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Objective: Atrial fibrillation (AF) is a common arrhythmia that increases morbidity and mortality, as well as healthcare costs. The induction of AF (IAF) during programmed atrial pacing in an electrophysiological study (EPS) is a prevalent phenomenon that has been underappreciated by electrophysiologists. Despite extensive research on AF, only a few studies have focused on this phenomenon. The aim of our study was to investigate the association between history of AF and IAF and the underlying pathophysiological factors such as arterial stiffness, subclinical atherosclerosis, and impaired endothelial function., Methods: This cross-sectional and observational study included 87 patients who had palpitations and were scheduled for EPS. Patients underwent biochemical investigations, transthoracic echocardiography, carotid ultrasound, carotid-femoral artery pulse wave velocity (PWV), and flow-mediated dilatation (FMD) measurements before EPS. Patients were divided into two groups, AF-induced and non-induced in EPS, for further statistical analysis., Results: AF was induced in 16 of 87 patients (18.3%) included in the analysis. The FMD (%) was significantly lower (16.01 ± 10.1 vs. 8.7 ± 5.7, P = 0.022) and, remarkably, the proportion of patients with a history of AF was significantly higher (2.8% vs. 37.5%, P < 0.001) in the IAF group. ROC analysis showed that a documented AF and FMD predicted IAF, with AUC of 0.741 (p = 0.012) and 0.740 (p = 0.001), respectively. Logistic regression analysis revealed that FMD and history of AF were strong predictors of IAF (odds ratio [OR], 0.853; 95% confidence interval [CI] 0.737-0.988; P = 0.034, OR: 10.1, 95% CI 4.9-20.5; P = 0.003, respectively)., Conclusion: Endothelial dysfunction and documented AF were associated with IAF during EPS., Competing Interests: Declaration of competing interest The authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Individuals with type 2 diabetes and increased albuminuria, a well-established marker of microvascular complications, are at a higher risk for cardiovascular disease (CVD) and premature mortality. Therefore, a better understanding of the underlying pathophysiology is needed to improve risk stratification and tailor prevention and intervention., Methods: We conducted a cross-sectional study including 463 individuals with type 2 diabetes, various degrees of albuminuria and without CVD. We analysed the association between albuminuria and markers of endothelial function (thrombomodulin and syndecan-1), thrombin generation (thrombin-antithrombin complex, prothrombin fragment 1 + 2), fibrinogen, platelet function (activation using soluble plasma selectin and aggregation using Multiplate® Analyzer) using regression models., Results: In the study cohort 33 % were women, the mean ± SD age was 65 ± 9 years, and median [IQR] diabetes duration was 15 [9-20] years. In total, 344 (74 %) individuals had normal albuminuria, 87 (19 %) moderately- and 32 (7 %) severely increased albuminuria levels. Higher markers of endothelial function and fibrinogen were independently associated with higher albuminuria levels (p < 0.01). No association between albuminuria and markers of thrombin generation and platelet was demonstrated., Conclusion: We demonstrated an independent association between albuminuria and markers of endothelial function and fibrinogen in individuals with type 2 diabetes and no history of CVD., Competing Interests: Declaration of competing interest LFFD, CGP, VRC, OBP, MFM, TWH and AMH report no conflicts of interest. NT is a full-time employee of Novo Nordisk Inc. PR has received grants for research to Steno Diabetes Center Copenhagen from Astra Zeneca, Bayer and Novo Nordisk, and has received honoraria to Steno Diabetes Center Copenhagen from Abbott, AstraZeneca, Bayer, Novo Nordisk, Boehringer Ingelheim, Eli Lilly, Sanofi and Gilead., (Copyright © 2024. Published by Elsevier Inc.)

Objective: Hypertension has become a global medical and public health issue even in childhood. It is well accepted that hypertension is associated with impaired endothelium-dependent vascular reactivity in adult patients. However, there is a lack of data on hypertension-related endothelial dysfunction in hypertensive children. Thus, present study aimed to evaluate the association of primary hypertension in the pediatric population with macro- and microvascular function, and to assess the potential role of oxidative stress in that connection., Methods: Fifty-two children were enrolled in this study; 26 normotensive (NT) and 26 with primary hypertension (HT), both sexes, 9-17 years old. In addition to anthropometric, hemodynamic and biochemical measurements, peripheral microvascular responses to occlusion (postocclusive reactive hyperemia, PORH), local heating (local thermal hyperemia, LTH), iontophoretically applied acetylcholine (AChID) and sodium nitroprusside (SNPID) were evaluated by laser Doppler flowmetry (LDF). Furthermore, brachial artery flow-mediated dilation (FMD) was measured and biomarker of oxidative stress was determined., Results: PORH, AChID and LTH were impaired in hypertensive compared to normotensive children, while SNPID did not differ between groups. FMD was decreased in hypertensive compared to normotensive children. Serum concentration of 8- iso -PGF2α was significantly elevated in hypertensive compared to normotensive children., Conclusion: Even in childhood, primary hypertension is associated with attenuated endothelial function and reduced endothelium-dependent responses to various physiological stimuli. Juvenile hypertension is related to increased level of vascular oxidative stress. All changes are independent of BMI., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Obesity (OB) is highly prevalent in females after menopause, especially visceral adipose tissue (VAT) accumulation which contributes to endothelial dysfunction. The endothelium assists in regulating blood flow (BF) during exercise and is attenuated in females with OB. The purpose of this study was to examine upper and lower limb flow-mediated dilation (FMD) and BF regulation during graded low-intensity submaximal exercises in postmenopausal females with BMI in the lean (LN), overweight (OW) and OB categories., Methods: Participants were grouped by body mass index (BMI) into LN (BMI 18.5-24.9 kg/m 2 ; n = 11), OW (BMI 25.0-29.9 kg/m 2 ; n = 15), and OB (BMI 30.0-39.9 kg/m 2 ; n = 13). FMD of the brachial (BA-FMD) and superficial femoral arteries (FA-FMD) were assessed. Subsequently, BF and vascular conductance (VC) in the upper (BA-BF and BA-VC) and lower limbs (FA-BF and FA-VC) were measured during separate 3-stage incremental rhythmic handgrip and plantarflexion exercises., Results: Significantly lower FA-FMD (P < 0.05) were seen in OB than LN and OW groups with no differences in BA-FMD. Increases in FA-BF and FA-VC were attenuated during the last stage of plantarflexion exercise at 30% of 1RM in OB (both P < 0.001) compared to LN and OW, while upper-body exercise vasodilation was unchanged. FA-BF and FA-VC during plantarflexion exercise were correlated to FA-FMD (FA-BF: r = 0.423, P = 0.007, FA-VC: r = 0.367, P = 0.021) and BMI (FA-BF: r = -0.386, P = 0.015, FA-VC: r = -0.456, P = 0.004)., Conclusion: Postmenopausal females with OB have reduced lower-limb endothelial and exercise vasodilator function during submaximal dynamic plantarflexion exercise compared to LN and OW. Our findings indicate that obesity may predict diminished leg endothelial function, BF and VC during exercise in postmenopausal females., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Postmenopausal cardiovascular health is a critical determinant of longevity. Consumption of beetroot juice (BR) and other nitrate-rich foods is a safe, effective non-pharmaceutical intervention to increase systemic bioavailability of the vasoprotective molecule, nitric oxide, through the exogenous nitrate (NO 3 - )-nitrite (NO 2 - )-nitric oxide (NO) pathway. We hypothesized that a single dose of nitrate-rich beetroot juice (BR nitrate 600 mg NO 3 - /140 mL, BR placebo ∼ 0 mg/140 mL) would improve resting endothelial function and resistance to ischemia-reperfusion (IR) injury to a greater extent in early-postmenopausal (1-6 years following their final menstrual period (FMP), n  = 12) compared to late-postmenopausal (6+ years after FMP, n  = 12) women. Analyses with general linear models revealed a significant ( p  < 0.05) time * treatment interaction effect for brachial artery adjusted flow-mediated dilation (FMD). Pairwise comparisons revealed that adjusted FMD was significantly lower following IR-injury in comparison to all other time points with BR placebo (early FMD 2.51 ± 1.18%, late FMD 1.30 ± 1.10, p  < 0.001) and was lower than post-IR with BR nitrate (early FMD 3.84 ± 1.21%, late FMD 3.21 ± 1.13%, p  = 0.014). A single dose of BR nitrate significantly increased resting macrovascular function in the late postmenopausal group only ( p  = 0.005). Considering the postmenopausal stage-dependent variations in endothelial responsiveness to dietary nitrate, we predict differing mechanisms underpin macrovascular protection against IR injury., Competing Interests: The authors declare there are no competing interests.

