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High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03–1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01–1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes (T2D) patients are at a greater risk of cardiovascular events due to aggravated atherosclerosis. Oxidized LDL (oxLDL) has been shown to be increased in T2D plaques and suggested to contribute to plaque ruptures. Despite intensified statin treatment during the last decade the higher risk for events remains. Here, we explored if intensified statin treatment was associated with reduced oxLDL in T2D plaques and if oxLDL predicts cardiovascular events, to elucidate whether further plaque oxLDL reduction would be a promising therapeutic target. Methods: Carotid plaque OxLDL levels and plasma lipoproteins were assessed in 200 patients. Plaque oxLDL was located by immunohistochemistry. Plaque cytokines, cells and scavenger receptor gene expression were quantified by Luminex, immunohistochemistry and RNA sequencing, respectively. Clinical information and events during follow-up were obtained from national registers. Results: Plaque oxLDL levels correlated with markers of inflammatory activity, endothelial activation and plasma LDL cholesterol (r = 0.22-0.32 and p ≤ 0.01 for all). T2D individuals exhibited lower plaque levels of oxLDL, sLOX-1(a marker of endothelial activation) and plasma LDL cholesterol (p = 0.001, p = 0.006 and p = 0.009). No increased gene expression of scavenger receptors was identified in T2D plaques. The lower oxLDL content in T2D plaques was associated with a greater statin usage (p = 0.026). Supporting this, a linear regression model showed that statin treatment was the factor with the strongest association to plaque oxLDL and plasma LDL cholesterol (p < 0.001 for both). However, patients with T2D more frequently suffered from symptoms and yet plaque levels of oxLDL did not predict cardiovascular events in T2D (findings are summarized in Fig. 1a). Conclusions: This study points out the importance of statin treatment in affecting plaque biology in T2D. It also implies that other biological components, beyond oxLDL, need to be identified and targeted to further reduce the risk of events among T2D patients receiving statin treatment. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via the original article. [ABSTRACT FROM AUTHOR]

Data stream mining is an emergent research area that investigates knowledge extraction from large amounts of continuously generated data, produced by non-stationary distribution. Novelty detection, the ability to identify new or previously unknown situations, is a useful ability for learning systems, especially when dealing with data streams, where concepts may appear, disappear, or evolve over time. There are several studies currently investigating the application of novelty detection techniques in data streams. However, there is no consensus regarding how to evaluate the performance of these techniques. In this study, we propose a new evaluation methodology for multiclass novelty detection in data streams able to deal with: i) unsupervised learning, which generates novelty patterns without an association with the true classes, where one class may be composed of a novelty set, ii) confusion matrix that increases over time, iii) confusion matrix with a column representing unknown examples, i.e., those not explained by the model, and iv) representation of the evaluation measures over time. We propose a new methodology to associate the novelty patterns detected by the algorithm, in an unsupervised fashion, with the true classes. Finally, we evaluate the performance of the proposed methodology through the use of known novelty detection algorithms with artificial and real data sets. [ABSTRACT FROM PUBLISHER]

Abstract: Introduction: Elevated levels of markers for thrombin activation are associated with plaque echogenicity and degree of stenosis in patients with carotid artery stenosis. The Activated Protein C-Protein C Inhibitor (APC-PCI) complex reflects activation of the Protein C system and is a measure of thrombin generation. The aim of the present study was to examine APC-PCI complex in patients undergoing thrombendartherectomy for carotid artery stenosis, and to relate the findings to clinical characteristics and plaque morphology as determined by ultrasound. Materials and Methods: Blood was obtained from 125 patients (39 female, median age 71 years) with carotid artery stenosis admitted from September 2005 to May 2007. The APC-PCI complex was measured using a sandwich immunofluorometric method and compared to an age- and sex-matched healthy control-group. Clinical and demographic characteristics, routine laboratory markers and ultrasound characteristics were analysed using univariate and multivariate analysis. Results: APC-PCI complex concentration was significantly increased in patients with carotid artery stenosis (median 0.21 µg/L; 10th to 90th percentile 0.15–0.36) compared to a healthy control-group (0.19 µg/L; 0.11–0.31; P =.009). There was no significant difference in APC-PCI-values between asymptomatic (n=48) and symptomatic (n=77) patients with carotid artery stenosis (0.22 vs. 0.20 µg/L; p=0.626). Patients with minor stroke (n=31) had a higher median APC-PCI-concentration (0.27 µg/L; 0.15–0.63) than patients with amaurosis fugax (0.19 µg/L; 0.15–0.36) or transient ischemic attack (0.21 µg/L; 0.12–0.36) (p=0.016). No association was found between APC-PCI-values and the degrees of carotid artery stenosis or the time from the latest neurological symptoms to blood sampling. Patients with echolucent plaques had significantly lower APC-PCI concentrations (0.20 µg/L; 0.14–0.35 vs. 0.24 µg/L; 0.15–0.60; p=0.043), according to the Gray-Weale classification. Conclusions: Patients with carotid artery disease exhibit increased concentrations of APC-PCI compared to a healthy control-group, particularly those patients with echogenic plaques, who have significantly higher APC-PCI levels than patients with echolucent plaques. [Copyright &y& Elsevier]

