[Molecular and Cellular Aspects of the Endothelial-Mesenchymal Transition in Cardiovascular Diseases].

Endothelial cells (ECs), which form the inner surface of the blood vessels, contact the blood, withstand mechanical pressure, and demonstrate heterogeneous reactions to exogenous and endogenous stimuli. ECs have unique properties in accordance with their niches and play an important role in regulating vascular homeostasis. Endothelial cells may undergo a dynamic phenotypic switch in terms of its heterogeneity, which may lead to endothelial dysfunction and a number of associated pathologies. Endothelial-mesenchymal transition (EndMT) is one of the possible molecular and cellular mechanisms of this kind. EndMT is characterized by phenotypic changes in ECs through which endothelial cells acquire new properties, i.e., start producing mesenchymal markers such as alpha-SMA and vimentin, change morphology, and become able to migrate. EndMT is a complex biological process that can be induced by inflammation, hypoxia, or oxidative stress and be involved in pathogenesis of cardiovascular disease. This review describes the key markers, inhibitors, and inducers of endothelial-mesenchymal transition and overall state-of-the-art of EndMT in cardiovascular diseases.

Effect of Nitinol on Metabolic and Coagulation Activity of Endothelial Cells Culture.

We studied the effect of nitinol, the most prevalent material for endovascular stents, on metabolic and coagulation activity of a primary culture of human umbilical vein endothelial cells (HUVEC). Metabolic activity was evaluated using MTS-test and by the level of stable NO metabolites in the conditioned medium, coagulation activity was assessed by activity of von Willebrand factor (vWF) and levels of plasminogen activator inhibitor-1 (PAI-1) and soluble endothelial protein C receptors (sEPCR). Exposure to nitinol reduced metabolic activity of the cell culture by 11.1% in comparison with the control (p<0.001). Although absolute activity of vWF and absolute level of sEPCR were elevated, incubation with nitinol did not lead to a statistically significant elevation of these parameters in comparison with the control, which can indicate the absence of substantial hypercoagulation effects of nitinol.

[Study of gene expression in patients with peripheral artery disease]. / Izuchenie ékspressii genov u patsientov s zabolevaniiami perifericheskikh arterii.

Currently, there are no widely used available techniques for reliable prognosis of the onset and course of peripheral artery disease. Working out of optimal test systems including genetic ones for assessment of risks for the development of the disease, its progression or development of complications in patients with peripheral atherosclerosis is an important mission of modern medicine. This article deals with a promising technique of genetic studies in patients with peripheral artery disease, i. e., study of gene expression. Also provided herein is a literature review devoted to the main techniques used for the analysis of the profile of gene expression. This is followed by evaluating the possibility of using DNA chips, as well as describing the state of the art and unsolved problems of studying gene expression in patients with peripheral artery disease.

[Duration of treatment with phlebotonics in patients with chronic venous disease]. / Dlitel'nost' flebotropnoi terapii u patsientov s khronicheskimi zabolevaniiami ven.

Lower extremity chronic venous disease is a highly prevalent vascular pathology. Progression of the disease exerts a negative impact on the patients' quality of life and imposes a large economic burden on the healthcare systems. Conventional methods of conservative treatment of chronic venous disease include wearing compression knitwear and pharmacological therapy. Although highly effective, compression therapy appears to be associated with lower compliance due to difficulties putting on and taking off the compression stockings. Therefore, the majority of patients prefer pharmacological therapy with phlebotonic drugs. There are many phlebotropic agents possessing particular indications and recommendations regarding the duration of administration. This article presents a review of the available literature addressing the problems related to prescription of pharmacotherapy to patients with lower limb chronic venous disease, also describing the results of published clinical studies evaluating efficacy and safety of phlebotropic drugs, as well as those concerning the duration of the course administration of drugs depending on the severity of the disease, invasive nature of a surgical intervention performed, or sclerotherapy. Besides, analysed is the role of phleboactive agents in correction of pathophysiological mechanisms of the development and progression of venous disease. This is followed by a review of clinical trials studying the influence of phlebotonics on such links of pathogenesis as leukocyte activation, vein-specific inflammation, endothelial dysfunction, and activation of proteolytic enzymes promoting destruction of the extracellular matrix. Based on the above data, proposed herein are appropriate approaches to determining the duration of the courses of phlebotropic therapy with due regard for the patients' status, underlying once again the importance and necessity of a personalized approach to selection of the optimal duration of venotonic therapy.