There is no study that has investigated the impact of exercise in a combined hypoxic and hot environment on endothelial function. Therefore, we tested whether aerobic exercise in a combined hypoxic and hot conditions induces further enhancement of endothelial function. Twelve healthy males cycled at a constant workload (50% of their maximal oxygen uptake under normoxic/thermoneutral conditions) for 30 min in four different environments: exercise under normoxic condition (NOR: fraction of inspiratory oxygen or FiO 2  = 20.9%, 20°C), exercise under hypoxic condition (HYP: FiO 2  = 14.5%, 20°C), exercise under hot condition (HOT: FiO 2  = 20.9%, 30°C), and exercise under combined hypoxia and hot conditions (HH: FiO 2  = 14.5%, 30°C). Before, during, and after exercise, cardiovascular variables (e.g., heart rate, blood flow, and shear rate), blood variables, and endothelial function evaluated by flow-mediated dilation (FMD) were assessed. Heart rates were significantly higher throughout the HH trial's experimental period than the other trials (p < 0.05). However, in the HH trial, brachial artery blood flow and shear rate did not differ from those in other trials after exercise. Plasma catecholamines (epinephrine, norepinephrine, and dopamine) elevations in response to exercise were significantly higher in the HH trial than in the other three trials (p < 0.05). No considerable differences were observed in FMD responses among trials before and after the exercise. In conclusion, aerobic exercise in a combined hot and hypoxic environment further activated sympathetic nervous activity but did not considerably enhance blood flow, shear rate, or endothelial function., (© 2024 The Author(s). Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Transfusion dependent β-thalassemia is a genetic blood disorder characterized by chronic anaemia. Blood transfusion is lifesaving but comes at a cost. Iron overload emerges as a prime culprit as a free radicals damage endothelial cells. Chronic anaemia further disrupts oxygen delivery, exacerbating the oxidative stress. Increased levels of met-haemoglobin and malondialdehyde compromise endothelial function. This research sheds light on the impact of met-haemoglobin and oxidative stress on endothelial function in 50 patients with transfusion dependent β-thalassemia major compared to 50 healthy individuals as control. Blood samples were collected & subjected to CBC, biochemical analysis including creatinine, ferritin, CRP, LDH, and HCV antibodies. Oxidative stress was assessed using met-haemoglobin & malondialdehyde. Endothelial dysfunction was evaluated by endothelial activation and stress index (EASIX). EASIX, met-haemoglobin and malondialdehyde were significantly increased in patients (1.44 ± 0.75, 2.07 ± 0.2, 4.8 ± 0.63; respectively) compared to the control (0.52 ± 0.24,0.88 ± 0.34,0.8 ± 0.34; respectively). Significant strong positive correlation was found between EASIX and met-haemoglobin, malondialdehyde, serum ferritin and CRP (P = 0.00, r = 0.904, P = 0.00, r = 0.948, P = 0.00, r = 0.772, P = 0.00, r = 0.971; respectively. Met-haemoglobin as well as EASIX should be routinely estimated to assess endothelial function especially before the decision of splenectomy. Antioxidant drugs should be supplemented., (© 2024. The Author(s).)

Endometriosis is a prevalent gynecological condition, affecting around 10% of reproductive-age women. Inflammatory processes associated with endometriosis may contribute to endothelial dysfunction. Increased skin accumulation of advanced glycation end-products (AGEs), reflecting arterial stiffness, potentially links endometriosis with elevated risk of cardiovascular events. We hypothesized that patients with endometriosis have impaired endothelial function as well as increased arterial stiffness and AGE skin accumulation, compared to healthy controls. We compared endothelial function, arterial stiffness, and levels of AGEs in patients suffering from endometriosis and in healthy controls. The study included 45 women aged 20 to 40: 21 patients with endometriosis and 24 healthy controls, matched in terms of age, BMI, and blood pressure values. Endo-PAT 2000 device was used for non-invasive assessment of (i) endothelial function, expressed as Reactive Hyperemia Index (RHI), and (ii) arterial stiffness, expressed as Augmentation Index (AI) and Augmentation Index at 75 heart beats/min (AI@75). Endothelial dysfunction was defined as an RHI value ≤ 1.67. AGE Reader device was used for non-invasive evaluation of skin AGE level accumulation. Patients with endometriosis had lower mean RHI values (1.69 ± 0.54 vs. 2.02 ± 0.48, p = 0.037) and a higher prevalence of endothelial dysfunction, (52.4% vs. 20.8%, p = 0.027) compared to healthy controls. Skin AGE level was higher in patients with endometriosis, compared to controls (2.00 ± 0.57 vs. 1.70 ± 0.24, p = 0.013). There were no significant differences in AI and AI@75 between the two groups. Patients with endometriosis have impaired endothelial function and higher AGE skin accumulation, which are well-established preclinical manifestations of increased cardiovascular risk. There is a great need for comprehensive cardiovascular risk assessments in women with endometriosis to prevent the development of potential atherosclerotic-based complications., (© 2024. The Author(s).)

Introduction: Endothelial dysfunction (ED) promotes the development of atherosclerosis, and studies suggest an association with age-related neurocognitive disorders. It is currently unclear whether ED is also associated with the risk of perioperative neurocognitive disorders., Method: We included 788 participants aged ≥ 65 years of the BioCog study. Patients were scheduled to undergo elective surgery with expected duration > 60 min. Blood was collected before surgery for measurement of 5 biomarkers of ED: asymmetric and symmetric dimethylarginine (ADMA; SDMA), intercellular and vascular adhesion molecule (ICAM-1, VCAM-1), and von Willebrand factor (vWF). Patients were monitored for the occurrence of postoperative delirium (POD) daily until the 7th postoperative day. 537 (68.1%) patients returned for a 3-month follow-up. Post-operative cognitive dysfunction (POCD) was defined from the change in results on a battery of 6 neuropsychological tests between baseline and 3 months, compared to the change in results of a control group during the 3-month interval. The associations of each of the 5 ED biomarkers with POD and POCD respectively were determined using multiple logistic regression analyses with adjustment for age, sex, surgery type, pre-morbid IQ, body mass index, hypertension, diabetes, HbA1C, triglyceride, total and HDL cholesterol., Results: 19.8% of 788 patients developed POD; 10.1% of 537 patients had POCD at 3 months. Concentrations of ED biomarkers were not significantly associated with a POD. A higher VCAM-1 concentration was associated with a reduced POCD risk (adjusted odds ratio 0.55; 95% CI: 0.35-0.86). No further statistically significant results were found., Conclusion: Pre-operative concentrations of ED biomarkers were not associated with POD risk. We unexpectedly found higher VCAM-1 to be associated with a reduced POCD risk. Further studies are needed to evaluate these findings., (© 2024. The Author(s).)

Objective: To assess the changes in blood vessel stiffness and digital pulse wave amplitude because of flowmediated dilatation, and to explore how these two variables change when endothelial dysfunction is experimentally induced., Methods: The experimental study was conducted at the departments of physiology at the College of Medicine, Mustansiriyah University, and the College of Medicine, Al-Iraqia University, Baghdad, Iraq, from October 14, 2021, to May 31, 2022, and comprised healthy young males who were subjected to the flow-mediated dilatation technique on the left brachial artery. Pulse transit time and the amplitude of the digital pulse wave were measured during reactive hyperaemia for 2.5 minutes from the left middle finger using a piezoelectric pressure sensor and a simultaneous Lead I electrocardiogram. Endothelial dysfunction (ED) was induced by oscillatory and retrograde shear rates. The correlation between variables was calculated in Excel running on the Windows operating system., Results: There were 10 second-year medical students with mean age 22±0 years and mean body mass index 25.7±4.8kg/m2. During reactive hyperaemia, pulse transit time was significantly increased by 3-5% in both normal endothelium and experimentally induced endothelial dysfunction relative to the pre-occluded artery, and the difference was not significant (p>0.05). Digital pulse wave amplitude increased significantly in normal endothelium relative to the pre-occluded artery (p<0.05), but not in experimentally-induced endothelial dysfunction (p>0.05)., Conclusions: The pulse transit time and digital pulse wave amplitudes of the photo plethysmography signal may be used to detect changes in vessel wall diameter and tone throughout the reactive hyperaemia process. Digital pulse wave amplitude was better able to detect experimentally-induced endothelial dysfunction, as assessed by the flowmediated dilatation protocol, than pulse transit time.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is regarded as a liver manifestation of metabolic syndrome. It is linked to insulin resistance, obesity, and diabetes mellitus, all of which increase the risk of cardiovascular complications. Endothelial dysfunction (EnD) constitutes the main driver in the progression of atherosclerosis and coronary artery disease (CAD). Several pathophysiological alterations and molecular mechanisms are involved in the development of EnD in patients with NAFLD. Our aim is to examine the association of NAFLD and CAD with the parallel assessment of EnD, discussing the pathophysiological mechanisms and the genetic background that underpin this relationship. This review delves into the management of the condition, exploring potential clinical implications and available medical treatment options to facilitate the deployment of optimal treatment strategies for these patients.

