Eotaxin and cardio-ankle vascular index in patients with high and very high cardiovascular risk

Eotaxin is a chemokine, which is a chemoattractant mainly to eosinophils, as well as basophils and Th2 lymphocytes. According to studies, overexpression of eotaxin is found in endothelial and smooth muscle cells of blood vessels in the area of atherosclerotic plaque. In clinical medicine, cardio-ankle vascular index (CAVI) is widely used as an indicator of arteriosclerosis and a predictor of cardiovascular events. Few studies have shown the relationship of eotaxin with coronary atherosclerosis; in other studies, the relationship of eotaxin with atherosclerosis, myocardial infarction and pulse wave velocity was not revealed. The aim of the present study was to assess blood level of eotaxin and cardio-ankle vascular index and their association with major cardiovascular risk factors in patients with high and very high cardiovascular risk. We examined 65 patients with high and very high cardiovascular risk, due to documented coronary artery disease, type 2 diabetes mellitus, or combination of cardiovascular risk factors and who were undergoing generally accepted cardioactive, hypoglycemic therapy and lipid-lowering therapy. All patients were examined for the elastic properties of the vascular wall by volumetric sphygmography with assessment of CAVI. In the blood, the concentrations of eotaxin, high-sensitivity C-reactive protein, glycosylated hemoglobin and lipid spectrum indicators were determined. All examined were divided into two groups: with a normal value of CAVI (less than 8) and elevated. Patients with elevated CAVI had higher concentrations of eotaxin (p = 0.013), total cholesterol (p = 0.009), low-density lipoprotein cholesterol (p = 0.016), were older (p < 0.0001) and less likely to take statins (p = 0.002). In all those examined, correlations were found between serum eotaxin concentration and CAVI (rs = 0.34; p = 0.005), as well as age (rs = 0.32; p = 0.006). The age of the patients correlated with CAVI (rs = 0.35; p = 0.007). Thus, in our study, we for the first time showed the relationship between higher concentrations of eotaxin and an increased cardio-ankle vascular index in patients with high and very high cardiovascular risk. Cardio-ankle vascular index was associated with age, lipid metabolism and lipid-lowering therapy. The obtained results allow us to consider eotaxin as a factor associated with atherogenesis and arterial stiffness

Serum cytokines levels in patients with myocardial infarction with non-obstructive and obstructive coronary arteries

Aim. To compare the concentrations of proinflammatory and anti-inflammatory cytokines in patients with myocardial infarction with non-obstructive (MINOCA) and obstructive coronary arteries (MIOCA) in the early postinfarction period and after 1-year follow-up.Material and methods. The study included 40 patients with myocardial infarction (experimental group, 19 patients; control group, 21 patients). Three (15,7%) patients with diagnosed acute myocarditis were excluded from the final analysis. Blood samples were taken upon admission, on the 2nd, 4th and 7th days from hospitalization, and also after 1-year follow-up. Twenty-three parameters were analyzed using multiplex analysis and the Multiplex Instrument FLEXMAP 3D system (Luminex Corporation), as well as the MILLIPLEX map Human Cytokine/ Chemokine Panel II.Results. According to multiplex analysis of blood serum of the studied groups, a comparable increase in proinflammatory cytokines CCL-15, CCL-26, CCL-27 in the early postinfarction period and after 1-year follow-up, as well as antiinflammatory and regenerative cytokines CXCL-12, TPO in the early postinfarction period and after 1-year follow-up. In patients with MINOCA, higher concentrations of the following proinflammatory cytokines were determined: IL-16 upon admission (p=0,03), IL-20 on days 2 and 4 of the early postinfarction period (p=0,005 and p = 0.03), as well as CCL-15 on days 4 and 7 (p=0,05 and p=0,02). After 1-year follow-up, among the proinflammatory cytokines, a greater increase in CCL-21 (p=0,02) was noted in the patients of experimental group. Also, in patients with MINOCA, a greater increase in TPO was determined upon admission and on the 2nd day (p=0,02 and p=0,02), SCF — on the 7th day and after 1-year follow-up (p=0,04 and p=0,04), and LIF on the 4th day of early postinfarction period (p=0,007). In contrast, MIOCA patients showed a greater increase in CXCL-12 levels upon admission (p=0,04). At the same time, patients with MINOCA showed a higher level of C-reactive protein on the 1st day, as well as a higher relative monocyte count after 1-year follow-up.Conclusion. Despite a comparable increase in the cytokines CCL-8, CCL-13, CCL26, CCL-27 in patients of both groups, in patients with MINOCA there was a greater increase in proinflammatory cytokines IL-16, IL-20, CCL-15, CCL-21, and also CXCL-12, LIF, TPO, SCF, which have anti-inflammatory and regenerative activity. After 1 year follow-up, MINOCA patients showed a significant increase in CCL-21 and SCF, with a comparable increase in other proinflammatory cytokines in patients of both groups. A greater increase in proinflammatory cytokines in patients with MINOCA may indicate a more aggressive atherosclerosis course and lead to plaque destabilization followed by ischemic event

