Pro-Inflammatory Biomarkers and Progression of Atherosclerosis in Patients with Myocardial Infarction with Non-Obstructive Coronary Artery Disease: 1-Year Follow-Up.

The objective of our study was to evaluate the concentrations of pro-inflammatory biomarkers in patients with acute myocardial infarction with non-obstructive coronary arteries (MINOCA) compared to patients with acute myocardial infarction with obstructive coronary arteries (MI-CAD) in the early post-infarction period and after 1 year and to perform a comparative analysis of the relationship between laboratory biomarkers and atherosclerosis progression in patients with MINOCA and MI-CAD. METHODS: Samples of peripheral venous blood were collected upon admission and on days 2, 4, and 7 of hospitalization and after 1 year. An extended multiplex analysis was performed in blood serum. Multidetector-computed tomography coronary angiography was performed on day 7 and 1 year after acute myocardial infarction to assess the progression of atherosclerosis. RESULTS: The level of high-sensitive C-reactive protein (hsCRP) was elevated upon admission in MINOCA patients compared to MI-CAD patients (p = 0.05), but it was comparable in two groups at other time points and did not exceed the reference range after 1 year. Despite comparable levels of cytokines CXCL-6, LIGHT, CCL-8, and endocan-1 in patients in both groups, MINOCA patients had a greater increase in pro-inflammatory cytokines PlGF, oncostatin M, IL-20, and CCL-15 sVCAM-1 in the early post-infarction period and in CCL-21, sVCAM-1, oncostatin M, and PlGF after 1 year. We observed significant differences in the dynamics of the following biomarkers between patients with MI-CAD and MINOCA: the dynamics of concentrations of CCL21 (p = 0.002), LIGHT (p = 0.03), and endocan-1 (p = 0.03) after 1 year compared to day 1 in MI-CAD and MINOCA patients was opposite, while the dynamics of CXCL6 (p = 0.04) and endocan-1 (p = 0.02) differed between groups when evaluated after 1 year compared to day 7 of the early post-infarction period. In the MINOCA group, factors associated with atherosclerosis progression were concentrations of sVCAM-1 and CCL-21, while in the MI-CAD group, concentrations of CCL-8 and CXCL6 were the main determinants of atherosclerosis progression. CONCLUSIONS: This small study showed that MINOCA and MI-CAD patients exhibited differences in a pro-inflammatory biomarker profile in the early post-infarction period and after 1-year follow-up, which implies distinct inflammatory pathways involved in atherogenesis during MINOCA. The key factors that were associated with atherosclerosis progression in MINOCA patients are sVCAM-1 and CCL-21, which may suggest a complex genesis of atherosclerosis progression due to structurally altered plaques and changes in the microcirculatory bed. In MI-CAD patients, CCL-8 and CXCL-6 were the key biomarkers associated with atherosclerosis progression. Further large-scale studies are required to confirm our data.

Intermediate Monocytes and Circulating Endothelial Cells: Interplay with Severity of Atherosclerosis in Patients with Coronary Artery Disease and Type 2 Diabetes Mellitus.

The aim was to investigate the association of monocyte heterogeneity and presence of circulating endothelial cells with the severity of coronary atherosclerosis in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (T2DM). We recruited 62 patients with CAD, including 22 patients with DM2. The severity of atherosclerosis was evaluated using Gensini Score. Numbers of classical (CD14++CD16-), intermediate (CD14++CD16+), and non-classical (CD14+CD16++) monocyte subsets; circulating endothelial progenitor cells; and the presence of circulating endothelial cells were evaluated. Counts and frequencies of intermediate monocytes, but not glycaemia parameters, were associated with the severity of atherosclerosis in diabetic CAD patients (rs = 0.689; p = 0.001 and rs = 0.632; p = 0.002, respectively). Frequency of Tie2+ cells was lower in classical than in non-classical monocytes in CAD patients (p = 0.007), while in patients with association of CAD and T2DM, differences between Tie2+ monocytes subsets disappeared (p = 0.080). Circulating endothelial cells were determined in 100% of CAD+T2DM patients, and counts of CD14++CD16+ monocytes and concentration of TGF-ß predicted the presence of circulating endothelial cells (sensitivity 92.3%; specificity 90.9%; AUC = 0.930). Thus, intermediate monocytes represent one of the key determinants of the appearance of circulating endothelial cells in all the patients with CAD, but are associated with the severity of atherosclerosis only in patients with association of CAD and T2DM.

