Aim. The purpose of this study was to access clinical application of the 9p21.3 locusgenotype in patients with myocardial infarction (MI).Material and methods. Totally 500 (411 male, 89 female) patients with MI youngerthan 65 years old [Ме 54,0; Q25 48,0; Q 59,0] and 31 autopsy data (24 male,7 female) in case of fatal MI were collected. All participants were included in the 75study after written informed consent form. Control group consisted of 535 participants (423 male, 112 female) without coronary artery disease [Ме 42,6;Q25 39,0; Q 44,3]. Genome DNA was extracted from venous blood or myocardialtissue using the phenol-chloroform extraction method. Two SNPs rs10757278 andrs1333049 (locus 9p21.3) were tested. Prospective follow-up period lasted 2 years.
Results. We revealed a direct strong association of the locus 9р21.3 (rs1333049)with MI. Logistic regression odds ratio (OR) of MI for homozygous genotype CCrs1333049 was 1,71 [95% CI: 1,16-2,52], р=0,006. In patient who didn’t underwent PCI and carried of risk allele C rs1333049 had significant higher risk of recurrent 75acute coronary syndrome (ACS): during 1 year after MI – OR=4,91 [95% CI: 1,4516,66];during2yearafterMI–OR=3,77[95%CI:1,50-9,52].
Conclusion.We suppose these data might be effectively utilized for improvement of onset of MI and long-term outcome prognosis.

Aim. To study the clinical and predictive importance of polymorphism of rs1800629 (G-308A) of TNF gene in patients with STEMI.
Material and methods. Research included patients (171 persons with STEMI), hospitalized to the Kemerovo cardiological center and 188 individuals without the diagnosed cardiovascular diseases. In all patients the genotype had the polymorphism of rs1800629 of TNF gene. Investigation was carried out with help the original DNA microarray.
Results. Associations of the rs1800629 (G-308A) polymorphic variant in the TNF gene with the concentration of the tumor necrosis factor alpha (TNFa) in the blood serum and cardiovascular complications in patients with myocardial infarction with the elevated ST segment (MIST) have been studied. Allele A rs1800629 frequency in patients with MIST (n=171) was 11,7% which did not differ from the frequency in healthy controls (n=188) – 12,2%. Allele A careerstatus was associated with the higher levels of the TNFa concentration in the blood serum measured at the day 10th-14th after MI: 11,02 pg/ml compared to 9,49 in G homozygotes (p=0,045). While analyzing the clinical status of MIpatients after one year follow up, it was revealed that A allele has the frequency 19% in patients with progressive angina pectoris (AP) compared to 10% in  patients without progressive AP, and 16% in patients with cardiovascula rcomplications (CVC) such as repeated MI, stroke, instable AP or death from cardiovascular reasons compared to 9% frequency in patients without CVC, which was not statistically significant. We had shown in earlier s tudy that TNFa high level in patients with MI is related to the risk of CVC. Although, in current study we did not detect an association of the rs1800629 with progression of the AP, chronic heart failure decompensation, CVC or death from cardiovascularreasons in one year after IM. Thus, rs1800629 allele A does influence TNFa concentrations, but there is no data supporting the fact that this variant is an independent risk factor for IM and its complications.

Conclusion. The results indicate possible predictive value of rs1800629 polymorphism of TNF gene to predict the cardiovascular events in patients with STEMI during 12 months of follow up.

Aim. To evaluate the relationship of 8 mononucleotide polymorphisms (MNP) with negative longterm prognosis of the acute coronary syndrome.
Material and methods. Totally 280 patients with acute coronary syndrome included (ACS), who during 1 year follow up were underwent the solid endpoints evaluation (cardiovascular death, hospitalization for recurrent ischemic event and repeated revascularization).
Results. In the analysis of rs4804611 in group with negative outcomes there is significantly more prevalent genotype GG (9,1% vs. 1,8%), chances relation 5,57 (95% CI 1,35-22,96); credibility of the differences kept in men (p=0,021). In the analysis rs2549513 in the group with positive prognosis the AA genotype was more prevalent (70,6% vs. 53%), hazard ratio 0,47 (95% CI 0,26-0,85), and in the group with negative prognosis genotype AC, chances relation 2,32 (95% CI 1,28-4,20; р=0,007).
While separated by gender credible differences were shown only in men (p=0,008).