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20–80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin–angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies. [ABSTRACT FROM AUTHOR]

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02–1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship. [ABSTRACT FROM AUTHOR]

Background: The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the inter-relationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM). Methods: In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s′) and early diastolic (e′) longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12. Results: T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL (P < 0.05–0.0001). They had also higher cIMT, IADiam, ccaWS, cfPWV and LV mass, and lower e′ velocity (P < 0.005–0.0001). Both in T2DM patients and nonT2DM subjects, MMP-12 increased with IL-6 (r = 0.43 and 0.39; P < 0.0001) and IL-18 (r = 0.32 and 0.42; P < 0.0001), and HDL decreased with MMP-12 (r = − 0.29 and − 0.42; P < 0.0001). In both populations, MMP-12 was directly associated with IADiam, ccaWS, cfPWV and LV mass (r = 0.42, 0.32, 0.26 and 0.29; P < 0.0001 in T2DM patients, and r = 0.39, 0.28, 0.32 and 0.27; P < 0.01–0.0001 in nonT2DM subjects). In multivariate analysis, MMP-12 remained independently related to IADiam, ccaWS, cfPWV and LV mass in T2DM patients, and to IADiam only in nonT2DM subjects. Conclusions: This cross-sectional study demonstrated a direct association between ILs and MMP-12, as well as an inverse association between MMP-12 and HDL, both in T2DM patients and in nonT2DM subjects. In T2DM patients, who had higher levels of ILs and MMP-12, the latter was independently related to several structural and functional markers of preclinical CV organ damage. [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) remodeling is one of the key components in the formation of vulnerable atherosclerotic plaques and cardiovascular events. We recently showed that the full-length ECM-proteoglycan osteoglycin was associated with plaque vulnerability and future cardiovascular events. In the present study, we aimed to investigate the association of cleaved osteoglycin with plaque phenotype. Two-hundred human carotid plaques were analyzed by immunohistochemistry. Cleaved osteoglycin and active caspase-3 were assessed by ELISA. ECM components (collagen, elastin and glycosaminoglycans) were assessed by colorimetric assays in plaque tissue homogenates. Matrix metalloproteinases (MMPs) were assessed using Milliplex. MMP-cleavage of osteoglycin and its effect on apoptosis were studied in vitro. Cardiovascular events were recorded during follow-up using national registries. Plaque levels of cleaved osteoglycin were significantly higher in asymptomatic plaques and correlated to α-actin plaque area, collagen, elastin and inversely to lipids, active. caspase-3 and a histological vulnerability index. Cleaved osteoglycin correlated to several MMPs, especially MMP-12, which was also shown to cleave osteoglycin in vitro. In vitro cleavage of osteoglycin was also associated with less smooth muscle cell apoptosis. Patients with high plaque levels of cleaved osteoglycin had a significantly lower risk to suffer from future cardiovascular events. The current study shows that cleaved osteoglycin is associated with a stable plaque phenotype and lower risk for future cardiovascular events. Potentially due to reduced cell apoptosis and ability to retain LDL. These results indicate that targeting the cleavage of osteoglycin may be a potential therapeutic strategy to stabilize plaques. [Display omitted] • Plaque levels of cleaved osteoglycin are higher in plaques from asymptomatic patients and patients without diabetes. • High plaque levels of cleaved osteoglycin are associated with a stable plaque phenotype and a lower risk for cardiovascular events. • The cleavage process of osteoglycin may be a potential therapeutic target for the stabilization of vulnerable plaques. [ABSTRACT FROM AUTHOR]

