Endothelial Vasomotor Function Research Articles

Specific features of arterial stiffness and endothelial vasomotor dysfunction in patients with joint hypermobility syndrome

Introduction. Joint hypermobility syndrome (JHS) is characterized by a multisystem lesion of organs, including the cardiovascular system, which determines the presence of cardiovascular risks in this pathology. Aim. Studying of arterial stiffness and endothelial dysfunction parameters in patients with JHS. Material and methods. Study population included 105 adults with JHS (90 women and 15 men) and 57 healthy controls (49 women and 8 men) aged 20 to 28 years (mean age 22 [21; 23] years). All persons underwent a general clinical examination; examination of endothelial vasomotor function (EVF) and pulse wave velocity at the carotid-radial segment (PWVcr) by rheography (IMPECARD-M, Belarus); investigation of arterial stiffness parameters: cardio-ankle vascular index (CAVI), cardio-ankle pulse wave velocity (PWVha), ankle-brachial index (ABI), augmentation index (AI) by sphygmography (VaSeraVS-1500N Fukuda Denshi, Japan); determination of T786C polymorphism of the eNOS gene by polymerase chain reaction (Litech, Russia), determination of endothelin-1 and transforming growth factor beta-1 (TGF-β1) levels by enzyme immunoassay (Fine Test, Wuhan Fine Biotech Co., China). Results. According to the main clinical and laboratory indicators, the groups were matched. In patients with JHS, the values of PWV at the carotid-radial and cardio-ankle segments were higher, in other parameters (EVF, CAVI, ABI, AI) the groups were matched. In the group with JHS, pathological values of EVF, PWVcr, CAVI, AI were more often determined. Among patients with JHS, an excess of vascular age over the passport age is detected 8.6 times more often (95% CI from 1.103 to 67.321). These changes are not associated with mutations of the eNOS T786C gene and changes in endothelin-1 and TGF-β1 concentrations. Conclusion. These data indicate the importance of further study of the mechanisms of early vascular changes in the arteries in JHS, in order to develop optimal methods of therapy and improve the cardiovascular prognosis of patients with this pathology

Arterial stiffness and endothelial function in the long-term period after a coronavirus disease 2019

Aim. To assess endothelial function and arterial stiffness over time in patients after hospitalization with coronavirus disease 2019 (COVID-19) and compare them with a control group.Material and methods. A total of 53 patients over 18 years of age were hospitalized for COVID-19 in June — August 2021 was examined at two visits: the first — 10-16 months, the second — 14-23 months after discharge from the hospital. Control group included 53 patients from the ESSE-RF epidemiological study of a St. Petersburg population who did not have COVID-19, selected by sex, status of smoking, hypertension and type 2 diabetes. Endothelial function was assessed by the levels of vascular cell adhesion molecule 1 (VCAM-1) and von Willebrand factor (vWF) in plasma and the reactive hyperemia index (lnRHI) on the EndoPAT 2000 system. Carotid-femoral pulse wave velocity (cfPWV) was determined using the SphygmoCor device, while cardio-ankle vascular index (CAVI) and ankle-brachial index (ABI) — using the VaSera device.Results. The prevalence of endothelial vasomotor function disorders at the first and second visits in the active group did not differ significantly as follows: lnRHI £0,51 — 21% and 21%, cfPWV >10 m/s — 17% and 14%, and SLSI >9 — 28% and 34%, respectively. Plasma VCAM-1 levels were significantly higher during hospitalization than at the first and second visits — no differences were found between visits. The levels of lnRHI, vWF, cfPWV, CAVI, ABI at the first and second visits did not differ significantly. Post-COVID-19 patients differed from the control group only by a significantly higher ABI level at the second visit. According to the analysis of covariance, COVID-19 is associated with a CAVI increase at the first visit, as well as with an increase in ABI at both visits.Conclusion. The 1,5-2-year follow-up of patients after COVID-19, which required hospitalization, showed a decrease in the plasma endothelial dysfunction parameter VCAM-1. There is no changes in endothelial function and arterial stiffness over a period of time from 10-16 months to 14-23 months after hospitalization with COVID-19.

Effects of Myocardial Infarction-induced Heart Failure on Diaphragm Arteriolar Vasorelaxation