CIRCULATING BIOMARKERS OF SYSTEMIC INFLAMMATORY RESPONSE IN THE ASSESSMENT OF POSTPERICARDIOTOMY SYNDROME IN PATIENTS AFTER CARDIAC SURGERY

Postpericardiotomy syndrome (PCTS) is one of the most frequent cardiac surgery complications seen in 9-65% of patients. Despite its widespread occurrence, the mechanisms of the development of PCTS are still understudied. drug. The use of colchicine in cardiac surgery patients is of particular interest. Due to the ability of this drug the colchicine mechanisms of action are able to inhibit the mobilization of the NLRP3 inflammasome assembly, to suppress the activation of caspase-1. As a result, it can prevent the release of proinflammatory cytokines, namely IL-1β and IL-18. There are conflicting data on the effect of colchicine on the PCTS progression within the systemic inflammatory response after cardiac surgery. In this regard, it was important to study the dynamics of serum levels of IL-6, IL-10, IL-1β, and TNFα in patients before coronary artery bypass grafting (T1), 6 hours (T2), and 10 days (T3) after surgery, and to evaluate the effect of colchicine on the development of PCTS. The results of our research showed a significant increase of IL-10 in both groups 6 hours after surgery. However, on the 10th day, the increase in the level of IL-10, compared with the initial values, was higher in the 1st group – 2 times, compared with the 2nd group. In both groups, showed significant increase in serum concentration of IL-6 after 6 h surgery, with a subsequent decrease in the expression at the stage of T3, while the IL-6 levels in the 2nd group was statistically notably higher than T1. The incidence of pleurisy was lower in the group of patients taking colchicine. Only in the 1st group IL-6 levels were directly associated with IL-10. In patients with pleurisy, the level of released IL-10 and TNFα was significantly higher in the 2nd group. There were no significant intergroup differences in serum levels of IL-1β and TNFα, as well as significant changes in IL-1β between the stages of observation. Analysis of TNFα expression revealed significant differences in TNFα content in the 1st group between the T1-T3 and T2-T3 stages. In both groups, multiple positive associations were found between the studied indicators. Thus, data were obtained indicating the antiinflammatory effect of colchicine in cardiac surgery patients. This was clinically expressed in a tendency to a lower incidence of pleurisy, and was accompanied by increased expression of IL-10, which has an antiinflammatory and immunomodulatory effect against the background of the drug in the postoperative period

DYNAMIC CHANGES IN CARDIOVASCULAR RISK BIOMARKERS AND CYTOKINES OF MYOCARDITIS-FREE PATIENTS WITH DECOMPENSATED HEART FAILURE AND ISCHEMIC SYSTOLIC DYSFUNCTION

