Aim. To assess the possibility of familial hypercholesterolemia (FH) detection among patients with early coronary artery disease (CAD) in practice in comparison with data from different populations. Patients with early manifestations of CAD are a promising group for identifying a proband with FH and subsequent cascade screening. The question remains open about the sufficiency of clinical criteria for diagnosing this disease. Material and methods. We examined 651 patients with CAD manifestations aged £55 years in men and £60 years in women. FH was diagnosed according to the Dutch Lipid Clinic Network (DLCN) criteria, and cardiovascular risk was assessed using the Montreal-FH-SCOR E. In 35 phenotype-positive patients with FH, as well as 5 with lowdensity lipoprotein cholesterol levels ³5,5 mmol/l and 23 with age of manifestation of coronary artery disease £35 years, the coding sequence of the genes for apolipoprotein B ( APOB ), low-density lipoprotein receptor ( LDLR ), low-density lipoprotein receptor adapter protein 1 ( LDLRAP1 ), proprotein convertase subtilisin/kexin type 9 ( PCSK9 ). Results. Definite FH was in 8 (1,2%), probable in 27 (4.2%), possible in 339 (52,1%) patients, while 277 (42,5%) patients had DLCN score of <3 points; 31 (88,6%), of 35 phenotype-positive patients had a high Montreal-FH-SCORE risk. Six carriers of pathogenic variants were identified, 2 of which were among phenotype-negative patients. A meta-analysis of 16 studies with 13065 patients (2012-2023) showed that the incidence of FH is 5,22 (4,848-5,619)% (fixed model) and 5,93 (4,528-7,515)% (random model). Conclusion. The use of existing diagnostic scales does not provide guaranteed detection of FH among patients with early CAD. It is likely that DLCN modification by additional gradation of the criterion for the age of CAD manifestation will help increase its diagnostic value.

Cardiolipidology – a new direction in cardiology – is developing intensively owing to the method of mass spectrometry. This method has acquired particular importance for the determination of molecular types of sphingolipids, the metabolism of which is closely related to the metabolism of cholesterol. Changes in the level of a number of sphingolipids claiming to be markers of cardiovascular diseases (CVDs) (molecular forms of sphingomyelins, ceramides, glucosylceramides, sphingosine, and sphinganin), in the blood plasma of patients with hereditary forms of early atherosclerosis (familial hyperlipidemia, FHL) were studied by chromatography–mass spectrometry. The study group (52 people) consisted of patients with acute manifestations of atherosclerosis, with postinfarction cardiosclerosis, and with dyslipidemia or early CVD. In patients with FHL, there was an increase in the proportion of long-chain sphingomyelin SM18:1/22:0 and the level of ceramides with carbon chains C20-1 and C22-1. An increase in the level of sphingosine, possessing proapoptotic properties, which can be considered as a marker of an additional risk of cardiovascular complications, was revealed in patients with a high clinical probability of FHL. The search for new CVD markers will improve personalized approach to the management of such patients and improve the results of their treatment.

Gipolipidemicheskie preparaty vliyayut na standartnye lipoproteiny, no kak izmenyayutsya pri lechenii drugie lipidy plazmy — ne izvestno. Cel'yu raboty bylo ocenit' dinamiku holesterina (HS), lipoproteinov vysokoj i nizkoj plotnosti (LVP i LNP), trigliceridov (TG) i sfingolipidov u pacientov s prezhdevremenno razvivshejsya ishemicheskoj bolezn'yu serdca, aterosklerozom i giperholisterinemiej na fone gipolipidemicheskoj terapii. V issledovanie vklyucheno 18 bol'nyh (srednij vozrast 53 ± 6,7 goda): v 1-j gruppe 6 pacientov poluchili startovye dozy statinov; vo 2-yu gruppu voshli 6 pacientov, ne dostigshih na fone startovoj terapii statinami celevyh urovnej LNP i prinimavshih uvelichennye dozy statinov; 7 pacientov 3-j gruppy ne dostigli celevyh urovnej LNP na fone terapii maksimal'no perenosimymi dozami statinov i ezetimiba i poluchali alirokumab. Issledovanie urovnya sfingolipidov provodili metodom mass-spektrometrii. V 1-j gruppe otmecheno snizhenie urovnya ceramida Cer 14:1 (p = 0,046) i sfingomielinov SM 22:1, SM 22:0, SM 24:0 (p = 0,028). Urovni obshchego HS (OHS), HS LNP, HS LVP i TG sushchestvenno ne izmenilis'. Vo 2-j gruppe otmecheno dostovernoe snizhenie urovnya OHC (p = 0,028), LNP (p = 0,043), sfingomielinov SM 18:1, SM 24:1 i SM 26:1, ceramida Cer 16:1 (p = 0,028). Cer 22:1 dostoverno uvelichilsya (p = 0,028). V 3-j gruppe OHS snizilsya na 36,2%, HS LNP (p = 0,018) — na 60,1% ot iskhodnyh znachenij (ΔHS LNP = –2,67 ± 3,12), vyyavleno povyshenie urovnya ceramida Cer 22:1 (p = 0,028). Pokazano, chto snizhenie soderzhaniya sfingomielinov proiskhodit na fone terapii statinami i korreliruet so snizheniem urovnya HS LNP. Znachimoj dinamiki ceramidov i ceramidnogo riska na fone terapii statinami ne zaregistrirovano, odnako pri dobavlenii k terapii ingibitora PCSK9 proizoshlo umen'shenie sootnosheniya Cer 16:0/24:0.

