Safety and Effectiveness of Acceleration Training as Cardiac Rehabilitation Immediately After Open Heart Surgery　- A Pilot Study.

BACKGROUND: We examined the safety and efficacy of acceleration training (AT) in patients immediately after cardiac surgery. METHODS AND RESULTS: This randomized controlled study included patients who underwent open-heart surgery using cardiopulmonary bypass. Of these patients, 31 received regular cardiac rehabilitation (CR) and 39 received AT in addition to regular CR (AT group). AT was provided using a vibration platform (Power Plate®Pro7TMand Power plate®personal; Performance Health System, Chicago, IL, USA). The AT group performed 5 static resistance training sessions: squats, wide stance squats, toe stands, banded squats, and front lunges. Each vibration session lasted 30 s. We evaluated the short physical performance battery, anterior mid-thigh thickness, maximum voluntary isometric contraction of the knee extensors, and serum intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) concentrations as indicators of endothelial function. The observation period was during hospitalization and lasted approximately 20 days. No adverse events occurred during AT. Ultrasound revealed a significantly lower reduction in muscle mass at discharge in the AT group. No significant differences were observed in ICAM-1 and VCAM-1 concentrations between the 2 groups preoperatively, postoperatively, or at discharge. CONCLUSIONS: AT is considered safe and effective for patients immediately after open-heart surgery. AT, along with regular CR, may prevent skeletal muscle mass loss, muscle weakness, and physical function loss immediately after open-heart surgery.

Progranulin, sICAM-1, and sVCAM-1 May Predict an Increased Risk for Ventricular Arrhythmias in Patients with Systemic Sclerosis.

In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.

Serum Vascular Adhesion Protein-1 and Endothelial Dysfunction in Hepatic Cirrhosis: Searching for New Prognostic Markers.

Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of this study was to explore and correlate the behavior of sVAP-1 with that of the soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) and with the severity of liver cirrhosis. A cross-sectional study was carried out by enrolling 28 controls, 59 cirrhotic patients without hepatocellular carcinoma, and 56 patients with hepatocellular carcinoma (HCC), mainly caused by alcohol abuse. The levels of adhesion molecules and of the pro-inflammatory cytokines (IL-6 and TNF-αα) were determined by immunoassay and the enzymatic activity of sVAP-1 by a fluorometric assay. In non-diabetic patients without HCC, a specific behavior of sVAP-1 was highlighted. Differently from sVCAM-1, sICAM-1, and cytokines, the sVAP-1 level was significantly increased only in the early stage of disease, and then, it decreased in the last stage (866 ± 390 ng/mL vs. 545 ± 316 ng/mL, in Child-Pugh class A vs. C, respectively, p < 0.05). Bivariate analysis correlates sVAP-1 to sVCAM-1, in the absence of HCC (Spearman's rho = 0.403, p < 0.01). Multiple linear regression analysis revealed that sVCAM-1 appears to be a predictor of sVAP-1 (ß coefficient = 0.374, p = 0.021). In conclusion, in non-diabetic and non-HCC cirrhotic patients, sVAP-1 may be a potential prognostic biomarker that, together with sVCAM-1 and pro-inflammatory cytokines, may provide information on the progression of sinusoidal liver endothelium damage.

Comparison of serum Vascular Cell Adhesion Molecule (VCAM) level among epithelial ovarian cancer patients and healthy women.

