Antibodies Against β2-Glycoprotein I Complexed With an Oxidised Lipoprotein Relate to Intima Thickening of Carotid Arteries in Primary Antiphospholipid Syndrome

To explore whether antibodies against β2-glycoprotein I (β2GPI) complexed to 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) and to oxidised low-density lipoproteins (oxLDL) relate to paraoxonase activity (PONa) and/or intima media thickness (IMT) of carotid arteries in primary antiphospholipid syndrome (PAPS). As many as 29 thrombotic patients with PAPS, 10 subjects with idiopathic antiphospholipid antibodies (aPL) without thrombosis, 17 thrombotic patients with inherited thrombophilia and 23 healthy controls were investigated. The following were measured in all participants: β2GPI−oxLDL complexes, IgG anti-β2GPI−oxLig-1, IgG anti-β2GPI−oxLDL antibodies (ELISA), PONa, (para-nitrophenol method), IMT of common carotid (CC) artery, carotid bifurcation (B), internal carotid (IC) by high resolution sonography. β2GPI−oxLDL complex was highest in the control group (p < 0.01), whereas, IgG anti-β2GPI−oxLig1 and IgG anti-β2GPI−oxLDL were highest in PAPS (p < 0.0001). In healthy controls, β2GPI−oxLDL complexes positively correlated to IMT of the IC (p = 0.007) and negatively to PONa after correction for age (p < 0.03). PONa inversely correlated with age (p = 0.008). In PAPS, IgG anti-2GPI−oxLig-1 independently predicted PONa (p = 0.02) and IMT of B (p = 0.003), CC, (p = 0.03) and of IC (p = 0.04). In PAPS, PONa inversely correlated to the IMT of B, CC and IC (p = 0.01, 0.02 and 0.003, respectively). IgG anti-2GPI−oxLig-1 may be involved in PAPS related atherogenesis via decreased PON activity

ApoE−/− PGC-1α−/− Mice Display Reduced IL-18 Levels and Do Not Develop Enhanced Atherosclerosis

BACKGROUND: Atherosclerosis is a chronic inflammatory disease that evolves from the interaction of activated endothelial cells, macrophages, lymphocytes and modified lipoproteins (LDLs). In the last years many molecules with crucial metabolic functions have been shown to prevent important steps in the progression of atherogenesis, including peroxisome proliferator activated receptors (PPARs) and the class III histone deacetylase (HDAC) SIRT1. The PPARγ coactivator 1 alpha (Ppargc1a or PGC-1α) was identified as an important transcriptional cofactor of PPARγ and is activated by SIRT1. The aim of this study was to analyze total PGC-1α deficiency in an atherosclerotic mouse model. METHODOLOGY/PRINCIPAL FINDINGS: To investigate if total PGC-1α deficiency affects atherosclerosis, we compared ApoE(-/-) PGC-1α(-/-) and ApoE(-/-) PGC-1α(+/+) mice kept on a high cholesterol diet. Despite having more macrophages and a higher ICAM-1 expression in plaques, ApoE(-/-) PGC-1α(-/-) did not display more or larger atherosclerotic plaques than their ApoE(-/-) PGC-1α(+/+) littermates. In line with the previously published phenotype of PGC-1α(-/-) mice, ApoE(-/-) PGC-1α(-/-) mice had marked reduced body, liver and epididymal white adipose tissue (WAT) weight. VLDL/LDL-cholesterol and triglyceride contents were also reduced. Aortic expression of PPARα and PPARγ, two crucial regulators for adipocyte differentiation and glucose and lipid metabolism, as well as the expression of some PPAR target genes was significantly reduced in ApoE(-/-) PGC-1α(-/-) mice. Importantly, the epididymal WAT and aortic expression of IL-18 and IL-18 plasma levels, a pro-atherosclerotic cytokine, was markedly reduced in ApoE(-/-) PGC-1α(-/-) mice. CONCLUSIONS/SIGNIFICANCE: ApoE(-/-) PGC-1α(-/-) mice, similar as PGC-1α(-/-) mice exhibit markedly reduced total body and visceral fat weight. Since inflammation of visceral fat is a crucial trigger of atherogenesis, decreased visceral fat in PGC-1α-deficient mice may explain why these mice do not develop enhanced atherosclerosis

Early Palaeozoic ocean anoxia and global warming driven by the evolution of shallow burrowing

The evolution of burrowing animals forms a defining event in the history of the Earth. It has been hypothesised that the expansion of seafloor burrowing during the Palaeozoic altered the biogeochemistry of the oceans and atmosphere. However, whilst potential impacts of bioturbation on the individual phosphorus, oxygen and sulphur cycles have been considered, combined effects have not been investigated, leading to major uncertainty over the timing and magnitude of the Earth system response to the evolution of bioturbation. Here we integrate the evolution of bioturbation into the COPSE model of global biogeochemical cycling, and compare quantitative model predictions to multiple geochemical proxies. Our results suggest that the advent of shallow burrowing in the early Cambrian contributed to a global low-oxygen state, which prevailed for ~100 million years. This impact of bioturbation on global biogeochemistry likely affected animal evolution through expanded ocean anoxia, high atmospheric CO2 levels and global warming

Percentage White: A New Feature for Ultrasound Classification of Plaque Echogenicity in Carotid Artery Atherosclerosis.

