Biomarkers Of Endothelial Dysfunction Research Articles

Migraine and ergot use increase plasma pentraxin 3 levels: an Egyptian study

ABSTRACT Background Endothelial dysfunction and inflammation are linked to migraine, which may contribute to atherogenesis and increase the risk of ischemia. In migraineurs, preclinical vascular involvement manifested as compromised structural characteristics of vessel wall has not received enough attention or evaluation. Objectives To measure plasma pentraxin 3 as an indicator of endothelial dysfunction in migraine in comparison to controls and to examine its correlation with clinical characteristics, headache severity, and brain magnetic resonance imaging findings. Subjects and methods This study was conducted on 40 migraineurs and 40 healthy matched control subjects. The severity and intensity of headaches were quantified using the Headache Impact Test and the translated Arabic version of Migraine Disability assessment questionnaires. Both patients and controls underwent routine laboratory assessment, brain MR imaging, and measurement of plasma pentraxin 3 level. Results Patients with migraine had a significantly higher mean plasma pentraxin 3 when compared to controls. Patients with chronic migraine and those taking ergots also had significantly higher plasma pentraxin 3 levels. Additionally, there were statistically significant positive correlation between frequency of headaches and duration of the disease with plasma pentraxin 3 level. For diagnosing endothelial dysfunction in migraine patients, the sensitivity and specificity of pentraxin 3 levels were 85% and 95%, respectively, with cut-off value of 3.100 ng/ml. Conclusion Pentraxin 3 levels could be used as a chemical biomarker for endothelial dysfunction in migraines with high sensitivity and specificity. Higher plasma levels of pentraxin 3 in patients receiving ergots may influence the selection of treatment for migraine patients.

Plasma Humanin and Non-Coding RNAs as Biomarkers of Endothelial Dysfunction in Rheumatoid Arthritis: A Pilot Study

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder associated with an increased risk of cardiovascular disease (CVD), largely driven by peripheral endothelial dysfunction (ED). Humanin, a mitochondrial-derived peptide, has been suggested to play a protective role in endothelial function. However, the relationship between Humanin levels and ED in RA, as well as the interaction between Humanin and non-coding RNAs such as Long Non-Coding RNA GAS5, microRNA-21 (miR-21), and microRNA-103 (miR-103), remains unclear. Objective: This study aimed to investigate the relationship between circulating Humanin levels, non-coding RNAs (GAS5, miR-21, miR-103), and endothelial dysfunction (ED) in patients with RA. Additionally, we explored the correlation between Humanin expression and specific non-coding RNAs (GAS5, miR-21, and miR-103) to better understand their potential role in vascular health. Methods: Peripheral ED was assessed using flow-mediated pulse amplitude tonometry, with Ln-RHI values <0.51 indicating dysfunction. Humanin levels, GAS5, miR-21, and miR-103 were measured in RA patients. Univariate and multivariate analyses were conducted to determine the relationship between these biomarkers and ED. Kaplan–Meier survival analysis and ROC curve analysis were used to assess the prognostic value of Humanin. Results: Higher Humanin levels were significantly associated with better endothelial function (OR = 0.9774, p = 0.0196). Kaplan–Meier analysis demonstrated that higher Humanin levels correlated with improved survival (p < 0.0001). The non-coding RNAs (GAS5, miR-21, and miR-103) did not show significant associations with ED. Conclusions: Humanin is a potential protective biomarker for endothelial dysfunction and survival in RA patients. Further research is needed to explore the interaction between Humanin and non-coding RNAs in the context of vascular health.

VAMP8 as a biomarker and potential therapeutic target for endothelial cell dysfunction in atherosclerosis.