Objectives: To compare serum vascular cell adhesion molecule levels among ovarian cancer patients of different standardised grades, and in relation to healthy controls. METHODS: The case-control study was conducted from 6.2.2018 to 1.8.2021 after approval form the ethics review board of the University of Health Sciences, Lahore, Pakistan, and comprised females aged 20-70 years diagnosed with ovarian cancer and tentatively planned for surgical procedures in group A, and healthy controls in group B. From all the subjects, 2.5ml blood was taken in a green-top tube. The tubes were centrifuged, and the serum was separated within an hour of sample collection. The Eppendorf tubes were labelled and stored at -20°C. The samples were thawed, and, following the manual protocol, they were subjected to vascular cell adhesion molecule enzyme-linked immunosorbent assay. Cancer antigen 125 values before surgery and 6-8 months post-surgery were recorded from available laboratory reports. Also, group A was categorised in line with the International Federation of Gynaecology and Obstetrics stage classification. Data was analysed using SPSS 24. RESULTS: Of the 80 female subjects, 40(50%) were group A cases and 40(50%) were group B controls. The overall mean age was 48±12 years. Overall, 55(68.7%) women were aged <55 years and 25(31.3%) were aged >55 years. Within group A, 20(50%) had cancer stage I-II and 20(50%) had stage III-IV. Overall median vascular cell adhesion molecule was 72.40ug/L (interquartile range: 1857.40ug/L), with 71.15ug/L (interquartile range: 616.60ug/L) in group A and 74.10ug/L (interquartile range: 1848.70ug/L) in group B. Significant correlation was found between cancer stage and vascular cell adhesion molecule level (rho=0.73; p=0.003). CONCLUSIONS: There was a decreased level of vascular cell adhesion molecule level in epithelial ovarian cancer cases compared to healthy controls. A positive association was observed between ovarian cancer stage and vascular cell adhesion molecule level.

Angiogenesis outcomes of metformin utilization in diabetes mellitus: a systematic review and meta-analysis.

OBJECTIVE: To review relevant literature regarding the role of metformin in angiogenesis among diabetic patients. METHODS: The systematic review and meta-analysis conducted from May to September 2022, and comprised search on Medline, ScienceDirect, ProQuest, Web of Science, EBSCOhost and Cochrane Library databases. The studies included were published in the English language and were human studies having angiogenesis endothelial markers as the outcomes of interest among patients of type 2 diabetes mellitus undergoing metformin therapy. Endothelial markers, including vascular endothelial growth factor, von-Willebrand-factor, plasminogen activator inhibitor-1, soluble vascular adhesion molecule- 1, intercellular adhesion molecule-1, soluble endothelialselectin, tissue plasminogen activator, urinary albumin excretion, platelet endothelial cell adhesion molecule-1 and thrombin-activatable fibrinolysis inhibitor, were assessed as angiogenesis outcomes. Data was statistically analysed using Review Manager 5.4. RESULTS: Of the 413 studies identified, 8(1.9%) were included; 5(62.5%) randomised control trials, 2(25.0%) cross-sectional, and 1(12.5%) cohort studies, with overall 1199 patients. Among the outcomes, von-Willebrandfactor (p=0.01), soluble vascular adhesion molecule-1 (p<0.00001), intercellular adhesion molecule-1 (p=0.0003), soluble endothelial-selectin (p=0.007), and tissue plasminogen activator (p<0.00001) showed significantly lower levels after metformin treatment using the random effect methods. CONCLUSIONS: Metformin was found to have an additional effect of endothelial function improvement.

Immunological alterations in intracranial aneurysm: a prospective study on selected biomarker profiles in blood collected during endovascular neurointervention.

INTRODUCTION: Previous studies showed that the concentrations of selected chemokines are locally elevated in samples collected from the lumen of intracranial aneurysms (IA). Our objective was to determine whether the observed differences in analyte concentrations were influenced by the origin of the blood samples (i.e. cerebral versus peripheral), thus providing insight into the localised nature of these alterations and their significance in IA pathogenesis. MATERIAL AND METHODS: This prospective study included 24 patients with IA who underwent endovascular embolisation. Concentrations of selected analytes were analysed in blood samples from the IA lumen, feeding artery, and aorta. The analytes included MPO, Lipocalin-2/NGAL, sICAM-1, sVCAM-1, and serum amyloid A. RESULTS: Higher median plasma concentrations of MPO, lipocalin-2/NGAL, sVCAM-1, and SAA were found in samples obtained from the IA lumen and the feeding artery compared to the aorta. The concentration of sICAM-1 was significantly higher in the IA compared to the aorta, but did not differ between the proximal artery and the aorta. No significant differences in any analyte concentration were observed between the IA and the proximal artery. CONCLUSIONS: These findings suggest that the IA and the proximal vessel share similarities in the local immunological environment, which is different from that observed in the aorta. Further studies are needed to fully understand and elucidate these observations.

Mechanisms of Ischemic Stroke in Patients with Cancer: A Prospective Study.