INTRODUCTION: Diaphragm atrophy and contractile dysfunction are prevalent in heart failure (HF), diminishing physical capacity and quality of life. The delivery of blood flow and oxygen necessary to support the metabolic demand of contractions is largely governed by the resistance vasculature (i.e., arterioles) with the endothelium playing a central role in arteriolar vasorelaxation. Adequate perfusion and blood flow distribution, and thus resistance vessel vasodilation, is a major determinate of diaphragm contractile function. While the mechanistic bases of HF-induced diaphragm dysfunction continue to be elucidated, the impact of HF on diaphragm vasomotor control has not been investigated. METHODS: Adult (6 mo) Sprague-Dawley rats (n=7) were divided into two groups: 1) Healthy Control (HC; n=4) and 2) MI-induced heart failure (HF; n=3). First-order arterioles (1A) from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O and allowed to equilibrate for 60 min to develop spontaneous tone. Thereafter, endothelium-dependent and -independent vasorelaxation responses to cumulative doses of acetylcholine (ACh; 10−9 to 10−4M) and sodium nitroprusside (SNP; 10−9 to 10−4M) were determined. RESULTS: There were no differences in spontaneous development (%) or maximal diameter (μm) between HC (20 ± 4%; 178 ± 11 μm) and HF (18 ± 2%; 184 ± 29 μm) diaphragm 1As ( P > 0.05). Maximal ACh-mediated relaxation (%) was significantly reduced in HF rats compared to HC rats (52 ± 2 versus 68 ± 5%; P < 0.05). Maximal endothelial-independent vasorelaxation with SNP, was not different between HC and HF rats (71 ± 3 versus 73 ± 1%; P > 0.05). CONCLUSION: The preliminary data herein demonstrate that HF impaired endothelial function and vasomotor function in the medial costal diaphragm resistance vasculature. This suggests that, in HF, there may be a redistribution of blood flow to less effcient regions of the diaphragm (e.g., ventral costal) to sustain contractile function and compensate for the diminished medial costal vasomotor function demonstrated herein. Studies including a larger sample size are warranted to investigate the impact of HF on regional blood flow distribution and resistance vessel function in the diaphragm. Such investigations would yield novel mechanistic insights into HF-induced diaphragm dysfunction. National Institute of Aging 1R15AG078060, Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute 1F31HL167618-01, and Sustained Momentum for Investigators with Laboratories Established (SMILE) Grants at Kansas State University. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Endothelin Receptor Blockade Improves Cerebral Blood Flow-Mediated Dilation in a Mouse Model of Alzheimer’s Disease

Introduction: Cerebral blood flow (CBF) is reduced in patients with Alzheimer’s disease (AD). Flow-mediated dilation (FMD), which plays a key role in the regulation of blood flow, is attenuated by endothelin-1. We hypothesized that endothelin receptor blockade may improve CBF in AD. Methods: We investigated cerebrovascular reactivity in a mouse model of AD (APP-PS1; 5-6-month-old male subjects). We assessed the in vivo response to normoxic hypercapnia and in vitro FMD in isolated cerebral and mesenteric resistance arteries before and after endothelin receptor blockade (bosentan). Results: Normoxic hypercapnia increased basilar trunk blood flow velocity (+12.3 ± 2.4%; p = 0.006, n = 6) in wild-type (WT) mice but reduced blood flow in APP-PS1 mice (−11.4 ± 1.2%; p < 0.0001, n = 8). Bosentan (50 mg/kg, acute intraperitoneal injection) restored cerebrovascular reactivity in APP-PS1 mice (+10.2 ± 2.2%; p < 0.0001, n = 8) but had no effect in WT. FMD was reduced in the posterior cerebral artery of APP-PS1 compared to WT and was normalized by bosentan (1 μmol/L, 30 min, or 50 mg/kg/day for 28 days). FMD was similar in the mesenteric artery of APPS-PS1 and WT. Conclusion: APP-PS1 mice exhibited cerebrovascular endothelial dysfunction. Acute and chronic blockade of endothelin receptors restored endothelial vasomotor function, suggesting a promising therapeutic approach to restoring cerebral vasoreactivity in AD.

Impaired Endothelial Vasomotor Function with Borderline-High Triglycerides

Approximately 1 in 3 adults in the United States have a triglyceride (TG) concentration above 150 mg/dL and 1 in 5 adults have TG levels 200 mg/dL or higher. Moreover, the prevalence of suboptimal TGs (&gt;150 mg/dL) has increased 5-fold in middle-aged and older adults over the last 3 decades. While much attention has focused on the cardiovascular effects of high and very high TG levels, where other lipid and metabolic abnormalities are often present, there are currently little data on the influence of borderline-high TG concentrations on vascular health. This represents a critical void in our understanding of the pathogenesis of cardiovascular disease (CVD) with TGs. Impaired endothelial vasomotor function is a central etiologic feature in the development of CVD and associated thrombotic events. We tested the hypothesis that endothelium-dependent vasomotor function is impaired in adults with borderline-high TG concentrations. Thirty-two sedentary, adults were studied: 15 (7M/8F, age: 56±1 yr; BMI: 26.8±0.6 kg/m2) with normal TG (35-140 mg/dL) and 17 (9M/8F, age: 57±1 yr; BMI: 28.7±0.8 kg/m2) with borderline-high TG (150-199 mg/dL) levels. Forearm blood flow (FBF; plethysmography) was determined in response to the intra-arterial infusion: acetylcholine (ACh) (4.0, 8.0, and 16.0 mg/100 mL tissue/min), sodium nitroprusside (1.0, 2.0, and 4.0 mg/100 mL tissue/min) and selective ETa receptor blocker (BQ-123, 100 nmol/min for 60 min). FBF response to ACh was significantly lower (~20%) in the borderline-high TG (from 4.7±0.3 to 11.6+0.6 mL/100 mL tissue/min) vs normal TG (from 4.3±0.3 to 14.6±0.5 mL/100 mL tissue/min) group. There were no significant group differences in the FBF responses to sodium nitroprusside. BQ-123 elicited a significant vasodilator response (~20%) in the borderline-high TG adults but did not alter FBF in the normal TG adults. Co-infusion of BQ-123 did not affect FBF responses to ACh in normal TG group but resulted in an ~30% increase in Ach-induced vasodilation (from 4.3±0.4 to 15.1±0.7 mL/100 mL tissue/min; P&lt;0.05) in borderline-high TG group. Triglyceride levels were significantly and inversely associated with total FBF response to ACh (r=-0.63) and positively associated with the peak FBF response to BQ-123 (r=0.53; P&lt;0.05). These results indicate that borderline-high TG concentrations are associated with diminished endothelium-dependent vasodilation and enhanced ET-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor function may underlie the increased risk of CVD in adults with borderline-high TG levels. Nothing to disclose This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Validation of an ex vivo Flow Model Including Magnetic Resonance Imaging to Study the Effects of Endovascular Treatments on the Arterial Wall