Introduction: Endothelial dysfunction is an early precursor of atherosclerosis and is common in patients with psoriasis, presumably primarily due to psoriasis-related inflammation. We investigated endothelial function, arterial stiffness, and circulating markers of endothelial activation in young patients with psoriasis vulgaris of varying severity, all of whom were effectively treated achieving PASI 90., Methods: We conducted a cross-sectional study of 80 patients (54 men/26 women, 30-45 years) who were effectively treated with topical therapy, methotrexate, adalimumab, secukinumab or guselkumab, and 20 healthy controls. Endothelial dysfunction was measured by flow-mediated dilation and arterial stiffness was measured by pulse wave velocity and common carotid artery stiffness. The following circulating biomarkers of endothelial activation were measured: ICAM-1, VCAM-1, E- and P-selectin, GDF-15, and TRAIL., Results: Endothelial function and arterial stiffness parameters did not differ between patients with effectively treated psoriasis and the control group. Circulating endothelial activation biomarkers did not show relevant differences between the groups of effectively treated patients or controls., Discussion: Although cardiovascular disease is the leading cause of morbidity and mortality in patients with psoriasis, effective antipsoriatic treatment appears to slow the progression of atherosclerosis, even when there are cardiovascular risk factors, such as smoking or obesity. This may suggest that antipsoriatic treatment exerts a cardioprotective effect., Conclusions: Our results suggest that early and effective treatment of varying-severity psoriasis vulgaris in young patients appears to prevent arterial dysfunction related to psoriasis and consequent cardiovascular risk.The study is registered at http://clinicaltrials.gov (identifier: NCT05957120)., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Endothelial dysfunction is an integral pathophysiologic mechanism in sickle cell disease (SCD), and can lead to many complications. Sleep-disordered breathing (SDB) is a SCD complication with diverse incidence and pathophysiology. This study aimed to determine the prevalence of SDB in children with SCD and to assess its relation to endothelial dysfunction., Methods: Sixty children with SCD and 60 healthy controls were enrolled. The levels of TNF-α, IL-6, and IL-17A were evaluated in the entire cohort using enzyme-linked immunosorbent assay (ELISA) kits. Polysomnography (PSG) was performed for all SCD patients after completion of the Pediatric Sleep Questionnaire (PSQ)., Results: TNF-α, IL-6, and IL-17A levels were significantly greater in children with SCD than in controls (p-values < 0.001, < 0.001, and 0.006, respectively). The PSQ revealed symptoms suggestive of SDB in 50 children with SCD (83.3%), and PSG revealed obstructive sleep apnea (OSA) in 44 children with SCD (73.3%); 22 patients had mild OSA, and 22 had moderate-to-severe OSA according to the apnea-hypopnea index (AHI). TNF-α was significantly greater in SCD children who reported heavy or loud breathing, trouble breathing or struggle to breathe, and difficulty waking up in the morning (p-values = 0.002, 0.002, and 0.031, respectively). The IL-6 levels were significantly greater in SCD children who stopped growing normally (p-value = 0.002). The levels of IL-6 and IL-17A were significantly greater in SCD children with morning headaches (p-values = 0.007 and 0.004, respectively)., Conclusion: Children with SCD showed a high prevalence of SDB with significantly elevated levels of markers of endothelial function, highlighting the interplay of SDB and endothelial dysfunction in SCD., (© 2024. The Author(s).)

T-cell accumulation within the aorta promotes endothelial dysfunction and the genesis of cardiovascular disease, including hypertension and atherosclerosis. Viral infection during pregnancy is also known to mediate marked acute endothelial dysfunction, but it is not clear whether T cells are recruited to the aorta and whether the dysfunction persists postpartum. Here, we demonstrate that influenza A virus (IAV) infection during pregnancy in a murine model resulted in endothelial dysfunction of the aorta, which persisted for up to 60 days postinfection and was associated with higher levels of IFN-γ mRNA expression within the tissue. In the absence of infection, low numbers of naïve CD4 + and CD8 + T cells, central memory T cells, and effector memory T cells were observed in the aorta. However, with IAV infection, these T-cell subsets were significantly increased with a notable accumulation of IAV-specific CD8 + effector memory T cells. Critically, this increase was maintained out to at least 60 days. In contrast, IAV infection in nonpregnant female mice resulted in modest endothelial dysfunction with no accumulation of T cells within the aorta. These data, therefore, demonstrate that the aorta is a site of T-cell recruitment and retention after IAV infection during pregnancy. Although IAV-specific memory T cells could theoretically confer protection against future influenza infection, nonspecific memory T-cell activation and IFN-γ production in the aorta could also contribute to future endothelial dysfunction and cardiovascular disease. NEW & NOTEWORTHY Pregnancy is a risk factor for cardiovascular complications to influenza A virus (IAV) infection. We demonstrate that gestational IAV infection caused endothelial dysfunction of the maternal aorta, which persisted for 60 days postinfection in mice. Various T cells accumulated within the aorta at 60 days because of the infection, and this was associated with elevated levels of the proinflammatory cytokine, IFN-γ. Our study demonstrates a novel "long influenza" cardiovascular phenotype in female mice.

Coronary vasomotor dysfunction, an important underlying cause of angina and nonobstructive coronary arteries (ANOCA), encompassing coronary vasospasm, coronary endothelial dysfunction, and/or coronary microvascular dysfunction, is clinically assessed by invasive coronary function testing (ICFT). As ICFT imposes a high burden on patients and carries risks, developing noninvasive alternatives is important. We evaluated whether coronary vasomotor dysfunction is a component of systemic microvascular endothelial and smooth muscle dysfunction and can be detected using laser speckle contrast analysis (LASCA). Forty-three consecutive patients with ANOCA underwent ICFT, with intracoronary acetylcholine, adenosine, and flow measurements, to assess coronary vasomotor dysfunction. Cutaneous microvascular function was assessed using LASCA in the forearm, combined with vasodilators acetylcholine, sodium nitroprusside, and insulin and using EndoPAT, by measuring the reactive hyperemia index (RHI). Of the 43 included patients with ANOCA (79% women, 59 ± 9 yr old), 38 patients had coronary vasomotor dysfunction, including 28 with coronary vasospasm, 26 with coronary endothelial dysfunction, and 18 with coronary microvascular dysfunction, with overlapping endotypes. Patients with and without coronary vasomotor dysfunction had similar peripheral flow responses to acetylcholine, insulin, and RHI. In contrast, coronary vasomotor dysfunction was associated with lower peripheral flow responses to sodium nitroprusside ( P < 0.001). An absolute flow response to sodium nitroprusside of 83.95 APU resulted in 86.1% sensitivity and 80.0% specificity for coronary vasomotor dysfunction (area under the ROC curve, 0.883; P = 0.006). In conclusion, this study provides evidence of systemic vascular smooth muscle dysfunction in patients with ANOCA with coronary vasomotor dysfunction and the diagnostic value of peripheral microvascular function testing as a noninvasive tool for detecting coronary vasomotor dysfunction. NEW & NOTEWORTHY This study provides proof of concept that assessment of the peripheral vasculature, particularly vascular smooth muscle cells measured using the LASCA technology holds potential as a noninvasive tool for detecting coronary vasomotor dysfunction. This finding highlights the potential of the LASCA technology in, for example, medication studies for coronary vasomotor dysfunction, especially when investigating whether medication improves vascular function, as repeated peripheral measurements are less invasive than invasive coronary function testing, the current gold standard.

