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.

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 compare the diagnostic value of different bleeding risk scales in patients with acute coronary syndrome (ACS).Material and methods. The study included 1502 patients with ACS from the observational, open-label, multicenter trial ORACUL II. The mean age was 65,7±12,9 years. At follow-up visits (hospital discharge, 25, 90, 180 and 360 days from the index event), all cases of bleeding were recorded with a description of bleeding characteristics, source, severity, treatment, and classification according to the BARC, TIMI, and ISTH scales.Results. During the follow-up period, bleeding was recorded in only 170 (11,3%) patients: within the index hospitalization — in 39 (2б6%), within a year after the index hospitalization — in 131 (8,6%). In 19 (1,2%) patients, recurrent bleeding at several visits was recorded. In comparison with such scores as CRUSADE, ACTION-ICU, ACUITY, PARIS, the ORACUL scale had the highest predictive value in relation to the in-hospital bleeding risk. The only scale with comparable diagnostic value was the BleeMACS score. It should be noted that the ORBIT and HASBLED scores had a lower predictive value for the in-hospital bleeding risk. In general, all scores were better at predicting major bleeding and slightly worse for clinically relevant ones.Conclusion. The ORACUL scale seems to be the most acceptable tool for assessing the bleeding risk in patients after ACS in actual clinical practice in Russia.

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.

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.

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 (≤55 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 mmol / l (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.

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder with a prevalence of 1/200-1/500 in the general population. The aim of the study was to assess the specific features of coronary angiography in young patients with acute coronary syndrome (ACS) and FH diagnosed using Dutch Lipid Clinic Network (I) and Simone Broome Register (II) criteria. 224 pts with early onset of ACS who underwent coronary angiography were selected (≤ 55 years of age for men and ≤ 60 years of age for women). Two, three vessel disease/left coronary artery (LCA) impairment was observed in 12 of 13 (92,3%) pts with definite/possible FH (I, p=0,036) and in 28 of 29 (96,6%) pts with probable FH (II, p=0,001). In patients with family history of cardiovascular disease three ves-sel disease or LCA impairment was observed in 54 of 73 (74%) pts (p=0,024). Comparing two groups of patients with LDL over and below 4,6 mmol/l (the concentration was obtained by ROC analysis) it was shown that 20 of 29 (69%) and 58 of 144 (40,3%) pts (p=0,036) respectively had culprit vessel thrombosis. Thus, we can suppose that in pts with higher LDL level atherosclerotic plaque rupture is observed more frequently in case of ACS. Therefore, it has been shown that multivessel and LCA stem impairment in young patients with ACS and FH is associated with both main factors used for not genetic FH diagnosis: high LDL cholesterol level and family history of cardiovascular disease.