proportions, the Pearson chi-square test was used.To assess the informativeness and resolution of the diagnostic test, we conducted a ROC analysis and evaluated sensitivity (Se), which is defined as the proportion of patients who actually have cardiovascular events among those with a positive test (high risk), and specificity (Sp), which is defined as the proportion of people who do not have cardiovascular events among all those with a negative test (low risk). The maximum Youden index was used as the criterion for selecting the optimal cutoff threshold for alipokine levels (total score), which influences the sensitivity-specificity ratio of the model. The critical significance level of the null hypothesis (p) was set to 0.05.

[0020] A total of 18 men experienced cardiovascular events. Men with cardiovascular events were older and had higher BMI, WC, and levels of TG, LDL-C, TC, and non-HDL-C compared with men without cardiovascular events (Table 1).

[0021] Notes: BMI - body mass index, WC - waist circumference, TG - triglycerides, HDL-C - high-density lipoprotein cholesterol, LDL-C - low-density lipoprotein cholesterol, TC - total cholesterol, non-HDL-C - non-high-density lipoprotein cholesterol.

[0022] In men, the risk of developing cardiovascular events increased with an increase in WC by 1 cm, non-HDL-C by 1 mmol / L, and leptin by 1 ng / ml (Table 2).

[0023]

[0024] In men, the development of cardiovascular events was associated with changes in BMI, WC, TC, TG, LDL-C, and non-HDL-C levels. Using ROC analysis, the cutoff points were determined for WC - 98 cm (sensitivity 72%, specificity 70%), TG - 1.3 mmol / L (sensitivity 65%, specificity 78%), non-HDL-C - 4.5 mmol / L (sensitivity 61%, specificity 75%) (Fig. 1), therefore, we included only men in further analysis.

[0025] For leptin, using ROC analysis, the prognostic cutoff point for the development of cardiovascular events in men was determined to be 4.56 ng / mL (sensitivity 56%, specificity 74%) (Fig. 2).

[0026] In men with cardiovascular events, WC≥98 cm was recorded 2.4 times more often, TG≥1.3 mmol / L was recorded 2 times more often, non-HDL-C≥4.5 mmol / L was recorded 2.5 times more often, and leptin ≥4.56 ng / ml was recorded 2.1 times more often than in men without cardiovascular events (Table 3).

[0027]

[0028] The score was calculated using the OR from the logistic regression analysis of the risk of developing cardiovascular events in men, adjusted for age. Individuals with a WC≥98 cm were assigned 5 points, those with a TG≥1.3 mmol / L were assigned 5 points, those with non-HDL-C≥4.5 mmol / L were assigned 4 points, and those with a leptin level≥4.56 ng / ml were assigned 3 points (Table 4).

[0029] The maximum possible score that can be assigned is 17, and the minimum score is 0. ROC analysis was performed to determine the cutoff point for the score. The area under the curve was 0.792 (0.694-0.889), p<0.0001. The cutoff point was determined at 8 points (sensitivity 83%, specificity 63%) (Fig. 3).

[0030] DESCRIPTION OF DRAWINGS

[0031] Fig. 1 - ROC curve of the prognostic significance of metabolic indicators on the risk of developing cardiovascular events in men.

[0032] Fig. 2 - ROC curve of the prognostic significance of lipocalin levels on the risk of developing cardiovascular events in men.

[0033] Fig. 3 - ROC curve of the prognostic significance of the scoring risk assessment of cardiovascular events in men.

[0034] IMPLEMENTATION OF THE INVENTION

[0035] Example 1.

[0036] A 27-year-old man was examined in 2015. At the time of examination, he denied any cardiovascular disease. The examination revealed dyslipidemia and abdominal obesity. Triglyceride levels (2.78 mmol / L), non-HDL-C (4.7 mmol / L), and leptin (7.26 ng / mL) were determined, and his WC (100 cm) was measured. All of the parameters studied exceeded the cutoff points. The total score was 17 (more than 8).

[0037] After 10 years, the man developed acute Q-wave myocardial infarction.

[0038] Example 2.

[0039] A 44-year-old man was examined in 2014. The examination revealed dyslipidemia and abdominal obesity. Triglyceride levels (1.18 mmol / L), non-HDL-C (5.04 mmol / L), and leptin (3.20 ng / ml) were determined, and WC was measured (103 cm). Two of the studied parameters (non-HDL-C and WC) exceeded the cutoff points. The total score was 9 (more than 8).

[0040] After 3 years, the man developed an ischemic stroke, which resulted in death.

[0041] Example 3.

[0042] A 30-year-old man. He was examined in 2014. Triglyceride levels were determined (0.92 mmol / L), non-HDL-C (4.08 mmol / L), and leptin (5.25 ng / mL), and his waist circumference was measured (83 cm). Only one of the parameters (leptin) exceeded the cutoff point. The total score was 3 (less than 8).

[0043] During 10 years of observation, the man did not develop any cardiovascular events.

[0044] The proposed method allows for determining the risk of developing cardiovascular disease in young men over a 10-year period. This method is inexpensive, can be performed in a clinical biochemistry laboratory, and is not affected by the changing conditions of real-world clinical practice. It is minimally invasive, cost-effective, and can be performed on an outpatient basis.

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