Atherosclerotic stenotic and nonstenotic plaques of the carotid artery with low echogenicity have been shown to be associated with cardiovascular disease. The aim was to develop a new method for semiautomated ultrasound image analysis to classify nonstenotic carotid plaques, evaluate cases with multiple plaques and examine the association between a new image analysis feature of echogenicity and predictors of cardiovascular disease. The new image analysis feature, percentage white (PW), represents the fraction of bright structures inside a plaque and is integrated in an objective semiautomated method to evaluate echogenicity (SAMEE) in carotid plaques. PW was constructed to take into account overall echogenicity of the image as well as noise surrounding the plaque. Consecutive ultrasound examinations of carotid plaques from a population-based screening of 64-year-old women with varying risk for cardiovascular disease were selected for the present project; 92 far-wall and 47 near-wall plaques were used as a training dataset to develop the SAMEE algorithm with visual classification according to Gray-Weale as reference; 273 plaques were used to validate the method. All plaques were included in an analysis relating predictors of cardiovascular to average PW in all plaques, PW in the biggest plaque and to the plaque with lowest PW in each subject, respectively. In the training dataset the intermethodological variability between SAMEE and visual classification showed a kappa of 0.78 and a sensitivity and specificity of 96% and 81%, respectively. In the validation set, SAMEE and visual classification showed a kappa of 0.77, a sensitivity of 96% and a specificity of 80%. The reproducibility of PW was high, evidenced by r = 0.96 and CV = 9.85% at repeated examinations. Average PW values were associated with several predictors of cardiovascular risk: lipoprotein (a), HbA1c, blood glucose, apolipoproteinB/apolipoproteinA-I; and associated negatively with the levels of adiponectin and apolipoprotein A-I. In conclusion, PW integrated within a SAMEE is a new feature for assessment of echogenicity in carotid plaques and shows excellent reproducibility and agreement with visual assessment

Percentage White: A New Feature for Ultrasound Classification of Plaque Echogenicity in Carotid Artery Atherosclerosis.

Atherosclerotic stenotic and nonstenotic plaques of the carotid artery with low echogenicity have been shown to be associated with cardiovascular disease. The aim was to develop a new method for semiautomated ultrasound image analysis to classify nonstenotic carotid plaques, evaluate cases with multiple plaques and examine the association between a new image analysis feature of echogenicity and predictors of cardiovascular disease. The new image analysis feature, percentage white (PW), represents the fraction of bright structures inside a plaque and is integrated in an objective semiautomated method to evaluate echogenicity (SAMEE) in carotid plaques. PW was constructed to take into account overall echogenicity of the image as well as noise surrounding the plaque. Consecutive ultrasound examinations of carotid plaques from a population-based screening of 64-year-old women with varying risk for cardiovascular disease were selected for the present project; 92 far-wall and 47 near-wall plaques were used as a training dataset to develop the SAMEE algorithm with visual classification according to Gray-Weale as reference; 273 plaques were used to validate the method. All plaques were included in an analysis relating predictors of cardiovascular to average PW in all plaques, PW in the biggest plaque and to the plaque with lowest PW in each subject, respectively. In the training dataset the intermethodological variability between SAMEE and visual classification showed a kappa of 0.78 and a sensitivity and specificity of 96% and 81%, respectively. In the validation set, SAMEE and visual classification showed a kappa of 0.77, a sensitivity of 96% and a specificity of 80%. The reproducibility of PW was high, evidenced by r = 0.96 and CV = 9.85% at repeated examinations. Average PW values were associated with several predictors of cardiovascular risk: lipoprotein (a), HbA1c, blood glucose, apolipoproteinB/apolipoproteinA-I; and associated negatively with the levels of adiponectin and apolipoprotein A-I. In conclusion, PW integrated within a SAMEE is a new feature for assessment of echogenicity in carotid plaques and shows excellent reproducibility and agreement with visual assessment

Circulating matrix metalloproteinase 9 levels in relation to sampling methods, femoral and carotid atherosclerosis.

OBJECTIVES To examine whether circulating levels of matrix metalloproteinase 9 (MMP-9) were associated with ultrasound-assessed intima-media thickness (IMT) and echolucent plaques in the carotid and femoral arteries. To examine preanalytical sources of variability in MMP-9 concentrations related to sampling procedures. SUBJECTS AND DESIGN Plasma and serum MMP-9 levels were compared with ultrasound assessed measures of femoral and carotid atherosclerosis, in a cross-sectional study of 61-year-old men (n = 473). Preanalytical sources of variability in MMP-9 levels were examined in 10 healthy subjects. Main outcome measures were circulating levels of MMP-9 in serum and plasma, IMT of the carotid and femoral arteries, and plaque status based on size and echolucency. SETTING Research unit at university hospital. RESULTS Plasma concentrations of total and active MMP-9 were associated with femoral artery IMT independently of traditional cardiovascular risk factors, and were higher in subjects with moderate to large femoral plaques. Plasma MMP-9 concentration was higher in men with echolucent femoral plaques (P = 0.006) compared with subjects without femoral plaques. No similar associations were found for carotid plaques. MMP-9 concentrations were higher in serum than in plasma, and higher when sampling was performed with Vacutainer than with syringe. MMP-9 levels in serum were more strongly associated with peripheral neutrophil count compared with MMP-9 levels in plasma. CONCLUSIONS Plasma MMP-9 levels were associated with atherosclerosis in the femoral artery, and total MMP-9 concentration was higher in men with echolucent femoral plaques. The choice of sample material and sampling method affect the measurements of circulating MMP-9 levels