The review summarizes current knowledge about biomarkers in personalized medicine. Classification of biomarkers, the process of validation and challenges in implementation are discussed. The role of biobanks for new biomarkers is also included.

Background. Cerebral AVMs are not static congenital lesions, but can grow, recur, and appear de novo after complete resection, embolization, or radiosurgery. Understanding the complex molecular biology of AVMs is critical to predicting their behavior during treatment and improving treatment outcomes. Objective. To study the dynamics of angiogenesis factors in the process of cerebral AVM embolization in order to develop a strategy for their personalized treatment. Methods. The study included 314 patients with AVM who received surgical treatment at the Department of Brain Vascular Surgery of the Polenov Neurosurgical Research Institute. Determined the level of vascular endothelial growth factor (VEGF), angiopoietin-2 (ANG-2) and matrix metalloproteinase-9 (MMP-9) in blood serum before and 24 hours after endovascular embolization using enzyme-linked immunosorbent assay (Personal Lab, Adaltis, Italy). Results. 48.4 % of primary patients with AVM showed an increase in VEGF, MMP-9, ANG-2. A high level of VEGF and MMP-9 demonstrated AVM III grades according to SpetzlerMartin, AVM with a hemorrhagic flow type, with a deep drainage pattern, with afferents from the external carotid artery. The return to control values of all elevated growth factors after total embolization confirms the lack of potency for AVM recurrence. The absence of a decrease in aniogenesis factors after radical, according to angiographic criteria, embolization is a sign of subtotal AVM shutdown. A personalized concept of embolization in patients with a high risk of growth and recurrence has been formulated.

Introduction. It has been proven that patients with thrombosis and with a high risk of systemic thromboembolic complications (TEС), including patients with non-valvular atrial fibrillation (AF) should receive effective and safe antithrombotic therapy [1–3]. A personalized approach to prolonged AVK therapy is associated with an improvement in hemostasiological markers of thrombinemia and clinical outcomes in patients with VTE and non-valvular AF [4–8]. Materials and methods. Prospective study was carried out on the basis of the anticoagulant clinic (AC) of the Department of hemostasis and atherothrombosis laboratory of the state budgetary health institution of the Arkhangelsk region “First city clinical hospital named after names E. E. Volosevich” (GBUZ AR FCCH). The object of the study is patients of the AVK registry who applied to the RCATT (n = 107) who underwent pharmacogenetic testing (CYP2C9, CYP4F2, VKORC1 genotype) with calculation of individual doses of warfarin and assessment of quality of life using validated questionnaires. The analysis of the effectiveness and safety of warfarin therapy was carried out. Results. It was found that complications of warfarin therapy developed regardless of the presence of the genotype (CYP2C9, CYP4F2, VKORC1) and the warfarin dosing algorithm under observation in AC. It has been shown that pharmacogenetic testing in patients with VTE and AF is an additional method under the condition of observation in AC. Conclusion. A personalized approach to prolonged VKA therapy using pharmacogenetic testing is appropriate for patients of the older age group, patients with a aggravated hemorrhagic history, frequent minor bleeding at target INR values and the presence of concomitant therapy with cytochrome P450 inhibitors.

Inter-individual differences in anti-tuberculosis chemotherapy outcomes have been demonstrated in clinical practice, such as, achievement of intended therapeutic effect in some patients, and insufficiency or absence of response to treatment in others, with development of adverse drug reactions, especially, isoniazid-induced liver injury. Isoniazid-induced liver injuries are the main reason for isoniazid discontinuation, which further leads to considerably reduced effectiveness of anti-tuberculosis chemotherapy, increased relapse risk, and secondary drug-resistance of M. tuberculosis. Hepatotoxic reactions to chemotherapy are predicated by mutations in genes encoding enzymes participating in isoniazid biotransformation: N-acetyltransferase 2 (NAT2), cytochrome P450 2Е1, and glutathione-S-transferase.
NAT2 gene polymorphism has been identified as risk factor for isoniazid hepatotoxicity. Nucleotide substitutions in NAT2 gene cause modification of enzyme protein structure, reduction of enzyme synthesis and alteration of its activity. Based on genetically-determined isoniazid acetylation rate, patients are referred to three acetylator types: rapid, intermediate, and slow. Correlations have been established in meta-reviews and systematic reviews between slow acetylator type and frequency of hepatotoxic reactions to isoniazid.
Based on study findings, interrelation was shown between cytochrome P450 CYP2E1 gene polymorphism and increased risk of liver injury during chemotherapy with isoniazid. Contribution of GSTM1 and GSTT1 genotypes to isoniazid toxicity requires further exploration, as the obtained results were ambiguous and controversial.

