Aim. Lipoproteide (a) (Lpa) is a pathogenetic risk factor of cardiovascular atherosclerotic disease. On the role of Lpa in the development of cardiovascular complications (CVC) after lower limbs arteries revascularization, there is lack of data. The aim of the study was assessment of Lpa relation to CVC occurrence after revascularization of lower extremities during 1 year follow-up.

Material and methods. In the study, 111 patients were included (97 males, 14 females, mean age 66±9 y.o.), who had undergone revascularization of lower libms arteries due to atherosclerosis. As CVC during 1 year follow-up, the following were taken: recurrent intermittent claudication, lower extremity amputation, ischemic stroke, transient cerebral ischemia, non-fatal myocardial infarction, unstable angina, repeat revascularization and cardiovascular death. In all patients, in the blood serum, there were measured lipids and Lpa.

Results. Within 1 year after revascularization there were 45 (41%) CVC. In the group with raised Lpa ≥30 mg/dL there were more CVC than in Lpa <30 mg/dL: relative risk 2,1 (95% CI 1,3-3,5; p=0,004). Hence the increased level of Lpa is an independent predictor of CVC after revascularization of lower extremities arteries.

Conclusion. In prospective study, during 1 year after revascularization the level of Lpa ≥30 mg/dL is associated with double increase of the risk of CVC.

Aim. To investigate on the relation of lipoproteide(a) (Lpa), subfractions of atherogenic lipoproteides and titers of specific autoantibodies (autoAb) with the presence and severity of carotid arteries (CA) lesion in statin-naïve patients with severe hypercholesterolemia.

Material and methods. To the study, 133 statin-naïve patients included, age 18 to 75 y.o., with absent clinical signs of coronary heart disease, and with first time diagnosed severe hypercholesterolemia (total cholesterol >7,5 mM/L and/or low density lipoproteides cholesterol >4,9 mM/L) with ultrasound duplex scan data of CA. All patients underwent measurement of Lpa concentration, lipid profile, subfractional content of apoB-100-containing lipoproteides and autoAb titer against them.

Results. According to the data from duplex CA scan, patients were selected to 2 groups: control group (n=76) with no CA atherosclerosis; main group — patients with CA stenosis >20% (n=57). The participants of main group were older than controls, with no other clinical or lipid profile differences. Titre of autoAb IgM specific for Lpa and its oxidized modifications was significantly lower in CA atherosclerosis comparing to controls. The grade of CA stenosis in severe hypercholesterolemia patients positively correlated with age (r=0,24, p=0,005) and negatively — with autoAb IgM to apoB100-containing lipoproteides (r=-0,28 and r=-0,26, p<0,005). Also, a correlation found for CA stenosis grade with subfractions of intermediate density lipoproteides of moderate size (r=0,21, p=0,032). AutoAb titre against Lpa was an independent predictor of CA lesion severity regardless the age and traditional risk factors by the data from multifactorial regression. By ROCanalysis with the highest diagnostic value (square under AUC =0,68) the level of autoAb IgM to Lpa lower than 0,083 lab. units, with sensitivity 40% and specificity 88% is related to the lesion of common CA.

Conclusion. In patients with severe hypercholesterolemia Lpa is an autoantigen, and IgM autoantibodies to Lpa play antiatherogenic role.

Objective. This study was devoted to examinationof some factors of blood coagulation (factor II, factor VII, factor XII, antithrombin III) in order to find their associations with biomarkers of endothelial dysfunction (endothelin 1, monocyticchemoattractant protein type 1, MCP-1, lipoprotein (a), LP (a), adhesive molecules sVCAM-1, asymmetric dimethylarginin, ADMA, homocysteine), inflammation (interleukins, IL-6, IL - 8, C-reactive protein, CRP) and with unstable atherosclerotic plaques in the coronary arteries in men with coronary atherosclerosis.

Material and methods. In 93 men with coronary atherosclerosis without acute coronary syndrome, blood coagulation factors concentrations (factor II, factor VII, factor XII, antithrombin III) were studied in the blood with goal to find their associations with biomarkers of endothelial dysfunction (endothelin 1, MCP-1, LP(a), adhesion molecules sVCAM-1, ADMA, homocysteine), of inflammation (IL-6, IL-8, CRP) and with the presence of unstable plaques in the coronary arteries.

