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Using the combined application of L-arginine with HMG-Co-A reductase inhibitors simvastatin, atorvastatin, rosuvastatin and nanoparticulated rosuvastatin on the background of modeling of sepsis-induced disease through the introduction of strain 603 Staphylococcus aureus shows endotelio- and cardioprotective effects, manifesting itself in preventing the proliferation of endothelial dysfunction coefficient (CED), adrenoreactivity, maintenance of myocardial reserve and the normalization of biochemical markers values (Total NO, eNOS expression, C-reactive protein, IL-6, TNF). In this case, the combined therapy was so effective that the values obtained thereunder did not differ from those obtained from control animals.

Posterior reversible encephalopathy syndrome (PRES) is an acute neurological disorder characterized by variable symptoms and radiological images characteristic of vasogenic parietal-occipital edema. It is associated with clinical conditions such as high blood pressure, infection / sepsis, or cytotoxic / immunosuppressive drugs, among others. It is characterized pathophysiologically by endothelial damage with breakdown of blood-brain barrier (BBB), cerebral hypoperfusion, and vasogenic edema.The cases are presented on two critical COVID-19 patients who were admitted to pneumonia requiring mechanical ventilation and who, after removing sedation, developed acute and reversible neurological symptoms consisting of epilepsy and encephalopathy, associated with hyperintense subcortical lesions on brain magnetic resonance imaging (MRI) compatible with PRES.SARS-CoV-2 coronavirus would activate an inflammatory response that would damage brain endothelium. It could be triggered by cytokine release, as well as by direct viral injury, given that endothelium expresses ACE2 receptors. It could explain the possible association between PRES and COVID-19.

Background: Several studies have revealed the link between Coronavirus Disease 2019 (COVID-19) and endothelial dysfunction. To better understand the global pattern of this relationship, we conducted a meta-analysis on endothelial biomarkers related to COVID-19 severity. Methods: We systematically searched the literature up to March 10, 2021, for studies investigating the association between COVID-19 severity and the following endothelial biomarkers: Intercellular Adhesion Molecule 1 (ICAM-1), Vascular Cell Adhesion Molecule 1 (VCAM-1), E-selectin, P-selectin, Von Willebrand Factor Antigen (VWF-Ag), soluble Thrombomodulin (sTM), Mid-regional pro-adrenomedullin (MR-proADM), and Angiopoietin-2 (Ang-2). Pooled estimates and mean differences (PMD) for each biomarker were reported. Results: A total of 27 studies (n=2213 patients) were included. Critically ill patients presented with higher levels of MR-proADM (PMD: 0.71 nmol/L, 95% CI: 0.22 to 1.20 nmol/L, p=0.02), E-selectin (PMD: 13,32 pg/ml, 95% CI: 4,89 to 21,75 pg/ml, p=0.008), VCAM-1 (PMD: 479 ng/ml, 95% CI: 64 to 896 ng/ml, p=0.03), VWF-Ag (PMD: 110.5 IU/dl, 95% CI: 44.8 to 176.1 IU/dl, p=0.04) and Ang-2 (PMD: 2388 pg/ml, 95% CI: 1121 to 3655 pg/ml, p=0.003), as compared to non-critically ill ones. ICAM-1, P-selectin and thrombomodulin did not differ between the two groups (p>0.05). Conclusion: Endothelial biomarkers display significant heterogeneity in COVID-19 patients, with higher MR-proADM, E-selectin, VCAM-1, VWF-Ag, and Ang-2 levels being associated with increased severity. These findings strengthen the evidence on the key role of endothelial dysfunction in disease progress.

Background: Diabetic retinopathy (DR) is a severe complication of diabetes; however, the pathogenesis of DR has not been completely clarified, which is mostly dependent on the molecular pathology. To investigate key serum-derived miRNAs associated with DR. Methods: miRNA expression profile arrays of human umbilical vein endothelial cells (HUVECs) treated with glucose were downloaded from the Gene Expression Omnibus (GEO) database (GSE74296). Weighted gene co-expression network analysis (WGCNA) was performed to obtain hub miRNAs, which were verified in HUVECs treated with 40 mM and 5 mM glucose, respectively. Meanwhile, serum samples of patients with DR and healthy controls were collected, and EVs were extracted from the patients’ serum by ultracentrifugation. Hub miRNAs associated with endothelial dysfunction were verified in healthy individuals before and after treatment of patients with DR, by qRT-PCR. Results: These miRNAs were categorized into six modules, among which miR-26b-5p had a strong association with other modules. This miRNA was also one of the hyperglycemia-induced miRNAs related to endothelial dysfunction. miR-26b-5p was upregulated in HUVECs treated with 40 mM glucose and in the serum of patients with DR before and after treatment Furthermore, miR-26b-5p was slightly up-regulated in serum-derived EVs but not in serum without EVs in DM patients. Conclusion: Our results suggest that EVs derived from miR-26b-5p are up-regulated in the serum of patients with DR.

Cardiovascular complications such as cardiomyopathy and endothelial dysfunction, which are frequently seen in patients with acromegaly, are among the most important causes of morbidity and mortality. In this study, we aimed to investigate arterial stiffness, carotid intima-media thickness, endocan level, and A disintegrin and metalloproteinase with thrombospondin type I motif 9 level and their relationship with disease activity in patients with acromegaly with and without cardiovascular risk factors.A total of 60 patients with acromegaly-25 with active disease, 26 with well-controlled disease, and 9 with newly diagnosed disease-and 60 age-, sex-, and body mass index (BMI)-matched healthy control subjects were enrolled in this study. All the subjects' height, weight, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG) level, insulin, hemoglobin A1C (HbA1C), C-reactive protein , lipid, endocan, A disintegrin and metalloproteinase with thrombospondin type I motif 9 levels, pulse wave velocity (PWV), and carotid intima-media thickness were measured.The SBP, DBP, FPG level, HbA1C level, and PWV of the acromegaly group were higher than those of the control group. In patients with acromegaly with cardiovascular disease (CVD) risk factors, the PWV was higher than that in the control group, and in patients with acromegaly without CVD risk factors, the PWV was similar to that in the control group. In a correlation analysis, a positive correlation was found between PWV and age, BMI, SBP, DBP, FPG level, and HbA1C level in the acromegaly group.In our study, we found that arterial stiffness increased in patients with acromegaly with CVD risk factors and that increased arterial stiffness was associated with hemodynamic (SBP and DBP) and metabolic (BMI, FPG level, and HbA1C level) parameters.

Aims Previous studies suggested that implantation with a 1st-generation DES was associated with coronary endothelial dysfunction, which was associated with Rho-kinase activation. Second-generation drug-eluting stents (DESs) may preserve coronary endothelial function in stented coronary arteries; however, because of methodological limitations, further study is needed to clarify the association between 2nd-generation DESs and coronary endothelial dysfunction. Methods We retrospectively analysed the CuVIC trial database, where we identified 112 patients who underwent coronary stenting in the left coronary arteries with either a bare metal stent (BMS, n=53) or 2nd-generation DES (n=59). We compared vasomotions of target vessels with stents and non-target vessels without stents. Furthermore, we measured the Rho-kinase activation detected in mononucleocytes from aortic and coronary sinus blood. Results ACh-induced vasoconstrictive responses of target vessels were not enhanced with a 2nd-generation DES (45±21% vs. 44±20%, P=0.56, paired t-test), but significantly enhanced in the coronary arteries with a BMS (50±18% vs. 42±20%, P=0.002). Rho-kinase activation did not differ between patients with a BMS and 2nd-generation DES. In the target vessels with a BMS, large late lumen loss and acute coronary syndrome (ACS) at the index percutaneous coronary intervention (PCI) were associated with ACh-induced enhanced coronary vasoconstrictive responses. Conclusions Evaluation of ACh-induced vasomotion of target vessels comparing with non-target vessels revealed that 2nd-generation DESs were not associated with coronary endothelial dysfunction in target vessels, nor activation of Rho-kinase in the coronary sinus blood 6-8 months after stenting.

