Soluble Intercellular Adhesion Molecule-1 Research Articles

Angiogenesis-related factors associated with nivolumab efficacy in patients with advanced gastric cancer after refractory or intolerant to ramucirumab-based therapy.

234 Background: Nivolumab (Nivo) is a standard therapy after ramucirumab (RAM)-based second-line chemotherapy in patients (pts) with advanced gastric cancer (AGC). However, the relationship between angiogenesis-related factors and the efficacies of immune-checkpoint inhibitors after anti-angiogenic chemotherapy is unclear. Methods: We retrospectively evaluated pts with AGCs who received Nivo after RAM-based second-line chemotherapy at a single institution from Nov 2017 to Aug 2019. Clinical benefit of Nivo was defined as CR, PR, or >4 months of SD and non-CR/non-PD. In addition, preserved serum samples at time points of pre-RAM, pre-Nivo, and post-Nivo (within 12 weeks from the start of Nivo) were analyzed by using the designated panel, containing vascular endothelial growth factor-A/D (VEGF-A/D), placental growth factor (PlGF), soluble vascular endothelial growth factor receptor-1/2/3 (sVEGFR-1/2/3), Interleukin-6/8 (IL-6/8), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), angiopoietin-2, hepatocyte growth factor (HGF), interferon gamma (INF-γ), osteopontin (OPN), soluble neuropilin-1, and thrombospondin-2 (TSP-2). We investigated the association between angiogenesis-related factors and clinical outcomes with Nivo. Results: We evaluated 167 samples from 58 pts, including 10 pts (17.2%) exhibiting clinical benefit. Characteristics of pts were as follows: median age, 68; male, 74%; PS, 0/1-2, 17/83%; HER2 positive, 16%; prior gastrectomy, 40%; histology, intestinal/diffuse, 16/84%; disease status, metastatic/recurrent, 69/31%; lung metasstasis, 14%; liver metasstasis, 26%; peritoneum metastasis, 67%; lymph node metastasis, 31%. The median progression-free survival (PFS) and overall survival (OS) of Nivo were 1.7 and 6.2 months, respectively, with a median follow-up of 5.0 months. There were no correlations between pre-Nivo levels of angiogenesis-related factors and clinical benefit; however, the median post-Nivo/pre-Nivo VEGF-A ratio was significantly lower in pts with clinical benefit than in those without clinical benefit (0.44 versus 0.94, p = 0.008). By multivariate analysis using characteristics of pts and data from pre-Nivo samples, VEGF-A above the median level of 1400 pg/mL and sVCAM-1 below the median level of 1640000 pg/mL were independent prognostic factors for poor PFS (hazard ratio, 1.90, p = 0.033) and OS (hazard ratio, 2.02, p = 0.037), respectively. Conclusions: Our study suggests that rapid decline of serum VEGF-A level after Nivo and higher VEGF-A before Nivo were respectively associated with the clinical benefit of Nivo and poor survival in pts with AGC treated with Nivo after RAM-based second-line chemotherapy.

ICU Admission Levels of Endothelial Biomarkers as Predictors of Mortality in Critically Ill COVID-19 Patients.

Endotheliopathy is suggested to be an important feature of COVID-19 in hospitalized patients. To determine whether endotheliopathy is involved in COVID-19-associated mortality, markers of endothelial damage were assessed in critically ill COVID-19 patients upon intensive care unit (ICU) admission. Thirty-eight critically ill COVID-19 patients were included in this observational study, 10 of whom died in the ICU. Endothelial biomarkers, including soluble (s)E-selectin, sP-selectin, angiopoietin 1 and 2 (Ang-1 and Ang-2, respectively), soluble intercellular adhesion molecule 1 (sICAM-1), vascular endothelial growth factor (VEGF), soluble vascular endothelial (VE)-cadherin, and von Willebrand factor (vWf), were measured upon ICU admission. The ICU cohort was subsequently divided into survivors and non-survivors; Kaplan–Meier analysis was used to explore associations between biomarkers and survival, while receiver operating characteristic (ROC) curves were generated to determine their potential prognostic value. sE-selectin, sP-selectin, Ang-2, and sICAM-1 were significantly elevated in ICU non-survivors compared to survivors, and also associated with a higher mortality probability in the Kaplan–Meier analysis. The prognostic values of sE-selectin, Ang-2, and sICAM-1 from the generated ROC curves were greater than 0.85. Hence, we conclude that in our cohort, ICU non-survivors had higher levels of specific endothelial markers compared to survivors. Elevated levels of these markers upon ICU admission could possibly predict mortality in COVID-19.

Inhibition of COX-2 Impairs Colon Cancer Liver Metastasis through Reduced Stromal Cell Reaction.

