RESUMO
BACKGROUND AND PURPOSE: Myeloid-related protein (Mrp) 8/14 complex is the functional relevant form of Mrp-8 and Mrp-14. Mrp-8/14 complex is actively formed in the cytoplasm of circulating neutrophils and monocytes and then secreted. Plasma Mrp-8/14 complex is emerging as a new biomarker that may discriminate between patients with an acute coronary syndrome and those with stable coronary heart disease. Little is known about the predictive value of Mrp-8/14 plaque and plasma levels for cardiovascular events after atherectomy. METHODS: Plasma and plaque Mrp-8/14 levels were determined by ELISA in 230 consecutive patients (mean age 73) who underwent carotid endarterectomy. Patients were followed for 3 years for recurrent cardiovascular events (vascular death, nonfatal vascular event, and peripheral intervention). During follow-up, 62 patients experienced an event. Baseline Mrp-8/14 levels were higher in patients who experienced an event than in event-free patients (plasma 0.78+/-0.63 versus 0.57+/-0.67 mg/L; P=0.030 and plaque 0.54+/-1.23 versus 0.08+/-1.51 mg/kg; P=0.027). In a Cox model, a 1 U increase in log Mrp-8/14 was associated with an increased risk of recurrent events (plasma, hazard ratio [HR], 1.51; 95% CI, 1.02 to 2.23, P=0.040; and plaque, HR, 1.23, 95% CI, 1.04 to 1.46, P=0.018). After multivariate adjustment for risk factors (both plasma and plaque Mrp-8/14) and plaque characteristics (only plaque Mrp-8/14), the HR remained the same for both plasma (HR, 1.50, 95% CI, 1.01 to 2.30; P=0.046) and plaque (HR, 1.20, 95% CI, 1.01 to 1.44; P=0.042). CONCLUSIONS: High Mrp-8/14 plasma and plaque levels are related to an increased risk of adverse cardiovascular events after a carotid endarterectomy, independent of traditional cardiovascular risk factors.
Assuntos
Doenças Cardiovasculares/sangue , Endarterectomia das Carótidas , Complexo Antígeno L1 Leucocitário/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Prospectivos , Risco , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: To score the number of plaque neutrophils and relate the score to plaque morphology and inflammatory status. METHODS AND RESULTS: Neutrophils are inflammatory cells with tissue destruction capabilities that have been found at the site of an atherosclerotic plaque rupture or erosion. Poor evidence exists for neutrophil infiltration in human carotid atherosclerotic plaques, and its association with plaque morphology has not yet been described. A set of 355 human carotid plaques was stained for the neutrophil marker CD66b. High neutrophil numbers were found in plaques with a large lipid core, high macrophage numbers, and low collagen amount and smooth muscle cell numbers. High neutrophil numbers were associated with high interleukin 8 (P<0.001) and matrix metalloproteases 8 (P=0.005) and 9 (P<0.001) plaque levels. High microvessel density within plaques was correlated with high neutrophil numbers (P=0.01). In addition, low numbers of neutrophils were associated with female sex and use of beta-blockers. CONCLUSIONS: For the first time to our knowledge, these results show that neutrophil numbers are strongly associated with the histopathologic features of rupture-prone atherosclerotic lesions and suggest a role for neutrophils in plaque destabilization.
