Inflammatory response to percutaneous coronary intervention in stable coronary artery disease.

Percutaneous coronary intervention (PCI) can be regarded as a model for mechanical induced plaque rupture. The objective of this study was to evaluate the inflammatory response to PCI in stable coronary artery disease (CAD) by analysing plasma levels of a wide range of inflammatory mediators. Consecutively, we included 36 patients with stable angina pectoris after successful revascularization by PCI with implantation of a bare metal stent (BMS) or a drug eluting stent (DES). Patients were followed for 7 days with serial measurements of inflammatory mediators in plasma. C-reactive protein (CRP) and Pentraxin 3 showed a statistical significant early increase after PCI peaking at 3 days and 3 h, respectively. Vascular cell adhesion molecule-1 (VCAM-1) increased significantly with a peak at 3 days, while E-selectin showed a statistical significant gradual decrease. Markers of platelet mediated inflammation showed increasing (CD40 ligand) and decreasing (P-selectin) levels after PCI. While monocyte chemoattractant protein, CCL21 and CXCL16 increased rapidly in response to PCI, Interleukin-8, CCL19 and RANTES decreased. Patients with DES had significantly lower levels of VCAM-1 and RANTES compared to those with BMS. A femoral access site was associated with higher CRP levels than a radial access site. The use of glycoprotein-IIb/IIIa-inhibitors was associated with significantly higher CD40L and RANTES levels. Our findings underscore the complex nature of the inflammatory responses during PCI in stable CAD, and suggest that simultaneous measurements of several markers may be needed to characterize these PCI-related responses. The responses were only in a minor degree influenced by stent type, access site and the use of glycoprotein-IIb/IIIa-inhibitors.

Inflammatory markers in patients with coronary artery disease with and without inflammatory rheumatic disease.

OBJECTIVES: Patients with inflammatory rheumatic diseases (IRDs) have a higher morbidity and mortality from accelerated atherosclerosis than the general population. We hypothesized that patients with the combination of IRD and coronary artery disease (CAD) would have a certain inflammatory phenotype compared with CAD patients without this comorbidity. METHODS: Four groups of patients were included: patients with IRD, referred to coronary artery bypass grafting (CABG) (CAD-IRD, n = 67), patients without IRD, referred to CABG (CAD, n = 52), patients with IRD without CAD (IRD, n = 32) and healthy controls (n = 30). Plasma levels of several inflammatory markers were analysed by enzyme immunoassays. RESULTS: (i) Plasma levels of markers of endothelial cell activation [i.e. vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor] and osteoprotegerin (OPG) were significantly increased and plasma levels of CCL21 significantly decreased in CAD-IRD patients as compared with CAD patients without IRD. (ii) Within the CAD-IRD group, acute coronary syndrome was a significant predictor of OPG, suggesting an enhanced inflammatory response during plaque destabilization in CAD-IRD patients. (iii) Plasma levels of VCAM-1, OPG and CCL21, but not lipid parameters, IRD characteristics and several other inflammatory markers (e.g. CRP), were significant predictors of CAD-IRD as opposed to CAD in two logistic regression models. CONCLUSION: Our findings further support a role for inflammation in the accelerated form of atherosclerosis in IRD patients, and suggest that certain inflammatory pathways, such as the enhanced endothelial cell activation and the RANK ligand/RANK/OPG system, may be of particular importance.

A potential role of the CXC chemokine GROalpha in atherosclerosis and plaque destabilization: downregulatory effects of statins.

OBJECTIVE: We examined the role of the CXCR2 ligand growth-related oncogene (GRO) alpha in human atherosclerosis. METHODS AND RESULTS: GROalpha levels were examined by enzyme immunoassay, real-time quantitative RT-PCR, and cDNA microarrays. The in vitro effect of statins on GROalpha was examined in endothelial cells and THP-1 macrophages. Our main findings were: (1) GROalpha was among the 10 most differentially expressed transcripts comparing peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) and healthy controls. (2) Both patients with stable (n=41) and particularly those with unstable (n=47) angina had increased plasma levels of GROalpha comparing controls (n=20). (3) We found increased expression of GROalpha within symptomatic carotid plaques, located to macrophages and endothelial cells. (4) GROalpha enhanced the release of matrix metalloproteinases in vascular smooth muscle cells, and increased the binding of acetylated LDL in macrophages. (5) Atorvastatin downregulated GROalpha levels as shown both in vitro in endothelial cells and macrophages and in vivo in PBMCs from CAD patients. (6) The effect on GROalpha in endothelial cells involved increased storage and reduced secretion of GROalpha. CONCLUSIONS: GROalpha could be involved in atherogenesis and plaque destabilization, potentially contributing to inflammation, matrix degradation, and lipid accumulation within the atherosclerotic lesion.

