Регистр пациентов с семейной гиперхолестеринемией и пациентов очень высокого сердечно-сосудистого риска с недостаточной эффективностью проводимой гиполипидемической терапии (РЕНЕССАНС)

Background and aims: lipoprotein(a) (Lp(a)) is a genetically determined risk factor for coronary artery disease and its complications, although data on the association with other vascular beds and the severity of atherosclerosis is limited. The aim of this study was to evaluate the association of atherosclerosis of various vascular beds with Lp(a), as well as its autoantibodies and generalized inflammatory markers. Material and methods: this study included 1288 adult patients with clinical and imaging examination of three vascular beds (coronary, carotid, and lower limb arteries). Patients were categorized according to the number of affected vascular beds (with at least one atherosclerotic stenosis ≥50%): 0 (n = 339), 1 (n = 470), 2 (n = 315), 3 (n = 164). We assessed blood cell count, lipid profile, C-reactive protein, circulating immune complexes, Lp(a), and its autoantibodies. Results: the number of affected vascular beds was associated with an increasing level of Lp(a) and a lower level of IgM autoantibodies to Lp(a). Hyperlipoproteinemia(a) (Lp(a) ≥ 30 mg/dL) was detected more frequently in patients with atherosclerosis. In logistic regression analysis adjusted for age, sex, hypertension, type 2 diabetes, and smoking, an elevated Lp(a) level was independently associated with stenotic atherosclerosis and lesion severity. There was a positive association of the number of affected vascular beds with C-reactive protein (r = 0.21, p < 0.01) and a negative association with circulating immune complexes (r = −0.29, p < 0.01). The neutrophil-to-lymphocyte ratio was significantly higher and the lymphocyte-to-monocyte ratio was significantly lower in patients with atherosclerosis compared to the controls (p < 0.01). Conclusion: Lp(a), C-reactive protein, circulating immune complexes, and neutrophil-to-lymphocyte ratio are associated with the stenotic atherosclerosis of different vascular beds. Lp(a) levels increase and IgM autoantibodies to Lp(a) decrease with the number of affected vascular beds.

Background: Despite high-intensity lipid-lowering therapy, there is a residual risk of cardiovascular events that could be associated with lipoprotein(a) (Lp(a)). It has been shown that there is an association between elevated Lp(a) level and cardiovascular outcomes in patients with coronary heart disease. Data about the role of Lp(a) in the development of cardiovascular events after peripheral revascularization are scarce. Purpose: To evaluate the relationship of Lp(a) level with cardiovascular outcomes after revascularization of carotid and lower limbs arteries. Methods: The study included 258 patients (209 men, mean age 67 years) with severe carotid and/or lower extremity artery disease, who underwent successful elective peripheral revascularization. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The secondary endpoint was the composite of primary endpoint and repeated revascularization. Results: For 36-month follow-up, 29 (11%) primary and 128 (50%) secondary endpoints were registered. There was a greater risk of primary (21 (8%) vs. 8 (3%); hazard ratio (HR), 3.0; 95% confidence interval (CI) 1.5–6.3; p < 0.01) and secondary endpoints (83 (32%) vs. 45 (17%), HR, 2.8; 95% CI 2.0–4.0; p < 0.01) in patients with elevated Lp(a) level (≥30 mg/dL) compared to patients with Lp(a) < 30 mg/dL. Multivariable-adjusted Cox regression analysis revealed that Lp(a) was independently associated with the incidence of cardiovascular outcomes. Conclusions: Patients with peripheral artery diseases have a high risk of cardiovascular events. Lp(a) level above 30 mg/dL is significantly and independently associated with cardiovascular events during 3-year follow-up after revascularization of carotid and lower limbs arteries.