Background: Preeclampsia (PE) is a pregnancy complication with serious maternal and neonatal consequences worldwide. Our understanding of PE pathophysiology has significantly evolved over the last decades by recognizing that endothelial dysfunction and systemic inflammation, with an associated angiogenic imbalance, are key pieces of this incomplete puzzle. In the present era, where no single treatment to cure or treat this obstetric condition has been developed so far, PE prevention and early prediction are the most useful clinical approach to reduce the PE burden. Introduction: Although most PE episodes occur in healthy nulliparous women, the identification of specific clinical conditions that increase the risk of PE dramatically provides a critical opportunity to improve outcomes by acting on potentially reversible factors, and also contributes to better understand this pathophysiologic enigma. Methods: Pertinent studies were searched in PubMed/Medline and Google Scholar (updated August 2020) using common keywords applied in the field of preeclampsia, inflammation and endothelial dysfunction. Given the design of this work as a narrative review, no formal criteria for study selection or appraisal were utilized. Conclusion: In this review, we highlight major clinical contributors of PE and shed light on their potential link with endothelial dysfunction and inflammation.

Persistent hyperglycemia in type 1 diabetes triggers numerous signaling pathways, which may prove deleterious to the endothelium. As hyperglycemia damages the endothelial layer via multiple signaling pathways, including enhanced oxidative stress, downregulation of angiotensin-converting enzyme 2 signaling, and exacerbation of endoplasmic reticulum (ER) stress, it becomes difficult to prevent injury using monotherapy. Thus, the present study was conceived to evaluate the combined effect of ER stress inhibition along with angiotensin-converting enzyme 2 activation, two major contributors to hyperglycemia-induced endothelial dysfunction, in preventing endothelial dysfunction associated with type 1 diabetes. Streptozotocin-induced diabetic animals were treated with either diminazene aceturate (5 mg·kg−1 per day, p.o.) or tauroursodeoxycholic acid, sodium salt (200 mg·kg−1 per day i.p.), or both for 4 weeks. Endothelial dysfunction was evaluated using vasoreactivity assay, where acetylcholine-induced relaxation was assessed in phenylephrine pre-contracted rings. Combination therapy significantly improved vascular relaxation when compared with diabetic control as well as monotherapy. Restoration of nitrite levels along with prevention of collagen led to improved vasodilatation. Moreover, there was an overall reduction in aortic oxidative stress. We conclude that by simultaneously inhibiting ER stress and activating angiotensin-converting enzyme 2 deleterious effects of hyperglycemia on endothelium were significantly alleviated. This could serve as a novel strategy for the prevention of endothelial dysfunction.

The global propagation of SARS-CoV-2 leads to an unprecedented public health emergency. Despite that the lungs are the primary organ targeted by COVID-19, systemic endothelial inflammation and dysfunction is observed particularly in patients with severe COVID-19, manifested by elevated endothelial injury markers, endotheliitis, and coagulopathy. Here, we review the clinical characteristics of COVID-19 associated endothelial dysfunction; and the likely pathological mechanisms underlying the disease including direct cell entry or indirect immune overreactions after SARS-CoV-2 infection. In addition, we discuss potential biomarkers that might indicate the disease severity, particularly related to the abnormal development of thrombosis that is a fatal vascular complication of severe COVID-19. Furthermore, we summarize clinical trials targeting the direct and indirect pathological pathways after SARS-CoV-2 infection to prevent or inhibit the virus induced endothelial disorders., Graphical abstract Unlabelled Image

BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.

Preeclampsia is a common hypertensive disorder of pregnancy associated with considerable neonatal and maternal morbidities and mortalities. However, the exact cause of preeclampsia remains unknown; it is generally accepted that abnormal placentation resulting in the release of soluble antiangiogenic factors, coupled with increased oxidative stress and inflammation, leads to systemic endothelial dysfunction and the clinical manifestations of the disease. Statins have been found to correct similar pathophysiological pathways that underlie the development of preeclampsia. Pravastatin, specifically, has been reported in various preclinical and clinical studies to reverse the pregnancy-specific angiogenic imbalance associated with preeclampsia, to restore global endothelial health, and to prevent oxidative and inflammatory injury. Human studies have found a favorable safety profile for pravastatin, and more recent evidence does not support the previous teratogenic concerns surrounding statins in pregnancy. With reassuring and positive findings from pilot studies and strong biological plausibility, statins should be investigated in large clinical randomized-controlled trials for the prevention of preeclampsia.

Background Cerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers. Methods Cross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI. Results The eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52). Conclusion A compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Introduction. In the pathogenesis of the formation of vascular diseases of the brain, an important role is played by not only external negative (spondylogenic) factor, but also an imbalance of various endogenous systems (endothelial, lipid), affecting the cerebral hemodynamics. Hence, the relevance of the study of these relationships has both theoretical and practical importance.The objective of the study was to examine the state of lipid metabolism and endothelial function in young patients with spondylogenic vertebrobasilar insufficiency.Materials and methods. We have examined 98 patients (women — 56, men — 42) with the manifestations of vertebrobasilar insufficiency on the background of the muscular-reflex, neurovascular and radicular syndromes of cervical osteochondrosis. The study included patients aged 18 to 40 years (mean age 28.5 ± 3.8 years).All patients underwent functional X-ray of the cervical spine with flexion and extension, magnetic resonance imaging of the cervical spine, Doppler ultrasound examination of the neck vessels and cerebral arteries using functional loads with head rotation, as well as duplex scanning of neck vessels. Serum lipid parameters were determined by spectrophotometry, the concentration of endothelin-1 in the blood serum — using enzyme immunoassay, S-NO contents — spectrofluorometry.The study found that spondylogenic vertebrobasilar insufficiency is associated with a violation of lipid metabolism characterized by multi-directional changes in the level of cholesterol, low-density lipoproteins, very-low-density lipoproteins and high-density lipoproteins, indicating a shift in plasma parameters of lipid-transport system towards atherogenesis. Endothelial dysfunction in this cohort of patients is characterized by increased concentrations of endothelin-1, a vasoconstrictor factor, against the background of reduction of the active metabolite of nitric oxide — S-NO, which has vasodilating properties., Актуальность. В патогенезе формирования сосудистой патологии мозга значимую роль играет не только внешний негативный (спондилогенный) фактор, но и дисбаланс различных эндогенных систем (эндотелиальной, липидной), влияющих на церебральную гемодинамику. Следовательно, актуальность изучения этих взаимосвязей имеет не только теоретическое, но и важное практическое значение.Целью исследования было изучение состояния липидного обмена и функции эндотелия у пациентов молодого возраста со спондилогенной вертебрально-базилярной недостаточностью. Материалы и методы. Нами было обследовано 98 пациентов (женщин — 56, мужчин — 42) с проявлениями вертебрально-базилярной недостаточности на фоне мышечно-рефлекторных, нейрососудистых и корешковых синдромов остеохондроза шейного отдела позвоночника. В исследование были включены больные от 18 до 40 лет (средний возраст 28,5 ± 3,8 года). Всем пациентам проводилась функциональная рентгенография шейного отдела позвоночника со сгибанием и разгибанием, МРТ шейного отдела позвоночника, а также ультразвуковое допплерографическое исследование сосудов шеи и магистральных артерий головы с применением функциональных нагрузок с ротацией головы, а также дуплексное сканирование сосудов шеи. Показатели липидного обмена в сыворотке крови определяли спектрофотометрическим методом, концентрацию эндотелина-1 в сыворотке крови — методом иммуноферментного анализа, cодержание S-NO — спектрофлюориметрическим методом.В результате проведенного исследования было выявлено, что спондилогенная вертебрально-базилярная недостаточность сопровождается нарушением обмена липидов, характеризующимся разнонаправленными сдвигами уровня холестерина, липопротеидов низкой плотности, липопротеидов очень низкой плотности и липопротеидов высокой плотности, свидетельствующим о сдвиге плазменных показателей липидтранспортной системы в сторону атерогенеза. Эндотелиальная дисфункция у данного контингента больных характеризуется увеличением концентрации эндотелина-1, являющегося вазоконстрикторным фактором на фоне уменьшения активного метаболита оксида азота — S-NO, обладающего вазодилатирующими свойствами., Актуальність. Формування судинної патології мозку у хворих зі спондилогенною вертебробазилярною недостатністю включає в себе не тільки зовнішній негативний (спондилогенний) фактор, але й дисбаланс функціонування ендогенних систем (ендотеліальної, ліпідної), що впливає на гемодинаміку мозку. Отже, вивчення цих взаємозв’язків має не тільки теоретичне, а й важливе практичне значення.Метою дослідження було вивчення стану ліпідного обміну та функції ендотелію в пацієнтів молодого віку зі спондилогенною вертебрально-базилярною недостатністю.Було обстежено 98 пацієнтів (жінок — 56, чоловіків — 42) із проявами вертебрально-базилярної недостатності на фоні м’язово-рефлекторних, нейросудинних і корінцевих синдромів остеохондрозу шийного відділу хребта. У дослідження були включені хворі від 18 до 40 років (середній вік 28,5 ± 3,8 року).Усім пацієнтам проводилася функціональна рентгенографія шийного відділу хребта зі згинанням і розгинанням, МРТ шийного відділу хребта, а також ультразвукове допплерографічне дослідження судин шиї і магістральних артерій голови із застосуванням функціональних навантажень із ротацією голови, а також дуплексне сканування судин шиї.Показники ліпідного обміну в сироватці крові визначали спектрофотометричним методом, концентрацію ендотеліну-1 в сироватці крові визначали методом імуноферментного аналізу, стан S-NO визначали спектрофлюориметричним методом.У результаті проведеного дослідження було виявлено, що спондилогенна вертебробазилярна недостатність супроводжується порушенням обміну ліпідів, що характеризується різноспрямованими змінами рівня загального холестерину, тригліцеридів, ліпопротеїдів низької щільності, ліпопротеїдів дуже низької щільності і ліпопротеїдів високої щільності, що свідчить про зсуви плазмових показників ліпідтранспортної системи у бік атерогенезу.Ендотеліальна дисфункція в даного континтента хворих характеризується збільшенням концентрації ендотеліну-1, який є вазоконстрикторним фактором, на фоні зменшення активного метаболіту оксиду азоту — S-NO, якому притаманні вазодилатуючі властивості.