OBJECTIVE: The objective of this study was to examine the pathophysiology of ischemic stroke with cancer. METHODS: We conducted a prospective cross-sectional study from 2016 to 2020 at 2 hospitals. We enrolled 3 groups of 50 adult participants each. The main group included patients with active solid tumor cancer and acute ischemic stroke. The control groups included patients with acute ischemic stroke only or active cancer only. The patients with stroke-only and patients with cancer-only were matched to the patients with cancer-plus-stroke by age, sex, and cancer type, if applicable. The outcomes were prespecified hematological biomarkers and transcranial Doppler microemboli detection. Hematological biomarkers included markers of coagulation (D-dimer and thrombin-antithrombin), platelet function (P-selectin), and endothelial integrity (thrombomodulin, soluble intercellular adhesion molecule-1 [sICAM-1], and soluble vascular cell adhesion molecule-1 [sVCAM-1]). Hematological biomarkers were compared between groups using the Kruskal-Wallis and Wilcoxon Rank-Sum tests. In multivariable linear regression models, we adjusted for race, number of stroke risk factors, smoking, stroke severity, and antithrombotic use. Transcranial Doppler microemboli presence was compared between groups using chi-square tests. RESULTS: Levels of all study biomarkers were different between groups. In univariate between-group comparisons, patients with cancer-plus-stroke had higher levels of D-dimer, sICAM-1, sVCAM-1, and thrombomodulin than both control groups; higher levels of thrombin-antithrombin than patients with cancer-only; and higher levels of P-selectin than patients with stroke-only. Findings were similar in multivariable analyses. Transcranial Doppler microemboli were detected in 32% of patients with cancer-plus-stroke, 16% of patients with stroke-only, and 6% of patients with cancer-only (p = 0.005). INTERPRETATION: Patients with cancer-related stroke have higher markers of coagulation, platelet, and endothelial dysfunction, and more circulating microemboli, than matched controls. ANN NEUROL 2021;90:159-169.

Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC.

BACKGROUND: High circulating levels of cellular adhesion molecules (CAMs) in non-small cell lung cancer (NSCLC) have been supposed to act as a negative prognostic factor. Here, we explored the predictive role of pre-treatment levels of CAMs in previously treated patients receiving nivolumab for NSCLC. MATERIALS AND METHODS: Seventy one patients with advanced NSCLC, treated with nivolumab at the dose of 3 mg/kg every 14 days, were enrolled. Maximum follow-up time was 3 years. Serum levels of Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intracellular Adhesion Molecule-1 (ICAM-1) were measured at baseline and before each nivolumab administration. Endpoints of the study were a composite outcome of survival ≥2 years or absence of disease progression at the end of the follow-up, and the overall survival. RESULTS: Composite outcome and overall survival were positively associated with VCAM-1 baseline levels and with the reduction of VCAM-1 during the treatment. After adjustment for potential confounders, the change in VCAM-1 serum levels during the treatment was an independent predictor of overall survival. CONCLUSIONS: High baseline serum levels of VCAM-1 are associated with a longer survival in patients treated with nivolumab as second line treatment for NSCLC. Surviving patients experience also a significant reduction in CAMs expression during the treatment. Hence, CAMs might be promising prognostic factors in patients with NSCLC underoing immunotherapy.

Plasma levels of VEGF-A and VCAM-1 as predictors of drug-induced hypertension in patients treated with VEGF pathway inhibitors.

AIMS: Hypertension is a common toxicity induced by vascular endothelial growth factor (VEGF) pathway inhibitors. There are no validated markers of hypertension induced by these drugs. METHODS: We previously discovered that cancer patients with lower plasma levels of angiopoietin-2, VCAM-1 and VEGF-A are at high risk of developing severe hypertension when treated with bevacizumab. This study aimed to validate the predictive value of these markers in pretreatment plasma samples of an additional cohort of 101 colorectal cancer patients treated with regorafenib. The levels of angiopoietin-2, VCAM-1 and VEGF-A were measured by enzyme-linked immunosorbent assay (ELISA). The association between proteins and grade ≥2 regorafenib-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for hypertension were estimated. RESULTS: Lower levels of VCAM-1 (P = .015, OR = 3.11, 95% CI 1.27-8.08) and VEGF-A (P = .007, OR = 3.47, 95% CI 1.40-8.75) were associated with a higher risk of hypertension. Levels of angiopoietin-2 were not associated with hypertension. The multivariable model indicates an independent effect of VCAM-1 (P = .018, OR = 3.18, 95% CI 1.25-8.68) and VEGF-A (P = .008, OR = 3.77, 95% CI 1.44-10.21). The presence of low levels of both VCAM-1 and VEGF-A had an OR of 9.46 (95% CI 3.08-33.26, P = 1.70 × 10-4 ) for the risk of hypertension (sensitivity of 41.4%, specificity of 93.1%, PPV of 70.6% and NPV of 79.8%). CONCLUSIONS: This study confirmed the value of VCAM-1 and VEGF-A levels in predicting hypertension induced by regorafenib, another VEGF pathway inhibitor.