Endovascular revascularization is the preferred treatment for peripheral arterial disease. Restenosis often occurs as a response to procedure-induced arterial damage. Reducing vascular injury during endovascular revascularization may improve its success rate. This study developed and validated an ex vivo flow model using porcine iliac arteries, obtained from a local abattoir. Twenty arteries (of 10 pigs) were equally allocated to two groups: a mock-treated control group and an endovascular intervention group. Arteries of both groups were perfused with porcine blood for 9 min, including 3 min of balloon angioplasty in the intervention group. Vessel injury was assessed by calculating the presence of endothelial cell denudation, vasomotor function, and histopathological analysis. MR imaging displayed balloon positioning and inflation. Endothelial cell staining showed 76% of denudation after ballooning compared to 6% in the control group (p < 0.001). This was confirmed by histopathological analysis, showing a significantly reduced endothelial nuclei count after ballooning compared to the controls (median: 22 vs. 37 nuclei/mm, p = 0.022). In the intervention group, vasoconstriction and endothelium-dependent relaxation were significantly reduced (p < 0.05).We present an ex vivo flow model to test the effects of endovascular therapy on the vessel’s wall morphology, endothelial denudation, and endothelial-dependent vasomotor function under physiological conditions. Additionally, it allows the future testing of human arterial tissue.

Лакунарный инсульт у мужчин молодого возраста

Background: ischemic strokes at a young age are one of the urgent problems of modern reality, since they occur in persons of working age. These vascular catastrophes are of great economic importance. Lacunar stroke (LS), or small vessel occlusion, is one of the main ischemic stroke (IS) subtypes with a variety of modifiable risk factors for its development. Aim: to evaluate the main risk factors, the stroke patterns and the endothelial function state in young male patients (18—50 y.o.) with LS. Patients and Methods: 46 male patients aged 18–50 y.o. with LS were included in the study. The NIHSS neurological deficit assessment scale, the Modified Rankin Scale and the Rivermead Mobility Index were used to objectify the severity of existing clinical symptoms and assess the IS severity. The patients underwent brain CT and/or MRI, ultrasound and duplex scanning of neck and head vessels, ECG, ECHO cardioscopy and laboratory examination. Shoulder ultrasound (SU) was used to assess the endothelial vasomotor function. Results: in the examined patients, the main risk factors were hypertension (97.8%), smoking (67.4%), dyslipidemia (41.3%) and obesity (8.7%). At the same time, the combination of hypertension and smoking was noted in 67.4% of cases, the combination of hypertension, smoking and regular alcohol consumption — in 17.4% of cases, atherosclerosis of the major arteries of the head — in 56.5% of cases. Isolated common carotid artery (CCA) stenosis was observed in 22.2% of cases, the degree of which varied from 20 to 35%, in 50% — internal carotid artery (ICA) stenosis (20—40%) and in 33.3% — combined stenoses of the CCA and ICA (25—60%). SU revealed a disorder in the form of a decreased vasomotor reactivity in 20 (58.8%) of the 34 examined patients. Conclusion: in male patients aged 18–50 y.o. with LS, multiple modifiable risk factors were identified. Ultrasound signs of endothelial dysfunction were detected in more than half of the patients. KEYWORDS: lacunar stroke, young age, modifiable risk factors, endothelial dysfunction, shoulder ultrasound. FOR CITATION: Pizov N.A., Baranova N.S., Pizova N.V., Bakucheva M.V. Lacunar stroke in young male patients. Russian Medical Inquiry. 2023;7(10):614–619 (in Russ.). DOI: 10.32364/2587-6821-2023-7-10-1.

Актуальні аспекти взаємозв’язків між судиноруховою функцією ендотелію та артеріальним тиском В осіб з початковими проявами хронічної ішемії мозку