The article presents the main directions of comprehensive treatment for cerebrovascular disorders. Particular attention is given to the drugs, normalizing endothelial function, as well as providing neuroprotection. The principles of modern neurorehabilitation of stroke patients are considered.

Introduction. Arterial hypertension (AH) is one of the major modified cardiovascular risk factors of chronic cerebral ischemia (ChCI). Endothelial dysfunction is associated with AH and is claimed to be one of the pathogenic mechanisms of the ChCI. We have conducted a study, the objective of which was to evaluate autoimmune reactivity to the structural components of the cardiovascular system, depending on the presence of AH and endothelial dysfunction in patients with initial manifestations of ChCI. Material and methods. We have examined 55 patients of middle age (51.3 ± 7.0 years) with initial manifestations of the ChCI. All patients underwent general clinical, clinical and neurological, clinical and instrumental, clinical and laboratory tests. The level of autoantibodies (autoAB) to platelet antigens, cardiomyocytes and vascular endothelium in the blood serum of patients was determined by the method of O.B. Poletaiev. Endothelial function was assessed in terms of flow-dependent vasodilation, the level of nitrite and endothelin‑1. Results and discussion. Patients with AH and those without AH statistically significantly differed only by the levels of autoAB to PAPP-A and CoM‑02. Depending on the degree of blood pressure (BP) deviation (AH degree I and II, clinical hypotension or normal BP), the patients differed only in terms of average individual level of immune reactivity (AILI) (p = 0.001) and the level of autoAB to DNA (p = 0.015). Statistical analysis showed that patients with AH (stage I and II) and individuals without AH were statistically significantly different in terms of AILI (χ2(3) = 11.5; p = 0.009) and the level of autoAB to DNA (χ2(3) = 8.6; p = 0.04). The percentage of flow-dependent vasodilation statistically significantly correlated with AILI (r = 0.409; p = 0.003), as well as with the level of autoAB to c-ANCA (r = –0.309; p = 0.027) and PAPP-A protein (r = 0.361; p = 0.009). Evaluation of vasomotor endothelial function by content of the biochemical markers discovered that nitrite levels statistically significant correlated with relative content of autoAB to CoS‑05 (r = 0.326; p = 0.033) and the c-ANCA (r = –0.312; p = 0.042) in contrast to endothelin‑1 level, which showed no statistically significant correlations. Conclusions. Patients with AH had an increased activity of cardiodegenerative processes against the background of disturbed regulatory influences on the lipid and carbohydrate metabolism in comparison with individuals without AH, as indicated by the evaluation of autoimmune reactivity in patients with initial manifestations of ChCI depending on the degree of BP disorders. With the development of endothelial dysfunction, according to compression test in patients with initial manifestations of ChCI, there was a downward trend in immune reactivity, endothelial activation and violation of lipid and carbohydrate metabolism regulation.

Ендотелій відіграє винятково важливу роль у фізіології та патології людини. Ендотеліальна дисфункція: формування прозапального та протромботичного фенотипу ендотеліальних клітин, надлишкова продукція цитокинів запалення, зниження продукції вазодилататорів і збільшення вазоконстрикторів та протромботичних медіаторів — основа патогенезу системного запалення (СЗ) та асоційованих із ним хвороб: артеріальної гіпертонії, атеросклерозу, ішемічної хвороби серця, ожиріння, цукрового діабету 2-го типу. Ядерний транскрипційний фактор каппа В (NFkB) є головним індуктором СЗ в ендотеліальних клітинах, а рецептори, що активуються проліфераторами пероксисом (PPAR-α, -β/-δ і -γ), — антагоністи NFkB — регуляторами інтенсивності СЗ. Вивчення молекулярних механізмів дії NFkB і PPAR дозволяє використовувати антагоніст NFkB — метформін і агоніст PPAR-γ — піоглітазон у лікуванні захворювань, пов’язаних із СЗ, а також сподіватися на створення нових препаратів.

У статті представлені матеріали наукової конференцій «Карпатські читання 2016». Доповідь С.М. Кузнєцової була присвячена можливостям корекції енергетичного обміну та ендотеліальної дисфункції у хворих на церебральний атеросклероз. Представлені функції і значення ендотелію в організмі. А також обгрунтовано показання та переваги застосування препарату Капікор у хворих із дисциркуляторною енцефалопатією. У доповіді Воронкова Л.Г. відображена важливість своєчасної корекції функції ендотелію як ключової ланки превентивної судинної медицини. Соломенчук Т.М. розповіла про можливості метаболічної терапії при різних формах ішемічної хвороби серця.

Background. Ankylosing spondylitis is a risk factor for severe vascular disease, which is characterized by a violation of vascular endothelial function, but clinical and pathogenetic role of these changes is not sufficiently studied. The purpose and objectives of the study: to evaluate the nature of endothelial dysfunction and vascular adsorption-rheological properties of the blood in patients with ankylosing spondylitis, to determine its characteristics in the presence of angiopathy, to establish correlation with the cli-nical and instrumental parameters of vascular disease and the state of immunity. Materials and methods. The study included 79 patients aged 15 to 66 years (mean 38 years), among whom there were 95 % of men and 5 % of women. The duration of the disease from its first manifestations was 11 years, I degree of activity occurred in 32 % of cases, II — in 39 % and III — in 29 %, and the ratio of slow progressive and rapidly progressive course of the pathological process was 4 : 1. Peripheral monooligoarthritis was detected in 47 % of patients, polyarthritis — in 53 %. Levels of vascular endothelial growth factor, endothelin-1, thromboxane A2, homocysteine, prostacyclin, cyclic guanosine monophosphate, E- and P-selectin were examined by immune-enzyme analysis in the blood serum, and surface parameters of viscosity, elasticity, tension, relaxation and modulus of viscoelasticity — by the method of interphase tensiometry. Results. Endothelial vascular dysfunction occurs in every second patient with ankylosing spondylitis, which in the presence of clinical and instrumental vascular pathology is accompanied by an increase in serum concentration of cyclic guanosine monophosphate and even greater reduction in prostacyclinemia parameters. The severity of disorders of vascular endothelial function in these patients is associated with disease duration, activity of the pathological process, the defeat of the peripheral nervous system, the severity of spondylopathies and sacroiliitis, at the same time there are correlations between certain immune parameters and vascular-rheological properties of the blood. The latest in ankylosing spondylitis are involved in the pathogenesis constructions of enthesopathies, tendovaginitis, uveitis and scleritis, determine the rate of progression of articular syndrome and integrated severity of angiopathy, and the content of cyclic guanosine monophosphate in the blood has prognostic significance.

