Expression of Genes Encoding Nuclear Factors PPARγ, LXRß, and RORα in Epicardial and Subcutaneous Adipose Tissues in Patients with Coronary Heart Disease.

The nuclear factors PPARγ, RORα, and LXRß are involved in transcriptional control of adipogenesis and implicated in glucose and lipid metabolism. In adipose tissues, they regulate inflammation. This study focuses on expression of the PPARG, RORA, and LXRß (NR1H2) genes in epicardial and subcutaneous adipose tissues in patients with coronary heart disease as well as with concomitant abdominal obesity. In patients with coronary heart disease and abdominal obesity, PPARG mRNA level in subcutaneous adipose tissue was reduced in comparison with control group. In patients with total coronary occlusions, LXRß mRNA level in epicardial adipose tissue was reduced, and it positively correlated with plasma HDL cholesterol. Thus, in cases of concomitant abdominal obesity and chronic total coronary occlusions, coronary heart disease is characterized by down-regulated expression of the genes of various transcriptional adipogenesis-regulating factors in adipose tissue.

[The Expression of Genes Encoding ABCA1 and ABCG1 Transporters and PPARγ, LXRß, and RORα Transcriptional Factors in Subcutaneous and Visceral Adipose Tissue in Women with Metabolic Syndrome].

The study aimed to investigate tissue-specific gene expression of ABCA1 and ABCG1, encoding cholesterol transporters, as well as PPARG, LXRß (NR1H2), and RORA, encoding the most important transcriptional regulators of lipid metabolism, in subcutaneous and visceral adipose tissue (SAT and VAT) in women with metabolic syndrome. It was shown that the ABCG1 mRNA SAT/VAT ratio decreases with age and correlates with the development of metabolic syndrome. After age adjustment, women have reduced chances of metabolic syndrome development when ABCG1 gene expression in SAT is higher relative to VAT than women with VAT ABCG1 gene expression higher or comparable to SAT: OR = 0.15 (95% CI 0.03-0.76), p = 0.023. The ABCA1 mRNA SAT/VAT ratio positively correlated with HDL cholesterol levels (after age adjustment ß = 0.350, p = 0.046), therefore individuals with higher ABCA1 mRNA level in SAT relative to VAT had elevated HDL levels. The ABCA1 mRNA level in SAT was decreased in smokers (p = 0.001). There was a negative correlation between the PPARG mRNA level in SAT with body mass index and waist circumference in the general sample (ß = -0.602, p = 0.003 and ß = -0.642, p = 0.001, respectively, after age adjustment). A decrease of the PPARG mRNA SAT/VAT ratio was associated with elevated plasma insulin level and the insulin resistance index HOMA-IR ß = -0.819, p = 0.004 and ß = -1.053, p = 0.008, respectively, after age adjustment). Thus, the study has shown that the ratio of ABCA1, ABCG1, and PPARG genes expression in different types of adipose tissue (SAT/VAT) could be a significant factor that predicts the development of atherogenic dyslipidemia, metabolic syndrome, and insulin resistance in obesity.

[Epicardial and subcutenious adipose tissue adiponectin gene expression in coronary artery disease patients].

Aim To determine the expression of adiponectin gene (ADIPOQ) and the content of high-molecular-weight adiponectin (HMWA) in epicardial (EAT) and subcutaneous adipose tissue (SCAT) in patients with ischemic heart disease (IHD).Material and methods Paired samples of EAT and SCAT and blood serum were withdrawn from patients with IHD after bypass surgery and 16 subjects without IHD (comparison group). Matrix RNA (mRNA) level was measured using real-time polymerase chain reaction. HMWA levels in EAT and SCAT were evaluated by Western blotting. Serum adiponectin concentration was measured immunoenzymatically. For all patients, echocardiography was performed to measure the EAT thickness; coronarography was performed to determine severity of coronary atherosclerosis.Results Serum adiponectin concentration was lower in IHD patients than in the comparison group (p<0.001). Levels of ADIPOO gene mRNA and HMWA in SCAT were lower in IHD patients than in the comparison group (р=0.020 and p=0.003, respectively). The HMWA level in EAT was lower with the EAT thickness of 8 mm compared to the HMWA level in IHD patients with EAT ≤8 mm (p=0.034).Conclusion The decreased serum concentration of antiatherogenic adiponectin and the reduced expression of ADIPOQ gene in SCAT (mRNA, HMWA) are associated with IHD.