[Review of the proceedings of the 68th International Congress of the European Society of Cardiovascular and Endovascular Surgery (May 22-25, 2019)]. / Obzor materialov 68-go Mezhdunarodnogo kongressa Evropeiskogo obshchestva kardiovaskuliarnykh i éndovaskuliarnykh khirurgov (22-25 maia 2019 g.).

This article covers the main trends of the work of the 68th International Congress of the European Society of Cardiovascular and Endovascular Surgery, reviewing the papers encompassing current problems in not only vascular but also cardiac surgery.

[Current aspects of performing treadmill test in patients with peripheral artery disease]. / Sovremennye aspekty provedeniia tredmil testa u patsientov s zabolevaniiami perifericheskikh arterii.

The protocols of performing treadmill tests (TMT) in patients presenting with peripheral artery disease have over the last decades undergone significant changes, with the alterations concerning not only the speed and time values of the load, but also the parameters measured. Currently, there is no unified generally accepted method of TMT, hence the need for an optimal protocol for carrying out this type of examination, which would help obtain reliable results in assessment of everyday life functional activity of patients and efficacy of various methods of treatment for peripheral atherosclerosis. The choice of an optimal methodology of performing a TMT in patients with intermittent claudication is extremely important because studying the haemodynamic parameters alone not always clearly reflect functional peculiarities of the course of the disease, since they depend not only on the presence of arterial stenoses or occlusions, but also on the activity of oxidative enzymes, endothelial and mitochondrial dysfunction, taking therapeutic agents, concomitant pathology and a series of other factors. The article is a review of the related literature contained in such databases as the Medline, PubMed, Russian Science Citation Index (RSCI) and Scopus and concerning TMT in patients with peripheral artery disease. The authors summarized the information from a total of 63 literature sources over the period from the 1970s to 2018.

[Effect of genetic polymorphisms on functioning of a permanent vascular access in patients on dialysis]. / Vliianie geneticheskikh polimorfizmov na funktsionirovanie postoiannogo sosudistogo dostupa u patsientov na dialize.

Thromboses and stenoses of permanent vascular access appear to be a serious hazard for patients with end-stage kidney disease on programmed haemodialysis. Relapses of these pathological conditions are the cause of repeated hospitalization, secondary surgical interventions and may eventually lead to impossibility of carrying out procedures of haemodialysis. Often, vascular access dysfunction occurs for no apparent reason, thus underlying the importance of studies aimed at revealing additional factors of intravascular thrombogenesis and neointimal formation in a vascular access, including the works dedicated to studying genetic predictors of the development of the above-mentioned complications. The authors examined herein the role of polymorphisms of the genes of endothelin-1 (END-1), nitric oxide synthase-3 (NOS-3), angiotensinogen-2 (AGT-2), angiotensinogen-1 (AGT-1), angiotensinogen 2 receptor type 1 (AGTR1), mitochondrial superoxide dismutase-2 (SOD-2), catalase (CAT) superoxide dismutase-1 (SOD-1) and angiotensin converting enzyme (ACE) in the functional state of permanent vascular access in patients on dialysis. The obtained results demonstrated direct cause-and-effect relationships between polymorphisms lys-198 asn in the END-1 gene, C60T, T58C in the SOD-2 gene and the function of vascular access. The presence of END-1 gene lys-198 asn polymorphism in a homozygous state (allele 1) was associated with a high risk of an unsatisfactory condition of permanent vascular access (p=0.019).

[Promising methods of studying perfusion in patients with atherosclerosis of peripheral arteries]. / Perspektivnye metody issledovaniia perfuzii u patsientov s aterosklerozom perifericheskikh arterii.