Histology is a long standing and well-established gold standard for pathological characterizations. In recent years however, synchrotron radiation-based micro-computed tomography (SRμCT) has become a tool for extending the imaging of two-dimensional thin sections into three-dimensional imaging of tissue blocks, enabling so-called virtual histology with arbitrary clipping planes, volumetric rendering and automatic segmentation. In this study, we present a thorough characterization of human carotid plaques after endarterectomy of patients with stroke or transient ischemic attack (TIA), investigating several different pathologic structures using both SRμCT and histology. Phase-contrast SRμCT was performed with two different magnifications (voxel sizes 6.5 μm and 0.65 μm, respectively), and histology was performed with multiple different stainings (Alpha-actin, Glycophorin A, von Kossa, Movat, CD68). The 0.65 μm high-resolution SRμCT was performed on selected areas with plaque typical relevant morphology, identified on the 6.5 μm low-resolution SRμCT. The tomography datasets were reconstructed with additional 3D volume rendering and compared to histology. In total, nine different regions with typical pathologic structures were identified and imaged with high-resolution SRμCT. The results show many characteristics typical for advanced atherosclerotic plaques, clinically relevant, namely ruptures with thrombosis, neo-vascularization, inflammatory infiltrates in shoulder regions, lipid rich necrotic cores (LRNC), thin fibrous cap, calcifications, lumen irregularities, and changes in vessel wall structures such as the internal elastic membrane. This method's non-destructive nature renders details of micro-structures with an excellent visual likeness to histology, with the additional strength of multiplanar and 3D visualization and the possibility of multiple re-scans. [ABSTRACT FROM AUTHOR]

Recent studies highlight the importance of lipotoxic damage in aortic cells as the major pathogenetic contributor to atherosclerotic disease. Since the STE20-type kinase STK25 has been shown to exacerbate ectopic lipid storage and associated cell injury in several metabolic organs, we here investigate its role in the main cell types of vasculature. We depleted STK25 by small interfering RNA in human aortic endothelial and smooth muscle cells exposed to oleic acid and oxidized LDL. In both cell types, the silencing of STK25 reduces lipid accumulation and suppresses activation of inflammatory and fibrotic pathways as well as lowering oxidative and endoplasmic reticulum stress. Notably, in smooth muscle cells, STK25 inactivation hinders the shift from a contractile to a synthetic phenotype. Together, we provide several lines of evidence that antagonizing STK25 signaling in human aortic endothelial and smooth muscle cells is atheroprotective, highlighting this kinase as a new potential therapeutic target for atherosclerotic disease. Silencing of STK25, an STE20-type kinase, in human aortic endothelial and smooth muscle cells reduces lipid accumulation and suppresses inflammation and fibrotic pathways, ultimately exerting atheroprotective effects. [ABSTRACT FROM AUTHOR]

The severity of the atherosclerotic burden is hardly quantifiable in subjects at high cardiovascular (CV) risk under intensive pharmacological therapy. Several molecules have been proposed as circulating biomarkers of atherosclerosis, but none has emerged as clinically meaningful. Circulating proteins involved in inflammation, plaque remodeling, smooth muscle cell migration, apoptosis and endothelial activity were measured by Proximity Extension Assay in the SUMMIT study cohort (n = 1500), including patients with type 2 diabetes (66%) and established CV disease (50%), who underwent ultrasound assessment of carotid atherosclerosis with total plaque area quantification. In patients with evidence of carotid artery atherosclerosis (n = 1174), seven biomarkers were identified as the more closely related to atherosclerosis extension. Compared with a multivariable model including major traditional CV risk factors, the percentage gain of explained variability in total plaque area was the greatest (33%) after inclusion of CD40 receptor (CD40R) ligand, followed by PDGF (30%), CD40R (26%), EGF (22%), CXCL1 (15%), HBEGF and MMP-17 (both 11%). The relationship of total plaque area with CD40R, PDGF was hyperbolic. In the whole study cohort, including subjects without carotid plaques, CD40R was the strongest predictor of the presence and extension of carotid atherosclerosis. Subjects in the third CD40R tertile had a more than two-fold greater atherosclerotic burden compared with lower CD40R tertiles, despite an only marginally higher load of CV risk factors. CD40R stands among an extended set of plausible atherosclerosis-related biomarkers as the most powerful predictor of carotid atherosclerosis burden in a high CV risk cohort. [Display omitted] • The extension of atherosclerosis cannot be accurately predicted using clinical variables. • This holds true particularly in populations at high/very-high cardiovascular risk. • Several circulating proteins have been evaluated, but none proved powerful enough. • 19 plausible biomarkers were ranked in terms of strength and predictive power. • CD40R emerged as a the most powerful biomarker of carotid atherosclerosis extension. [ABSTRACT FROM AUTHOR]