Liver colonization is initiated through the interplay between tumor cells and adhesion molecules present in liver sinusoidal endothelial cells (LSECs). This crosstalk stimulates tumor COX-2 upregulation and PGE2 secretion. To elucidate the role of the LSEC intercellular adhesion molecule-1 (ICAM-1) in the prometastatic response exerted by tumor and stromal COX-2, we utilized celecoxib (CLX) as a COX-2 inhibitory agent. We analyzed the in vitro proliferative and secretory responses of murine C26 colorectal cancer (CRC) cells to soluble ICAM-1 (sICAM-1), cultured alone or with LSECs, and their effect on LSEC and hepatic stellate cell (HSC) migration and in vivo liver metastasis. CLX reduced sICAM-1-stimulated COX-2 activation and PGE2 secretion in C26 cells cultured alone or cocultured with LSECs. Moreover, CLX abrogated sICAM-1-induced C26 cell proliferation and C26 secretion of promigratory factors for LSECs and HSCs. Interestingly, CLX reduced the protumoral response of HSC, reducing their migratory potential when stimulated with C26 secretomes and impairing their secretion of chemotactic factors for LSECs and C26 cells and proliferative factors for C26 cells. In vivo, CLX abrogated the prometastatic ability of sICAM-1-activated C26 cells while reducing liver metastasis. COX-2 inhibition blocked the creation of a favorable tumor microenvironment (TME) by hindering the intratumoral recruitment of activated HSCs and macrophages in addition to the accumulation of fibrillar collagen. These results point to COX-2 being a key modulator of processes initiated by host ICAM-1 during tumor cell/LSEC/HSC crosstalk, leading to the creation of a prometastatic TME in the liver.

Multi-omic signatures of atherogenic dyslipidaemia: pre-clinical target identification and validation in humans

BackgroundDyslipidaemia is a major risk factor for atherosclerosis and cardiovascular diseases. The molecular mechanisms that translate dyslipidaemia into atherogenesis and reliable markers of its progression are yet to be fully elucidated. To address this issue, we conducted a comprehensive metabolomic and proteomic analysis in an experimental model of dyslipidaemia and in patients with familial hypercholesterolemia (FH).MethodsLiquid chromatography/mass spectrometry (LC/MS) and immunoassays were used to find out blood alterations at metabolite and protein levels in dyslipidaemic ApoE−/−/LDLR−/− mice and in FH patients to evaluate their human relevance.ResultsWe identified 15 metabolites (inhibitors and substrates of nitric oxide synthase (NOS), low-molecular-weight antioxidants (glutamine, taurine), homocysteine, methionine, 1-methylnicotinamide, alanine and hydroxyproline) and 9 proteins (C-reactive protein, proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III, soluble intercellular adhesion molecule-1, angiotensinogen, paraoxonase-1, fetuin-B, vitamin K-dependent protein S and biglycan) that differentiated FH patients from healthy controls. Most of these changes were consistently found in dyslipidaemic mice and were further amplified if mice were fed an atherogenic (Western or low-carbohydrate, high-protein) diet.ConclusionsThe alterations highlighted the involvement of an immune-inflammatory response system, oxidative stress, hyper-coagulation and impairment in the vascular function/regenerative capacity in response to dyslipidaemia that may also be directly engaged in development of atherosclerosis. Our study further identified potential biomarkers for an increased risk of atherosclerosis that may aid in clinical diagnosis or in the personalized treatment.

The prognosis evaluation of sICAM-1, KL-6 combined with EVLWI in severe pneumonia patients with acute respiratory distress syndrome