[Prognostic value of epicardial fat thickness in coronary heart disease patients after myocardial revascularization].

Objective To study the role of epicardial adipose tissue (EAT) in determination of risk for adverse course of ischemic heart disease (IHD) in patients after myocardial revascularization.Materials and Methods This study included 217 subjects, 182 IHD patients and 35 evaluated individuals without IHD. Percutaneous coronary intervention (PCI) was performed for 104 patients and coronary bypass (CB) was performed for 78 patients. Also echocardiography (EchoCG) and cardiac computed tomography were performed.Results In IHD patients, EAT volume and thickness were greater than in evaluated subjects without IHD. The composite endpoint (CEP) was observed after PCI more frequently than after CB. In IHD patients with an EAT thickness of 8.5 to 10.2 mm measured with EchoCG in the atrioventricular groove, the risk of CEP was 4.3 times higher after myocardial revascularization than with thicker or thinner EAT regardless of the revascularization method.Conclusion An EAT thickness of 8.5 to 10.2 mm in the atrioventricular groove as measured with EchoCG was associated with a risk of adverse IHD course in patients who have underwent myocardial revascularization.

[Common Carotid Intima-Media Thickness, Levels of Total and High-Molecular Weight Adiponectin in Women With Abdominal Obesity].

OBJECTIVE: to investigate influence of different forms of adiponectin on carotid intima-media thickness (CIMT) in women with abdominal obesity (AO) in St.­Petersburg. It has been recognized before that AO is associated with cardiovascular diseases, including atherosclerosis, but mechanism of this association remains unclear. AO leads to imbalance of adipokines, in particularly decrease of adiponectin, which may lead to atherosclerotic lesion of carotid arteries. MATERIALS AND METHODS: We investigated 81 women with AO (IDF criteria, 2005) and 21 women with normal waist circumference. СIMT was evaluated by an ultrasound scanner. RESULTS: Among patients with AO 54.9 % had CIMT >0.9 mm and 38.5 % had atherosclerotic plaques in common carotid arteries. The total adiponectin level (TA) was lower in women with CIMT> 0.9 mm, than in women with normal CIMT (23.20 [2.55; 40.65] and 18.09 [1.60; 38.92] µg/ml, respectively; р0.9 mm, than in women with normal CIMT (2.21 [0.50; 6.85] and 2.88 [1.29; 15.45] µg/ml, respectively; р0.9 mm, than in women with CIMT >0.9 mm and atherosclerotic plaques in carotid arteries (3.09 [1.34; 6.85] and1.82 [0.50; 2.94] mcg/ml, respectively; р0.9 mm depended on waist circumference, diastolic blood pressure and level of C-reactive protein (CRP), while presence of atherosclerotic plaques was associated with levels of HMWA and CRP. CONCLUSIONS: Factors that make the greatest contribution at early stages of atherosclerosis development in carotid arteries in women with AO can be increased waist circumference, high diastolic blood pressure, and high level of CRP. At later stages of atherosclerosis development lowered HMWA level can contribute to the formation of atherosclerotic plaques.

ITLN1, PPARg AND TNFa GENE EXPRESSION IN VISCERAL ADIPOSE TISSUE.