Мета роботи — визначити наявність небажаних ефектів базисної терапії у дітей, хворих на алергічну бронхіальну астму (БА).Матеріали та методи. Обстежено 224 дитини з алергічною БА віком від 6 до 17 років із визначенням вмісту гомоцистеїну та судинного ендотеліального фактора росту, проведенням ультрасонографії сон­ної та плечової артерій на апараті Philips HD11 XE у В-режимі з кольоровим допплерівським картуванням потоків.Результати. Порівнюючи показники вмісту гомоцистеїну та судинний ендотеліальний фактор росту у дітей, хворих на БА, залежно від наявності базисної протизапальної терапії (БПЗТ), нами було встановлено, що їх уміст вірогідно нижчий у дітей, які не отримували БПЗТ (р < 0,05). Лікування середніми та високими дозами інгаляційних глюкокортикоїдів є чинником ризику підвищення вмісту гомоцистеїну (ОR 1,504; 95% CI 1,141–7,519 та ОR 2,456; 95% CI 1,427–29,343 відповідно). Вміст судинного ендотеліального фактора росту вірогідно підвищується при застосуванні низьких (OR 1,385; 95% CI 1,117–4,602) та середніх (OR 2,462; 95% CI 1,200–30,275) доз інгаляційних глюкокортикоїдів. Потовщення комплексу інтими-медії понад 0,9 мм (OR 1,157; 95% CI 1,080–4,777) не мало дозозалежного ефекту.

Coronary no-reflow phenomenon is a lethal mechanism of ongoing myocardial injury following successful revascularization of an infarct-related coronary artery. Incidence of this phenomenon is high following percutaneous intervention and is associated with adverse in-hospital and long-term outcomes. Several mechanisms such as ischemia-reperfusion injury and distal microthromboembolism in genetically susceptible patients and those with preexisting endothelial dysfunction have been implicated. However, the exact mechanism in humans is still poorly understood. Several investigative and treatment strategies within and outside the cardiac catheterization laboratory have been proposed, but they have not uniformly shown success in reducing mortality or in preventing adverse left ventricular remodeling resulting from this condition. The aim of this article is to provide a brief and concise review of the current understanding of the pathophysiology, clinical predictors, and investigations and management of coronary no-reflow phenomenon.

Unrestrained activation of the complement system till the terminal products, C5a and C5b-9, plays a pathogenetic role in acute and chronic inflammatory diseases. In endothelial cells, complement hyperactivation may translate into cell dysfunction, favoring thrombus formation. The aim of this study was to investigate the role of the C5a/C5aR1 axis as opposed to C5b-9 in inducing endothelial dysfunction and loss of antithrombogenic properties. In vitro and ex vivo assays with serum from patients with atypical hemolytic uremic syndrome (aHUS), a prototype rare disease of complement-mediated microvascular thrombosis due to genetically determined alternative pathway dysregulation, and cultured microvascular endothelial cells, demonstrated that the C5a/C5aR1 axis is a key player in endothelial thromboresistance loss. C5a added to normal human serum fully recapitulated the prothrombotic effects of aHUS serum. Mechanistic studies showed that C5a caused RalA-mediated exocytosis of von Willebrand factor (vWF) and P-selectin from Weibel-Palade bodies, which favored further vWF binding on the endothelium and platelet adhesion and aggregation. In patients with severe COVID-19 who suffered from acute activation of complement triggered by severe acute respiratory syndrome coronavirus 2 infection, we found the same C5a-dependent pathogenic mechanisms. These results highlight C5a/C5aR1 as a common prothrombogenic effector spanning from genetic rare diseases to viral infections, and it may have clinical implications. Selective C5a/C5aR1 blockade could have advantages over C5 inhibition because the former preserves the formation of C5b-9, which is critical for controlling bacterial infections that often develop as comorbidities in severely ill patients. The ACCESS trial registered at www.clinicaltrials.gov as #NCT02464891 accounts for the results related to aHUS patients treated with CCX168.

Aging is accompanied by declining lung function and increasing susceptibility to lung diseases. The role of endothelial dysfunction and vascular remodeling in these changes is supported by growing evidence, but underlying mechanisms remain elusive. In this review we summarize functional, structural, and molecular changes in the aging pulmonary vasculature and explore how interacting aging and mechanobiological cues may drive progressive vascular remodeling in the lungs.

Introduction Electronic cigarettes (e-cigs) have increased in popularity as a potentially less harmful alternative to tobacco smoking; however, the literature suggests “vaping” can cause endothelial damage, which can adversely affect erectile function. While there is a known link between smoking cigarettes and erectile dysfunction (ED), the effect of e-cigs on erectile function has been understudied. Objectives To review the evidence for e-cig use causing endothelial dysfunction, to explore endothelial dysfunction as a potential mechanism for ED, and to determine if there is literature to support e-cigs as a cause of ED. Methods A literature review was performed to identify publications pertaining to e-cig consumption and ED. Publications regarding e-cig consumption and vascular or endothelial damage were also included. The search was conducted through PubMed, MEDLINE database, the Cochrane Library Central Search, Web of Science, and Google Scholar. We identified 40+ publications for review, including 6 clinical trials and 3 basic science studies. Results The literature suggests that e-cig use induces oxidative stress, including the direct formation of reactive oxygen species and hydroxyl radicals, leading to endothelial damage. Endothelial dysfunction is a potential mechanism for ED, but there is a paucity of studies evaluating the relationship between e-cig use and ED. Conclusion E-cig use may cause ED in men, but more studies, specifically clinical trials, are needed to establish a relationship between e-cigs and ED. E-cig-induced endothelial dysfunction is a potential mechanism for ED that is worth exploring further. J Pincus, V Sandoval, B Dick, et al. E-Cigarette-Associated Endothelial Damage: A Potential Mechanism for Erectile Dysfunction. Sex Med Rev 2021;XX:XXX–XXX.

Background and aims Recent evidence links trimethylamine oxide (TMAO) to endothelial dysfunction, an early indicator of cardiovascular disease. We aimed to determine whether short-term consumption of a diet patterned after the 2010 Dietary Guidelines for Americans (DGA) would affect endothelial function, plasma TMAO concentrations, and cardiovascular disease risk, differently than a typical American Diet (TAD). Methods and results An 8-wk controlled feeding trial was conducted in overweight/obese women pre-screened for insulin resistance and/or dyslipidemia. Women were randomized to a DGA or TAD group (n = 22/group). At wk0 (pre-intervention) and wk8 (post-intervention) vascular age was calculated; endothelial function (reactive hyperemia index (RHI)) and augmentation index (AI@75) were measured using EndoPAT, and plasma TMAO was measured by LC-MS/MS. Vascular age was reduced in DGA at wk8 compared to wk0 but TAD wk8 was not different from wk0 (DGA wk0: 54.2 ± 4.0 vs. wk8: 50.5 ± 3.1 (p = 0.05), vs. TAD wk8: 47.7 ± 2.3). Plasma TMAO concentrations, RHI, and AI@75 were not different between groups or weeks. Conclusion Consumption of a diet based on the 2010 Dietary Guidelines for Americans for 8 weeks did not improve endothelial function or reduce plasma TMAO. ClinicalTrials.gov NCT02298725.

