PATHOGENESIS OF IMMUNE DYSFUNCTION IN THE SETTING OF METABOLIK SYNDROME IN CORONARY HEAT DISEASE. QUALIFYING SCENTIFYING WORK ON THE RIGHTS OF THE MANUSCRIPT
Authors: Shchurko M. M. , Akimova V. M. 
Published: January 2024

Introduction. Cardiovascular diseases are the cause of disability among the younger and younger population. Taking into account the frequency of cardiovascular diseases, the severity of the course and their lethality, the study of this topic remains one of the biggest urgent problems of medicine. It is known from scientific sources that metabolic syndrome increases the risk of cardiovascular diseases and mortality from them by 1.5-3 times. However, it is often not possible to identify the metabolic syndrome in time, because nothing bothers the patients, which makes it much more difficult to estimate its prevalence.

Therefore the search for new biochemical markers for early diagnosis and prognosis of this pathology is urgent.

The aim of the study. The dissertation studies the pathogenesis of coronary heart disease in the setting of the metabolic syndrome. It also identifies the pathogenic role of the immune system in coronary heart disease in the setting of the metabolic syndrome.

Research methods.The objectives of the study were: to determine indicators of the hormonal, lipid, carbohydrate spectrum of blood serum, indicators of cellular and humoral immunity, markers of inflammation, and to study cytokine dysfunction, correlations of the studied indicators in coronary heart disease (CHD) in the setting of metabolic syndrome.

The object of the study was ischemic heart disorders in combination with metabolic syndrome.

The subject of the study is the identification of markers associated with cardiovascular risk.

Applied methods: biochemical, immunoenzymatic, immunological, statistical.

150 patients were selected for the study at the Department of Family Medicine of the Communal City Clinical Emergency Medical Hospital of Lviv. Patients were chosen based on their clinical data and age. They were all over 47 years old (mean age (56.17 ± 4.12) years), and 68.4% of them were men.

60 patients had verified coronary heart disease(CHD) without metabolic syndrome - group 1, the other 60 patients had verified CHD with metabolic syndrome - group 2. The obtained laboratory indicators were compared with the control group of 30 practically healthy individuals, which included male and female aged 47 to 67 years without accompanying pathology. They were donors of Lviv Communal City Clinical Hospital of Emergency Medical assistance transfusion department.

Results and discussion. The level of N-terminal prohormone of brain natriuretic peptide (NT-proBNP), as well as growth factor (ST 2) in the blood serum of patients was determined to diagnose the functional state of the heart. According to the results of our research, the concentration of ST 2 in the blood serum of patients with ischemic heart disease in the setting of metabolic syndrome (MS) exceeded the normal values by 2.32 times (p < 0.05), in patients with coronary heart disease by 2.16 times (p < 0.05), which indicates more profound violations of the functional state of the myocardium in coronary heart disease in the setting of metabolic syndrome.

The content of NT-proBNP in the blood serum of patients with coronary heart disease (CHD) in the setting of metabolic syndrome exceeded the normal value by 2.6 times (p <0.05), in patients with coronary heart disease, it was within the normal range (p>0.05).

Examining indicators of hormonal activity, it was found that the level of leptin in patients with coronary heart disease probably exceeded the indicator of the control group in women by 16% (p<0.05), and in men by 22% (p<0.05). Indicators of leptin level in patients with coronary heart disease in the setting of MS exceeded the indicators of the control group in women by 5.5 times (p<0.05), and in men - by 4 times (p<0.05)

Leptin gender indicator (LGI) in the group of patients with coronary heart disease was 1.81 ± 0.10, which was not statistically significantly different from the control indicator (1.95 ± 0.15; p > 0.05). In the group of patients with coronary heart disease in the setting of MS, the LGI was 2.75 ± 0.20, which was statistically significantly higher than the control value by 41%.