Lipid-lowering drugs affect standard lipoproteins. However, we have no knowledge of changes in other plasma lipids upon treatment. The study was aimed to assess the dynamic changes in cholesterol, high- and low-density lipoproteins (HDL and LDL), triglycerides, and sphingolipids against the background of lipidlowering therapy in patients with premature coronary artery disease, atherosclerosis and hypercholesterolemia. A total of 18 patients were enrolled (the average age was 53 ± 6.7 years): in group 1, six patients received starting statin doses; group 2 included six patients, who failed to achieve LDL target levels against the background of treatment with starting statin doses, and received escalated statin doses; seven patients in group 3 failed to achieve LDL target levels against the background of treatment with maximum tolerated doses of statins and ezetimibe, and received alirocumab. Sphingolipid levels were assessed by mass spectrometry. In group 1, the decreased levels of ceramide Cer 14:1 (p = 0.046) and sphingomyelins SM 22:1, SM 22:0, SM 24:0 (p = 0.028) were observed. There were no significant changes in the levels of total cholesterol, LDL-C, HDL-C, and triglycerides. In group 2, the significantly decreased levels of total cholesterol (p = 0.028), LDL (p = 0.043), sphingomyelins SM 18:1, SM 24:1 and SM 26:1, and ceramide Cer 16:1 (p = 0.028) were observed. The level of Cer 22:1 significantly increased (p = 0.028). In group 3, total cholesterol decreased by 36.2%, and LDL-C (p = 0.018) decreased by 60.1% compared to baseline (ΔLDL-C = –2.67 ± 3.12); the elevated levels of ceramide Cer 22:1 (p = 0.028) were observed. It has been shown, that decreased sphingomyelin levels are associated with statin therapy and correlate with decreased levels of LDL-C. No significant dynamic changes in ceramides and ceramide risk against the background of statin therapy were observed, however, PCSK9 inhibitor added to therapy reduced the Cer 16:0/24:0 ratio.

Abstract Background The cardiovascular death rate significantly declined last decades. But premature atherosclerosis burden remains an unresolved problem. Purpose The study aimed to assess the association of clinical factors with types of premature atherosclerosis onset. Methods Date of 702 patients (pts) (523 men and 179 women) with premature atherosclerosis (men ≤55 (48.6±6.2), women ≤60 (52.7±7.0) years of age) were analyzed with decision tree method using SPSS 23.0 program with the Python GUI module. Clinical and instrumental variables (n=109) were used. The test sample was formed by the cross-validation method. Results Myocardial infarction at the onset of atherosclerosis (n=542, 77.2%) was associated with the presence of peripheral atherosclerosis (1st order node, p<0.0001, F=93.174). The 2nd order node was a uric acid level (p<0.0001, F=26.493) in pts without peripheral atherosclerosis. In pts with uric acid level, less than 225 mmol/L-the left ventricle posterior wall thickness more than 10 mm was a 3d order node (p<0.0001, F=30.143). Area under the ROC-curve 0.916, p=0.011. Multivessel lesion according to coronary angiography data (102 patients) was associated with family history of cardiovascular disease (p=0.001, F=13.238), the area under the ROC-curve was 0.667, p=0.041. For pts. with peripheral atherosclerosis (n=66, 9,4%) the aortic root diameter obtained by an echo was the 1st order node (p<0.0001, F=36.057). In pts with aortic root diameter over 27 mm, a 2nd order node was creatinine level above 90 mmol/L (p=0.036, F=9.945) and in pts with a smaller diameter of aortic root was the history of hypertension emergency (p=0.001, F=13.897). Area under the ROC-curve 0.676, p=0.02. For pts. with ischemic stroke (n=26, 3,7%) as atherosclerosis onset 1st order node was brachiocephalic atherosclerosis lesion (p<0.0001, F=30.259). Among them, untarget BP level was 2nd order node (p=0.033, F=4.958). For pts without atherosclerosis age over 46.7 yrs was a 2nd order node (p<0.0001, F=24.515), and for pts younger than 46.7 yrs admission glucose higher than 11.06 mmol/L was a 3rd order node (p=0.026, F=12.382). This model had high predictive accuracy (area under the ROC-curve 0.963, p<0.0001). Conclusion Thus multiple clinical variants of premature atherosclerotic cardiovascular disease onset appeal to develop an individualized approach to early diagnosis and management of this kind of patient. Funding Acknowledgement Type of funding sources: None.