Rationale: Vascular calcification is a prominent feature of late‐stage diabetes, renal and cardiovascular disease (CVD), and has been linked to adverse events. Recent studies in patients reported that plasma levels of osteomodulin (OMD), a proteoglycan involved in bone mineralisation, associate with diabetes and CVD. We hypothesised that OMD could be implicated in these diseases via vascular calcification as a common underlying factor and aimed to investigate its role in this context. Methods and results: In patients with chronic kidney disease, plasma OMD levels correlated with markers of inflammation and bone turnover, with the protein present in calcified arterial media. Plasma OMD also associated with cardiac calcification and the protein was detected in calcified valve leaflets by immunohistochemistry. In patients with carotid atherosclerosis, circulating OMD was increased in association with plaque calcification as assessed by computed tomography. Transcriptomic and proteomic data showed that OMD was upregulated in atherosclerotic compared to control arteries, particularly in calcified plaques, where OMD expression correlated positively with markers of smooth muscle cells (SMCs), osteoblasts and glycoproteins. Immunostaining confirmed that OMD was abundantly present in calcified plaques, localised to extracellular matrix and regions rich in α‐SMA+ cells. In vivo, OMD was enriched in SMCs around calcified nodules in aortic media of nephrectomised rats and in plaques from ApoE−/− mice on warfarin. In vitro experiments revealed that OMD mRNA was upregulated in SMCs stimulated with IFNγ, BMP2, TGFβ1, phosphate and β‐glycerophosphate, and by administration of recombinant human OMD protein (rhOMD). Mechanistically, addition of rhOMD repressed the calcification process of SMCs treated with phosphate by maintaining their contractile phenotype along with enriched matrix organisation, thereby attenuating SMC osteoblastic transformation. Mechanistically, the role of OMD is exerted likely through its link with SMAD3 and TGFB1 signalling, and interplay with BMP2 in vascular tissues. Conclusion: We report a consistent association of both circulating and tissue OMD levels with cardiovascular calcification, highlighting the potential of OMD as a clinical biomarker. OMD was localised in medial and intimal α‐SMA+ regions of calcified cardiovascular tissues, induced by pro‐inflammatory and pro‐osteogenic stimuli, while the presence of OMD in extracellular environment attenuated SMC calcification. [ABSTRACT FROM AUTHOR]

After aortic coarctation (CoA) repair, patients still suffer from cardiovascular complications. The aim of this study was to measure cardiovascular markers, intima-media thickness (IMT) and plaques in controls and patients with CoA. Sixty-four patients with CoA (66% male, mean age 48 ± 15 years) and controls (54% men, mean age 47 ± 16 years) underwent ultrasound of their arteries. A multiplex platform to analyze circulating blood levels biomarkers reflecting inflammation, tissue remodeling and repair was used. In men following CoA repair, a significantly increased carotid bulb IMT was observed in comparison to the control group (1.05 [0.72–1.24] vs. 0.67 [0.59–0.95] mm; p = 0.003). Median common carotid artery (CCA) IMT was increased in men compared to controls (0.82 [0.61–0.97] mm vs. 0.58 [0.53–0.76] mm, p < 0.003) and in women compared to controls (0.83 [0.70–0.92] vs. 0.60 [0.55–0.69], p < 0.004). CoA demonstrated an independent association with IMT in both men and women. Men with CoA were also more likely to have a plaque in their carotid arteries (p = 0.010). In women with CoA, we observed significantly lower levels of stem cell factor (SCF, p = 0.004) while in men with CoA we observed significantly lower levels of matrix metalloproteinase-3 (MMP-3, p = 0.048), tumor necrosis factor receptor 1 (TNF-R1, p = 0.032), tumor necrosis factor receptor superfamily member 10B (TRAIL-R2, p = 0.019) and monocyte chemotactic protein 1 (MCP-1, p = 0.015). This is the first study to show that despite successful CoA repair, patients have more carotid atherosclerosis than can be explained by changes in tissue remodeling and repair. [Display omitted] • Generalized vascular disease in patients with aortic coarctation. • A relationship between atherosclerosis and markers for vascular repair and apoptosis. • Apoptosis and repair mechanisms involved in cardiovascular risk. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMP) and tumor necrosis factor receptor superfamily members have been recently proposed as surrogate markers of atherosclerosis in the general population. The aim of this study was to examine their predictive role in type 2 diabetes (T2D). Plasma levels of MMP-12, MMP-7, CD40 and its ligand (CD40-L) were measured by Proximity Extension Assay in a well-characterized cohort of 1,144 patients with carotid atherosclerosis from the SUMMIT study (age= 69 [64 - 75], males 66.7%, T2D 66.5%). Carotid plaque area was measured by plaque contours using the ultrasound trace function. The associations were adjusted for age, sex, waist, hypertension, history of cardiovascular diseases (CVD), smoke load, plasma triglycerides, LDL-cholesterol (LDL-c) and HDL-cholesterol (HDL-c), and serum creatinine levels. All measured biomarkers were associated with carotid plaque area, independently of potential confounders, with CD40 showing the strongest effect and MMP12 showing a significant interaction with T2D. In subgroup analyses, the effect of MMP-12 and MMP-7 remained significant only in T2D, while the effect of CD40 and CD40-L was similar in both subgroups. This study demonstrates the ability of MMP-12, MMP-7, CD40, and CD40-L in predicting carotid atherosclerotic burden in a population at high cardiovascular risk and identifies MMP-12 as a specific biomarker for T2D. Disclosure: S. Leonetti: None. D. Trico: None. I. Goncalves: None. A. Shore: None. F. Khan: None. J. Nilsson: None. A. Natali: None. Funding: Innovative Medicines Initiative (IMI-2008/115006) [ABSTRACT FROM AUTHOR]

