Anna Vitalievna Kiseleva

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.

Circulating microRNAs (miRNAs) are promising biomarkers of cardiovascular disease (CVD) and three-point major adverse cardiovascular events (3P-MACE): CVD death, non-fatal myocardial infarction (MI), and non-fatal stroke. The associations between plasma miRNA levels and 3P-MACE in a prospective cohort from an epidemiological study were evaluated. This nested case–control study included 479 participants: 166 cases with 3P-MACE and 313 controls matched individually for sex, exact baseline age, and region of residence. Median follow-up was 10.4 years [7.0; 11.7]. Total RNA was isolated from EDTA plasma using the miRNeasy Serum/Plasma Advanced Kit. Libraries were prepared with the QIAseq miRNA UDI Library Kit and sequenced on a NextSeq 550 (1 × 75 bp). After adjustment for six and twelve preanalytical and clinical covariates, eleven and five differentially expressed (DE) miRNAs retained significant associations with 3P-MACE or CVD death, respectively. Although these findings support plasma miRNA profiles as potential MACE biomarkers, all DE miRNAs remain exploratory. Further studies in larger independent populations with cross-validation are required before integration with traditional risk markers to predict future MACE.

Chronic total occlusion (CTO) occurs in 16–52% of patients with coronary artery disease (CAD) and is often accompanied by variable development of coronary collateral circulation (CCC). The aim of this work was to study the associations between circulating plasma microRNAs (miRNAs) and the development of CCC in patients with CTO. This exploratory study included 43 patients: a control group—patients without significant coronary artery stenosis (n = 20), and two CTO groups with good (n = 13) and poor (n = 10) CCC based on the Rentrop classification. The study was performed simultaneously on two types of plasma samples (K2EDTA and sodium citrate). Total RNA was isolated using the miRNeasy Serum/Plasma Advanced Kit. Libraries were prepared using the QIAseq miRNA UDI Library Kit and then sequenced on the NextSeq 550 using a 1 × 75 bp protocol. A total of 18 miRNAs were found to be differentially expressed (DE) in EDTA plasma and 13 in citrate plasma; only one miRNA in citrate plasma (hsa-miR-92a-3p) was differentially expressed between the good and poor CCC groups. However, given the limited sample size, the findings should be considered hypothesis-generating, and further studies are required for validation in larger, independent cohorts and to establish the roles of these miRNAs in CCC development.

Aim . To evaluate the penetrance of the ε2/ε2 genotype and pathogenic APOE variants associated with familial dysbetalipoproteinemia (FD). Material and methods . The study included 51 patients with a genetic cause of FD — carriers of the ε2/ε2 genotype or pathogenic APOE variants, whose genotyped blood samples were stored in the Biobank laboratory of the National Medical Research Center for Therapy and Preventive Medicine. A triglyceride level ≥1,5 mmol/L was considered as the phenotypic manifestation of the genetic cause associated with FD. The penetrance of the ε2/ε2 genotype and the most frequent APOE variants (p.Arg154Cys and p.Gly145Asp) was estimated using the Bayesian method. Differences in the age of phenotypic manifestation onset by sex and genetic cause of FD were assessed using the Mann-Whitney U test. Results . The ε2/ε2 genotype was identified in 35 (68,6%) patients, and pathogenic APOE variants in 16. Triglyceride levels were higher in carriers of APOE variants than in carriers of the ε2/ε2 genotype (median 7,38 vs 4,03 mmol/L; p=0,046). The penetrance of ε2/ε2, p.Arg154Cys, and p.Gly145Asp was 16,3%,21,9%, and 50,0%, respectively. Phenotypic manifestation was detected earlier in men than in women (median age 48 and 55 years, respectively; p=0,017). There was no significant difference in the age of phenotypic manifestation onset between carriers of the ε2/ ε2 genotype and those with pathogenic APOE variants (p=0,932). Conclusion . For the first time in a Russian patient cohort, we showed that genetic causes of FD are characterized by incomplete penetrance. The penetrance of APOE variants associated with autosomal dominant FD was estimated to be higher than that of the ε2/ε2 genotype. The age of phenotypic manifestation onset was lower in men but did not differ between carriers of the ε2/ε2 genotype and pathogenic APOE variants.