Defects in the low-density lipoprotein receptor (LDLR) are associated with familial hypercholesterolemia (FH), manifested by atherosclerosis and cardiovascular disease. LDLR deficiency in hepatocytes leads to elevated blood cholesterol levels, which damage vascular cells, especially endothelial cells, through oxidative stress and inflammation. However, the distinctions between endothelial cells from individuals with normal and defective LDLR are not yet fully understood. In this study, we obtained and examined endothelial derivatives of induced pluripotent stem cells (iPSCs) generated previously from conditionally healthy donors and compound heterozygous FH patients carrying pathogenic LDLR alleles. In normal iPSC-derived endothelial cells (iPSC-ECs), we detected the LDLR protein predominantly in its mature form, whereas iPSC-ECs from FH patients have reduced levels of mature LDLR and show abolished low-density lipoprotein uptake. RNA-seq of mutant LDLR iPSC-ECs revealed a unique transcriptome profile with downregulated genes related to monocarboxylic acid transport, exocytosis, and cell adhesion, whereas upregulated signaling pathways were involved in cell secretion and leukocyte activation. Overall, these findings suggest that LDLR defects increase the susceptibility of endothelial cells to inflammation and oxidative stress. In combination with elevated extrinsic cholesterol levels, this may result in accelerated endothelial dysfunction, contributing to early progression of atherosclerosis and other cardiovascular pathologies associated with FH.

The LDLR locus has clinical significance for lipid metabolism, Mendelian familial hypercholesterolemia (FH), and common lipid metabolism-related diseases (coronary artery disease and Alzheimer’s disease), but its intronic and structural variants are underinvestigated. The aim of this study was to design and validate a method for nearly complete sequencing of the LDLR gene using long-read Oxford Nanopore sequencing technology (ONT). Five PCR amplicons from LDLR of three patients with compound heterozygous FH were analyzed. We used standard workflows of EPI2ME Labs for variant calling. All rare missense and small deletion variants detected previously by massively parallel sequencing and Sanger sequencing were identified using ONT. One patient had a 6976 bp deletion (exons 15 and 16) that was detected by ONT with precisely located breakpoints between AluY and AluSx1. Trans-heterozygous associations between mutation c.530C>T and c.1054T>C, c.2141-966_2390-330del, and c.1327T>C, and between mutations c.1246C>T and c.940+3_940+6del of LDLR, were confirmed. We demonstrated the ability of ONT to phase variants, thereby enabling haplotype assignment for LDLR with personalized resolution. The ONT-based method was able to detect exonic variants with the additional benefit of intronic analysis in one run. This method can serve as an efficient and cost-effective tool for diagnosing FH and conducting research on extended LDLR haplotype reconstruction.

Aim. To evaluate the prevalence of familial hypercholesterolemia (FH) and hyperlipoproteinemia(a) (HLP(a)) in patients with premature acute coronary syndrome (ACS).Material and methods. The study included 120 patients with ACS up to 60 years (mean age, 53±7 years, 104 (87%) men) and 44 people from the comparison group without atherosclerotic cardiovascular diseases and dyslipidemia (mean age, 48±11 years, 19 (43%) men). All patients with ACS underwent coronary angiography. The lipid profile and lipoprotein(a) (Lp(a)) were determined in all patients.Results. The prevalence of HLP(a) in patients with premature manifestation of ACS was 41% (n=49), possible FH — 25% (n=30), combination of FH and HLP(a) — 13% (n=15). In the comparison group, an increased concentration of Lp(a) was detected in 14% (n=6). Based on the analysis of operating characteristic curves, Lp(a) ≥30 mg/dL had the maximum significance for ACS with a sensitivity of 40% and a specificity of 86% (area under the curve, 0,6; 95% confidence interval (CI), 0,5-0,7, p15 mg/dl was associated with two or more coronary artery lesions with a sensitivity of 67% and a specificity of 65% (area under the curve, 0,7; 95% CI, 0,6-0,7, p<0,01). On logistic regression analysis, age (odds ratio (OR). 1,1; 95% CI, 1,0-1,2, p<0,05), smoking (OR, 7,5; 95% CI, 2,5-22,0, p<0,001) and Lp(a) ≥30 mg/dl (OR, 6,7; 95% CI, 1,1-39,7, p<0,05) are independently associated with premature ACS. Only Lp(a) ≥15 mg/dL was associated with multivessel coronary artery disease in these patients (OR, 3,8; 95% CI, 1,52-9,74, p<0,01).Conclusion. Every fourth patient with premature ACS has FH, while almost every second has HLP(a), and every eighth has a combination of FH and HLP(a). HLP(a) is associated with ACS up to 60 years of age and multivessel coronary artery disease in these patients.