Tatyana Ivanova-Razumova

Introduction. Cardiovascular diseases, including atherosclerosis (AS), are the leading cause of morbidity and mortality worldwide, including in Kazakhstan. Lipid metabolism disorders, in particular, hypertriglyceridemia, which is recognized as an independent risk factor, play an important role in the development of AS. Genetic features associated with genes regulating lipid and carbohydrate metabolism (GCKR, SLC22A5, LPL, FLCN, LDLR, APOE) have a significant impact on the formation of dyslipidemia and determine individual metabolic characteristics. Studying the prevalence and effects of these genetic variants in the Kazakh population is particularly important, given its underrepresentation in global genetic research. Aim. The objective of this study was to study the frequency of genetic polymorphisms in genes involved in the regulation of lipid metabolism (GCKR, SLC22A5, LPL, FLCN, LDLR, APOE) in a group of Kazakhstani patients with hypertriglyceridemia and atherosclerosis. Additionally, we analyzed the relationship of the identified genetic variants with the biochemical parameters of the lipid profile. Materials and methods. The study analyzed data from 402 patients with cardiovascular diseases, 144 of whom had hypertriglyceridemia. To identify the genetic determinants of lipid metabolism disorders, full-exome sequencing was performed with a focus analysis of the GCKR, SLC22A5, LPL, and FLCN genes. The identified genetic variants were annotated and classified according to the recommendations of ACMG/AMP. The association of genetic polymorphisms with lipid profile parameters in patients with AS was studied. Results. Sequencing of the entire exome of patients with varying degrees of cardiovascular risk revealed genetic variations affecting triglyceride metabolism. Elevated triglyceride levels were reported in patients of all risk categories, with the highest frequency in very high-risk individuals (82 patients). Analysis of the lipid profile showed that total cholesterol was significantly higher in the high-risk group compared with the low-risk group (228.8±35.2 versus 207.8±30.3 mg/dl; p=0.0467). The level of HDL-C showed an inverse relationship with the level of risk, being the lowest in the very high-risk group (44.6±10.5 versus 50.1±9.9 mg/dl; p=0.0411). Although LDL and non-lipoprotein cholesterol did not show statistically significant differences, there was a tendency to increase them. Triglycerides also tended to increase, but without achieving statistical significance (p>0.05). There was a significant decrease in apolipoprotein A at high risk (p0.05). Conclusions. The study did not reveal a statistically significant association between APOE (p.T388C) and GCKR genotypes with cardiovascular risk. Larger-scale studies are required, taking into account additional factors and an increased sample size. Введение. Сердечно-сосудистые заболевания, в том числе атеросклероз (АС), являются основной причиной заболеваемости и смертности во всем мире, включая Казахстан. Важную роль в развитии АС играют нарушения липидного обмена, в частности, гипертриглицеридемия, которая признана самостоятельным фактором риска. Генетические особенности, связанные с генами, регулирующими метаболизм липидов и углеводов (GCKR, SLC22A5, LPL, FLCN, LDLR, APOE), оказывают значительное влияние на формирование дислипидемий и определяют индивидуальные метаболические характеристики. Изучение распространенности и влияния этих генетических вариантов в казахстанской популяции особенно важно, учитывая ее ограниченное представительство в глобальных генетических исследованиях. Целью данного исследования было изучить частоты встречаемости генетических полиморфизмов в генах, участвующих в регуляции липидного обмена (GCKR, SLC22A5, LPL, FLCN, LDLR, APOE), в группе казахстанских пациентов с гипертриглицеридемией и атеросклерозом. Дополнительно мы анализировали взаимосвязь выявленных генетических вариантов с биохимическими параметрами липидного профиля. Материал и методы. В рамках исследования были проанализированы данные 402 пациентов с сердечно-сосудистыми заболеваниями, из которых 144 имели гипертриглицеридемию. Для выявления генетических детерминант нарушений липидного обмена было выполнено полноэкзомное секвенирование с анализом генов GCKR, SLC22A5, LPL и FLCN. Выявленные генетические варианты были аннотированы и классифицированы в соответствии с рекомендациями ACMG/AMP. Проведена оценка ассоциации генетических полиморфизмов с нарушениями липидного профиля в казахстанской популяции пациентов с сердечно-сосудистыми заболеваниями....

