Development Of Atherothrombosis Research Articles

Metabolic dysfunction-associated steatotic liver disease and atherosclerosis.

To update information about the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and atherosclerosis. This review emphasizes the potential mechanisms linking MASLD with atherosclerosis and the possible causal relationships between these conditions. An increased risk of cardiovascular disease is related to MASLD. Several molecular, cellular, and metabolic mechanisms have been described to explain the development of atherothrombosis in MASLD patients. These include atherogenic dyslipidemia, low-grade vascular inflammation, endothelial dysfunction, foam cell formation, proliferation of vascular smooth muscle cells, insulin resistance, gut microbiota dysbiosis, activation of renin-angiotensin and sympathetic nervous systems, hypercoagulability, and decreased fibrinolysis. Also, there is recent evidence suggesting an association between genetically driven liver fat and coronary heart disease mediated by the causal effect of apoB-containing lipoproteins. Several meta-analyses and systematic reviews have reported a strong association between MASLD and cardiovascular outcomes. MASLD is an important and independent risk factor for atherosclerosis development. Multiple mechanisms may be involved in this association. Further research is required to establish a causal association between MASLD and atherosclerosis.

Inflammation, platelets and diabetes

Type 2 diabetes is a key player in atherothrombosis. Inflammation participates in metabolic homeostasis interacting with adipose tissue-specific macrophages. Platelets appear as addresses and players carrying and transducing metabolic derangement into vascular injury. AGE-RAGE pathway is recognized as the driver of metabolic memory. Human platelets have insulin receptors that participate in the regulation of platelet function and platelets are potential sites of insulin resistance. The present mini-review addresses key pathophysiological aspects including i) the role of inflammation in the pathogenesis of diabetes; ii) platelets as inflammatory cells; iii) the involvement on inflammation in the interindividual variability in aspirin response. Taken together, these aspects may contribute to expand knowledge about the link between the extent of inflammation, platelet activation and turnover, and interindividual variability in the development of atherothrombosis and its prevention, in a view of precision medicine.

Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) Beyond Lipids: The Role in Oxidative Stress and Thrombosis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9), mainly secreted in the liver, is a key regulator of cholesterol homeostasis inducing LDL receptors’ degradation. Beyond lipid metabolism, PCSK9 is involved in the development of atherosclerosis, promoting plaque formation in mice and human, impairing the integrity of endothelial monolayer and promoting the events that induce atherosclerosis disease progression. In addition, the PCSK9 ancillary role in the atherothrombosis process is widely debated. Indeed, recent evidence showed a regulatory effect of PCSK9 on redox system and platelet activation. In particular, the role of PCSK9 in the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2) system, of MAP-kinase cascades and of CD36 and LOX-1 downstream pathways, suggests that PCSK9 may be a significant cofactor in atherothrombosis development. This evidence suggests that the serum levels of PCSK9 could represent a new biomarker for the occurrence of cardiovascular events. Finally, other evidence showed that PCSK9 inhibitors, a novel pharmacological tool introduced in clinical practice in recent years, counteracted these phenomena. In this review, we summarize the evidence concerning the role of PCSK9 in promoting oxidative-stress-related atherothrombotic process.

The role of platelets in the pathogenesis of atherosclerosis

The participation of platelets in the development of atherothrombosis in acute forms of cardiovascular diseases is generally recognized and well studied, while their significance in the pathogenesis of vascular atherosclerosis, starting from the earliest stages, requires further study. This article analyzes the role of platelets in the pathogenesis of atherosclerosis. Modern views on the pathogenesis of atherosclerosis, platelet-endothelial interactions, molecular mechanisms of platelet activation, platelet immune function from the point of view of the initial stages of atherogenesis, studies of the effect of antiplatelet therapy in primary and secondary prevention of atherosclerosis are considered. The leading role of platelets in the inflammatory and immune reactions of the human body is indicated, which is realized due to a complex of immune receptors, adhesion molecules and mediators.

Chronic Coronary Syndrome: Overcoming Clinical Practice Guidelines. The role of the COMPASS Strategy.