Neurohumoral Markers of Cardiac Autonomic Denervation after Surgical Ablation of Long-Standing Persistent Atrial Fibrillation.

Although the autonomic nervous system has an evident impact on cardiac electrophysiology and radiofrequency ablation (RFA) is the conventional technique for treating persistent atrial fibrillation, the specific effects of RFA have been insufficiently studied to date. Here, we investigated whether RFA affects neurohumoral transmitter levels and myocardial 123I-metaiodobenzylguanidine (123I-MIBG) uptake. To perform this task, we compared two groups of patients with acquired valvular heart disease: patients who had undergone surgical AF ablation and patients with sinus rhythm. The decrease in norepinephrine (NE) level in the coronary sinus had a direct association with the heart-to-mediastinum ratio (p = 0.02) and a negative correlation with 123I-MIBG uptake defects (p = 0.01). The NE level decreased significantly after the main surgery, both in patients with AF (p = 0.0098) and sinus rhythm (p = 0.0039). Furthermore, the intraoperative difference between the norepinephrine levels in the ascending aorta and coronary sinus (ΔNE) of -400 pg/mL was determined as a cut-off value to evaluate RFA efficacy, as denervation failed in all patients with ΔNE < -400 pg/mL. Hence, ΔNE can be utilized to predict the efficacy of the "MAZE-IV" procedure and to assess the risk of AF recurrence after RFA.

Association of Epicardial Adipose Tissue Adipocytes Hypertrophy with Biomarkers of Low-Grade Inflammation and Extracellular Matrix Remodeling in Patients with Coronary Artery Disease.

The aim of the study was to compare the morphological features of epicardial adipose tissue (EAT) adipocyte with the circulating inflammatory biomarkers and parameters of extracellular matrix remodeling in patients with coronary artery disease (CAD). We recruited 42 patients with CAD (m/f 28/14) who were scheduled for coronary artery bypass graft surgery (CABG). EAT adipocytes were obtained by the enzymatic method from intraoperative adipose tissue samples. Concentrations of secreted and lipoprotein-associated phospholipase A2 (sPLA2 and LpPLA2), TNF-α, IL-1ß, IL-6, IL-10, high-sensitive C-reactive protein (hsCRP), metalloproteinase-9 (MMP-9), MMP-2, C-terminal cross-linking telopeptide of type I collagen (CTX-I), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were measured in blood serum. Patients were divided into two groups: group 1-with mean EAT adipocytes' size ≤ 87.32 µm; group 2-with mean EAT adipocytes' size > 87.32 µm. Patients of group 2 had higher concentrations of triglycerides, hsCRP, TNF-α, and sPLA2 and a lower concentration of CTX-I. A multiple logistic regression model was created (RN2 = 0.43, p = 0.0013). Concentrations of TNF-α, sPLA2 and CTX-I appeared to be independent determinants of the EAT adipocyte hypertrophy. ROC analysis revealed the 78% accuracy, 71% sensitivity, and 85% specificity of the model, AUC = 0.82. According to our results, chronic low-grade inflammation and extracellular matrix remodeling are closely associated with the development of hypertrophy of EAT adipocytes, with serum concentrations of TNF-α, sPLA2 and CTX-I being the key predictors, describing the variability of epicardial adipocytes' size.

Characterization of the novel HLA-DQB1*02:02:23 allele in a Russian hematopoietic stem cell donor.