Objective To evaluate the prognostic value of extravascular lung water index (EVLWI), soluble intercellular adhesion molecule-1(sICAM-1) and Krebs yon den lungen-6 (KL-6) in severe pneumonia patients with Severe Acute Respiratory Syndrome (ARDS). Methods A prospective study was conducted in Respiratory Intensive Care Unit of the Affiliated Zhengzhou Central Hospital of Zhengzhou University from October 2017 to February 2020. The study included 65 severe pneumonia patients with ARDS, who was performed by measurement of pulse index continuous cardiac output and survived more than 3days after admission. The Extravascular Lung Water Index（EVLWI）, sICAM-1, KL-6 and Oxygenation Index(OI) on 1st, 3rd and 5th day were detected. APACHE Ⅱ score, patient survival events (days) and survival outcome were recorded. Correlation analysis between EVLWI, sICAM-1, KL-6 and OI was performed on the 1st，3rd and 5th day after admission. Independent risk factors of mortality in severe pneumonia patients with ARDS were analyzed by multiple logistic regression. Receiver operating characteristic curve was drawn，and the prognostic value of each parameter was assessed finally. Results The PCT, EVLWI, sICAM-1, KL-6 and APACHE Ⅱ score in the death group were significantly higher than those in the survival group (P 0.05）. These parameters including levels of EVLWI, sICAM-1, KL-6, Procalcitonin and APACHE Ⅱ score in the death group were significantly higher than those in the survival group on the 1st，3rd and 5th day (P<0.05), whereas the OI was significantly lower than that of the survival group on the 3rd and 5th day (P<0.05). Logistic regression analysis showed that EVLWI, sICAM-1, KL-6 level were significantly related with the mortality of these patients. The levels of sICAM-1, kl-6 and EVLWI on 1st，3rd and 5th day after RICU admission showed a significant negative correlation with OI (P<0.001). Whereas, The levels of sICAM-1, kL-6 on 1st，3rd and 5th day showed a significant positive correlation with EVLWI (P<0.001). The sensitivity and specificity of sICAM-1, KL-6 combined with EVLWI in prognosis evaluation on 1st，3rd and 5th day were 75.0%，84.4%, 85.0%，66.7%，80.0%，86.7%, respectively. The AUC was 0.864，0.881，0.892 on 1st，3rd and 5th day, respectively (P<0.001), which had a better prognostic value than each of them. Conclusions EVLWI, sICAM-1 and KL-6 were independent risk factors for the prognosis of severe pneumonia patients with ARDS. The combination of EVLWI, sICAM-1 and KL-6 might be important in early predicting the prognosis of the 28d mortality. © 2021 Chinese Medical Association. All rights reserved.

KOAH Hastalarında Endotel Disfonksiyonu ve Sistemik İnflamasyon Belirteçleri Olarak Serum Endokan ve sICAM-1 Düzeylerinin Değerlendirilmesi ve Bunların Komorbiditelerle Olan İlişkisi

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) has systemic effects and is accompanied by numerous comorbidities. Systemic inflammation and endothelial dysfunction increase incidence of comorbidities in COPD. Endocan and Intercellular Adhesion Molecule-1 (ICAM-1) can be used as indicators for determining endothelial dysfunction and systemic inflammation. We aimed to investigate endothelial dysfunction and systemic inflammation using endocan and sICAM-1 levels and determine associations of these indicators with comorbidities in COPD patients. METHODS: COPD patients who presented to Outpatient Chest Diseases Clinic between May 2018 and May 2019 and a control group were included in the study. Demographic data, comorbidities, forced vital capacity (FVC)%, forced expiratory volume 1-second (FEV1)%, and FEV1/FVC, Modified Medical Research Council (mMRC) dyspnea scores, and COPD-assessment-questionnaire (CAT) scores of COPD patients were recorded. COPD patients were divided into two groups as those with/without comorbidities. Besides, they were classified into four groups (A-D) according to the GOLD classification. Serum endocan and soluble ICAM-1 (sICAM-1) levels were measured by the ELISA method. RESULTS: Endocan and sICAM-1 levels of the COPD group were higher (p&lt;0.001 and p=0.031, respectively). COPD and Control Groups had similar incidences of comorbidities except for coronary artery disease. Serum endocan and sICAM-1 levels of COPD patients with/without comorbidities and COPD subgroups were similar. Endocan had negative correlations with FVC% and FEV1% and was positively correlated with CAT, mMRC, and smoking, whereas sICAM-1 was positively correlated with the amount of smoking. DISCUSSION AND CONCLUSION: Endothelial dysfunction and systemic inflammation are present independent of comorbidities and disease severity in COPD patients. Endocan and sICAM-1 can be used to indicate this situation. Endocan can be used, but sICAM-1 is insufficient to predict airway obstruction severity.

Endothelial Function in Patients With Von Willebrand Disease

In patients with von Willebrand disease (vWD) the interest in age-related comorbidities has grown, because the life expectancy of these patients has increased. The research question of this study was whether patients with vWD show a different endothelial function compared to the general population. A total of 37 patients with type 1 (n = 23), type 2 (n = 10) and type 3 (n = 4) vWD, 14 controls and 38 patients with coronary artery disease (CAD) were included in this study. Five markers of endothelial dysfunction (MOED) were determined. Moreover, the endothelial function was examined using the Itamar Endo-PAT. The reactive hyperemia index (RHI) was calculated from the results. The markers soluble intercellular adhesion molecule-1 (p = 0.171), P-Selectin (p = 0.512), interleukin-6 (p = 0.734) and monocyte chemoattractant protein-1 (p = 0.761) showed higher levels in patients with vWD, but were not significantly different compared to the control group. RHI was impaired in CAD-patients (1.855), whereas vWD patients had mean results of 1.870 and controls 2.112 (p = 0.367). In this study, the endothelial function measurements of patients with von Willebrand disease were not significantly different compared to healthy controls.

