Endothelial Dysfunction Formation Research Articles

Role ofpreconception endothelial dysfunction in development of obstetric complications

The article highlights the pathogenetic mechanisms of endothelial dysfunction formation and its role in the occurrence of gestational complications. The main tasks of the pregravid preparation of patients with diseases associated with endothelial dysfunction are considered. The relevance of early detection of risk factors for gestational complications caused by endothelial dysfunction is emphasized, and methods for its indirect assessment are described. A list of measures aimed at preventing the clinical implementation of endothelial dysfunction is given, and the possibilities of its therapeutic correction are described.

THE ROLE OF ENDOTHELIAL DYSFUNCTION AS A PART OF SYSTEMIC INFLAMMATORY RESPONSE IN PATHOGENESIS OF AGGRESSIVE AND INDOLENT NON-HODGKIN’S LYMPHOMAS

Objective. To study of manifestation of angiogenic and hemostatic forms of endothelial dysfunction and systemic inflammatory response in patients with non-Hodgkin’s lymphomas at the onset of disease. Material and methods. A total of 99 patients were enrolled in this study, including 55 patients with aggressive variants and 44 patients with indolent variants. The average age was 60.71±10.63 years. The serum level of vascular endothelial growth factor (VEGF) was measured as a marker of angiogenic form of endothelial dysfunction, the serum levels of thrombomodulin, D-dimers, soluble fibrin-monomer complex (SFMC) and level of Willebrand factor activity were used for evaluation of hemostatic form of endothelial dysfunction. To assess the degree of systemic inflammation response the serum levels of proinflammatory cytokines – TNF-α, IL-1β, IL-6 were measured, as well as serum level of acute phase proteins – C-reactive protein (CRP), fibrinogen. The serum level of IL-4 was used to evaluate antinflammation resistance. Results and discussion. Proinflammatory cytokine (TNF-α, IL-1β and IL-6) content was higher in both studied groups compare to the control group. Serum concentration of anti-inflammatory cytokine IL-4 in studied groups did not differ from the level in the controls group. CRP and fibrinogen serum content was increased only in group of patients with aggressive variants. There was a significant correlation between the level of CRP and proinflammatory cytokines in aggressive lymphoma group. Serum content of VEGF, thrombomodulin, D-dimers, SFMC and Willebrand factor activity were increased in both studied group in comparison with the control group. Concentration of thrombomodulin, D-dimers, SFMC and Willebrand factor activity was higher in patients with aggressive than in patients with indolent lymphomas. Conclusion. The signs of angiogenic and hemostatic forms of endothelial dysfunction in patients with aggressive and indolent variants of non-Hodgkin’s lymphoma were detected, as well as manifestation of systemic inflammatory response and attenuation of anti-inflammatory resistance with development of cytokines imbalance with proinflammatory cytokines predominance. The manifestations of systemic inflammatory response and hemostatic type of endothelial dysfunction with activation of coagulation were displayed more prominently in the aggressive lymphoma group.

NEW PREDICTIVE FACTORS OF DIABETIC MACULOPATHY DEVELOPMENT IN DIABETES MELLITUS TYPE 2

Relevance. In diabetes mellitus (DM), a cascade of pathological reactions unfolds in the vascular endothelium with the formation of endothelial dysfunction (EDF). Its main factors are endothelium hormone – endothelin-1 (ET1), nitric oxide (NO), endothelial NO-synthase (eNOS), and also tumor necrosis factor-α (TNFα). But the unexplored question remains whether EDFs can be used as prognostic markers for the development of diabetic maculopathy.
 Objective: to find out the prognostic value of EDF factors in the development of diabetic maculopathy (DM) in type 2 diabetes.
 Material and methods. This study included 152 patients (304 eyes) with type 2 diabetes, which were divided into groups according to the degree of diabetic retinopathy (DR): 1st – initial non-proliferative DR, 2nd – moderate or severe non-proliferative DR and 3rd – proliferative DR. DM was determined by the presence of specific diabetic retinal changes in the macular area according to the International Clinical Gravity Scale of the American Academy of Ophthalmology (2002). The control group consisted of 95 people. The content of ET1, eNOS and TNFα was determined by ELISA; the content of the final NO metabolites (NOx) was determined spectrophotometrically. Statistical data processing was performed using Statistica 10 (StatSoft, Inc., USA).
 Results. With the progression of DR, there was an increase in the frequency and severity level of DM (p=2.0e-06), which was accompanied by an increase in the blood levels ET1 (3.7-4.7 times), NOx (1.4-1.5 times) and TNFα (4.2-6.5 times), with a progressive decrease in the level of eNOS (P<0.01). Multifactorial logistic regression analysis (GLZ package; StatSoft, Inc., USA) showed that pathogenetic factors for the DM development were multiple increase in blood levels of ET1 and TNFα, which was confirmed by building a logistic regression model with satisfactory results of adequacy (p=0.039).
 Conclusions. This study confirmed the significant role of EDF in type 2 diabetes and proved the prognostic value of ET1 and TNFα blood levels for the development of DM.