During the study of carbohydrate metabolism, it was established that the level of glucose in the blood plasma of patients with coronary heart disease exceeded the normal values by 35% (p < 0.05) and in patients with MS by 43% (p < 0.05). Detected hyperglycemia in patients with metabolic syndrome is one of the pathogenetic factors underlying the development of diseases of the cardiovascular system.

The level of glycated hemoglobin (Hb A1c) in the blood of patients with coronary heart disease and in the setting of MS - exceeded the control by 58% (p < 0.05), and this indicator does not differ statistically between the groups (p > 0.05).

A 2.7 times decrease in the content of C-peptid in the blood of patients with coronary artery disease was found, and a 3.1 times decrease in patients with coronary artery disease in the setting of MS (p < 0.05), which indicates the development of insulin resistance.

A study of lipid metabolism indicators were conducted. It was found that the concentration of total cholesterol in the blood serum of patients with coronary heart disease did not exceed normal values (p > 0.05), and in patients with coronary heart disease in the setting of MS, the cholesterol concentration exceeded normal values by 28% (p < 0.05).

The concentration triacylglycerols in the blood serum of patients with coronary heart disease probably exceeded the normal values by 1.75 times (p < 0.05), in patients with coronary heart disease in the setting of MS by 2.6 times (p < 0.05), which indicates a violation of lipid metabolism.

The concentration of high-density lipoprotein cholesterol (HDL-cholesterol) in blood serum was reduced in patients of both groups by 1.6 times compared to the control group.

The concentration of low- density lipoprotein cholesterol (LDL-cholesterol) in the blood serum of patients with coronary heart disease exceeded the indicators of the control group by 19% (p < 0.05), in patients with coronary heart disease in the setting of MS, exceeded the control group by 35%, and the indicators of patients with coronary heart disease - by 14% (p < 0.05).

We found a probable excess of the control indicator of Atherogenic Coefficient (AC) in patients with CHD by 2.2 times, in patients with CHD in the setting of MS by 4 times (p < 0.05), AC in patients with IHD in the setting ound of MS exceeded the indicators of patients with CHD by 1, 5 times (p < 0.05).

Therefore, more pronounced changes in carbohydrate and lipid metabolism indicators were found in patients with coronary heart disease in the setting of metabolic syndrome, which indicates the severity of the clinical course in such patients.

To assess the functional capacity of the kidneys in ischemic heart disease in combination with metabolic syndrome, the level of creatinine clearance was determined. The results of the data showed that in the group of patients with CHD, kidney damage with normal glomerular filtration was detected in 50%, and in the group of patients with CHD in the setting of MS - in 39%, which indicates more frequent manifestations of chronic renal failure with reduced glomerular filtration in CHD in the setting MS.

The level of Ig A in the blood serum of patients in both groups exceeded the normal values by 6.5 times (p < 0.05). The level of Ig G in the blood serum of patients in both groups exceeded the normal values by 2 times, which indicates the presence of a chronic inflammatory process. The level of Ig M in the blood serum of patients with coronary heart disease exceeded the normal values by 4 times, and in patients with coronary heart disease in the setting of MS, it exceeded the normal values by 3 times.

The level of circulating immune complexes (CIC) in the blood serum of patients with coronary heart disease probably exceeded the indicators of the control group by 1.5 times (p < 0.05), in patients with coronary heart disease in the setting of MS - by 2 times, in patients with coronary heart disease - by 1, 4 times (p < 0.05), which indicates the presence of type III hypersensitivity reactions in patients with coronary heart disease and in the setting of MS.

The level of interleukin 1β (IL 1β) in the blood serum of patients with coronary heart disease was within the normal range (p > 0.05), in patients with coronary heart disease of metabolic syndrome, the level of IL 1β exceeds the normal level by 65% and in patients with coronary heart disease by 54% (p < 0.05).

The level of interleukin IL 6 (IL 6) in patients with coronary heart disease exceeded the control group by 29% and was 2.16 times lower than in patients with coronary heart disease complicated by MS (p < 0.05). The level of IL 6 in the blood serum of patients with coronary heart disease complicated by MS exceeded the level in healthy people by 2.8 times (p < 0.05).