Results. In men with unstable atherosclerotic plaques in the coronary arteries, the blood levels of factor VII and factor XII were 1.3 and 1.3 times higher, respectively, compared to men who had stable plaques in the coronary arteries. Correlation links between the blood levels of factor II and factor XII and the presence of unstable atherosclerotic plaques in the coronary arteries (r=0.239 and r=0.250, p <0.05, respectively) have been revealed, as well as between coagulation factors and blood levels of LP(a), sVCAM-1, IL-6 and CRP. Results of logistic regression analysis showed that the relative risk of present of unstable atherosclerotic plaques in the coronary arteries is associated with an elevated blood level of factor XII (OR=1.008, 95 % CI 1.000-1.017, p=0.048).

Conclusion. Our results indicate that elevated blood levels of the Hageman factor may be a new biomarker of probability of unstable atherosclerotic plaques presence in the coronary arteries.

 

Aim. The search for genetic markers of ADIPOQ, associated with the level of adiponectin and development of coronary atherosclerosis.

Material and methods. To the study, patients included, who had undergone diagnostic coronary arteriography in 2011-2012 in the NMRCPM with assessment of the severity of coronary atherosclerosis. The level of adiponectin was measured in plasma with the test-system based on the immune enzyme analysis. Genetic variants rs17300539, rs182052 and rs266729 gene ADIPOQ were measured realtime (Applied Biosystems, 7500 Real Time PCR System). Alleles of the studied variants were summarized by a unified score of genetic risk (SGR).

Results. To the study, 447 patients included, of those 319 males (70,7%). Median of age was 61 [55-69] y.o. All patients were selected to 2 groups by SGR (≤2 and >2, respectively). Groups differed by the level of adiponectin 7,64 vs 8,29 mcg/mL (р=0,01), total cholesterol 4,60 vs 5,00 mM/L (p=0,03), cholesterol of low density lipoproteides 2,8 vs 3,09 mM/L (p=0,03), and the rate of unstable angina development 2,15% vs 6,8% (р=0,02) and type 2 diabetes 11,8% vs 21,1% (р=0,01), respectively. There was no difference in the groups by Syntax and Gensini score.

Conclusion. Genetic score based on the three variants of ADIPOQ does determine the plasmatic level of adiponectin and risk of unstable angina and diabetes, but not the grade of coronary atherosclerosis.

Aim. Analysis of possible associations of polymorphisms of the urokinase system and matrix metalloproteases genes with criteria of atherosclerotic plaques instability.

Material and methods. Totally, 50 patients were investigated, with carotid atherosclerosis (32 males and 18 females). Inclusion criteria were carotid stenosis ≥70% and carotid endarterectomy. Patients were selected to groups according to macroscopic signs of instability of the lesions and thickness of fibrous cap. The groups were compared by the rates of mononucleotide polymorphisms С(-1306)Т (rs243865) gene MMP2, С(-1562)T (rs3918242) and A855G (Gln279Arg, rs17576) gene MMP9, Pro141Leu (C7240T, rs2227564) and С/T 3′-UTR (rs4065) gene PLAU, Lys220Arg (A659G, rs2302524) and T(-516)C (rs344781) gene PLAUR, (-675)4G/5G (rs1799768)gene SERPINE1.

Results. Monofactorial analysis showed the association of the variants 279Gln/Gln of gene MMP9 and 141Leu/Leu gene PLAU with development of macroscopically stable plaques. By multifactorial analysis, only the carriage of genotype 141Leu/Leugene PLAU was associated with development of stable plaques. For the group of genotype carriers 141Pro/Leu and 141Leu/Leu odds ratio is 0,22 (95% confidence interval 0,05-0,93). With the development of plaques with capsule less than 65 mcm, by monofactorial analysis, the associated variants are 3′-UTR C/T gene PLAU and (-516)T/C gene PLAUR, and normal body mass. Presence of obesity and the carriage of allele (-516) C gene PLAUR are protective against the thin cap plaques development. In patients with absent obesity and genotype (-516)T/T gene PLAUR odds ratio for the thin cap plaque occurrence is 10,16 (95% confidence interval 2,5740,16).

Conclusion. In the work, an association is shown of the polymorphism of urokinase system gene (urokinase plasminogen activator and receptor) with criteria of atherosclerotic lesion instability. Also, an association demonstrated of obesity with more stable plaques.