The adipose tissue is considered today as an endocrine organ in which tissue-specific regulation of gene expression plays a key role in the processes of development of obesity and comorbidities, such as diabetes and cardiovascular disease. The present study is focused on ITLN1, PPARã and TNFá gene expression in intra-abdominal adipose tissue and its effect on the serum levels of omentin 1 and TNFa in individuals with different body mass. It has been shown that serum TNFa level is significantly higher in the subgroup of patients with overweight and obesity (BMI ≥ 25 kg/m2) as compared to individuals with normal body weight (BMI < 25 kg/m2)( p < 0.03). We have demonstrated that the expression level of the PPARã gene is positively correlated with the ITLN1 gene expression level in the intra-abdominal adipose tissue (r = 0.516, p = 0.020). Serum level of omentin 1 positively correlates with PPARã mRNA and protein levels in intra-abdominal adipose tissue (r = 0.550, p < 0.05 and r = 0.581, p < 0.03, respectively). For the subgroup of patients with overweight and obesity, we have shown negative correlation of the level of TNFá mRNA with PPARã and ITLN1 mRNA levels was shown (r = ­0.549, p < 0.05 and r = ­0.475, p < 0.05, respectively). This study is the first to show a correlation relationship between PPARã gene expression level in the intra-abdominal adipose tissue and the expression and secretion levels of omentin 1.

[Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue]. / Reguliatsiia ékspressii genov transporterov ABCA1 i ABCG1 v intraabdominal'noi zhirovoi tkani.

Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis - LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels. ABCA1 and ABCG1 gene expression positively correlated with obesity indicators such as body mass index (BMI) (r=0.522, p=0.004; r=0.594, p=0.001, respectively) and waist circumference (r=0.403, p=0.033; r=0.474, p=0.013, respectively). The development of obesity is associated with decreased IAT levels of RORa and LXRb mRNA (p=0.016 and p=0.002, respectively). These data suggest that the nuclear factor RORa can play a significant role in the regulation of cholesterol metabolism and control IAT expression of ABCA1 and ABCG1, while the level of IAT LXRb gene expression may be an important factor associated with the development of obesity.

[Leptin and metabolic syndrome].

Obesity is characterized by increased concentration of leptin and disturbance of the feedback between hyperleptinaemia and enhanced appetite. The hyperleptinaemia is often combined with hyperglycaemia and arterial hypertension and seems to be a predictor of acute cardiovascular events. Leptin inhibitors might be used in the future for therapy in case of the metabolic syndrome.

[Genetic variants of platelet ADP receptor P2Y12 associated with changed platelet functional activity and development of cardiovascular diseases].

The key role in platelet aggregation is played by the platelet ADP receptor P2Y12, which is the target for antiaggregant drugs, clopidogrel and ticlopidine. At present, only sporadic data on genetic variants of platelet ADP receptor P2Y12 are available from literature, and their association with thromboembolic and cardiovascular diseases still remains obscure. Analysis of the group of subjects with high platelet reactivity resulted in identification of two nucleotide substitutions, C18T and G36T, in the coding region of the P2Y12 gene. The frequency of the P2Y12 T1 8 allele was higher in control group than in the group of patients survived from myocardial infarction at the age under 45 years (39% versus 28%, respectively, P = 0.04). Moreover, in the T18 carriers, platelet aggregation activity was lower than in the carriers of the wild-type genotype (0.84 +/- 0.05% versus 1.01 +/- 0.08%, respectively, P = 0.03). In the group of patients with early myocardial infarctions, a tendency towards the increased frequency of 16T allele in comparison with control group (20 and 12%, respectively, P = 0.07) was observed. The rate of ADP-induced platelet aggregation in the carriers of 16T allele from the control group was somewhat higher than in the subjects with the GG36 genotype (1.31 +/- 0.16% versus 1.12 +/- 0.06%, respectively, P = 0.07). The nucleotide substitutions identified were in absolute disequilibrium, i.e., allele T18 conformed to allele G36. On the contrary, allele C18 conformed to allele T36. Haplotype T18G36 was found to be responsible for the decreased risk of myocardial infarction and decreased platelet reactivity. It is suggested that polymorphisms of the P2Y12 gene identified can be used for determination of the risk group for myocardial infarction in the young males.

[Genetic risk factors for development of myocardial infarction in young men living in North-West region of Russia].