Prevalence of atherosclerotic peripheral artery disease (PAD) has steadily been increasing all over the world, affecting approximately 10% of the population. PAD dramatically decreases the patients' quality of life and is accompanied by high risks of limb amputation and death. Reconstructive and restorative interventions make it possible to achieve the highest success in treatment of PAD. Their results largely depend on the state of the patient's peripheral bed. Currently, the periphery is objectively assessed by means of ultrasonographic duplex examination, digital subtraction angiography, roentgen computed tomographic angiography (CTA), and in a series of cases magnetic resonance tomographic angiography (MRA). Widely known are the scale of assessing peripheral vascular resistance, suggested by R. Rutherford and the Bollinger scoring system. All these methods study predominantly the major blood flow, only slightly touching the microcirculatory bed. Promising methods in this area are radionuclide methods - single-photon emission computed tomography (SPECT) and positron-emission tomography (PET). Used singly, they possess high sensitivity but low spatial resolution, therefore they are supplemented by CTA or MRA. It is supposed that the use of radionuclide methods would make it possible to accurately assess the state of an atherosclerotic plaque and angiogenesis in conditions of ischaemia. Yet another method of diagnosis of microperfusion is contrast-enhanced ultrasonography (CEUS). CEUS reveals deficit of perfusion of the gastrocnemius muscles of patients with PAD in accordance with severity of the disease and degree of the development of collaterals. It is also used for determining the results of therapy with agents improving microcirculation. The degree of blood supply to tissues may be evaluated with the help of perfusion computed tomography (PCT). The main area of its application is diagnosis of impairments of cerebral circulation. Under study is a possibility of using PCT in atherosclerosis of lower-limb arteries, as well as assessing the efficacy of the reconstructive and restorative procedures performed.

[Hemostatic changes in patients with peripheral artery disease before and after bypass surgery]. / Pokazateli gemostaza u patsientov s aterosklerozom perifericheskikh arterii pri rekonstruktivno-vosstanovitel'nykh operatsiiakh.

AIM: To assess intrinsic coagulation pathway factors activity and hemostatic markers of endothelial dysfunction in patients with peripheral artery disease (PAD) before and after lower extremity bypass surgery. MATERIAL AND METHODS: 80 patients with PAD Fontaine grade IIB-III were enrolled. 40 patients underwent open aorto-femoral-popliteal repair (group A) and 40 patients - medication (group B). Before and in 3 months after surgery peripheral venous blood samples were collected to assess the activity of factors VIII, IX, XI, von Willebrand factor (VWF), protein C (PrC), and metabolites of nitric oxide II (NO). RESULTS: Increased preoperative activity of VIII, IX, XI, and VWF factors compared with normal values was observed in group A. After 3 months there was an additional increase of VIII and VWF factors' activity. Activity of IX and XI factors remained increased on background of reduced level of NO metabolites. In group B increased activity of IX, XI, and VWF factors was revealed while levels of NO metabolites and PrC were normal. CONCLUSION: Thus, PAD is followed by prothrombotic state especially in patients after surgery. Surgical procedures are associated with more severe hypercoagulation.

[Gene-mediated induction of angiogenesis in inoperable patients with atherosclerosis and diabetes mellitus]. / Gennaia induktsiia angiogeneza u neoperabel'nykh patsientov s aterosklerozom i sakharnym diabetom.

Analysed in the article are the results of a comprehensive approach to treatment of patients presenting with lower limb critical ischaemia and diabetes mellitus by means of gene-induced angiogenesis. The study comprised a total of 65 patients found to have an ill-suited for surgical reconstruction peripheral arterial bed and undergoing conservative therapy. The patients were divided into two groups. The Study Group patients additionally to the conventional conservative therapy received 2 intramuscular injections of therapeutic agent Neovasculgen at a course dose of 2.4 mg. The active period of follow up amounted to 6 months followed by evaluating limb salvage and lethal outcomes at a further 6 months thereafter. Efficacy of treatment was determined both by primary criteria (lethality rate, amputations, dynamics of necrosis healing, clinical relief of critical ischaemia) and secondary criteria (pain-free walking distance, ankle-brachial index, transcutaneous oxygen tension, linear velocity of blood flow, the Michigan Neuropathy Screening Instrument (MNSI) and Neurological Symptom Score (NSS) scale). After 6 months of follow up, the statistical significance in the intragroup and intergroup comparisons was reached for the pain-free walking distance (increment up to 72.9±9.2 m, p=0.032), transcutaneous oxygen tension (increment by 34.4%, p=0.028), linear velocity of blood flow (increment by 65.3%, p=0.047). Induction of angiogenesis also made it possible to statistically significantly decrease the manifestations of diabetic neuropathy, as was evidenced by the data of the MSNI (p=0.009) and the NSS scale (p=0.044). The findings of the study also demonstrated the best value of the limb salvage rate (p=0.049) and a lower number of lethal complications at 1 year of follow up.