The development and progression of heart failure is associated with a variety of pathophysiological mechanisms, of particular interest is the study of the inflammatory response as a fundamental link in the pathogenesis of CHF and its main component – decompensation. An open, non-randomized, prospective study was carried out to evaluate the clinical and morphological features of subclinical inflammation in patients with acute decompensation of ischemic chronic heart failure with a reduced ejection fraction. The study included 25 patients with decompensated ischemic CHF with left ventricular ejection fraction < 40% aged 35 to 75 years (60.12±9.3 y. o.). In this study the dynamics of the serum content of C-reactive protein (CRP), N-terminal fragment of the brain natriuretic peptide precursor protein (NT-proBNP), soluble ST2(sST2), insulin-like growth factor-1 receptor (IGF-1R), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-α (TNFα) was performed by multiplex immunoassay using the FLEXMAP 3D. All studied patients were divided into two groups depending on the diagnosed myocarditis: patients with no signs of myocarditis and patients with myocarditis. It was found that in the group of patients with diagnosed myocarditis there was an increased content of CRP, IGF-1R, IL-6 and IL-10, TNFα compared to the group of patients without myocarditis. The median concentrations of the NT-proBNP and sST2 in both groups did not differ. At the follow-up visit a year later, there was a decrease in the content of CRP, NT-proBNP, IL-6 in both groups. In the group of patients with myocarditis, an increase in the content of sST2, IGF-1R, IL-10 was observed. Thus, the study carried out in dynamics revealed significant differences in the degree of changes in the serum activity of pro- and anti-inflammatory cytokines and biomarkers of cardiovascular risk in patients with decompensated heart failure with systolic dysfunction with diagnosed myocarditis and in its absence

Evaluation of the CD40 receptor-ligand system in the patients with atrial fibrillation of non-valvular genesis

Thromboembolic syndrome is the most dangerous complication of atrial fibrillation which develops in about 8-15% of cases, thus presuming the role of persisting left-heart thrombosis in presence of anticoagulant therapy in some patients. When activated, the blood platelets express multiple copies of CD40L on their membrane. Hence, the soluble form of CD40 ligand is considered a marker of platelet activation and pathogenic processes associated with increased activity of the thrombotic system. Our aim was to study the content of CD40, soluble CD40 ligand and thrombomodulin in the patients with atrial fibrillation of non-valvular genesis receiving anticoagulant therapy, discerning those with a history of thrombotic complications, and the cases with atrial fibrillation, however, free of thrombotic complications. The study group included 22 healthy volunteers and 60 patients diagnosed with atrial fibrillation who received anticoagulant therapy, of whom 21 patients have developed thrombotic complications in the course of adequate anticoagulant therapy. Quantitative assays of CD40, soluble CD40 ligand and soluble thrombomodulin were performed by enzyme immunoassay using Core Facility “Medical Genomics”, Tomsk National Research Medical Center. Concentration of soluble CD40 ligand in both groups of the patients with atrial fibrillation significantly exceeded appropriate values in the group of healthy volunteers. CD40L content was increased in the group of patients with thrombotic complications against the group of patients without thrombotic complications. Thrombomodulin content in blood serum was decreased in the patients with thrombotic complications, as compared to both thrombosis-free patients, and to practically healthy volunteers. The study of CD40/CD40L system and thrombomodulin showed that the patients with thrombotic complications exhibited higher serum level of soluble CD40L, with a simultaneous decrease of thrombomodulin, a physiological anticoagulant. A comparative analysis of the CD40/sCD40L system showed increased concentrations of the biomarkers in females, when compared to males

Влияние терапии β-адреноблокаторами на уровень растворимой формы белка ST2 в сыворотке крови пациентов с сердечной недостаточностью с сохраненной и умеренно сниженной фракцией выброса