Conclusion. Evaluation of genetic  markers  rs4804611  and rs2549513  can significantly increase prognostic value in riskometry of ACS outcomes.

Aim. To study the association of polymorphic markers of C-reactive protein genes (CRP), interleukine-6 (IL6), interleukine-10 (IL10), lymphotoxine alpha (LTA) and tumornecrosis factor alpha (TNFA) with LVH in patients with hypertensive disease (AH).
Material and methods. Totally 468 patients studied with AH (290 – 62% of men, 178 – 38% of women). Mean age 60,8±11,54 y. o., 49 – with diabetes mellitus 2 type (10,5%), 44 (9,4%) had stroke, 175 (37,3%) – current smokers. LVH was absent in 111 and was found in 357.
Results. No any association found for echocardiographic parameters with genotypes C(-3014)T, A(-3872)G, G(-2667)C, A(-5237)G gene CRP, G(-1082) A gene IL10, C(252)T gene LTA и A(-308)G gene TNFA. Allele G carriers of polymorphic marker C(-174)G gene IL6 had significantly more prominent LVMM, comparing to the CC genotype carriers (67,29±4,137 g and 241,5±3,15 g resp., р=0,020), LVMMI(140,3±2,12 g/m 2 and 129,0±3,15 g/m2, р=0,037), peak velocity A (69,6±2,41 m/s и 64,9±1,36 m/s, р=0,007) and relation Е/А (1,18±0,111 и 1,01±0,032 resp., р=0,0001). During multifactorial analysis it was found that LVH in those with AH theris association of G polymorphism C(-174)G gene IL6 and diastolic BP level.
Conclusion. As the result of the study the new additional evidence was found for impact of systemic inflammation on left ventricular myocardium hypertrophy.

Aim. To reveal genetic predictors of the ischemic stroke in patients with AF.
Material and methods. Totally 121 patient studied with AF and 155 their relatives of I-III grade of relation. First group consisted of 43 probands with AF and stroke anamesis and 54 their relatives, the second group – 78 probands with AF without stroke and 101 their relative. Control group consists of 188 subjects. The patients underwent ECG, EchoCG, Holter ECG-monitoring, VEM, TELAS, molecular-genetic investigation.
Results. Genotype AA of polymorphism -455 G>A of gene FGB statistically significantly predominated in subjects with AF and stroke comparing to those with AF without stroke (20,94% vs 6,4%; p=0,036). Risk relation shows that the chance of stroke development with AA homozygous genotype at rare allele is 3,9 times higher than in its absence. Overall the genotypes CT and TT by the rare allele 807C>T gene ITGA2 statistically significantly predominated in the patients with AF and stroke comparing to controls (76,7% vs 56,9%, p=0,026). The chance of stroke development while carrying CT and TT by the rare allele is 2,5 times higher than in their absence. Genotypes TC and CC by the rare polymorphism 5 T>C gene GPIBA statistically more significantly were found in patients with AF and credibly increases
the chance for stroke 2,3 times. Allele A of polymorphism 10796 G>A gene F7 statistically more significant rarer found in patients with AF and stroke comparing to controls (6,98% vs 16,22%; p=0,043). Chance of stroke in absence of allele A is 2,6 times higher, than in its presence.
Conclusion. The study revealed that homozygous genotype AA by the rare polymorphism -455G>A gene FBG, heterozygous CT and homozygous TT by the rare allele 807C>T gene ITGA2, heterozygous TC anf homozygous CC by the rare – 5 T>C gene GPIAB are set as genetic predictors for ischemic stroke development in AF. Allele A of the polymorphism 10976 G>A gene F7 show protective effect in the ischemic stroke development in AF. Genetic risk estimation might improve the primary ischemic stroke prevention in AF.