Marfan syndrome is an autosomal dominant hereditary disorder of connective tissue characterized by pronounced phenotypic variability. The presented case describes a family with clinical manifestations ranging from isolated ectopia lentis to severe aortic disease without a characteristic phenotype. Furthermore, the age of onset and rate of progression of cardiovascular disease in the relatives also varied significantly. Genetic testing identified a missense variant in exon 10 of the FBN1 gene, resulting in a substitution of a cysteine residue in the TB1 domain of fibrillin-1, which was considered likely pathogenic. Verification of the diagnosis of Marfan syndrome allowed for timely referral of the proband to a cardiovascular surgeon to determine further treatment and adjust therapy. This case also demonstrates that a causative variant does not allow for a definitive prognosis of the disease course. Therefore, all carriers of the identified variant require regular multidisciplinary monitoring, regardless of the severity of clinical manifestations at the time of diagnosis.

Aim . To analyze the profile of cardiac arrhythmias and conduction disorders in patients with familial hypertrophic cardiomyopathy (HCM) based on data from the registry of the National Medical Research Center for Therapy and Preventive Medicine and the Lomonosov Moscow State University (2021-2026). Material and methods . The analysis included 136 patients (48 men, 88 women; aged 19-78 years) — probands and relatives with a verified diagnosis or pathogenic variants in genes associated with HCM. All patients underwent additional examination, including electrocardiography (ECG) and Holter ECG monitoring. Based on this examination, 81 patients with arrhythmias and conduction disorders were identified. Genetic testing identified variants in the MYH7 , MYBPC3 , MYL2 , DSG2 , JPH2 , FLNC , ALPK3 , CACNA1C , ACTC1 , LDB3 , and TNNI3 genes in 60 patients. Results . Atrial fibrillation was recorded in 13,9% of cases (permanent in 3,7%, paroxysmal in 9,6%), ventricular premature beats in 59,6%, and ventricular fibrillation in 2,2%. Ventricular tachycardia (VT) was detected in 24,3% of all registry patients and in 34% of patients with gene variants (n=60). Degree I atrioventricular (AV) block was detected in 11% of cases, and degree II-III AV block — in 4,4%, left bundle branch block — in 5,9%. In genetic analysis, VT (80 vs 20%, p=0,001) and first degree AV block (45 vs 8%, padj=0,027) were more common in carriers of variants in the MYBPC3 gene (n=20) compared with MYH7 (n=25). The groups did not differ in interventricular septal thickness and left ventricular mass index after adjustment for sex, age and body mass index (BMI), whereas LV posterior wall thickness was higher in the MYBPC3 group (padj=0,028). The median risk of sudden cardiac death, calculated according to the Hypertrophic Cardiomyopathy. Risk-Sudden Cardiac Death (HCM Risk-SCD) score was 4,9% [3,4; 7,2] over 5 years n carriers in the MYBPC3 gene variants, compared to 3,1% [2,2; 6,8] (p=0,916) in carriers of MYH7 variants. However, no significant differences were found between the groups. Conclusion . The incidence of VT in familial HCM varies significantly depending on the genotype, reaching 80% in carriers of MYBPC3 variants. Patients with familial HCM, especially those carrying MYBPC3 variants, are recommended to undergo follow-up monitoring with Holter ECG every 6-12 months for the early detection of VT. Detection of VT allows for stratification of sudden cardiac death risk according to the HCM Risk-SCD score and determines indications for implantable cardioverter-defibrillator (ICD).

Severe hypertriglyceridemia (HTG) is genetically heterogeneous, but its genetic architecture remains incompletely characterized. We investigated the genetic determinants of severe HTG in 123 patients with triglyceride (TG) levels > 5.0 mmol/L and available NGS data. We analyzed rare variants in LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE; the ε2/ε2 APOE genotype; and TG-polygenic risk score (PRS) based on 40 variants. Major genetic determinants were identified in 65.0% of individuals, including rare variants in chylomicronemia genes (24.4%; 28 variants, including 10 novel, 53.6% in LPL), rare APOE variants or the ε2/ε2 genotype (18.7%, overlapping with chylomicronemia variants in 4.1%), and an extreme polygenic burden (35.8%; PRS > 90th percentile), including 26.0% with isolated polygenic HTG. The remaining 35.0% had moderate-to-low PRS. The cohort was categorized into familial chylomicronemia syndrome (FCS, n = 7), multifactorial chylomicronemia syndrome (MCS, n = 21), polygenic HTG (n = 32), familial dysbetalipoproteinemia (FD, n = 20), and moderate-to-low PRS (n = 43) groups based on genetic determinants. FCS had the lowest PRS percentile (median 26) and the most distinct clinical profile, with the highest TG levels (median 30.60 mmol/L) and 6–24-fold higher odds of pancreatitis compared with other groups (p < 0.05), alongside a lower body mass index (median 23.0 kg/m²) than all groups except MCS, whereas FD had the lowest TG levels (10.20 mmol/L, p < 0.05). These results further advance the understanding of the complex genetic architecture of severe HTG and demonstrate that broader genetic analysis, including APOE and TG-PRS, may increase the yield of genetic determinants in severe HTG.