Purpose of the study: To assess the contribution of clonal hematopoiesis of indeterminate potential (CHIP) to the development of atherosclerotic disease in the Kazakhstani cohort, focusing on TET2 and DNMT3A genes, based on next-generation sequencing (NGS) data. Materials and Methods: This study employed an observational cross-sectional design. The cohort comprised 177 women and 225 men, with a mean age of 53.0 ± 9.04 years overall (men: 52.2 ± 9.0 years; women: 53.7 ± 9.0 years). Patients were stratified by degree of cardiovascular risk category (low, high, very high) according to the ESC/EAS (2019) recommendations. In this sample, 74 participants (18.4%) were classified as low-risk, 136 (33.8%) as high-risk, and 192 (47.8%) as very high-risk. For the initial phase of analysis, the two most studied genes, TET2 and DNMT3A, were selected from a total list of 8 priority genes: ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SFRS2, TET2, and TP53associated with CHIP, based on their high clinical significance and frequency of occurrence in previously published studies. By filtering the data and selecting two priority genes for primary analysis, 41 patients with atherosclerotic disease were selected from the total cohort. Genetic analyses were performed using high-throughput whole-exome sequencing to cover a wide range of genetic variants potentially associated with CHIP and the atherosclerotic process. Variant annotation was performed using international databases (ClinVar, ExAC, 1000 Genomes, etc.), and mutations were interpreted according to the ACMG/AMP classification using the InterVar platform. Statistical data processing included the nonparametric Kruskal-Wallis test, Dunn's test for pairwise comparisons, and Fisher's exact test; a value of p < 0.05 was considered statistically significant. Results: Variants were detected in TET2 (n=35) and DNMT3A (n=6). The median VAF value for TET2 was 50%. The age of patients differed significantly between risk groups (p = 0.026). Most of the variants detected had an ultra-rare frequency according to international databases (<0.1%). One pathogenic variant was identified according to the InterVar classification; the others were predominantly of uncertain significance (VUS). The distribution of variants by risk groups showed no statistically significant differences (p = 0.341). Conclusions: The results demonstrate a potential role of CHIP-associated mutations in the pathogenesis of atherosclerosis. Mutations in TET2 were found to be the most significant. Given the identified genetic features and their association with cardiovascular risk, the findings justify extending the analysis to the full spectrum of CHIP-associated genes to improve the accuracy of risk stratification. Цель исследования: Оценить вклад клонального гемопоэза неопределенного потенциала (КГНП) в развитие атеросклеротического заболевания в казахстанской когорте с упором на гены TET2 и DNMT3A на основе данных секвенирования нового поколения (NGS). Материалы и методы: Проведено обсервационное поперечное исследование. Когорта состояла из 177 женщин и 225 мужчин, средний возраст которых в целом составил 53,0 ± 9,04 года (мужчины: 52,2 ± 9,0 года; женщины: 53,7 ± 9,0 года). Пациенты были распределены по категориям сердечно-сосудистого риска (низкий, высокий, очень высокий) в соответствии с рекомендациями ESC/EAS(2019). В этой выборке 74 участника (18,4%) были отнесены к группе низкого риска, 136 (33,8%) – к группе высокого риска и 192 (47,8%) – к группе очень высокого риска. Для начальной фазы анализа два наиболее изученных гена, TET2 и DNMT3A, были выбраны из общего списка из 8 приоритетных генов: ASXL1, DNMT3A, JAK2, PPM1D, SF3B1, SFRS2, TET2 и TP53, ассоциированных с КГНП, на основании их высокой клинической значимости и частоты встречаемости в ранее изученных исследованиях. опубликованные исследования. Путем фильтрации данных и выбора двух приоритетных генов для первичного анализа из общей когорты был отобран 41 пациент с атеросклеротическим заболеванием. Генетический анализ был проведен с использованием высокопроизводительного секвенирования всего экзома (NGS, whole-exome sequencing), чтобы охватить широкий спектр генетических вариантов, потенциально связанных с КГНП и атеросклеротическим процессом. Аннотирование вариантов проводилось с использованием международных баз данных (ClinVar, ExAC, 1000 геномов и др.), а мутации интерпретировались в соответствии с классификацией ACMG/AMP с использованием платформы InterVar. Статистическая обработка данных включала непараметрический критерий Крускала-Уоллиса, критерий Данна для парных...