Current European guidelines on chronic coronary syndromes recommend the use of low-dose aspirin (or clopidogrel if intolerance or contraindication occurs) throughout life. However, as the risk of recurrent vascular events is high, particularly in some patients (i.e. diffuse multivessel coronary artery disease, diabetes, recurrent myocardial infarction, peripheral artery disease, or chronic kidney disease,…), these guidelines also consider that in those patients at moderate or high risk of ischemic events, but without a high bleeding risk, dual antithrombotic therapy should be considered. According to these guidelines, treatment options for dual antithrombotic therapy in combination with aspirin may include clopidogrel 75 mg/daily, prasugrel 10 mg/daily, ticagrelor 60 mg bid or rivaroxaban 2.5 mg bid. Remarkably, despite the results of the clinical trials that sustain these recommendations clearly diverge, guidelines do not differentiate between them. However, although all these drugs have demonstrated a significant reduction in major cardiovascular events in patients with stable atherosclerotic disease, only the addition of rivaroxaban has been associated with a reduction in cardiovascular and overall mortality in the secondary analysis. This may be related to the fact that the activation of platelets and factor X plays a key role in the development of atherothrombosis, and, consequently, both targets should be considered for the appropriate management of these patients.

Oxidative Stress Triggers Defective Autophagy in Endothelial Cells: Role in Atherothrombosis Development

Atherothrombosis, a multifactorial and multistep artery disorder, represents one of the main causes of morbidity and mortality worldwide. The development and progression of atherothrombosis is closely associated with age, gender and a complex relationship between unhealthy lifestyle habits and several genetic risk factors. The imbalance between oxidative stress and antioxidant defenses is the main biological event leading to the development of a pro-oxidant phenotype, triggering cellular and molecular mechanisms associated with the atherothrombotic process. The pathogenesis of atherosclerosis and its late thrombotic complications involve multiple cellular events such as inflammation, endothelial dysfunction, proliferation of vascular smooth muscle cells (SMCs), extracellular matrix (ECM) alterations, and platelet activation, contributing to chronic pathological remodeling of the vascular wall, atheromatous plague formation, vascular stenosis, and eventually, thrombus growth and propagation. Emerging studies suggest that clotting activation and endothelial cell (EC) dysfunction play key roles in the pathogenesis of atherothrombosis. Furthermore, a growing body of evidence indicates that defective autophagy is closely linked to the overproduction of reactive oxygen species (ROS) which, in turn, are involved in the development and progression of atherosclerotic disease. This topic represents a large field of study aimed at identifying new potential therapeutic targets. In this review, we focus on the major role played by the autophagic pathway induced by oxidative stress in the modulation of EC dysfunction as a background to understand its potential role in the development of atherothrombosis.

Уровни высокочувствительного с-реактивного белка у работающих мужчин молодого и среднего возраста

Cardiovascular diseases remain the leading cause of death in the working age population. In recent decades, more and more attention has been attracted to a subacute chronic inflammatory process as the cause of the progression of atherosclerosis and the development of atherothrombosis. A high-sensitivity C-reactive protein (hs-CRP) is recognized as an independent marker of cardiovascular disease risk, comparable in value to cholesterol or blood pressure. Aim. Measurement of hs-CRP levels in the group of initially healthy young and middle-aged working men. Materials and methods. The study included 349 men aged 28 to 56 years, who undergo periodic medical examination at the Diagnostic and Rehabilitation Center of “Gazprom transgaz Moscow” OOO from November 2018 to February 2020.The examination was carried out according to an employee occupation by order of the Ministry of Health and Social Development of Russia No. 302n. dated 12.04.2011. Additionally, a blood test for hs-CRP was performed. Results. An increase in hs-CRP ≥2 mg/L was found in 26.7% of the men examined. In the majority of cases (89.2%), the increase in CRP ranged between 2 and 5 mg/L, in 7.5% of cases – between 5 and 10 mg/L, and only in 3,2% it exceeded 10 mg/L. All patients with elevated hs-CRP levels showed no signs of an acute inflammatory reaction. A direct correlation of hs-CRP levels with overweight and abdominal obesity, which increases with age, was revealed. In 151 men, hs-CRP levels were assessed in dynamics, of which baseline increase of ≥2 mg / l was noted in 28.5%, and after a year – in 23.2%. When assessing the absolute value of biomarker concentration, an increase in this indicator after a year was registered in 45.3% of men. Conclusion. The high incidence of increased baseline hs-CRP levels in the group of relatively healthy young and middle-aged working men, and the tendency for this indicator to increase after a year in 45.3% of men makes it appropriate to include routine measurement of the basal hs-CRP concentration in men over 40 years of age in screening programs and standards of medical examinations. Keywords: high-sensitivity C-reactive protein, atherosclerosis, cardiovascular diseases For citation: Kirichenko AA, Poliakova OA, Dubovskaia IN. Levels of high-sensitivity C-reactive protein in young and middle-aged working men. Consilium Medicum. 2021; 23 (1): 99–102. DOI: 10.26442/20751753.2021.1.200577

