Defense of the dissertation of Zhalbinova Madina Ruslanovna for the degree of Doctor of Philosophy (PhD) in the specialty «6D060700 - Биология»
L.N. Gumilyov Eurasian National University, a dissertation defense for the degree of Doctor of Philosophy (PhD) by Zhalbinova Madina Ruslanovna on the topic «Рathogenetic aspects of hemostasis disorders in cardiac implantation surgeries» in the field of «6D060700 – Biology».
The dissertation was completed at the Department of «General Biology and genomics» of the Eurasian National University named after L.N. Gumilyov and in the laboratory of genomic and personalized medicine at the Center for Life Sciences, PI «National Laboratory Astana».
The language of defense is russian
Official reviewers:
Momynaliev Kuvat Temirgalievich - Doctor of biological sciences, Associate Professor, assistant of general director of FSBI «All-Russian Research and Testing Institute of Medical Technology of Roszdravnadzor» (Moscow, Russian Federation), specialty: 1.5.3. – Molecular biology.
Mankovskaya Svetlana Vladimirovna - Candidate of biological sciences, Professor, Deputy Director for Scientific and Innovative Work at the Institute Physiology, National Academy Sciences of Belarus, (Minsk, Belarus), specialty: 03.01.07 - Мolecular genetics.
Temporary members of the Dissertation Committee:
Ogay Vyacheslav Borisovich - Candidate of biological sciences, Professor, Managing Director for Science at the LLP «National Center of Biotechnology» (Astana, Republic of Kazakhstan), specialty: 03.00.02 – Biophysics.
Saliev Тimur Muidinovich - MD, PhD, Director of the Research Institute of Fundamental and Applied Medicine named after B. Atchabarov at the Kazakh National Medical University named after S. Asfendiyarov (Almaty, Republic of Kazakhstan), specialty: 03.00.02 – Biophysics.
Kulmambetova Gulmira Nigmetzhanovna – PhD, Associate Professor, Leading Researcher of the National scientific shared laboratory of biotechnology, LLP «National Center of Biotechnology» (Astana, Republic of Kazakhstan), specialty: 03.00.00 - Biological sciences.
Kozhakhmetov Samat Serikovich - Candidate of biological sciences, Associate Professor, Leading Researcher of the Laboratory of Microbiome, Center for Life Sciences, PI «National Laboratory Astana», Nazarbayev University (Astana, Republic of Kazakhstan), specialty: 03.00.07 – Мicrobiome.
Academic Advisors:
Akilzhanova Ainur Rakhmetulovna - Doctor of Medical Sciences, M.D., PhD, Professor, Head of the Laboratory of genomic and personalized medicine, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, (Astana, Republic of Kazakhstan), specialty: 14.00.33 - Public health and healthcare.
Wei Wang - M.D, PhD, professor of the School of Medical and Health Sciences at Edith Cowan University (Perth, Australia).
The defense will take place on March 14, 2024, at 11:00 AM in the Dissertation Council fin the field of training «8D051-Biological and related sciences» majoring in «6D060700 – Biology» at the Eurasian National University named after L.N. Gumilyov. Conducting a dissertation council meeting online and offline.
Link: https://us06web.zoom.us/j/84497111574?pwd=Jyjxr9DT3bqxwCBKylVqJuZlnUfCJo.1
Conference ID: 844 9711 1574
Access code: 740021
Address: Astana, K.Munaitpasov str. 13, №333 auditorium of №3 of the academic building of L.N. Gumilyov Eurasian National University.
Abstract (English): General description of work. The dissertation work is devoted to investigate the association of genetic gene polymorphisms in patients with chronic heart failure with the risk of development of the complications with an implanted left ventricular assist device (LVAD). Significance of the research topic. Chronic heart failure (CHF) is one of the most significant healthcare problems worldwide, including in the Republic of Kazakhstan (RK), which has increased 5-7 times over the past decades. Today, the annual cost of patient care exceeds $30 billion, which is predicted to increase to $70 billion by 2030. The main causes of CHF are arterial hypertension, diabetes, rheumatic heart disease, chronic obstructive pulmonary disease and coronary artery disease (CAD). There are also important causes such as cardiomyopathy, valvular disease, prolonged arrhythmias, toxins and infections. Common causes in the development of CHF are cardiovascular diseases such as CAD and dilated cardiomyopathy (DCM). The heart cannot supply the tissues with enough blood for metabolism, and an increase in pulmonary or systemic venous pressure can lead to plethora in peripheral organs in CHF. A similar condition can occur with violations of both systolic and diastolic function of the heart (more often both). CHF patients have symptoms of fatigue, shortness of breath, edema, as well as reduced physical activity, with severe symptoms of decompensation, hospitalization is necessary. Manifestations of heart failure differ depending on which ventricle is affected primarily - right or left. The severity of the clinic varies greatly and is determined according to the classification of the New York Heart Association (NYHA). Patients with CHF have a process of pathological thrombosis during high activation of the hemostasis system due to the formation of excessive amounts of thrombin, increasing the risk of venous thromboembolism, deep vein thromboembolism, dysfunction of muscle contraction, stroke, and the risk of sudden death. One of the factors in the formation of pathological thrombosis and dysfunction of muscle contraction might be genetically hereditary factors which are the cause of the early development of CHF in early age of the patient. Heart