Aim. To study the prognostic value of high serum concentration of soluble ST2 protein (sST2) in the development of cardiovascular events after endovascular myocardial revascularization and the possibility of using this biomarker as a target for β-blocker therapy in patients with chronic heart failure (CHF) with preserved (HFpEF) and mildly reduced (HFmrEF) left ventricular ejection fraction.Materials and methods. The study included 72 patients (aged 57–69 years, 81.94% were men) with class I–III CHF of ischemic etiology with HFpEF and HFmrEF. The patients were admitted to the cardiology department for endovascular myocardial revascularization. Before myocardial revascularization, serum concentrations of sST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) in all patients were analyzed by enzyme-linked immunosorbent assay (ELISA). Doses of β-blockers used in all patients were recalculated into a total daily dose equivalent to metoprolol succinate. Patients were divided into 2 groups depending on the median equivalent dose of metoprolol succinate (“high” ≥ 100 mg / day and “low” < 100 mg / day).Results. In patients of group 1, the serum concentration of sST2 was 30.7% higher (p < 0.001) than in patients of group 2 (40.26 [34.39; 48.92] ng /ml and 27.9 [23.05; 35.27] ng / ml, respectively), the serum NT-proBNP level in group 1 was 22.8% higher (p = 0.049) than in group 2 (167 [129; 330] ng / ml vs. 129 [125; 147] ng / ml, respectively). In patients receiving an equivalent dose of metoprolol succinate < 100 mg / day, the incidence of cardiovascular events was 34% higher (p = 0.002) than in patients receiving an equivalent dose of metoprolol succinate ≥ 100 mg/day. The ROC analysis showed that serum sST2 level ≥ 34.18 ng / ml (sensitivity 78.0%, specificity 90.0%, area under the curve (AUC) 0.906; p < 0.0001) predicts a high risk of cardiovascular events within one year. However, the serum NT-proBNP level was not an informative predictor of cardiovascular events. Conclusion. It was confirmed that increased sST2 serum concentration has high prognostic value in the development of cardiovascular events within a year after endovascular myocardial revascularization. The possibility of using this biomarker as a target for β-blocker therapy in patients with HFpHF and HFmrEF was substantiated. Aggressive use of β-blockers in the group of patients with HFpEF and HFmrEF and sST2 overexpression is preferable in order to reduce the incidence of cardiovascular events.Цель – изучение прогностического значения высокой концентрации в сыворотке крови растворимой формы белка ST2 (sST2) в развитии сердечно-сосудистых событий после эндоваскулярной реваскуляризации миокарда и возможности использования этого биомаркера в качестве мишени для терапии β-блокаторами у пациентов с хронической сердечной недостаточностью (ХСН) с сохраненной (СНсФВ) и умеренно сниженной (СНусФВ) фракцией выброса левого желудочка.Материалы и методы. В исследование включены 72 пациента (в возрасте 57–69 лет, 81,94% мужчин) с ХСН I–III функционального класса ишемической этиологии с СНсФВ и СНусФВ, госпитализированных в кардиологическую клинику для выполнения эндоваскулярной реваскуляризации ишемизированного миокарда. У всех пациентов перед реваскуляризацией миокарда анализировали концентрацию в сыворотке крови sST2 и N-терминального промозгового натрийуретического пептида (NT-proBNP) с помощью иммуноферментного анализа (ELISA). Дозы применяемых у всех пациентов β-блокаторов были пересчитаны в общую суточную дозу, эквивалентную метопрололу сукцинату. Больные были разделены на две группы в зависимости от медианы эквивалентной дозы β-блокатора метопролола сукцината («высокая» ≥100 мг/сут и «низкая» <100 мг/сут).Результаты. У пациентов первой группы сывороточная концентрация sST2 была на 30,7% (p < 0,001) больше, чем у больных, вошедших во вторую группу (40,26 [34,39; 48,92] нг/мл и 27,9 [23,05; 35,27] нг/мл соответственно), уровень NT-proBNP в сыворотке крови больных первой группы также был выше (на 22,8%; p = 0,049), чем у пациентов второй группы (167 [129; 330] нг/мл против 129 [125; 147] нг/мл соответственно). У пациентов, получавших эквивалентную дозу метопролола сукцината <100 мг/сут, частота сердечно-сосудистых событий была выше на 34% (p = 0,002), чем у пациентов, получавших эквивалентную дозу метопролола сукцината ≥ 100 мг/сут. По данным ROC-анализа установлено, что сывороточный уровень sST2 ≥ 34,18 нг/мл (чувствительность 78,0%, специфичность 90,0%, AUC 0,906; p < 0,0001) позволяет прогнозировать высокий риск развития сердечно-сосудистых событий в течение ближайшего года. Уровень NT-proBNP в сыворотке крови при этом не являлся информативным предиктором сердечно-сосудистых событий.Заключение. Подтверждено высокое прогностическое значение повышения концентрации в сыворотке крови sST2 в развитии сердечно-сосудистых событий в течение года после эндоваскулярной реваскуляризации миокарда и обоснована возможность использования этого биомаркера в качестве мишени для терапии β-блокаторами у пациентов с СНсФВ и СНусФВ. Агрессивное применение β-блокаторов в группе пациентов с СНсФВ и СНусФВ и гиперэкспрессий sST2 предпочтительнее с целью снижения частоты сердечно-сосудистых событий