Вступ. Одним із найбільш агресивних судинних факторів ризику розвитку хронічної й гострої ішемії мозку є артеріальна гіпертензія (АГ), що тривалий час має асимптомний перебіг. Виявлення ознак ушкодження судинної системи під впливом судинних факторів ризику у вигляді ендотеліальної дисфункції (ЕД) на ранніх етапах розвитку патологічного процесу дає підставу для більш ретельного скринінгу ризиків та активних профілактичних заходів. Нами було проведено дослідження, метою якого стала оцінка судинорухової функції ендотелію при початкових проявах хронічної ішемії мозку відповідно до наявності, ступеня та стадії АГ. Матеріали й методи. Нами було обстежено 306 осіб з початковими проявами хронічної ішемії мозку — із судинними факторами ризику, відповідними клінічними проявами та нейровізуалізаційними ознаками ураження головного мозку легкого ступеня. Групу контролю становили 15 осіб без анамнестичних, клінічних, інструментальних та лабораторних ознак судинних та інших тяжких соматичних захворювань. Усім пацієнтам проводилися загальноклінічні, клініко-неврологічні, клініко-інструментальні та клініко-лабораторні обстеження. З метою оцінки судинорухової функції ендотелію проводилася компресійна проба на потокозалежну вазодилатацію (ПЗВД), а також визначалися рівні ендотеліну‑1 та нітриту (стабільного метаболіту NO) у сироватці крові пацієнтів. Результати та їх обговорення. Аналіз зв’язків між показниками судинорухової функції ендотелію в контрольній групі показав наявність значущих (р = 0,000) зв’язків між ними: між ЕТ‑1 і відсотком ПЗВД (обернений зв’язок, r = –0,74); нітритом і відсотком ПЗВД (прямий, r = 0,63); нітритом і ЕТ‑1 (обернений, r = –0,865).Тоді як зв’язок (за коефіцієнтом Спірмена) між наведеними показниками в основній клінічній групі був менш тісним, а саме: між відсотком ПЗВД і ЕТ‑1 — r = –0,278 (р = 0,002), відсотком ПЗВД і нітритом — r = 0,316 (р = 0,000), ЕТ‑1 і нітритом — r = –0,367 (р = 0,000), що оцінюється як слабка кореляція. У 202/306 (66,0 %) обстежених пацієнтів була виявлена АГ. У 124/202 (61,4 %) хворих визначалася АГ І ступеня (АТ = 140–159/90–99 мм рт.ст.), у 78/194 (38,6 %) пацієнтів — АГ ІІ ступеня (АТ = 160–179/100–109 мм рт.ст.). Пацієнти з АГ ІІІ ступеня у дослідження не включалися. У 86/202 (42,6 %) пацієнтів була виявлена І стадія АГ та у 116/202 (57,4 %) хворих — ІІ стадія АГ. Порівняння пацієнтів з початковими проявами хронічного інфаркту міокрада і з різними ступенями та стадіями АГ за показниками судинорухової функції ендотелію, а саме біохімічними показники та відсотком ПЗВД, показало, що групи невипадково відрізнялися між собою за деякими показниками, але для уточнення, за якими саме, проводилося попарне порівняння груп за допомогою критерію Манна — Уїтні. Виснов­ки. Виявлено, що початкові прояви хронічної ішемії мозку розвивалися на тлі порушення взаємозв’язків між протилежно направленими чинниками, що вивільняються з ендотеліоцитів. Було встановлено, що підвищення рівня ЕТ‑1 мало значення для ініціації АГ в осіб з початковими проявами хронічної ішемії мозку та відігравало значущу роль у субклінічному ураженні органів-мішеней на тлі АГ порівняно з особами без АГ та з початковими проявами хронічної ішемії мозку. Тоді як рівень нітриту та відсоток ПЗВД значущо знижувалися в міру підвищення ступеня АГ, особливо у пацієнтів з субклінічним ураженням органів-мішеней, порівняно з особами без АГ та субклінічного ураження органів-мішеней на тлі АГ.

Взаємозв’язок показників автоімунореактивності та судинорухової функції ендотелію у пацієнтів із початковими проявами хронічної ішемії мозку

Вступ. Артеріальна гіпертензія (АГ) є одним з основних модифікованих судинних факторів ризику хронічної ішемії мозку (ХІМ). Ендотеліальна дисфункція супроводжує АГ і претендує на роль одного з патогенетичних механізмів розвитку ХІМ. Нами проведено дослідження, метою якого була оцінка показників автоімунореактивності до структурних компонентів серцево-судинної системи залежно від наявності АГ і ендотеліальної дисфункції у пацієнтів із початковими проявами ХІМ. Матеріал і методи. Нами було обстежено 55 осіб середнього віку (51,3 ± 7,0 року) з початковими проявами ХІМ. Усім пацієнтам проводилися загальноклінічне, клініко-неврологічне, клініко-інструментальні та клініко-лабораторні обстеження. Рівень автоантитіл (автоАТ) до антигенів тромбоцитів, кардіоміоцитів і ендотелію судин у сироватці крові пацієнтів визначали за методикою О.Б. Полетаєва. Ендотеліальна функція оцінювалася за показниками потокозалежної вазодилатації, рівнем нітриту та ендотеліну‑1. Результати та обговорення. Пацієнти з АГ та особи без АГ статистично значущо відрізнялися лише за рівнями автоАТ до PAPP-A та СоМ‑02. Залежно від ступеня відхилення артеріального тиску (АТ) (АГ І та ІІ ступеня, клінічна артеріальна гіпотензія або нормальний АТ) пацієнти відрізнялися лише за показниками середнього індивідуального рівня імунореактивності (СІРІ) (р = 0,001) та рівнем автоАТ до ДНК (р = 0,015). Статистичний аналіз показав, що пацієнти з АГ (І та ІІ стадії) та особи без АГ статистично значущо відрізнялися за показником СІРІ (χ2(3) = 11,5; р = 0,009) і рівнем автоАТ до ДНК (χ2(3) = 8,6; р = 0,04). Відсоток потокозалежної вазодилатації статистично значущо корелював з СІРІ (r = 0,409; p = 0,003), а також із рівнем автоАТ до с-ANCA (r = –0,309; p = 0,027) та білка PAPP-A (r = 0,361; p = 0,009). Оцінка судинорухової функції ендотелію за вмістом біохімічних маркерів виявила, що рівень нітриту статистично значущо корелював з відносним умістом автоАТ до СоS‑05 (r = 0,326; p = 0,033) та с-ANCA (r = –0,312; p = 0,042) на відміну від ендотеліну‑1, з рівнем якого не було виявлено статистично значущих кореляційних зв’язків. Висновки. За оцінкою показників автоімунореактивності у пацієнтів із початковими проявами ХІМ залежно від ступеня порушення АТ у пацієнтів з АГ спостерігалося підвищення активності кардіодистрофічних процесів на фоні порушення регулюючих впливів на ліпідний і вуглеводний обмін порівняно з особами без АГ. У міру розвитку ендотеліальної дисфункції, за даними компресійної проби у пацієнтів із початковими проявами ХІМ, спостерігалася тенденція до зниження рівня імунореактивності, активації ендотелію та порушення регулювання ліпідного і вуглеводного обміну.