With the aim to detect genetic factors of risk of development of early myocardial infarction (MI) we studied 29 allele variants of 19 genes in 206 men who had survived MI in the age before 45 years and in 195 men of similar age without cardiovascular diseases. All subjects were inhabitants of North-West region of Russia. The following factors were associated with history of myocardial infarction: genotype RR191 of paraoxonase-1 (PON1) gene (RR 2.8 [95% CI: 1.24 - 6.30]), P1A2 allele of glycoprotein (GP) IIIa subunit of platelet fibrinogen receptor GPIIb/IIIa (RR 1.8 [95% CI: 1.11 - 2.93]), and Met145 allele of GPIbalpha platelet von Willebrand factor receptor gene. Genotype CC ( - 108) PON1 was associated with lowered risk of MI development (RR 0.6 [95% CI: 0.40 - 0.91]). During 7 years of follow-up 30 men from MI group died of recurrent acute coronary syndromes. In the group of those who died we noted increased prevalence of P1A2 GPIIIa allele compared with those who survived (p < 0.03). The results allow to suggest that contribute to development of MI in young men factors associated with elevation of functional state of platelets and levels of oxidized lipids in blood plasma.

[Allele Frequency Analysis of Four Single Nucleotide Polymorphisms Locating in Promoter and 5'-Untranslated Regions of ABCAI Gene in Young Men - Survivors From Myocardial Infarction]. / Analiz chastoty vyiavleniia chetyrekh strukturnykh polimorfizmov DNK v promotornoi i 5'-netransliruemykh oblastiakh gena ABCA1 u muzhchin, perenesshikh infarkt miokarda v molodom vozraste.

Analysis of allele distribution of four single nucleotide polymorphisms (C-17G, C69T, G-191C and 319insG) of promoter and 5'-untranslated regions of the ABCA1 gene was carried out in a sample of 171 men, who had survived myocardial infarction before 45 years, and in controls. Two-fold increase of T69 and C-191 allele frequencies were observed in Russian population in comparison to Dutch one. While comparing allele and genotype distributions of the polymorphisms in the samples under study no statistically significant differences were found, so as no influence of different alleles on lipid spectrum data was observed. Role of polymorphisms under study appears to be insignificant in formation of genetic susceptibility to myocardial infarction in young men.

[Effect of phenofibrate treatment on endothelial dysfunction in patients with history of myocardial infarction in young age]. / Vliianie terapii fenofibratom na éndotelial'nuiu disfunktsiiu u bol'nykh, perenesshikh infarkt miokarda v molodom vozraste.

AIM: To evaluate the severity of endothelial dysfunction in patients with a history of myocardial infarction in young age and its changes during therapy with lipantil 200 M. MATERIAL AND METHODS: The percentage of dilatation of the brachial artery during reactive hyperemia test, number of circulating desquamated endotheliocytes, and lipid metabolism parameters were evaluated in 40 men with a history of myocardial infarction before the age of 45 years and 40 healthy men. RESULTS: Endothelial dysfunction was detected in coronary patients: the percentage of dilatation of the brachial artery was decreased, the number of circulating endotheliocytes increased, and lipid metabolism disordered. After 3-month lipantil 200 M therapy the severity of endothelial dysfunction significantly decreased and lipid metabolism parameters improved. CONCLUSION: Patients with a history of myocardial infarction in young age develop endothelial dysfunction, whose severity decreases after hypolipidemic therapy.

[Effects of hypolipidemic therapy on the endothelial dysfunction in patients with myocardial infarction at young age]. / Vliianie gipolipidemicheskoi terapii na éndotelial'nuiu disfunktsiiu u bol'nykh, perenesshikh infarkt miokarda v molodom vozraste.

AIM: To evaluate the degree of endothelial dysfunction in patients who survived myocardial infarction (MI) at young age, its response to therapy with lipantil. MATERIAL AND METHODS: Dilation of the brachial artery in response to reactive hyperemia, number of circulating desquamated endotheliocytes, lipid metabolism were assessed in 40 males who had survived MI at the age under 45 years and in 40 healthy males. RESULTS: Patients with ischemic heart disease had endothelial dysfunction: decreased dilation of the brachial artery, increased count of circulating endotheliocytes, defective lipid metabolism. A 3-month lipantil therapy resulted in a significant reduction of endothelial dysfunction, improvement of lipid metabolism. CONCLUSION: Patients who survived MI at young age have endothelial dysfunction the severity of which diminish in hypolipidemic therapy.

