MO096ROLE OF THE ENDOTHELIN SYSTEM IN THE INTERACTIONS OF THE VASOPRESSOR SYSTEMS IN VIVO IN MEN - IMPORTANCE OF GENETIC HOST FACTORS

Background and Aims Arterial hypertension is one of the most common diseases of the cardiovascular system worldwide and is still the cause of most deaths in Germany. Data on interactions of the endothelin-system with the renin-angiotensin- and the sympathoadrenergic system in the regulation of systemic hemodynamics in humans are lacking. In our present investigation we study the effects of Endothelin A-, Alpha1- and Angiotensin II-type-1-receptor antagonization on the systemic pressor effects of intravenous Endothelin-1-application in young, healthy men. In addition, we analyzed the effects of the genetic variations of the GNB3 C825T-polymorphism on hemodynamic changes. GNB3 825CT/TT-allele-carriers are considered to have a higher risk for multiple diseases with structural, vascular degeneration, such as arterial hypertension, diabetes mellitus and obesity. Method 21 healthy male volunteers were included in this double- blind, randomized, placebo-controlled cross-over study and were studied on four days. Endothelin-1 (ET-1) (0.5, 1, 2.5, 5 ng/kg/min for 20 min each) was given intravenous 2.0 hours after oral application of either placebo or Doxazosin, 3.5 hours after oral application of Candesartan (Candesartan 8 mg) or in the presence of a continuous infusion of the ET-A-selective antagonist BQ123 (60 μg/min). Blood pressure (BP) and heart rate (HR) were recorded and total peripheral resistance (TPR) was measured using impedance cardiography. ET-1-dose-response curves were analyzed with ANOVA. Data are presented as mean ± SD. Since we suspected an effect of the GNB3 C825T-polymorphism we divided the overall collective into 2 sub-collectives according to the GNB3 C825T-genotypes (n = 21, GNB3 825CC: n = 10, GNB3 825CT/TT: n = 11). Our analyses considered the overall collective and compared the sub-collectives intraday and interday. Results ET-1 increased systolic blood pressure (SBD) (p ≤ 0,01), diastolic blood pressure (DBD) and mean arterial pressure (MBP) as well as total peripheral resistance (TPR) (each p ≤ 0,001) with decreasing heart rate (HR5) (p ≤ 0,05). Elevation of blood pressure existed in both sub-collectives (GNB3 825CC: SBD & MBD: p ≤ 0,01, DBP & TPR: p ≤ 0,05, GNB3 825CT/TT: DBD, MBD & TPR: p ≤ 0,01, SBP p ≤ 0,05). Antagonization of ETA-receptors reversed the effect in the overall collective as well as in the sub-collectives. Both, Doxazosin, as well as Candesartan led to a decrease in blood pressure, however, dose-response relationship was influenced more by doxazosin (DBD: p ≤ 0,001, MBD: p ≤ 0,01) than by candesartan (all values: p > 0,05). For both drugs, blood pressure and TPR remained elevated under maximum ET-1-application compared to baseline measurement. Blood pressure dependent heart rate changes were observed in the overall collective and in GNB3 825CC-allele-carriers under sole ET-1-therapy (p ≤ 0.05) (Fig. 1). Candesartan reversed the effect of ET-1 on the sub-collectives (p > 0.05). GNB3 825CT/TT-allele-carriers showed no reduction in heart rate under ET-1-application, but with accompanying candesartan therapy (p ≤ 0.01) (Fig. 2). The genotype collectives thus behaved oppositely to the drugs in this respect. Conclusion In summary, ET-1 increased systolic, diastolic and mean arterial blood pressure as well as systemic vascular resistance. Doxazosin, Candesartan and BQ123 led to a decrease in blood pressure. Blood pressure and TPR remained elevated under maximum ET-1 application plus Candesartan or Doxazosin. The heart rate changes of the genotype-separated sub-collectives were opposite when ET-1 was administered compared to ET-1 and Candesartan.

