[Analysis of mitochondrial haplogroups in persons with subclinical atherosclerosis based on high-throughput mtDNA sequencing].

Genetic predisposition plays an important role among other risk factors in multifactorial socially significant diseases such as atherosclerosis and its clinical manifestations. This pilot study was aimed to identify the relationship between the type of mitochondrial haplogroup and the risk of subclinical atherosclerosis in humans. For accurate detection of mitochondrial haplogroups, high-throughput sequencing of the mitochondrial genome using the Roche 454 technology was carried out. The results have shown that in Russian population, the belonging to haplogroup H is associated with an increased risk of atherosclerosis, but belonging to haplogroups T and U--with reduced risk. The data obtained can be used to assess individual risk of atherosclerosis and for further studies on the role of mitochondrial genome mutations in the development of atherosclerosis and its clinical manifestations.

[Prolongation of enoxaparin therapy to one month promotes recanalization of the occlusively thrombosed deep veins].

AIM: To compare effects of prolongation of the treatment with therapeutic doses of enoxaparin to 1 month on recanalization of occlusively thrombosed deep veins (OTDV) of the limbs with results of standard therapy with unfractionated heparin (UFH). Both treatments were followed by warfarin administration. MATERIAL AND METHODS: Thirty patients were selected from 111 patients with a history of deep vein thrombosis (DVT) and/or pulmonary artery embolism according to the following criteria: the presence of occlusive thrombosis of one deep vein minimum; the absence of DVT for 12 months of follow-up. Patients of group 1 (n = 15) received standard therapy (UFH for at least 5 days) with switch to warfarin. Patients of group 2 (n = 15) received therapeutic doses of enoxaparin (1 mg/kg each 12 hours) for 30 days minimum with switch to warfarin. Follow-up was 12 months. Ultrasonic duplex angioscanning of the limbs was made at baseline, 1, 3, 6 and 12 months after treatment start. RESULTS: After follow-up month 1, 3 and 6 number of patients with occlusive DVT was significantly less in group 2. All the patients given enoxaparin achieved recanalization of OTDV within 3 months of treatment. OTDV recanalization was not achieved in 20% patients of group 1 even 12 months after treatment start. CONCLUSION: Prolongation of enoxaparin treatment to 1 month followed by warfarin treatment is superior to standard UFH treatment followed by warfarin in providing recanalization of OTDV within 3 months of treatment. Moreover, this treatment predicts persistence of recanalization within 12 months of anticoagulant therapy.

[Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage].

AIM: To investigate frequency of carriage of genetic polymorphisms CYP2C9 and VKORC1 in patients with venous thromboembolic complications (VTEC) in Moscow population given warfarin treatment and effects of this carriage on stability of anticoagulation and frequency of hemorrhagic complications (HC) in warfarin treatment. MATERIAL AND METHODS: The study included 111 patients with the history of deep vein thrombosis and/ or pulmonary artery thromboembolism. All the patients received non-fractionated or low-molecular heparin for at least 5 days, then warfarin (target INR 2.0-3.0). Warfarin dose was selected empirically. Gene CYP2C9 and VKORC1 polymorphisms were studied. HC were endpoints. RESULTS: Genotype CYP2C9*1/*1 (a "wild" type) was detected in 94 (84.7%) patients. Of other genotypes - heterozygotes CYP2C9*1/*2 (4.5%) and CYP2C9*1/*3 (10.8%). Genotyping by VKORC1 detected genotype GG (a wild type) in 42.3%, genotype GA--in 48.6%, genotype AA--in 9.1% patients. A mean warfarin dose, supporting an adequaite INR, was asspciated with both genotype CYP2C9 and VKORC1. Warfarin doses were highest in carriers of wile genotypes CYP2C9 and VKORC1 (6,9 and 8,8 mg/day), the lowest--in patients with genotypes CYP2C9*1/*3 and VKORC1 (4,5 and 4,0 mg/day). The carriers of polymorphisms CYP2C9*1/*3 and VKORC1 showed less stable anticoagulation vs carriers of allele variants CYP2C9*1/*1, CYP2C9*1/*2 and genotypes GG, GA VKORC1. An HC rate depended, as a rule, on carriage of genotypes CYP2C9*1/*3 and AA VKORC1. The highest risk of HC was associated with genotype CYP2C9*1/*3. The results of multifactorial regression analysis also indicated that carriage of genotype CYP2C9*1/*3, a female gender and the range of INR in warfarin treatment > or = 2,66 are independent predictors of HC in VTEC patients on warfarin treatment. CONCLUSION: Carriage of gene CYP2C9 and VKORC1 polymorphisms affects suppoting dose of warfarin and rate of hemorrhage in patients with VTEC in Moscow population. Frequency of HC is the highest in carriers of genotypes CYP2C9*1/*3 and AA VKORC1, they need minimal supporting dose of warfarin. Carriage of genotype CYP2C9*1/*3 in line with a female gender and instability of INR is an independent predictor of HC in VTEC patients in Moscow population on warfarin treatment.

[Thrombin-activated inhibitor of fibrinolysis and efficacy and safety of long-term warfarin treatment in patients with venous thromboembolic complications].