[Venous thromboembolic complications in patients with cardiovascular implantable electronic devices]. / Venoznye tromboémbolicheskie oslozhneniia u patsientov s serdechno-sosudistymi implantiruemymi élektronnymi ustroistvami.

The problem of venous thromboembolic complications (VTECs) in patients with cardiovascular implantable electronic devices (CIEDs) is extremely important today because of an annually increasing number of surgical interventions for life-threatening arrhythmias and chronic heart failure. There are hitherto no clearly defined reliable risk factors for VTECs due to heterogeneity of the available literature data. Some sources point to elevated thrombus formation in patients with a large number of electrodes, in repeat operative interventions, in the presence of a temporary pacemaker, in implantation on the left side, silicon cover of an electrode, others refute these facts. Still undetermined remains the choice of antithrombotic therapy for prevention and treatment of VTECs in this cohort of patients. Implantation of a VTEC may be accompanied by thrombosis of deep veins of the upper extremities up to the development of total occlusion of veins. In rare cases, thrombosis extends proximally, there appears superior vena cava syndrome which may require surgical treatment. Diagnosis of these diseases is complicated by their symptom-free course in the majority of cases. The most dangerous VTEC is pulmonary thromboembolism very commonly not accompanied by clinical symptomatology or taking its course under the mask of other more frequent diseases. Despite the fact that pulmonary thromboembolism with a source in the system of the superior vena cava is rarely massive, it may lead to the development of chronic postembolic pulmonary hypertension and to decreased quality of life. The article contains a review of the present-day literature and a clinical case report concerning the development of VTECs in a patient with a CIED in the form of thrombosis of the right internal jugular, subclavian and brachiocephalic veins, pulmonary embolism of small branches of the right pulmonary artery, suppuration of the pacemaker's bed and sepsis. Therapy with antibiotics, low-molecular-weight heparins, antiplatelet drugs and anti-inflammatory agents with regular sanitation of the pacemaker's bed turned out effective.

[Oxidative carbonylation of proteins in experimental hind-limb ischaemia-reperfusion injury]. / Okislitel'noe karbonilirovanie belkov pri éksperimental'noi ishemii i reperfuzii nizhnikh konechnostei.

Formation of carbonylated protein derivatives is one of the key signalling pathways in cellular damage and may be regarded as a reliable marker in cellular injury. It allows evaluating both direct effects of reactive oxygen species and indirect interrelations with the secondary by-products of oxidation. The present study was undertaken to investigate the activity of lysosomal cysteine proteinases (cathepsins B and L) in blood serum and the arterial wall in an experimental model of ischaemia and ischaemia-reperfusion injury. To this was added comprehensive assessment of oxidative modification of proteins derived from blood serum and the arterial wall, namely, calculating the area under the curve of the absorption spectrum of the products of protein carbonylation, the proportion of the primary and secondary markers of oxidative stress, as well as the reserve and adaptation potential. The obtained findings were indicative of the development of oxidative stress in the model of ischaemia-reperfusion injury from day 1 to day 7, and in the ischaemia model on day 3 and day 5 in both the vascular wall and blood serum, which was accompanied by activation of cathepsins B and L. Reversible oxidation of proteins was observed on days 3 and 5 in the experimental ischaemia model and on days 1 and 7 in the ischaemia-reperfusion injury model, which was confirmed by the predominance of the primary markers of oxidative stress. Irreversible oxidation of proteins, i. e., the predominance of the secondary markers, was suggestive of the enhancement of oxidative stress, its transition to the late stage, leading to the loss of biological properties of proteins and eventually followed by their aggregation and degradation as seen in the ischaemia-reperfusion injury model on days 3 and 5. Analysing the obtained findings revealed direct correlation between the total area under the curve of oxidative modification of proteins and overall activity of cathepsin L in the ischaemia model: in blood serum on days 3 and 5, in the vascular wall for cathepsins B and L on day 5; in the ischaemia-reperfusion injury model: the activity of cathepsin L in blood serum on day 3, in the vascular wall on day 5 for cathepsins B and L.