Endothelial cell dysfunction has a critical role in the pathophysiology of atherosclerosis. This study aims to uncover pivotal genes and pathways linked to endothelial cell dysfunction in atherosclerosis, as well as to ascertain the assumed causal effects and potential mechanisms. Datasets relevant to endothelial cell dysfunction in atherosclerosis were collected and divided into training and validation sets. Following differential analysis, we constructed a protein-protein interaction (PPI) network and a molecular interaction map of common-differentially expressed genes (co-DEGs) with proteins known to be involved in atherosclerotic endothelial cell dysfunction. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) were also conducted. Moreover, human umbilical vascular endothelial cells (HUVECs) were cultured in circumstances characterized by elevated glucose levels to establish a cellular injury model simulating atherosclerotic conditions, and quantitative Polymerase Chain Reaction (qPCR) experiments were conducted to validate the differences of co-DEGs. Subsequently, the Summary-data-based Mendelian Randomization (SMR) method was employed. Additionally, we employed the Western Blot (WB) technique to validate the differential expression of VAMP8. Finally, we identified the differential expression of VAMP8 in the validation set and further validated its differential expression by collecting fresh blood samples from 20 patients with atherosclerosis and 20 healthy individuals. 14 co-DEGs (FABP5, GULP1, COL4A5, VAMP8, FABP4, PFN2, ANGPT2, TFPI2, NUPR1, SULF1, FGF13, BASP1, EPB41L3, and PBK) were identified. SMR analysis confirmed 10 potential causal effect genes: PSRC1, VAMP8, FES, HNRNPUL1, CFDP1, SAP130, MDN1, OPRL1, UTP11, and HOXC4. The qPCR and WB experiments demonstrated that VAMP8 was significantly upregulated in the injured HUVECs group (p < 0.0001). Compared to the control group, VAMP8 was markedly increased in the blood samples of patients with atherosclerosis (p < 0.0001). VAMP8 may potentially serve as a pathogenic gene in the process of endothelial dysfunction in atherosclerosis.

Endocan expression and correlation with other endothelial determinants in developing a score for early identification of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus that has dire outcomes, affecting the economic profile of a country. Despite the multifactorial background of the pathogenesis of this disease, the mechanism underlying peripheral neuropathy is still unclear. Endothelial damage is a new determinant of pathogenesis, with endocan as a potential biomarker for endothelial dysfunction in diabetic peripheral neuropathy patients. In this cross-sectional study, with 49 patients with diabetes with peripheral neuropathy and 48 patients with diabetes without neuropathy, endothelial biomarkers such as endocan, hs-CRP, vitamin D, and lipid profiles were measured and analyzed in both groups. The standardized scores for dyslipidemia, inflammation, vitamin D and endocan were calculated. All of these biomarkers were significantly altered in peripheral neuropathy patients. A strong correlation between endocan levels and lipid profiles and between hs-CRP and vitamin D levels was detected. The inflammatory score and a combined score including all the above biomarkers might help in the early stratification of diabetic patients who are at greater risk of developing peripheral neuropathy.

Attenuation of Endothelial Dysfunction in Diabetes Mellitus: An Integral Characteristic of Anti-Diabetic Medications

Abstract Background: The complications of diabetes mellitus (DM) have incapacitated many patients, especially in poor-income countries. DM is an endocrine disease but its far-reaching complications arise from cardiovascular derangements. The cardiovascular complications usually stem from endothelial dysfunction, which culminates in atherosclerosis. Progressively, atherosclerosis results in microvascular and macrovascular complications. Materials and Methods: Literature searches were carried out in Google, PubMed, and MEDLINE using the following keywords: DM, endothelial dysfunction, biomarkers, anti-diabetic drugs, C-reactive protein (CRP), and intercellular adhesion molecule. Original articles, systematic reviews, and meta-analytic articles were reviewed, and important findings were incorporated into this review. Summary: The review aims to evaluate mechanisms responsible for endothelial dysfunction in diabetes. Endothelial dysfunction may arise from one or a combination of these molecular mechanisms: (i) decreased nitric oxide synthesis, (ii) activation of protein kinase C and reactive oxygen species generation, (iii) activity of advanced glycation endproducts, (iv) activation of tumor necrosis factor-alpha, and (iv) defective insulin signaling and so on. The biomarkers of endothelial dysfunction were also explored and they include CRP, intracellular adhesion molecule-1, vascular cell adhesion molecule-1, microalbuminuria, asymmetric dimethylarginine, Toll-like receptors, and others. The review also evaluated the effectiveness of anti-diabetic medications in modulating the biomarkers of endothelial dysfunction in diabetic patients.

Identifying biomarker-driven subphenotypes of cardiogenic shock: analysis of prospective cohorts and randomized controlled trials.