The contribution of the AGT, GNB3, MTHFR, MTRR, ApoE, and PPARα polymorphisms to the development of masked arterial hypertension in patients with low and moderate cardiovascular risk

Aim: To assess the probability of masked arterial hypertension (MAH) in patients with low and moderate cardiovascular risk depending on polymorphisms in selected genes.Materials and methods: Ninety two (92) patients (mean age, 41.93±8.92 years) with low and moderate cardiovascular risk without any documented cardiovascular disorders were assessed clinically and had 24-hour ECG monitoring performed, as well as genotyping on the following markers: AGT Thr174Met rs4762, GNB3 C825T rs5443, MTHFR C677T rs1801133, MTRR Ile22Met rs1801394, ApoE Cys130Arg rs 429358, and PPARα G/C rs4253778. Depending on the presence of MAH, the patients were divided into two groups: with newly diagnosed arterial hypertension corresponding to the MAH criteria (n=58, 63%) and with normal office-based and ambulatory blood pressure and normal blood pressure according to the results of 24-hour ECG monitoring (n=34, 37%).Results: Two groups were not different by their age, cardiovascular risk factors, concomitant diseases and clinical characteristics. There were more men than women in the MAH group (р=0.028). In MAH patients, the most prevalent was Ile22Met rs1801394 A/G polymorphism of the MTRR gene (the odds ratio (OR) and relative risk (RR) for MAH were 4.23 [95% сonfidence interval (CI) 1.56–11.72] and 2.17 [1.25–4.12], respectively). The Cys130Arg rs 429358 Т/С genotype polymorphism of the АроЕ gene was also significant. The probability of MAH in the patients with АроЕ Т/С genotype was more than 3-fold higher: OR 3.67 [95% CI 1.34–10.28], RR 2.15 [95% CI 1.17–4.36]. The correlation analysis showed a moderate association between MAH and MTRR and АроЕ gene polymorphisms (Q=0.62 and Q=0.57, respectively).Conclusion: In patients with low and moderate cardiovascular risk, the probability of MAH depends not only from their gender, but also from their genetic background. The candidate genes for MAH in such patients are Ile22Met rs1801394 A/G polymorphism of the MTRR gene and Cys130Arg rs 429358 Т/С polymorphism of the АроЕ gene.

P3571Genes polymorphism and renal dysfunction formation in arterial hypertension patients with high adherence to treatment

Objective To evaluate the contribution of gene polymorphism to the formation of renal dysfunction in patients with hypertension with high adherence to treatment. Methods and materials 88 working-aged subjects with non-complicated arterial hypertension (average age 48,65±7,24 yrs). All patients underwent evaluation of genotype for markers AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met. To assess the glomerular function, cystatin C was measured in serum by ELISA, and serum level of NGAL was determined by ELISA to assess the function of the tubules.Depending on genotype peculiarities the following groups were formed: 1) 39 patients who had polymorphism of AGT Thr174Met in homozygous and 49 subjects without one; 2) 62 subjects who had polymorphism of GNB3 C825T in heterozygous and 26 subjects without one; 3) 52 subjects with polymorphism of MTHFR C677T in heterozygous and 36 subjects without one; 4) 48 subjects with polymorphism of MTRR Ile22Met in heterozygous and 40 subjects without one. Results Patients in the groups did not differ in sex, age, risk factors, comorbidities, concomitant medications, BP level, lipid spectrum. In the groups with the presence of the genes GNB3 and MTHFR polymorphism in the heterozygous form, the level of NGAL was significantly higher than in the groups with normal genotypes: 1.67±0.86 ng/ml versus 1.2±0.87 pg/ml (p=0.022), 1.49±0.61 pg/ml versus 1.21±0.56 ng/ml (p=0.034), respectively. At the same time, in these groups, the level of cystatin C was not significantly different. The AGT gene polymorphism groups differed significantly in cystatin C (p<0.001), but did not differ in the level of NGAL. In the group with the presence of the MTRR gene polymorphism, the level of cystatin C and the level of NGAL were significantly higher (p=0.042 and p=0.004, respectively). The correlation analysis revealed a moderate direct interconnections between cystatin C levels and the presence of the AGT gene polymorphism (r=0.46; p=0.017) and MTRR (r=0.33; p=0.039), as well as between the NGAL level and the presence of the GNB3 gene polymorphism (r=0.42; p=0.031), MTHFR (r=0.39; p=0.023) and MTRR (r=0.43; p=0.007). Conclusions In working-aged patients with uncomplicated hypertension with high adherence to treatment, the formation of renal dysfunction with a primary glomerular lesion is associated with the presence of polymorphism of the AGT gene in the heterozygous form. Formation of renal dysfunction with predominant tubular lesion is associated with the presence of GBN3 and MTHFR genes polymorphism of in the heterozygous form. And the formation of renal dysfunction with the damage of both glomeruli and tubules is associated with the presence of the MTRR gene polymorphism of the in the heterozygous form.