Association of neutrophil-to-lymphocyte ratio with non-calcified coronary artery burden in psoriasis: Findings from an observational cohort study

BackgroundInflammation in the form of elevated high-sensitivity c-reactive protein (hs-CRP) has been shown to be critical in the development of atherothrombosis. Psoriasis, a chronic inflammatory skin disease, is associated with high systemic-inflammation, elevated neutrophil-to-lymphocyte ratio (NLR) and accelerated non-calcified coronary artery burden (NCB) by coronary computed tomography angiography (CCTA). We hypothesized that NLR would associate with early, rupture-prone atherosclerosis assessed as NCB independent of hs-CRP. Methods316 consecutive psoriasis participants were recruited with 233 having one-year follow-up as part of a prospective, observational cohort study design. CCTA scans were performed to assess NCB in all three major epicardial coronary arteries. ResultsPatients with above average NLR (>mean: 2.29 ​± ​1.21) were older (mean ​± ​SD; 52.0 ​± ​12.8 vs. 47.9 ​± ​12.6, p ​= ​0.002), had higher hs-CRP (med. IQR: 2.3 (0.9–7.3) vs. 1.4 (0.7–3.2), p ​= ​0.001) and had higher NCB (mean ​± ​SD; 1.21 ​± ​0.58 vs. 1.13 ​± ​0.49, p ​= ​0.018) when compared to patients with below average NLR. NLR associated with psoriasis area severity index score (β ​= ​0.14, p ​= ​0.017), hs-CRP (β ​= ​0.16, p ​= ​0.005), as well as NCB independent of traditional risk factors, body mass index, statin use and hs-CRP (β ​= ​0.08, p ​= ​0.009). One year of biologic therapy for psoriasis was associated with a reduction in NLR (−14.5%, p ​< ​0.001), and this change in NLR associated with change in NCB in fully adjusted models and beyond hs-CRP (β ​= ​0.17, p ​= ​0.002). ConclusionNLR associated with psoriasis severity, hs-CRP and NCB at baseline. Biologic therapy reduced NLR over time and this change in NLR associated with the change in NCB at one-year. Taken together, these findings suggest that NLR may capture psoriasis patients at higher risk of NCB due to residual inflammation not fully captured by hs-CRP.

Features of the phenotypic and genotypic lipid status of the indigenous ethnic group of the Arctic in the conditions of island living

Introduction. Dyslipidemia and obesity are interdisciplinary and “multi-metabolic” diseases, pathogenetically associated with the development of atherothrombosis, which creates practical health problems. The development of both dyslipidemia and obesity is influenced by socio-demographic, environmental, genetic and many physiological and behavioral factors, while the contribution of genetic factors is 40-70%. The goal is to identify the genetic characteristics oflipid status and fat metabolism in the indigenous ethnic group of the Arctic region of the Russian Federation under conditions of permanent islandliving.Methods. A cross-sectional population study of an indigenous ethnic group (n = 44) living on Vaygach Island (70 ° 01 ' Nlat 59 ° 33 ' E). The reported study was funded by RFBR according to the research project №18-00-00814-(18-00-00478). Serum cholesterol and triglycerides were determined as markers oflipid metabolism in blood serum. To analyze the genetic profile, the polymorphism of the FTO A23525T gene and the LPL Ser447Ter gene was determined by polymerase chain reaction.Results. In the sample of the indigenous ethnic group, BMI was 26.0 [21.5; 29.75] kg/m2. BMI for men is 23.0 [18.0; 28.0] kg/m2, for women - 25.0 [18.0; 29.25] kg / m2. Carriers of the unfavorable allele A had a higher BMI than carriers of the T allele. Analysis of the effect of rs9939609 genetic polymorphism on thelevel of total cholesterol did not show statistically significant differences between the FTO gene genotypes. A minimal triglyceride concentration was observed in carriers of the protective genotype Ter/Ter.Conclusion. Understanding the similarities and differences in genetic susceptibility among different ethnic groups can ultimately contribute to a more focused primary prevention and patient-oriented approach of cardiovascular pathology.