Cardiogenic shock (CS) is a heterogeneous clinical syndrome, making it challenging to predict patient trajectory and response to treatment. This study aims to identify biological/molecular CS subphenotypes, evaluate their association with outcome, and explore their impact on heterogeneity of treatment effect (ShockCO-OP, NCT06376318). We used unsupervised clustering to integrate plasma biomarker data from two prospective cohorts of CS patients: CardShock (N=205 [2010-2012, NCT01374867]) and the French and European Outcome reGistry in Intensive Care Units (FROG-ICU) (N=228 [2011-2013, NCT01367093]) to determine the optimal number of classes. Thereafter, a simplified classifier (Euclidean distances) was used to assign the identified CS subphenotypes in three completed randomized controlled trials (RCTs) (OptimaCC, N=57 [2011-2016, NCT01367743]; DOREMI, N=192 [2017-2020, NCT03207165]; and CULPRIT-SHOCK, N=434 [2013-2017, NCT01927549]) and explore heterogeneity of treatment effect with respect to 28-day mortality (primary outcome). Four biomarker-driven CS subphenotypes ('adaptive', 'non-inflammatory', 'cardiopathic', and 'inflammatory') were identified separately in the two cohorts. Patients in the inflammatory and cardiopathic subphenotypes had the highest 28-day mortality (p (log-rank test)=0.0099 and 0.0055 in the CardShock and FROG-ICU cohorts, respectively). Subphenotype membership significantly improved risk stratification when added to traditional risk factors including the Society for Cardiovascular Angiography and Interventions (SCAI) shock stages (increase in Harrell's C-index by 4% (p=0.033) and 6% (p=0.0068) respectively in the CardShock and the FROG-ICU cohorts). The simplified classifier identified CS subphenotypes with similar biological/molecular and outcome characteristics in the three independent RCTs. No significant interaction was observed between treatment effect and subphenotypes. Subphenotypes with the highest concentration of biomarkers of endothelial dysfunction and inflammation (inflammatory) or myocardial injury/fibrosis (cardiopathic) were associated with mortality independently from the SCAI shock stages. Dr Sabri Soussi was awarded the Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award (DFSA) and the Merit Awards Program (Department of Anesthesiology and Pain Medicine, University of Toronto, Canada) for the current study.

Treatment with Sulodexide Downregulates Biomarkers for Endothelial Dysfunction in Convalescent COVID-19 Patients.

Persistent elevation of biomarkers associated with endothelial dysfunction in convalescent COVID-19 patients has been linked to an increased risk of long-term cardiovascular complications, including long COVID syndrome. Sulodexide, known for its vascular endothelial affinity, has demonstrated pleiotropic protective properties. This study aims to evaluate the impact of sulodexide on serum levels of endothelial dysfunction biomarkers in patients during the convalescent phase of COVID-19. We conducted a double-blind, single-center, randomized, placebo-controlled trial in Mexico, comparing sulodexide (250 LRU orally, twice daily) with placebo over 8 weeks in adult patients during early COVID-19 convalescence. Differences in serum biomarkers between the groups were analyzed using repeated measures and post hoc tests, with Thrombomodulin (TM) as the primary endpoint. Among 206 analyzed patients (103 in each group), at week 8, the sulodexide group exhibited significantly lower mean levels of Thrombomodulin (TM) (25.2 ± 7.9 ng/mL vs 29.9 ± 14.7 ng/mL, P = .03), von Willebrand Factor (vWF) (232 ± 131 U/dL vs 266 ± 122 U/dL, P = .02) and Interleukin-6 (IL-6) (12.5 ± 13.2 pg/mL vs 16.2 ± 16.5 pg/mL, P = .03) compared to the placebo group. D-dimer and C reactive protein (CRP) in the sulodexide group were also lowered. No significant differences were observed for P-selectin, fibrinogen, VCAM-1, or ICAM-1 levels. Patients in the convalescent phase of COVID-19 who received sulodexide for eight weeks showed a reduction in TM, vWF, D-dimer, CRP, and IL-6 serum levels compared to placebo. These findings suggest a potential protective effect of sulodexide against thromboinflammation and endothelial damage.

Association between serum endocan levels and organ failure in hospitalized patients with cirrhosis.