[I/D polymorphism in the angiotensin-converting enzyme gene in men with myocardial infarction at young age]. / I/D polimorfizm gena angiotenzinprevrashchaiushchego fermenta u muzhchin, perenesshikh infarkt miokarda v molodom vozraste.

The rate of D allele did not differ between patients with ischemic heart disease (IHD) who had myocardial infarction before the age 45, and healthy males. The DD genotype of the ACE gene was much more frequently encountered in the patients than in healthy males. The findings suggest that the DD genotype is an independent risk factor of the IHD and myocardial infarction in young patients.

[Endothelium disfunction in patients with myocardial infarction at the younger age]. / Disfunktsiia éndoteliia u bol'nykh, perenesshikh infarkt miokarda v molodom vozraste.

The endothelium was studied in males who had sustained myocardial infarction (MI) at young age (under 45 years). The parameters of endothelium-dependent dilatation of the brachial artery were estimated during a reactive hyperemia test and the blood count of circulating (desquamated) endotheliocytes was measured. The values obtained in patients groups randomized by different parameters were compared with each other and with control values. The patients who had experienced in youth were found to have endothelial dysfunction, as appeared as both a larger number of circulating blood endotheliocytes and an altered vascular response during the reactive hyperemia test. It was found that endothelial function was not clearly related to the risk factors of atherosclerosis though the association was more marked when coronary heart disease is concurrent with arterial hypertension and hypercholesterolemia.

[Diagnostic value of evaluation of desquamated endothelial cells in blood]. / Diagnosticheskaia tsennost' opredeleniia deskvamirovannykh éndotelial'nykh kletok v krovi.

Circulating endotheliocytes as indicator of endothelial dysfunction were evaluated in the blood by Hladovec's method (1978) in patients with coronary disease, coronary stroke, insulin-dependent diabetes mellitus, and gestosis. The content of circulating (desquamated) endotheliocytes was increased in all patients, which reflected endothelial damage. The most pronounced changes were detected in patients with gestosis. Endotheliocyte content correlated with the concentration of Willebrandt's factor in the blood, which recommends using endotheliocyte count as a marker of endothelial damage.

[Multicenter Study of Efficacy and Safety of a Preparation of Lovastatin in Patients With Ischemic Heart Disease and Mild or Moderate Hypercholesterolemia] / Rossiiskoe mnogotsentrovoe issledovanie éffektivnosti i bezopasnosti lovastatina u bol'nykh ishemicheskoi bolezn'iu serdtsa so slaboi i umerennoi stepen'iu giperkholesterinemii.

Ninety patients with ischemic heart disease and mild or moderate hypercholesterolemia were included in a multicenter study of efficacy and safety of a preparation of lovastatin (Holetar, KRKA). After 6 weeks of a diet period 46 patients remained on diet and in 44 patients lovastatin was added to diet for 12 weeks. All patients received 20 mg/day for 6 weeks. If after 6 weeks on lovastatin target level of low density lipoprotein cholesterol (LDL CH, 3.0 mmol/l) was not achieved the dose was doubled. Target LDL CH level was achieved in 47% and 58% of patients by the end of 6 and 12 weeks, respectively. The 20 mg dose lowered levels of LDLCH by 27% and of triglycerides by 10%. The drug was well tolerated.

[Changes in the concentration of atrial hormone in hypertensive crises]. / Izmeneniia kontsentratsii predserdnogo gormona pri gipertonicheskikh krizakh.

The paper presents concentrations of atrial sodium-uretic hormone (AH) in the plasma of hypertensive subjects during a hypertensive crisis and in stable blood pressure, in healthy subjects (12, 19 and 7 females, respectively). AH levels were the highest in hypertensives in the crisis. Mean AH concentrations in the crisis and short after the pressure normalization did not differ much. Mechanisms of these phenomena are discussed, relations between AH levels, clinical and hemodynamic characteristics of hypertensive crises are considered.