Aim. To study the relationship of combined genetic signs that include the genes from the cytokine, growth factors and matrix metalloproteases families with proinflammatory and proangiogenic activity in patients with myocardial infarction (MI).
Material and methods. Totally 363 europeoid men studied at the age of 33 to 84 y.o. (mean age 55,3±0,5 y.o.), including 268 after MI and 95 healthy individuals. The mononucleotide polymorphism of promotor region of cytokine genes (TNF-308, TNF-238, TNF-863, IL1B-511, IL1B-31, IL4-590, IL6-174, IL10-592, IL10-1082), endothelial growth factor (VEGF+936, VEGF-2578) and matrix metalloproteases (MMP2-1306, MMP3-1171, MMP9-1562) studied. Genotyping was performed by the restrict analysis method of amplification products (RFLP).

Results. In general 30 genetic combination found, associated with predisposition to MI, and 37 combinations, associated with endurance to it with the level of statistical significance at p<0,005. Combinations, that were actively associated with the MI development, included VEGF, containing in their homo- and heterozygous variants allele C, associated with high level of endothelial growth factor production. Among gene polymorphisms, negatively associated with MI, that differs from positively associated genotype combinations, the MMP genotypes predominate. Among the latter the homozygous CC gene MMP9 in polymorphic position C1562T, that provides high level of this enzyme synthesis.

Conclusion. High specificity of gene groups in MI with proinflammatory and proangiogenic activity makes possible to use these complex signs as personified biological markers for MI prognosis in group of patients with coronary disorders and to findout the subjects required preventive activities, that decrease the risk of the disease.

Aim. To search and study the association of some candidate genes polymorphysms of various cardiovascular diseases and sudden cardiac death in men.
Material and methods. The sudden cardiac death group (SCD) is collected by the WHO criteria with suddenly died men underwent court-medicine expertise (n=274). Control group was matched by the age and gender from the DNA bank of HAPIEE and MONICA trials. Genotyping of groups was done according to polymorhysms SCN5A, rs187238 gene IL-18, rs1799864 gene CCR2, rs3864180 gene GPC5, rs1799983 gene eNOS, rs2228314 gene SREBF-2, rs1800588 gene HL, rs10757278, rs1333049 with methods of PDRF and realtime PCR.
Results. No significant differences found between the SCD group and control group by the prevalence of genotypes SCN5A, rs187238 gene IL-18, rs3864180 gene GPC5, rs1799983 gene eNOS, rs1800588 gene HL.
In SCD group the decrease of homozygotes by CC polymorphism rs2228314 found in gene SREBF-2 and the decrease of heterozygotes GC comparing to control group (HR=4,074, 95% CI 1,843-9,002, р=0,0002; HR=0,442, 95% CI 0,302-0,647, р=0,0001, reap.). In SCD group carriers of GG genotype polymorphism rs10757278 and CC poly morphism rs1333049 are significantly more prevalent than in control group (HR=1,814, 95% CI 1,159-2,839, р=0,011; HR=1,744, 95% CI 1,104-2,754, р=0,019, resp.). The part of GA carriers of polymorphism rs1799864 gene CCR2 is more prevalent in SCD group comparing to control (HR=1,558, 95% CI 1,051-2,308, р=0,029).
Conclusion. Polymorphisms rs10757278, rs1333049, rs2228314 gene SREBF-2, rs1799864 gene CCR2 are associated with sudden cardiac death in men.