The level of total interleukin IL 18 (IL 18) in the blood serum of patients with coronary heart disease did not exceed the normal values (p > 0.05), in patients with coronary heart disease in the setting of MS the level of IL 18 exceeded the normal values by 29% (p < 0.05).

The level of interleukin IL 8 (IL 8) was likely to increase in both examined groups: its content in the blood of patients with coronary heart disease was 6.7 times higher than that of the control group (p < 0.05), and in patients with coronary heart disease on the background of MS, it was 22.4 times higher than the control and 3.33 times the indicators of patients with coronary heart disease (p < 0.05).

The level of Tumor Necrosis Factor-α (TNF-α) was significantly increased in patients with coronary heart disease by 8 times, compared to the values of healthy people (p < 0.05), and in patients with coronary heart disease in the setting of MS - by 9 times and by the 13% of the values of patients with coronary heart disease (p < 0.05).

Also the level of C-reactive protein (CRP) in blood serum was determined as an early marker of the inflammatory process. The level of C-reactive protein in patients with coronary heart disease did not differ statistically significantly from the level in the control group and was 1.3 times lower than in patients with coronary heart disease in the setting of MS. The obtained results indicate an inflammatory process, more pronouncedagainst in the setting of metabolic syndrome.

The indicators of "red blood" in both groups of examinees probably do not differ and were within the reference values. The main differences are observed in the composition of "white blood", the elements of which provide immune protection. The total number of leukocytes in the examined groups was within the reference limits, but the average values probably differed. In patients with coronary heart disease, the total number of leukocytes exceeded the control indicators by 44% (respectively: 7.49 ± 0.5 G/l and 5.2 ± 0.45 G/l, p < 0.05). In patients with coronary heart disease in the setting of MS, the total number of leukocytes exceeded the control indicators by 67% (8.66 ± 0.55 G/l), and the indicators of patients with coronary heart disease by 16% (p < 0.05).

In patients with coronary heart disease, the absolute number of segmented neutrophils exceeded the control level by 25% (respectively: 4.38 ± 0.4 G/l and 3.5 ± 0.3 G/l, p < 0.05). In patients with coronary heart disease in the setting of MS, the number of neutrophil segments exceeded the control indicators by 45% (5.09 ± 0.55 G/l), and the indicators of patients with coronary heart disease - by 16% (p < 0.05).

In patients with coronary heart disease, the number of band neutrofils exceeded the average value in controls by 25 times (respectively: 0.25 ± 0.01 G/l and 0.10 ± 0.2 G/l, p < 0.05). In patients with coronary heart disease in the setting of MS, the number of band neutrophils exceeded the control by 31 times (0.31 ± 0.25 G/l), and the indicators of patients with coronary heart disease - by 24% (p < 0.05), which indicates the activation of nonspecific immunity. The content of eosinophilic granulocytes in patients with coronary heart disease exceeded the average value in controls by 1.4 times (respectively: 0.10 ± 0.01 G/l and 0.14 ± 0.01 G/l, p < 0.05), and in patients with coronary heart disease in the setting of MS - by 1.83 times (0.183 ± 0.25 G/l (p < 0.05), the number of basophils exceeded the control by 1.4 times (respectively: 0.014 ± 0.001 G/l and 0. 01 ± 0.001 G/l, p < 0.05). The number of monocytes in the examined groups probably exceeds the control values: by 1.9 times, which indicates the chronicity of the inflammatory process.

The indicators of the absolute number of lymphocytes in the patient groups probably exceed the values of the control group: by 37% and by 48%.

A decrease in the absolute number of T-lymphocytes (CD3+) was observed in patients with coronary heart disease (by 22% lower than in the control group and by 30% of the indicators in complicated MS, p<0.05). In the group of patients with coronary heart disease in the setting of MS, the absolute number of T-lymphocytes probably did not exceed the control indicator (p>0.05).

