[Ceramids and their role in the development of cardiovascular diseases (review of literature).]

Almost all known stress stimuli, including inflammatory agonists, chemotherapeutic agents and saturated fatty acids, cause the synthesis of ceramide and its metabolites. In recent studies, it has been shown that excessive synthesis of ceramides causes the development of various metabolic diseases, such as obesity, diabetes and cardiovascular diseases. Currently, the role of cеramids in the development of obesity and diabetes has been studied quite well. At the same time, studies devoted to the study of lipid data in the development of cardiovascular disease are not large. In this review, we generalize the data on this new class of bioactive lipids for understanding their role in the development of cardiovascular diseases.

The role of perivascular adipose tissue in the development of cardiovascular diseases. The importance of diagnosis for assessing the risk stratification of cardiovascular diseases.

Obesity is closely associated with metabolic and cardiovascular diseases, including dyslipidemia, coronary artery disease, hypertension, and heart failure. Adipose tissue (AT) is identified as a complex endocrine organ, with a wide range of regulatory functions at the cellular, tissue and systemic levels. Various terms, including paracardiac, epicardial and pericardial, are used to describe the fatty deposits surrounding the heart. Among all the fat depots, perivascular AT (PVAT) is of great biological significance for the cardiovascular system due to its anatomical proximity to the vessels. Recent studies have shown the presence of a complex, bidirectional paracrine and vasocardial signaling system between the vascular wall and PVAT. In the review, we will discuss the biological role of PVAT in both the physiological state and cardiovascular pathology, emphasizing its dual proatherogenic and antiatherogenic role. Let us consider PVAT as a target for various therapeutic agents in cardiovascular diseases. We will also analyze data on the role of non-invasive techniques as a diagnostic tool for assessing coronary artery inflammation.

Influence of visceral obesity on the secretion of adipokines with epicardial adipocytes in patients with coronary heart disease.

AIM: To study adipokine-cytokine profile of epicardial adipocytes (EAT) and subcutaneous adipose tissue (SAT) in conjunction with the area of visceral adipose tissue (VAT), biochemical and clinical characteristics of patients with coronary heart disease. MATERIALS AND METHODS: Examined 84 patients (70 men and 14 women) with coronary artery disease. In fact the presence of visceral obesity (VO) the patients were divided into two groups. Patients VO the sampling of adipocytes of EAT and SAT, with subsequent cultivation and evaluation of adipokine and provospalitelna activity. Carried out the determination of carbohydrate and lipid metabolism, adipokine and pro-inflammatory status in the blood serum. RESULTS: It was found that adipokine-cytokine profile of adipocytes of EAT and SAT differ. Adipocytes art of the disease on the background characterized by an increase IL-1, TNF-α, leptin-adiponectin relationships and a decrease in the content of protective factors: adiponectin and anti-inflammatory cytokine IL-10. While the SAT adipocytes was characterized by a decrease in the concentration of soluble receptor for leptin and the more pronounced leptinresistance, and the increase in proinflammatory cytokines was offset by the increase in the concentration of IL-10. The presence associated with multi-vessel coronary bed lesion, multifocal atherosclerosis, insulin resistance, atherogenic dyslipidemia, an imbalance of adipokines and markers of inflammation. So the value of the square VAT determined higher concentrations of leptin, TNF-α in adipocytes and serum, lipid and carbohydrate metabolism and a lower content of soluble receptor for leptin. CONCLUSION: Thus, the disease on the background of the status of the adipocytes of EAT characterized as a "metabolic inflammation", and may indicate the direct involvement of adipocytes in the pathogenesis of coronary artery disease, due to the formation of adipokine imbalance and the activation of proinflammatory reactions.

Adipokine and Cytokine Profiles of Epicardial and Subcutaneous Adipose Tissue in Patients with Coronary Heart Disease.