transplantation (HT) is one of the effective treatment methods for CHF patients. HT is the gold standard of the treatment for patients at their end-stage of CHF. However, not all patients can undergo HT due to the limited number of the heart donors. There are about 4,000 transplantations performed every year in the world. Nowadays, implantation of the mechanical circulatory support device of the left ventricle (left ventricular assist device, LVAD) is an alternative treatment method for CHF patients. LVAD device improves quality of life and prolongs the life of the CHF patient with a survival rate of about 80%. The LVAD device has a rotating pump with a constant flow of blood, which mechanically unloads the left ventricle of the heart, thereby providing hemodynamic support. Since November 2011, the treatment of CHF patients with an LVAD device has become possible in Kazakhstan due to the creation of a surgical treatment program at the JSC National Research Cardiac Surgery Center (NRCC). There are four types of LVAD devices are implanted at NRCC such as HeartMate II, CentriMag VAD, HeartMate 3 (St Jude Medical, Huntingdon, Cambridgeshire, UK) and HearWare HVAD (HeartWare International, Framingham MA, USA). Complications development occur despite to the prolongation of life in CHF patients after implantation of the LVAD device. The development of thrombosis and bleeding events are the most common complications. CHF patients with developed complications should undergo rehospitalization with reoperation of pump replacement to reduce the risks of the mortality. The cause of complications is the presence of a rough surface of the pump and the presence of the high non-physiological shear stress of the mechanical LVAD device, which rotates from 5000 to 12000 rpm. Shear stress causes dysfunction, damage, loss and activation of the platelet adhesive receptors such as GPIbα, GPVI and GPIIb/IIIa. Thus, shear stress causes damage of the normal hemostasis function, which becomes cause of thrombosis and bleeding events during implanted LVAD device. However, it is necessary to take into account the genetically inherited dysfunction of the platelet receptors, which could be the cause of the development of complications with an implanted device in CHF patients. Patients are prescribed anticoagulant and antiplatelet therapy to prevent thromboembolic complications after LVAD implantation. Warfarin and acetylsalicylic acid (aspirin) are commonly prescribed drugs for prevention thrombosis events in CHF patients with LVAD. However, during antithrombotic therapy thrombosis and bleeding events still occur in patients due to incorrect dosage of the drugs. Nowadays, the risks of complications can be prevented by prescribing an individual warfarin dosage based on the genotyping test results for genetic polymorphisms of the vitamin K reductase (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes, which affect to the warfarin dose variability for about 50%. On the other hand, the enzymes of cytochrome P450 (CYP2C9), uridine diphosphate (Uridine diphosphate, UDP) - glucuronosyltransferase (UGT) and acyl-coenzyme A synthetase ACSM2B (Acyl-coenzyme A synthetase, ACSM2B) are involved in the metabolism of aspirin. Aspirin drug metabolites excrete with various speed rate of the enzymes during metabolism (biodistribution) of aspirin. The genetically inherited factors of the CHF patient also influence to the development of the LVAD complications apart from the non-physiological shear stress of the device. Genetically hereditary factors cause development of the thrombophilia, the presence of rapid activation of platelet cells and blood coagulation factors, increase the level of homocysteine, fibrinogen, which predispose CHF patients to the formation of complications. Therefore, it is necessary to study the genetic variants of gene polymorphisms in CHF patients with an implanted LVAD device, which could allow to predict and reduce the risks of complications. The aim of the study is to study the pathogenetic basis of hemostasis disorders in patients with CHF with an implanted auxiliary mechanical device for the left ventricle LVAD. Research tasks 1. To identify the effect of an implanted LVAD device on clinical and pathogenetic disorders in CHF patients. 2. To identify genetic polymorphisms of genes associated with the development of the thrombosis and bleeding complications in CHF patients with an implanted LVAD device. 3. To reveal the influence of genetic gene polymorphisms on anticoagulant (warfarin) and antiplatelet (aspirin) drug therapy in CHF patients. 4. To develop recommendations for the prevention of complications in CHF patients with an implanted LVAD device. The object of the study are samples of genomic DNA isolated from the whole blood of 98 CHF patients with an implanted LVAD device, as well as 95 healthy people - the control group. The dissertation work was carried out on the basis of the PI "National Laboratory Astana", Center for Life Sciences, Nazarbayev University, Astana. Research methods In the dissertation work, methods for analyzing clinical, demographic, and instrumental indicators of CHF patients with LVAD implantation, molecular genetic methods for studying gene polymorphisms, and statistical analysis methods were used. Scientific novelty of the research For the first time were: - associations of polymorphisms rs9934438; rs9923231 in VKORC1 gene were revealed and their impact on warfarin dose variability in CHF patients with an implanted LVAD device in Kazakhstan; - an association of the polymorphism rs5918 in ITGB3 gene, encoding the