Background. Polymorphisms of the CYP17A1 gene are known for their association with the risk of coronary artery disease (CAD), and essential hypertension (EH), dyslipidemia, and with the levels of sex hormones. However, pharmacogenetics aspects of these polymorphisms have not so far been investigated. Objective. To study the association of rs1004467 and rs11191548 variants at CYP17A1 with the effectiveness of rosuvastatin therapy in terms of change in plasma lipids and carotid intima-media thickness (CIMT), and the association with the risk of CAD and EH in Russians. Design and methods. The pharmacogenetics study included 116 patients with CAD, stable angina pectoris, observation period was 12 months; genetic association study — 749 patients with CAD, 737 EH patients. Genotyping was performed using the MassARRAY-4 system. Results. Both CYP17A1 polymorphisms were not associated with CAD and EH risk. The most significant associations with the attenuated decrease in LDL-C were observed in 1 month of therapy (in variant homozygotes of both polymorphisms, p = 0,0002), and with triglyceride level change in 6 months (in heterozygotes of rs1004467 and rs11191548, p = 0,0015 и 0,0013, respectively). Attenuated CIMT regression in 6 months was associated with rs11191548 variant (p = 0,034). Conclusion. We have found for the first time the associations of rs1004467 and rs11191548 of CYP17A1 with the effectiveness of rosuvastatin therapy, and the associations were the strongest in the early period of treatment.

Background. Clopidogrel is often used in patients undergoing coronary stenting for acute coronary syndrome. However, the CYP2C19 variants rs4244285(*2), rs4986893 (*3) affect the metabolism of clopidogrel. These alleles occur with different frequencies in patients of different nationalities, so the clopidogrel efficacy may differ in ethnic groups living in Russia. Objective. to assess the associations between genetic determinants of the risk of thrombotic complications during clopidogrel treatment and the clinical characteristics of Buryat and Russian patients, in order to search for personalized informative prognosis markers. Design and methods. The study included 142 Buryat and 150 Russian patients undergoing coronary stent placement for acute coronary syndrome. All patients received clopidogrel. Patients were stratified by the presence of CYP2C19*2, CYP2C19*3 alleles. In all patients efficacy endpoints were assessed, as well as corresponding therapy. Results. In Buryat patients CYP2C19*3 allele was significantly more common (11,6 % versus 1,3 %, p < 0,001) than in Russian. In Buryat patients, recurrence of anginal pain during exercise was associated with the CYP2C19*3 and/ or CYP2C19*2 genotypes (p = 0,015), as well as with the taking omeprazole (p = 0.015). In Russian patients, efficacy endpoints in clopidogrel treatment were associated with the presence of CYP2C19*2 and/or CYP2C19*3 alleles (p = 0.036). Conclusion. The presence of minor CYP2C19*3 and CYP2C19*2 alleles, along with the reports of recurrence of anginal pain during moderate and light exercise in Buryat patients may be considered as a prognostic sign of thrombotic complications.

Congenital and acquired valvular heart diseases are a global problem of the healthcare system. A huge number of prosthetic heart valve surgeries are performed annually, but there is still no ideal artificial substitute for a heart valve. The development of new prosthetic heart valves continues continuously, and includes an assessment of the functioning of prosthetic valves and the study of their hydrodynamic characteristics. Hardware pulse duplication systems (pulse duplicators) have been developed and used for such studies. The article discusses the purpose and functions, mechanical components, the principle of operation of the device, software, analysis capabilities, advantages and disadvantages of such systems.

Aneurysm of the aortic root accompanied by aortic insufficiency is a common cardiovascular pathology. The optimal method of surgical treatment of this pathology is the reimplantation of the aortic valve into the aortic root synthetic prosthesis (David procedure). Currently, there is no comprehensive data on the influence of initial geometric parameters of the aortic root structures on the functioning of the reimplanted aortic valve after valve-preserving aortic root replacement. We have introduced a novel technique for creation and segmentation of a three-dimensional reconstruction of the aortic valve and root, which involves the sequential application of two computer-aided design environments: In Vesalius v 3.1.1 (Centro de Tecnologia da Informação Renato Archer (CTI)) and 3- Matic v. 13.0 (Materialise, Leuven, Belgium). The proposed method allows accurate measurement and evaluation of spatial parameters of the AV leaflets, fibrous ring, sinuses of Valsalva and sinotubular junction. The developed technique was used to evaluate the anatomical and functional features of the aortic valve in a 68-year-old patient who underwent David I procedure. Segmentation and measurement of the geometric parameters of the aortic root were performed before operation, as well as 18 months after surgical treatment. To assess the function of the reimplanted aortic valve during the long-term follow-up, a detailed echocardiographic assessment was used. Echocardiographic assessment included measuring volume and area of the regurgitation flow, the width of vena contracta, and the regurgitation fraction. The application of high-precision 3D reconstruction opens up additional opportunities in the field of surgical treatment of the aortic root and AV pathology: advantages in choosing an individual patient-oriented surgical tactics, parameters of the implanted surgical material and/or device, and in predicting long-term results of surgical treatment.

