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Petri M.H.,Karolinska University Hospital | Laguna-Fernandez A.,Karolinska University Hospital | Gonzalez-Diez M.,Atherosclerosis Research Unit | Paulsson-Berne G.,Karolinska University Hospital | And 2 more authors.
Cardiovascular Research | Year: 2015

Aims The formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ ALX signalling in atherosclerosis. Methods and results Expression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations,we generated Ldlr-/-xFpr2-/- mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr-/-xFpr2+/+ mice. These findings were reproduced by transplantation of Fpr2-/- bone marrowinto Ldlr-/- mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2-/- macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr-/-xFpr2-/- mice exhibited decreased collagen content, and Fpr2-/- SMCs exhibited a profile of increased collagenase and decreased collagen production pathways. Conclusion FPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability. © The Author 2014. Source

Overton M.,University of North Carolina at Chapel Hill | Wu K.,Endocrinology and Metabolism | Wu K.,Wuhan University | Fazio S.,Atherosclerosis Research Unit | And 2 more authors.
Journal of Lipid Research | Year: 2012

Mechanisms underlying changes in HDL composition caused by obesity are poorly defined, partly because mice lack expression of cholesteryl ester transfer protein (CETP), which shuttles triglyceride and cholesteryl ester between lipoproteins. Because menopause is associated with weight gain, altered glucose metabolism, and changes in HDL, we tested the effect of feeding a high-fat diet (HFD) and ovariectomy (OVX) on glucose metabolism and HDL composition in CETP transgenic mice. After OVX, female CETP-expressing mice had accelerated weight gain with HFD-feeding and impaired glucose tolerance by hyperglycemic clamp techniques, compared with OVX mice fed a low-fat diet (LFD). Sham-operated mice (SHAM) did not show HFD-induced weight gain and had less glucose intolerance than OVX mice. Using shotgun HDL proteomics, HFD-feeding in OVX mice had a large effect on HDL composition, including increased levels of apoA2, apoA4, apoC2, and apoC3, proteins involved in TG metabolism. These changes were associated with decreased hepatic expression of SR-B1, ABCA1, and LDL receptor, proteins involved in modulating the lipid content of HDL. In SHAM mice, there were minimal changes in HDL composition with HFD feeding. These studies suggest that the absence of ovarian hormones negatively influences the response to high-fat feeding in terms of glucose tolerance and HDL composition. CETP-expressing mice may represent a useful model to define how metabolic changes affect HDL composition and function. Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Source

Baldassarre D.,University of Milan | Baldassarre D.,Centro Cardiologico Monzino | Veglia F.,Centro Cardiologico Monzino | Hamsten A.,Atherosclerosis Research Unit | And 12 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-To investigate whether several different measures of carotid intima-media thickness (IMT) progression are associated with subsequent vascular events and whether such associations are independent of baseline carotid atherosclerotic profile and Framingham risk factors. Approach and Results-A longitudinal cohort study (the Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population study) was performed in 7 centers in 5 European countries (Finland, France, Italy, the Netherlands, and Sweden). Three thousand four hundred eighty-two subjects (median age 64.1 years; 47.8% men) with ≥3 vascular risk factors were recruited and monitored for a postprogression median follow-up of 21.5 months, during which time 129 subjects experienced a first vascular event (incidence of 20.4 per 1000 person-years). The 15th month progression of mean and maximum carotid IMT of the left and right common carotids, bifurcations, internal carotid arteries, and their composite measures, as well as the fastest IMTmax progression (Fastest-IMTmax-progr) detected in the whole carotid tree regardless of location, were used in statistical analyses. All carotid IMT measures showed significant progression during the first 15 months (P<0.001), but only the Fastest-IMTmax-progr was significantly associated with the risk of subsequent vascular events. The Fastest-IMTmax-progr association persisted after Bonferroni correction for multiple comparisons and after adjustments for Framingham risk factors and pharmacological treatments (all P<0.005). The use of Framingham Risk Score in place of Framingham risk factors provided almost identical results (P=0.003). CONCLUSIONS-The Fastest-IMTmax-progr, a novel approach to assess carotid IMT progression, identifies focal increases of carotid IMT and, in contrast to other progression variables, is associated with cardiovascular risk. © 2013 American Heart Association, Inc. Source

Yancey P.G.,Atherosclerosis Research Unit | Blakemore J.,Atherosclerosis Research Unit | Ding L.,Atherosclerosis Research Unit | Fan D.,Atherosclerosis Research Unit | And 4 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

Objective: The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis. Method and results: LRP-1-/- macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1-/- cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1 macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1 vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1-/- phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1 -/- lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion: Macrophage LRP-1-/- deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1-/- macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation. © 2010 American Heart Association, Inc. Source

Polyzos K.A.,Alfa Institute of Biomedical science AIBS | Polyzos K.A.,Atherosclerosis Research Unit | Konstantelias A.A.,Alfa Institute of Biomedical science AIBS | Falagas M.E.,Alfa Institute of Biomedical science AIBS | Falagas M.E.,Tufts University
Europace | Year: 2015

Infectious complications after cardiac implantable electronic device (CIED) implantation are increasing over time and are associated with substantial mortality and healthcare costs. The aim of this study was to systematically summarize the literature on risk factors for infection after pacemaker, implantable cardioverter-defibrillator, and cardiac resynchronization therapy device implantation. Electronic searches (up to January 2014) were performed in PubMed, Scopus, and Web of Science databases. Sixty studies (21 prospective, 9 case-control, and 30 retrospective cohort studies) met the inclusion criteria. The average device infection rate was 1-1.3%. In the meta-analysis, significant host-related risk factors for infection included diabetes mellitus (odds ratio (OR) [95% confidence interval] = 2.08 [1.62-2.67]), end-stage renal disease (OR = 8.73 [3.42-22.31]), chronic obstructive pulmonary disease (OR = 2.95 [1.78-4.90]), corticosteroid use (OR = 3.44 [1.62-7.32]), history of the previous device infection (OR = 7.84 [1.94-31.60]), renal insufficiency (OR = 3.02 [1.38-6.64]), malignancy (OR = 2.23 [1.26-3.95]), heart failure (OR = 1.65 [1.14-2.39]), pre-procedural fever (OR = 4.27 [1.13-16.12]), anticoagulant drug use (OR = 1.59 [1.01-2.48]), and skin disorders (OR = 2.46 [1.04-5.80]). Regarding procedure-related factors, post-operative haematoma (OR = 8.46 [4.01-17.86]), reintervention for lead dislodgement (OR = 6.37 [2.93-13.82]), device replacement/revision (OR = 1.98 [1.46-2.70]), lack of antibiotic prophylaxis (OR = 0.32 [0.18-0.55]), temporary pacing (OR = 2.31 [1.36-3.92]), inexperienced operator (OR = 2.85 [1.23-6.58]), and procedure duration (weighted mean difference = 9.89 [0.52-19.25]) were all predictors of CIED infection. Among device-related characteristics, abdominal pocket (OR = 4.01 [2.48-6.49]), epicardial leads (OR = 8.09 [3.46-18.92]), positioning of two or more leads (OR = 2.02 [1.11-3.69]), and dual-chamber systems (OR = 1.45 [1.02-2.05]) predisposed to device infection. This systematic review on risk factors for CIED infection may contribute to developing better infection control strategies for high-risk patients and can also help risk assessment in the management of device revisions. © The Author 2015. Source

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