Mechanisms of Arrhythmogenesis and Risk Factors for Thromboembolic Events in Patients with Atrial Fibrillation without Concomitant Coronary and Valvular Heart Disease

Aimsidentification the correlates between parameters of tissue Doppler imaging, EF thickness by MRI and biochemical markers of fibrosis and inflammation in patients with nonvalvular AF. Retrospectively to evaluate clinical and instrumental parameters influencing the development of thromboembolic events.Methods.Data analysis was performed on 151 patients with different type of AF. A retrospective analysis included 112patients. 15 (13%) had a history of LAA thrombosis and/or thromboembolic events (stroke, TIA). The prospective analysis included 39patients. We identified groups with idiopathic AF (N = 21), AF with arterial hypertension (N = 18). And also a group with normal or slightly enlarged (4.5 sm) LA s (N = 29), and with LA 4.5 sm (N = 10). Echocardiography with tissue Doppler imaginе and cardiac MRI were performed. The level of: matrix metalloproteinases (MMP-2, MMP-9), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), transforming growth factor beta-1 (TGF beta-1), soluble intercellular adhesion molecule (sICAM) was assessed.Results.The following parameters were significantly associated with LA thrombosis and thromboembolic events: age over 50 years (p = 0.001), obesity (p = 0.036), persistent AF (p = 0.003), the phenomenon of spontaneous ECHO contrast in LA (p = 0.03), the blood flow velocity in the LAA less than 30 sm / s (p = 0.005), morphological type III of LAA (p = 0.012). The greatest correlation between the thickness of the EFT and biomarkers was observed relative to: MMP-9 ( =0.65; Tcr= 0.16), TIMP-1 ( = 0.71; Tcr= 0.18) in the group of idiopathic AF; and TGF-beta1 ( = 0.22; Tcr= 0.19) in the general group. The percentage of left atrial myocardial fibrosis was correlated with TIMP-1 levels. There was a correlation between E/e and MMP-9, TIMP-1 in patients with idiopathic AF ( = 0.65; Tcr= 0.16 and = 0.56; Tcr= 0.21 respectively).Conclusion.The increasing levels of MMP-9 and TIMP-1 are associated with epicardial fat thickness by MRI. In addition to CHA2DS2VASc scale, we identified novel predictors of LA thrombosis and/or thromboembolic events, which are: chronic type AF, low LAA blood flow velocity, the phenomenon of spontaneous ECHO contrast in LA and the morphological LAA type III by CT.

Retinal Microcirculation and Cytokines as Predictors for Recurrence of Macular Edema after Intravitreal Ranibizumab Injection in Branch Retinal Vein Occlusion.

Purpose: To investigate the relationship between retinal blood flow, presence or absence of recurrence of macular edema, and levels of cytokines, after intravitreal ranibizumab injection (IRI) in patients with branch retinal vein occlusion (BRVO). Methods: In 47 patients with BRVO and macular edema, we used laser speckle flowgraphy (LSFG) to measure the relative flow volume (RFV) of the retinal arteries and veins passing through the optic disc in the occluded and non-occluded regions of the retina before and after IRI. Aqueous humor samples were obtained at the time of IRI. Levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)-1, sVEGFR-2, placental growth factor (PlGF), platelet-derived growth factor (PDGF)-AA, soluble intercellular adhesion molecule (sICAM)-1, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL)-6, IL-8, IL-12 (p70), IL-13 and interferon-inducible 10-kDa protein (IP-10) were measured by the suspension array method. Patients were categorized into two groups on the basis of whether or not macular edema recurred at 2 months after IRI: the nonrecurrent group, n = 24; and the recurrent group, n = 23. Results: In the veins of the occluded region, RFV showed a significant difference between baseline and 1 month after IRI (p < 0.001) in the recurrent group and the percent change of RFV showed a significant difference between the recurrent and nonrecurrent groups (p = 0.005). Furthermore, we found a significant negative correlation between RFV in the veins of the occluded region and aqueous levels of MCP-1, IL-8 and IP-10 at baseline (p = 0.029, p = 0.035, and p = 0.039, respectively). In the recurrent group, the arteries and veins of the non-occluded and occluded regions showed no significant association between RFV and the aqueous levels of any factors. Conclusions: These findings suggested that a decrease in RFV in the veins of the occluded region might be associated with the recurrence of macular edema and that the recurrence might depend on the change in RFV in the veins of the occluded region rather than the levels of cytokines.

Quercetin protects against diabetic retinopathy in rats by inducing heme oxygenase-1 expression.