Aim. To compare echocardiographic parameters in patients with familial hypertrophic cardiomyopathy and confirmed variants in the MYH7 and MYBPC3 genes. Material and methods. This study included a comprehensive assessment of echocardiographic parameters in 48 patients with hypertrophic cardiomyopathy, including 14 men and 34 women, aged 18-77 years. Subjects were divided into two groups based on confirmed variants in the MYH7 and MYBPC3 genes. Results. Patients with a MYBPC3 gene variant had significantly larger right atrial size and left ventricular (LV) posterior wall thickness (p=0,42, p=0,002), while LV systolic function, assessed using the additional speckle tracking echocardiography, was significantly lower compared to patients with a variant in the MYH7 gene (p=0,021). Conclusion. Patients with a variant in the MYBPC3 gene showed significant changes in structural and functional echocardiography parameters, indicating a less favorable prognosis for this group of patients.

Introduction. Loss-of-function (LOF) variants of the LRP5 gene are associated with primary osteoporosis. Heterozygous carriers typically have a milder phenotype, manifested primarily by decreased bone mass in childhood. Homozygotes and compound heterozygotes for the LRP5 gene may also exhibit the phenotype of familial exudative vitreoretinopathy, which disrupts the growth and development of retinal blood vessels, and osteoporosis-pseudoglioma syndrome. Furthermore, LRP5 is essential for normal cholesterol and glucose metabolism. The impact of LRP5 gene variants on the development of atherosclerosis and its complications is controversial. On the one hand, impaired function contributes to elevated blood cholesterol levels, lipid and macrophage retention in the vascular wall, increased systemic inflammation, and osteoporosis, which itself is a risk factor for atherosclerosis. On the other hand, this pathology is characterized by the absence of plaque and aortic leaflet calcification. Brief description. This article presents a case of a patient with osteoporosis complicated by a right tibia fracture. Genetic testing revealed a previously undescribed, likely pathogenic LOF variant in the LRP5 gene (p.Leu17ArgfsTer128). At the time of examination (at age 64), the patient had no subclinical manifestations of carotid atherosclerosis, except for increased intima-media thickness, and total coronary calcium score was 0. Six years after visit, it was learned that at age 65, she had an acute myocardial infarction and underwent transluminal balloon angioplasty with stenting of the anterior descending artery. Conclusion. This case presents with a combination of osteoporosis complicated by a right tibia fracture and severe hypercholesterolemia, with progressive coronary atherosclerosis without plaque calcification, ultimately resulting in myocardial infarction. This patient carried a previously undescribed, likely pathogenic, LOF variant in the LRP5 gene.

Aim. To evaluate the effectiveness of lipid-lowering therapy (LLT) in patients with genetically confirmed familial hypercholesterolemia (FH). Material and methods. The study included 140 patients with genetically confirmed FH, followed at the Lipid Center of the National Medical Research Center for Therapy and Preventive Medicine. Participants ranged in age from 19 to 80 years. Lipid profile parameters, clinical and genetic data were analyzed. Results. In 89% of the patients studied, a variant in the LDLR gene was identified as the cause of FH, while in 11%, a variant in the APOB gene was identified. No variants in the PCSK9 gene were detected. High penetrance of the identified FH variants was demonstrated. In patients with a LDLR gene, low-density lipoprotein cholesterol (LDL-C) levels without LLT (median [interquartile range] 8,49 [7,43; 9,31] mmol/L) were higher than in patients with a variant in the APOB gene (7,55 [6,22; 8,33] mmol/L) (pConclusion. The study results demonstrate that patient genetic characteristics influence baseline LDL-C levels but do not affect the efficacy of LLT. To achieve the target LDL-C level of 36,4%, patients in the very high CVD group should add bempedoic acid or lipid apheresis to the triple therapy (statin/ezetimibe/PCSK9 inhibitors).