HLA-DQB1*02:02:23 differs from HLA-DQB1*02:02:01:01 by one synonymous nucleotide substitution at codon -6 in exon 1.

Association of increased oncostatin M with adverse left ventricular remodeling in patients with myocardial infarction.

Background: The study of laboratory biomarkers that reflect the development of adverse cardiovascular events in the postinfarction period is of current relevance. The aim of the present study was evaluation of oncostatin M (OSM) concentration changes in the early and late stages of myocardial infarction and evaluation of the possibility of its use in prediction of adverse left ventricular (LV) remodeling in patients with myocardial infarction with ST-elevated segment (STEMI). Methods: The study involved 31 patients with STEMI admitted in the first 24 hours after the onset of MI and 30 patients with chronic coronary artery disease as a control group. Echocardiographic study was performed on day 3 and in 6 months after STEMI. The serum levels of biomarkers were evaluated on the day of hospital admission and 6 months after MI using multiplex immunoassay. Results: OSM level increased during the first 24 h after the onset of the disease, with the following decrease in 6 months. OSM concentration at admission had correlated with echocardiography parameters and Nt-proBNP, troponin I, CK-MB levels. Our study has demonstrated association of the increased levels of OSM at the early stages of STEMI with development of the adverse LV remodeling in 6 months after the event. Conclusions: Elevation of OSM levels in the first 24 h after STEMI is associated with the development of the adverse LV remodeling in the long-term post-infarction period.

Effect of Mono- and Multichlorinated Organic Compounds-Chlorocyclohexane and Hexachloro-p-xylene-On the Catalytic Properties of Titanium-Magnesium Catalysts in the Homo- and Copolymerization of Ethylene with 1-Hexene.

Ethylene polymerization and ethylene/1-hexene copolymerization over the titanium-magnesium catalytic system in the presence of chlorocyclohexane (CHC) and hexachloro-p-xylene (HCPX) has been studied. Modification of TMC with chlorocyclohexane and hexachloro-p-xylene increased catalyst activity severalfold for both ethylene polymerization and ethylene/1-hexene copolymerization. The key kinetic regularities of ethylene homopolymerization and ethylene/1-hexene copolymerization in the presence of CHC and HCPX were determined, and the copolymerization constants were measured. Molecular characteristics and the copolymer composition were determined for the synthesized samples of ethylene homopolymers and ethylene/hexene copolymers. Modification of the titanium-magnesium catalyst with chlorinated organic compounds reduced 1-hexene content in the copolymer; polymerization was sensitive to 1-hexene as a regulator of polymer molecular weight. The potential mode of action of chlorinated organic modifiers on catalytic properties of titanium-magnesium catalyst is discussed.

Production of Reactive Oxygen Species by Epicardial Adipocytes Is Associated with an Increase in Postprandial Glycemia, Postprandial Insulin, and a Decrease in Serum Adiponectin in Patients with Severe Coronary Atherosclerosis.