Aim.To identify the risk factors for bleeding of BARC scale 2-5 types in patients after acute coronary syndrome (ACS).Material and methods.The data of 1502 patients from the open multicenter study, ORACUL II, were used — 894 men (59,5%) and 608 women (40,5%), mean age — 65,7±12,9 years. Five hundred sixty (37,3%) patients had ACS with ST-segment elevation and 942 (62,7%) — ACS without ST-segment elevation. Bleeding was recorded in 164 patients (10,9%), including index admission — in 39 (2,6%) patients, of which severe (types 3-5) — 0,5%, significant — 1,7% (types 2-5).Results.Within a year after discharge, bleeding was observed in 126 (8,4%) patients, large — 0,8%, significant — 2,4%. The development of bleeding type 2-5 was associated with the presence of gastric ulcer and duodenal ulcer, gastrointestinal bleeding in history, decreased creatinine, hemoglobin clearance, age of patients, the use of anticoagulants in the composition of triple or double antithrombotic therapy, conducting of percutaneous interventional procedures, the presence of heart failure 2-4 Killip class at admission. ROC analysis showed that the predictive value of the ORACLE bleeding risk scale is 0,762, sensitivity — 62%, specificity — 78%.Conclusion.Thus, we based on routine clinical practice have created a simple scale for assessing the risk of bleeding in patients with ACS.

Разработка современных методов оценки метаболома, таких как хромато-масс-спектрометрия, позволяет существенно расширить представления о липидном обмене в конкретных клинических ситуациях. Целью исследования было изучить особенности липидома у больных с различной вероятностью семейной гиперхолестеринемии (СГХС). В исследовании приняли участие 35 пациентов — 15 мужчин (42,9%) и 20 женщин (57,1%) с дислипидемией или ранними сердечно-сосудистыми заболеваниями, развившимися в возрасте до 55 лет у мужчин и до 60 лет у женщин. Средний возраст пациентов составил 49,8 ± 9,96 лет. Вероятность семейной дислипидемии оценивали по критериям сети голландских липидных клиник. У 10 пациентов вероятность СГХС оценивали как низкую (1–2 балла), у 22 пациентов диагноз расценивали как вероятную СГХС (3–5 баллов). У 3 пациентов присутствовала возможная или определенная СГХС (2 пациента — 6 баллов, один пациент — 9 баллов). Определение молекулярных видов сфингомиелинов, церамидов и сфингоидных оснований (сфингозина, сфинганина), а также галактозоцерамида проводили методом хромато- масс-спектрометрии. Пациенты с определенной/вероятной СГХС имели достоверно более высокий уровень сфингозина по сравнению с пациентами с низкой клинической вероятностью СГХС (144,36 ± 107,863 и 50,14 ± 62,409 нг/мл; р = 0,01). В случае семейной СГХС отмечали увеличение доли длинноцепочечного сфингомиелина SM 18 : 1/22 : 0 и существенное увеличение уровня церамидов с длинной углеродной цепью С 20 : 1 и С 22 : 1. Была выявлена значимая прямая корреляция уровня липопротеинов низкой плотности (ЛНП) и сфингозина (r = 0,344; p = 0,047) наряду с обратными корреляциями уровня липопротеинов высокой плотности (ЛВП), сфинганина (r = –0,52; p = 0,002) и галактозилцерамида (r = –0,56; p = 0,001). Таким образом, у пациентов с высокой клинической вероятностью СГХС были выявлены изменения липидома, являющиеся маркерами риска сердечно- сосудистых осложнений.