Aim. Forecasting of emergence of cardiac conduction defects (CCD) by means of a method of multiple logistic regression for implementation of early diagnostics, primary prevention and the personified approach to treatment.
Material and methods. To all probands with CCD and to their relatives clinicinstrumental research on the following program was conducted: clinical examination, electrocardiography, echocardiography, Holter monitoring, stresstest, genealogical and molecular and genetic researches. For the differential diagnosis between primary and secondary CCD to probands and their relatives according to indications coronarography and an isotope scanning was carried out. According to design of research, it was selected 81 probands with CCD (26 families with RBBB (right bundle branch block) and 55 families with LBBB (left bundle branch block). Patients were subdivided into 2 subgroups: 1 subgroup – 61 patients from idiopathic RBBB (26 пробандов and 35 sick relatives with RBBB); The 2nd subgroup – 121 patients with idiopathic LBBB (55 пробандов and 66 sick relatives with LBBB);
Results. We presented an innovative technique of an assessment of risk of development of CCD, such as RBBB and LBBB. This mathematical model of forecasting of CCD in families of Krasnoyarsk. For forecasting of level of determination of RBBB the logistic regression model expressed by the following equation was received. Measure of definiteness of RBBB – 28,0%. For forecasting of a measure of determination of LBBB the logistic regression model expressed by the following equation was received. Determination level for LBBB – 29,0%.
Conclusion. The logistic regression model of forecasting of CCD is an additional mathematical method of the forecast of level of CCD in families. It is on the practical level important that relatives of patients with CCD are truly threatened concerning development of these pathologies of carrying-out system of heart since this pathology has genetic determinacy and is accurately traced in families with monogenic type of inheritance. It is necessary to emphasize that as emergence of a disease is caused by a complex of hereditary and environmental factors, existence of genetic predisposition at an individual isn’t fatal inevitability of his incidence. Therefore forecasting of these diseases in families by means of computer technologies will allow to carry out an early stage of primary prevention for incidence prevention.

The review concerns he etiology of polygenic hyperlipidemias. The most prominent and prevalent in more than 1% of inhabitants genetic markers are discussed. The mechanisms of minor alleles influence on the hypercholesterolemia are shown: APOAI 75G>A (rs670), CETP (rs5882), LIPC (rs1800588), APOE (E2/E3/E4), hypertrigliceridemia: APOA5 (rs3135506), FABP2 rs1799883, LPL rs328. Also the genetic markers discussed that influence food-seeking behavior and by various ways do increase daily fat intake: CD36 (rs1761667), FTO (rs8050136), MC4R (rs17782313). Carrying of several pathologic alleles in a patients does significantly increase the risk of primary hyperlipidemias. More studies needed to evaluate the effect of different genetic markers combination to invent these tests as an instrument of personified predictive medicine in clinical practice.

Aim. By the observation of aortic coarctation victims families, to reveal factors predisposing to the disease development, and to evaluate the prevalence of NOTCH1 genes mutation/replacements in patients with this kind of defect.
Material and methods. Totally 68 patients included with aortic coarctation. All patients underwent echocardiographic investigation, direct and indirect manometry, multispiral computed aortography and intraoperational revision of coarctation zone. 51 patient underwent screening of 10 from 34 exones of NOTCH1 gene. Control group consisted 200 patients without IHD.
Results. In more than a half of the cases coarctation coexisted with bicuspid aortic valve and in circa a hlaf of the cases there was combination of coarctation with arc or descending hypoplasia. Totally 29 NOTCH1 gene types were found. Four from those led to aminoacids exchange, of those only one, R1279H, was revealed in patients group and control group either. This type was much more prevalent in patients with aortic coarctation comparing to control group (p<0,05).
Conclusion. The most important factors in coarctation development are heredity (33,8%) and complicated pregnancy (57,4%). The exchange of R1279H in gene NOTCH1 was much more prevalent in patients with the defect studied and might be an associated with the disease allele.

The review concerns on the data about ED in CVD pathogenesis as the leading cause of  death.   The  morphofunctional  characteristic  of  endothelium  is  discussed, its synthetic activity and regulators. Also the regulatory role of NO-synthase and its gene polymorphism, as their clinical significance as the ED development  factors. Also the vasodilator  and  vasoconstrictor balancing  mechanisms of  ET, showing  different functions. Polymorphism of genes  influences ET-1 activity, that has significant value for RAAS regulation with ACE and the influence of rare polymorphisms in CHD risk, MI, diabetic nephropathy. Pathogenetic significance of ED in the conditions of oxidative stress defines  clinicists attention  onthis pathology, related  to atherosclerosis, and molecular and genetic aspects of CHD formation do dictate inevitability of personalized medicine  for prognosis  and  prevention,  as  pharmacogenomics – for endothelial pathology correction of cardiovascular system in general.