Purpose. This work investigates the relations between the production of reactive oxygen species (ROS) by epicardial adipose tissue (EAT) adipocytes and parameters of glucose/insulin metabolism, circulating adipokines levels, and severity of coronary atherosclerosis in patients with coronary artery disease (CAD); establishing significant determinants describing changes in ROS EAT in this category of patients. Material and methods. This study included 19 patients (14 men and 5 women, 53−72 y.o., 6 patients with diabetes mellitus type 2; 5 patients with prediabetes), with CAD, who underwent coronary artery bypass graft surgery. EAT adipocytes were isolated by the enzymatic method from intraoperative explants obtained during coronary artery bypass grafting. The size of EAT adipocytes and ROS level were determined. Results. The production of ROS by EAT adipocytes demonstrated a direct correlation with the level of postprandial glycemia (rs = 0.62, p < 0.05), and an inverse correlation with serum adiponectin (rs = −0.50, p = 0.026), but not with general and abdominal obesity, EAT thickness, and dyslipidemia. Regression analysis demonstrated that the increase in ROS of EAT adipocytes occurs due to the interaction of the following factors: postprandial glycemia (ß = 0.95), postprandial insulin (ß = 0.24), and reduced serum adiponectin (ß = −0.20). EAT adipocytes in patients with diabetes and prediabetes manifested higher ROS production than in patients with normoglycemia. Although there was no correlation between the production of ROS by EAT adipocytes and Gensini score in the total group of patients, higher rates of oxidative stress were observed in EAT adipocytes from patients with a Gensini score greater than median Gensini score values (≥70.55 points, Gr.B), compared to patients with less severe coronary atherosclerosis (<70.55 points, Gr.A). Of note, the frequency of patients with diabetes and prediabetes was higher among the patients with the most severe coronary atherosclerosis (Gr.B) than in the Gr.A. Conclusions. Our data have demonstrated for the first time that systemic impairments of glucose/insulin metabolism and a decrease in serum adiponectin are significant independent determinants of oxidative stress intensity in EAT adipocytes in patients with severe coronary atherosclerosis. The possible input of the interplay between oxidative stress in EAT adipocytes and metabolic disturbances to the severity of coronary atherosclerosis requires further investigation.

Distribution of HLA-A, -B, -C, -DRB1, -DQB1, -DPB1 allele frequencies in patients with COVID-19 bilateral pneumonia in Russians, living in the Chelyabinsk region (Russia).

In this population-based case-control study conducted in the Chelyabinsk region of Russia, we examined the distribution of HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1, in a group of 100 patients with confirmed COVID-19 bilateral pneumonia. Typing was performed by NGS and statistical calculations were carried out with the Arlequin program. HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles were compared between patients with COVID-19 and 99 healthy controls. We identified that COVID-19 susceptibility is associated with alleles and genotypes rs9277534A (disequilibrium with HLA-DPB1*02:01, -02:02, -04:01, -04:02, -17:01 alleles) with low expression of protein products HLA-DPB1 (pc < 0.028) and homozygosity at HLA-C*04 (p = 0.024, pc = 0.312). Allele HLA-A*01:01 was decreased in a group of patients with severe forms of bilateral pneumonia, and therefore it may be considered as a protective factor for the development of severe symptoms of COVID-19 (p = 0.009, pc = 0.225). Our studies provide further evidence for the functional association between HLA genes and COVID-19.

Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of Inflammation and Repair After Myocardial Infarction.

The burden of heart failure (HF), developing after myocardial infarction MI, still represents a major issue in clinical practice. Failure of appropriate resolution of inflammation during post-myocardial injury is associated with unsuccessful left ventricular remodeling and underlies HF pathogenesis. Cells of the immune system have been shown to mediate both protective and damaging effects in heart remodeling. This ambiguity of the role of the immune system and inconsistent results of the recent clinical trials question the benefits of anti-inflammatory therapies during acute MI. The present review will summarize knowledge of the roles that different cells of the immune system play in the process of post-infarct cardiac healing. Data on the phenotype, active molecules and functions of the immune cells, based on the results of both experimental and clinical studies, will be provided. For some cellular subsets, such as macrophages, neutrophils, dendritic cells and lymphocytes, an anti-inflammatory activity has been attributed to the specific subpopulations. Activity of other cells, such as eosinophils, mast cells, natural killer (NK) cells and NKT cells has been shown to be highly dependent of the signals created by micro-environment. Also, new approaches for classification of cellular phenotypes based on the single-cell RNA sequencing allow better understanding of the phenotype of the cells involved in resolution of inflammation. Possible perspectives of immune-mediated therapy for AMI patients are discussed in the conclusion. We also outline unresolved questions that need to be solved in order to implement the current knowledge on the role of the immune cells in post-MI tissue repair into practice.

Serum Levels of Bone Morphogenetic Proteins 2 and 4 in Patients with Acute Myocardial Infarction.