Acute-on-chronic liver failure is a syndrome characterized by organ failure and high short-term mortality. The lack of reliable biomarkers for the early detection of acute-on-chronic liver failure is a significant challenge. Endothelial dysfunction plays a key role in the development of organ failure. Serum endocan is a potential new biomarker for endothelial dysfunction. Therefore, this study aimed to assess the association between endocan and organ failure and 28-day mortality in patients with cirrhosis. Hospitalized patients with cirrhosis with and without organ failure were prospectively enrolled according to the criteria of the European Association for the Study of Liver-Chronic Liver Failure consortium. The comparative performances of serum endocan, procalcitonin, and interleukin-6 for diagnosing organ failure and predicting mortality were studied. The study included 116 hospitalized patients with cirrhosis, 55 of whom had organ failure on admission. Patients with organ failure had significantly higher endocan, procalcitonin, and interleukin-6 levels than those without it. At a cut-off value of 15.8 ng/mL, endocan showed a sensitivity of 63.6% and specificity of 67.2% for the diagnosis of organ failure, with an area under the receiver operating characteristic curve of 0.65, which is comparable to procalcitonin and interleukin-6. Multivariate analysis identified serum endocan, creatinine, and total bilirubin as independent factors for organ failure in hospitalized patients with cirrhosis. Patients who died within 28 days had significantly higher baseline biomarker levels than those who survived. Liver failure, hospital-acquired infection, mechanical ventilator use, and interleukin-6 ≥37 pg/mL were independent predictors of 28-day mortality. Serum endocan is associated with organ failure and is an independent risk factor of organ failure in hospitalized patients with cirrhosis.

Relationship Between Serum Myostatin and Endothelial Function in Non-Dialysis Patients with Chronic Kidney Disease.

Myostatin, primarily produced by skeletal muscle, inhibits muscle growth and promotes protein degradation. It has been implicated in conditions such as obesity, insulin resistance, and cardiovascular disease. However, its association with endothelial function in chronic kidney disease (CKD) patients remains unclear. This study aimed to investigate the relationship between serum myostatin levels and endothelial function in 136 non-dialysis CKD patients at stages 3-5. Fasting blood samples were collected to measure serum myostatin levels using enzyme-linked immunosorbent assay kits. Endothelial function was evaluated non-invasively by measuring the vascular reactivity index (VRI) with a digital thermal monitoring test. VRI values were classified as poor (<1.0, n = 25, 18.4%), intermediate (1.0 to <2.0, n = 63, 46.3%), or good (≥2.0, n = 48, 35.3%). Factors associated with poor vascular reactivity included older age (p = 0.026), elevated serum blood urea nitrogen (p = 0.020), serum creatinine (p = 0.021), urine protein-to-creatinine ratio (UPCR, p = 0.013), and myostatin levels (p = 0.003), along with reduced estimated glomerular filtration rate (p = 0.015). Multivariate regression analysis identified older age, higher serum creatinine, and log-transformed myostatin levels as significant independent predictors of lower VRI. These findings suggest that myostatin may serve as a potential biomarker for endothelial dysfunction in CKD patients. Future large-scale, longitudinal studies are warranted to confirm and extend our preliminary findings.

Early and concomitant administration of norepinephrine and ilomedin improves microcirculatory perfusion without impairing macrocirculation in an intestinal ischemia-reperfusion injury swine model : a randomized experimental trial.

Intestinal ischemia-reperfusion injury is associated with both macrocirculatory and microcirculatory failure. Association of a vasoconstrictor in combination with a vasodilator such as ilomedin may improve macrocirculation parameters, microcirculation perfusion and reduce endothelial dysfunction. The primary objective was to demonstrate a difference in mean arterial pressure (MAP) after intestinal reperfusion with the concomitant administration of norepinephrine and ilomedin during ischemia compared with traditional hemodynamic treatment strategies (fluid resuscitation and vasopressors only). Secondary objectives were to demonstrate an improvement in peripheral and intestinal microcirculatory perfusion and endothelial dysfunction after intestinal reperfusion using this association. We conducted a randomized preclinical trial in twenty-one large white pigs, in which a 2-hour small bowel ischemia was performed using a segmental mesenteric occlusion model, followed by a 2-hour reperfusion. Pigs were randomized into 3 groups: goal directed fluid therapy, early administration of norepinephrine before reperfusion and early administration of ilomedin and norepinephrine before reperfusion. Macrocirculatory (MAP and Cardiac Index (CI)), microcirculatory (Sublingual with SideStream Dark Field system and intestinal hemoglobin oxygen saturation with hyperspectral imaging (HSI)) measurements and biological analysis (biomarkers of endothelial dysfunction) were performed. There were no significant differences in the MAP (p = 0.499) and the CI (p = 0.659) between the 3 groups. Perfused Vessel Density (PVD) in sublingual microcirculation was significantly higher immediately after reperfusion and 2 hours after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other 2 groups (p < 0.05). Hemoglobin oxygen saturation measured at the intestinal level was significantly higher immediately after reperfusion in the early administration of ilomedin and norepinephrine group compared with the other 2 groups (p < 0.01). There were no significant differences in biomarkers of endothelial dysfunction between the 3 groups. Creatinine, AST and alkaline phosphatases increased significantly 2 hours after reperfusion in the early administration of ilomedin and norepinephrine group compared with baseline (p < 0.05). Early administration of norepinephrine and ilomedin during ischemia improved short-term post-reperfusion sublingual and intestinal microcirculation without worsening macrocirculatory parameters in an intestinal ischemia-reperfusion injury model. However, use of this strategy seemed to worsen both liver and kidney function.