Quercetin is a widely-occurring flavonoid that protects against cancer, and improves memory and cardiovascular functions. However, whether quercetin exhibits therapeutic effects in diabetic retinopathy remains unclear. In this study, we established a rat model of streptozocin-induced diabetic retinopathy. Seventy-two hours later, the rats were intraperitoneally administered 150 mg/kg quercetin for 16 successive weeks. Quercetin markedly increased the thickness of the retinal cell layer, increased the number of ganglion cells, and decreased the overexpression of the pro-inflammatory factors interleukin-1β, interleukin-18, interleukin-6 and tumor necrosis factor-α in the retinal tissue as well as the overexpression of high mobility group box-1 and the overactivation of the NLRP3 inflammasome. Furthermore, quercetin inhibited the overexpression of TLR4 and NF-κBp65, reduced the expression of the pro-angiogenic vascular endothelial growth factor and soluble intercellular adhesion molecule-1, and upregulated the neurotrophins brain-derived neurotrophic factor and nerve growth factor. Intraperitoneal injection of the heme oxygenase-1 inhibitor zinc protoporphyrin blocked the protective effect of quercetin. These findings suggest that quercetin exerts therapeutic effects in diabetic retinopathy possibly by inducing heme oxygenase-1 expression. This study was approved by the Animal Ethics Committee of China Medical University, China (approval No. 2016PS229K) on April 8, 2016.

Detection of Citrullinated Fibrin in Plasma Clots of Rheumatoid Arthritis Patients and Its Relation to Altered Structural Clot Properties, Disease-Related Inflammation and Prothrombotic Tendency

AimsThe risk of cardiovascular events in patients with Rheumatoid Arthritis (RA) is disproportionately heightened as a result of systemic inflammation. The relative effect of autoimmune-associated citrullination on the structure and thrombotic potential of fibrin(ogen) remains unknown. We therefore compared indices of vascular function, inflammation, coagulation and fibrin clot composition in RA patients with healthy controls and evaluated parameter association with disease presence.MethodsBlood samples were collected from 30 RA patients and 30 age- and gender-matched healthy volunteers. Levels of serum amyloid A (SAA), c-reactive protein (CRP), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1) was measured using a sandwich immunoassay. Whole blood coagulation was assessed using Thromboelastography (TEG®). Fibrin clot networks and fiber structure was investigated using Scanning Electron Microscopy. The detection and quantification of citrullination in formed fibrin clots was performed using a fluorescently labeled Citrulline monoclonal antibody with Fluorescence Wide Field Microscopy.ResultsConcentrations of SAA, CRP and ICAM-1 were significantly elevated in RA patients compared to controls. TEG parameters relating to coagulation initiation, rate of fibrin cross-linking, and time to reach maximum thrombus generation were attenuated in RA patients. Microscopic analysis revealed denser networks of thicker fibrin fibers in RA patients compared to controls and multiple citrullinated regions within fibrin clot structures in RA patients were present.ConclusionOur findings provide novel evidence for the citrullination of fibrin within vasculature is more prominent in RA plasma compared to control plasma and plasma is more accessible than synovial fluid. Citrullinated fibrinogen could play a role as a determinant of thrombotic risk in RA patients.

Serum Inflammation Markers in Tuberculosis

Abstract Tuberculosis remains one of the leading infectious cause of death in the world. The goals of screening are to detect active tuberculosis early enough and to identify individuals eligible for preventive therapy to reduce a po tential co-infection by tuberculosis. Plasma/serum screening for selected potential biomarkers could represent a suitable method of tuberculosis diagnosis and treatment outcome. Furthermore, monitoring of tuberculosis treatment is crucial to clinical decision-making and besides the plasmatic concentration of administered antituberculosis drugs, the biomarkers appear to play a significant role in the estimation of the real therapeutical impact. The current standard remains focused on culture conversion, especially two-month culture status, which has a relatively low sensitivity. Identification of non-sputum-based biomarkers of the treatment respond would be beneficial for individual monitoring of tuberculosis patients. This mini-review describes several serological/plasmatic markers that can be analyzed by simple immunoassays as ELISA method, e.g. C-reactive protein, soluble intercellular adhesion molecule-1, soluble urokinase plasminogen activator receptor, soluble lymphocyte activation gene-3, granzyme B and soluble tumor necrosis factor receptor one and two as reliable enough as an indicator of successful treatment of tuberculosis.

