Familial hypercholesterolemia (FH) is a common autosomal codominant disorder, characterized by elevated low-density lipoprotein cholesterol levels causing premature atherosclerotic cardiovascular disease. About 2900 variants of LDLR, APOB, and PCSK9 genes potentially associated with FH have been described earlier. Nevertheless, the genetics of FH in a Russian population is poorly understood. The aim of this study is to present data on the spectrum of LDLR, APOB, and PCSK9 gene variants in a cohort of 595 index Russian patients with FH, as well as an additional systematic analysis of the literature for the period of 1995–2020 on LDLR, APOB and PCSK9 gene variants described in Russian patients with FH. We used targeted and whole genome sequencing to search for variants. Accordingly, when combining our novel data and the data of a systematic literature review, we described 224 variants: 187 variants in LDLR, 14 variants in APOB, and 23 variants in PCSK9. A significant proportion of variants, 81 of 224 (36.1%), were not described earlier in FH patients in other populations and may be specific for Russia. Thus, this study significantly supplements knowledge about the spectrum of variants causing FH in Russia and may contribute to a wider implementation of genetic diagnostics in FH patients in Russia.

Mitochondrial dysfunction and oxidative stress are likely involved in atherogenesis. Since the mitochondrial genome variation can alter functional activity of cells, it is necessary to assess the presence in atherosclerotic lesions of mitochondrial DNA (mtDNA) heteroplasmic mutations known to be associated with different pathological processes and ageing. In this study, mtDNA heteroplasmy and copy number (mtCN) were evaluated in the autopsy-derived samples of aortic intima differing by the type of atherosclerotic lesions. To detect mtDNA heteroplasmic variants, next generation sequencing was used, and mtCN measurement was performed by qPCR. It was shown that mtDNA heteroplasmic mutations are characteristic for particular areas of intimal tissue; in 83 intimal samples 55 heteroplasmic variants were found; mean minor allele frequencies level accounted for 0.09, with 12% mean heteroplasmy level. The mtCN variance measured in adjacent areas of intima was high, but atherosclerotic lesions and unaffected intima did not differ significantly in mtCN values. Basing on the ratio of minor and major nucleotide mtDNA variants, we can conclude that there exists the increase in the number of heteroplasmic mtDNA variants, which corresponds to the extent of atherosclerotic morphologic phenotype.

Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress.

In the present work, a pilot creation of four cybrid cultures with high heteroplasmy level was performed using mitochondrial genome mutations m.12315G>A and m.1555G>A. According to data of our preliminary studies, the threshold heteroplasmy level of mutation m.12315G>A is associated with atherosclerosis. At the same time, for a mutation m.1555G>A, such a heteroplasmy level is associated with the absence of atherosclerosis. Cybrid cultures were created by fusion of rho0-cells and mitochondria from platelets with a high heteroplasmy level of the investigated mutations. To create rho0-cells, THP-1 culture of monocytic origin was taken. According to the results of the study, two cybrid cell lines containing mutation m.12315G>A with the heteroplasmy level above the threshold value (25% and 44%, respectively) were obtained. In addition, two cybrid cell lines containing mutation m.1555G>A with a high heteroplasmy level (24%) were obtained. Cybrid cultures with mtDNA mutation m.12315G>A can be used to model both the occurrence and development of atherosclerosis in cells and the titration of drug therapy for patients with atherosclerosis. With the help of cybrid cultures containing single nucleotide replacement of mitochondrial genome m.1555G>A, it is possible to develop approaches to the gene therapy of atherosclerosis.

Background. The study of morphological features of vascular endothelium is necessary for a comprehensive assessment of age-related changes in blood vessels. The purpose of this study is to find out how the shape and size of vascular endothelium in the arteries of the pulmonary circulation and the ascending aorta changes in elderly people. Material and methods. En face preparations of the pulmonary trunk, pulmonary arteries, lobar and segmental arteries and the ascending aorta taken during autopsy from 33 deceased patients were studied. In the immunohistochemical study, monoclonal antibodies to monocytes and macrophages (CD68, DAKO, Denmark), T lymphocytes (CD3, CD4, CD-8, Beckman Coulter, France) and antibodies to PECAM-1 adhesion molecules (CD31 antigen) were used. Statistical analysis of qualitative features was performed using Fisher's exact test in Statistica 6.0. Results were considered statistically significant at p<0.05. Results. Polygonal cells of different sizes were found in the pulmonary trunk, while in the lobar and segmental arteries the cells had an elongated shape and formed layers extended along the blood flow. Endothelial cells of the ascending aorta were of different sizes and had a polygonal shape similar to the cells of the pulmonary trunk.

Pseudohypertriglyceridemia (pseudo-HTG) is a rare laboratory phenomenon in which serum triglyceride levels are falsely elevated due to analytical interference from endogenous glycerol, most often caused by glycerol kinase deficiency (GKD), an X-linked disorder caused by pathogenic variants in the GK gene. We report a 50-year-old man referred for persistent hypertriglyceridemia (4.98–7.42 mmol/L) over two years despite dietary modification and statin–fibrate therapy. He had no history of pancreatitis, alcohol intake, diabetes, renal or thyroid dysfunction. Physical examination showed no xanthomas or corneal arcus; body mass index was 26.9 kg/m². Serum samples were repeatedly visually clear, and lipoprotein electrophoresis revealed an unexpectedly normal lipid distribution. Given the discordance between triglyceride concentrations and the clinical and electrophoretic findings, pseudo-HTG due to GKD was suspected. Glycerol-specific biochemical testing was locally unavailable. Thus, we performed whole genome sequencing (WGS), which identified a likely pathogenic GK nonsense variant, c.1324C>T (p.Gln442Ter), consistent with isolated GKD. Peripheral atherosclerosis and hepatic steatosis were also noted, indicating coexisting cardiometabolic disease. This case highlights isolated GKD as an underrecognized cause of prominent treatment-refractory HTG. In patients with discordant triglyceride results, clear fasting serum, and normal lipoprotein electrophoresis, pseudo-HTG should be considered; genetic evaluation may be informative when glycerol-specific assays are unavailable.