The content of adipokines, pro- and anti-inflammatory cytokines were studied in adipocytes isolated from epicardial and subcutaneous adipose tissue of 24 coronary heart disease patients. The content of leptin and soluble leptin receptor in adipocytes of epicardial adipose tissue was higher by 28.6 and 56.9% and the level of adiponectin was lower by 33% than in adipocytes of the subcutaneous fat. In culture of epicardial adipocytes, the levels of proinflammatory cytokines TNF-α and IL-1 were higher. Subcutaneous adipose tissue adipocytes were characterized by higher levels of anti-inflammatory cytokines IL-10 and FGF-ß. In epicardial adipocytes of coronary heart disease patients, the concentrations of leptin, TNF-α, and IL-1 were higher, while the levels of defense regulatory molecules (adiponectin, IL-10, and FGF-ß) were lower than in subcutaneous adipocytes.

[THE ROLE OF LOW-FREQUENCY PIEZOTHROMBOELASTOGRAPHY IN THE COMPREHENSIVE EVALUATION OF HEMOSTASIS IN CORONARY BYPASS SURGERY WITH CARDIOPULMONARY BYPASS].

Aim: To monitor the hemostatic system during platelet concentrate transfusions using low-frequency piezothromboelastography in patients with coronary bypass surgery given aspirin therapy. Materials and Methods: The study involved 148 patients with coronary bypass surgery, with 76 ones undergoing intraoperative transfusion of platelet concentrate and 72 treated without transfusion. The control group consisted of 20 healthy individuals. In the perioperative period indicators of vascular-platelet, coagulation, anticoagulant and fibrinolytic components of hemostasis were evaluated by low-frequency pezotromboelastography using the ARP-01M "Mednord" hardware and software system (Russia). Results: It was shown that the antiplatelet effect of aspirin in the preoperative period was manifest as inhibition of the initial stage of blood coagulation accompanied by increased thrombin potential, the total gain of anticoagulant and fibrinolytic activity of the blood. Heart-lung bypass was accompanied by structural and chronometric anticoagulation, reduction of anticoagulation and increase of blood fibrinolytic activity. In the postoperative period, structural and chronometric anticoagulation was more pronounced in patients who did not undergo transfusion of platelet concentrate than in the group of patients with transfusion. Donor platelets further increased the blood hemostatic potential by neutralizing the antiplatelet effect of aspirin. Perioperative thrombohemorrhagic complications were absent in both groups. Conclusion: Low-frequency piezothromboelastography provides a tool for real-time monitoring the functional state of hemostasis system. Transfusion of platelet concentrate is not advisable given that the thrombin potential is preserved as confirmed by the results of low-frequency piezothromboelastography.

[RELATIONSHIP BETWEEN SMOKING AND INDICATORS OF SYSTEMIC INFLAMMATION IN PATIENTS WITH CORONARY HEART DISEASE].

Aim: To estimate the severity of systemic inflammation in subjects with coronary artery disease (CAD) without bronchopulmonary system comorbidity depending on smoking factor. Materials and methods: The subjects were divided into groups depending on smoking factor. We estimated the following laboratory markers of nonspecific inflammation: interleukine (IL)-12, -1ß, tumour necrosis factor-α, matrix metalloproteinase-9, C-reactive protein. The examination of lungs respiratory function included spirometry, body plethysmography and assessment of diffusing lung capacity. Results: 29.9% of the subjects with CAD smoked, 40% reported discontinuation of smoking in their histories. Smoking in CAD subjects without the history of bronchopulmonary system comorbidity was associated with a higher level of inflammatory markers (IL-12, IL-1ß, TNF-α, ММР-9 and CRP) than in subjects who ceased to smoke and those who have never smoked. No differences in the levels of inflammatory markers were revealed in subjects who had smoked before and never smoked. Conclusion: Smoking is widespread among CAD subjects. It is associated with a higher level of markers of nonspecific inflammation as compared to subjects who have never smoked before or ceased smoking.

[The physiologic and pathophysiologic role of stimulating growth factor ST2.]