The subpopulation of T-helpers (CD 4+) in patients with coronary heart disease was 1.53 times lower than the normal rate, and in the case of complications of MS - 22% lower than normal (p<0.05). The absolute number of T-effectors (СD 8+) in CHD exceeded the indicators of the control group by 18%, and in the setting of MS - by 65% (р<0.05).

The level of activated T-lymphocytes (CD 25+) in both examined groups exceeded the control by more than 2.5 times, which indicates immunodeficiency.

In both groups of patients, a probable decrease in Immunoregulatory Index (IRI) compared to the control was found (p < 0.05): in patients with coronary heart disease by 79%, and in the case of complications of MS - twice, which indicates an imbalance in the regulation of the cellular link of immunity

The amount of B-lymphocytes (CD 19+) in patients with coronary heart disease was higher than the norm by 43% (p<0.05). The subpopulation of activated B-lymphocytes (CD 23+) increased 2.6 times compared to the content in the control group (p<0.05).

The absolute number of B-lymphocytes in patients with coronary heart disease in the setting of MS was 24% higher than the level in the control group and 15% lower than the level in patients with coronary heart disease (p<0.05). The content of activated B-lymphocytes in patients with coronary heart disease complicated by MS was 3.4 times higher than the normal level and 22% higher than that of patients with coronary heart disease (p<0.05).

The level of NK cells (CD 56+) in patients with CHD was 3 times higher than the normal value (p<0.05), and in patients with CHD in the setting of MS -it was 3.5 times higher than the normal value, indicating more pronounced activation of the killer link of immunity in patients with coronary heart disease in the setting of MS.

The CD23+ / CD19+ ratio in patients with coronary heart disease was twice as high as in controls (p<0.05), and in the case of complications of MS, this index exceeded the control indicator by 2.9 times, and the indicator of patients with coronary heart disease by 40% (p< 0.05).

The CD3+/CD19+ ratio in the control group exceeds the index in patients with coronary heart disease by 75%, and in the case of complications of MS by 17% (p<0.05), which indicates T-cell immunodeficiency.

The CD56+ /CD3+ ratio in patients with coronary heart disease exceeds the control values by 3.75 times, and in complicated by the MS – by 3.25 times. This index in patients with coronary heart disease exceeds the index of patients with coronary heart disease in the setting of MS by 15% (p<0.05), which indicates a more pronounced activation of the killer link of immunity against the background of a decrease in T-cell immunity in patients with coronary heart disease.

Conclusions. It was established that the content of the N-terminal fragment of the brain natriuretic peptide precursor positively correlates with the content of growth factor ST 2 in the blood of patients with coronary heart disease in combination with metabolic syndrome, which can be a diagnostic marker in the assessment of ischemic and metabolic disorders.

Leptin resistance has a clear gender relationship and is more pronounced in women with CAD, which more often leads to obesity and metabolic syndrome.

The obtained results indicate a hidden violation of carbohydrate metabolism in patients with coronary artery disease.

The detected deviations of lipid metabolism indicators indicate the presence of type II dyslipoproteinemia in patients with CHD, and type IV dyslipoproteinemia in patients with CHD against the background of metabolic syndrome.

The obtained indicators of creatinine clearance indicate more frequent manifestations of chronic renal failure with reduced glomerular filtration in patients with coronary heart disease complicated by metabolic syndrome. Creatinine clearance correlates positively with the indicators of "red blood", negatively - with the age of patients.

According to the degree of increase in the production of pro-inflammatory cytokines, a more pronounced inflammatory process was found in patients with coronary heart disease complicated by metabolic syndrome.

The presence of T-cell immunodeficiency against the background of activation of the cellular and humoral links of immunity in conditions of complications of cardiovascular diseases by metabolic syndrome, which is a pathogenetic link in the development of cardiovascular pathology, was established.