Background: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). Methods: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. Results: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). Conclusions: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought. [ABSTRACT FROM AUTHOR]

Background: Chronic Kidney Disease (CKD) is associated with an increased risk for cardiovascular events such as stroke. However, it is still unclear if decreased kidney function is associated with a vulnerable atherosclerotic plaque phenotype. To explore if renal function was associated with carotid plaque vulnerability we analyzed carotid plaques obtained at surgery from the Carotid Plaque Imaging Project (CPIP). Methods: Patients were enrolled through the CPIP cohort. The indication for surgery was plaques with stenosis >70%, associated with ipsilateral symptoms or plaques with stenosis >80% not associated with symptoms. Transversal sections from the most stenotic plaque region were analyzed for connective tissue, calcium, lipids, macrophages, intraplaque hemorrhage, and smooth muscle cells. Homogenates were analyzed for collagen and elastin. Results: Carotid endarterectomy specimens from 379 patients were obtained. The median GFR was 73 ml/min/1.73 m2. Plaque characteristics showed no significant association with eGFR, neither when eGFR was divided in CKD groups nor when eGFR was handled as a continuous variable and adjusting for other known risk factors (ie, age, diabetes, hypertension, and smoking). Conclusions: The higher risk of cardiovascular disease such as stroke in CKD is not associated with increased plaque vulnerability and other factors have to be sought. [ABSTRACT FROM AUTHOR]

The pro-inflammatory alarmin S100A12 (EN-RAGE) and the soluble form of its receptor, the receptor for advanced glycation endproducts (sRAGE), have diverging roles in cardiovascular disease. In experimental studies, S100A12 promoted atherosclerosis while sRAGE treatment was anti-atherogenic and reduced myocardial infarction size by scavenging RAGE ligands. Here, we aimed to explore the links between S100A12, sRAGE, and long-term prognosis after an acute coronary syndrome (ACS). We measured S100A12 and sRAGE in 524 patients within 24 h after an ACS, and again 6 weeks later in a subgroup of 114 patients. This subgroup also completed a follow-up echocardiography after 1 year. The median follow-up time for recurrent major adverse cardiovascular events (MACE), defined as recurrent ACS or cardiovascular death, was 25.7 ± 12.6 months. In Cox proportional hazard analyses, baseline S100A12 and sRAGE were positively associated with the risk of MACE, independently of traditional cardiovascular risk factors. The association between sRAGE and MACE remained significant after additional adjustment for troponin T, NT-proBNP and hsCRP [HR 95%CI for highest versus lowest tertile 3.2 (1.5–6.5), p = 0.002]. High sRAGE was also associated with deteriorating left ventricular function and an increased rate of heart failure hospitalization post-discharge. In contrast, patients with increasing sRAGE at 6 weeks compared to baseline had lower incidence of recurrent ACS. Our data suggest that sRAGE has a dual, phase-dependent association with residual cardiovascular risk after ACS. These findings are important for the design and interpretation of future studies on sRAGE as biomarker and potential treatment in ACS patients. Image 1 • Acute coronary syndrome patients with high S100A12 and sRAGE have worse prognosis. • Elevated S100A12 and sRAGE are linked to high risk for recurrent coronary events. • High S100A12 and sRAGE are associated with cardiac dysfunction and heart failure. • Patients with increasing sRAGE during follow-up are at low risk for re-infarction. [ABSTRACT FROM AUTHOR]