Endothelial function status in hypogonadal men

Background: Type 2 diabetes mellitus (T2DM) and hypogonadism are mutually aggravating diseases associated with the development and progression of cardiovascular pathology. The status of endothelial function in men with T2DM and hypogonadism hasn’t been studied.Aims: To assess the effect of hypogonadism on endothelial function in men with T2DM.Materials and methods: Patients underwent clinical studies, assessment of carbohydrate and lipid metabolism, the content of sex hormones (total testosterone (T), sex hormones binding globulin, free T, luteinizing hormone) and markers of endothelial function (nitric oxide (NO), endothelial nitric oxide synthase type 3 (eNOS3), endothelin, adhesion molecules ICAM-1, VCAM-1, p- and e-selectins, cadherin), ultrasound examinations of endothelium-dependent vasodilation (EDVD) of the brachial artery (BA) and carotid arteries with an assessment of the thickness of intima-media complex (TIM) were performed.Results: The study included 276 men with T2DM (age 54.0[49;60] years), who were divided into 2 groups: 1–124 patients with hypogonadism; 2–152 eugonadal patients. Reduction of the endothelial vasomotor function was detected in 32.4% of patients in the 2st group and in 55.3% of the 1nd group (χ2=6.1; p=0.01), which was associated with a decrease in EDVD by 29.8 % (p&lt;0.001) and an increase in the time of development of maximal BA vasodilation by 30 seconds in patients with hypogonadism (p&lt;0.001). The TIM of the carotid arteries was 10% more in group 1 compared with group 2 (p=0.03). The ­level of NO in the 1st group was reduced by 1.6 times (p=0.001), eNOS3–by 1.5 times (p=0.038) compared with the 2nd group. The concentrations of adhesion molecules were higher in group 1 compared to group 2: VCAM-1 by 32.5% (p&lt;0.001), ICAM-1 by 43.5% (p&lt;0.001), p-selectin–by 19.3% (p=0.004), cadherin–6 times (p&lt;0.001).Conclusion: Hypogonadism in men with T2DM is associated with the development of endothelial dysfunction, which manifests in a weakening of the EDVD and a slowdown in its development, as well as disturbances of the secretory activity of endothelium–a decrease in NO synthesis and activation of the adhesion molecules expression, which can be regarded as an universal pathogenetic mechanism of the development of cardiovascular diseases in combination of T deficiency and T2DM.

Characterization of Cardiac, Vascular, and Metabolic Changes in Young Childhood Cancer Survivors.

Background: Childhood cancer survivors (CCS) are at an increased risk for cardiovascular diseases (CVD). It was the primary aim of this study to determine different measures of cardiac, carotid, lipid, and apolipoprotein status in young adult CCS and in healthy controls.Methods: Cardiac and common carotid artery (CCA) structure and function were measured by ultrasonography. Lipids and apolipoproteins were measured in the blood. Peripheral arterial endothelial vasomotor function was assessed by measuring digital reactive hyperemia index (PAT-RHI) using the Endo-PAT 2000.Results: Fifty-three CCS (20–30 years, 35 men) and 53 sex-matched controls were studied. The CCS cohort was divided by the median dose of anthracyclines into a low anthracycline dose (LAD) group (50–197 mg/m2, n = 26) and a high anthracycline dose (HAD) group (200–486 mg/m2, n = 27). Carotid distensibility index (DI) and endothelial function determined by PAT-RHI were both lower in the CCS groups compared with controls (p < 0.05 and p = 0.02). There was no difference in carotid intima media thickness. Atherogenic apolipoprotein-B (Apo-B) and the ratio between Apo-B and Apoliprotein-A1 (Apo-A1) were higher in the HAD group compared with controls (p < 0.01). Apo-B/Apo-A1-ratio was over reference limit in 29.6% of the HAD group, in 15.4% of LAD group, and in 7.5% of controls (p = 0.03). Measured lipid markers (low density lipoprotein and total cholesterol and triglycerides) were higher in both CCS groups compared with controls (p < 0.05). Systolic and diastolic function were measurably decreased in the HAD group, as evidenced by lower EF (p < 0.001) and lower é-wave (p < 0.005) compared with controls. CCA DI correlated with Apo-B/Apo-A1-ratio and Apo-A1. Follow-up time after treatment correlated with decreased left ventricular ejection fraction (p = 0.001).Conclusion: Young asymptomatic CCS exhibit cardiac, vascular, lipid, and apolipoprotein changes that could account for increased risk for CVD later in life. These findings emphasize the importance of cardiometabolic monitoring even in young CCS.

Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis.