The interplay between the immune system, coagulation, and endothelium is critical in regulating the host response to infection. However, in sepsis and other critical illnesses, a dysregulated immune response can lead to excessive alterations in these mechanisms, resulting in coagulopathy, endothelial dysfunction, and multi-organ dysfunction. This review aims to provide a comprehensive analysis of the pathophysiological mechanisms that govern the complex interplay between immune dysfunction, endothelial dysfunction, and coagulation in sepsis. It emphasises clinical significance, evaluation methods, and potential therapeutic interventions. Understanding these mechanisms is essential for developing effective treatments that can modulate the immune response, mitigate thrombosis, restore endothelial function, and ultimately improve patient survival., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K + (Kir2.1) channels. The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from 32 subjects: normotensive [ n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive ( n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension. NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K + (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

Excess sodium consumption contributes to arterial dysfunction in humans. The C57BL/6 strain of mice has been used to identify mechanisms by which arterial dysfunction occurs after excess sodium consumption. However, there are concerns that C57BL/6 mice have strain-specific resistance to high-sodium (HS) diet-induced hypertension. To address this concern, we performed a meta-analysis to determine if excess sodium consumption in C57BL/6 mice induces arterial dysfunction. Databases were searched for HS versus standard diet studies that measured arterial function [i.e., systolic blood pressure (BP), endothelium-dependent dilation (EDD), and central arterial stiffness] in C57BL/6 mice. A total of 39 studies were included, demonstrating that the HS condition resulted in higher systolic BP than control mice with a mean difference of 9.8 mmHg (95% confidence interval [CI] = [5.6, 14], P < 0.001). Subgroup analysis indicated that the systolic BP was higher in HS compared with the control condition when measured during night compared with daytime with telemetry ( P < 0.001). We also identified that the difference in systolic BP between HS and control was ∼2.5-fold higher when administered through drinking water than through food ( P < 0.001). A total of 12 studies were included, demonstrating that the HS condition resulted in lower EDD than control with a weighted mean difference of -12.0% (95% CI = [-20.0, -4.1], P = 0.003). It should be noted that there was considerable variability across studies with more than half of the studies showing no effect of the HS condition on systolic BP or EDD. In summary, excess sodium consumption elevates systolic BP and impairs EDD in C57BL/6 mice. NEW & NOTEWORTHY C57BL/6 mice are perceived as resistant to high-sodium diet-induced arterial dysfunction. This meta-analysis demonstrates that excess sodium consumption elevates blood pressure and impairs endothelium-dependent dilation in C57BL/6 mice. Nighttime measurements show more pronounced blood pressure elevation. In addition, sodium administration via drinking water, compared with food, induces a greater blood pressure elevation. These findings may be influenced by outlier studies, as the majority of studies showed no adverse effect of excess sodium consumption on arterial function.

The lining of blood vessels is constantly exposed to mechanical forces exerted by blood flow against the endothelium. Endothelial cells detect these tangential forces (i.e., shear stress), initiating a host of intracellular signaling cascades that regulate vascular physiology. Thus, vascular health is tethered to the endothelial cells' capacity to transduce shear stress. Indeed, the mechanotransduction of shear stress underlies a variety of cardiovascular benefits, including some of those associated with increased physical activity. However, endothelial mechanotransduction is impaired in aging and disease states such as obesity and type 2 diabetes, precipitating the development of vascular disease. Understanding endothelial mechanotransduction of shear stress, and the molecular and cellular mechanisms by which this process becomes defective, is critical for the identification and development of novel therapeutic targets against cardiovascular disease. In this review, we detail the primary mechanosensitive structures that have been implicated in detecting shear stress, including junctional proteins such as platelet endothelial cell adhesion molecule-1 (PECAM-1), the extracellular glycocalyx and its components, and ion channels such as piezo1. We delineate which molecules are truly mechanosensitive and which may simply be indispensable for the downstream transmission of force. Furthermore, we discuss how these mechanosensors interact with other cellular structures, such as the cytoskeleton and membrane lipid rafts, which are implicated in translating shear forces to biochemical signals. Based on findings to date, we also seek to integrate these cellular and molecular mechanisms with a view of deciphering endothelial mechanotransduction of shear stress, a tenet of vascular physiology.

The endothelium, lining the inner surface of blood vessels and spanning approximately 3 m 2 , serves as the largest organ in the body. Comprised of endothelial cells, the endothelium interacts with other bodily components including the bloodstream, circulating cells, and the lymphatic system. Functionally, the endothelium primarily synchronizes vascular tone (by balancing vasodilation and vasoconstriction) and prevents vascular inflammation and pathologies. Consequently, endothelial dysfunction disrupts vascular homeostasis, leading to vascular injuries and diseases such as cardiovascular, cerebral, and metabolic diseases. In this opinion/perspective piece, we explore the recently identified mechanisms of endothelial dysfunction across various disease subsets and critically evaluate the strengths and limitations of current therapeutic interventions at the pre-clinical level., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

