These results suggest that anti-ApoA-1 IgG might be associated with increased atherosclerotic plaque vulnerability in humans and mice.

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Background and Purpose-The concept of "vulnerable plaque" has been extended to the more recent definition of the "cardiovascular vulnerable patient," in which "intraplaque" and "systemic" factors contribute to the cumulative risk of acute cardiovascular events. Thus, we investigated the possible role of systemic and intraplaque inflammation in patients asymptomatic versus symptomatic for ischemic stroke. Methods-Regions upstream and downstream the blood flow were isolated from internal carotid plaques of patients asymptomatic (nϭ63) or symptomatic (nϭ18) for ischemic stroke. Specimens were analyzed for lipid, collagen, macrophage, lymphocyte, neutrophil, mast cell and smooth muscle cell content, and chemokine and cytokine mRNA expression. Chemokine receptors and adhesion molecules were assessed on circulating leukocytes by flow cytometry. Systemic inflammatory markers and biochemical parameters were measured on total blood, plasma, and serum. Results-Tumor necrosis factor-␣ and CCL5 serum levels as well as intercellular adhesion molecule-1 expression on circulating neutrophils were increased in symptomatic as compared with asymptomatic patients. Collagen content and smooth muscle cell infiltration were decreased in symptomatic plaques. In upstream regions of symptomatic plaques, lipid content and lymphocyte infiltration were increased. In downstream regions of symptomatic plaques, macrophage, neutrophil, and mast cell infiltration were increased. Intraplaque collagen content was positively correlated with smooth muscle cell infiltration and inversely correlated with macrophages, neutrophils, or serum tumor necrosis factor-␣. Collagen reduction in downstream regions and serum tumor necrosis factor-␣ were independently associated with the likelihood of being symptomatic. Conclusions-Inflammatory mediators are increased in ischemic stroke. Despite statistically significant, the correlation between tumor necrosis factor-␣ serum level and intraplaque vulnerability was weak and probably of limited biological importance. (Stroke. 2010;41:1394-1404.)Key Words: carotid artery Ⅲ carotid endarterectomy Ⅲ inflammation Ⅲ leukocytes V ariations in plaque composition, size, and severity of lumen stenosis have been identified as crucial aspects of plaque vulnerability. 1,2 Inflammation, thin or fissured cap with large lipid core, and severe stenosis increase plaque vulnerability. In addition, superficial calcified nodules, hemorrhages, endothelial dysfunction, and expansive (positive) remodeling could also contribute to atherosclerotic plaque destabilization. More recently, clinical studies suggested that acute ischemic events could be also influenced by systemic factors and peripheral tissue resistance to hypoxia. 3 Nonspecific serum markers of altered lipid profile, inflammation, and hypercoagulability have been identified. 4 Thus, the concept of "vulnerable plaque" has been extended to the more recent definition of the "cardiovascular vulnerable patient," in which "intraplaque" and systemic factors contribute to the cumulati...

Background-Toll-like receptors (TLRs) have long been considered to be major culprits in the development of atherosclerosis, contributing both to its progression and clinical complications. However, evidence for most TLRs beyond TLR2 and TLR4 is lacking. Methods and Results-We used experimental mouse models, human atheroma cultures, and well-established human biobanks to investigate the role of TLR7 in atherosclerosis. We report the unexpected finding that TLR7, a receptor recognizing self-nucleic acid complexes, is protective in atherosclerosis. In Apoe Ϫ/Ϫ mice, functional inactivation of TLR7 resulted in accelerated lesion development, increased stenosis, and enhanced plaque vulnerability as revealed by Doppler ultrasound and/or histopathology. Mechanistically, TLR7 interfered with macrophage proinflammatory responses to TLR2 and TLR4 ligands, reduced monocyte chemoattractant protein-1 production, and prevented expansion of Ly6C hi inflammatory monocytes and accumulation of inflammatory M1 macrophages into developing atherosclerotic lesions. In human carotid endarterectomy specimens TLR7 levels were consistently associated with an M2 anti-inflammatory macrophage signature (interleukin [IL]-10, IL-1RA, CD163, scavenger and C-type lectin receptors) and collagen genes, whereas they were inversely related or unrelated to proinflammatory mediators (IL-12/IL-23, interferon beta, interferon gamma, CD40L) and platelet markers. Moreover, in human atheroma cultures, TLR7 activation selectively suppressed the production of key proatherogenic factors such as monocyte chemoattractant protein-1 and tumor necrosis factor without affecting IL-10. Conclusions-These findings provide evidence for a beneficial role of TLR7 in atherosclerosis by constraining inflammatory macrophage activation and cytokine production. This challenges the prevailing concept that all TLRs are pathogenic and supports the exploitation of the TLR7 pathway for therapy. (Circulation. 2012;126:952-962.)Key Words: atherosclerosis Ⅲ immune system Ⅲ inflammation Ⅲ macrophage Ⅲ Toll-like receptor C hronic inflammation is an integral part of the pathogenesis of atherosclerosis. 1,2 Accumulation of lipoproteins in the vessel wall, especially at areas of disturbed blood flow such as bifurcations and the lesser curvature of the aortic arch, induces a chronic inflammatory response characterized by the mobilization of monocytes in the periphery, the infiltration of macrophages, dendritic cells, and lymphocytes in the arterial intima, and the expression of proinflammatory cytokines, chemokines, and matrix metalloproteinases. This leads to luminal narrowing and often plaque rupture and myocardial infarction or stroke, the most severe clinical complications of atherosclerosis. Therefore, identifying ratelimiting molecular processes and pathways that contribute to the development or persistence of inflammation in the vessel wall is key to the future treatment of this disease. 3 Clinical Perspective on p 962Toll-like receptors (TLRs) have recently taken center stage in a...

Cannabinoid receptor type 2 receptor is down-regulated in unstable human carotid plaques. Since CB(2) activation prevents neutrophil release of MMP-9 in vivo and in vitro, this treatment strategy might selectively reduce carotid vulnerability in humans.

Treatment with anti-CCL5 mAb significantly reduced both infarct size and post-infarction heart failure in a mouse model of chronic cardiac ischaemia. Cardioprotective effects were associated with the reduction of leucocyte recruitment within infarcted hearts.

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Nampt inhibition appears as a new strategy to dampen CXCL2-induced neutrophil recruitment and thereby reduce neutrophil-mediated tissue injury in mice.