Increased Levels of VCAM-1 in Sera and VLA-4 Expression on Neutrophils in Dermatomyositis with Interstitial Lung Disease.

Vascular cell adhesion molecule-1 (VCAM-1) and its ligand very late antigen (VLA-4) play important roles in many autoimmune diseases. Our study aimed to investigate the serum level of VCAM-1 and VLA-4 expression on peripheral blood neutrophil surface in patients with dermatomyositis (DM), especially focusing on patients with interstitial lung disease (ILD). Blood specimens of 42 patients with DM and 42 healthy controls matched for age and gender were recruited. Total serum VCAM-1 level was measured using commercial enzyme-linked immunosorbent assay (ELISA) and the percentages of VLA-4 expression on neutrophils were analyzed by flow cytometry. We divided patients into subgroups according to whether they had ILD and whether they exhibited diffuse alveolar damage (DAD) via high-resolution computed tomography (HRCT). sVCAM-1 was increased in classical DM (cDM) and clinical amyopathic dermatomyositis (CADM) compared with healthy controls (both p < .01). DM-ILD had higher sVCAM-1 levels than the none-ILD group (p < .01). sVCAM-1 was also significantly increased in the DAD group compared to the none-DAD group (p < .01). The percentages of VLA-4 expression on neutrophils in cDM and CADM patients were significantly elevated than that in healthy controls (both p < .01). The percentage of VLA-4 expression on neutrophils in DM patients with ILD was higher than none-ILD group (p < .01). In the patients with ILD, DAD group had a higher percentage of VLA-4 expression on neutrophils than none-DAD group (p < .01). Our findings indicated that serum VCAM-1 levels combined with VLA-4 expression on neutrophils might be useful for detecting the severity of lung disease in patients with DM.

Analysis of the Increase of Vascular Cell Adhesion Molecule-1 (VCAM-1) Expression and the Effect of Exposure in a Hyperbaric Chamber on VCAM-1 in Human Blood Serum: A Cross-Sectional Study.

Background and Objectives: Vascular cell adhesion molecule-1 (VCAM-1) was identified as a cell adhesion molecule that helps to regulate inflammation-associated vascular adhesion and the transendothelial migration of leukocytes, such as macrophages and T cells. VCAM-1 is expressed by the vascular system and can be induced by reactive oxygen species, interleukin 1 beta (IL-1ß) or tumor necrosis factor alpha (TNFα), which are produced by many cell types. The newest data suggest that VCAM-1 is associated with the progression of numerous immunological disorders, such as rheumatoid arthritis, asthma, transplant rejection and cancer. The aim of this study was to analyze the increase in VCAM-1 expression and the impact of exposure in a hyperbaric chamber to VCAM-1 levels in human blood serum. Materials and Methods: The study included 92 volunteers. Blood for the tests was taken in the morning, from the basilic vein of fasting individuals, in accordance with the applicable procedure for blood collection for morphological tests. In both groups of volunteers, blood was collected before and after exposure, in heparinized tubes to obtain plasma and hemolysate, and in clot tubes to obtain serum. The level of VCAM-1 was determined using the immunoenzymatic ELISA method. Results: The study showed that the difference between the distribution of VCAM-1 before and after exposure corresponding to diving at a depth of 30 m was at the limit of statistical significance in the divers group and that, in most people, VCAM-1 was higher after exposure. Diving to a greater depth had a much more pronounced impact on changes in VCAM-1 values, as the changes observed in the VCAM-1 level as a result of diving to a depth of 60 m were statistically highly significant (p = 0.0002). The study showed an increase in VCAM-1 in relation to the baseline value, which reached as much as 80%, i.e., VCAM-1 after diving was almost twice as high in some people. There were statistically significant differences between the results obtained after exposure to diving conditions at a depth of 60 m and the values measured for the non-divers group. The leukocyte level increased statistically after exposure to 60 m. In contrast, hemoglobin levels decreased in most divers after exposure to diving at a depth of 30 m (p = 0.0098). Conclusions: Exposure in the hyperbaric chamber had an effect on serum VCAM-1 in the divers group and non-divers group. There is a correlation between the tested morphological parameters and the VCAM-1 level before and after exposure in the divers group and the non-divers group. Exposure may result in activation of the endothelium.