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria’s effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria’s link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease., Graphical Abstract Graphical Abstract

The haemostatic system acts in concert with inflammation, so that after inflammatory response various mediators activate the haemostatic system through endothelial dysfunction, platelet activation and coagulation promoting thrombosis, which is termed thromboinflammation. In this process, the inflammasome acquires special relevance; its stimulation promotes innate and adaptive immune responses. Inflammasome activation plays an important physiopathological role in several disorders with inflammatory and thrombotic phenomena. The role of thromboinflammation has become relevant in the COVID-19 pandemic, in which a cytokine storm has been described as one of the responsible mechanisms.

Background: Cardiovascular disease (CVD) prevalence is rising among persons with HIV (PLWH) in sub-Saharan Africa. Oxidative stress and endothelial activation, resulting in reduced vascular compliance, are contributors to CVD risk. However, there is a paucity of vascular health data in this population. Objectives: To assess the relationships of oxidative stress and endothelial activation with vascular stiffness among PLWH. Method: Fifty-four PLWH on antiretroviral therapy > 5 years and 57 HIV-negative controls, all aged 18–45 years, were enrolled from the University Teaching Hospital, Lusaka, Zambia. Oxidative stress was measured by nitrotyrosine, a peroxynitrite biomarker, and endothelial activation by soluble intercellular adhesion molecule-1 (sICAM-1) plasma levels. Vascular compliance was measured using carotid-radial pulse wave velocity (crPWV) and arterial stiffness index (crASI). Results: PLWH had higher sICAM-1 levels (median 345 ng/mL) compared to controls (275 ng/mL, p < 0.01), as well as higher nitrotyrosine levels (297 versus 182 nM; p = 0.02). Median crPWV was similar between the groups, but PLWH had higher crASI (2.4 versus 2.2 cm/ms; p < 0.05). After adjusting for age, fat mass, and blood pressure, the estimated effect of a one unit increase in nitrotyrosine on crPWV were twofold higher in the PLWH, but neither reached significance. In a model pooling all participants, there were significant differences in the relationship of nitrotyrosine with crPWV and crASI by HIV status. Conclusion: PLWH in sub-Saharan Africa had significantly greater oxidative stress and endothelial activation compared to HIV-negative individuals. These factors may contribute to increased arterial stiffness and higher CVD prevalence in this population.

Many researchers have proven the relationship between periodontal disease and somatic pathology. Analysis of the data obtained from 348 patients showed that patients under the age of 49 were most often diagnosed with various forms of gingivitis — 36.3–51.65 % and generalized periodontitis (GP) I–II degree — 48.35–59.42 %. However, in patients aged 50–69 years, GP was the predominant disease and accounted for 93.2 %, with 56.03 % of patients having concomitant cardiovascular disease (CVD). Our studies showed that despite the significant prevalence of periodontal disease in patients with CVD, they did not systema-tically visit dentists for treatment. Our studies demonstrated a significant role of autoimmune processes in the formation and progression of chronic generalized periodontal disease in patients with concomitant comorbid conditions, in particular with cardiovascular disease. The data obtained by us demonstrated that one of the important autoantigens that determine the forms of syste-mic inflammatory response and progression of local and systemic endothelial dysfunction in GP with CVD is heat shock proteins. Taking this into consideration, a new differentiated approach to the treatment of GP in CVD was developed based on a new concept of pathogenesis. Pathogenetic therapy of GP in CVD is based on the simultaneous treatment of diseases (including the regenerative method of therapy) taking into account the severity of pathological processes that have an aggravating course. Interdisciplinary integration of dentists and cardiologists will optimize management protocols considering the presence and severity of somatic pathology and, therefore, will improve the quality of GP treatment in conditions of comorbidity.

Purpose of the study. Development of a non-invasive method for the diagnosis of non-alcoholic hepatic steatosis.Material and methods. The study involved 21 patients with confrmed non-alcoholic hepatic steatosis on ultrasound examination with an average age of 42.1 ± 10.1 years. The control group consisted of 10 apparently healthy individuals. The following indicators were determined: body mass index (BMI), the level of gamma-glutamyl transpeptidase (GGTP), vasculoendothelial growth factor (VEGF) and interleukin-6 (IL-6) in serum, and the steatosis index (IS) was calculated using the formula IS = –1.2390 + 0.0575 × BMI + 0.0064 × GGTP +0.0006 × VEGF + 0.0001 × IL-6. The index of the presence of hepatic steatosis according to liver ultrasound data was used as a dependent variable.Results. According to the examination results, BMI and serum concentrations of GGTP, VEGF, and IL-6 in patients with steatosis were signifcantly higher than in the control group (p < 0.001, p < 0.001, p < 0.001, and p < 0.001, respectively), which indicates the presence of cholestasis syndrome, signs of inflammation and endothelial dysfunction. The correlation coeffcient between BMI and the presence of non-alcoholic hepatic steatosis was 0.9; between GGTP and the presence of steatosis was 0.80; between VEGF and the presence of steatosis was 0.85; between IL-6 and the presence of steatosis was 0.80. The predictive value of each parameter of the model was assessed using a scale of values of the area under the ROC-curve (AUC). The model is effective (multiple correlation coeffcient R = 0.809; the share of the influence of the sum of the factors included in the model is R2 • 100 = 65.5%), statistically signifcant (criterion F = 12.318; p < 0.0001) and has excellent diagnostic characteristics.Conclusion. The proposed non-invasive method makes it possible to diagnose hepatic steatosis with a sensitivity of 95.2% and a specifcity of 97.0%: with IS equal to 0.5 or more, the presence of non-alcoholic hepatic steatosis is diagnosed, with IS less than 0.5 is not.

Обстежено 93 хворих віком від 52 до 85 років із метаболічним синдромом та супутнім ускладненим мікотичним ураженням нігтів. У всіх пацієнтів визначено вміст оксиду азоту та ендотеліну-1. Проведено дослідження вмісту вітамінів В1, В2, РР, В6 і С у крові та екскреції дериватів із сечею до і в процесі лікування хворих на деструктивний оніхомікоз. Констатовано, що в більшості хворих (вік понад 50 років) на поліоніхомікоз із коморбідним фоновим метаболічним синдромом наявна ендотеліальна дисфункція та полівітамінна недостатність, що потребує корекції.

Introduction and objectives The vasomotor function of new-generation drug-eluting stents designed to enhance stent healing and reendothelialization is unknown. This study aimed to compare the endothelial function of the infarct-related artery (IRA) treated with bioactive circulating endothelial progenitor cell-capturing sirolimus-eluting stents (COMBO) vs polymer-free biolimus-eluting stents (BioFreedom) in ST-segment elevation myocardial infarction patients at 6 months. Secondary objectives were to compare the microcirculatory function of the IRA and stent healing at 6 months. Methods Sixty patients were randomized to bioactive sirolimus-eluting stent vs polymer-free biolimus-eluting stents implantation. At 6 months, patients underwent coronary angiography with vasomotor, microcirculatory and optical coherence tomography examinations. Endothelial dysfunction of the distal coronary segment was defined as ≥ 4% vasoconstriction to intracoronary acetylcholine infusion. Results Endothelial dysfunction was similarly observed between groups (64.0% vs 62.5%, respectively; P = .913). Mean lumen diameter decreased by 16.0 ± 20.2% vs 16.1 ± 21.6% during acetylcholine infusion (P = .983). Microcirculatory function was similar in the 2 groups: coronary flow reserve was 3.23 ± 1.77 vs 3.23 ± 1.62 (P = .992) and the index of microcirculatory resistance was 24.8 ± 16.8 vs 21.3 ± 12.0 (P = .440). Optical coherence tomography findings were similar: uncovered struts (2.3% vs 3.2%; P = .466), malapposed struts (0.1% vs 0.3%; P = .519) and major evaginations (7.1% vs 5.6%; P = .708) were observed in few cases. Conclusions Endothelial dysfunction of the IRA was frequent and was similarly observed with new-generation drug-eluting stents designed to enhance stent reendothelialization at 6 months. Endothelial dysfunction was observed despite almost preserved microcirculatory function and complete stent coverage. Larger and clinically powered studies are needed to assess the role of residual endothelial dysfunction in ST-segment elevation myocardial infarction patients. Registered in ClinicalTrials.gov: NCT04202172