Carotid imaging changes and serum IL-1\u03b2, sICAM-1, and sVAP-1 levels in benign paroxysmal positional vertigo

Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo. This study was performed to evaluate serum levels of inflammatory factors and changes in B-mode carotid ultrasound findings in patients with BPPV. The study population consisted of 90 BPPV patients and 90 age- and sex-matched controls. ELISA was used to compare the levels of inflammatory factors, such as interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), soluble intercellular adhesion molecule-1 (sICAM-1), prostaglandin-E2 (PG-E2), and soluble vascular adhesion protein-1 (sVAP-1), between BPPV patients and controls. In addition, the results of ultrasonographic imaging to determine carotid intima-media thickness (C-IMT), carotid atheromatous plaque, and vertebral artery stenosis were also compared between the BPPV and control groups. Serum levels of IL-1β, sICAM-1, and sVAP-1 were significantly higher in BPPV patients than controls (P < 0.001, P < 0.05, and P < 0.001, respectively). C-IMT and vertebral artery stenosis were significantly different in BPPV patients compared to controls (both P < 0.05). There were no significant relations between other parameters and BPPV. IL-1β, sICAM-1, and sVAP-1 are potentially associated with the pathogenesis of BPPV, and C-ITM and carotid vertebral stenosis may be useful reference imaging findings for the diagnosis of BPPV.

Abstract 17095: Association of Cigarette and Electronic Cigarette Use Behaviors With Levels of Inflammatory and Oxidative Stress Biomarkers Among United States Adults, Path 2013-2014

Introduction: Electronic cigarette (e-cigarette) use has increased rapidly in recent years; however, the cardiovascular risks of e-cigarettes remain unclear. Using data from the Population Assessment of Tobacco and Health Survey, this study assesses the cross-sectional association of cigarette and e-cigarette use behaviors with markers of inflammation (high-sensitivity C-reactive protein [hsCRP], soluble intercellular adhesion molecule [sICAM], interleukin-6 [IL-6], fibrinogen), oxidative stress (8-isoprostane [F2PG2a]), and nicotine exposure (cotinine). Methods: We analyzed data from adults (18+ years) who provided urine and blood specimens at wave 1 (2013-2014). Biomarkers were examined as continuous and categorical variables using the clinical cut points of ≥3 mg/L for hsCRP &gt;10 ng/mL for cotinine, and the upper quartiles of fibrinogen (≥381mg/dL), IL-6 (≥2.32 pg/mL), sICAM (≥288.77 ng/mL), and 8-isoprostane (≥788 pg/mL). Progressively adjusted negative binomial and generalized structural equation models were used, as well as sensitivity checks to assess the robustness of associations. Results: Of the 7,019 participants (58.6% non-users, 1.8% current vapers, 29.7% current smokers, 9.9% dual users), 67.2% had ≥1 high inflammatory or oxidative stress marker. Current vapers had increased risk of high hsCRP (IRR 1.28; 95% CI,1.02-1.59) and sICAM (IRR 2.01; 95% CI,1.42-2.85) compared to non-users. Relative to current smokers, current vapers who were former smokers had lower risk of having ≥1 high inflammatory or oxidative stress marker (IRR 0.80; 95% CI,0.69-0.94). Dual users had higher levels of all 5 inflammatory and oxidative stress markers compared to never smokers in both continuous and categorical models, with similar levels compared to current smokers. Current smokers and dual users had higher levels of cotinine compared to exclusive vapers. Conclusions: This study suggests that current vapers may have lower levels of inflammatory and oxidative stress markers compared to current smokers, but only after complete cessation of combustible cigarettes. Our findings strengthen the need for longitudinal studies investigating the association of vaping with markers of cardiovascular risk, particularly among dual users.

Abstract 13479: Association of Plasma Branched Chain Amino Acid With Biomarkers of Inflammation and Lipid Metabolism in Women

Introduction: We previously observed that circulating branched-chain amino acids (BCAAs) were associated with a higher risk of cardiovascular disease (CVD). However, the relationships of BCAAs with other cardiometabolic pathways other than type 2 diabetes (T2D) are unclear, including inflammation, dyslipidemia, and impaired glucose metabolism. Hypothesis: We hypothesized plasma BCAAs are correlated with cardiometabolic dysfunction in women, independent of shared risk factors. Methods: We conducted a cross-sectional analysis of 19,472 participants (mean age=54.9 years, SD=7.2) in the Women’s Health Study without a history of T2D, CVD, or cancer at baseline blood collection. We used multivariable linear regression models comparing quartiles of BCAAs (sum of fasting isoleucine, leucine and valine concentrations via NMR spectroscopy) with biomarkers of inflammation, lipids, and glucose metabolism, adjusting for age, body mass index, smoking, diet, and other CVD risk factors. Results: Women in the highest vs. lowest quartiles of plasma BCAAs had higher inflammatory markers including high-sensitivity C-reactive protein (hsCRP; adjusted mean: 2.7 vs. 2.0 mg/L), fibrinogen (390 vs. 384 mg/dL), GlycA (420 vs. 384 μmol/L), and soluble intercellular cell adhesion molecule-1 (sICAM-1; 350 vs. 341 ng/mL) (p&lt;0.001 for linear trends across quartiles). Similarly for lipids, women with higher BCAAs had lower HDL-c (48.8 vs. 54.7 mg/dL), and higher LDL-c (142 vs. 135 mg/dL) and triglycerides (142 vs. 114 mg/dL) (p&lt;0.001). BCAAs were positively associated with insulin resistance (lipoprotein insulin resistance [LPIR] score [54.8 vs. 40.0]) and HbA1c (5.2 vs. 5.1%). BCAAs remained associated with GlycA and hsCRP, but not fibrinogen or sICAM-1, when we further adjusted for LPIR and HbA1c, and remained associated with lipids after additional adjustment for HbA1c. Conclusions: Circulating BCAAs are concurrently associated with biomarkers of inflammation, dyslipidemia and impaired glucose metabolism indicative of an overall poorer cardiometabolic health profile. BCAAs remained positively associated with some of these pathways when adjusted for impaired glucose metabolism, suggesting elevated BCAAs may be an independent CVD risk factor in women.

