Soluble vascular cell adhesion molecule-1 levels and severity of dengue hemorrhagic fever in children

Background The clinical manifestations of dengue infection vary widely, ranging from asymptomatic to severe forms that can cause death. In severe infections, the expression of soluble vascular cell adhesion molecule-1 (sVCAM-1) in endothelial cells is reportedly excessive, causing endothelial cell gaps through VE-cadherin and plasma leakage, which is the basic mechanism for shock in dengue hemorrhagic fever (DHF). Objective To determine the association between sVCAM-1 levels and severity of dengue hemorrhagic fever in children. Methods This cross-sectional study was done in children with DHF at Dr. M. Djamil Hospital, Padang, West Sumatera. Subjects were diagnosed according to the 2011 WHO criteria and selected by consecutive sampling. They were grouped as DHF with or without shock. Examination of sVCAM-1 levels was done by ELISA method. Mann-Whitney test with a significance of P<0.05 was used for statistical analysis. Results A total of 66 patients were collected from January 2018 to December 2019, but 2 patients were excluded. The 64 subjects who met the inclusion criteria consisted of 32 (50%) DHF without shock and 32 (50%) DHF with shock. Median sVCAM-1 was significantly higher in the DHF with shock group (840 ng/mL) than in DHF without shock group (598 ng/mL) (P<0.05). Conclusion There was a significant association between higher sVCAM-1 levels and greater severity of dengue hemorrhagic fever in children.

Two Novel PET Radiopharmaceuticals for Endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1) Targeting

Atherosclerosis is a chronic progressive disease involving inflammatory events, such as the overexpression of adhesion molecules including the endothelial Vascular Cell Adhesion Molecule-1 (VCAM-1). VCAM-1 is rapidly overexpressed in the first stages of atherosclerosis, thus representing a promising target for early atheroma detection. Two novel Positron Emission Tomography (PET) radiopharmaceuticals (MacroP and NAMP), based on the VCAM-1-binding peptide having sequence VHPKQHRGGSKGC, were synthesized and characterized. MacroP is derived from the direct conjugation of a DOTA derivative with the peptide, while NAMP is a biotin derivative conceived to be employed in a three-step pretargeting system, involving the use of a double-chelating derivative of DOTA. The identity of the newly synthesized radiopharmaceuticals was confirmed by mass spectrometry and, after radiolabeling with 68Ga, both showed high radiochemical purity; in vitro tests on human umbilical vein endothelial cells evidenced their VCAM-1 binding ability, with higher radioactive uptake in the case of NAMP. Moreover, NAMP might also be employed in a theranostic approach in association with functionalized biotinylated nanoparticles.

Arterial Platelet Adhesion in Atherosclerosis‐Prone Arteries of Obese, Insulin‐Resistant Nonhuman Primates

Background Platelet–endothelial interactions are thought to contribute to early atherogenesis. These interactions are potentiated by oxidative stress. We used in vivo molecular imaging to test the hypothesis that platelet–endothelial interactions occur at early stages of plaque development in obese, insulin‐resistant nonhuman primates, and are suppressed by NADPH‐oxidase‐2 inhibition. Methods and Results Six adult rhesus macaques fed a Western‐style diet for a median of 4.0 years were studied at baseline and after 8 weeks of therapy with the NADPH‐oxidase‐2‐inhibitor apocynin (50 mg/kg per day). Six lean control animals were also studied. Measurements included intravenous glucose tolerance test, body composition by dual‐energy X‐ray absorptiometry, carotid intimal medial thickness, carotid artery contrast ultrasound molecular imaging for platelet GPIbα (glycoprotein‐ Ibα) and vascular cell adhesion molecule‐1, and blood oxidative markers on mass spectrometry. Compared with lean controls, animals on a Western‐style diet were obese (median body mass: 16.0 versus 8.7 kg, P =0.003; median truncal fat: 49% versus 20%, P =0.002), were insulin resistant (4‐fold higher insulin–glucose area under the curve on intravenous glucose tolerance test, P =0.002), had 40% larger carotid intimal medial thickness ( P =0.004), and exhibited oxidative signatures on proteomics. In obese but not lean animals, signal enhancement on molecular imaging was significantly elevated for GPIbα and vascular cell adhesion molecule‐1. The signal correlated modestly with intimal medial thickness but not with the degree of insulin resistance. Apocynin significantly ( P <0.01) reduced median signal for GPIbα by >80% and vascular cell adhesion molecule‐1 signal by 75%, but did not affect intimal medial thickness, body mass, or intravenous glucose tolerance test results. Conclusion In nonhuman primates, diet‐induced obesity and insulin resistance leads to platelet–endothelial adhesion at early atherosclerotic lesion sites, which is associated with the expression of pro‐inflammatory adhesion molecules. These responses appear to be mediated, in part, through oxidative pathways.

Abstract P778: Hypertension and Vascular Cell Adhesion Molecule 1 Relate To % Change in National Institutes of Health Stroke Scale Score in Ischemic Stroke After Mechanical Thrombectomy

Introduction: The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol utilizes thrombectomy to isolate intracranial (i.e. distal to thrombus) arterial blood and systemic (i.e. carotid) arterial blood from thrombectomy procedures to study stroke. Here, we investigate the relationship among Vascular Cell Adhesion Molecule 1 (VCAM1), hypertension (HTN), and stroke recovery in patients undergoing mechanical thrombectomy for emergent large vessel occlusion (ELVO) stroke. Methods: Intracranial and systemic plasma samples from 25 subjects underwent cardiometabolic proteomic analysis at Olink Proteomics. Demographic data including HTN status and both admission NIHSS and discharge NIHSS were included. Linear regression analysis was run on both intracranial and systemic VCAM1 expression levels against % change in NIHSS ((Admittance NIHSS - Discharge NIHSS)/Admittance NIHSS)) and two-tailed t-tests were run assessing VCAM1 expression with HTN vs. no HTN. Results: Increased expression of intracranial VCAM1 significantly correlated with a smaller % change in NIHSS (p=0.001). Similarly, increased systemic VCAM1 expression was also found to have a significant relationship with smaller % change in NIHSS (p=0.005). Subjects with hypertension had significantly higher intracranial (p=0.03) and systemic (p=0.001) VCAM1 levels compared to those without HTN. Discussion: VCAM1 mediates leukocyte-endothelial cell adhesion and has been shown to play a role in stroke. This study takes a novel approach of sampling both intracranial and systemic arterial blood during an ELVO stroke. We found increased intracranial and systemic VCAM1 independently correlate with a smaller % change in NIHSS, an indicator of poorer initial recovery. Although preliminary, these results suggest an informative role of VCAM1 levels at the time of infarct. Additionally, those with HTN had higher levels of intracranial and systemic VCAM1. These data are in line with previous studies suggesting VCAM1 is a marker of endothelial damage due to HTN leading to negative clinical outcomes. To better understand our findings, we plan to perform subset analyses investigating VCAM1 levels in relation to dyslipidemia, infarct time and infarct volume.