Endothelial Dysfunction and Impaired Wound Healing Following Radiation Combined Skin Wound Injury.

Currently, there are no U.S. Food and Drug Administration (FDA)-approved medical countermeasures (MCMs) for radiation combined injury (RCI), partially due to limited understanding of its mechanisms. Our previous research suggests that endothelial dysfunction may contribute to a poor prognosis of RCI. In this study, we demonstrated an increased risk of mortality, body weight loss, and delayed skin wound healing in RCI mice compared to mice with skin wounds alone or radiation injury (RI) 30 days post-insult. Furthermore, we evaluated biomarkers of endothelial dysfunction, inflammation, and impaired wound healing in mice at early time points after RCI. Mice were exposed to 9.0 Gy total-body irradiation (TBI) followed by skin wound. Samples were collected on days 3, 7, and 14 post-TBI. Endothelial dysfunction markers were measured by ELISA, and skin wound healing was assessed histologically. Our results show that endothelial damage and inflammation are more severe and persistent in the RCI compared to the wound-alone group. Additionally, RCI impairs granulation tissue formation, reduces myofibroblast presence, and delays collagen deposition, correlating with more severe endothelial damage. TGF signaling may play a key role in this impaired healing. These findings suggest that targeting the endothelial dysfunction and TGF-β pathways may provide potential therapeutic strategies for improving delayed wound healing in RCI, which could subsequently influence outcomes such as survival after RCI.

WMH Contributions to Cognitive Impairment: Rationale and Design of the Diverse VCID Study.

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter injury, their risk factors, and comorbidities on cognitive performance among a diverse, nondemented, stroke-free population with cognitive complaints over an extended period of observation. The Diverse VCID (Diverse Vascular Cognitive Impairment and Dementia) study is designed to fill this knowledge gap through 3 assessments of clinical, behavioral, and risk factors; neurocognitive and magnetic resonance imaging measures; fluid biomarkers of Alzheimer disease, vascular inflammation, angiogenesis, and endothelial dysfunction; and measures of genetic risk collected prospectively over a minimum of 3 years in a cohort of 2250 individuals evenly distributed among Americans of Black/African, Latino/Hispanic, and non-Hispanic White backgrounds. The goal of this study is to investigate the basic mechanisms of small vessel cerebrovascular injury, emphasizing clinically relevant assessment tools and developing a risk score that will accurately identify at-risk individuals for possible treatment or clinical therapeutic trials, particularly individuals of diverse backgrounds where vascular risk factors and disease are more prevalent.

Abstract 4145829: Fatty Acid Binding Protein 4 as Potential Indicator for Gestational Diabetes Mellitus-Induced Fetal Endothelial Dysfunction

Introduction/Background: Gestational diabetes mellitus (GDM) is the most common complication during pregnancy. GDM is leading to an elevated risk for the development of cardiovascular diseases both in the mother and the child in later life. Previous studies have identified fatty acid-binding protein 4 (FABP4) as a prime candidate involved in the pathophysiology of GDM. Indeed, women with GDM exhibit elevated blood levels of FABP4, suggesting its potential role as a biomarker for endothelial dysfunction and cardiovascular risk assessment in GDM. Research Question/Hypothesis: Does FABP4 affect the function of human endothelial cells from patients with GDM? Goals/Aim: Our aim is a better understanding of the role of FABP4 in fetal endothelial dysfunction of patients with GDM and the development of potential therapeutic strategies. Methods/Approach: Primary human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords obtained from normoglycemic and GDM pregnancies. Total mRNA from HUVECs was used for bulk RNA sequencing to compare gene expression pattern. HUVECs were subjected to functional analyses assessing proliferation, migration, NO and insulin signaling. Finally, human endothelial cells were exposed to high laminar flow (30 dyn/cm 2 ) or simvastatin (10 nM) treatment to investigate their impact on FABP4 expression and endothelial function. Results/Data: Bulk RNA sequencing data analysis revealed FABP4 as a gene overexpressed in GDM HUVECs compared to normoglycemic controls. Gene set enrichment analysis showed in addition an enrichment of genes involved in angiogenesis and Notch signaling pathways in human endothelial cells from GDM patients. GDM HUVECs had a significantly higher wound healing capacity compared to normoglycemic controls. The PI3K/AKT/mTOR pathway was enriched in GDM HUVECs. GDM HUVECs displayed impaired activation of AKT and eNOS (expression and phosphorylation) after stimulation with insulin, suggesting a possible insulin resistance. Finally, subjecting HUVECs to high laminar shear stress or simvastatin treatment caused a reduction of FABP4 mRNA expression and an increase of eNOS expression, indicating potential therapeutic strategies to improve endothelial function. Conclusions: We provided evidence that FABP4 could be involved in fetal GDM-induced endothelial dysfunction. High laminar shear stress and medications activating eNOS signaling could protect the endothelium against the negative impact of FABP4 in GDM.