Aim. To evaluate the risk of muscle tissue damage in patients taking statins, and usefulness of the gene SLCO1B1 typifying for the risk estimation of such an unpleasant adverse drug reaction (ADR).
Material and methods. The observation of 258 patients with ischemic heart disease, taking statins, was conducted. To evaluate the credibility of causeoutcome relation “ADR – statin” the WHO classifications and criteria were used together with Naranjo algorithm.
Results. The 3 groups were stratified: I – patients with muscle pain or weakness and with probable to definite chance of the cause-outcome relation (n=31); II – patients with muscle symptoms and possible or doubtful degree of credibility for causeoutcome relation (n=27); III – patients without muscle symptoms (n=200); of those into further study we included 35 subjects. Among those with muscle symptoms women were more prevalent (I group – 61,3% (19/35); (p>0,05 in all groups). Mean time of hypolipidemic therapy of 1st group patients was 48,8 months (p<0,0001 vs 2nd and 3rd groups). Manifecting of muscle symptomatic in a majority of patients (19/35) was during the first year of therapy (RR 2,5; p=0,0841). Average doses of statins were higher in those of the 1st group: 38,3 mg/day (p I vs II=0,0004); p I vs III=0,0139). As a result of allele SLCO1B1*5 typifying a tendency of more frequent C-allele in the 1st group was found comparing to 2nd and 3rd groups: HR I vs II 2,35 (p=0,1242); RR I vs III 2,37 (p=0,0732); RR II vs III 1,00 (p>0,9999). The algorithm for statin-induced myopathy was invented.
Conclusion. In patients with CHD the ADR as myopathy were found in 12% of cases. The most significant predictors: duration of hypolipidemic therapy more than12 months (RR 7,7; p=0,0002), atorvastatin usage in dose more than 40 mg per day (RR 2,67, p=0,0139). The prevalence of statin-associated muscle events was higher in women (RR 1,88, p=0,23) and carriers of allele type SLCO1B1*5 (RR 2,37; p=0,0732).

Aim. To check whether the mononucleotide polymorphisms (MNP), identified in recent studies do match a risk marker criteria for arterial hypertension (AH) in Siberian population.
Material and methods. The group of subjects with AH and control group (relation 2:1) were formed from the population selection of 45-69 years old citizens of Novosibirsk (9400 subjects), which had been collected during the work in HAPIEE project. Totally 514 subjects included, of those controls – 168 (127 men and 41 women) with BP not higher than “normal” by the data of 2 and more examinations during the last years, with interval not more than 6 months. Group with AH consists of 346 subjects (206 men and 140 women) with the diagnosis of AH. Genomic DNA was extracted from venous blood by the method of phenol-chloroform extraction. Gene polymorphism was tested by PCR in real time according to the protocol of equipment manufacturer (zonds TagMan, Applied Biosystems, USA) on the device ABI 7900HT. These MNP were included into the study: rs699 gene AGT, rs5068 gene NPPB, rs17367504 gene MTHFR, rs2681492 gene ATP2B1, rs4343 gene АСЕ, rs1801253 gene ADRB1, rs11240692 gene REN, rs2846679 gene KCNJ1, rs239345 gene SCNN1B, rs1799983 gene NOS3.

Results. The risk relation to develop AH in men – carriers of GG rs699 gene AGT was1,95 (95% CI 1,08-3,53; p=0,003) comparing to the carriers of two other genotypes. Carriage of AA genotype rs699, opposite, is probably protective factor for AH development in men (HR 0,47; 95% CI 0,27-0,81; p=0,007).

Conclusion. For two from ten MNP studied the association with AH was confirmed in men: rs699 gene AGT and rs5068 gene NPPB.