Association of mean platelet volume with angiographic thrombus burden and short-term outcome in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Abstract Background Coronary artery disease (CAD) represents a leading cause of death worldwide. Given it adverse prognosis, risk stratification of patients with an acute coronary syndrome (ACS) remains a challenging issue. In this regard, different biomarkers are becoming more and more important in the diagnosis, assessment and outcome prediction. For the development of atherothrombosis, platelets have a huge part to play. Mean platelet volume (MPV), a unique measure of platelet size, is an indicator of platelet reactivity and suggests that MPV could be a biomarker of the risk and prognosis of patients with STEMI. Aim and Objectives:to test the predictive value of MPV for angiographic thrombus burden and short term outcomes in patients with ST segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Patients and Methods all patients presented with acute STEMI to the cardiology department of Ain Shams university hospitals, with Pain to door time less than 12 hours and underwent PPCI. MPV was measured on admission. Angiographic thrombus burden and post interventional thrombolysis in myocardial infarction (TIMI) flow grade and myocardial blush grade (MBG) were recorded. Patients were followed up for 3 to 6 months. Results This study included 72 patients with STEMI who underwent PPCI. The patients’ ages ranged between 33 and 73 years old (mean age 53.22 ± 9.96years). This study included 62 males and 10 females. The MPV of the studied cases was 9.97 ± 1.31 fl. MPV was higher among patients with HTB (11.42±1.007 vs. 9.53±1.039.P 0.00) and patients with (MBG (0-1) and TIMI flow&amp;gt;3) (10.59±1.839vs. 9.81±1.092, P 0.004 and 10.49±1.191vs. 9.81±1.309, P 0.04 respectively).with short term follow up12 patients had heart failure requiring hospitalization and they had a higher MPV (10.81 ± 1.21 vs. 9.74 ± 1.3, p 0.01). In binary logistic regression analysis, the MPV was an independent predictor of TG after STEMI (odds ratio 7.278, and P value (0.000), CI (2.518-21.036)). Conclusion MPV may be a useful biomarker that can help in identification of higher-risk patients with large intracoronary thrombus burden, who might require more potent antiplatelet therapy.

ALOX5, LPA, MMP9 and TPO gene polymorphisms increase atherothrombosis susceptibility in middle-aged Mexicans.

Atherothrombosis is the cornerstone of cardiovascular diseases and the primary cause of death worldwide. Genetic contribution to disturbances in lipid metabolism, coagulation, inflammation and oxidative stress increase the susceptibility to its development and progression. Given its multifactorial nature, the multiloci studies have been proposed as potential predictors of susceptibility. A cross-sectional study was conducted to explore the contribution of nine genes involved in oxidative stress, inflammatory and thrombotic processes in 204 subjects with atherothrombosis matched by age and gender with a healthy group (n = 204). To evaluate the possibility of spurious associations owing to the Mexican population genetic heterogeneity as well as its ancestral origins, 300 unrelated mestizo individuals and 329 Native Americans were also included. ALOX5, LPA, MMP9 and TPO gene polymorphisms, as well as their multiallelic combinations, were twice to four times more frequent in those individuals with clinical manifestations of atherothrombosis than in the healthy group. Once adjusting for population stratification was done, these differences remained. Our results add further evidence on the contribution of ALOX5, LPA, MMP9 and TPO polymorphisms to atherothrombosis development in the middle-aged group, emphasizing the multiethnic studies in search of gene risk polymorphisms.