CONNECTION OF THE ENDOTHELIAL DYSFUNCTION FACTORS AND DIABETES MELLITUS 2 TYPE SEVERITIES

Relevance. In the case of diabetes mellitus (DM), a whole cascade of pathological reactions unfolds in the endothelium of the vessels that afflict glucose toxicity, excessive action of stimulating hypertension and inflammatory factors, thrombotic activators, and the intensification of oxidative stress, which leads to the formation of endothelial dysfunction (EDF). On the other hand, the damaged endothelium itself is included in the pathogenesis of diabetes and causes the development of further violations.
 Objective: to investigate the association of EDF factors: endothelin 1 (ET1), endothelial NO-synthase (eNOS), nitric oxide (NO), tumor necrosis factor (TNFα), and diene conjugates (DC) with severity of type 2 diabetes.
 Materials and methods. Data were used for 152 hospital patients with type 2 diabetes at the age from 34 to 80 years (53.9±8.4 years). Women were 95 (62.5%), men – 57 (37.5%). According to the degree of severity of patients was divided into three groups: 1st (37.5% of patients) – the average stage in the compensation stage (HbA1s 7-9%), 2nd (41.4%) – the average stage in the stage of decompensation (HbA1s more than 9%), 3rd (21,1%) – a severe degree in the stage of decompensation. The control group included 95 practically healthy individuals. The plasma levels of the blood were determined by the enzyme-linked method: ЕТ1 (Biomedica Immunoassays, Austria), eNOS (BCM Diagnostics, USA) і TNFα (Bender Medsystems, Austria). The level of blood NO and DC were determined biochemically (spectrophotometer Specord, Germany). Statistica 10 (StatSoft, Inc., USA) was used to statistically process the data obtained.
 Results. Levels of EDF factors depended on the severity of DM 2 type. Thus, the level of ETI in patients exceeded control in 3.7-4.7 times (p<0.001) with the maximum values in the 2nd and 3rd groups; also increased blood levels of NO (1.4-1.5 times; p<0.001). The highest increase was observed in TNFα levels (4.2-6.5 times; p<0.001) and DC (2.3-2.7 times; p<0.001). The blood content of eNOS in the patients' groups was lower when compared with control (1.3-1.9 times; p<0.001). Single-factor regression analysis showed that ET1 caused high glycemia, albuminuria, increased the degree of decompensation of DM 2 type and the degree of diabetic nephropathy. NO accumulation in the blood affects the decrease in glomerular filtration rate and the deterioration of renal function. TNFα and DC contributed to almost all key indicators of DM 2 type, which had a synergistic effect with other EDF factors.
 Conclusion. Factors of EDF are closely linked with clinical and laboratory indicators of severity of DM 2 type, which highlights them in the pathogenesis of the disease.