The ST2 is a member of family of receptors of interleukin I (IL-I) and consists of two isoforms: a trans-membrane of cellular one (ST2L) and soluble or circulating one (sST2). The ST2 is a receptor of IL-33 that represents IL-I like cytokine. The IL-33 manifests its cellular functions binding receptor complex consisted of accessory protein ST2L and IL-IR. The system IL-33/ST2 is activated in cardiomyocytes and fibroblasts in response to mechanical irritation or damage. It was demonstrated that interaction between IL-33 and ST2L is a cardioprotective one. The experimental models were used to demonstrate decreasing of myocardium fibrosis, prevention of development of hypertrophy of cardiomyocytes, decreasing of apoptosis and amelioration of functional capacity of myocardium at interaction of IL-33 and ST2L. In particular, the positive effects of IL-33 are related to receptor of ST2L. In turn, sST2 by binding with IL-33 sets blocking of interaction between IL-33/ST2L hence eliminating cardioprotective effects. During last years, the knowledge about the role of ST2 in pathophysiology of cardio-vascular diseases broadened and now the role of ST2 is related to myocardium dysfunction, fibrosis and remodeling. The system IL-33/ST2L, besides its myocardial role, can play an additional role in development and progressing of atherosclerosis. The system IL-33/ST2L can have a therapeutic potential in case of myocardial overload or trauma. On the contrary, sST2 acts as a false receptor of IL-33 blocking cardioprotective effects of interaction of IL-33/ST2L.

[The advantage of test on thrombin generation for evaluation of hemostasis potential under implementation of coronary bypass surgery in patients with ischemic heart disease.]

The purpose of study is to evaluate peri-operational parameters of testing of generation of thrombin and its relationship with indices of coagulation hemostasis, fibrinolytic system and anti-coagulants in patients with ischemic heart disease under coronary bypass surgery in conditions of artificial blood circulation. The examined sampling included 200 patients with ischemic heart disease. The planned primary operation of coronary bypass surgery in conditions of artificial blood circulation was applied to all of them. The testing of generation of thrombin was implemented using automated analyzer CEVERON-ALPHA (Technoclone, Vienna, Austria). The indices of testing of generation of thrombin were compared with common techniques of evaluation of hemostasis (INR, PTT, fibrinogen, Qick's prothrombin testing, thrombin time, AT-III, protein C, factor VIII), von Willebrand factor, inhibitor of activation of plasminogen type I (PAI-I), tissue and urokinase plasminogen activator. It is demonstrated that application of testing of thrombin generation duplicates enumerated indices and permits at the same time instant to detect both pro-coagulation and anti-thrombotic shifts. The advantage of testing of thrombin generation is in evaluation of thrombin potential that is most actual in cardiologic practice.

[Diagnostic value of the stimulating growth factor ST2 during hospitalization for myocardial infarction]. / Diagnosticheskoe znachenie stimuliruyushchego faktora rosta ST2 v gospital'nom periode infarkta miokarda.

AIM: To determine the concentration of the stimulating growth factor ST2 and its relationship to the clinical course of myocardial infarction (MI) over time during hospitalization. MATERIALS AND METHODS: Eighty-eight MI patients whose mean age was 59±8.36 years were examined. On days 1 and 12 of MI, the serum levels of ST2 and N-terminal pro-brain natriuretic peptide (NT-proBNP) were determined by ELISA. A control group consisted of 30 people. RESULTS: On day 1 of hospitalization for MI, the concentrations of ST2 and NT-proBNP were higher 2.4 and 4.5 times, respectively, than those in the controls; by day 12, there was a statistically significant decrease in the level of ST2 while that of NT-proBNP was unchanged. During hospitalization, the investigators recorded MI complications, according to which the patients were divided into favorable and unfavorable MI groups. On day 1 of hospitalization, the level of ST2 in the patients with unfavorable MI was twice higher than in those with favorable MI and 3.7 times higher than in the control group. On day 12, both favorable and unfavorable MI groups showed a reduction in the level of the marker. On day 1 of MI, the concentration of NT-proBNP in the patients with a poor prognosis was 6.8 times greater than in the controls and 1.8 times more than in the patients with a good prognosis. On day 12, NT-proBNP levels remained elevated in both groups. Logistic regression analysis revealed that the determination of ST2 in combination with NT-proBNP increased their diagnostic significance (odds ratio, 1.92; 95% CI, 1.7-3.2; area under characteristic curve, 0.89; p=0.004). CONCLUSION: The level of ST2 was a more sensitive indicator of hospitalization for MI than that of NT-proBNP. The combined use of ST2 and NT-proBNP was found to have a high diagnostic sensitivity and specificity.