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis.Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation.Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor.Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Relationship between the volume of perivascular adipose tissue and the vascular wall lesion

Aim. To study the relationship between the volume of perivascular adipose tissue (PVAT) and the vascular wall lesion.Material and methods. The study included 318 patients without cardiovascular disease (mean age, 63,5±13,7 years). Hypertension was detected in 268 (84,3%) patients. All patients underwent assessment of anthropometric characteristics, lipid profile, arterial wall stiffness with the estimation of cardio-ankle vascular index, intima-media thickness, brachial artery endothelial vasomotor function. Chest computed tomography was performed with the estimation of the volumes of PVAT and pericardial adipose tissue (PAT).Results. The volume of PVAT, on average, was 0,3 [0,2; 0,4] cm3 . The VAT volume was significantly higher in obese individuals when compared with patients with normal body weight: 0,4 [0,3; 0,5] vs 0,25 [0,2; 0,4] cm3 (p=0,0007). The VAT volume was higher in individuals with an increased CAVI level when compared with patients with normal CAVI values: 0,4 [0,3; 0,5] vs 0,3 [0,25; 0,3] (p=0,02). A significant correlation was found between the VAT volume and body mass index (r=0,27, p&lt;0,005), waist circumference (r=0,41, p&lt;0,005), CAVI (r=0,49, p&lt;0,05), impaired endothelium-dependent brachial artery vasodilation (r=0,38, p&lt;0,05). When performing multiple linear regression, a significant relationship of CAVI was found with age (β±SE, 0,51±0,15; p=0,002) and volume of PVAT (β±SE, 0,41±0,13; p=0,005).Conclusion. The results indicate the relationship of PVAT with visceral obesity and vascular wall stiffness parameters.

Glucose‐Derived Extracellular Endothelial Microvesicles Induce a Pathologic Endothelial Phenotype

Hyperglycemia is associated with an increased risk and prevalence of cardiovascular disease (CVD), due in large part to the adverse effects of glucose on endothelial cells. Indeed, hyperglycemic conditions can damage endothelial cells, in turn, impairing endothelial vasomotor and fibrinolytic function, exacerbating inflammatory and oxidative processes and propagating a proapoptotic phenotype. In addition to these primary effects, glucose also stimulates the release of extracellular microvesicles from endothelial cells. Extracellular endothelial microvesicles (EMVs) have emerged as causative agents in vascular pathology owing to their numerical increase in disease states, including diabetes, and cellular effects. The effects of glucose-derived EMVs on endothelial cell function is not clear. The experimental aim of this study was to determine, in vitro, the effect of glucose-derived EMVs on endothelial cell inflammation, oxidative stress, and nitric oxide (NO) production. Human umbilical vein endothelial cells (HUVECs) were cultured (3rdpassage) and incubated with RPMI 1640 media containing 25mM D-glucose (concentration representing a diabetic glycemic state) or 5mM D-glucose (control, normoglycemic condition) for 48 h to generate EMVs. EMVs (CD144-PE) were counted and isolated by flow cytometry. Thereafter, HUVECs (2 x106cells/condition) were treated with EMVs (2:1 EMV:cell ratio) generated from either the high (hgEMV) or normal (ngEMV) glucose condition for 24 h. EMV release was markedly higher (~280%; P<0.05) in cells treated with high vs normal glucose (134.7±15.6 vs. 35.4±3.2 EMV/µL). hgEMVs induced significantly higher release of cytokines IL-6 (26.6±1.5 vs. 20.7±1.6 pg/mL) and IL-8 (40.5±4.1 vs. 26.4±2.9 pg/mL); in addition, expression of active NF-κB p65 (Ser-536) was higher in the hgEMV treated cells (7.6±1.0 vs. 3.4±0.5 AU; P<0.05). Intracellular ROS production was higher(~26%) in the cells treated with hgEMVs (72.5±3.4 %) vs ngEMVs (57.7±1.8%). Active endothelial nitric oxide synthase (p-eNOS Ser1177) (10.6±1.6 vs 31.7±5.2 AU) and NO production (7.7±0.2 vs. 11.6±1.1 umol/L) were both significantly lower (~30% and 20%, respectively) in hgEMV treated cells. Blocking NF-kB activation using IKK-2 inhibitor IV abolished the increase in IL-6 and IL-8 release in response to hgEMVs, verifying hgEMV induced NF-kB-mediated inflammation. Inhibiting endocytosis prevented the proinflammatory, pro-oxidative and anti-NO effects of hgEMVs; whereas, RNase-inactivation (RNase A/T1) of hgEMVs eliminated their negative effects on endothelial proteins regulating inflammation, oxidative stress and NO production. These data demonstrate that: 1)high glucose-derived EMVs induce a proinflammatory, pro-oxidative, proatherogenic endothelial phenotype; and 2) EMV internalization and intracellular delivery of RNA regulatory cargo are central mechanisms underlying these deleterious cellular effects.

Original Method for Evaluating Endothelial Vasomotor Function of Isolated Vessel in Experiment.

We describe a method for experimental assessment of endothelial dysfunction in an isolated using extracorporeal machine perfusion and vasoactive substrates agents (norepinephrine and acetylcholine). Quantitative assessment of endothelial vasomotor dysfunction was proposed, based on registration of changes in volumetric perfusate flow rate through the isolated vessel. Functional activity of the isolated aorta endothelium and total content of stable NO degradation products in blood plasma were studied in outbred white male rats after subtotal liver resection. Impaired vasodilation ability of the aorta and increased content of NO degradation products in blood plasma observed after surgery indicate the development of vasomotor endothelial dysfunction associated with oxidative stress, cholemia, and endotoxemia.