CONNECTION OF THE ENDOTHELIAL DYSFUNCTION FACTORS AND DIABETES MELLITUS 2 TYPE SEVERITIES

Relevance. In the case of diabetes mellitus (DM), a whole cascade of pathological reactions unfolds in the endothelium of the vessels that afflict glucose toxicity, excessive action of stimulating hypertension and inflammatory factors, thrombotic activators, and the intensification of oxidative stress, which leads to the formation of endothelial dysfunction (EDF). On the other hand, the damaged endothelium itself is included in the pathogenesis of diabetes and causes the development of further violations.
 Objective: to investigate the association of EDF factors: endothelin 1 (ET1), endothelial NO-synthase (eNOS), nitric oxide (NO), tumor necrosis factor (TNFα), and diene conjugates (DC) with severity of type 2 diabetes.
 Materials and methods. Data were used for 152 hospital patients with type 2 diabetes at the age from 34 to 80 years (53.9±8.4 years). Women were 95 (62.5%), men – 57 (37.5%). According to the degree of severity of patients was divided into three groups: 1st (37.5% of patients) – the average stage in the compensation stage (HbA1s 7-9%), 2nd (41.4%) – the average stage in the stage of decompensation (HbA1s more than 9%), 3rd (21,1%) – a severe degree in the stage of decompensation. The control group included 95 practically healthy individuals. The plasma levels of the blood were determined by the enzyme-linked method: ЕТ1 (Biomedica Immunoassays, Austria), eNOS (BCM Diagnostics, USA) і TNFα (Bender Medsystems, Austria). The level of blood NO and DC were determined biochemically (spectrophotometer Specord, Germany). Statistica 10 (StatSoft, Inc., USA) was used to statistically process the data obtained.
 Results. Levels of EDF factors depended on the severity of DM 2 type. Thus, the level of ETI in patients exceeded control in 3.7-4.7 times (p<0.001) with the maximum values in the 2nd and 3rd groups; also increased blood levels of NO (1.4-1.5 times; p<0.001). The highest increase was observed in TNFα levels (4.2-6.5 times; p<0.001) and DC (2.3-2.7 times; p<0.001). The blood content of eNOS in the patients' groups was lower when compared with control (1.3-1.9 times; p<0.001). Single-factor regression analysis showed that ET1 caused high glycemia, albuminuria, increased the degree of decompensation of DM 2 type and the degree of diabetic nephropathy. NO accumulation in the blood affects the decrease in glomerular filtration rate and the deterioration of renal function. TNFα and DC contributed to almost all key indicators of DM 2 type, which had a synergistic effect with other EDF factors.
 Conclusion. Factors of EDF are closely linked with clinical and laboratory indicators of severity of DM 2 type, which highlights them in the pathogenesis of the disease.

TO THE QUESTION OF DIAGNOSES OF ENDOTHELIAL DYSFUNCTION UNDER THE CONDITIONS OF THE TRANSPORTED FLIGHT IN THE ARCTIC

The aim of the study was to assess the state of endothelial function in conditions of in the work, individual biochemical (homocysteine, folate, vitamin B12 levels) and functional (by peripheral arterial tonometry) markers of endothelial dysfunction during a marine trans-latitude voyage in the Arctic were studied. The design of the study is a prospective cohort nonrandomized study. The object of the study was practically healthy people - members of the Arctic scientific expedition and crew members of the marine scientific research vessel. The preliminary analysis of the obtained data allows to state that in healthy participants of short-term transhort maritime voyage in the Arctic abnormalities of endothelium-dependent vasodilation function were detected using the method of peripheral arterial tonometry on EndoPaT-2000 device with a test with active hyperemia and homocysteine exchange results, which indicates the presence of endothelial dysfunction. The unfavorable influence of high latitudes of the Arctic on the formation of endothelial dysfunction in healthy participants of the expedition and members of the research vessel crew was revealed.

УЧАСТИЕ НЕНАСЫЩЕННЫХ ЖИРНЫХ КИСЛОТ В АКТИВАЦИИ МЕСТНОГО ГЕМОСТАЗА ПРИ НЕЙРОХИРУРГИЧЕСКИХ ОПЕРАЦИЯХ

Введение. Оперативные вмешательства на спинном мозге связаны с потенциальным риском развития тромбоза, что связано с поступлением в кровоток тромботически активных веществ. Известно, что при нейрохирургических операциях нарушения в системе гемостаза возникают в 4–6% случаев. Цель работы. Исследование механизма активации местного гемостаза при операционной дискэктомии с межстволовым спондилодезом титановым винтовым имплантатом. Материалы и методы. В пробах крови, взятых из хирургической раны у 38 пациентов (18 мужчин и 20 женщин), исследовали спектр жирных кислот (ЖК). Результаты. В исследованных методом газовой хроматографии с масс-спектрометрией пробах крови, взятых из операционной раны до и после постановки имплантата, было выявлено статистически значимое снижение относительного содержания эйкозаноидов С18–С22 во второй пробе крови и, соответственно, повышение удельной концентрации ЖК с числом атомов углерода больше 25 и меньше 16. Установлено, что спонтанная остановка кровотечения и местный гемостаз в операционной ране сразу после установки имплантата связаны со статистически значимыми изменениями относительного содержания в раневом отделяемом ненасыщенных ЖК. Заключение. Эффект активации местного гемостаза, возможно, связан с удельным содержанием ЖК (арахидоновой, линолевой и линоленовой), которые обеспечивают тромбогенный и вазодилатирующий эффекты. Рекомендации пациентам, готовящимся для планового хирургического лечения: включать в рацион продукты с повышенным содержанием ЖК (С18–С22) с двумя или тремя ненасыщенными двойными связями (оливковое и льняное масла, рыбий жир) для уменьшения и профилактики операционной кровопотери. Introduction. Surgical interventions on spinal medulla are associated with a potential thrombosis risk that is associated with entering of thrombotic active substances in blood fl ow. It is known that in neurosurgery hemostatic disorders occur in 4–6% of cases. The aim was to study the mechanism of local hemostasis activation at operative discectomy with interbody spondylosyndesis by titanium screw implant. Materials and methods. In 38 patients (18 men and 20 women) fatty acid (FA) spectrum in blood samples taken from a surgical wound was examined. Results. By method of gas chromatography with mass spectrometry we examined blood samples taken from surgical wound before and after implant installation. We found statistically significant decreasing in relative content of C18–C22 eicosanoids in second blood sample and accordingly increasing of specifi c FA concentration with the number of carbon atoms greater than 25 and less than 16. It was found that spontaneous stop of bleeding and local hemostasis in surgical wound immediately after implant installation were associated with statistically signifi cant changes in the relative content of unsaturated FA. Conclusion. The effect of local hemostasis activation may be associated with specific FA (arachidonic, linoleic and linolenic) content that provide thrombogenic and vasodilating effects. Recommended guideline for patients who are preparing for planned surgery: to include in the diet foods with high content of FA (C18–C22) with two or three unsaturated double bonds (olive and flaxseed oil, fish oil) for reduction and prevention of intraoperative blood loss.