Polimorfismos Genéticos Associados ao Aparecimento de Hipertensão Arterial Numa População Portuguesa

Introduction: Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors.Objective: Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology.Material and Methods: Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0.Results: The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018).Discussion: According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology.Conclusion: In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model.

GENES POLYMORPHISM INVOLVED IN REGULATION OF BLOOD VESSELS FUNCTION IN WOMAN WITH THREATENED PRETERM DELIVERY

Введение. Изучение механизмов возникновения угрозы преждевременных родов имеет большую медицинскую и социальную значимость. В настоящее время в условиях демографического кризиса в России остро встает вопрос о предупреждении невынашивания беременности. Это диктует необходимость проведения дальнейших, в том числе и генетических исследований для наиболее эффективной диагностики и прогноза развития данной патологии. Цель исследования. Изучение особенностей полиморфизма генов системы гемостаза у женщин с физиологическим течением беременности и угрожающими преждевременными родами (ПР) в популяции Ивановской области. Материалы и методы. Обследовано 176 беременных в сроки гестации 22–36 недель в популяции Ивановской области: 73 женщины с физиологически протекавшей беременностью и 103 женщины с угрожающими ПР. Изучали особенности полиморфизмов генов (ADD1 G1378T, AGT T704C, AGT C521T, AGTR1 A1166C, AGTR2 G1675A, CYP11B2-344C/T, GNB3 C825T, NOS3 -786 T/C, NOS3 G894T), участвующих в регуляции функций сосудов. Результаты. Полиморфизмы генов, негативно влияющие на состояние сосудистой стенки, широко распространены у женщин в популяции Ивановской области; ряд полиморфизмов достоверно чаще встречается у пациенток с угрожающими ПР. Вероятно, это может быть причастно к нарушению маточно-плацентарного кровообращения и развитию угрожающих ПР. Заключение. Реализация неблагоприятного генетического фона сопряжена с участием определенных факторов внешней среды, комбинация которых индивидуальна. Introduction. Threatened preterm delivery is a great medical and social problem. At present, prevention of miscarriage is very actual question because of demographic crisis in Russia. So for most effective diagnostics and prognosis of this pathology further genetic investigations are needed. The aim: to study polymorphism of hemostasis-associated genes at women with physiological pregnancy and those with threatened preterm delivery among the population of Ivanovo region. Materials and methods. We examined 176 pregnant women at 22–36 weeks of gestation among population of Ivanovo region: 73 women with physiological pregnancy and 103 women with threatened preterm delivery. We studied the peculiarities of genes polymorphisms (ADD1 G1378T, AGT T704C, AGT C521T, AGTR1 A1166C, AGTR2 G1675A, CYP11B2 -344 C/T, GNB3 C825T, NOS3 -786 T/C, NOS3 G894T) involved in regulation of vascular function. Results. Genes polymorphisms adversely aff ecting the vascular wall are common at women in Ivanovo region; some of polymorphisms signifi cantly are more frequent at women with threatened preterm delivery. Probably this can be responsible for disorders of utero-placental blood fl ow and development of threatened preterm delivery. Conclusion. Realization of adverse genetic background might be caused by unfavorable environmental factors, their combination is individual.