Background. Atherosclerosis-associated cardiovascular diseases exhibit significant ethnic and regional variability in risk factors. Kazakhstan’s high cardiovascular disease mortality rates necessitate population-specific profiling, particularly given urban-rural disparities and lifestyle differences unique to Central Asia. Methods. This cross-sectional study (2023–2024) analyzed 368 Kazakhstani adults stratified by European Atherosclerosis Society risk tiers: low (n=67), high (n=127), and very high risk (very high-risk group, n=174). Assessments included lipid profiles (low density lipoprotein, high density lipoprotein, and apolipoprotein B to apolipoprotein A ratio), lifestyle factors (smoking, diet, physical activity), and residence (urban/rural). Statistical analyses employed multiclass logistic regression (MNLogit) with FDR-adjusted p-values. Results. Age (OR=8.01, 95% CI:4.40–14.58, p<0.001), male sex (OR=3.27, CI:1.82– 5.88), and smoking (OR=7.19, CI:1.52–34.15) were strongly associated with very highrisk group. Rural residents faced 2.6-fold higher very high-risk group odds (CI:1.52– 5.68, p=0.002) versus urban counterparts. Protective effects emerged for physical activity (OR=0.03, CI:0.004–0.32) and female sex (High-Density Lipoprotein: +8.1 mg/dL vs. males, p<0.001). No alcohol association was observed (p=0.836). Conclusion. A thorough study of the gender aspect of the development of atherosclerotic pathology is required. Physical activity has a strong protective effect. It is interesting that, according to the comparative analysis of binary variables, rural residents have a higher risk of developing atherosclerosis.

The use of CFTR modulators in patients with cystic fibrosis (CF) during pregnancy and the impact of this therapy on the health of the mother and fetus are actively discussed in the international CF medical literature. Clinical data are accumulating to build consensus recommendations on this issue.The aim of the article is to present the first case of pregnancy and childbirth during CF treatment with a CFTR modulator in the Republic of Kazakhstan. This is also the first published experience of using the generic triple combination targeted medication elexacaftor/tezacaftor/ivacaftor+ ivacaftor (Trilexa®, Tuteur S.A.C.I.F.I.A., Argentina) in a patient with CF during pregnancy. The clinical course of the disease before and after the initiation of pathogenetic therapy are highlighted. Significant clinical improvement was observed, including a reduction in the frequency of infectious exacerbations, improved lung function, and weight gain. Pregnancy occurred during targeted therapy and was successfully carried to term.Conclusion. The presented case illustrates the high clinical efficacy and safety of the three-component targeted CF therapy in general and the used generic medication in particular. Considering the obtained data, it is advisable to expand the number of patients with CF receiving targeted therapy in Kazakhstan, both children and adults.

Objective. To assess the impact of the place of birth and transportation of newborns with transposition of the great arteries (TGA) on perioperative status; to investigate the impact of restrictive patent foramen ovale (PFO) on transportability of these patients. Material and methods. A retrospective case-control study included 149 consecutive newborns with TGA between 2012 and 2020. Two patients died at the preoperative stage; 147 ones underwent arterial switch surgery. Comparative analysis was carried out in 2 groups: “Astana+” group (born in Astana, n=74), “Astana–“ group (transported from outside, n=75). Along with demographic and perioperative data, we evaluated immediate outcomes (transportation-related mortality, in-hospital mortality). Results. Along with prenatally diagnosed patients (94.6% vs. 25.3%, p<0.001), patients with restrictive PFO at admission (43.2% vs. 21.3%, p=0.01) and arterial switch surgeries within the first week of life prevailed (46.6% vs. 16.2%, p<0.001) in the “Astana+” group. Transportation-related mortality was 0% and 1.3%, in-hospital mortality — 6.8% and 13.3%, respectively (p=0.2). Conclusion. Birth of children with TGA near cardiac surgery center contributes to arterial switch surgery in the first week of life. Transportation of newborns with TGA in a country with a vast territory and low population density does not affect preoperative survival and in-hospital mortality. If long-distance transportation is necessary, restrictive PFO is a factor limiting transportability of newborns with TGA.

Atherosclerosis remains a leading cause of cardiovascular morbidity and mortality worldwide, traditionally linked to elevated cholesterol levels, particularly low-density lipoprotein cholesterol (LDL-C). However, despite aggressive lipid-lowering strategies, residual cardiovascular risk persists, underscoring the need to explore additional contributing factors. This review examines emerging risk factors beyond cholesterol, including chronic inflammation, gut microbiota composition, oxidative stress, and environmental exposures. Inflammation plays a pivotal role in atherogenesis, with markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) serving as indicators of disease activity. The gut microbiome, particularly metabolites like trimethylamine N-oxide (TMAO), has been implicated in vascular inflammation and plaque development, while beneficial short-chain fatty acids (SCFAs) demonstrate protective effects. Oxidative stress further exacerbates endothelial dysfunction and plaque instability, driven by reactive oxygen species (ROS) and lipid peroxidation. Additionally, environmental factors, including air pollution, heavy metal exposure, endocrine disruptors, and chronic psychological stress, have emerged as significant contributors to cardiovascular disease. Understanding these novel risk factors offers a broader perspective on atherosclerosis pathogenesis and provides new avenues for targeted prevention and therapeutic interventions.