РОЛЬ ЭНДОТЕЛИАЛЬНОЙ ДИСФУНКЦИИ В ФОРМИРОВАНИИ ОСЛОЖНЕНИЙ САХАРНОГО ДИАБЕТА И ПЕРСПЕКТИВЫ ЕЕ КОРРЕКЦИИ РЕЦЕПТОРНЫМ АНТАГОНИСТОМ ИНТЕРЛЕЙКИНА-1

Цукровий діабет (ЦД) – неухильно прогресуюче захворювання, що вражає переважно осіб працездатного віку і швидко приводить до розвитку системних ускладнень. ЦД посідає третє місце в статистиці смертності після серцево-судинних і онкологічних захворювань. Основною причиною інвалідизації і летальності при ЦД є мікро- і макросудинних ускладнення, що призводять до розвитку серцево-судинних та цереброваскулярних захворювань. Діабет асоціюється з підвищеним ризиком розвитку інфаркту міокарда та ішемічного інсульту і з їх менш успішним результатом.Мета дослідження – провести загальний огляд і теоретичний аналіз репрезентативних фактів у галузі досліджень різних аспектів формування та прогресування ендотеліальної дисфункції при цукровому діабеті.Матеріали і методи. У статті використано дані з наукових праць, літературних джерел, офіційних документів, архівів, статистичних збірників, що опираються на фактичний матеріал. Застосовано поаспектний метод вирішення завдань оптимізації оцінки взаємозв'язків, взаємозалежності та значимості фактів, аргументованих доказів і теоретичних узагальнень, обґрунтування логічних висновків і практичних рекомендацій.Результати досліджень та їх обговорення. Основним фактором, що ушкоджує, є гіперглікемія, яка через активацію сорбітолового шляху, протеїнкінази С і глікування білків призводить до розвитку оксидативного стресу, зменшення утворення оксиду азоту, активації прозапального шляху NF-kB, що сприяє прискореному прогресуванню макроангіопатій, а також викликає ушкодження мікросудинного русла. Церебральна мікроангіопатія є частиною генералізованих судинних ускладнень, що спостерігаються при діабеті, і більш частий несприятливий результат у цих хворих може бути зумовлений системним характером судинного ураження і негативним впливом гіперглікемії на перебіг ішемічного процесу. Передбачається, що при ЦД раніше спостерігається пошкодження внутрішнього шару судинної стінки – ендотелію. Ендотелій у нормі забезпечує трофічну і захисну функції відносно інших верств судинної стінки. Саме ендотелію належить головна роль у підтримці тонусу судин і гемостазу, в розвитку ремоделювання і місцевого запалення (вироблення про- і протизапальних факторів). Порушення функції ендотелію і формування дисфункції ендотелію у хворих з інсулінорезистентністю призводить до підвищення судинної реактивності. Дисбаланс вазоконстрикторів і вазодилататорів є одним із ланок патогенезу діабетичних ангіопатій, оскільки тригерні фактори включають процеси запалення зі зміною функції гладком’язового шару і надмірним утворенням прозапальних цитокінів.Висновки. Застосування препаратів з ендотеліопротекторними властивостями можна розглядати як першочергову лінію ефективного попередження судинних і неврологічних ускладнень у хворих на ЦД. У статті обґрунтовуються перспективи корекції ендотеліальної дисфункції протизапальним цитокіновим препаратом – рецепторним антагоністом інтерлейкіну-1.