Aim. To assess the influence of coronary heart disease patients (CHD) therapy with statins or PCSK9 inhibitors influence on the level of oxidatively modified low density lipoproteides (LDL) and activity of erythrocyte Se-glutathione peroxidase (GSH-Px).

Material and methods. To the study, CHD patients were included (9-10 males per group), who during 6 months were undergoing statin therapy — 40 mg per day of pravastatin (group 1) or 0,4 mg per day of cerivastatin (group 2), as the therapy with PCSK9 inhibitor — 420 mg per month evolocumab (group 3) during 1 year. The level of lipohydroperoxide in LDL (LOOH-LDL) was measured in the groups 1 and 2 with the modified method and usage of Fe-xilenolorange; content of oxidized LDL (oxLDL) in the group 3 — with immune chemistry method (assays Mercodia, Sweden). Activeness of GSH-Px in all groups was assessed with the modified methods bound with glutathione reductase system and tret-buthyl hydroperoxide as a substrate.

Results. Simultaneously with the decrease of LDL cholesterol in the groups 1 and 2 there was significant increase (in the group 2 — 6-7 times in 3-6 months of therapy) of the level of LOOH-LDL. In the group 2 there was marked significant decrease of GSH-Px activity beginning from the month 3. In the group 3, with decreased LDL cholesterol there was significant decline in oxLDL with changed activity of GSH-Px.

Conclusion. Statins, effectively decreasing the level of LDL cholesterol, simultaneously induce the oxidation of LDL and decrease the activity of GSH-Px. Inhibitor PCSK9 not only does effectively decrease the level of LDL cholesterol, but also the content of oxLDL, not leading to decreased GSH-Px activity.

Aim. Clinical economical grounding of necessity for continuation of a “State Managed Program of Omsk Region “Development of Healthcare in Omsk Region” (the Program) in allowance granted supply with life saving medications of patients after endovascular treatment of acute coronary syndrome.

Material and methods. To the study, by a continuous sampling method, 255 patients included, after endovascular treatment of coronary arteries in acute coronary syndrome during July 1 to December 31 2015, who monthly attended cardiologists office and received free acetylsalicylic acid, clopidogrel and atorvastatin for 12 months. Method of clinical and economical analysis was applied “Increment efficacy of expenses”, and a threshold for self-payment by patients was evaluated.

Results. One-year mortality of the Program participants was 1,2% versus 3,5% in non-participants. Hospitalization rate for repeated acute coronary syndrome was 3,5% versus 9% in non-participants; serious adverse event hospitalization rate was less than 1%. All economically active patients were discharged “to work”.

Calculated parameter of increment efficacy of expenses with the technology “stenting of coronary arteries and drug supply in 2018 (statin, acetylsalicylic acid, clopidogrel or ticagrelor)” was 215906,93 Rub for every additional survived patient with no hospitalizations for repeated acute coronary syndrome during one year after stenting.

Conclusion. Technology of medication supply with life saving drugs of patients underwent endovascular interventions on coronary arteries for acute coronary syndrome is an advantageous investment of budget funds to life quality of patients. The results of the analysis have grounded the necessity to continue program targeted method in acute coronary syndrome patients management after percutaneous intervention taken current clinical guidelines.

Aim. To analyze differential expression of metalloproteases genes, involved into the processes of stabilization/destabilization of atherosclerotic plaque, with the method of full genome sequencing of RNA, and to evaluate the level of metalloproteases in homogenates of plaques of various types by immune enzyme assay method (IEA).

Material  and  methods.  The study has been conducted on the specimens of atherosclerotic plaques of patients aged 45-65 y.o., inhabitants of Western Siberia with angiographically proven coronary atherosclerosis and no acute coronary syndrome, with stable angina II-IV functional class. Specimens collection from the plaques was done during an operation if there were intraoperational indications. Histology performed. In intima/media homogenates by IEA method, with BCM Diagnostics assays the levels of destructive markers were measured: MMP-1, MMP3, MMP-7, MMP-9, TIMP-1 on the Multiscan EX (Thermo Fisher Scientific, USA). Libraries preparation for full genomic sequencing of RNA was done with Illumina’s TruSeq RNA Sample Preparation Kit (Illumina, USA). Expression profile in tissues was done on HiSeq 1500 (Illumina, USA).