Vasculo-toxic and pro-inflammatory action of unbound haemoglobin, haem and iron in transfusion-dependent patients with haemolytic anaemias.

Increasing evidence suggests that free haem and iron exert vasculo-toxic and pro-inflammatory effects by activating endothelial and immune cells. In the present retrospective study, we compared serum samples from transfusion-dependent patients with ß-thalassaemia major and intermedia, hereditary spherocytosis and sickle cell disease (SCD). Haemolysis, transfusions and ineffective erythropoiesis contribute to haem and iron overload in haemolytic patients. In all cohorts we observed increased systemic haem and iron levels associated with scavenger depletion and toxic 'free' species formation. Endothelial dysfunction, oxidative stress and inflammation markers were significantly increased compared to healthy donors. In multivariable logistic regression analysis, oxidative stress markers remained significantly associated with both haem- and iron-related parameters, while soluble vascular cell adhesion molecule 1 (sVCAM-1), soluble endothelial selectin (sE-selectin) and tumour necrosis factor α (TNFα) showed the strongest association with haem-related parameters and soluble intercellular adhesion molecule 1 (sICAM-1), sVCAM-1, interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF) with iron-related parameters. While hereditary spherocytosis was associated with the highest IL-6 and TNFα levels, ß-thalassaemia major showed limited inflammation compared to SCD. The sVCAM1 increase was significantly lower in patients with SCD receiving exchange compared to simple transfusions. The present results support the involvement of free haem/iron species in the pathogenesis of vascular dysfunction and sterile inflammation in haemolytic diseases, irrespective of the underlying haemolytic mechanism, and highlight the potential therapeutic benefit of iron/haem scavenging therapies in these conditions.

Serum cytokine levels associated with myocardial injury in systemic lupus erythematosus.

OBJECTIVES: To identify cytokines, markers of endothelial activation [soluble vascular cell adhesion molecule-1 (sVCAM-1)] and myocyte strain [soluble ST2 (sST2)] associated with myocardial injury (MInj) in SLE, classified by cardiac magnetic resonance (CMR) criteria. METHODS: CMR was performed on patients with SLE, identifying stages of MInj (inflammation and necrosis or fibrosis). Data captured included: clinical assessment, laboratory and serological analyses, cytokine (IL-1ß, IL-1Ra, IL-2, IL-6, IL-10, IL-17, IL-18, TNF-alpha), sVCAM-1 and sST2 levels. Cytokines were compared with regard to SLE features and evidence of CMR MInj. Predictors of CMR MInj were determined through regression analyses. RESULTS: Forty-one patients with high disease activity (SLEDAI-2K: 13; IQR: 3-17) were included. SLE features included: LN (n = 12), neurolupus (n = 6) and clinical lupus myocarditis (LM) (n = 6). Nineteen patients had CMR evidence of MInj. Patients with a SLEDAI-2K ≥ 12 had higher sVCAM-1 (P = 0.010) and sST2 (P = 0.032) levels. Neurolupus was associated with higher IL-1Ra (P = 0.038) and LN with lower IL-1Ra (P = 0.025) and sVCAM-1 (P = 0.036) levels. Higher IL-1Ra (P = 0.012), IL-17 (P = 0.045), IL-18 (P = 0.003), and sVCAM-1 (P = 0.062) levels were observed in patients with CMR MInj compared with those without. On multivariable logistic regression, IL-1Ra predicted CMR inflammation and fibrosis/necrosis (P < 0.005) while anti-Ro/SSA [odds ratio (OR): 1.197; P = 0.035] and the SLE damage index (OR: 4.064; P = 0.011) predicted fibrosis/necrosis. CONCLUSION: This is a novel description of associations between cytokines and SLE MInj. IL-18 and IL-1Ra were significantly higher in patients with MInj. IL-1Ra independently predicted different stages of CMR MInj. Exploration of the role of these cytokines in the pathogenesis of SLE MInj may promote targeted therapies for LM.

Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.

OBJECTIVES: Vasculopathy is an important hallmark of systemic chronic inflammatory connective tissue diseases (CICTD) and is associated with increased cardiovascular risk. We investigated disease-specific biomarker profiles associated with endothelial dysfunction, angiogenic homeostasis and (tissue) inflammation, and their relation to disease activity in rare CICTD. METHODS: A total of 38 serum proteins associated with endothelial (dys)function and inflammation were measured by multiplex-immunoassay in treatment-naive patients with localized scleroderma (LoS, 30), eosinophilic fasciitis (EF, 8) or (juvenile) dermatomyositis (34), 119 (follow-up) samples during treatment, and 65 controls. Data were analysed by unsupervised clustering, Spearman correlations, non-parametric t test and ANOVA. RESULTS: The systemic CICTD, EF and dermatomyositis, had distinct biomarker profiles, with 'signature' markers galectin-9 (dermatomyositis) and CCL4, CCL18, CXCL9, fetuin, fibronectin, galectin-1 and TSP-1 (EF). In LoS, CCL18, CXCL9 and CXCL10 were subtly increased. Furthermore, dermatomyositis and EF shared upregulation of markers related to interferon (CCL2, CXCL10), endothelial activation (VCAM-1), inhibition of angiogenesis (angiopoietin-2, sVEGFR-1) and inflammation/leucocyte chemo-attraction (CCL19, CXCL13, IL-18, YKL-40), as well as disturbance of the Angiopoietin-Tie receptor system and VEGF-VEGFR system. These profiles were related to disease activity, and largely normalized during treatment. However, a subgroup of CICTD patients showed continued elevation of CXCL10, CXCL13, galectin-9, IL-18, TNFR2, VCAM-1, and/or YKL-40 during clinically inactive disease, possibly indicating subclinical interferon-driven inflammation and/or endothelial dysfunction. CONCLUSION: CICTD-specific biomarker profiles revealed an anti-angiogenic, interferon-driven environment during active disease, with incomplete normalization under treatment. This warrants further investigation into monitoring of vascular biomarkers during clinical follow-up, or targeted interventions to minimize cardiovascular risk in the long term.

Clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with lupus nephritis.

OBJECTIVE: We investigated the clinico-pathological associations of serum VCAM-1 and ICAM-1 levels in patients with biopsy-proven Class III/IV±V lupus nephritis (LN). METHODS: Serum VCAM-1 and ICAM-1 levels were determined by ELISAs. Sera from patients with non-renal SLE or non-lupus chronic kidney disease (CKD), and healthy subjects served as controls. RESULTS: Seropositivity rate for VCAM-1 and ICAM-1 was 93.10% and 37.93% respectively at the time of nephritic flare, and 44.83% and 13.79% respectively at remission, with both showing higher levels during flare (P < 0.05, for both). VCAM-1 level correlated with proteinuria, serum creatinine, and anti-dsDNA antibodies, and inversely correlated with C3. VCAM-1 level also correlated with leukocyte infiltration and fibrinoid necrosis/karyorrhexis scores in active LN kidney biopsies. ICAM-1 level correlated with proteinuria, but not anti-dsDNA or C3, nor histopathological features. VCAM-1 level increased 4.5 months before renal flare, while ICAM-1 increase coincided with flare, and both decreased after treatment. ROC analysis showed that VCAM-1 distinguished active LN from healthy subjects, LN in remission, active non-renal lupus, and CKD (ROC AUC of 0.98, 0.86, 0.93 and 0.90 respectively). VCAM-1 level in combination with either proteinuria or C3 was superior in distinguishing active LN from remission compared to the measurement of individual markers. Serum ICAM-1 level distinguished active LN from healthy subjects and LN patients in remission (ROC AUC of 0.75 and 0.66 respectively), but did not distinguish between renal versus non-renal lupus. ICAM-1 level in combination with markers of endothelial cell activation (syndecan-1, hyaluronan and thrombomodulin) was superior to proteinuria, anti-dsDNA, or C3 in distinguishing active LN from quiescent disease. CONCLUSION: Our findings suggest potential utility of serum VCAM-1 and ICAM-1 in clinical management. Monitoring VCAM-1 may facilitate early diagnosis of flare. Combining selected biomarkers may be advantageous in diagnosing active LN. VCAM-1 may have a pathogenic role in renal parenchymal inflammation in active LN.