TNF-α–driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging

AbstractAging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Large triglyceride-rich lipoproteins from fasting patients with type 2 diabetes activate platelets

AimsType 2 diabetes (T2D) patients present with risk factors for atherothrombosis such as fasting hypertriglyceridaemia and platelet hyperactivity. Our study objective was to determine the effect of large triglyceride-rich lipoproteins (TGRL) from fasting T2D patients on platelet aggregation and, if any, to identify the signaling pathway involved. MethodsLarge TGRL were isolated from the plasma of 25 T2D patients by ultracentrifugation (density < 1.000 g/mL). Platelets were isolated from healthy blood donors (HBD) and suspended in buffer, then preincubated in the presence or absence of TGRL and stimulated with either collagen or thrombin. Platelet aggregation and the arachidonic acid (AA) signaling pathway were studied. ResultsFasting T2D large TGRL were mostly of hepatic origin (apoB100/apoB48 ratio: 42 ± 7) and rich in triglycerides (TG/total apoB ratio: 4.2 ± 0.5), and able to potentiate agonist-stimulated platelet aggregation (collagen: +68%, P < 0.05; thrombin: +771%, P < 0.05). It should also be mentioned that TGRL from the plasma of HBD (n = 7) had no effect on platelet aggregation. In addition, T2D large TGRL increased thromboxane B2 (TxB2) concentration in platelets stimulated with either collagen (+34%, P < 0.05) or thrombin (+37%, P < 0.05) compared with platelets stimulated with either of these agonists without TGRL. Phosphorylation of p38 MAPK and cytosolic phospholipase A2 (cPLA2) was enhanced after incubation of platelets with T2D TGRL and thrombin (+87% and +32%, respectively, P < 0.05) compared with platelets incubated with thrombin only. ConclusionLarge TGRL from fasting T2D patients may play a role in the development of atherothrombosis by increasing platelet aggregation and activating the platelet AA signaling pathway.

Platelet parameters: Can they serve as biomarkers of glycemic control or development of complications in evaluation of type 2 diabetes mellitus?

Background: Platelet function plays a crucial pathophysiological role in the development of atherothrombosis in patients with type 2 diabetes mellitus (DM). Platelet count (PC) and mean platelet volume (MPV) are simple, effective, and cheap tests that may be used to predict angiopathy in type 2 DM. Objectives: The aims of this study were to analyze various platelet parameters including PC, plateletcrit (total mass of platelets) (PCT), and mean platelet indices that are MPV, platelet distribution width (PDW), and platelet-large cell ratio (PLCR) in the type 2 DM patients, to compare various platelet indices between DM patients (with and without complications) and controls. Materials and Methods: This was a cross-sectional study conducted over a period of 3 months. Complete blood count along with blood glucose and HbA1c was estimated. The study population was divided into three groups: Group 1: Normal controls (n = 30); Group 2: DM patients without complications (n = 30); and Group 3: DM patients with complications (n = 30). Based on HbA1c levels among the diabetic patients, the diabetic groups were also classified as DM with HbA1c 7%. Results: All the platelet parameters were found to be higher among DM with complication as compared to DM without complication, and this was found to be statistically significant. Among the platelet parameters, MPV, PCT, and PDW were found to be higher among DM with HbA1c >7% as compared to DM with HbA1c Conclusion: Monitoring of DM to prevent the occurrence of vascular complications is the need of the hour. The results of the study suggest a role of various platelet indices as a simple and cost-effective tool to monitor the progression and control of DM.

Microvesicles in Atherosclerosis and Angiogenesis: From Bench to Bedside and Reverse.