Results. There are differences in expression of the genes MMP2, MMP7, MMP8, MMP9, MMP12, и MMP14 in different types of plaques. There was 8 times higher significant raise in increase of the expression level of ММР9 (p<0,001) in unstable plaque of dystrophic-necrotic type. Study by IEA of MMP-7 content, which is an activator of pro-MMP-9, as well as the content of MMP-9 itself, showed their increased levels in unstable plaques comparing to fatty streaks (1,5 and 2,4 times) and young stable plaques (1,4 and 2,1 times).

Conclusion. For the gene ММР9 there were significant differences obtained, of expression levels in stable atherosclerotic fibrous plaque and unstable plaque of dystrophic-necrotic type. With the IEA it was found that fatty streaks and young stable atheromas of coronary arteries have an increased concentration of MMP-3 and decreased activity of tissue inhibitor of metalloproteases. In unstable plaques with the tendency to rupture/ulceration there are increased levels of MMP-1, MMP-7, MMP-9.

Aim. To compare the influence of “lipophilic” atorvastatin and “hydrophilic” rosuvastatin on the parameters of cellular immunity in atherosclerosis patients.

Material and methods. Totally, 35 participants included, mean age 62 [57;68] y.o., 18 males and 17 females, directed for follow-up to Myasnikov Cardiovascular Center with preliminary diagnosis coronary heart disease, atherosclerosis of coronary and carotid arteries, and with indications for intensified statin therapy. In 17 patients the dosage of atorvastatin was increased from 20 to 80 mg, in 18 — dosage of rosuvastatin from 10 to 40 mg. All patients at baseline and in 1 month, by the methods of direct immune fluorescence and cytofluometry underwent the measurement of content of monocytes and lymphocyte populations in peripheral blood, incl. regulatory and effectory subpopulations of the latter. Under the circumstances of cellular culture the influence studied, of atorvastatin and rosuvastatin on CD4+ T-lymphocytes populations, as the lipopolysaccharideinduced synthesis of cytokines by monocytes of donors blood.

Results. At the background of atorvastatin, there was marked increase of relative content of circulating regulatory T-lymphocytes (Treg), increase of the relation of Treg/Thelper 17 (Th17) and changes of cellular immunity parameters. Statins did not influence subpopulations of blood monocytes. There was dose-dependent inhibition by statins of CD4+ T-lymphocytes proliferation: atorvastatin action was noted in 10 nM/L, rosuvastatin — in 10 times higher concentration. Introduction ofstatins, 10-100 nM/L, to the culture of monocytes did not influence neither spontaneous, nor endotoxin induced secretion of cytokines.

Conclusion. In therapeutic dosages atorvastatin shows immune modulating activity presenting with an increase of relative content of regulatory T-lymphocytes subpopulations that might be determined by suppression of effectory cells proliferation.

Aim. To consider an opportunity for application of different combinations of biochemical and bioimaging parameters to create different multimarker diagnostic panels designed for assessment of risk of coronary atherosclerosis and its complications.

Material and methods. To the analysis, data included, obtained from patients 18 y.o. and older (n=502), investigated at NMRCPR of the Ministry of Health in 2011-2013, who had undergone diagnostic coronary arteriography and duplex carotid scanning. Atherosclerosis burden was measured according the Gensini score. Subfractional spectrum of apoB-lipoproteides was assessed with the Quantimetrix Lipoprint LDL System (USA), biochemistry was done with standard lab. methods. Statistics was done with software Statistica v.10, IBM SPSS Statistics v.20, SAS v.9.4.

Results. Several multimarker combinations (panels) for non-invasive estimation of risk of coronary atherosclerosis detection and its severity were proposed. These are 1) an index K, calculated as ratio of the sum of potentially atherogenic subfractions to the large physiologically active LDL1 particles; index K >1,7 indicates an increased atherogenic potential of apo B-containing particles even with normal lipid profile, and can be used for non-invasive prediction of coronary atherosclerosis; 2) duplex complexes as adiponectin to endothelin ratio which <7,0 is associated with coronary atherosclerosis risk only in men, and as leptin to insulin ratio which <3,5 is associated with elevated atherosclerosis risk only in women; 3) integrated biomarker BIO represented the combination of individual visual and biochemical variables and permitted to discriminate patients from those with no coronary atherosclerosis or having subclinical or severe atherosclerotic lesions.