First trimester angiogenic and inflammatory factors in women with chronic hypertension and impact of blood pressure control: a case-control study.

OBJECTIVES: To assess first trimester serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFLT-1), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α), endothelin and vascular cell adhesion molecule (VCAM) in women with chronic hypertension (CH) stratified according to blood pressure (BP) control. DESIGN: Case-control. SETTING: Tertiary referral centre. POPULATION: 650 women with CH, 142 normotensive controls. METHODS: In the first trimester, patients with CH were subdivided into four groups. Group 1 included women without pre-pregnancy CH presenting with BP ≥140/90 mmHg. Groups 2-4 had pre-pregnancy CH; in group 2 the BP was <140/90 mmHg without antihypertensive medication, in group 3 the BP was <140/90 mmHg with antihypertensive medication, and in group 4 the BP was ≥140/90 mmHg despite antihypertensive medication. PLGF, sFLT-1, IL-6, TNF-α, endothelin and VCAM were measured at 11+0 -13+6 weeks' gestation and converted into multiples of the expected median (MoM) using multivariate regression analysis in the controls. MAIN OUTCOME MEASURE: Comparisons of MoM values of PLGF, sFLT-1, endothelin, IL-6, TNF-α and VCAM between the entire cohort of women with CH and the control group were made using Student's t-test or Mann-Whitney U-test. Comparisons between the four CH groups were made using analysis of variance or Kruskal-Wallis tests. RESULTS: Compared with the control group, women with CH had significantly lower MoM of PLGF, sFLT-1 and IL-6 and a significantly higher MoM of endothelin. Between the four groups of women with CH, there were no significant differences in the MoM of sFLT-1, PLGF, sFLT-1/PLGF ratio, endothelin, IL-6 or VCAM, or in the levels of TNF- α. CONCLUSION: In women with CH, differences exist in first trimester angiogenic and inflammatory profiles when compared with normotensive pregnancies. However, these differences do not assist in the stratification of women with CH to identify those with more severe underlying disease and worse pregnancy outcomes. TWEETABLE ABSTRACT: First trimester blood pressure control impacts on serum PLGF, sFLT-1, endothelin and IL-6 in women with chronic hypertension.

Metformin Is Associated with Reduced Tissue Factor Procoagulant Activity in Patients with Poorly Controlled Diabetes.

PURPOSE: Metformin is the first-line antidiabetic drug and shown to reduce cardiovascular risk independent from its glucose lowering action. Particularly in poorly controlled diabetes, tissue factor (TF) is expressed in the vasculature and accounts for thromboembolic complications. Here, we aimed to assess the effect of metformin on TF activity and markers of vascular inflammation in poorly controlled type 2 diabetes. METHODS: In a cohort of patients with uncontrolled type 2 diabetes (glycosylated hemoglobin 8.39 ± 0.24%, 68.1 ± 2.6 mmol/mol, n = 46) of whom half of the individuals were treated with metformin and the other half did not receive metformin as part of an anti-diabetic combination therapy, we assessed TF activity and markers of vascular inflammation. In vitro, human monocytic cells (THP-1) were exposed to metformin and TF expression measured in the presence and absence of the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide riboside (AICAR) or the AMPK inhibitor compound C. RESULTS: In the patients, metformin treatment was associated with lower levels of TF protein (241.5 ± 19 vs. 315.4 ± 25 pg/mL, p = 0.03) and reduced TF activity (408.9 ± 49 vs. 643.8 ± 47 U/mL, p = 0.001) compared with controls. Moreover, the patients on metformin showed lower levels of vascular cell adhesion molecule (VCAM)1 (26.6 ± 1.4 vs. 35.03 ± 3.1 ng/mL, p = 0.014) and higher expression of miR-126-3p/U6sno (11.39 ± 2.8 vs. 4.26 ± 0.9, p = 0.006), a known post-transcriptional down regulator of TF and VCAM1. In vitro, metformin dose-dependently reduced lipopolysaccharide (LPS)-induced TF expression in THP-1 cells. The AMPK activator AICAR alone lowered TF expression in THP-1, while the AMPK inhibitor compound C abrogated the metformin-dependent reduction in TF expression. CONCLUSIONS: Our data are the first to report that metformin is associated with reduced plasma TF procoagulant activity possibly explaining-at least in part-the vasculoprotective properties of metformin.