[Evaluation of the hemostatic potential at coronary artery bypass surgery during long-term aspirin therapy]. / Otsenka gemostaticheskogo potentsiala krovi pri operatsiyakh koronarnogo shuntirovaniya na fone dlitel'noi terapii atsetilsalitsilovoi kislotoi.

AIM: To estimate thrombin generation test parameters in patients with coronary heart disease during coronary artery bypass surgery under extracorporeal circulation after transfusion of donor platelet concentrates during long-term therapy with acetylsalicylic acid (ASA). SUBJECTS AND METHODS: A total of 148 patients with coronary heart disease who had undergone elective primary coronary artery bypass surgery under extracorporeal circulation during preserved therapy with ASA (75-100 mg/day) were examined. According to donor platelet concentrate transfusion, all the patients were divided into 2 groups: 1) 76 patients undergoing donor platelet transfusion and 2) 72 without this procedure. A control group consisted of 20 apparently healthy individuals. At the pre-, intra-, and early postoperative stages, the investigators evaluated the following thrombin generation test parameters: lag time (min); peak thrombin concentration (nM/l); time to peak (min); the area under the thrombin generation curve (nM), and thrombin generation rate (nM/min). RESULTS: During long-term ASA therapy, the patients were found to have an activated endogenous thrombin potential in the pre- and intraoperative periods, as evidenced by the high peak concentration of thrombin and the increased rate of its generation. At the same time, the time of prothrombinase complex activation and that of thrombin generation were longer than those in the control group. In the early postoperative period, the patients who had not been transfused with platelet concentrates with a further increase in the temporal parameters, showed a decreased hemostatic potential, reaching the control level, whereas donor platelet transfusion stimulated endogenous thrombin generation: the time to initiate clotting and that to reach the peak were shorter; in this case, the thrombin generation rate and concentrations increased, but the preoperative level was not reached. No perioperative (hemorrhagic or thrombotic ischemic) events were noted in the examined groups. CONCLUSION: The hemostatic potential was preserved in patients receiving long-term therapy for ASA. Taking into account laboratory and clinical findings, platelet concentrate transfusions are unnecessary for preventive purposes. The appropriateness of donor platelet transfusion should be strictly individually approached with regard to the laboratory parameters of the thrombin generation test, by minimizing the risk of perioperative ischemic and hemorrhagic events in each specific patient.

[The possibility of application of stimulant growth factor (ST2) for verifying postinfarction remodeling of myocardium.]

PURPOSE OF STUDY: To detect level ST2 in blood serum of patients with myocardium infarction in dynamics of hospital period and their relationship with remodeling of myocardium. MATERIALS AND METHODS: The study sampling included 87 patients (65 males and 22 females) with myocardium infarction and the ST-segment elevation and average age of 59 years. All patients were allocated in two groups: with adaptive alternative of remodeling of myocardium (67 patients) and deadaptive alternative (20 patients). The control group consisted of 30 individuals. At the first and twelfth days after myocardium infarction in blood serum content of ST2 and NT-proBNP were detected using immune-enzyme technique with application of test-systems produced by Critical Diagnostics (USA) and Biomedica (Slovakia) correspondingly. The data statistical analysis was processed using non-parametric criteria. THE RESULTS: He content of ST2 and NT-proBNP at the first day of myocardium infarction increased in 2.4 and 4.5 times correspondingly as compared with control group. The patients with deadaptive remodeling were characterized by in 1.5 times higher content of ST2 at the first day than in group of adaptive remodeling and in 5.3 times higher that in control group. In the end of hospital period (twelfth day) in both groups decreasing of level of ST2 was observed. The concentration of NT-proBNP at the first day was increased in 1.8 times in patients of both groups and decreased at twelfth day. At that there were no differences between both groups. The high level of ST2 at the first day increases the risk of development of deadaptive remodeling in 4.5 times, NT-proBNP only in 2.3 times. CONCLUSION: The high level of stimulant growth factor ST2 at the first day of myocardium infarction was associated with deadaptive alternative of post-infarction remodeling that permits using ST2 as prognostic marker with high sensitivity and specificity.

[Effect of Statins on Development of Early Cognitive Dysfunction After Coronary Artery Bypass Grafting].