Assuntos
Artérias Carótidas/imunologia , Doenças das Artérias Carótidas/imunologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Antagonistas Adrenérgicos beta/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/análise , Biomarcadores/análise , Artérias Carótidas/química , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Moléculas de Adesão Celular/análise , Colágeno/análise , Progressão da Doença , Feminino , Proteínas Ligadas por GPI , Humanos , Imuno-Histoquímica , Interleucina-8/análise , Contagem de Leucócitos , Lipídeos/análise , Modelos Logísticos , Macrófagos/patologia , Masculino , Metaloproteinase 8 da Matriz/análise , Metaloproteinase 9 da Matriz/análise , Microvasos/patologia , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , Países Baixos , Razão de Chances , Medição de Risco , Fatores de Risco , Ruptura , Índice de Gravidade de Doença , Fatores Sexuais , Regulação para CimaRESUMO
Innate immunity is important in the pathogenesis and progression of cardiovascular disease. Innate immune cells express various pattern-recognition receptors, among which also Toll-like receptors (TLRs). TLRs occur in atherosclerotic lesions where they are triggered by both exogenous (bacterial and viral pathogens) and endogenous (tissue damage-associated) molecules. Several endogenous TLR activators are described in relation to atherosclerotic disease or ischemia-induced cardiac injury. Experimental animal models have proved the role of TLR endogenous activators in disease initiation and further development. Nowadays, researchers aim to unravel the exact mechanisms involved in the endogenous ligand-dependent TLR signaling and to discover new potential activators, released during pathological conditions such as atherosclerosis and related ischemic manifestations. This review provides an overview of the currently known endogenous molecules which trigger innate immunity via TLRs in cardiovascular disease.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Doenças Cardiovasculares/imunologia , Proteínas de Choque Térmico/metabolismo , Inflamação/metabolismo , Ligantes , Receptores Toll-Like/metabolismo , Animais , Humanos , Inflamação/imunologia , CamundongosRESUMO
OBJECTIVE: Atherosclerotic plaque rupture can lead to severe complications such as myocardial infarction and stroke. Myeloid related protein (Mrp)-14, Mrp-8, and Mrp-8/14 complex are inflammatory markers associated with myocardial infarction. It is, however, unknown whether Mrps are associated with a rupture-prone plaque phenotype. In this study, we determined the association between Mrp-14, -8, -8/14 plaque levels and plaque characteristics. METHODS AND RESULTS: In 186 human carotid plaques, levels of Mrp-14, -8, and -8/14 were quantified using ELISA. High levels of Mrp-14 were found in lesions with a large lipid core, high macrophage staining, and low smooth muscle cell and collagen amount. Plaques with high levels of Mrp-14 contained high interleukin (IL)-6, IL-8, matrix metalloprotease (MMP)-8, MMP-9, and low MMP-2 concentrations. Mrp-8 and Mrp-8/14 showed a similar trend. Within plaques, a subset of nonfoam macrophages expressed Mrp-8 and Mrp-14 and the percentage of Mrp-positive macrophages was higher in rupture-prone lesions compared to stable ones. In vitro, this subset of macrophages does not acquire a foamy phenotype when fed oxLDL. CONCLUSIONS: Mrp-14 is strongly associated with the histopathologic features and the inflammatory status of rupture-prone atherosclerotic lesions, identifying Mrp-14 as a local marker for these plaques.
Assuntos
Aterosclerose/metabolismo , Calgranulina B/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/metabolismo , Aterosclerose/patologia , Aterosclerose/cirurgia , Biomarcadores/metabolismo , Calgranulina A/metabolismo , Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/cirurgia , Endarterectomia das Carótidas , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Macrófagos/metabolismo , Macrófagos/patologia , Estudos Retrospectivos , Ruptura EspontâneaRESUMO
UNLABELLED: During collateral artery growth, monocytes adhere to the endothelium and secrete cytokines from the perivascular space promoting arteriogenesis. Recently, the endothelial glycocalyx has been shown to modulate leucocyte infiltration in atherogenic regions. The role of this endothelial surface coating in arteriogenesis, however, has not been investigated so far. We now report that local plasma levels of hyaluronic acid are specifically increased in collateral arterial blood of coronary artery disease patients and hypothesized that components of the endothelial glycocalyx are shed during arteriogenesis, resulting in decreased glycocalyx dimensions and an increased leucocyte extravasation. In a rabbit model of femoral artery ligation, electron microscopy revealed a decrease in glycocalyx dimensions in collateral arteries compared with quiescent anastomoses (67.5 +/- 47.2 nm versus 101.0 +/- 11.3 nm; P < 0.001). This decrease was correlated with a higher number of perivascular macrophages around collateral arteries. The additional glycocalyx perturbation by local hyaluronidase infusion almost completely removed the endothelial surface layer and temporarily stimulated leucocyte accumulation in the perivascular space. However, complete perturbation of the glycocalyx by hyaluronidase infusion resulted in a significant attenuation of collateral artery growth assessed by microsphere-based perfusion measurements (ml/min/100 mmHg: hyaluronidase: 27.5 +/- 3.5; CONTROLS: 47.1 +/- 3.83; P < 0.001) and a lower percentage of actively proliferating vascular smooth muscle cells. A decreased expression of the shear-stress regulated pro-arteriogenic genes eNOS and TGF-beta1 suggests an impaired mechanotransduction as the underlying mechanisms. For the first time, we describe the role of the endothelial glycocalyx in collateral artery growth. Although complete abrogation led to attenuated arteriogenesis, shedding of glycocalyx components is observed during collateral artery growth.