Assessing Vascular Biomarkers and Their Association with Hypertension in Paediatric Chronic Kidney Disease

Objectives: This study aims to examine the correlation between children with chronic kidney disease (CKD) and endothelial dysfunction biomarkers, including asymmetric dimethylarginine (ADMA), angiopoietin-2 (Ang-2), and vascular endothelial growth factor-A (VEGF-A), as well as blood pressure and cardiovascular risk. Methods: A cross-sectional study included 90 children divided into two groups: 45 with CKD with different stages and 45 healthy controls. Blood pressure was taken, and levels of ADMA, Ang-2, and VEGF-A were determined. November 2021 to October 2022 was the time frame of the study. Results: The results showed that children with CKD had significantly higher levels of ADMA, Ang-2, and VEFG-A compared to the control group. Systolic and diastolic blood pressure showed a positive connection with the elevated biomarkers but estimated glomerular filtration rate (eGFR) showed a negative association. Conclusion: Increased cardiovascular risk and antihypertensive have been associated with elevated levels of VEFG-A, Angiopoietin-2, and ADMA in children with chronic kidney disease. These biomarkers might be useful in clinical evaluations to improve therapy and results for children with CKD.

Ultrasound assessment of endothelial dysfunction in Egyptian migraine patients

BackgroundIt becomes clearer that migraine is associated with vascular risks; however, preclinical vascular involvement is not sufficiently addressed. Evidences point that migraine attacks affect vascular endothelium. The aim of this study was to investigate endothelial dysfunction in migraineurs through assessment of carotid intima-media thickness (CIMT) and flow-mediated dilatation (FMD) of the brachial artery and their correlation with clinical characteristics of migraine, headache severity, and brain magnetic resonance imaging (MRI) findings.ResultsA statistically significant difference was found between migraineurs and controls where carotid IMT was significantly higher and FMD of the brachial artery was significantly lower in migraineurs compared to controls. Carotid IMT was significantly higher and FMD was significantly lower in chronic migraine compared to episodic migraine patients. Mean IMT values were significantly higher in patients receiving ergots and in patients with subcortical white matter lesions in brain MRI. Mean FMD values were significantly lower in patients receiving ergots. There was a significant negative correlation between FMD and carotid IMT, age of the patients, disease duration, duration of headache attacks, headache frequency, and migraine disability assessment questionnaire (MIDAS) score. There were significant positive correlations between carotid IMT and age of patients, disease duration, headache frequency, MIDAS score, and number of MRI white matter lesions. For diagnosing endothelial dysfunction in migraineurs, the sensitivity and specificity of IMT were 72.5 and 70%, respectively, with a cut-off value of 0.575 mm and that of FMD were 82.5 and 90%, respectively, with a cut-off value of 20.55%.ConclusionMigraine coincides with endothelial dysfunction which promotes atherogenesis and increased risk of cerebral ischemia. FMD could be used as a potential biomarker for endothelial dysfunction in migraine. The affection of IMT and FMD is more in patients receiving ergots which may influence the selection of treatment in migraineurs in the future.