BACKGROUND: Bone morphogenetic proteins-2 and -4 (BMPs) have been implicated in left ventricular remodeling (LVR) processes such as an inflammation and fibrogenesis. We hypothesized that this knowledge could be translated into clinics. METHODS: We studied the dynamics of serum levels of BMPs, its correlation with markers of LVR and with parameters of echocardiography in patients (n = 31) during the six-month follow-up period after myocardial infarction (MI). RESULTS: Elevated serum levels of BMPs decreased by the six-month follow-up period. BMP-2 decreased from the first day after MI, and BMP-4 decreased from the Day 14. The elevated level of BMP-2 at Day 1 was associated with a lower level of troponin I, reperfusion time and better left ventricular ejection fraction (LV EF) at the six-month follow-up. Elevated serum level of BMP-4 at Day 1 was associated with a lower level of a soluble isoform of suppression of tumorigenicity 2 (sST2), age and reperfusion time. An elevated level of BMP-2 at the six-month follow-up was associated with higher levels of BMP-4, high-sensitivity C-reactive protein (hCRP) and sST2. High serum level of BMP-2 correlated with high levels of hCRP and matrix metalloproteinase (MMP)-9 on Day 7. High serum level of BMP-4 correlated with low levels of hCRP, MMP-9 at Day 3, sST2 at Day 1 and with decreased LV EF on Day 7. The findings of multivariate analysis support the involvement of BMP-2 in the development of post-infarction LVR. CONCLUSIONS: Our research translates experimental data about the BMPs in the development of adverse LVR into the clinic. Elevated serum levels of BMPs decreased by the end of the six-month period after MI. BMP-2 decreased from the first day and BMP-4 decreased from Day 14. BMP-2 and BMP-4 were associated with the development of LVR. Their correlations with markers of inflammation, degradation of the extracellular matrix, hemodynamic stress and markers of myocardial damage further support our hypothesis. Diagnostic and predictive values of these BMPs at the development of post-infarction LVR in vivo should be investigated further.

Frequency of monocyte subsets is linked to the severity of atherosclerosis in patients with ischemic heart disease: A case-control study.

BACKGROUND: Monocytes are recognized as central cells in the progression of atherosclerosis, and are subcategorized into classical (CD14++CD16lo), intermediate (CD14++CD16hi) and non-classical (CD14+CD16hi) subsets. PURPOSE: The present study aimed to assess the relationships between different subsets of monocytes, metabolic and inflammatory factors in patients with stable coronary heart disease. METHODS: A total of 26 patients (both men and women) with stable ischemic heart disease (IHD) were recruited. Among all the recruited patients, 17 patients had significant coronary artery disease defined as diameter stenosis more than 70%. Severity of CHD was assessed by the Gensini score (GS). Counts of CD14++CD16lo, CD14++CD16hi, and CD14+CD16hi monocytes were evaluated by flow cytometry. Gating was verified and expression of CD163 was determined by imaging flow cytometry. Key cardiac markers, cytokines, and chemokines were detected in serum and in 24-hour-culture medium for peripheral blood mononuclear cells (PBMC) by multiplex analysis. The Mann-Whitney U-test and Spearman's rank correlation coefficient (r) were used for statistical analysis. RESULTS: Patients with stenosis <70% tended to have higher frequency of CD14+CD16hi monocytes compared to patients with coronary artery stenosis >70%. The frequencies of CD163+CD14++CD16hi and CD163+CD14+CD16hi monocytes were elevated in patients with stenosis >70%. In patients with stenosis <70%, the frequency of classical monocytes positively correlated and the frequency of non-classical monocytes negatively correlated with the value of GS (R =0.757; p =0.018 and R = -0.757; p = 0.018, respectively). CONCLUSIONS: In patients with ischemic heart disease, the frequency of classical monocytes was directly correlated with the severity of atherosclerosis, while the frequency of non-classical monocytes was correlated inversely. The effects of these monocyte subsets in the development of myocardial ischemia still need to be elucidated.