The endothelium plays a pivotal role in the regulation of vascular tone by synthesizing and liberating endothelium-derived relaxing factors inclusive of vasodilator prostaglandins (eg, prostacyclin), nitric oxide (NO), and endothelium-dependent hyperpolarization factors in a distinct blood vessel size–dependent manner. Large conduit arteries are predominantly regulated by NO and small resistance arteries by endothelium-dependent hyperpolarization factors. Accumulating evidence over the past few decades has demonstrated that endothelial dysfunction and coronary vasomotion abnormalities play crucial roles in the pathogenesis of various cardiovascular diseases. Structural and functional alterations of the coronary microvasculature have been coined as coronary microvascular dysfunction (CMD), which is highly prevalent and associated with adverse clinical outcomes in many clinical settings. The major mechanisms of coronary vasomotion abnormalities include enhanced coronary vasoconstrictive reactivity at epicardial and microvascular levels, impaired endothelium-dependent and endothelium-independent coronary vasodilator capacities, and elevated coronary microvascular resistance caused by structural factors. Recent experimental and clinical research has highlighted CMD as the systemic small artery disease beyond the heart, emerging modulators of vascular functions, novel insights into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will summarize the current knowledge on the endothelial modulation of vascular tone and the pathogenesis of coronary macrovascular and microvascular diseases from bench to bedside, with a special emphasis placed on the mechanisms and clinical implications of CMD.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible virus with significant global impact, morbidity, and mortality. The SARS-CoV-2 virus may result in widespread organ manifestations including acute respiratory distress syndrome, acute renal failure, thromboembolism, and myocarditis. Virus-induced endothelial injury may cause endothelial activation, increased permeability, inflammation, and immune response and cytokine storm. Endothelial dysfunction is a systemic disorder that is a precursor of atherosclerotic vascular disease that is associated with cardiovascular risk factors and is highly prevalent in patients with atherosclerotic cardiovascular and peripheral disease. Several studies have associated various viral infections including SARS-CoV-2 infection with inflammation, endothelial dysfunction, and subsequent innate immune response and cytokine storm. Noninvasive monitoring of endothelial function and identification of high-risk patients who may require specific therapies may have the potential to improve morbidity and mortality associated with subsequent inflammation, cytokine storm, and multiorgan involvement.

Backgrounds: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. Methods: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. Results: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3–41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). Conclusion: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

Little is known about the mechanisms of aging on vascular beds and its relationship with tetra and di-hydrobiopterin (BH4 and BH2) levels. This observational clinical study analyzed the impact of aging on plasma and platelet biopterins, cutaneous blood flow (CBF), and coronary flow reserve (CFR) in healthy adults. The study enrolled healthy adults in 3 age groups: 18–30, 50–59, and 60–70 years (n = 25/group). Biopterins were assessed by LC-MS/MS using newly defined pre-analytical conditions limiting BH4 oxidation and improving long-term stability. CBF was measured by Laser Speckle Contrast Imaging coupled with acetylcholine-iontophoresis and CFR by adenosine stress cardiac magnetic resonance. In healthy adults, aging (60–70 years vs 18–30 years) significantly increased platelet BH2 (+75%, P = 0.033) and BH2 + BH4 (+31%, P = 0.033), and to a lesser extent plasma BH2 (+29%, P = 0.009) without affecting BH4 and BH4/BH2. Simultaneously, CBF was decreased (-23%, P = 0.004) but not CFR, CBF being inversely correlated with platelet BH2 (r = -0.42, P = 0.001) and BH2 + BH4 (r = -0.41, P = 0.002). The proportion of adults with abnormal platelet BH2 increased with age (+28% in 60-70y). These abnormal BH2 levels were significantly associated with reduced CBF and CFR (-16%, P = 0.03 and -26%, P = 0.02). In conclusion, our study showed that age-related peripheral endothelial dysfunction was associated with an increase in circulating BH2 without decreasing BH4, the effect being more marked in platelets, the most relevant blood compartment to assess biopterin bioavailability. Peripheral but not coronary vascular function is progressively impaired with aging in healthy adults. All these findings support biopterins as therapeutic targets to improve vascular function.

Significance Statement Posttranslational guanidinylation of ApoC3, a major constituent of triglyceride-rich lipoproteins, enhances ApoC3?s proinflammatory properties in uremia. Guanidinylated ApoC3 (gApoC3) is generated by guanidine and urea, and accumulates significantly in the plasma of patients with CKD, and in the kidneys of mouse models of CKD. In humanized mice, gApoC3 promotes kidney tissue fibrosis and suppresses regeneration after vascular injury. Importantly, in a large observational trial examining the clinical relevance of this posttranslational modification in patients with CKD, higher plasma gApoC3 intensity was associated with adverse renal and cardiovascular outcomes. Therefore, gApoC3 represents a novel mediator of kidney injury and CKD-associated vascular disease and offers a potential treatment target to halt progression and to prevent vascular disease in patients with CKD.Background Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway.Methods To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients.Results We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro. In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events.Conclusions Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.

Oxidative stress is a common sign of aging and cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, diabetes mellitus and other diseases of the vascular system. In this regard, in recent years, researchers have shown increased interest in sirtuins (SIRTs) — stress adapters and epigenetic enzymes involved in cellular mechanisms for controlling age-related pathologies, cancer and CVD. Among sirtuins, of which there are seven in mammals (SIRT1-SIRT7), SIRT1 and SIRT6 possess the most cardioprotective, anti-inflammatory, atheroprotective and anti-aging properties. In this review, we present a comprehensive analysis of the latest developments in the field of cellular and molecular signaling pathways controlled by two post-translational modifiers — SIRT1 and SIRT6, which have proven their worth as tools to reduce inflammation and oxidative stress at the level of the cardiovascular system. A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 exert their cardioprotective effect will have widespread implications and will accelerate the development of selective and effective pharmacological agents for modulating sirtuins for the prevention and treatment of CVD.

Made available in DSpace on 2022-05-01T10:19:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-01-01 Objective: The aim of this study was to identify determinants of endothelial dysfunction in patients hospitalized with acute COVID-19. Methods: A total of 109 hospitalized COVID-19 patients in noncritical status were cross-sectionally studied. Clinical data (age, sex, comorbidities, and medications) and BMI were assessed. Laboratory tests included serum hemoglobin, leukocytes, lymphocytes, platelets, C-reactive protein, ferritin, D-dimer, and creatinine. Physical status was evaluated using a handgrip dynamometer. Endothelial function was assessed noninvasively using the flow-mediated dilation (FMD) method. Results: The sample average age was 51 years, 51% of patients were male, and the most frequent comorbidity was obesity (62%). Univariate analysis showed association of lower FMD with higher BMI, hypertension, use of oral antihypertensive, higher blood levels of creatinine, and larger baseline artery diameter. After adjusting for confounders, the multivariate analysis showed BMI (95% CI: −0.26 to −0.11; p < 0.001) as the major factor associated with FMD. Other factors associated with FMD were baseline artery diameter (95% CI: −1.77 to −0.29; p = 0.007) and blood levels of creatinine (95% CI: −1.99 to −0.16; p = 0.022). Conclusions: Increased BMI was the major factor associated with endothelial dysfunction in noncritically hospitalized COVID-19 patients. This may explain one of the pathways in which obesity may increase the risk for severe COVID-19. Cardiopulmonary Physiotherapy Laboratory Department of Physical Therapy Federal University of São Carlos Exercise and Chronic Disease Research Laboratory Department of Physical Education School of Sciences São Paulo State University Department of Physical Therapy Universidad Industrial de Santander Department of Gerontology Federal University of São Carlos Department of Physical Therapy Sacred Heart University Center Exercise and Chronic Disease Research Laboratory Department of Physical Education School of Sciences São Paulo State University