Low levels of fine particulate matter increase vascular damage and reduce pulmonary function in young healthy adults

BackgroundFine particulate matter (PM2.5) related mild inflammation, altered autonomic control of cardiovascular function, and changes to cell function have been observed in controlled human exposure studies.MethodsTo measure the systemic and cardiopulmonary impacts of low-level PM exposure, we exposed 20 healthy, young volunteers to PM2.5, in the form of concentrated ambient particles (mean: 37.8 μg/m3, SD 6.5), and filtered air (mean: 2.1 μg/m3, SD 2.6). In this double-blind, crossover study the exposure order was randomized. During the 4 h exposure, volunteers (7 females and 13 males) underwent light intensity exercise to regulate ventilation rate. We measured pulmonary, cardiac, and hematologic end points before exposure, 1 h after exposure, and again 20 h after exposure.ResultsLow-level PM2.5 resulted in both pulmonary and extra-pulmonary changes characterized by alterations in systematic inflammation markers, cardiac repolarization, and decreased pulmonary function. A mean increase in PM2.5 concentration (37.8 μg/m3) significantly increased serum amyloid A (SAA), C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1), 1 h after exposure by 8.7, 9.1, 10.7, and 6.6%, respectively, relative to the filtered air control. SAA remained significantly elevated (34.6%) 20 h after PM2.5 exposure which was accompanied by a 5.7% decrease in percent neutrophils. Decreased pulmonary function was observed 1 h after exposure through a 0.8 and 1.2% decrease in forced expiratory volume in 1 s (FEV1) and FEV1/ forced vital capacity (FEV1/FVC) respectively. Additionally, sex specific changes were observed in repolarization outcomes following PM2.5 exposure. In males, P-wave and QRS complex were increased by 15.4 and 5.4% 1 h after exposure.ConclusionsThis study is the first controlled human exposure study to demonstrate biological effects in response to exposure to concentrated ambient air PM2.5 particles at levels near the PM2.5 US NAAQS standard.Clinical trial registration informationclinicaltrials.gov; Identifier: NCT03232086. The study was registered retrospectively on July 25, 2017, prior to final data collection on October 25, 2017 and data analysis.

Recurrent versus new-onset depressive symptoms: Relationships with biomarkers of cardiovascular health following acute coronary syndrome

ObjectiveNew-onset depressive symptoms commonly arise among persons without a history of major depressive disorder (MDD) in the setting of acute medical illness. Although depressive symptoms in general are associated with alterations in prognostic biomarkers following acute coronary syndrome (ACS), the nature of specifically new-onset depressive symptoms is less well-characterized. It is unclear whether such symptoms neurobiologically resemble recurrent symptoms of MDD or instead represent a distinct condition. In this exploratory analysis, we aimed to examine the effects of prior MDD history on the relationships between post-ACS depressive symptoms and cardiovascular biomarkers. MethodsOne-hundred sixty-four participants attended study visits 2 weeks and 6 months after ACS to complete self-report measures and provide biomarker samples. MDD history was identified by a psychiatrist through systematic electronic medical record review. Generalized estimating equations were performed to examine the moderating effects of MDD history on concurrent relationships between depressive symptoms and several biomarkers (endothelin-1, soluble intercellular adhesion molecule-1, high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). ResultsTwenty percent (n = 33) of participants had a history of MDD. Depressive symptoms were more strongly associated with levels of endothelin-1 in patients with prior MDD compared to those without (B = 0.024, 95% CI [0.005, 0.043], p = .012), adjusting for age, sex, medical factors, and anxiety. MDD history did not moderate relationships between depressive symptoms and other biomarkers. ConclusionRecurrent post-ACS depressive symptoms are more strongly associated with elevated endothelin-1 levels than new-onset symptoms. Further work is needed to clarify the mechanism and clinical implications of this relationship.