Distribution of the HLA-DPB1 alleles in a Russian population living in the Chelyabinsk region (South Ural of Russia).

The purpose of this work was to establish the distribution of HLA-DPB1 alleles in Russians living in the Chelyabinsk region (Russia). DPB1 frequencies were determined in 100 unrelated Russian, living in the Chelyabinsk region. All subjects were healthy unrelated blood donors, between 18 and 55 years of age. Typing was performed by NGS (DNA-technology, Moscow). For population genetics analysis GENE[RATE] (https://hla-net.eu/tools/) software was used. DPB1*04:01 prevails in this population (gf = 0.3667). Other frequent HLA-DPB1 alleles were: DPB1*04:02, DPB1*02:01, DPB1*03:01 (gf = 0.1490; 0.1481; 0.1385, respectively). Rare alleles (gf ≤ 0.03) were DPB1*17:01, DPB1*01:01, DPB1*06:01, DPB1*14:01, DPB1*05:01, DPB1*13:01, DPB1*09:01, DPB1*10:01, DPB1*11:01, DPB1*23:01, DPB1*124:01, DPB1*15:01, DPB1*16:01, DPB1*105:01, DPB1*150:01.

Serum Soluble ST2 and Adverse Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction.

OBJECTIVE: To assess the dynamics of serum levels of soluble isoform of suppression of tumorigenicity 2 (sST2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) and their correlations with the development of adverse left ventricular remodeling (LVR) through 6 months in patients with primary myocardial infarction with ST-segment elevation (STEMI). METHODS: Subjects were 31 patients with STEMI (median age: 58 years), who underwent percutaneous coronary intervention (PCI) during the first 24 hours of the onset of myocardial infarction (MI). Blood samples and parameters of echocardiography were assessed at days 1, 3, 7, and 14 and 6 months after STEMI. RESULTS: Serum levels of sST2 and NT-proBNP decreased during the 6-month period. Levels of sST2 decreased by 48% from admission to day 7, and levels of NT-proBNP decreased by 40% from day 7 to 6 months after STEMI. Serum levels of sST2 at day 1 (r = 0.5, P < .05) and day 3 (r = 0.4, P < .05) were associated with adverse LVR by 6 months after STEMI. Logistic regression analysis showed that a high concentration of sST2 at day 7 increased the risk of adverse LVR (95% confidence interval [CI], 0.5-0.9; areas under curve [AUC] = 0.8; P = .002), with 92% sensitivity and 70% specificity. A multivariate analysis model revealed that adverse LVR was associated with the level of sST2 (P = .003) and with complete revascularization (P = .01) at the admission. CONCLUSIONS: The dynamics of serum levels of sST2 and NT-proBNP were different. The level of sST2 normalized by the 7th day; NT-proBNP decreased only by the end of the 6-month period after MI. Increased serum levels of sST2 by the 7th day of MI were associated with the development of adverse LVR by the end of the 6-month period.

Relationships of growth factors, proinflammatory cytokines, and anti-inflammatory cytokines with long-term clinical results of autologous bone marrow mononuclear cell transplantation in STEMI.

AIM: The aim of the study was to test the hypothesis suggesting that the pre-intervention levels of proinflammatory cytokines, anti-inflammatory cytokines, and angiogenic growth factors predict the long-term clinical results of autologous bone marrow-derived mononuclear cell (ABMMC) transplantation in patients with primary ST elevation myocardial infarction (STEMI). METHODS AND RESULTS: From 2003 to 2006, a total of 62 patients with primary STEMI were enrolled in an open randomized study registered under the title ESTABOMA. Patients were randomized into two groups: group 1 included patients treated with percutaneous coronary intervention (PCI) and ABMMC transplantation (n = 28); group 2 comprised patients treated only with PCI (n = 34). Follow-up study was performed 7.96 ± 0.96 years after STEMI and involved physical examination, six-minute walk test, echocardiography, and determination of brain natriuretic peptide (BNP) levels. The total and cardiovascular mortality rates were higher in group 1 compared with group 2: 36% (n = 10) vs. 12% (n = 4) (p = 0.02) and 29% (n = 8) vs. 6% (n = 2) (p = 0.03), respectively. Lower levels of proinflammatory cytokines were observed in group 1 after PCI and ABMMC transplantation. Serum levels of FGF, VEGF, and IL-10, determined before PCI and ABMMC transplantation were prognostically significant long-term indicators of unfavorable course of CAD after STEMI.