Calcific aortic stenosis is one of the most common valvular heart diseases, which may require surgery. Regardless of the etiology, the consequence of this disease is concentric hypertrophy of the left ventricle and progressive myocardial fibrosis, independently affecting the long-term survival of patients after aortic valve replacement. “Open” surgical or transcatheter aortic valve replacement is the only effective way to treat aortic stenosis. “Open” surgical procedure remains the “gold standard”, however, transcatheter aortic valve replacement is characterized by rapid development and expansion to the population of moderate and low-risk patients. For a comparative assessment of the effectiveness and safety of transcatheter and “open” surgical procedures in patients of different risk categories, OBSERVANT, NOTION, PARTNER, PARTNER 2, PARTNER 3 studies were conducted, but on their basis, it is impossible to draw an unambiguous conclusion about the advantage of one or another method. An “intermediate” option for surgical correction of aortic stenosis in conditions of extracorporeal circulation and cardioplegia, possibly combining the advantages of classical surgical and transcatheter methods, is the replacement of the aortic valve with mini-invasive access and, in some cases, using seamless aortic valve prostheses. Thus, the question of the optimal method of correction of severe aortic stenosis in patients with moderate and high surgical risk remains open. In the process of managing such patients, it is important to take into account the individual characteristics of patients and strive to personalize treatment.

Extracellular vesicles are a heterogeneous group of particles surrounded by a phospholipid bilayer and having a diameter from 30 nm to 5 microns. In recent years, the involvement of extracellular vesicles in the pathogenesis of many diseases, as well as the possibility of their use in diagnosis and therapy, has been actively studied. It is known that vesicles can carry nucleic acids, in particular micro-RNA, mRNA, etc., what often leads to their participation in the regulation of many pathological and physiological processes in the body, as well as in intercellular cooperation. The repertoire of micro-RNAs carried by vesicles can vary significantly depending on their cellular origin and the functional state of the cells. To study the role of micro-RNAs carried by extracellular vesicles, it is necessary to develop and validate new approaches for the targeted production of these objects, followed by the study of the cargo carried by them. The purpose of this study was to determine the possibilities of using the method of highly sensitive fluorescence-activated sorting to obtain single extracellular vesicles with a given phenotype from blood plasma samples. A standard number of platelet and erythrocyte vesicles with the phenotype CD41+CD235a- and CD41-CD235a+, respectively, with a ranking from 1 to 15,625 pieces per sample were obtained from blood plasma samples of healthy donors by highly sensitive fluorescence-activated sorting. The level of miR-451a, miR-199a-3p, miR-21-5p in all samples of sorted vesicles was assessed by quantitative PCR. The obtained results indicate that to determine the level of micro-RNA in extracellular vesicles, regardless of their cellular origin, the number of particles in the sample should be more than 3125. At the same time, given the high variability of the number of specific micro-RNAs depending on the cellular origin of the vesicles, it is advisable to specify the target threshold of extracellular vesicles during each individual experiment.

Calcification of the heart and blood vessels is a common pathological condition, leading to numerous complications. One of the most common forms of calcification is aortic valve calcification. To date, there is no drug therapy that can stop the progression of calcification, so the only radical method of treatment remains surgery. Fundamental molecular biological studies and, accordingly, a relevant in vitro model are necessary to search for an anticalcifying therapy. In the article, we present the organization of the work of a translational group, consisting of clinicians, surgeons, and molecular biologists, working with cellular models of calcification. As cell models, a description is given of obtaining cell lines of interstitial and endothelial cells of the aortic valve, as well as smooth muscle and endothelial cells of the aorta. The preparatory clinical and surgical stages of obtaining a biomaterial, and the laboratory stage of working with the material are described.

This review is devoted to one of the integral tests for assessing the hemostasis system — the thrombin generation test (TGT), its technical characteristics, problems in standardization and possible clinical use. Evaluation of thrombin generation (TG) is more sensitive to changes occurring in the hemostasis system, since it takes into account the effect of both procoagulant and anticoagulant factors in the process of TG. It is important to note that there are options for setting TGT in platelet-rich plasma or in whole blood, which brings the researcher closer to in vivo conditions. However, despite the obvious advantages of this analysis when compared with routine screening tests for assessing the hemostasis system, there are number of limitations, including the lack of standardization, which does not currently allow the introduction of TGT into clinical practice. This review discusses the technical characteristics of TGT and variants of reagent kits depending on the clinical task, and provides the results of recent studies in the field of clinical use of TGT, demonstrating the prospects of GT analysis for assessing the risk of both hemorrhagic complications and thrombotic events.