Adhesion pathway proteins and risk of atrial fibrillation in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The cellular adhesion pathway has been suggested as playing an important role in the pathogenesis of atrial fibrillation (AF). However, prior studies that have investigated the role of adhesion pathway proteins in risk of AF have been limited in the number of proteins that were studied and in the ethnic and racial diversity of the study population. Therefore we aimed to study the associations of fifteen adhesion pathway proteins with incident AF in a large, diverse population. METHODS: Multi-Ethnic Study of Atherosclerosis participants from four races/ethnicities (n = 2504) with protein levels measured were followed for incident AF (n = 253). HGF protein was measured on Exam 1 samples (N = 6669; AF n = 851). Cox proportional hazards regression was used to assess the association of AF with 15 adhesion pathway proteins. Bonferroni correction was applied to account for multiple comparisons. RESULTS: After adjusting for potential confounding variables (age, sex, race/ethnicity, height, body mass index, systolic blood pressure, antihypertension therapy, diabetes status, current smoker, current alcohol use, and total and HDL cholesterol), and accounting for multiple testing (P < 0.05/15 = 0.0033), circulating levels of the following proteins were positively associated with a higher risk of AF: MMP-2 (HR per standard deviation increment, 1.27; 95% CI 1.11‒1.45), TIMP-2 (HR 1.28; 95% CI 1.12‒1.46), VCAM-1 (HR 1.32; 95% CI 1.16‒1.50), and SLPI (HR 1.22; 95% CI 1.07‒1.38). The association between proteins and AF did not differ by race/ethnicity. CONCLUSIONS: Circulating levels of MMP-2, TIMP-2, VCAM-1, and SLPI were positively associated with an increased risk of incident AF in a diverse population. Our findings suggest that adhesion pathway proteins may be important risk predictors of AF.

The impact of OSA and CPAP treatment on cell adhesion molecules' night-morning variation.

PURPOSE: Obstructive sleep apnea (OSA) has been related to vascular inflammation and production of endothelial cell adhesion molecules (CAMs). We aimed to determine night-morning variation of CAMs in patients with OSA compared to controls and the effect of one-night continuous positive airway pressure (CPAP) treatment on them. METHODS: Nonsmoking men went through a full-attended polysomnography (PSG) study. Participants with moderate to severe OSA went through another PSG study while being treated with CPAP. Participants who did not have OSA composed the control group. Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin were measured before and after sleep on both nights. RESULTS: Of 30 men, 20 had moderate to severe OSA while 10 did not. Night and morning ICAM-1 levels of patients with OSA were significantly higher than controls (p = 0.002 and p < 0.0001 respectively), while both night and morning VCAM-1 and E-selectin levels were not. Morning ICAM-1 levels of controls were significantly lower than night levels (p = 0.031), while morning ICAM-1, VCAM-1, and E-selectin levels of patients with OSA and morning VCAM-1 and E-selectin levels of controls were not. After CPAP treatment, the morning ICAM-1 levels, but not VCAM-1 levels, of patients with OSA were significantly lower than night levels (p = 0.006) and E-selectin levels showed a tendency for reduction (p = 0.06). CONCLUSIONS: OSA is associated with elevated night and morning ICAM-1 levels in adult men with OSA. Even one night of CPAP treatment restores the normal night-morning variation of ICAM-1 levels and may have an effect on E-selectin levels, as well.

Elevated Expression of Serum Endothelial Cell Adhesion Molecules in COVID-19 Patients.

In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.