The Frequency of CCR5del32 Mutation in Populations of Russians, Tatars and Bashkirs of Chelyabinsk Region, Russia.

The distribution of genetic variants associated with natural resistance to viral infections can vary among human ethnic groups due to evolutionary factors, defining the different epidemiologic background of world populations. The polymorphisms, defining the natural resistance to HIV-infection and the rate of progression up to AIDS, are very important since epidemic is still on rise. We have studied the distribution of allele and genotype frequencies of CCR5delta32 mutation in major populations inhabiting Chelyabinsk region of the Russian Federation. Genetic survey included the population of 509 potential blood marrow donors: Russians (N = 300), Bashkirs (N = 118) and Tatars (N = 91). The genotyping assay was performed using real-time polymerase chain reaction (real-time PCR). The genotypes were defined by melting curve analysis. The CCR5delta32 allele and CCR5delta32/delta32 genotype are presented in population of Russians in Chelyabinsk region with the frequencies of F x  = 10.83% and P x  = 1.67, for the CCR5delta32 allele and its homozygosity, respectively. In populations of Bashkirs and Tatars CCR5delta32 allele and CCR5delta32/delta32 genotype are presented at lower frequencies of F x  = 6.36%/P x  = 0.85 and F x  = 7.14%/P x  = 1.10, respectively. These data are consistent with the theory of northern origin of the CCR5delta32 mutation.

Platelet hemostasis in patients with metabolic syndrome and type 2 diabetes mellitus: cGMP- and NO-dependent mechanisms in the insulin-mediated platelet aggregation.

Patients with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) have high risk of microcirculation complications and microangiopathies. An increase in thrombogenic risk is associated with platelet hyperaggregation, hypercoagulation, and hyperfibrinolysis. Factors leading to platelet activation in MetS and T2DM comprise insulin resistance, hyperglycemia, non-enzymatic glycosylation, oxidative stress, and inflammation. This review discusses the role of nitric oxide (NO) in the regulation of platelet adhesion and aggregation processes. NO is synthesized both in endotheliocytes, smooth muscle cells, macrophages, and platelets. Modification of platelet NO-synthase (NOS) activity in MetS patients can play a central role in the manifestation of platelet hyperactivation. Metabolic changes, accompanying T2DM, can lead to an abnormal NOS expression and activity in platelets. Hyperhomocysteinemia, often accompanying T2DM, is a risk factor for cardiovascular accidents. Homocysteine can reduce NO production by platelets. This review provides data on the insulin effects in platelets. Decrease in a number and sensitivity of the insulin receptors on platelets in T2DM can cause platelet hyperactivation. Various intracellular mechanisms of anti-aggregating insulin effects are discussed. Anti-aggregating effects of insulin are mediated by a NO-induced elevation of cGMP and upregulation of cAMP- and cGMP-dependent pathways. The review presents data suggesting an ability of platelets to synthesize humoral factors stimulating thrombogenesis and inflammation. Proinflammatory cytokines are considered as markers of T2DM and cardiovascular complications and are involved in the development of dyslipidemia and insulin resistance. The article provides an evaluation of NO-mediated signaling pathway in the effects of cytokines on platelet aggregation. The effects of the proinflammatory cytokines on functional activity of platelets are demonstrated.