Atherosclerosis (AT) is a progressive chronic disease involving lipid accumulation, fibrosis, and inflammation in medium and large-sized arteries, and it is the main cause of cardiovascular disease (CVD). AT is caused by dyslipidemia and mediated by both innate and adaptive immune responses. Despite lipid-lowering drugs have shown to decrease the risk of cardiovascular events (CVEs), there is a significant burden of AT-related morbidity and mortality. Identification of subjects at increased risk for CVE as well as discovery of novel therapeutic targets for improved treatment strategies are still unmet clinical needs in CVD. Microvesicles (MVs), small extracellular plasma membrane particles shed by activated and apoptotic cells have been widely linked to the development of CVD. MVs from vascular and resident cells by facilitating exchange of biological information between neighboring cells serve as cellular effectors in the bloodstream and play a key role in all stages of disease progression. This article reviews the current knowledge on the role of MVs in AT and CVD. Attention is focused on novel aspects of MV-mediated regulatory mechanisms from endothelial dysfunction, vascular wall inflammation, oxidative stress, and apoptosis to coagulation and thrombosis in the progression and development of atherothrombosis. MV contribution to vascular remodeling is also discussed, with a particular emphasis on the effect of MVs on the crosstalk between endothelial cells and smooth muscle cells, and their role regulating the active process of AT-driven angiogenesis and neovascularization. This review also highlights the latest findings and main challenges on the potential prognostic, diagnostic, and therapeutic value of cell-derived MVs in CVD. In summary, MVs have emerged as new regulators of biological functions in atherothrombosis and might be instrumental in cardiovascular precision medicine; however, significant efforts are still needed to translate into clinics the latest findings on MV regulation and function.

Modern principles of antiplatelet antithrombotic therapy

Antiplatelet agents play a key role in preventing the development of atherothrombosis of various location. There are 4 classes of antiplatelet agents having different mechanisms of action. There are peculiarities of their prescription to patients with brain, heart, peripheral artery ischemia as regards their selection, duration of application, etc.

The physical chemical and biological features of triglycerides. The cell absorption of functionally different palmitic+oleic lipoproteins of very low and density and linoleic+linolenic lipoproteins of low density.

The earlier insulin-independent low-density lipoproteins and more late insulin-dependent very low-density lipoproteins implement different functions at the stages of phylogenesis. The disorder of biological function of trophology, alteration of fatty acids in triglycerides, prevalence of palmitic very low-density lipoproteins over oleic very low-density lipoproteins supply mitochondria of cells with non-optimal substrate - palmitic saturated fatty acid for gaining energy, ATP synthesis. Physiologically, cells implement oleic alternative of fatty acids metabolism, oxidizing mainly ω-9 endogenous oleic mono-unsaturated fatty acid. The pathology of low density lipoproteins is primary deficiency of poly-unsaturated fatty acids in cells, atherosclerosis and atheromotosis of intima of arteries of elastic type with development of dense plaques from poly-unsaturated fatty acids in the form of polyethers of cholesterol. The pathology of very low-density lipoproteins includes: a) syndrome of resistance to insulin; b) pathology of phylogenetically earlier insulin-independent visceral fatty tissue - metabolic syndrome; c) pathology of phylogenetically later insulin-dependent subcutaneous adipocytes - obesity; d) secondary atherosclerosis, under cumulation of palmitic low-density lipoproteins in blood with development of atherothrombosis of intima of arteries, soft plaques rich with triglycerides. As for the prevention of disorders of transfer of fatty acids to very low-density lipoproteins and low-density lipoproteins is common in many ways - minimization of aphysiological effect of surplus amount of food, biological function of diet. The prevention at the level of population includes: a) maximal limitation of content of palmitic saturated fatty acid in food; b) moderate increasing of polysaturated fatty acids, ω-3 poly-saturated fatty acids predominantly; c) increasing of physical activity. The pharmaceuticals are not provided by biology in primary prevention of metabolic pandemics under aphysiological impact of environment factors.

Serum Interleukin-23 in Polish Patients with Systemic Lupus Erythematosus: Association with Lupus Nephritis, Obesity, and Peripheral Vascular Disease