Produced as a tissue defence response to hypoxia and inflammation, growth differentiation factor‐15 (GDF‐15) is elevated in people receiving metformin treatment. To gain insight into the relationship of GDF‐15 with metformin and major cardiovascular risk factors, we analysed the data from the SUMMIT cohort (n = 1438), a four‐centre, nested, case–control study aimed at verifying whether biomarkers of atherosclerosis differ according to the presence of type 2 diabetes and cardiovascular disease. While in univariate analysis, major cardiovascular risk factors, with the exception of gender and cholesterol, increased similarly and linearly across GDF‐15 quartiles, the independent variables associated with GDF‐15, both in participants with and without diabetes, were age, plasma creatinine, N‐terminal pro‐brain natriuretic peptide, diuretic use, smoking exposure and glycated haemoglobin. In participants with diabetes, metformin treatment was associated with a 40% rise in GDF‐15 level, which was independent of the other major factors, and largely explained their elevated GDF‐15 levels. The relatively high GDF‐15 bioavailability might partly explain the protective cardiovascular effects of metformin. [ABSTRACT FROM AUTHOR]

Objective: Cardiovascular disease (CVD) risk prediction represents an increasing clinical challenge in the treatment of diabetes. We used a panel of vascular imaging, functional assessments, and biomarkers reflecting different disease mechanisms to identify clinically useful markers of risk for cardiovascular (CV) events in subjects with type 2 diabetes (T2D) with or without manifest CVD.Research Design and Methods: The study cohort consisted of 936 subjects with T2D recruited at four European centers. Carotid intima-media thickness and plaque area, ankle-brachial pressure index, arterial stiffness, endothelial function, and circulating biomarkers were analyzed at baseline, and CV events were monitored during a 3-year follow-up period.Results: The CV event rate in subjects with T2D was higher in those with (n = 440) than in those without (n = 496) manifest CVD at baseline (5.53 vs. 2.15/100 life-years, P < 0.0001). New CV events in subjects with T2D with manifest CVD were associated with higher baseline levels of inflammatory biomarkers (interleukin 6, chemokine ligand 3, pentraxin 3, and hs-CRP) and endothelial mitogens (hepatocyte growth factor and vascular endothelial growth factor A), whereas CV events in subjects with T2D without manifest CVD were associated with more severe baseline atherosclerosis (median carotid plaque area 30.4 mm2 [16.1-92.2] vs. 19.5 mm2 [9.5-40.5], P = 0.01). Conventional risk factors, as well as measurements of arterial stiffness and endothelial reactivity, were not associated with CV events.Conclusions: Our observations demonstrate that markers of inflammation and endothelial stress reflect CV risk in subjects with T2D with manifest CVD, whereas the risk for CV events in subjects with T2D without manifest CVD is primarily related to the severity of atherosclerosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. RESULTS: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globuleepidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. CONCLUSIONS: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis. [ABSTRACT FROM AUTHOR]

Background: Galectin-3 (Gal-3) has been suggested to have both pro- and anti-atherogenic properties. High plasma Gal-3 levels are associated with increased risk for cardiovascular (CV) death. However, it has so far not been investigated if plasma Gal-3 levels can predict the risk for future stroke in patients suffering from carotid atherosclerosis. The aim of this study was to investigate whether Gal-3 could be used as a marker to predict postoperative cerebrovascular ischemic events among patients who underwent carotid endarterectomy (CEA). Methods: Plasma samples were obtained from 558 CEA patients and Gal-3 levels were analyzed by the proximity extension assay technique. The Swedish national inpatient health register was used to identify postoperative cerebrovascular events during the follow-up period (42.6 ± 26.2 months). Results: Plasma Gal-3 was increased in patients treated for a symptomatic carotid stenosis (p = 0.013). Patients with Gal-3 levels above the median value had an increased incidence of stroke as shown by Kaplan-Meier curves of event-free survival (p = 0.007). Gal-3 was a predic-tor of postoperative stroke among women (hazard ratio 15.1, 95% CI 1.3-172.2; p = 0.028) even after correction for traditional CV risk factors. Conclusions: This study is the first to show that increased plasma levels of Gal-3 can help in predicting the occurrence of postoperative strokes among female subjects who undergo CEA, independently of traditional risk factors for cerebrovascular disease. This finding suggests that Gal-3 could be used as a marker to identify patients in need of intensified postoperative medical care. [ABSTRACT FROM AUTHOR]