We studied the effect of rosuvastatin on the development of early postoperative cognitive dysfunction (POCD) in patients after coronary artery bypass grafting (CABG). One hundred nine men aged 45-70 year was divided into two groups. Group 1 comprised 69 patients (mean age 56.8 ± 5.2 years) who were given 20 mg of rosuvastatin for 10-14 days before CABG and until discharge. Patients of group 2 (n=40, mean age 55.9 ± 5.3 years) did not take rosuvastatin. It was shown that patients of group 2 had better neuropsychological parameters after CABG in comparison with the patients of group 2. Patients of group 1 had lower concentrations of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor α, high sensitivity C reactive protein, and higher concentrations of IL-10. Group 2 patients had worse neuropsychological parameters which were associated with higher concentrations of proinflammatory cytokines. These results may indicate that preoperative therapy with rosuvastatin had decreased the severity of systemic inflammatory response and reduced the development of early POCD after CABG.

[THE SYSTEM OF SOLUBLE LEPTIN RECEPTORS AND PROINFLAMMATORY FACTORS IN MYOCARDIAL INFARCTION].

The present study was motivated by the lack of data on the role ofvariations in the levels of leptin and its soluble receptors and their interaction with proinflammatory factors in the development of acute coronary syndrome. The study included patients suffering myocardial infarction with and without type 2 diabetes mellitus. Hyperleptinemia and its relationship with myocardial necrosis markers (creatine phosphokinase, creatine phosphokinase-MB, troponin) give reason to suggest the important role of leptin in the development of inflammatory process associated with myocardial infarction in patients with and without diabetes mellitus. The results of the study provide a basis for the elaboration of a new therapeutic strategy for the correction of metabolic disorders in patients with acute coronary syndrome.

[Role of kidney injury molecule-1 (KIM-1) for inhospital event risk assessment after coronary artery bypass surgery].

AIM: To assess value of kidney injury molecule-1 (KIM-1) for prediction of inhospital events in CAD patients undergoing coronary artery bypass graft (CABG) surgery. MATERIAL AND METHODS: We analyzed postoperative course of 719 patients subjected to CABG in Research Institute for Complex Issues of Cardiovascular Diseases between March, 2011 and April, 2012. In all patients we measured creatinine concentrations, glomerular filtration rate (GFR) by MDRD and urine KIM-1 levels before and on day 7 after CABG. Major unfavorable events (myocardial infarction, stroke or transient ischemic attack, acute or decompensated chronic renal failure or remediastinotomy) were registered during hospital stay. The EuroSCORE (European System for Cardiac Operative Risk Evaluation) risk of operative mortality was calculated for each patient. RESULTS: Patients with different EuroSCORE risk had similar serum creatinine levels while KIM-1 concentrations in urine were significantly higher in patients with moderate and high EuroSCORE risk as compared with low-risk patients. Patients who experienced postoperative events had significantly higher KIM-1 both before and after surgery while there were no differences in such renal dysfunction markers as creatinine and GFR. CONCLUSION: Preoperative elevated KIM-1 can act as a marker of complicated postoperative period after CABG.

[Biochemical characteristics associated with diabetes mellitus one year after myocardial infarction].

AIM: To evaluate the most informative parameters of adipokine, anti-inflammatory, and prothrombogenic status associated with diabetes mellitus. MATERIALS AND METHODS: The study included 200 patients with myocardial infarction (MI) in whom markers of adipokine status, grelin, anti-inflammatory factors, CRP and plasminogen activator inhibitor were measured by biochemical methods on days 1 and 12 after admission. RESULTS: In the period of acute MI, the adipokine status was disturbed, FFA and grelin levels decreased, pro-inflammatory and thrombotic potential increased. Patients who developed diabetes within 1 year after MI were characterized by more pronounced changes of the parameters of interest. CONCLUSION: Adiponectin, retinol-binding protein, grelin, TNF-α, and plasminogen activator inhibitor are the most informative biochemical parameters associated with diabetes mellitus developing 1 year after MI.

[Lipid, adipokine and ghrelin concentrations in myocardial infarction patients with insulin resistance].