In this narrative review, we assess the pathophysiology of severe adverse events that presented after vaccination with DNA and mRNA vaccines against COVID-19. The focus is on the perspective of an undersulfated and degraded glycocalyx, considering its impact on immunomodulation, inflammatory responses, coagulation and oxidative stress. The paper explores various factors that lead to glutathione and inorganic sulfate depletion and their subsequent effect on glycocalyx sulfation and other metabolites, including hormones. Components of COVID-19 vaccines, such as DNA and mRNA material, spike protein antigen and lipid nanoparticles, are involved in possible cytotoxic effects. The common thread connecting these adverse events is endotheliopathy or glycocalyx degradation, caused by depleted glutathione and inorganic sulfate levels, shear stress from circulating nanoparticles, aggregation and formation of protein coronas; leading to imbalanced immune responses and chronic release of pro-inflammatory cytokines, ultimately resulting in oxidative stress and systemic inflammatory response syndrome. By understanding the underlying pathophysiology of severe adverse events, better treatment options can be explored., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objective: This paper was aimed at unveiling the effect of low-molecular-weight heparin calcium (LMWH) combined with magnesium sulfate and labetalol on coagulation, vascular endothelial function, and pregnancy outcome in early-onset severe preeclampsia (EOSP)., Methods: Pregnant women with EOSP were divided into the control group and the study group, each with 62 cases. Patients in the control group were treated with labetalol and magnesium sulfate, and those in the study group were treated with LMWH in combination with the control grou Blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]), 24-h urine protein, coagulation indices [D-dimer (D-D), plasma fibrinogen (Fg), prothrombin time (PT), activated partial thromboplastin time (APTT), and prothrombin time (TT)], endothelial function [endothelin (ET-1) and nitric oxide (NO)], oxidative stress indices [oxidized low-density lipoproteins (ox-LDL), lipid peroxidation (LPO), superoxide dismutase (SOD), and malondialdehyde (MDA)], pregnancy outcome, and adverse effects occurred in the two groups were compared., Results: After treatment, lower SBP, DBP, and 24-h urine protein levels; lower Fg and D-D levels; higher PT, APPT, and TT levels; higher NO levels; lower ET-1 levels; lower ox-LDL, MDA, and LPO levels; higher SOD levels; and lower incidence of adverse pregnancy and adverse reactions were noted in the study group in contrast to the control group., Conclusion: EOSP patients given with LMWH combined with magnesium sulfate and labetalol can effectively reduce the patient's blood pressure and urinary protein level; improve coagulation function, oxidative stress, and vascular endothelial function indices; reduce the adverse pregnancy outcomes; and improve the safety of treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Chronic venous disease (CVD) is a prevalent pathology, and endothelial dysfunction is recognized as a core of its physiopathology. Flow-mediated dilation (FMD) is one of the most widely used tests for evaluating endothelial function. The aim of this study is to evaluate the influence of varicose vein (VV) surgery on FMD., Methods: A prospective study with patients with superficial CVD and saphenous incompetence on Doppler ultrasonography that were proposed for VV surgery. The FMD test was performed before and 6 months after the procedure. The operator performing the post-operative evaluation was blinded to the pre-operative result., Results: A total of 42 patients were included in the analysis. The median pre-operative percent change of FMD was 4.20% (±1.30) and the post-operative was 4.56% (±1.25) ( p = 0.819)., Conclusions: Our findings do not corroborate the presence of an overall endothelial dysfunction prone to modulation by surgery. Nevertheless, further studies are needed to confirm our findings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ankylosing Spondylitis (AS) stands as a chronic inflammatory arthritis within the spondyloarthritis spectrum, notably increasing cardiovascular (CV) risk and mortality through accelerated atherosclerosis compared to the non-affected population. While evidence in some studies supports a higher cardiovascular morbidity in AS patients, results from other studies reveal no significant disparities in atherosclerotic markers between AS individuals and healthy controls. This discrepancy may arise from the complex interaction between traditional CV risk factors and AS inflammatory burden. Endothelial dysfunction, a recognized antecedent of atherosclerosis prevalent among most individuals with AS, demonstrates the synergistic impact of inflammation and conventional risk factors on endothelial injury, consequently hastening the progression of atherosclerosis. Remarkably, endothelial dysfunction can precede vascular pathology in AS, suggesting a unique relationship between inflammation, atherosclerosis, and vascular damage. The role of adhesion molecules in the development of atherosclerosis, facilitating leukocyte adherence and migration into vascular walls, underscores the predictive value of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) levels for cardiovascular events. Despite significant progress in comprehending the pathogenesis of AS and its associated cardiovascular implications, the interplay among inflammation, endothelial dysfunction, and atherosclerosis remains partially elucidated. Investigations into the efficacy of therapeutic approaches involving angiotensin receptor blockers and statins have demonstrated reduced cardiovascular risk in AS patients, underscoring the imperative for additional research in this domain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nowadays, cardiovascular diseases are the most common cause of death worldwide. Besides, atherosclerosis is a cardiovascular disease that occurs with persistent narrowing of arteries, especially medium and large-sized arteries. Atherosclerosis begins with a local elevation in the permeability of the arterial wall as a result of endothelial inflammation. Subsequently, excess LDL permeates into the arterial wall. Then, through several chemical responses and reactions, foam cells are produced. These foam cells serve as a crucial indicator for assessing the development of atherosclerosis within the arteries. In this study, the effect of endothelial layer modeling, heart rate (HR) and hypertension on the foam cell accumulation is numerically investigated in a patient-specific geometry of the human thoracic aorta. Navier-Stokes, Darcy, and mass transfer equations are used to obtain the velocity and concentration field within the domain. Regarding the dependence of endothelial cell properties on time-averaged wall shear stress, it is observed that foam cells are mainly concentrated in the outer curvature of the aortic arch, downstream of the left subclavian artery. However, considering oscillatory-shear-rate as the determinant of endothelial cell properties leads to the accumulation of foam cells in the inner curvature of the descending aorta. Regarding the HR, with the increase of HR, the volume average concentration of the foam cell decreases. However, there is no substantial difference between the cases of different HRs. Moreover, foam cell concentration significantly increases in the hypertension case. This result implies that a slight increase in the blood pressure may induce irreparable problems in the circulatory system., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Viscosity-vaso-occlusion (VVO) and haemolysis-endothelial dysfunction (HED) are pathophysiological mechanisms and clinical subphenotypes of sickle cell disease (SCD). Recurrent vaso-occlusive crises (VOC) may lead to neuroplastic changes and pain sensitization. Among 257 SCD participants, we assessed the relationship of subphenotypes with pain sensitivity using quantitative sensory testing to identify heat pain thresholds (HPT) and pressure pain thresholds (PPT). VOC history and sleep, social and emotional functioning were assessed using the Adult Sickle Cell Quality of Life Measurement Information System. The 'elbow method' determined the optimal number of clusters as three. Clustering was performed using K-prototypes. Among clusters 2 and 3, VOC frequency and severity were higher. Clusters 1 and 3 had lower haemoglobin, higher reticulocytes and lactate dehydrogenase and more leg ulcers. In multivariate regression, cluster 3 was associated with approximately 13.6% lower PPT compared to cluster 1, and female sex was associated with decreases in PPT and HPT at the hands and feet (p < 0.001). Hydroxyurea use and unit increases in sleep functioning and age were associated with approximately 20.1% higher foot-PPT, 6.8% higher hand-PPT and 2.5% higher hand-HPT and foot-HPT respectively. Findings suggest that a third subphenotype with mixed VVO and HED features and worse pain sensitization may exist., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater lifetime risk of developing cardiovascular disease and type 2 diabetes compared with women who had an uncomplicated pregnancy (HC). Microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation secondary to increases in oxidative stress, persists after pregnancy complicated by GDM. We examined whether this microvascular dysfunction reduces insulin-mediated vascular responses in women with a history of GDM. We assessed in vivo microvascular endothelium-dependent vasodilator function by measuring cutaneous vascular conductance responses to graded infusions of acetylcholine (10 -10 -10 -1 M) and insulin (10 -8 -10 -4 M) in control sites and sites treated with 15 mM l-NAME [ N G -nitro-l-arginine methyl ester; NO-synthase (NOS) inhibitor] or 5 mM l-ascorbate. We also measured protein expression of total endothelial NOS (eNOS), insulin-mediated eNOS phosphorylation, and endothelial nitrotyrosine in isolated endothelial cells from GDM and HC. Women with a history of GDM had reduced acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation, and the NO-dependent responses to both acetylcholine ( P = 0.006) and insulin ( P = 0.006) were reduced in GDM compared with HC. Insulin stimulation increased phosphorylated eNOS content in HC ( P = 0.009) but had no effect in GDM ( P = 0.306). Ascorbate treatment increased acetylcholine ( P < 0.001)- and insulin ( P < 0.001)-mediated dilation in GDM, and endothelial cell nitrotyrosine expression was higher in GDM compared with HC ( P = 0.014). Women with a history of GDM have attenuated microvascular vasodilation responses to insulin, and this attenuation is mediated, in part, by reduced NO-dependent mechanisms. Our findings further implicate increased endothelial oxidative stress in this microvascular insulin resistance. NEW & NOTEWORTHY Women who have gestational diabetes during pregnancy are at a greater risk for cardiovascular disease and type 2 diabetes in the decade following pregnancy. The mechanisms mediating this increased risk are unclear. Herein, we demonstrate that insulin-dependent microvascular responses are reduced in women who had gestational diabetes, despite the remission of glucose intolerance. This reduced microvascular sensitivity to insulin may contribute to increased cardiovascular disease and type 2 diabetes risk in these women.

Preeclampsia is a common pregnancy complication affecting 5% to 7% of all pregnancies worldwide annually. While the pathogenesis is not fully understood, maternal endothelium dysfunction is thought to be a central component to preeclampsia development. Studies to dissect maternal endothelial dysfunction, particularly on a patient-specific basis, are hampered by limited access to systemic primary endothelial cells (ECs). The objective of this study was to establish a replenishable, patient-specific in vitro EC model to allow robust mechanistic studies to dissect endothelial dysfunction in preeclampsia. Induced pluripotent stem cells (iPSCs) from three women with a history of normotensive pregnancies were differentiated into ECs. The established ECs were exposed to pooled sera from normotensive pregnancies, preeclamptic pregnancies, normotensive postpartum for non-pregnant comparison and controls. Endothelial functions including nitric oxide (NO) release, cell migration, tube formation and viability were evaluated. Levels of NO release were significantly lower after incubation with preeclamptic sera compared to the fetal bovine serum (FBS) control, and normotensive and non-pregnant (postpartum) sera treatments were also lower than FBS but higher than preeclamptic sera treatments. Tube formation and cell migration were also impaired with preeclamptic sera compared to FBS controls. Cell viabilities remained unaffected by any sera treatment. Consistent outcomes were obtained across all three patient-specific lines treated with the same pooled sera. Establishment of patient-derived iPSC-ECs treated with pregnancy sera serves as a novel model to explore the interplay between individual maternal endothelial health and circulating factors that lead to endothelial dysfunction in preeclampsia., (© 2024. The Author(s).)

Kinase inhibitors (KIs) targeting oncogenic molecular pathways have revolutionized cancer therapy. By directly targeting specific tumor-driving kinases, targeted therapies have fewer side effects compared with chemotherapy. Despite the enhanced specificity, cardiovascular side effects have emerged with many targeted cancer therapies that limit long-term outcomes in patients with cancer. Endothelial cells lining all blood vessels are critical to cardiovascular health and are also exposed to circulating levels of systemic anticancer therapies. Both on- and off-target perturbation of signaling pathways from KIs can cause endothelial dysfunction, resulting in cardiovascular toxicity. As such, the endothelium is a potential source, and also a therapeutic target for prevention, of cardiovascular toxicity. In this review, we examine the evidence for KI-induced endothelial cell dysfunction as a mechanism for the cardiovascular toxicities of vascular endothelial growth factor inhibitors, BCR-Abl (breakpoint cluster region-Abelson proto-oncogene) KIs, Bruton tyrosine inhibitors, and emerging information regarding endothelial toxicity of newer classes of KIs., Competing Interests: I.Z. Jaffe is a consultant at Boeringer Ingelheim. The other authors report no conflicts.