Development of modern methods for metabolome assessment, such as gas chromatography–mass spectrometry, allows one to expand the knowledge about the features of lipid metabolism in various clinical conditions. The study was aimed to investigate lipidome features in patients with different probability of family hypercholesterolemia (FH). The study involved 35 patients: 15 men (42.9%) and 20 women (57.1%) with dislipidemia or early cardiovascular diseases which manifested below 55 in men and 60 in women (average age of patients was 49.8 ± 9.96). The family dislipidemia probability was evaluated using the Dutch Lipid Clinic Network Score. In 10 patients the probability of FH was low (score 1–2), 22 patients had possible FH (score 3–5). Three patients had probable or definite FH (score 6 in 2 patients, score 9 in one patient). Determination of molecular species of sphingomyelins, ceramides and sphingoid bases (sphingosine, sphinganine) as well as galactosylceramide was carried out using gas chromatography–mass spectrometry. In patients with definite/probable FH the sphingosine level was significantly higher compared with patients having low probability of FH (144.36 ± 107.863 and 50.14 ± 62.409 ng/ml; р = 0.01). In patients with FH, an increase in the proportion of long chain sphingomyelin SM 18 : 1/22 : 0 as well as a significant increase in the level of long chain ceramides with С 20 : 1 and С 22 : 1 was determined. Positive correlation of low-density lipoproteins and sphingosine level (r = 0.344; p = 0.047) together with negative correlation of high-density lipoproteins (HDL), sphinganine (r = –0.52; p = 0.002), and galactosylceramide level (r = –0.56; p = 0.001) were detected. Thus, in patients with high probability of FH the lipidome changes were observed, which could be considered the cardiovascular risk markers.

The aim of the study was to analyze clinical features of patients with premature acute coronary syndrome (ACS) in relation to family history of cardiovascular disease (CVD) and familial hypercholesterolemia (FH). Materials and methods. Of 2832 patients included in ORACUL 1 and ORACUL 2 multicenter observational trials 512 pts who developed premature ACS years for men, <= 60 years for women) and had known family history and LDL level were selected for this study. Of these patients 297 had positive family history (51 with FH, 246 no FH), 215 had negative family history. Results. Among patients with positive family history there were more women (31 vs 20.9%), while among patients with negative family history there were more men (79.1 vs 69%). The fact of regular alcohol consumption was significantly more frequently observed among patients with positive family history but without FH, compared to patients with positive family history with FH (69.6 vs 47.1%). Women with positive family history smoked more frequently than females with negative family history (51.1 vs 31.1%). Among patients with negative family history compared with patients with positive family history there were more people who at admission had hyperglycemia exceeding 11.1 mmo1/1 (10.3 vs 4.4%). Multiple vessel disease and coronary calcinosis were present in 73.2 and 24.7%, respectively, of patients with positive family history, and in 56.9 and 9.8%, respectively, of those with negative family history. Among patients with positive family history multivessel disease was more frequent in the subgroup with FH, while coronary calcinosis was more frequent in the subgroup without FH. Conclusion. Thus, premature development of ACS might be associated not only with genetic factors but also with family history ("inheritance") of adverse habits. Herewith coronary calcinosis is more prevalent in patients with FH.

Aim. To analyze possible association of the risk of adverse outcomes development in patients post acute coronary episode (ACS), with the polymorphism of gene TNF. Material and methods. To the study, patients included, that were under observation in 2 registry studies ORACLE I and II (Exacerbation of coronary heart disease: logic-probability ways of course prediction and treatment optimization). In overall, 2012 ACS patients assessed. Mean age 64,7±12,69 y.o. There were 1205 males (59,8%) and 807 females (40,2%). 741 patients (36,8%) included with ST elevation ACS, 1271 (63,2%) — with non-ST elevation ACS. Follow-up started at the 10th day from clinical stabilization. Clinical outcomes were gathered based on phone calls with the patients and their relatives, as during the outpatient office visits. Assessment of polymorphisms of gene TNF done with PCR.Results. In the assessed group, the frequency of alleles and gene TNF genotypes were measured: 18 patients carried genotype АА (0,9%), 561 patients — AG (279%), 1433 — GG (71,2%). In those with the allele А gene TNF, more commonly the episodes of SCD were noted (9,8% comparing to 6,6% of GG carriers, p<0,001); rate of non-cardiac death did not differ significantly (3,5% and 3,1%, respectively). There were no significant differences in the rate of fatal and non-fatal strokes, number of non-complicated cases of peripheral atherosclerosis. In the group of patients with allele A, there were more common the repeated ACS episodes (21,4% vs 12,8% in GG carriers, p<0,001). The rate of repeated after discharge interventions did not differ significantly. Independent factors for any adverse outcome (death, ACS, stroke, complicated atherosclerosis, repeated coronary interventions) were myocardial infarction (OR 1,235 (1,041-1,464)) and heart failure (OR 1,22 (1,02-1,44)) in anamnesis, decreased GFR (OR 1,04 (0,87-1,43)) and carriage of АА and AG gene TNF (OR 1,35 (1,14-1,60)). Conclusion. Carriage of the rare A allele of polymorphic marker G(-308)A gene TNF is associated with more common development of adverse outcomes in patients after exacerbation of CHD.