Significance: Under homeostatic conditions, the endothelium dynamically regulates vascular barrier function, coagulation pathways, leukocyte adhesion, and vasomotor tone. During sepsis and acute inflammation, endothelial cells (ECs) undergo multiple phenotypic and functional modifications that are initially adaptive but eventually become harmful, leading to microvascular dysfunction and multiorgan failure. Critical Issues and Recent Advances: Sepsis unbalances the redox homeostasis toward a pro-oxidant state, characterized by an excess production of reactive oxygen species and reactive nitrogen species, mitochondrial dysfunction, and a breakdown of antioxidant systems. In return, oxidative stress (OS) alters multiple EC functions and promotes a proinflammatory, procoagulant, and proadhesive phenotype. The OS also induces glycocalyx deterioration, cell death, increased permeability, and impaired vasoreactivity. Thus, during sepsis, the ECs are both a significant source and one of the main targets of OS. Future Directions: This review aims at covering the current understanding of the role of OS in the endothelial adaptive or maladaptive multifaceted response to sepsis and to outline the therapeutic potential and issues of targeting OS and endothelial dysfunction during sepsis and septic shock. One of the many challenges in the management of sepsis is now based on the detection and correction of these anomalies of endothelial function.

Heart transplantation remains the gold standard in the treatment of end-stage heart failure (HF). Heart transplantation patients present lower exercise capacity due to cardiovascular and musculoskeletal alterations leading thus to poor quality of life and reduction in the ability of daily self-service. Impaired vascular function and diastolic dysfunction cause lower cardiac output while decreased skeletal muscle oxidative fibers, enzymes and capillarity cause arteriovenous oxygen difference, leading thus to decreased peak oxygen uptake in heart transplant recipients. Exercise training improves exercise capacity, cardiac and vascular endothelial function in heart transplant recipients. Pre-rehabilitation regular aerobic or combined exercise is beneficial for patients with end-stage HF awaiting heart transplantation in order to maintain a higher fitness level and reduce complications afterwards like intensive care unit acquired weakness or cardiac cachexia. All hospitalized patients after heart transplantation should be referred to early mobilization of skeletal muscles through kinesiotherapy of the upper and lower limbs and respiratory physiotherapy in order to prevent infections of the respiratory system prior to hospital discharge. Moreover, all heart transplant recipients after hospital discharge who have not already participated in an early cardiac rehabilitation program should be referred to a rehabilitation center by their health care provider. Although high intensity interval training seems to have more benefits than moderate intensity continuous training, especially in stable transplant patients, individualized training based on the abilities and needs of each patient still remains the most appropriate approach. Cardiac rehabilitation appears to be safe in heart transplant patients. However, long-term follow-up data is incomplete and, therefore, further high quality and adequately-powered studies are needed to demonstrate the long-term benefits of exercise training in this population.

Mechanical stress from haemodynamic perturbations or interventional manipulation of epicardial coronary atherosclerotic plaques with inflammatory destabilization can release particulate debris, thrombotic material and soluble substances into the coronary circulation. The physical material obstructs the coronary microcirculation, whereas the soluble substances induce endothelial dysfunction and facilitate vasoconstriction. Coronary microvascular obstruction and dysfunction result in patchy microinfarcts accompanied by an inflammatory reaction, both of which contribute to progressive myocardial contractile dysfunction. In clinical studies, the benefit of protection devices to retrieve atherothrombotic debris during percutaneous coronary interventions has been modest, and the treatment of microembolization has mostly relied on antiplatelet and vasodilator agents. The past 25 years have witnessed a relative proportional increase in non-ST-segment elevation myocardial infarction in the presentation of acute coronary syndromes. An associated increase in the incidence of plaque erosion rather than rupture has also been recognized as a key mechanism in the past decade. We propose that coronary microembolization is a decisive link between plaque erosion at the culprit lesion and the manifestation of non-ST-segment elevation myocardial infarction. In this Review, we characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for prevention and treatment., In this Review, Kleinbongard and Heusch characterize the features and mechanisms of coronary microembolization and discuss the clinical trials of drugs and devices for the prevention and treatment of this phenomenon., Key points Coronary microembolization results from spontaneous or interventional erosion or rupture of an epicardial coronary atherosclerotic plaque.Atherothrombotic plaque debris causes physical obstruction of coronary microvessels and results in microinfarcts with an inflammatory response.The surviving myocardium around the patchy microinfarcts has reduced contractile function as a result of inflammatory signal transduction leading to myofibrillar oxidation.Atherosclerotic plaque erosion or rupture releases soluble substances that induce coronary microvascular endothelial dysfunction, vasoconstriction, platelet aggregation and coagulation.Routine use of interventional protection devices does not improve patient outcomes but these devices are indicated in cases of high atherothrombotic plaque burden.Plaque stabilization with statins and canakinumab prevents coronary microembolization, whereas platelet inhibitors, vasodilators and interleukin antagonists attenuate coronary microvascular impairment.

A global pandemic instigated by SARS-CoV-2 virus has been going strongly for almost two years. There have been almost 240 million cases with almost 5 million fatalities all over the world so far. COVID has affected almost every aspect of people’s lives halting the world in immeasurable ways. Although COVID-19 is mostly affecting the respiratory system, it is also responsible for a significant amount of cardiovascular system involvement. On one hand, it deteriorates any pre-existing cardiovascular condition, on another hand, it triggers other inflammation-facilitated acute events. They comprise of inflammatory heart disease, severe pericardial effusion, ventricular arrhythmias, endothelial dysfunction, pulmonary hypertension, heart failure, and many more. In this article, we summarize the features, management, and treatment of several important COVID-19 induced cardiovascular complications. Recent advances in the treatment of these diseases along with the justification and concerns of specific therapeutic measures are also discussed.

Background. Diabetic retinopathy (DR) is a leading cause of blindness in working-age populations. Proper in vitro DR models are crucial for exploring pathophysiology and identifying novel therapeutic targets. This study establishes a rational in vitro diabetic retinal neuronal-endothelial dysfunction model and a comprehensive downstream validation system. Methods. Human retinal vascular endothelial cells (HRMECs) and retinal ganglion cells (RGCs) were treated with different glucose concentrations with mannitol as matched osmotic controls. Cell proliferation and viability were evaluated by the Cell Counting Kit-8. Cell migration was measured using a transwell migration assay. Cell sprouting was assessed by a tube formation assay. The VEGF expression was assessed by ELISA. RGCs were labeled by neurons and RGC markers TUJ1 and BRN3A for quantitative and morphological analysis. Apoptosis was detected using PI/Hoechst staining and TUNEL assay and quantified by ImageJ. Results. Cell proliferation and migration in HRMECs were significantly higher in the 25 mM glucose-treated group ( p < 0.001 ) but lower in the 50 mM and 100 mM groups ( p < 0.001 ). The permeability and the apoptotic index in HRMECs were statistically higher in the 25 mM, 50 mM, and 100 mM groups ( p < 0.05 ). The tube formation assay found that all the parameters were significantly higher in the 25 mM and 50 mM groups ( p < 0.001 ) concomitant with the elevated VEGFA expression in HRMECs ( p = 0.016 ). Cell viability was significantly lower in the 50 mM, 100 mM, and 150 mM groups in RGCs ( p 50 mM = 0.013 , p 100 mM = 0.019 , and p 150 mM = 0.002 ). Apoptosis was significantly elevated, but the proportion of RGCs with neurite extension was significantly lower in the 50 mM, 100 mM, and 150 mM groups ( p 50 mM < 0.001 , p 100 m M < 0.001 , and p 150 mM < 0.001 ). Conclusions. We have optimized glucose concentrations to model diabetic retinal endothelial (25-50 mM) or neuronal (50-100 mM) dysfunction in vitro, which have a wide range of downstream applications.