The reaction of [MoO2CI2(di-tBu-bipy)] (i) (di-tBu-bipy = 4,4'-di-tert-butyl-2,2'-bipyridinë) with water at 100-120 °C in a Teflon-lined stainless steel autoclave, in an open reflux system, or in a microwave synthesis system gave the octanudear complex {Mo4O8(OH)4(di-tBu-bipy)4] (2) as a microcrystalline powder in good yields. Single crystals of 2 suitable for X-ray dith action were obtained by the reaction of MoO3 and di-tflu-bipy in water at 160 °C for 3 days. The molecular structure of 2 comprises a purely inorganic core, Mo4O8(μ3OH)2(μ2.O)2, attached to two peripheral oxobridged binudear units, Mo2O4(prO)2(OH)(di-tBu-bipy)2. The inorganic core is composed of a unique assembly of four (Mo05} distorted square pysanuds connected to each other iw edge-sharing. Overall, the octanudear complex adopts a highly distorted form strongly resembling an "S"-shaped molecular unit. Complex 2 was applied in the catalytic epoxidation of the biorenewable olefins DL-limonene ([Am) and methyl oleate (Ole), using tert-butylhydroperoxide (TBHP) as an oxygen donor, under mild reaction conditions (ss °C, air). The reactions of Lim and Ole gave the respective epoxide monomers in foirly high selectivities at high conversions (89% 1,2-epoxy-p-menth-8-ene selectivity at 96% Lim conversion; 99% methyl 9,10epoxystearate selectivity at 94% Ole conversion, reached within 24 h reaction). lodometric titrations revealed no measurable "non-productive" decomposition of TBHP. [ABSTRACT FROM AUTHOR]

Aims Alternative transcription and splicing of the allograft inflammatory factor-1 (AIF-1) gene results in the expression of two different proteins: AIF-1 and interferon responsive transcript-1 (IRT-1). Here, we explore the impact of AIF-1 and IRT-1 on vascular smooth muscle cell (VSMC) activation and neointima formation, the mechanisms underlying their alternative splicing, and associations of AIF-1 and IRT-1 mRNA with parameters defining human atherosclerotic plaque phenotype. Methods and results Translation of AIF-1 and IRT-1 results in different products with contrasting cellular distribution and functions. Overexpression of AIF-1 stimulates migration and proliferation of human VSMCs, whereas IRT-1 exerts opposite effects. Adenoviral infection of angioplasty-injured rat carotid arteries with AdAIF-1 exacerbates intima hyperplasia, whereas infection with AdIRT-1 reduces neointima. Expression of these variants is modulated by changes in nuclear factor of activated T-cells (NFAT) activity. Pharmacological inhibition of NFAT or targeting of NFATc3 with small interfering RNA (siRNA) lowers the AIF-1/IRT-1 ratio and favours an anti-proliferative outcome. NFAT acts as a repressor on the IRT-1 transcriptional start site, which is also sensitive to interferon-γ stimulation. Expression of AIF-1 mRNA in human carotid plaques associates with less extracellular matrix and a more pro-inflammatory plaque and plasma profile, features that may predispose to plaque rupture. In contrast, expression of IRT-1 mRNA associates with a less aggressive phenotype and less VSMCs at the most stenotic region of the plaque. Conclusion Inhibition of NFAT signalling, by shifting the AIF-1/IRT-1 ratio, may be an attractive target to regulate the VSMC response to injury and manipulate plaque stability in atherosclerosis. [ABSTRACT FROM PUBLISHER]

The reaction of [MoO2Cl2(bipy)) (1) (bipy = 2,2'-bipyridine) with water in a Teflon-lined stainless steel autoclave (100 °C, 19 h), in an open reflux system with oil bath heating (12 h) arm a microwave synthesis system (120 °C, 4 h), gave the molybdenum oxide/bipytidine hybrid material ((Mo03(bipy)][MoO3(H2O)]) n(2) as a microcrystalline powder in yields of 72-92%. The crystal structure of 2 determined from synchrotron X-ray powder diffraction data is composed of two distinct neutral one-dimensional polymers: an organic-inorganic polymer, [MoO3(bipy)]n, and a purely inorganic chain, [MoO3(H2O)]n, which are interconnected by O-H ∙∙∙ O hydrogen bonding interactions. Compound 2 is a moderately active, stable, and selective catalyst for the epoxidation of cis-cyclooctene at 55 °C with tert-butythydroperoxide (fBuOOH, 5.5 M in decane or 70% aqueous) as the oxidant. Biphasic solid-liquid or triphasic solid-organic-aqueous mixtures are formed, and 1 ,2-epoxycyclaoctane is the only reaction product. When n-hexane is employed as a cosolvent and fBuOOH(decane) is the oxidant, the catalytic reaction is heterogeneous in nature, and the solid catalyst can be recycled and reused without a loss of activity. For comparison, the catalytic performance of the precursor 1 was also investigated. The IR spectra of solids recovered after catalysis indicate that 1 transforms into the organic-inorganic polymer [MoO3(bipy)] when the oxidant is fBuOOH(decane) and compound 2 when the oxidant is 70% aqueous fBuOOH. [ABSTRACT FROM AUTHOR]