GPIIIa subunit of the glycoprotein receptor, was found in CHF patients with the development of complications with an implanted LVAD device; - developed method of the selection and correction the dose of aspirin according to the genotypes of polymorphism rs2070959 in UGT1A6 gene, which is involved in the metabolism of aspirin excretion, in CHF patients with an implanted LVAD device; - developed method of the selection and correction the dose of warfarin according to the genotypes of the polymorphism rs8050894, rs9934438; rs9923231 in VKORC1 gene in CHF patients with an implanted LVAD device. Theoretical and practical significance of the research The investigation allows to deepen the knowledge about the mechanisms of the development of thrombotic complications in CHF patients with an implanted mechanical circulatory device (LVAD). The obtained results of the study allow to identify the genetic predisposition of CHF patients to the development risks of thrombosis and bleeding events before and after implantation of mechanical LVAD device. The identification of genetic polymorphisms will make it possible to prevent and reduce the risk of complications, reduce the number of cases of rehospitalization of patients, optimize the method of personalized treatment of anticoagulant therapy, improve the well-being and quality of life of CHF patients with an implanted LVAD device in Kazakhstan. Based on the research results, methods of the selection and correction the dosage of warfarin and aspirin were developed and implemented according to the genotypes of the polymorphism rs8050894, rs9934438; rs9923231 in VKORC1 gene and rs2070959 in UGT1A6 gene in CHF patients with an implanted left ventricular mechanical device at the JSC National Research Cardiac Surgery Center (NRCC). Based on the investigation results of the dissertation work, a patent was obtained for the invention of the Republic of Kazakhstan No. 35979/09.12.2022 "Method of selection and correction of aspirin dose in patients with heart failure with an implanted mechanical device of left ventricle". The main provisions for the defense: 1. Implanted LVAD mechanical circulatory support devices (HM2, HM3, HW) causes changes in biochemical parameters of blood, as well as to the development of thrombosis and bleeding complications in CHF patients. 2. Polymorphisms rs9934438; rs9923231 in VKORC1 gene, rs5918 in ITGB3 gene, and rs2070959 in UGT1A6 gene are genetic variants which are associated with the development of complications in CHF patients with implanted LVAD. 3. Polymorphisms rs8050894; rs9934438; rs9923231 in VKORC1 gene, rs2070959 in UGT1A6 gene are genetic variants that can be used for correction dosage of the anticoagulant and antiplatelet drugs in CHF patients with LVAD implantation. 4. CHF patients are recommended to perform genetic testing for polymorphisms rs8050894, rs9934438, rs9923231 in VKORC1, rs5918 in ITGB3, rs2070959 in UGT1A6 and rs1801133 in MTHFR*1 genes to predict and prevent the risks of thrombosis and bleeding complications with an implanted LVAD device. Connection of the dissertation title with the plans of scientific works. The dissertation work was carried out in the scientific program 0072/PCF-14 "Creation and development of the foundations of genomic medicine in Kazakhstan", within the framework of the project "Genome-associated personalized antithrombotic therapy for patients with a high risk of developing thrombosis and bleeding". The main results of the study were reported at international and republican conferences: 1. XIV International Scientific and Practical Conference “Ecology. Radiation. Health” (Semey, 2019); 2. 39th Annual Meeting and Scientific Sessions of International Society for Heart and Lung Transplantation. (Florida, 2019); 3. International conference dedicated to the 10th anniversary of Center for Life Sciences, “Modern perspectives for biomedical sciences: from bench to bedside” (Nur-Sultan, 2020); 4. 24th Human Genome Meeting Conference, HGM 2020 (Perth, 2020); 5. 53rd European Society of Human Genetics Virtual Conference, 2020; 6. 40th Annual Meeting and Scientific Sessions of International Society for Heart and Lung Transplantation (Montreal, 2020); 7. X Anniversary International Scientific and Practical Conference "Molecular Diagnostics 2021" (Moscow, 2021); 8. 41st Annual Meeting and Scientific Sessions of International Society for Heart and Lung Transplantation 2021, Virtual Experience; 9. 54th European Society of Human Genetics Conference (Vienna, 2022); 10. International conference of center for life sciences “Modern perspectives for biomedical sciences” (Astana, 2022); 11. XIV International scientific and practical conference “Ecology. Radiation. Health” named after B.A.Atchabarov (Semey, 2023); Research publications Based on the research materials of the dissertation, 17 papers have been published: 2 articles in a foreign journal with an impact factor; 3 articles in the journal of the Republic of Kazakhstan; 6 abstracts in the International conferences; 1 abstract in the materials of conferences in the near abroad; 4 abstracts in the materials of international conferences of the Republic of Kazakhstan; 1 patent for an invention of the Republic of Kazakhstan. Dissertation structure The dissertation work is presented on 130 pages. The work consists of an introduction, scientific literature review, materials and methods of the research, results and discussion, conclusion, practical recommendations, a list of references, including 211 sources and 6 appendices. The dissertation work is illustrated with 15 figures and 31 tables.