The problem of acute kidney injury (AKI) in children undergoing cardiac surgery remains relevant even in the presence of modern medical technologies and methods. This complication, which occurs after pediatric cardiac surgery, has significant negative consequences, leading to the patient staying in the infant intensive care unit (IICU) for a longer period and even an increased risk of death. According to the literature, cardiac surgery-associated acute kidney injury (CSAKI) is a common complication after surgery to correct congenital heart defects in children, with a reported incidence rate of up to 42%. This fact is increasingly recognized as a serious problem affecting the health of pediatric patients. The aim of the study is to analyze modern concepts concerning the impact of cardiac surgery on the development of acute kidney injury in children, and to, identify the main trends and current scientific ideas about the mechanisms which form this complication in pediatric cardiac surgery. The review was compiled using literature search methods in databases such as Scopus, PubMed, MedLine, Cyberleninka, Google Scholar, Cochrane Library, and TripDataBase, covering the period from 2014 to 2024. Scientific studies aimed at identifying risk factors for the development of acute kidney injury in children after cardiac surgery have identified a number of important aspects, including the age of the patients, the duration of cardiopulmonary bypass, the level of surgical complexity of the operation, the need for mechanical ventilation, and inotropic support. Despite significant achievements in this area, some aspects remain under-researched. As the use of substitutive renal therapy as part of the comprehensive treatment of acute renal failure is increasing, understanding these problems becomes more urgent.

Objective. To assess the impact of prenatal diagnosis on immediate treatment outcomes in newborns with transposition of the great arteries (TGA) in a head cardiac surgery center of a country with a large territory and low population density. Material and methods. A retrospective analysis included 149 newborns with TGA treated at the National Research Cardiac Surgery Center between 2012 and 2020. Two patients died at the preoperative stage, 147 ones underwent arterial switch surgery. Comparative analysis was carried out in two groups: PreN group (diagnosed prenatally, n=89), PostN group (diagnosed postnatally, n=60). Bemographic, pre-, intra- and postoperative data, as well as immediate outcomes were evaluated: in-hospital mortality (for the entire cohort), 30-day postoperative mortality, morbidity, cumulative morbidity and hospital-stay (for postoperative patients). Results. About 59.7% of newborns with TGA were diagnosed prenatally. Newborns born in Astana (78.7% vs. 6.7%, p<0.001) and arterial switch procedures performed within the first week after birth (41.4% vs. 16.7%, p=0.01) prevailed in the PreN group. In both groups, the following outcomes were obtained: 30-day postoperative mortality 5.6% and 5% (p=0.7), in-hospital mortality 10.1% and 10% (p=0.7), incidence of complications 26.4% and 30% (p=0.7), cumulative morbidity 34.5% and 56.7% (p=0.01), respectively. Length of hospital-stay was similar. Conclusion. Prenatal diagnosis of TGA in a country with large territory and low population density does not affect 30-day mortality after arterial switch surgery and in-hospital mortality in newborns with TGA. However, prenatal diagnosis can favor delivery of children near a cardiac surgery center, contributes to arterial switch surgery in the first week of life and also reduces cumulative morbidity.