[Concentration of matrix metalloproteinases and magnesium ions in patients with varicose veins of lower limbs]. / Kontsentratsiya matriksnykh metalloproteinaz i ionov magniya pri varikoznoi bolezni ven nizhnikh konechnostei.

The study was aimed at investigating alterations in the concentration of matrix metalloproteinases (MMP-1, MMP-9) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as the level of magnesium ions (Mg2+) as an indicator of connective tissue dysplasia (CTD) in patients presenting with lower limb varicose veins. The study included a total of 110 people. Of these, the Study Group comprised 90 patients with lower limb varicose veins of clinical class C2-C6 (according to the CEAP classification) and the Control Group was composed of 20 apparently healthy volunteers. Samples of peripheral blood were examined. The content of MMP-9, MMP-1 and TIMP-1 in blood serum was determined by means of the quantitative solid-phase immunoenzymatic assay. The concentration of Mg2+ was determined by the colorimetric method. We revealed a statistically significant interrelationship between the concentrations of matrix metalloproteinases and severity of varicose transformation of lower-limb veins, with the highest level of matrix metalloproteinases being observed in patients with cutaneous alterations and trophic ulcers. Determination of the level of matrix metalloproteinases and magnesium ions, characterizing connective tissue dysplasia, makes it possible to predict the development of lower limb chronic venous insufficiency and to evaluate the degree of its severity.

[Possibilities of pharmacotherapy for chronic venous insufficiency with diosmin preparations from the position of the endothelial functional state].

Despite a high level of the development of modern angiology and vascular surgery, the problem of chronic venous insufficiency (CVI) complicating the course of various venous diseases seems to have no tendency towards being solved, thus calling forth permanent search for optimization of methods of treatment and rehabilitation of patients presenting with the above-mentioned syndrome. The article presents a review of contemporary studies dedicated to the problem of correcting CVI. Special attention is paid to the endothelial state in CVI and possibilities of correcting endothelial dysfunction with the use of bioflavonoids, in particular, diosmin. Also presented herein are the results of an original experimental study dedicated to peculiarities of the endothelial functional state, endothelial dysfunction, and correction thereof on the background of the existing CVI.

[Efficacy of using VEGF165 gene in comprehensive treatment of patients with stage 2A-3 lower limb chronic ischaemia].

The authors share their experience in treating a total of 100 patients presenting with stage 2A-3 chronic lower limb ischaemia according to the classification of Pokrovsky-Fontain (the clinical group was composed of 75 patients and the control group comprised 25 subjects), in whom it was impossible to perform surgical revascularization. The clinical group patients received in addition to the conventional vascular therapy local intramuscular injections of Neovasculogen (plasmid genetic construction containing human gene VEGF165) at a course dose of 2.4 mg. The results were assessed after 1 year. It was shown that administration of this gene therapeutic agent is safe with no local or systemic allergic reactions and free form neoplastic processes. Efficacy of treatment was assessed by registering the pain-free walking distance (PFWD), transcutaneous oxygen tension (TCPO2), linear velocity of blood flow, ankle-brachial index (ABI), angiography, and by means of SF-36 questionnaire. It was determined that after 12 months the statistical significance of intergroup and intragroup differences was reached for PFWD (increment 167.2%), TCPO2 (increment 20.4%). The highest clinical response for the PFWD was registered in patients with stage 3 of the disease (547.5%), as well as in those with multi-storey vascular lesions (269.1%). The obtained findings make it possible to consider gene therapy with Neovasculogen as an efficient component of comprehensive treatment of this cohort of patients.