Improvement in Brachial Endothelial Vasomotor Function and Brachial-Ankle Pulse Wave Velocity Reduces the Residual Risk for Cardiovascular Events after Optimal Medical Treatment in Patients with Coronary Artery Disease.

Aim: To examine whether improvement in flow-mediated endothelium-dependent dilatation (FMD) of the brachial artery and brachial-ankle pulse wave velocity (baPWV) has an additive effect on achieving optimal goals of traditional risk factors to reduce cardiovascular risk in patients with coronary artery disease (CAD). Methods: We assessed 323 patients with CAD and impaired vascular function, defined as an impaired FMD of the brachial artery (＜5.5%) and increased baPWV (＞1,440 cm/sec). After FMD and baPWV measurements at 24 weeks of optimal medical treatment (OMT), the study patients were followed up for ＜60 months or until a composite of cardiac death, nonfatal myocardial infarction (MI), unstable angina, or ischemic stroke occurs. Results: During the median follow-up period of 35 months, cardiovascular events occurred in 72 patients. Multivariate Cox hazards analysis showed that patients with an improvement in FMD and baPWV had the lowest probability of future cardiovascular events. In addition, the improvement in FMD and baPWV had a significant incremental effect on the predictive value of the achievement of optimal goals for blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), and hemoglobin A1c (HbA1c) using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Conclusions: The improvement in FMD and baPWV had additive effects on risk reduction of the achievement of the optimal goals of traditional risk factors in patients with CAD. Thus, serial measurements of FMD and baPWV may be useful for identifying CAD patients at residual risk for adverse cardiovascular events following OMT.

Cardiac and vascular remodeling in arterial hypertension: the role of concomitant obesity

The aimof the study evaluation of the structural and functional changes of the heart and common carotid arteries (CCA) in patients with AH I–III degree with the definition of significant criteria for their remodeling in patients with the absence and presence of accompanying obesity (OB) of varying degrees.Materials and methods. 124 patients (86 men and 38 women) aged 27 to 81 years (average age 55.7 ± 1.01 years) were examined. In 19 of them (12 men and 7 women) AH of I degree, in 87 (65 men and 22 women) II degree AH, in 18 (9 men and 9 women) III degree AH was diagnosed. The diagnosis of AH and its degree was verified in accordance with the existing current clinical guidelines (European Society of Hypertension / European Society of Cardiology’s, 2013). Clinical-anamnestical and instrumental examination of patients were carried out with the assessment of their reflection of myocardial remodeling in accordance with the recommendations. Availability and degree of concomitant OB was carried out in accordance with the calculated body mass index and recommended gradations. Echocardiographic examination, ultrasound scanning were used to study the heart and CCA on both sides and reactive hyperemia test used for studying a number of parameters reflecting the remodeling of myocardium and arteries. Laboratory examination included determination of the main parameters of blood plasma lipid profile. The data analysis was carried out with the help of Statistica 12.6 application package.Results. Patients with AH and concomitant OB have a number of differences in the heart and arteries compared to patients with AH without OB. Heart: increased size and volume, myocardial mass, myocardial mass index, decreased contractility and more frequent detection of diastolic dysfunction of the left ventricle of the heart. Arteries: increase in thickness of the intimamedia complex, decrease in intraadventitial diameter of the right and left common carotid arteries, more frequent detection of endothelial vasomotor function impairment using the right brachial artery as an example. The analysis of the obtained data confirmed the presence of significant remodeling of the cardiovascular system (CVS) in patients with AH, which is dependent on the presence and degree of concomitant OB: a more pronounced progress in remodeling of the heart and arteries was observed in some patients with AH with concomitant OB, partly dependent on the degree of the latter and, apparently, associated with hormonal changes that lead to an acceleration of processes underlying the formation of CVS remodeling.Conclusion. The combination of AH with OB of different degrees leads to an increase in the frequency of cases of remodeling of the CVS as a whole in comparison with patients with AH without accompanying OB, with changes in the lipid profile of the blood at the accompanying AH OB of different degrees characterized by an increase in its atherogenic fractions, exacerbated with the increase in the degree of OB.

Atherothrombotic stroke in women: blood thrombogenicity and the vascular wall

Introduction. Haemostasis and functional changes of the vascular wall are the strategic and actively developing aspects in the study of ischaemic stroke pathogenesis. The aim of current work was to examine the relationship between hormonal status, thrombogenic blood factors, and the structural and functional changes in the vascular wall in women after atherothrombotic stroke in the internal carotid territory. Materials and methods . Twenty-nine women (mean age 55 years) in the first 3 months after atherothrombotic stroke, diagnosed using the international TOAST criteria, were included in the study. The severity of neurological impairment was evaluated using the NIH Stroke Scale. The follicular stimulating hormone (FSH) and homocysteine levels, along with haemostasis parameters and rheological properties of red blood cells were examined. Ultrasound of the major arteries of the head, assessment of the elastic properties and mural shear stress in the common carotid artery, as well as evaluation of the vasomotor function of the brachial artery endothelium were conducted. Results. Clinical differences in the atherosclerotic stroke were found in women depending on their FSH levels: moderate and severe neurological impairments were noted when the FSG level was ³30 mIU/mL, while mild impairments were present when the FSG level was <30 mIU/mL. It was found that a high FSH level in women is associated with significant arterial hypertension, obesity and type 2 diabetes mellitus. The group of women with high FSH levels had elevated fibrinogen, homocysteine, von Willebrand factor, erythrocyte aggregation amplitude, along with the accelerated formation of 3D aggregates and increased erythrocyte aggregate strength. In women with insufficient estrogen production in the ovaries (FSH ³30 mIU/mL), the stiffness index of the common carotid artery wall was significantly higher, while the mural shear stress and endothelial vasomotor function were lower than in the group of women with preserved ovarian function. Conclusions. A link between menopause, increased blood thrombogenicity, and structural and functional changes in the vascular wall (increased stiffness, reduced mural shear stress and endothelial vasomotor function) was found in women after atherothrombotic stroke.