Proinflammatory mediators and their associations with medication and comorbid traits in children and adults with ADHD

Peripheral immune activation can influence neurodevelopment and is increased in autism, but is less explored in attention deficit hyperactivity disorder (ADHD). Patients with ADHD often display comorbid autism traits and gastrointestinal (GI) symptoms. Plasma protein levels of two acute phase reactants, C-reactive protein (CRP) and serum amyloid A (SAA), and two endothelial adhesion molecules, soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1), which share important roles in inflammation, were analyzed in 154 patients with ADHD and 61 healthy controls. Their associations with ADHD diagnosis, severity, medication and comorbid autistic symptoms, emotion dysregulation and GI symptoms were explored. The ADHD patients had increased levels of sICAM-1 and sVCAM-1 compared to healthy controls (p = 8.6e–05, p = 6.9e–07, respectively). In children with ADHD, the sICAM-1 and sVCAM-1 levels were higher among those with ADHD medication than among children (p = 0.0037, p = 0.0053, respectively) and adults (p = 3.5e–09, p = 1.9e–09, respectively) without ADHD medication. Among the adult ADHD patients, higher sICAM-1 levels were associated with increased comorbid autistic symptoms in the domains attention to detail and imagination (p = 0.0081, p = 0.00028, respectively), and higher CRP levels were associated with more GI symptoms (p = 0.014). sICAM-1 and sVCAM-1 levels were highly correlated with each other, and so were CRP and SAA levels. To conclude, vascular inflammatory activity may be overrepresented in ADHD, with elevated sICAM-1 and sVCAM-1 levels and this may in children be a consequence of current ADHD medication, and in adults relate to increased comorbid autistic symptoms. Replication is warranted.

Endotheliopathy and Platelet Dysfunction as Hallmarks of Fatal Lassa Fever.

Lassa fever (LF) causes multisystem disease and has a fatality rate <70%. Severe cases exhibit abnormal coagulation, endothelial barrier disruption, and dysfunctional platelet aggregation but the underlying mechanisms remain poorly understood. In Sierra Leone during 2015–2018, we assessed LF patients’ day-of-admission plasma samples for levels of proteins necessary for coagulation, fibrinolysis, and platelet function. P-selectin, soluble endothelial protein C receptor, soluble thrombomodulin, plasminogen activator inhibitor 1, ADAMTS-13, von Willebrand factor, tissue factor, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 were more elevated in LF patients than in controls. Endothelial protein C receptor, thrombomodulin, intercellular adhesion molecule 1, plasminogen activator inhibitor 1, D-dimer, and hepatocyte growth factor were higher in fatal than nonfatal LF cases. Platelet disaggregation occurred only in samples from fatal LF cases. The impaired homeostasis and platelet dysfunction implicate alterations in the protein C pathway, which might contribute to the loss of endothelial barrier function in fatal infections.

Retinal vessel analysis as a novel screening tool to identify childhood acute lymphoblastic leukemia survivors at risk of cardiovascular disease

BACKGROUND Microvascular endothelial dysfunction is central to the pathogenesis of cardiovascular disease (CVD). The eye offers direct access for endothelial health assessment via the retinal microvasculature. The aim of the study was to investigate whether image-based retinal vessel analysis is a feasible method of assessing endothelial health in survivors of childhood acute lymphoblastic leukemia (cALL). MATERIALS AND METHODS Cardiovascular risk factors (CRFs) were estimated using the 30-year Framingham Risk Score in 73 childhood leukemia survivors (median age: 25; median years from diagnosis: 19) and 78 healthy controls (median age: 23). Radial arterial stiffness was measured using pulse wave analyzer, while endothelial activation markers were measured by soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Retinal fundus images were analyzed for central retinal artery/vein equivalents (CRAE/CRVE) and arteriolar-venular ratio (AVR). RESULTS cALL survivors had higher CRF (P<0.0001), arterial stiffness (P=0.001), and sVCAM-1 (P=0.007) compared with controls. Survivors also had significantly higher CRVE (P=0.021) while AVR was significantly lower (P=0.026) in survivors compared with controls, compatible with endothelial dysfunction. In cALL survivors with intermediate risk for CVD, CRAE, and AVR are significantly lower, while sVCAM-1 and sICAM-1 are significantly higher when compared with survivors with low CVD risk after adjusting with covariates (age, sex, and smoking status). CONCLUSIONS cALL survivors have an increased risk of CVD compared with age-matched peers. The survivors demonstrated microvasculopathy, as measured by retinal vascular analysis, in addition to physical and biochemical evidence of endothelial dysfunction. These changes predate other measures of CVD. Retinal vessel analysis may be utilized as a robust screening tool for identifying survivors at increased risk for developing CVD.