Aim: This study aimed to investigate the acute effects of dietary nitrate ingestion through l-arginine supplementation or dehydrated beet consumption on endothelial function in chronic obstructive pulmonary disease (COPD) patients. The secondary outcome was to analyze arterial stiffness, plasma nitrate, and nitrate/protein concentration., Methods: In this randomized crossover study, subjects with COPD underwent three series of supplementation: (1) l-arginine, (2) dehydrated beetroot, and (3) a placebo that appeared like the other supplements. Each intervention lasted 14 days, with a 7-day washout period between series. Participants underwent endothelial function assessment using flow-mediated dilatation (FMD), and plasma nitrate levels were measured at the end of each supplementation series., Results: Seventeen subjects (twelve male) completed the study protocol. Only five subjects presented endothelial dysfunction (RHI ≤0.51) at baseline. The mean baseline characteristics included age 66.5 ± 9.4 years, BMI 27.5 ± 4.5 kg/m 2 , FEV 1, 0.79 (0.67-1.06) L. There were no differences (p > 0.05) between the groups or from pre-to post-interventions for RHI and arterial stiffness index (AIx) values, as well as parameters of endothelium-dependent vasodilation, such as blood flow velocity (BFV), shear stress, shear rate, FMD (mm), and FMD%. There was also no differences (p > 0.05) between the groups or from pre-to post-interventions plasma nitrate levels., Conclusions: Acute dietary supplementation with nitrates, at the doses provided, did not show a significant improvement in endothelial function assessed by FMD, EndoPAT, or plasma nitrate levels in COPD. These findings suggest that a higher dose or prolonged supplementation might be required to achieve a therapeutic effect., Competing Interests: Declaration of competing interest On Behalf of the authors, I declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to investigate the effects of a 16-week aerobic exercise program on systolic blood pressure, intracellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and oxidized low-density lipoprotein of obese and nonobese elderly women with isolated systolic hypertension., Methods: Elderly women aged 70-85 years were recruited and grouped into the normal isolated systolic hypertension ( n  = 12) and obese isolated systolic hypertension groups ( n  = 13). The participants followed an aerobic exercise program, using a wireless heart rate monitor to maintain an appropriate heart rate reserve based on the American College of Sports Medicine exercise guidelines. The two-way repeated measures analysis of variance tested group × time interaction. Pearson's correlation and simple regression assessed the influence of each variable, which showed significant differences., Results: An interaction effect for systolic blood pressure, intracellular cell adhesion molecule-1, and vascular cell adhesion molecule-1 ( P  < 0.05) and a main time effect for oxidized low-density lipoprotein ( P  < 0.05) were observed. A correlation between the rates of change in systolic blood pressure and vascular cell adhesion molecule-1 ( P  < 0.05) with a 42.8% influence ( P  < 0.001) and in intracellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 ( P  < 0.05) with a 21.6% influence ( P  < 0.05) was observed., Conclusions: These findings collectively showed that the 16-week aerobic exercise program effectively lowered blood pressure in patients with isolated systolic hypertension, particularly in the normal group compared to the obese group. Thus, regular aerobic exercise for 16 weeks or more enhances vascular health, potentially improving the healthy life expectancy of elderly women., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Cerebral blood flow dynamics can be explored through analysis of endothelial frequencies. Our hypothesis posits a disparity in endothelial activity among neonates with perinatal asphyxia, stratified by the presence or absence of neuronal lesions., Methods: We conducted a retrospective longitudinal study involving newborns treated with hypothermia for moderate to severe asphyxia. Participants were grouped based on the presence or absence of neuronal damage to investigate temporal endothelial involvement in cerebral blood flow regulation. Regional cerebral oxygen saturation (rScO2) was measured using near-infrared spectroscopy (NIRS), and temporal series were analyzed in the frequency domain, utilizing the original frequency of the INVOS™ device., Results: The study included 88 patients, with 53% (47/88) being male and 33% (29/88) demonstrating brain lesions on magnetic resonance imaging. Among them, 86% (76/88) had a gestational age exceeding 37 weeks according to the Ballard scale, and 81% (71/88) had a birth weight exceeding 2500 g. Cohen's d effect size was calculated to assess differences in endothelial frequency between groups, indicating a small effect size based on cerebral MRI findings (Cohen's d values for Day 2 = 0.2351 and Day 3 = 0.2325)., Conclusion: NIRS represents a valuable tool for monitoring cerebral autoregulation in neonates affected by perinatal asphyxia, underscoring the utility of assessing endothelial frequency or energy on rScO2 measured by NIRS using the original INVOS™ device frequency., (© 2024. The Author(s).)

Major Depressive Disorder, or depression, has been extensively linked to dysregulated HPA axis function, chronic inflammation and cardiovascular diseases. While the former two have been studied in depth, the mechanistic connection between depression and cardiovascular disease is unclear. As major mediators of vascular homeostasis, vascular pathology and immune activity, endothelial cells represent an important player connecting the diseases. Exaggerated inflammation and glucocorticoid function are important topics to explore in the endothelial response to MDD. Glucocorticoid resistance in several cell types strongly promotes inflammatory signaling and results in worsened severity in many diseases. However, endothelial health and inflammation in chronic stress and depression are rarely considered from the perspective of glucocorticoid signaling and resistance. In this review, we aim to discuss (1) endothelial dysfunction in depression, (2) inflammation in depression, (3) general glucocorticoid resistance in depression and (4) endothelial glucocorticoid resistance in depression co-morbid inflammatory diseases. We will first describe vascular pathology, inflammation and glucocorticoid resistance separately in depression and then describe their potential interactions with one another in depression-relevant diseases. Lastly, we will hypothesize potential mechanisms by which glucocorticoid resistance in endothelial cells may contribute to vascular disease states in depressed people. Overall, endothelial-glucocorticoid signaling may play an important role in connecting depression and vascular pathology and warrants further study., (© 2024. The Author(s).)

Objective: This article focus on patients with moderate-to-severe periodontitis and periodontitis patients with cardiovascular disease. After they received periodontal initial therapy or antimicrobial drug treatment, was there any improvement in endothelial function during short- and long-term followups?, Method: Relevant randomized controlled trials and clinical trials up to 30th June 2024 were identified and retrieved from electronic databases including PubMed, Cochrane Library, Web of Science and CNKI databases, with periodontitis therapy, periodontal disease and endothelial function as the keywords. The weighted (WMD) or standardized mean difference (SMD) was calculated using a fixed- or random-effect model and assessed heterogeneous results., Result: Generally, 14 studies published between 2004 and 2022 were eligible for the meta-analysis, which are all randomised clinical trials. A total of 491 periodontitis patients were screened. All participants received whole-mouth supragingival and subgingival scaling and root planing of the teeth, some trials combined with antimicrobial drug treatment as well as extracting teeth that could not be saved. The outcome indicators were measured by flow-mediated dilatation(FMD) levels. The results of the short term (≤3 months) periodontitis initial therapy group showed positive results (WMD = -3.78,95%CI = [-5.49,-2.07], P<0.0001), while the results of the long term (6 months) periodontitis therapy group exhibited significant difference (WMD = -0.96,95%CI = [-2.06,0.14],P = 0.09). Furthermore, study population were categorized according to the severity of periodontitis, the presence of comorbidities, endothelial dysfunction, and the inclusion of extractions and antimicrobial therapy in the treatment process. The effects of each of these factors on FMD were explored and the results of these subgroups all support periodontitis therapy., Conclusion: The results showed that periodontal treatment enhances endothelial function. Additionally, after subgroup analysis of long-term and short-term follow-up, patients with severe periodontitis, and different periodontal treatments, periodontal therapy was shown to increase FMD levels., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lyu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown., Methods: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system., Results: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress., Conclusions: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739., Competing Interests: None.