IMMUNOREGULATORY IMBALANCE AND FUNCTIONAL STATE OF THE HEART IN THE PATIENTS WITH DIABETES MELLITUS TYPE 2

Diabetes mellitus type 2 is one of the most important non-infectious diseases in the modern world, being an important risk factor of cardiovascular disorders. Changes in left ventricular myocardial diastolic function are observed in diabetic patients independently from other comorbidities. Etiology of the heart failure during diabetes mellitus type 2 is multifactorial, exhibiting cellular,  molecular and metabolic aspects. However, its pathophysiological mechanisms are not completely understood. The aim of this study was to evaluate numbers of inflammatory T lymphocytes, i.e., T helper type 1 (Th1) and T helper type 17 (Th17) cells, and FoxP3+T regulatory lymphocytes, depending on the functional state of the heart assessed by two-dimensional echocardiography in patients with arterial hypertension and diabetes mellitus type 2. A total of twenty-five patients with a combination of arterial hypertension and diabetes mellitus type 2, and 14 patients with arterial hypertension without carbohydrate disturbances were recruited to a cross-ectional case-control study. All the patients underwent echocardiography with transthoracic access at the M-mode, B-mode and Doppler mode of imaging. We evaluated numbers of Th1 and Th17 lymphocytes by intracellular production of IL-17 and IFNγ by CD4+ lymphocytes, respectively. The numbers of FoxP3+T regulatory lymphocytes were estimated by expression of CD25 and FoxP3 transcription factor. A flow cytometry approach was used in both cases. We revealed some correlations between the numbers of Th17 lymphocytes, FoxP3+T regulatory lymphocytes and functional parameters of myocardium in patients with diabetes mellitus type 2, which were absent in patientswithout carbohydrate impairments. The numbers of FoxP3+T egulatory lymphocytes, Treg/Th17 lymphocyte ratio, and mean fluorescence intensity of IL-17 for Th17 cells was lower in patients with diabetes mellitus and diastolic dysfunction compared to the patients with diabetes free of diastolic dysfunction. Association of diastolic dysfunction with diabetes mellitus type 2 was accompanied by increase of IFNγ+Th1 lymphocyte numbers and concentrations of IL-10, IFNγ and TNFα in serum as compared to the patients with diastolic dysfunction in the absence of carbohydrate metabolism disturbances. The diabetic patients with diastolic dysfunction were characterized by hyperinsulinemia, hyperglycemia, higher index of insulin resistance, increase of waist circumference and visceral adiposity index when compared to the patients with diastolic dysfunction without diabetes. Visceral obesity and decrease of insulin sensitivity may be regarded as pathogenetically significant factors for the development of immune regulatory imbalance and diastolic dysfunction in the patients with diabetes mellitus type 2

Features of heart failure with preserved ejection fraction (HFpEF) in diabetic patients with resistant hypertension