Objectives To analyze the correlation between the serum concentration of interleukin- (IL-) 23 and atherosclerotic changes, traditional atherosclerotic risk factors, the autoantibody profile, and involvement of selected organs in systemic lupus erythematosus (SLE) patients. Patients and Methods We studied 94 SLE patients and 27 controls. We analyzed the IL-23 serum concentration, autoantibodies, carotid intima-media thickness and atherosclerotic plaque, the ankle-brachial index, atherosclerotic risk factors, and organ manifestations. Results Concentrations of IL-23 significantly differed between SLE patients and the controls (p = 0.0015). On the basis of multivariate stepwise analysis, we revealed that high levels of IL-23 were associated with atherosclerotic plaque in common femoral arteries (OR = 12.67; 95% CI: 1.41–113.84), lupus nephritis (OR = 3.69; 95% CI: 1.16–12.22), and obesity (OR = 4.21; 95% CI: 1.40–12.67). Autoantibodies related to IL-23 were anti-phosphatidylethanolamine antibodies (OR = 11.06; 95% CI: 1.24–98.65) and anti-SS-B/La antibodies (OR = 15.43; 95% CI: 1.73–137.25). Conclusions IL-23 may be involved in lupus nephritis pathogenesis. Through its association with obesity and selected antiphospholipid antibodies, IL-23 might promote a hypercoagulable state contributing to atherothrombosis development in SLE patients.

'Atherothrombosis-associated microRNAs in Antiphospholipid syndrome and Systemic Lupus Erythematosus patients'.

MicroRNAs markedly affect the immune system, and have a relevant role in CVD and autoimmune diseases. Yet, no study has analyzed their involvement in atherothrombosis related to APS and SLE patients. This study intended to: 1) identify and characterize microRNAs linked to CVD in APS and SLE; 2) assess the effects of specific autoantibodies. Six microRNAs, involved in atherothrombosis development, were quantified in purified leukocytes from 23 APS and 64 SLE patients, and 56 healthy donors. Levels of microRNAs in neutrophils were lower in APS and SLE than in healthy donors. Gene and protein expression of miRNA biogenesis-related molecules were also reduced. Accordingly, more than 75% of identified miRNAs by miRNA profiling were underexpressed. In monocytes, miR124a and -125a were low, while miR-146a and miR-155 appeared elevated. Altered microRNAs’ expression was linked to autoimmunity, thrombosis, early atherosclerosis, and oxidative stress in both pathologies. In vitro treatment of neutrophils, monocytes, and ECs with aPL-IgG or anti-dsDNA-IgG antibodies deregulated microRNAs expression, and decreased miRNA biogenesis-related proteins. Monocyte transfections with pre-miR-124a and/or -125a caused reduction in atherothrombosis-related target molecules. In conclusion, microRNA biogenesis, significantly altered in neutrophils of APS and SLE patients, is associated to their atherothrombotic status, further modulated by specific autoantibodies.

Abstract 134: Hypoxia in Coronary Plaque Enhance Thrombogenic Potential of Activated Macrophages

Background: Thrombogenic potential on disrupted atherosclerotic plaque is an important factor on the development of atherothrombosis, and inflammatory stimuli up-regulate thrombogenic factors. We have revealed that arterial glucose metabolism and hypoxia reflect the vascular wall thrombogenicity in rabbit. However, role of inflammation and/or hypoxia on the thrombogenicity in atherosclerotic plaque remain unclear. The present study aims to identify expression of hypoxic/metabolic markers and thrombogenic factors in human coronary plaques and also aims to evaluate the effect of of inflammatory and hypoxic stimuli on thrombogenicity in cultured macrophages. Methods: We immunohistochemically investigated numbers of inflammatory cells and microvessels, and expression of hexokinase (HK)-II, monocarboxylate transportor 4 (MCT4) (hypoxic/metabolic markers), and tissue factor (TF) in human vulnerable coronary plaques (n=22) and stable plaques (n=10). TF expression, procoagulant activity, and lactate production were assessed in THP-1 macrophages stimulated by tumor necrosis factor-α (10ng/mL) and interferon-γ (20ng/mL) under normoxic (21%O 2 ) or hypoxic (1%O 2 ) condition. Results: Numbers of macrophages, HK-II-, MCT4-, TF-immunopositive cells in the vulnerable plaques were significantly larger than those in the stable plaques. Many macrophages expressed HK-II, MCT4, and TF in the plaques. TF expression and procoagulant activity in the cultured macrophages were increased by the inflammatory stimuli, and were enhanced by hypoxia. The hypoxic condition also increased HK-II expression and lactate production, but the inflammatory stimuli did not affect them. Conclusion: Hypoxia in coronary plaque may enhance thrombogenic potential of macrophages activated by inflammatory stimuli.