Endothelial dysfunction, a term used to describe both the physical damage and dysregulated physiology of this endothelial lining, is an increasingly recognized pathophysiological state shared by many cardiovascular diseases. Historically, the role of endothelial dysfunction in atrial fibrillation (AF) was thought to be limited to mediating atrial thromboembolism. However, there is emerging evidence that endothelial dysfunction both promotes and maintains atrial arrhythmic substrate, predicts adverse outcomes, and identifies patients at high risk of recurrence following cardioversion and ablation therapy. Treatments targeted at improving endothelial function also represent a promising new therapeutic paradigm in AF. This review summarizes the current understanding of endothelial function in AF.

The rate of thrombosis and disseminated intravascular coagulation (DIC) has been increasing in COVID-19 patients. Key features related to such condition include minimal or no risk of bleeding, moderate thrombocytopenia, high plasma fibrinogen as well as complement components level in the areas of thrombotic microangiopathy. The clinical picture is not typical for classic DIC. This review systematizes the pathogenetic mechanisms of hypercoagulation in sepsis and its extreme forms in patients with COVID-19. The latter consist of the thrombosis-related immune mechanisms, the complement activation, the macrophage activation syndrome, the formation of antiphospholipid antibodies, the hyperferritinemia, and the dysregulation of the renin-angiotensin system. Taking into consideration the pathogenetic mechanisms, the biomarkers had been identified related to the prognosis of the disease development. Patients with pre-existing cardiovascular disease and other risk factors, including obesity, diabetes, hypertension, and aging pose the peak risk of dying from COVID-19. We also summarize new data on platelet and endothelial dysfunction, immunothrombosis, and, as a result, thrombotic storm as essential components of COVID-19 severe features.

Background Accumulating evidences indicate that periodontitis is closely associated with endothelial dysfunction. Trimethylamine-N-oxide (TMAO), a harmful microbiota generated metabolite, has been implicated as a nontraditional risk factor for impaired endothelial function. However, whether increased circulating levels of TMAO in periodontitis patients induces endothelial dysfunction remains unknown. Methods Patients with periodontitis and periodontally healthy controls were enrolled. Periodontal inflamed surface area (PISA) was calculated to assess the inflammatory burden posed by periodontitis. The circulating TMAO was measured by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Vascular endothelial function including peripheral endothelial progenitor cells (EPCs), brachial arterial flow-mediated vasodilation (FMD) and brachial-ankle pulse wave velocity (baPWV) were assessed. We also isolated and cultured EPCs from participants' peripheral blood to investigate the effect of TMAO on EPC functions in vitro. Results 122 patients with stage III-IV periodontitis and 81 healthy controls were included. Patients with periodontitis presented elevated TMAO (P = 0.002), lower EPCs (P = 0.025) and declined FMD levels (P = 0.005). The TMAO concentrations were correlated with reduced circulating EPCs and FMD levels. Moreover, TMAO can injury EPCs function in vitro, and may induce cell pyroptosis via Bax/caspase-3/GSDME pathway. Conclusions The present study demonstrates for the first time that circulating TMAO levels are increased in patients with stage III-IV periodontitis, and correlated with vascular endothelial dysfunction. These findings may provide a novel insight into the mechanism of vascular endothelial dysfunction in patient with periodontitis via TMAO-downregulated EPC functions. This article is protected by copyright. All rights reserved.

Aim. To study the relationship between the level of haptoglobin and the main indicators of microcirculation (MC) in patients with different phenotypes of chronic heart failure (CHF).Materials and methods. Patients with different phenotypes of functional class II-IV chronic heart failure according to NYHA (n=80) underwent a general clinical examination, determination of the serum haptoglobin level by enzyme-linked immunosorbent assay, as well as an assessment of the MC state on the medial surface of the upper third of the leg by laser Doppler flowmetry (LDF).Results. Patients with CHF included patients with preserved left ventricular ejection fraction (HFpEF; n=27, intermediate ejection fraction (HFmrEF; n=25) and reduced ejection fraction (HFrEF; n=28). The median value of haptoglobin in the HFpEF group was 1387.6 [ 747.5; 1946.9] mg/l, in the HFmrEF group was 1583.4 [818.9; 2201.4] mg/l, in the HFrEF group was 968.5 [509.5; 1324.4] mg/l. Correlation analysis revealed statistically significant relationships between haptoglobin and the amplitudes of the endothelial frequency range (Ae) in the groups of HFmrEF (r=-0.628, 95% confidence interval [CI] -0.256; -0.825, p=0.003) and HFrEF (r=-0.503, 95% CI -0.089; -0.803, p=0.02). A negative relationship between the haptoglobin level and Kv and σ was revealed, as well as a formula for calculating the value of haptoglobin was obtained, which is predicted on the basis of the amplitude index of the endothelial frequency range: [haptoglobin]=1787-(4053×Ae).Conclusion. The multifactorial effect of haptoglobin is realized in the central and peripheral mechanisms of MC regulation. Low values of haptoglobin in blood plasma should be considered as a potential marker for the development of complications and used in a comprehensive assessment of the state of patients with CHF. Evaluation of the diagnostic and prognostic significance of haptoglobin, especially in patients with HFmrEF, requires further study.

INTRODUCTION Systemic sclerosis (SSc) is a chronic debilitating disease characterized by vascular insufficiency, widespread fibrosis and immune activation. Current understanding of its pathophysiology remains incomplete, which translates into inefficient therapies. Notch signaling is a central player in the development of physiological and pathological fibrosis not only in general but also in the context of SSc and is most likely involved in the vascular dysfunction that characterizes the disease. AREAS COVERED This review explores the role of the Notch pathway in the pathophysiology of SSc and the potential implications for the diagnosis, evaluation, and management of this yet incurable disease. EXPERT OPINION Although major issues still exist about the comprehension of SSc and the design of effective treatments, the knowledge of the role of the Notch pathway in fibrogenesis and vascular biology has shed light and enthusiasm over the field. Drugs that target components of Notch signaling are currently in development including already some in clinical trials. As such, Notch may become a very important topic in the near future (considering both the pathophysiology and treatment perspectives), not only in the context of SSc but also in the vascular-dependent fibrotic processes present in a multitude of diseases.

Introduction Endothelial dysfunction occurs at the very beginning of hypertension. The primary goal of our study was to determine plasmatic levels of multiple endothelial substances in otherwise healthy patients with primary hypertension and compare them to healthy individuals. Secondary goals were to determine the change in NOx levels after initiation of treatment and to compare the NOx levels in patients with established resistant hypertension. Materials and methods 87 consecutive patients were enrolled. In the exploratory cohort of 22 healthy and 28 hypertensive individuals, plasmatic levels of big endotelin-1, asymmetric dimethylarginin, osteopontin, oxidized LDL, 3-nitro-L-tyrosine, growth/differentiation factor 15, intercellular adhesion molecule, vascular cell adhesion molecule, tumor necrosis factor-α, vascular endothelial growth factor, interleukins -1β, -6 and nitric oxide levels (NO, expressed as NOx) were determined. The remaining 27 individuals were used as a validation cohort. Ten patients with established resistant hypertension were enrolled from our Hypertension Clinic. Results There was a statistically significant difference in NOx levels between healthy controls and hypertensive patients/resistant hypertensive patients: 45.164 µmol/L ± 48.627 vs 17.763 µmol/L ± 10.333 (P=0.00004)/14.36 µmol/L ± 7.194 (P=0.00007). Conclusion We identified a decrease in total NOx plasmatic levels in otherwise healthy patients with primary hypertension that was more profound in patients with resistant hypertension. Plasmatic levels of other determined endothelial substances did not differ among the groups. However, due to the significant variability of plasmatic NOx levels even in healthy controls and many factors that affect it, we cannot recommend it to be used to assess endothelial function routinely.