Comparative investigation of hydroxycitric acid and apples phenolic compounds food concentrate on parameters of nitric oxide system under experimental insulin resistance in rats

Topicality . The insulin resistance syndrome development is usually correlated with endothelial dysfunction formation, which leads to cardiovascular complications. Accordingly, insulin resistance syndromes pharmacocorrectors should not contribute to endothelium functional state disturbances formation. Aim . Therefore, the aim of present work was a comparative investigation efficacy of hydroxycitric acid and food concentrate phenolic compounds of apples for correction endothelium functional state disturbances under experimental insulin resistance in rats. Materials and methods . The insulin resistance syndrome was modeled by prolonged intraperitoneal injection of dexamethasone and animal maintenance on a high-calorie diet. Serum glucose, immunoreactive insulin, total content of nitrates and nitrites, citrulline, arginine were determined and the insulin resistance index was calculated. Results and discussion . The results demonstrate that hydroxycitric acid and apples phenolic compounds food concentrate corrects hyperglycemia and hyperinsulinemia, have a beneficial effect preventing endothelial dysfunction formation, which is primarily due to pronounced antioxidant properties. Conclusions . In terms of effect on carbohydrate metabolism, a more pronounced effect was observed with hydroxycitric acid administration, and the effect on endothelium functional state parameters more pronounced effect was observed with the apples phenolic compounds food concentrate administration.

PREDICTING THE RATE OF LIVER FIBROSIS IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION BASED ON THE COMBINATION OF GENETIC AND ENVIRONMENTAL FACTORS

Rationale: Search for predictors of aggressive course of chronic hepatitis C virus (HCV) infection in individual patients, including genetic studies, is considered to be a major urgent goal. High rates of fibrosis progression in chronic HCV infection is associated with several gene polymorphisms coding for the components of renin-angiotensin system and involved in the formation of endothelial dysfunction and oxidative stress. Aim: To develop a predictive model to assess the probability of rapid fibrosis progression in patients with chronic HCV infection based on the combination of the known genetic markers, clinical and demographic parameters. Materials and methods : One hundred and nine patients with chronic HCV infection (79 women and 30 men) of known duration and liver fibrosis were categorized into the groups with “rapid fibrosis” (n = 54, the rate of fibrosis progression ≥ 0.13 fibrosis units / year) and with “slow fibrosis” (n = 55, the rate of progression < 0.13 fibrosis units / year). Polymorphisms of the studied genes were assessed by molecular genetic assays. Multivariate analysis of the influence of combination of genetic variants, as well as of the interaction of genetic, clinical and demographic factors on the rate of fibrosis progression in the patients with chronic HCV infection was performed by logistic regression method. Results: The rapid rate of fibrosis progression was significantly associated with patient's age at the time of infection (Wald statistics 14.955; p = 0.00011), male gender (Wald statistics 6.787; p = 0.00918), (-6)АА genotype of the AGT gene carriage (Wald statistics 6.512; p = 0.01072), 242ТТ-genotype of the CYBA gene (Wald statistics 4.347; p = 0.03708), and 235МТ genotype of the AGT gene (Wald statistics 4.306; p = 0.03799). The model to predict the probability of rapid fibrosis progression in individuals with chronic HCV infection included the above mentioned factors; its use was demonstrated with two clinical cases. Conclusion : The analysis of the AGT gene (M235T and G-6A loci) and the СYBA gene (C242T locus) polymorphisms are relevant to identify patients at risk of rapid liver fibrosis progression. In this case, 242ТТ genotype of the CYBA gene and (-6)AA and 235MT genotypes of the AGT gene are considered unfavorable. To refine the prognosis, it is necessary to take into account demographic parameters (gender and age at the moment of infection contraction), because male gender and older age of getting the infection would increase the probability of rapidly progressive of hepatitis C.

Deficiency of Magnesium and Pyridoxine as a Risk Factors for Coronary Heart Disease

Deficiency of magnesium and vitamin 6 is a modifiable risk factor for coronary heart disease (CHD). A combined deficiency of magnesium and vitamin 6 disrupts the functioning myocardial tissue due to the formation of endothelial dysfunction, prothrombotic changes in blood viscosity characteristics, improve vascular tone, failure of the mitochondria. Receiving organic magnesium salts in combination with adequate doses of pyridoxine can be effective in the prevention and treatment of CHD.