Increased circulating levels of standardized inflammatory and endothelial dysfunction biomarkers in patients with myocardial infarction with nonobstructive coronary arteries

Abstract Introduction Around 10% of patients with acute myocardial infarction (AMI) present with nonobstructive coronary arteries (MINOCA), for which the underlying pathophysiology is often uncertain. Our aim was to evaluate inflammatory burden and endothelial dysfunction in MINOCA patients by assessing biomarkers in both acute and stable phases. Methods An analytical and observational study at a University Hospital involving 166 MI patients admitted over the past 3years. Following ESC guidelines, patients were categorized into MINOCA or myocardial infarction with significant coronary artery disease (MI-CAD) groups. Circulating levels of inflammatory biomarkers (interleukin-6(IL-6), tumor necrosis factor-α(TNF-α) and high-sensitivity C-reactive protein(hs-CRP)) and of endothelial dysfunction (asymmetric dimethylarginine (ADMA)) were measured in 44 MINOCA patients and 122 MI-CAD patients at acute phase (admission and discharge) and stable phase (2months after MI). As biomarker levels may vary with MI size, each value was standardized by dividing it by the peak troponin, resulting in a biomarker/troponinT ratio. We evaluated the effects of standardized (SB) and non-standardized (NSB) biomarker values using a multivariate regression model adjusted for age and sex. Results We analyzed 166 patients (median age:68 years, 70% males). MI-CAD patients had higher peak high-sensitive troponinT (hs-TnT) levels upon admission compared to those with MINOCA (1491ng/L vs 247ng/L,p&amp;lt;0.001),likely due to larger infarctions generating higher levels of inflammation. When examining the association between infarct size, as measured by peak hs-TnT values, and biomarker levels, we observed a significant dose-response relationship for hs-CRP at admission (βcoefficient 0.16 [95%CI,0.02-0.29],p0.02) and IL-6 at admission (βcoefficient 0.15 [95%CI,0.04-0.27],p0.01). Significant positive associations were found between MINOCA and all SBs, both during the acute phase and in follow-up. During the acute phase ORs ranged from 1.35to2.7 (p&amp;lt;0.05) for inflammatory biomarkers and from 2.34 to 2.76 (p&amp;lt;0.01) for ADMA. In the stable phase ORs ranged from 1.49to3.06 (p&amp;lt;0.05) for inflammatory biomarkers, and OR was 2.79(p&amp;lt;0.01) for ADMA (Figure 1). In contrast, none of the NSBs were associated with MINOCA. Regarding temporal biomarker changes, during the acute phase of MI and 2 months post-event, both MINOCA and MI-CAD patients showed similar trends. However, MINOCA patients consistently maintained elevated inflammatory activity and ADMA concentrations only when biomarkers were standardized by infarct size (Figure 2). Conclusions Higher levels of SBs were consistently associated with MINOCA, both during the acute phase of the event and in follow-up, compared to MI-CAD. Consequently, this study suggests that the inflammatory burden, measured by heightened levels of standardized inflammatory biomarkers, and endothelial dysfunction, as measured by ADMA, may play a role in the pathophysiology of MINOCA.Boxplots for SBs at three time points.Temporal changes in biomarker levels.

The evolution of endothelial dysfunction according to the length of the implanted stent on the background of nebivolol therapy

Abstract Introduction The development of atherosclerosis is the driving cause for arterial interventions using coronary stents. Long-stent implantation can increase the vascular injury thereby contributing to the progression of endothelial dysfunction (ED) by the degradation and reduction bioavailability of the nitric oxide (NO) - thus increasing the risk of major cardiovascular events. Purpose Evaluation the evolution of endothelial dysfunction biomarker depending on the length of the stent implanted on the background of nebivolol therapy. Methods The study included 100 patients with stable angina pectoris II–III functional class (age 59.72±0.59 years) undergoing PCI with stent implantation who started the treatment with nebivolol 5mg per day tangent to the conventional treatment and were exposed to PCI with stent implantation, depending on the stent’s length they were divided in three groups: I group - 14 patients with implanted stent’s length ≤15 mm, II group - 57 subjects with implanted stent’s length =15-30 mm and the III group -29 cases where the implanted stent’s length was ≥30 mm. In all the groups was appreciated in blood the endothelial dysfunction’s marker - NO. This marker was assessed preprocedural, postprocedural (after 24 hours) and at intervals of one month, 3,6,12 months after coronary angioplasty, the NO level being compared between these groups and the reference pattern consisting of 20 healthy people. Results The circulating level of nitric oxide determined in I group -61,28±6,92 μM/L and in the II group -56.6±3.03 μM/L and the III group52.39±3.35 was compromised at the preprocedural stage versus the reference pattern - 78.67±2.72 μM/L. During the post- PCI period (first 24 hours), the biomarker level’s was reduced in I group -52.35±1.66 μM/ L, II group -53.74±2.77 μM/L and III group - 52.98±2.91 μM/L. After one month after the intervention on the backroung of the treatment with nebivolol, was recorded a gaing of the NO value in I group - 64.97±5.35 μM/L, II group -63.15±3.99 μM /L and the III group-59.38±4.46 μM/L. The NO serum concentration during the period 3 and 6 months continued to increase in all groups vs the reference pattern. At the 12-month period, the NO level remained high in all the studied groups versus the baseline: I group 99.2±1.1 μM / L (p&amp;gt;0.05), II group-97.96±2.2 μM/L (p&amp;lt;0.001) and the III group -97.65±1.9 μM/L (p&amp;lt;0.001). Conclusion The stent’s length = 15-30 mm and ≥30 mm reveals the presence of an expanded atherosclerotic process, the substrate of which is constituted by the endothelial dysfunction, this being confirmed by the low preprocedural level of NO. The stent implantation procedure induced the accentuation of endothelial dysfunction, and the 12-month nebivolol treatment favored the increase of NO serum concentraon in all groups by 24.9% vs the reference pattern and by 73.3% vs baseline.