AIM: To study effects of thrombin-activated fibrinolysis inhibitor (TAFI) on efficacy and safety of long-term anti-coagulant treatment in patients with venous thromboembolic complications (VTEC). MATERIAL AND METHODS: A total of 111 patients with a history of an episode of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE) entered the study. All the patients received unfractionated or low-molecular heparin for at least 5 days than switch on warfarin (target values of INR 2.0-3.0). Baseline blood levels of TAFI were measured. The patients were followed up for 18 months. Recurrent (DVT/TAFI and hemorrhagic complications (HC) were endpoints. Also, frequency of complete lysis of deep vein thrombi was assessed after 12 months of treatment. RESULTS: A TAFI level varied from 50 to 217% (median 106%, interquartile rage 90-133%). TAFI concentration positively correlated with fibrinogen and thromb size. The patients were divided into two groups depending on TAFI content: group 1 patients had low TAFI (under 25th percentile; < 90%); patients of group 2 had high TAFI (above 25th percentile; > 90%). Group 1 patients were characterized by less stable anticoagulation. This association did not depend on genetic characteristics which determine sensitivity to warfarin (CYP2C9 and VKORC1). Low TAFI was associated with reduced risk of DVT for 18 months and higher probability of complete lysis of the thrombi after 12 months of anticoagulant therapy compared to VTEC patients with high TAFI. No differences were found by TAFI level in patients with HC and without HC, but in HC patients low TAFI was associated with spontaneous hemorrhages and bleeding in therapeutic INR values. CONCLUSION: The results of this pilot study evidence that a TAFI level can be one of the factors influencing efficacy and safety of long-term anticoagulant therapy in patients with VTEC on warfarin treatment.

[ATR1 gene polymorphism in patients with hypertrophic cardiomyopathy and hypertensive heart].

Aim of the study was analysis of dependence of clinical picture and degree of severity of left ventricular hypertrophy (LVH) on polymorphism A/C of ATR1 gene in patients with hypertrophic cardiomyopathy (HCMP) and hypertensive disease (HD). With the method of polymerase chain reaction genotyping for polymorphic markers of A/C of ATR1 gene was carried out in 35 patients with HCMP and 33 patients with LVH developed at the background of long lasting HB. In the work we used clinico-instrumental methods of investigation (electrocardiography - ECG, echocardiography). It was revealed as result of the study that in HCMP type AA in comparison with type AC of ATR1 gene was associated with addition of arterial hypertension, presence of left ventricular outflow tract obstruction, greater severity of heart failure. In case of combination of HD with LVH type AA in comparison with types AC and CC of ATR1 gene is associated with more pronounced LVH.

[Independent predictors of deep vein thrombosis (results of prospective 18 months study)].

We followed for 18 months 90 patients who had had deep vein thrombosis (DVE) and/or pulmonary embolism (PE) and received therapy with anticoagulants either for 3-12 months or for indefinitely long time. During follow-up rate of recurrent DVE was 16.7%, no recurrences of PE were registered. Predictors of recurrent PE were selected among 165 demographic, anthropometric, anamnestic, clinical, genetic, instrumental, and laboratory parameters, as well as risk factors of development of thromboembolic complications. According to results of multifactorial regression analysis we established the following independent predictors recurrent DVE during 18 months of follow-up: elevated level of DAdimer after 1 month of anticoagulant therapy (p=0.005; relative risk--relative risk [RR] 8.1, 95% confidence interval [CI] 1.9 to 34.8), homozygosity for C249T polymorphism in beta-fibrinogen gene (p=0.044; RR 8.4 95% CI 1.1 to 65.7), and percentage of all values of international normalized ratio within therapeutic interval 2.0-3.0 (p=0.009; RR 0.94, 95 CI 0.89 to 0.98).

[Study of the genetic markers of thrombosis in hypertensive patients of the native population in the Republic of Mordovia].

The genetic markers (encoding factor of blood coagulation, the PAI-1 gene, the prothrombin gene, the GP IIb/IIIa gene, and the MTHFR gene) of thrombosis were studied in the Mordovians and Russians with essential hypertension (EH), who were residents of the Republic of Mordovia. One hundred and forty patients with TH and 90 healthy individuals of three nationalities, such as Russian, Moksha-Mordovian, and Erzya-Mordovian, were examined. Along with the routine clinical and instrumental studies, alleles of polymorphic markers were identified by the polymerase chain reaction (PCR). The polymorphic markers of the Arg 506 Gln gene, encoding factor V of blood coagulation, 4G5G of the PAI-1 gene, the G 20210 A prothrombin gene, the GP IIb/IIIa gene, and the A 1298 C MTHFR gene were also studied. The data were statistically analyzed using a package of the programs: Statistica for Windows 6.0 (Stat Soft), SPSS (version 14.0), and MS Excel XP (Microsoft). The authors used a chi-2 (chi-square) test was used to compare the incidence of genotypes and alleles in the patient groups. Hypertensive and normotensive persons were found to have no significant differences in the distribution of genotypes (encoding factor of blood coagulation, the PAI-1 gene, the prothrombin gene, and the GP IIb/IIIa gene) with regard to ethnicity in the Russian, and Moksha-Mordovian, and Erzya-Mordovian groups). Meanwhile, there was a significant preponderance of MTHFR gene mutation with the unfavorable genotype for Moksha-Mordovian patients with EH. The findings suggest that drug therapy for preventing venous thrombosis in patients with EH should be adjusted in relation to ethnicity.