The clinical significance of insulin resistance, impaired carbohydrate and lipid metabolism in the development of microcirculation pathology in patients with chronic heart failure and type 2 diabetes mellitus

Patients with chronic heart failure and diabetes mellitus type 2 experience continuous progression of organ damage as a result of hemodynamic and metabolic disorders. An important role in pathogenesis of organ damage belongs to pathological types of microcirculation, endothelial dysfunction and insulin resistance. But the role of insulin resistance and its contribution to the formation of endothelial dysfunction and peculiarities of microcirculation in patients with chronic heart failure and type 2 diabetes mellitus is unknown. This study shows significant association between insulin resistance, disorders of carbohydrate and lipid metabolism, development of microcirculatory disturbances and endothelial dysfunction.

Clinical and pathogenetic peculiarities of development of endothelial dysfunction and arterial rigidity in patients with chronic obstructive pulmonary disease

The purpose of the study was to examine the relationship between functional parameters, arterial rigidity, lipid profile, markers of systemic inflammation and endothelial dysfunction in patients with COPD and COPD + coronary heart disease. We examined 110 subjects divided into 3 groups. Ggroup 1 included 40 patients with severe and very severe COPD, group 2 consisted of 40 patients with severe and very severe COPD + coronary artery disease, the control group was comprised of 30 healthy volunteers. We studied parameters of respiratory function, the level of blood oxygenation, the main characteristics of arterial rigidity, plasma lipid, TNF-a, CRP, fibrinogen, sPECAM-1 levels and the expression of CD38/ADP-ribosylcyclase in peripheral blood lymphocytes. The study revealed increased rigidity of the central arteries in the patients of groups 1 and 2 regardless of the duration of observation and the presence of coronary artery disease, as evidenced by the increase of the pulse wave velocity in the aorta. Patients of both groups had elevated levels of TNF-a, CRP and fibrinogen indicating systemic inflammatory response. Taken together, the enhanced expression of CD38 in peripheral blood lymphocytes, elevated concentration of soluble CD31 (sPECAM-1) in both groups related to bronchial obstruction and neutrophil elastase activity as well as increased rigidity of the vascular bed gives evidence that the CD38 and sCD31 relationship plays a role in the formation of endothelial dysfunction, and dysregulation of vascular tone in COPD patients. Disorders of lipid metabolism combined with increased rigidity of the vascular wall, elevated levels of markers of systemic inflammation and endothelial dysfunction, suggest that patients with COPD are at risk of cardiovascular events.

Antihypertensive therapy in patients with coexisting hypertension and bronchial asthma

The aim of the research was to study the peculiarities of cardiac and pulmonary hemodynamics, the mechanisms of formation of endothelial dysfunction, as well as their correction with angiotensin converting enzyme inhibitor, Ramipril and angiotensin-II receptor blocker, Irbesartan, in patients with arterial hypertension (HTN) combined with bronchial asthma (BA). Design and methods . Altogether 80 patients with BA of moderate severity combined with HTN of 1, 2 degrees were enrolled in the study. The average age of the patients was 52,9 ± 4,2 years. The eligible patients were randomized for treatment with either Ramipril 5 mg/day or Irbesartan 150 mg/day in combination with bronchodilator inhalation and anti-inflammatory medications for BA (Formoterol/Budesonide 160/4,5 mcg 2 inhalations twice, Ipratropium bromide and Ambroxol through nebulizer devices). The program of instrumental examination included echocardiography (Aloka 1700, Japan; LOGIQ 500, Germany) with ultrasonic sensors of 3,5 MHz. The plasma level of endothelin 1 (ET‑1) was estimated by immune-enzyme assay (Biomedica set, category № 442–0052, Arkray, Japan). Results. Two-month monotherapy with Irbesartan allows to achieve the target blood pressure (BP), leads to the regression of cardiac remodeling and has a positive effect on endothelial function and bronchial patency. Conclusions. Irbesartan is able to provide a stable and reliable control of BP, and delays the progression of pathological cardiovascular changes; it has a favorable impact on the respiratory function, is well tolerated, easy to use, and may be considered as the best antihypertensive drug in patients with co-morbid HTN and BA.

Arterioles from Bariatric Patients with Diabetes Have Blunted Responses to Insulin but not Acetylcholine