Tetrakis(naphthoyltrifluoroacetonato)lanthanate(lll) complexes (Ln = Eu, Gd) containing the cations tetrabutylammoniurn, [NBu[sub4]][sup+] 1 -butyl-3-methylimidazolium, [C[sub4]mim][sup+] and 1 -butyl-3-methylpyridinium, [C4mpyr][sup+], have been prepared and structurally characterized by single-crystal X-ray diffraction. The (EuO[sub8]) coordination sphere in [NBu[sub4]][Eu(NTA)[sub4]] is best described as a distorted dodecahedron, where the metal ion is located at the 4-fold inversion axis with only one crystallographically independent NTA residue. In [C4mim][Eu(NTA)[sub4]] and [C[sub4]mpyr][Gd (NTA)[sub4]], the central Ln[sup3+] ions are coordinated by eight oxygen atoms from four distinct β-diketonate ligands, in an overall distorted square-antiprismatic geometry. Besides electrostatic interactions, the crystal packing in all three structures is stabilized by offset π-π interactions involving the naphthyl rings of neighboring complexes (and, for [C[sub4]mimI[Eu(NTA)[sub4]] and [C[sub4]mpyr][Gd(NTA)[sub4]], neighboring naphthyl/imidazolium and naphthyl/pyridinium rings) and C—]H⋯π contacts. The photoluminescence properties of the three Eu[supIII] complexes were studied at room temperature and -259 °C by measuring emission and excitation spectra, [sup5]D[sub0] emission decay curves, and absolute emission quantum yields. Under ligand excitation (λ[subex] = 290-395 nm), the quantum yields (room temperature) were in the range 0.72-0.77 for the 1 -butyl-3-methylimidazolium salt. An immobilized analogue of this complex was prepared by supporting [Eu(NTA)[sub4]][sup-] on an ordered mesoporous silica derivatized with 1 -propyl-3-methylimidazolium groups. The disappearance of the intra-4f[sup6] lines in the excitation spectrum of the supported material indicated an increase in the ligand's sensitization process of the Eu[sup3+] ions, relative to direct intra-4f[sup6] excitation. The emission quantum yield measured for the supported material (0.32-0.40, for excitations between 265 and 360 nm) is the highest so far reported for lanthanide-containing ordered mesoporous silicas. [ABSTRACT FROM AUTHOR]

Infants with cholestatic liver disease are at risk of various nutritional deficiencies. They require regular review with appropriate interventions to prevent complications and ensure optimum possible status if liver transplantation becomes necessary. We propose evidence based and internationally agreed guidelines for their care with recommendations for therapeutic strategies and for service organization. [ABSTRACT FROM AUTHOR]

Examines the stepwise hapticity changes in sequential one-electron redox reactions of indenyl-molybdenum complexes. Employment of cyclic voltammetry and bulk electrolysis to define charge-transfer kinetics of reactions; Effectiveness of X-ray diffraction in determining hapticity changes.

(1) Background: The unusual accumulation of Na,K-ATPase complexes in the brush border membrane of choroid plexus epithelial cells have intrigued researchers for decades. However, the full range of the expressed Na,K-ATPase subunits and their relation to the microvillus cytoskeleton remains unknown. (2) Methods: RT-PCR analysis, co-immunoprecipitation, native PAGE, mass spectrometry, and differential centrifugation were combined with high-resolution immunofluorescence histochemistry, proximity ligase assays, and stimulated emission depletion (STED) microscopy on mouse choroid plexus cells or tissues in order to resolve these issues. (3) Results: The choroid plexus epithelium expresses Na,K-ATPase subunits α1, α2, β1, β2, β3, and phospholemman. The α1, α2, β1, and β2, subunits are all localized to the brush border membrane, where they appear to form a complex. The ATPase complexes may stabilize in the brush border membrane via anchoring to microvillar actin indirectly through ankyrin-3 or directly via other co-precipitated proteins. Aquaporin 1 (AQP1) may form part of the proposed multi-protein complexes in contrast to another membrane protein, the Na-K-2Cl cotransporter 1 (NKCC1). NKCC1 expression seems necessary for full brush border membrane accumulation of the Na,K-ATPase in the choroid plexus. (4) Conclusion: A multitude of Na,K-ATPase subunits form molecular complexes in the choroid plexus brush border, which may bind to the cytoskeleton by various alternative actin binding proteins. [ABSTRACT FROM AUTHOR]

Background: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions.Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.Results: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis. [ABSTRACT FROM AUTHOR]