AIM: The estimate insulin resistance in myocardial infarction. PATIENTS AND METHODS: The study involved 200 patients with myocardial infarction, in which on the 1st and 12th day of hospitalization measured glucose, insulin, insulin resistance index (IR), lipid profile, the concentration of adipokines and ghrelin. RESULTS: IR was detected in 77% of patients and was associated with a history of factors of cardiovascular risk, adverse clinical course of the disease, lipid disorders. The most important marker was the level of free fatty acids. High risk associated with increased in 9 times the concentration of free fatty acids in blood plasma. Patients with IR observed increased concentrations of leptin, resistin, and reduced the protective effect of adiponectin. The high specificity and sensitivity characteristic of the concentration of ghrelin: its reduction by 4 times in the acute phase of myocardial infarction increases the risk of MI by 78%. CONCLUSIONS: Significant risk factors for MI myocardial infarction, along with insulinemia and glycemia, is to increase the concentration of free fatty acids and the disbalance in the system adipokines against deficiency of ghrelin in acute and early recovery periods of the disease. Free fatty acids and ghrelin are promising markers to stratify the risk of insulin myocardial infarction. resistance in patients with myocardial infarction.

[The detection of leptin and metabolic markers of insulin resistance in patients with myocardial infarction].

The shortage of data concerning the character of changes of leptin concentration and its role information of insulin resistance under development of acute coronary events determined the appropriateness of the present study. The cardiac infarction patients with and without diabetes type II were examined. The identified hyperleptinemia, its relationship with basal and post-prandial hyperglycemia and with increase of C-peptide concentration and free fatty acids made possible to consider leptin both as one of the important components in the series of carbohydrate and lipid metabolism disorders and the additional marker of development of insulin resistance under cardiac infarction. These study results can be applied to patients with diabetes anamnesis and to patients without this concomitant pathology. The study results can be used as a foundation for new diagnostic and therapy tactics of metabolic disorders correction in patients with acute coronary vascular pathology.

Study of anti-inflammatory action of aurothiomalate, an inhibitor of NF-κB.

We compared the effects of NF-κB inhibitor aurothiomalate and voltaren on NO production by mouse macrophages in vitro, their ability to cause local edema at the site of injection, and their effect on carrageenan-induced inflammation. High concentrations of aurothiomalate reduced NO production, while in low concentrations both aurothiomalate and voltaren stimulated this process. When injected into mouse footpad, aurothiomalate in a dose >1 mM and voltaren in a dose >1.6 µM induce paw edema. Both compounds suppressed carrageenan-induced inflammation, but the efficacy of aurothiomalate 2-fold exceeded that of voltaren.

In vitro effect of combined hybrid molecules from vitamin E analogues and betulinic acid on macrophage activity.

Macrophage activity was studied after treatment with hybrid molecules obtained by condensation of terpenic acid residues (betulinic and betulonic acids) and α-tocopherol analogues (α-tocopherol hemisuccinate and Trolox acid). As distinct from betulinic acid and α-tocopherol hemisuccinate, hybrid molecules did not exhibit cytotoxicity in relation to mouse peritoneal macrophages in the MTT test. Test substances inhibited the production of NO by mouse peritoneal macrophages. However, hybrid molecules had no effect on activity of macrophage arginase. Our results indicate that new molecules have anti-inflammatory activity. It can be hypothesized that these substances have immunomodulatory properties.

[Effect of plant polysaccharides on TH1-dependent immune response: screening investigation].

We have studied the influence of water-soluble polysaccharides isolated from Tussilago farfara L. leaves, Betula verrucosa Ehrh. leaves, Calendula officinalis L. flowers, Acorus calamus rhizomes, Inula helenium L. rhizomes, overground part of Trifolium pretense L., and overground part ofArtemisia absinthium L., on Thl immune response induced by sheep red blood cells and on NO production by murine peritoneal macrophages in vitro. All the investigated polysaccharides have stimulated a Th1 response. Polysaccharides isolated from Betula verrucosa leaves did not influence NO synthesis, while polysaccharides of Tussilago farfara leaves and Acorus calamus rhizomes stimulated NO synthase of murine macrophages on a level comparable with that of lipopolysaccharides (LPS). Polysaccharides from Inula helenium rhizomes, Calendula officinalis flowers, and overground parts of Trifolium pretense and Artemisia absinthium also stimulated NO production, but to a lower extent in comparison to LPS.