Obesity and type‐2 diabetes are associated with cardiovascular disease and endothelial dysfunction of which the mechanisms leading to aberrant insulin‐dependent vasodilation are incompletely understood. As not all obese individuals are diabetic, we hypothesize that reduced insulin‐dependent vasodilation is a specific endothelial dysfunction independent of the degree of obesity that accompanies the presence of overall insulin resistance. We tested this hypothesis in jejunal submucosal arterioles obtained from bariatric patients undergoing Roux‐en‐Y proximal gastric bypass surgery. Patients were 49±2 years old with a body mass index (BMI) of 48.5±2.4 Kg/m2. No differences in age or BMI were found between diabetics (n=22) and non‐diabetics (n=30). Maximal arteriolar responses to KCl, phenylephrine, acetylcholine, or sodium nitroprusside were not significantly different between diabetics and non‐diabetics. In contrast, insulin‐dependent vasodilation was smaller in diabetics (40.4±6.4 vs. 61.9±8.8%, respectively). This suggests that a blunted insulin‐vasodilation response is a form of endothelial dysfunction not correlated with BMI in type‐2 diabetes. The blunted‐response to insulin occurring in the absence of an abnormal acetylcholine‐induced dilation suggest that the mechanism responsible for the blunted insulin response is upstream of nitric oxide synthase activation.

Does radical nephrectomy increase the risk of erectile dysfunction compared with partial nephrectomy? A cohort analysis

Study Type - Therapy (prospective cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Erectile dysfunction (ED) is a form of endothelial dysfunction that is prevalent in patients with chronic kidney disease (CKD). We hypothesized that partial nephrectomy (PN) would limit development of ED compared with radical nephrectomy (RN), primarily due to renal function preservation, and found that patients undergoing RN had significantly higher de novo ED compared with a contemporary, well-matched cohort undergoing PN; in addition to RN, hypertension, CKD and diabetes mellitus were associated with developing ED. To our knowledge, this is the first study demonstrating an increased risk of ED after RN compared with PN. • To evaluate prevalence and risk factors for development of erectile dysfunction (ED) in patients who underwent radical nephrectomy (RN) and partial nephrectomy (PN). • ED is a form of endothelial dysfunction that is prevalent in patients with chronic kidney disease (CKD). PN confers superior renal functional preservation compared with RN; however, the impact on ED is unclear. • This was a retrospective study of 432 patients (264 RN/168 PN, mean age 58 years, mean follow-up 5.8 years) who underwent surgery for renal tumours between January 1998 and December 2007. • The primary outcome was rate of de novo ED postoperatively. Secondary outcomes included development of CKD (estimated GFR < 60 mL/min/1.73 m(2) ) and response to phosphodiesterase-5 inhibitors. • Multivariate analysis was performed to determine risk factors for de novo ED postoperatively. • RN and PN groups had similar demographics and comorbidities. • Tumour size (cm) was larger for RN (RN 7.0 vs PN 3.7, P < 0.001) and more preoperative ED existed in PN vs RN (P= 0.042). No differences were observed for preoperative CKD, hyperlipidaemia and diabetes mellitus. • Postoperatively, higher rates of de novo ED (29.5% vs 9.5%, P < 0.001) and CKD (33.0% vs 9.8%, P < 0.001) developed in RN vs PN cohorts, respectively. • Of men with ED, 63% responded to phosphodiesterase inhibitors, without significant difference between the two groups (P= 0.896). • Multivariate analysis demonstrated de novo ED to be associated with RN (odds ratio [OR] 3.56, P < 0.001), hypertension (OR 2.32, P= 0.014), preoperative (OR 8.77, P < 0.001) and postoperative (OR 2.64, P= 0.001) CKD, and postoperative diabetes mellitus (OR 2.93, P < 0.001). • Patients undergoing RN had significantly higher de novo ED compared with a contemporary, well-matched cohort undergoing PN. In addition to RN, hypertension, CKD and diabetes mellitus were associated with developing ED. • Further investigation on effects of surgically induced nephron loss on ED is requisite.

The relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy

Objectives. Diabetic nephropathy (DN) is a major manifestation of microangiopathy in patients with Diabetes Mellitus (DM). Inflammation is one of the major factors in the formation of endothelial dysfunction. Endothelial dysfunction is a major contributor to the complications of DM. The aim of the present study was to investigate the possible relationship between inflammation, endothelial dysfunction and proteinuria in patients with diabetic nephropathy. Materials and methods. Plasma TNF-α and IL-6, pro-inflammatory cytokines, concentrations were measured in 25 patients with DN and in 30 diabetic control subjects. Also, we evaluated the markers of endothelial dysfunction such as flow mediated dilatation (FMD), nitrate-mediated dilatation (NMD) and carotid intima-media thickness (CIMT). Results. TNF-α, IL-6 and high-sensitivity C-reactive protein concentrations were significantly higher (p = 0.012, p = 0.006 and p < 0.001, respectively) in the patients with DN than the controls. And, urinary protein concentrations were significantly higher (p < 0.001) but eGFR levels were significantly lower (p < 0.001) in the patients with DN. FMD was significantly lower in DN patients (p < 0.001). We have observed that FMD correlated negatively with body mass index (r = −0.424, p < 0.05). And there was also a positive correlation between TNF-α and urinary protein concentrations in the patients with DN (p < 0.05). Conclusion. TNF-α, IL-6, hsCRP and urinary protein concentrations are higher in the DN patients. There were no correlations among pro-inflammatory cytokines concentrations and markers of vascular endotelial disfunction. These findings did not show vascular endothelial dysfunction, but may indicate glomerular endothelial dysfunction.