BACKGROUND: It is expected that a steady increase in the incidence of diabetes and resistant hypertension (RHTN), along with an increase in life expectancy, will lead to a noticeable increase in the proportion of patients with heart failure with preserved ejection fraction (HFpEF). At the same time, data on the frequency of HFpEF in a selective group of patients with RHTN in combination with diabetes are still lacking, and the pathophysiological and molecular mechanisms of its formation have not been yet studied sufficiently.AIM: To assess the features of the development HFpEF in diabetic and non-diabetic patients with RHTN, as well as to determine the factors associated with HFpEF.MATERIALS AND METHODS: In the study were included 36 patients with RHTN and type 2 diabetes mellitus (DM) (mean age 61.4 ± 6.4 years, 14 men) and 33 patients with RHTN without diabetes, matched by sex, age and level of systolic blood pressure (BP). All patients underwent baseline office and 24-hour BP measurement, echocardiography with assess diastolic function, lab tests (basal glycemia, HbA1c, creatinine, aldosterone, TNF-alpha, hsCRP, brain naturetic peptide, metalloproteinases of types 2, 9 (MMP-2, MMP-9) and tissue inhibitor of MMP type 1 (TIMP-1)). HFpEF was diagnosed according to the 2019 AHA/ESC guidelines.RESULTS: The frequency of HFpEF was significantly higher in patients with RHTN with DM than those without DM (89% and 70%, respectively, p=0.045). This difference was due to a higher frequency of such major functional criterion of HFpEF as E/e’≥15 (p=0.042), as well as a tendency towards a higher frequency of an increase in left atrial volumes (p=0.081) and an increase in BNP (p=0.110). Despite the comparable frequency of diastolic dysfunction in patients with and without diabetes (100% and 97%, respectively), disturbance of the transmitral blood flow in patients with DM were more pronounced than in those without diabetes. Deterioration of transmitral blood flow and pseudo-normalization of diastolic function in diabetic patients with RHTN have relationship not only with signs of carbohydrate metabolism disturbance, but also with level of pulse blood pressure, TNF-alfa, TIMP-1 and TIMP-1 / MMP-2 ratio, which, along with the incidence of atherosclerosis, were higher in patients with DM than in those without diabetes.CONCLUSIONS: Thus, HFpEF occurs in the majority of diabetic patients with RHTN. The frequency of HFpEF in patients with DN is significantly higher than in patients without it, which is associated with more pronounced impairments of diastolic function. The progressive development of diastolic dysfunction in patients with diabetes mellitus is associated not only with metabolic disorders, but also with increased activity of chronic subclinical inflammation, profibrotic state and high severity of vascular changes

T regulatory lymphocytes and FoxP3 nuclear translocation in various adipose tissue depots in patients with coronary artery disease

T regulatory lymphocytes (Treg) are present is adipose tissue. Their frequency, as well as the level of FoxP3 nuclear translocation, in epicardial and thymus adipose tissue remains unexplored. Properties of adiposeresident Tregs may be of high significance in patients with coronary artery disease as potential pathophysiological factor in the development of atherosclerosis. The aim of the study was to compare frequency of FoxP3+Tregs and FoxP3 nuclear translocation in epicardial, thymus, subcutaneous adipose tissue and peripheral blood in patients with coronary artery disease. A pilot study was conducted in 11 patients with coronary artery disease scheduled for the coronary artery bypass graft surgery after prior selective coronary angiography. Frequency of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes and FoxP3 nuclear translocation were evaluated by imaging flow cytometry in peripheral blood and in stromal vascular fraction of epicardial, subcutaneous and thymus adipose tissue. Frequencies of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes were higher in epicardial adipose tissue compared to blood (3 and 5 times higher, p = 0.020); CD4+CD25loFoxP3+ cells frequency in subcutaneous adipose tissue was 4 times higher than in blood (p = 0.028). The level of FoxP3 nuclear translocation was the highest in blood and decreased in epicardial, subcutaneous and thymus adipose tissue (p = 0.020 both for CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ lymphocytes). Frequency of CD4+CD25loFoxP3+ cells was directly related to age in thymus (rs = 0.818; p = 0.002), and inversely in epicardial adipose tissue (rs = -0.618; p = 0.043). Frequencies of CD4+CD25hiFoxP3+ and CD4+CD25loFoxP3+ with FoxP3 nuclear translocation in subcutaneous adipose tissue negatively correlated with age (rs = -0.827; p = 0.002 and rs = -0.648; p = 0.031, respectively). Frequency of CD4+CD25loFoxP3+ cells with FoxP3 nuclear translocation in thymus adipose tissue negatively correlated with waist-to-hip ratio (rs = -0.700; p = 0.016). The severity of atherosclerosis was related only to the frequency of CD4+CD25loFoxP3+ cells in subcutaneous adipose tissue (rs = -0.655; p = 0.029). Thus, epicardial and subcutaneous adipose tissue are enriched with Tregs, but factors that influence Treg accumulation and FoxP3 nuclear translocation in these fat depots may be different. The obtained results may further be used for personalized immunomodulatory therapy in patients with atherosclerosis