Истинная распространенность генетических вариантов, стоящих за развитием семейной гиперхолестеринемии (СГХС), и характерных для каждой популяции, остается неизвестной. Целью работы было определение спектра патологических генетических вариантов у больных острым коронарным синдромом (ОКС) с клинически диагностированной СГХС с помощью таргетного секвенирования. Были отобраны 38 из 2081 пациентов двух многоцентровых наблюдательных исследований больных ОКС (2004–2007; 2014–2016 гг.) возрастом ≤ 55 лет (мужчины) и ≤ 60 лет (женщины) с СГХС, клинически диагностированной по критериям Голландской сети липидных клиник и критериям регистра Simon Broome. Молекулярно-генетическое исследование проводили с помощью таргетного секвенирования следующего поколения: сначала секвенировали 3 гена, ассоциированные с СГХС: LDLR, APOB, PCSK9; при отсутствии значимых изменений, панель расширяли. Из 38 пациентов у 24 (63,2%) были выявлены генетические изменения, которые могли обусловить клинические проявления СГХС и раннюю манифестацию ишемической болезни сердца. Все пациенты являлись гетерозиготными носителями генетических вариантов. Выявлены варианты в трех основных генах (LDLR, APOB, PCSK9), связанных с СГХС, и редкие варианты в других генах системы липидного обмена (APOE, ABCA1, ABCG5, ABCG8, LPL, ANGPTL3, MTTP). Пять генетических вариантов описаны впервые: патогенный вариант p.Val273_Cys313del гена LDLR; вероятно патогенный вариант p.Arg160His гена APOE; варианты неуточненной клинической значимости p.Glu612Lys и c.*415G>A гена PCSK9; вариант p.Ala776Ser гена LDLR. Таким образом, использование клинических критериев позволяет выявить среди пациентов с ОКС и СГХС носителей мутаций не только «классических» генов, связанных с СГХС, но и редких, способных приводить к фенотипическим проявлениям СГХС.

The actual prevalence of genetic variants causing familial hypercholesterolemia (FH) in every population remains unknown. The aim of this work was to determine the spectrum of pathogenic variants in patients with acute coronary syndrome (ACS) and clinically diagnosed FH using targeted sequencing. We selected 38 patients with ACS from the sample of 2,081 participants of two multicenter observational studies (2004–2007; 2014–2016) who had a clinical diagnosis of FH based on the Dutch Lipid Clinic Network score and Simon Broome criteria. The men and women included in the study were ≤ 55 and ≤ 60 years of age, respectively. Molecular genetic screening was done by targeted next-generation sequencing. We started by sequencing 3 genes associated with FH, including LDLR, APOB, and PCSK9. If no relevant variants were detected, the panel was expanded. Of 38 patients, 24 (63.2%) were shown to have mutations that could cause clinical manifestations of FH and premature coronary artery disease. All patients were heterozygous carriers. Mutations were detected in three “classic” genes LDLR, APOB, and PCSK9 associated with FH, as well as in other genes involved in lipid metabolism, such as APOE, ABCA1, ABCG5, ABCG8, LPL, ANGPTL3, and MTTP. Five variants detected in our study sample had not been described previously: the pathogenic p.Val273_Cys313del variant of the LDLR gene, the likely pathogenic p.Arg160His variant in the APOE gene, two variants of uncertain significance p.Glu612Lys and c.*415G>A in the PCSK9 gene, and the mutant variant p.Ala776Ser in the LDLR gene. We conclude that the use of clinical diagnostic criteria in patients with ACS and FH enables identification of carriers of both “classic” mutations associated with FH and rare genetic variants that can be phenotypically expressed as FH.