Aim. To analyze spread of alleles and genotypes of ACE gene in CHD patients of different gender and age and to study their realtion with MI risk.
Material and methods. Totally 326 individuals of both age, Tomsk city inhabitants, aged 34-79 y. o., included into the study. Of those 173 CHD patients having MI anamnesis and 153 healthy individuals. For the entire group the I/D polymorphism of ACE gene with PCR method using primers by AmpliKit Company (Saint-Petersburg). For the analysis of frequency spread of alleles and genotypes the χ2 criteria used, precise Fischer test and relative risk estimation.
Results. By the results of statistic analysis there were no difference between control and patient groups by the prevalence of ACE genes and alleles. While studying women separately there were no siginificant differences between patients and controls in genotypes and alleles. In men with MI in anamesis there was increase of DD genes prevalence comparing to healthy individuals (p=0,038). The analysis of MI prevalence and I/D polymorphism in men and women was performed with relation to age. It is shown that in men younger than 50 y.o. homozygotes there are moreprevalent II and DD genotypes, than in men older than 50 y.o., whom ID genotype is more prevalent (p=0,031). In women group the difference between those younger and older than 55 y.o. the spread of genotypes was similar, but there were more prevalent MIs in older group (p=0,020).
Conclusion. The important points of I/D polymorphism of ACE genes influence on MI risk was shown. Among women, sick and healthy, and of various age, there were no significant differences in genitypes prevalence. However there are statistically significant differences in the genotype spread was found in healthy men and men after MI, and in men with the age of 34-50 and 51-79 y.o.

Aim. To study relationship of idiopathic atrioventricular and intravenricular disorders of cardiac conductivity with mononucleotide polymorhism (MNP) A/G gene TBX5.
Material and methods. Totally 260 persons with primary cardiac conductivity disorders included (with AV-blocks of 1, 2, 3 grades, complete His right bundle branch block, complete His left bundle branch block, His rleft anterior bundle branch block) and 257 persons without any cardiovscular diseases. Patients were grouped according to their nosological type, age, gender. All patients underwent standard cardiological examination and molecular-genetic sampling of DNA. Results. The obtained results showed statistically significant predominance of the rare genotype GG (MNP marker rs3825214) gene TBX5 in the group of patients with conduction disorder at left His bundle branch and in subgroup of women with the pathology mentioned.
Conclusion. The data obtained makes clear that the presence of GG genotype (rs3825214) gene TBX5 increases chances for idiopathic rhythm disorders development mostly in women. These results can be used during the primary prevention of the pathology mentioned.

Aim. To study the influence of cardiac resynchronizing therapy (CRT) on autonomous cardiac regulation during follow-up in patients (pts) with chronic heart failure (CHF).
Material and methods. 22 pts (14 (63,6%) males, mean age 50±10,0 years) with implanted cardiac resynchronization devices were examined. 14 (63,6%) pts had ischemic cardiomyopathy, 12 pts (54,6%) were in NYHA class II, 6(27,3%) – III, 4(18,1%) – IV. Mean follow-up was 12,5 [9,3;13,3] months. Heart rate variability (HRV) analysis was performed on 5-minute ECG recordings made at rest and in active orthostatic test (AOT). Echocardiographic and electrocardiographic parameters were estimated. Pts with a decrease in left ventricular end-systolic volume ≥15% was classified as responders (n=11 – gr.I) and <15% – nonresponders (n=11 – gr. II).
Results. At baseline in gr.II higher pulmonary artery systolic pressure (PASP) and right ventricle dimension were detected. At baseline in gr.I significant LF/HF increase, SDNN and TP decrease in AOT were observed. During prospective study in gr.I LF/HF increase in AOT was significant and LF and LF% were higher as compared with initial. At baseline and during follow-up in gr.II HRV parameters were unchanged.
Conclusion. CRT exerts positive influence on autonomic cardiac regulation in CHF patients. Preservation of sympathetic reactivity in AOT probably can be used as a marker of a good CRT response.