Introduction. Established in 2021, the Lipid Clinic Network of Kazakhstan is dedicated to creating a global framework for consistent standards in diagnosing, managing, and treating lipid disorders, guided by the European Society of Cardiology and European Atherosclerosis Society (further - ESC/EAS) Guidelines on dyslipidaemia management. The aim is to evaluate pillars for LCN in Kazakhstan and assess the feasibility of dyslipidemia clinics and implementation atherosclerosis project in Kazakhstan. Materials and methods. This is a cross-sectional survey with 8 questions to explore the organization of a lipid clinic network in Kazakhstan. 28 clinics took part and respondents were anonymous. The questionnaire was based on EAS LCN evaluation. Results. 54 % of dyslipidemia clinics are located in outpatient department and 11% of clinics are located as a sub-department within a cardiology department or similar in the hospital. 71% of clinics (20) show connections to hospital departments including diabetes, endocrinology and rare disease units. The staff composition of LCN Kazakhstan is: physicians - 26, nurses - 20, geneticist expert in dyslipidemias’ - 1, dietitian – 4, nutritionist - 0. A majority of clinics (53.60%) are situated in outpatient departments, highlighting a prevalent reliance on outpatient care for lipid-related services. The physician and nurse staffing levels align with LCN-EAS standards, the lack of nutritionists, geneticists, and dietitians represents a significant gap in the multidisciplinary care model advocated by the EAS. Capacity to provide therapeutic education on lifestyle changes, cardiovascular disease (CVD) prevention, and adherence to treatment is present in 16 clinics. Conclusion. Some criteria of LCN Kazakhstan are aligned with EAS LCN requirements in terms of data management, location, facility and the, management of the interaction with the patients. However, composition of staff, clinical trial management and connection within the health service infrastructure and patient referral need to be enhanced. Введение: Липидная Клиническая Сеть (далее – ЛКС) Казахстана, созданная в 2021 году, посвящена созданию глобальной структуры для стандартизированного подхода к диагностике, управлению и лечению липидных нарушений, руководствуясь рекомендациями Европейского общества кардиологии и Европейского общества атеросклероза (далее – ЕОК/ЕОА) по управлению дислипидемией. Цель. Оценка основных направлений Липидной клинической сети Казахстана и оценка осуществимости работы клиник по лечению дислипидемий и реализации проекта по атеросклерозу в Казахстане. Материалы и методы: Исследование было выполнено методом поперечного опроса, состоящего из 8 вопросов, направленных на изучение организации сети липидных клиник в Казахстане. В исследовании приняли участие 28 клиник, респонденты опроса были анонимными. Анкета была разработана на основе оценки ЛКС Европейского общества атеросклероза. Результаты: 54% клиник дислипидемии расположены в амбулаторных отделениях, и 11% клиник функционируют в качестве подотделов в кардиологических отделениях или аналогичных подразделениях больниц. 71% клиник (20) демонстрируют связь с больничными отделениями, такими как диабетология, эндокринология и отделения редких заболеваний. Согласно результатам опроса, персонал ЛКС Казахстана распределен следующим образом: врачи – 26, медсестры – 20, специалист по генетике дислипидемий – 1, диетолог – 4, нутриционистов нет. Значительное большинство клиник (53,60%) расположено в амбулаторных отделениях, что подчеркивает зависимость от амбулаторной помощи в предоставлении липидных услуг. Количество врачей и медсестер соответствует стандартам ЛКС-ЕОА, однако нехватка нутриционистов, генетиков и диетологов представляет значительный пробел в многопрофильной модели ухода, рекомендованной ЕОА. Возможность предоставить терапевтическое обучение по изменению образа жизни, профилактике сердечно-сосудистых заболеваний (ССЗ) и соблюдению режима лечения присутствует в 57% клиник. Заключение: Некоторые критерии ЛКС Казахстана соответствуют требованиям ЕОА в части управления данными, местоположения, инфраструктуры и взаимодействия с пациентами. Однако...

Background. Bilirubin is a byproduct of the breakdown of erythrocytes. Bilirubin levels can potentially serve as a biomarker for cardiovascular risk assessment. In this study, we would be investigating most recent manuscripts, published in the last 5 years, that studied association of serum bilirubin level to atherosclerosis progression to elicit how strongly low level of total bilirubin can prognose the disease progression. Methods. Using Pubmed search engine, all articles that included keywords “bilirubin” and “atherosclerosis” were retrieved. In total 67 search results emerged for the 2019-2023 timeline, the last 5 years.6 population-based studies that studied association between total bilirubin concentration and atherosclerosis development were used for the meta-analysis. Results. Increasing blood total bilirubin level seems to decrease the odds of developing atherosclerosis, meaning that there is an inverse correlation between total bilirubin level and arterial plaque formation or stenosis. Pooled odds ratio was found to be 0.86 (95% CI 0.83-0.9), suggesting that there is 14% decreased chance of developing atherosclerosis for each mmol/L increase in bilirubin levels. Overall, higher total serum bilirubin levels were associated with a significantly decreased risk of progression to atherosclerosis. Conclusion. The meta-analysis indicates a significant inverse association between low total bilirubin levels and the risk of developing atherosclerosis, suggesting that higher bilirubin levels may be protective against the progression of this disease.