Conclusion. Proposed multimarker diagnostic panel could be regarded as novel potential biomarkers of coronary atherosclerosis risk and severity, however validation of these markers is necessary. The problem of cardiovascular risk stratification and further prevention activities should be solved with the search for novel markers and combinations of markers.

The first attempts to treat patients with homozygous familial hypercholesterolemia (HCH) were performed in the 60ies and 70ies using a total plasma exchange. Later on, more specific lipoprotein apheresis (LA) methods have been developed – the replacement with foreign proteins was no longer necessary. It could be demonstrated that LA is life-saving in these patients, lipid-lowering drugs were shown to be much less effective than in other HCH patients. A severe HCH became an accepted indication for LA when cardiovascular events appeared. An elevation of Lipoprotein(a) (Lp(a)) is an internationally accepted independent atherogenic risk factor. Thus, an increasing number of patients with high Lp(a) concentrations suffering from life-threatening cardiovascular events like a myocardial infarction or a stroke started to be treated extracorporeally. Russian specific Pocard^R anti-Lp(a) columns are produced, their position within the LA methods is discussed. In the future, an antisense oligonucleotide against apolipoprotein(a) will represent another therapeutic option.

Regardless the fact that type 2 diabetes (DM2) is related to higher risk of cardiovascular diseases (CVD) development and complications, incl. heart failure (HF), usage of the most of glucose lowering drugs (GLD) does not only improve life prognosis, but might increase the risk of HF. Inhibitors of SGLT2 (gliflozines), a novel group of GLD with a unique non-insulin dependent mechanism of action, in a range of large randomized trials passed not only the obligatory test on cardiovascular safety, but have demonstrated ability to decrease the risk of combination endpoint development (cardiovascular mortality, non-fatal MI and strokes) and possibility for HF hospitalization. The conclusions of randomized trials are confirmed by real clinical practice of DM2 patients management, analyzed in large multicenter trials CVD-REAL, CVD-REAL-2. Inthese trials, first time prescribed SGLT2 inhibitors (in Europe, in most cases dapagliflozin) showed significant benefits for other classes of firstly prescribed GLD in a matter of hospitalization risks for HF or all-cause mortality. However, the total period of the gliflozines usage is not that long, so an answer to the question on stability of their effects in broader perspective is expected by the end of ongoing trials in patients with high cardiovascular risk and in HF patients, including those with no DM2.

More than a half of cardiovascular events occur in low to moderate cardiovascular risk patients if assessed based on the traditional risk factors. At the same time, ultrasound examination of arteries makes it possible to reveal atherosclerosis even at early stages of its development. High prevalence of subclinical atherosclerosis in low to moderate risk patients, which is a realization of traditional and “unknown” risk factors, makes ultrasound examination a useful method for risk stratification. The review is focused on ultrasound markers of atherosclerosis with association to traditional risk factors, on the possibility to improve predictive role of current scores and influence on outcomes. Predictive significance of the markers is regarded for primary prevention in general population, in high risk persons and from the perspective of quantitative indicator of atherosclerotic lesion grade or plausibility as a surrogate cardiovascular diseases marker.

Development of innovational biotechnological medications based on humanized or completely human monoclonal antibodies or antisense oligonucleotides has opened a novel epoque in lipid disorders treatment. High efficacy of such biological drugs influencing the main chains of lipid metabolism (apoprotein B100, apoprotein (a), apoprotein CIII, proprotein-convertase subtilisin-kexin type 9, antipoetin like protein 3) does open a perspective for correction of severe and statin-resistant forms of dyslipidemias, with a possibility to achieve almost complete remission of the disease. However, the evidence of safety of antisense oligonucleotides drugs demands for broader investigation. Such drugs might be used in patients with orphan diseases or serious lipid disorders, not having alternative treatment. Vice versa, the drugs based on the human monoclonal antibodies thank to evidence are started to be in clinical use at the moment.

The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC)and of the European Association for Cardio-Thoracic Surgery(EACTS)

Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries.

Endorsed by: the European Stroke Organization (ESO) The Task Force for the Diagnosis and Treatment of Peripheral Arterial Diseases of the European Society of Cardiology (ESC) and of the European Society for Vascular Surgery (ESVS)