A profound decrease in maternal arginine uptake provokes endothelial nitration in the pregnant rat

While a specific role for nitric oxide (NO) in inducing the hemodynamic alterations of pregnancy is somewhat controversial, it is widely accepted that excess NO is generated during pregnancy. L-Arginine is the sole precursor for NO biosynthesis. Among several transporters that mediate L-arginine uptake, cationic amino acid transporter-1 (CAT-1) acts as the specific arginine transporter for endothelial NO synthase. The present study was designed to test the hypothesis that, during pregnancy, when arginine consumption by the fetus is significantly increased, compensatory changes in maternal arginine uptake affect the endothelium. Uptake of radiolabeled arginine (L-[3H]arginine) by freshly harvested maternal aortic rings from pregnant rats decreased by 65 and 30% in mid- and late pregnancy, respectively, compared with those obtained from virgin animals. This decrease was associated with a significant increase in endothelial protein nitration (the footprint of peroxynitrite generation), as shown by both Western blotting and immunohistochemistry utilizing anti-nitrotyrosine antibodies, reflecting endothelial damage. Northern blot analysis revealed that steady-state aortic CAT-1 mRNA levels did not change throughout pregnancy, whereas CAT-1 protein abundance was significantly increased, peaking at mid-pregnancy. Protein content of protein kinase C (PKC)-alpha, which was previously shown to decrease CAT-1 activity, increased significantly in the pregnant animals and was associated with a significant increase in CAT-1 phosphorylation. Intraperitoneal injection of alpha-tocopherol, a PKC-alpha inhibitor, prevented the decrease in arginine transport and attenuated protein nitration. In conclusion, aortic arginine uptake is reduced during pregnancy, through posttranslational modulation of CAT-1 protein, presumably via upregulation of PKC-alpha. The aforementioned findings are associated with an increase in protein nitration and, therefore, in selected individuals, may lead to the development of certain forms of endothelial dysfunction, like preeclampsia.

Arterial hypertension and endothelial dysfunction in chronic kidney diseases

Arterial hypertension is the important reason of the morbidity and mortality of the patients with chronic kidney disease. The aim of this study was to estimate the feature of the arterial hypertension, vasomotor form endothelial dysfunction and level of VCAM1 at patients with chronic kidney disease at groups with achievement and not achievement target arterial pressure. At the moment of the survey the target arterial pressure was achieved at 70 (1 group) and not achieved at 31 patients (2 group). During investigation it was applied the complex of biochemical, immune-enzyme and instrumental methods. The vasomotor form of endothelial dysfunction was detected at all of patients. The improvement of endothelium-dependent vasodilatation was defined at patients with achieved target arterial pressure. The VCAM1 concentration was elevated only at the patients 2 group. This group was differ from the 1 group with more high arterial pressure, left ventricular hypertrophy, atrium enlargement, complex intima-media enlargement, decrease glomerular filtration rate. It was made the conclusion that achievement target arterial pressure facilitate the correction of vasomotor form of endothelial dysfunction.

The interaction between oxidative stress and biomarkers of inflammation in atherosclerosis

A number of data demonstrated that there is a close relation between inflammation, oxidative stress and atherosclerosis. The initial event in atherogenesis is some form of endothelial dysfunction or activation. It can be triggered by mechanical, chemical, infectious or immunological insults, indicating that almost all risk factors for atherosclerosis could promote endothelial dysfunction. This triggers a cascade of inflammatory reactions, in which monocytes, macrophages, T lymphocytes and smooth muscle cells participate. These cells and the endothelium produce adhesion molecules, cytokines, growth factors and metalloproteinases, thus prolonging atherogenesis. An activation of oxidative producing enzymes such as NADPH oxidases and nitric oxide synthase (NOS) leads to oxidative stress and subsequent oxidative modification of LDL, and oxLDL can in turn activate the endothelial cells. Oxidatively modified LDL is uptaken by macrophages via scavenger receptors. This results in the accumulation of cholesterol within the macrophages and the formation of foam cells, a hallmark of atherosclerosis. The process continues with repeated cycles leading to the characteristic advanced lesions with the core of lipids and necrotic tissue which is covered by a fibrous cap.