Objective: Breast cancer is among the highest causes of morbidity and mortality in women. Trastuzumab therapy, which is known to be significantly cardiotoxic, is mainly used to treat patients with resistant breast cancer, including estrogen receptor-positive type. We aimed to show the effects of trastuzumab therapy on endothelial functions of breast cancer patients., Methods: In this study, a total of 26 participants (24 female and 2 male patients, minimum age: 38 years, maximum age: 79 years, and mean age 57.3±12.7 years) were enrolled in the study. For the statistical evaluation of data, we classified the participants of the study as follows: Pretreatment: Before trastuzumab therapy; Treatment Period 1: 1 month after the first dose of trastuzumab; Treatment Period 2: 4 months after the first dose of trastuzumab; Treatment Period 3: 12 months after the first dose of trastuzumab. We conducted repeated-measures analysis of variance (Greenhouse-Geisser) and paired-sample t-tests to statistically compare the groups using flow-mediated dilation measurements., Results: We determined that there are statistically significant differences between flow-mediated hyperemia and ratio values (flow-mediated dilation) of the groups (p<0.009 and p<0.001, respectively)., Conclusion: Our data indicate that trastuzumab therapy could have negative effects on endothelial functions in breast cancer patients.

Introduction: Heart failure (HF) is a complex syndrome that affects millions of people worldwide and leads to significant morbidity and mortality. Sacubitril/valsartan, a combination drug consisting of a neprilysin inhibitor and an angiotensin receptor blocker (ARB), has shown a greater improvement in the prognosis of HF than ACE inhibitors (ACEI) or ARB. Recent studies have found that ACEI/ARB or sacubitril/valsartan can increase flow-mediated dilation (FMD) and reduce pulse wave velocity (PWV), which are independent predictors of cardiovascular events and HF prognosis. The purpose of this study is to assess and compare the effect of sacubitril/valsartan and ACEI/ARB on FMD and PWV using meta-analysis and further provide a reference for the role of sacubitril/valsartan in the treatment of HF., Methods and Analysis: Clinical randomised controlled trials investigating the effect of sacubitril/valsartan and/or ACEI/ARB on FMD and PWV in patients with HF will be searched in the relevant database, including PubMed, Web of Science, Embase, Cochrane Library and China's National Knowledge Infrastructure up to January 2024. The outcomes of interest are changes in endothelial function assessed by FMD and changes in arterial stiffness assessed by PWV. The risk of bias was evaluated using the revised Cochrane risk of bias tool for randomised trials (RoB2.0). Review Manager V.5.3 software is used for meta-analysis data synthesis, sensitivity analysis, meta-regression analysis, subgroup analysis and risk of bias assessment. The reporting bias of studies will be evaluated using the funnel plot, in which symmetry will be assessed by Begg's and Egger's tests. The evidence quality of the included studies will be evaluated by the Grading of Recommendations Assessment, Development, and Evaluation., Ethics and Dissemination: This study only analyses research data from the published literature and therefore does not require ethical approval. We will submit the systematic review to a peer-reviewed journal., Prospero Registration Number: CRD42024538148., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In populations with chronic disease, skin autofluorescence (SAF), a measure of long-term fluorescent advanced glycation end-products (AGEs) accumulation in body tissues, has been associated with vascular endothelial function, measured using flow-mediated dilation (FMD). The primary aim of this study was to quantify the relationship between endothelial function and tissue accumulation of AGEs in adults from the general population to determine whether SAF could be used as a marker to predict early impairment of the endothelium., Methods: A cross-sectional study was conducted with 125 participants (median age: 28.5 y, IQR: 24.4-36.0; 54% women). Endothelial function was measured by fasting FMD. Skin AGEs were measured as SAF using an AGE Reader. Participant anthropometry, blood pressure, and blood biomarkers were also measured. Associations were evaluated using multivariable regression analysis and were adjusted for significant covariates., Results: FMD was inversely correlated with SAF (ρ = -0.50, P < 0.001) and chronological age (ρ = -0.51, P < 0.001). In the multivariable analysis, SAF, chronological age, and male sex were independently associated with reduced FMD (B [95% CI]; -2.60 [-4.40, -0.80]; -0.10 [-0.16, -0.03]; 1.40 [0.14, 2.67], respectively), with the multivariable model adjusted R 2  = 0.31, P < 0.001., Conclusions: Higher skin AGE levels, as measured by SAF, were associated with lower FMD values, in a predominantly young, healthy population. Additionally, older age and male participants exhibited significantly lower FMD values, corresponding with compromised endothelial function. These results suggest that SAF, a simple and inexpensive marker, could be used to predict endothelial impairment before the emergence of any structural artery pathophysiology or classic cardiovascular disease risk markers., Trial Registration: The study was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000821897) and concurrently entered into the WHO International Clinical Trials Registry Platform under the same ID number., (© 2024. The Author(s).)

Background and Aim: Patients with cyanosis secondary to congenital heart disease (CHD) are characterized by erythrocytosis and increased blood viscosity, which contribute to endothelial dysfunction, increased arterial stiffness, and impaired vascular function, which may affect the final clinical presentation. Asymmetric dimethylarginine (ADMA) and e-selectin (e-sel) are valuable biomarkers for endothelial and vascular dysfunction. Their concentration levels in blood serum have the potential to be an accessible tool that reflects the severity of the disease. We aimed to assess e-sel and ADMA levels and their relationship with the clinical status and endothelial and vascular function. Methods: A cross-sectional study, including 36 adult CHD cyanotic patients [(17 males) (42.3 ± 16.3 years)] with an arterial blood oxygen saturation less than 92% and 20 healthy controls [(10 males) (38.2 ± 8.5 years)], was performed. All the patients underwent a clinical examination, blood testing, and cardiopulmonary tests. Their endothelial function was assessed using the intima media thickness and flow-mediated dilatation. Vascular function, using applanation tonometry methods, was determined using the aortic systolic pressure, aortic pulse pressure, augmentation pressure, augmentation index, pulse pressure amplification, and pulse wave velocity. Results: The concentrations of e-sel and ADMA were significantly higher in the patients with CHD. The E-sel levels correlated positively with red blood cells, hemoglobin concentration, hematocrit, and augmentation pressure; they correlated negatively with blood oxygen saturation, the forced expiratory one-second volume, forced vital capacity, and oxygen uptake. The ADMA levels were found to correlate only with age. Conclusions: The E-sel level, unlike ADMA concentration, reflects the severity of erythrocytosis and hypoxia and, thus, the physical status of patients with cyanotic CHD.

Objectives: In childhood-onset SLE (cSLE), patients have an increased risk of premature atherosclerosis. The pathophysiological mechanisms for this premature atherosclerosis are not yet completely understood, but besides traditional risk factors, the endothelium plays a major role. The first aim of this study was to measure levels of SLE-associated markers involved in endothelial cell (EC) function and lipids in a cSLE cohort longitudinally in comparison with healthy controls (HC). Next aim was to correlate these levels with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and nailfold capillaroscopic patterns., Methods: Blood serum samples, videocapillaroscopy images and patient characteristics were collected in a multicentre longitudinal cSLE cohort and from age and sex comparable HC. Disease activity was evaluated by SLEDAI. A total of 15 EC markers and six lipids were measured in two longitudinal cSLE samples (minimum interval of 6 months) and in HC. Nailfold videocapillaroscopy images were scored according to the guidelines from the EULAR Study Group on Microcirculation in Rheumatic Diseases., Results: In total, 47 patients with cSLE and 42 HCs were analysed. Median age at diagnosis was 15 years (IQR 12-16 years). Median time between t=1 and t=2 was 14.5 months (IQR 9-24 months). Median SLEDAI was 12 (IQR 6-18) at t=1 and 2 (IQR 1-4) at t=2. Serum levels of angiopoietin-2, CCL2, CXCL10, GAS6, pentraxin-3, thrombomodulin, VCAM-1 and vWF-A2 were elevated in cSLE compared with HC at t=1. While many elevated EC markers at t=1 normalised over time after treatment, several markers remained significantly increased compared with HC (angiopoietin-2, CCL2, CXCL10, GAS6, thrombomodulin and VCAM-1)., Conclusion: In serum from patients with cSLE different markers of endothelial activation were dysregulated. While most markers normalised during treatment, others remained elevated in a subset of patients, even during low disease activity. These results suggest a role for the dysregulated endothelium in early and later phases of cSLE, possibly also during lower disease activity., Trial Registration Number: NL60885.018.17., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Noncoding RNA plays a pivotal role as novel regulators of endothelial cell function. Type 2 diabetes, acknowledged as a primary contributor to cardiovascular diseases, plays a vital role in vascular endothelial cell dysfunction due to induced abnormalities of glucolipid metabolism and oxidative stress. In this study, aberrant expression levels of circHMGCS1 and MIR4521 were observed in diabetes-induced human umbilical vein endothelial cell dysfunction. Persistent inhibition of MIR4521 accelerated development and exacerbated vascular endothelial dysfunction in diabetic mice. Mechanistically, circHMGCS1 upregulated arginase 1 by sponging MIR4521 , leading to decrease in vascular nitric oxide secretion and inhibition of endothelial nitric oxide synthase activity, and an increase in the expression of adhesion molecules and generation of cellular reactive oxygen species, reduced vasodilation and accelerated the impairment of vascular endothelial function. Collectively, these findings illuminate the physiological role and interacting mechanisms of circHMGCS1 and MIR4521 in diabetes-induced cardiovascular diseases, suggesting that modulating the expression of circHMGCS1 and MIR4521 could serve as a potential strategy to prevent diabetes-associated cardiovascular diseases. Furthermore, our findings provide a novel technical avenue for unraveling ncRNAs regulatory roles of ncRNAs in diabetes and its associated complications., Competing Interests: MZ, GD, LX, YX, WC No competing interests declared, (© 2024, Zhang et al.)