Algorithm of Differentiated Approach to the Treatment of CHD Patients with Impaired Homocysteine and Vitamin D Metabolism before and after Coronary Artery Bypass Grafting

For many years, cardiovascular diseases have been a major cause of morbidity and mortality worldwide. In modern society these have become one of the most pressing medical and social problems. To date, progression of coronary heart disease (CHD) and its complications is strongly associated with increased homocysteine (HC) level and hypovitaminosis D. However, medical literature does not sufficiently cover the issues of drug treatment of patients with metabolic disorders after coronary artery bypass grafting, therefore, more detailed study of this problem is required.&#x0D; The aim. To develop a differentiated approach to the medical treatment of CHD patients before and after direct myocardial revascularization.&#x0D; Materials and methods. The study analyzed the data of 133 patients, 117 (87.96%) men and 16 (12.03%) women, diagnosed with CHD. In these patients, the levels of homocysteine and vitamin D were evaluated. Depending on the levels of hyperhomocysteinemia and vitamin D, the patients were divided into 3 groups.&#x0D; Results. About 70% of the patients examined had elevated blood homocysteine levels greater than 15 ¤mol/L. Based on selective CAG (MSCT CA) findings and complete examination, myocardial revascularization was indicated in 133 patients, as recommended by the 2018 ESC/EACTS Guidelines on myocardial revascularization. In 95% of cases (126 patients), direct myocardial revascularization was performed. All the patients received standard therapy preoperatively, and after getting results of HC and vitamin D tests, metabolic therapy, including folic acid, vitamins B6, B12 and D, depending on HC and vitamin D levels, was prescribed.&#x0D; Conclusions. Hyperhomocysteinemia and hypovitaminosis D provoke impaired endothelial vasomotor function and activate neointimal hyperplasia. Patients with hyperhomocysteinemia and vitamin D deficiency should receive metabolic therapy based on folic acid, vitamins B 6 and B12, and vitamin D, both preoperatively and postoperatively. The first control of HC and vitamin D levels is carried out within 3 months after the treatment initiation.

Abstract 28: Regular Aerobic Exercise Counteracts Endothelial Vasomotor Dysfunction Associated With Insufficient Sleep

Insufficient sleep, defined as chronic short sleep duration (&lt;7 h/night), is an independent risk factor for cardiovascular disease (CVD). We have previously demonstrated that insufficient sleep is associated with reduced endothelium-dependent vasodilation and enhanced endothelin (ET)-1-mediated vasoconstrictor tone. Impaired endothelial vasomotor regulation is thought to contribute mechanistically to the increased risk of atherosclerotic vascular disease incurred with chronic insufficient sleep. Regular aerobic exercise is an effective lifestyle strategy for improving endothelial function and, in turn reducing cardiovascular risk. It is currently unknown if regular aerobic exercise can counteract the negative impact of insufficient sleep on endothelial vasomotor regulation. We tested the hypotheses that regular aerobic exercise would: 1) improve endothelial vasodilation; and 2) decrease ET-1-mediated vasoconstrictor tone in middle-aged adults who chronically sleep less than 7 h/night. We studied 36 healthy, middle-aged adults: 16 with normal sleep duration (10M/6F; age: 57±2 yr; sleep duration: 7.4±0.1 h/night) and 20 with short sleep duration (11M/9F; 56±1 yr; sleep duration: 6.2±0.1 h/night). The 20 short sleepers completed a 3-month aerobic exercise training intervention. Forearm blood flow (FBF; plethysmography) was determined in response to intra-arterial doses of acetylcholine (ACh), sodium nitroprusside (SNP), BQ-123 (ET A receptor antagonist) and ACh + BQ-123 in both groups and after the exercise intervention in the short sleepers. As expected, forearm vasodilator responses to ACh were lower (20%; P&lt;0.05) in the short (from 4.2±0.2 to 10.5±0.6 mL/100 mL tissue/min) vs normal (4.2±0.2 to 12.7±0.6 mL/100 mL tissue/min) sleepers. FBF responses to SNP were comparable between the groups. In response to BQ-123, short sleep group had a greater increase in resting FBF than normal sleep group (~25% vs ~8%; P&lt; 0.05). ACh+BQ-123 resulted in an ~25% increase in the ACh-vasodilation in the short sleep group only. After exercise training, although nightly sleep duration was not affected (6.4±0.1 h/night), ACh-mediated vasodilation was ~20% higher (P&lt;0.05), ET-1-mediated vasoconstriction was ~90% lower (P&lt;0.05) and vasodilator response to ACh was not significantly increased with ET A receptor blockade. These results indicate that regular aerobic exercise can reverse the negative influence of insufficient sleep on endothelial vasomotor function, independent of changes in nightly sleep duration.