Biochemical markers and carotid intima-media thickness in relation to cardiovascular risk in young women.

Cardiovascular disease (CVD) is a major cause of death in the female population. The current study aimed to examine the relationship between CVD risk and novel endothelial dysfunction biomarkers [i.e., endocan, adiponectin and intercellular adhesion molecule (ICAM)-1] and carotid intima-media thickness (cIMT), respectively in a cohort of disease-free women of reproductive age. A total of 129 women were selected. Serum endocan, adiponectin and ICAM-1 were measured by a commercial enzyme-linked immunosorbent assay and cITM was determined by ultrasound. Cardiovascular risk score (CVRS) was calculated. The lowest endocan (p for trend = 0.051) and adiponectin (p for trend = 0.040) levels were found in a group of subjects with the highest CVRS. The cIMT values were the highest in second tertile subgroups, with the highest 75th percentile in a third tertile CVRS group, while the lowest cIMT values were detected in the lowest CVRS tertile group (p for trend = 0.001). A significant positive correlation between cIMT and CVRS (ρ = 0.307, p < 0.001), and a negative correlation between adiponectin and endocan with CVRS, respectively (ρ = - 0.252, p = 0.004; ρ = - 0.179, p = 0.043) were observed, but only endocan retained the independent association with CVRS (p = 0.030) in the multiple linear regression analysis. Endocan could be useful diagnostic tool in the estimation of cardiovascular risk in young women.

Biomarkers of endothelial dysfunction and cognition: A two-step IPD meta-analysis.

This study assessed the association of plasma biomarkers of endothelial dysfunction with cognitive performance and decline. Data from 9414 individuals from eight Dutch cohorts were included (Ø age-range: 57-93 years). Plasma biomarkers of endothelial dysfunction (soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin) were combined into a standardized composite score. Cognitive outcomes included executive function, processing speed, immediate and delayed memory, attention, and language. Linear regressions and linear mixed models were run in the individual cohorts and standardized coefficients were subsequently pooled using random-effects meta-analyses. A higher endothelial dysfunction composite score was cross-sectionally associated with worse performance on executive function, processing speed, delayed memory, and attention, but not immediate memory or language (pooled β-range: -0.04, -0.02). We found no association with change in cognition over time. This comprehensive two-step, individual participant data (IPD) meta-analysis showed a small, consistent cross-sectional association between endothelial dysfunction and worse cognitive performance across multiple domains but no support for a longitudinal association. Prior evidence on endothelial dysfunction (ED) biomarkers and cognition is conflicting. This two-step, individual participant data (IPD) meta-analysis used data from eight Dutch cohorts. ED was consistently associated with concurrent cognition. ED was not associated with a change in cognition over time. The association of ED with current cognition may be generic.

The association of pre-operative biomarkers of endothelial dysfunction with the risk of post-operative neurocognitive disorders: results fromthe BioCog study.

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. 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. 19.8% of 788 patients developed POD; 10.1% of 537 patientshad POCDat 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 (adjustedodds ratio 0.55; 95% CI: 0.35-0.86). No further statistically significant results were found. Pre-operative concentrations of ED biomarkers werenot 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.