Importance: Soluble thrombomodulin is a marker of endotheliopathy, and iloprost may improve endothelial function. In patients with septic shock, high plasma levels of soluble thrombomodulin (>10 ng/mL) have been associated with worse organ dysfunction and mortality., Objective: To assess the effects of treatment with iloprost vs placebo on the severity of organ failure in patients with septic shock and plasma levels of soluble thrombomodulin higher than 10 ng/mL., Design, Setting, and Participants: This investigator-initiated, adaptive, parallel group, stratified, double-blind randomized clinical trial was conducted between November 1, 2019, and July 5, 2022, at 6 hospitals in Denmark. The trial had a maximum sample size of 380, with an interim analysis for futility only at 200 patients with 90 days of follow-up. In total, 279 adults in the intensive care unit (ICU) with septic shock and endotheliopathy were included., Interventions: Patients were randomized 1:1 to masked intravenous infusion of iloprost, 1 ng/kg/min (n = 142), or placebo (n = 137) for 72 hours., Main Outcomes and Measures: The primary outcome was mean daily Sequential Organ Failure Assessment (SOFA) score in the ICU adjusted for trial site and baseline SOFA score for the per-protocol population. SOFA scores for each of the 5 organ systems ranged from 0 to 4, with higher scores indicating more severe dysfunction (maximum score, 20). The secondary outcomes included serious adverse reactions and serious adverse events at 7 days and mortality at 90 days., Results: Of 279 randomized patients, data from 278 were analyzed (median [IQR] age, 69 [58-77] years; 171 (62%) male), 142 in the iloprost group and 136 in the placebo group. The trial was stopped for futility at the planned interim analysis. The mean [IQR] daily SOFA score was 10.6 (6.4-14.8) in the iloprost group and 10.5 (5.9-15.5) in the placebo group (adjusted mean difference, 0.2 [95% CI, -0.8 to 1.2]; P = .70). Mortality at 90 days in the iloprost group was 57% (81 of 142) vs 51% (70 of 136) in the placebo group (adjusted relative risk, 1.12 [95% CI, 0.91-1.40]; P = .33). Serious adverse events occurred in 26 of 142 patients (18%) for the iloprost group vs 20 of 136 patients (15%) for the placebo group (adjusted relative risk, 1.25 [95% CI, 0.73-2.15]; P = .52). Only 1 serious adverse reaction was observed., Conclusions and Relevance: In this randomized clinical trial of adults in the ICU with septic shock and severe endotheliopathy, infusion of iloprost, 1 ng/kg/min, for 72 hours did not reduce mean daily SOFA scores compared with placebo. In a clinical context, administration of iloprost will be unlikely to improve outcome in these patients., Trial Registration: ClinicalTrials.gov Identifier: NCT04123444.

Acute cerebral infarction poses a significant health risk and effective treatment is crucial. This randomized controlled trial assessed the impact of combining Butylphthalide and Atorvastatin on neurological function, quality of life and vascular endothelial function in 124 individuals with acute cerebral infarction. Participants were randomized into control and experimental groups, with the latter receiving the combination therapy. Objective assessments using NIHSS, SS-QOL, MBI and MoCA scales, along with biochemical markers, demonstrated improved outcomes in the experimental group. This study provides evidence for the clinical benefits of the drug combination in managing acute cerebral infarction.

Endothelial function declines with aging and independently predicts future cardiovascular disease (CVD) events. Diving also impairs endothelial function in humans. Yet, dolphins, being long-lived mammals adapted to diving, undergo repetitive cycles of tissue hypoxia-reoxygenation and disturbed shear stress without manifesting any apparent detrimental effects, as CVD is essentially nonexistent in these animals. Thus, dolphins may be a unique model of healthy arterial aging and may provide insights into strategies for clinical medicine. Emerging evidence shows that the circulating milieu (bioactive factors in the blood) is at least partially responsible for transducing reductions in age-related endothelial function. To assess whether dolphins have preserved endothelial function with aging because of a protected circulating milieu, we tested if the serum (pool of the circulating milieu) of bottlenose dolphins ( Tursiops truncatus ) induces the same arterial aging phenotype as the serum of age-equivalent humans. We incubated conduit arteries from young and old mice with dolphin and human serum and measured endothelial function ex vivo via endothelium-dependent dilation to acetylcholine. Although young arteries incubated with serum from midlife/older adult human serum had lower endothelial function, those incubated with dolphin serum consistently maintained high endothelial function regardless of the age of the donor. Thus, studying the arterial health of dolphins could lead to potential novel therapeutic strategies to improve age-related endothelial dysfunction in humans. NEW & NOTEWORTHY We demonstrate that, unlike serum of midlife/older adult humans, age-matched dolphin serum elicits higher endothelial function ex vivo in young mouse carotid arteries, suggesting that the circulating milieu of bottlenose dolphins may be geroprotective. We propose that dolphins are a novel model to investigate potential novel therapeutic strategies to mitigate age-related endothelial dysfunction in humans.

Chronic myeloid leukaemia (CML) management is complicated by treatment-emergent vascular adverse events seen with tyrosine kinase inhibitors (TKIs) such as nilotinib, dasatinib and ponatinib. Pleural effusion and pulmonary arterial hypertension (PAH) have been associated with dasatinib treatment. Endothelial dysfunction and impaired angiogenesis are hallmarks of PAH. In this study, we explored, at cellular and whole animal levels, the connection between dasatinib exposure and disruption of endothelial barrier integrity and function, leading to impaired angiogenesis. Understanding the mechanisms whereby dasatinib initiates PAH will provide opportunities for intervention and prevention of such adverse effects, and for future development of safer TKIs, thereby improving CML management., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: The current study aims to investigate the association between endothelial function and lower extremity perfusion in patients with peripheral artery disease (PAD). Patients and methods : In total 229 patients with PAD (Rutherford stage 0-3) were enrolled in the current study. Endothelial function was assessed by measuring flow-mediated dilation (FMD) and endothelial cell proliferation capacity (ECPC). Lower extremity perfusion was assessed by measuring oscillometry-based ankle brachial index (oABI) and pulse wave index (PWI). In addition, carotid intima-media-thickness (cIMT) was also measured as a surrogate marker for atherosclerosis. Correlations between FMD, ECPC, oABI, PWI, and cIMT were analysed using Pearson correlation coefficient. The relationship between the above variables and the severity of PAD was investigated using ordinal logistic regression analysis. Results : Correlation analysis showed that FMD negatively associated with PWI (r = -0.183, p = 0.005), ECPC positively associated with oABI (r = 0.162, p = 0.014), and oABI negatively associated with PWI (r = -0.264, p < 0.001). Ordinal logistic regression analysis showed that ECPC ( β = -0.009, p = 0.048), oABI ( β = -5.290, p < 0.001), and age ( β = -0.058, p = 0.002) negatively associated with the PAD Rutherford stages. In addition, PWI ( β = 0.006, p < 0.001), cIMT ( β = 18.363, p = 0.043) positively associated with the PAD Rutherford stages. Conclusions : Endothelial function significantly associates with lower extremity perfusion in patients with PAD, and both are related to the severity of PAD.