High levels and inflammatory effects of soluble CXC ligand 16 (CXCL16) in coronary artery disease: down-regulatory effects of statins.

AIMS: CXC ligand 16 (CXCL16) may be involved in inflammation and lipid metabolism, and we hypothesized a role for this chemokine in coronary artery disease (CAD). METHODS AND RESULTS: We performed clinical studies in CAD patients as well as experimental studies in cells with relevance to atherogenesis [i.e. endothelial cells, vascular smooth muscle cells (SMC), and peripheral blood mononuclear cells (PBMC)]. We also examined the ability of HMG-CoA reductase inhibitors (statins) to modulate CXCL16 levels both in vivo and in vitro. Our main findings were: (i) patients with stable (n = 40) and unstable (n = 40) angina had elevated plasma levels of CXCL16 compared with controls (n = 20); (ii) low-dose simvastatin (20 mg qd, n = 15) and high-dose atorvastatin (80 mg qd, n = 9) down-regulated plasma levels of CXCL16 during 6 months of therapy; (iii) in vitro, atorvastatin significantly decreased the interleukin (IL)-1beta-mediated release of CXCL16 from PBMC and endothelial cells; (iv) attenuating effect of atorvastatin on the IL-1beta-mediated release of CXCL16 in PBMC seems to involve post-transcriptional modulation as well as down-regulation of CXCL16 release through inhibition of the protease a disintegrin and metalloproteinase 10 (ADAM10); (v) soluble CXCL16 increased the release of IL-8, monocyte chemoattractant peptide 1, and matrix metalloproteinases in vascular SMC and increased the release of IL-8 and monocyte chemoattractant peptide 1 in PBMC, with particularly enhancing effects in cells from CAD patients. CONCLUSION: Our findings suggest that soluble CXCL16 could be linked to atherogenesis not only as a marker of inflammation, but also as a potential inflammatory mediator.

Statins affect the presentation of endothelial chemokines by targeting to multivesicular bodies.

BACKGROUND: In addition to lowering cholesterol, statins are thought to beneficially modulate inflammation. Several chemokines including CXCL1/growth-related oncogene (GRO)-α, CXCL8/interleukin (IL)-8 and CCL2/monocyte chemoattractant protein (MCP)-1 are important in the pathogenesis of atherosclerosis and can be influenced by statin-treatment. Recently, we observed that atorvastatin-treatment alters the intracellular content and subcellular distribution of GRO-α in cultured human umbilical vein endothelial cells (HUVECs). The objective of this study was to investigate the mechanisms involved in this phenomenon. METHODOLOGY/ PRINCIPAL FINDINGS: The effect of atorvastatin on secretion levels and subcellular distribution of GRO-α, IL-8 and MCP-1 in HUVECs activated by interleukin (IL)-1ß were evaluated by ELISA, confocal microscopy and immunoelectron microscopy. Atorvastatin increased the intracellular contents of GRO-α, IL-8, and MCP-1 and induced colocalization with E-selectin in multivesicular bodies. This effect was prevented by adding the isoprenylation substrate GGPP, but not the cholesterol precursor squalene, indicating that atorvastatin exerts these effects by inhibiting isoprenylation rather than depleting the cells of cholesterol. CONCLUSIONS/ SIGNIFICANCE: Atorvastatin targets inflammatory chemokines to the endocytic pathway and multivesicular bodies and may contribute to explain the anti-inflammatory effect of statins at the level of endothelial cell function.

Raised MCP-4 levels in symptomatic carotid atherosclerosis: an inflammatory link between platelet and monocyte activation.

AIMS: Several studies suggest a pro-atherogenic role for the CC chemokine receptor 2 (CCR2), thought to reflect interaction with monocyte chemoattractant protein (MCP)-1. Based on its ability to attract leucocytes into inflamed tissue, we hypothesized a pro-atherogenic role for MCP-4, another CCR2 ligand. METHODS AND RESULTS: Our main findings were: (i) patients with symptomatic carotid stenosis (n = 29), but not those with asymptomatic plaques (n = 31), had significantly raised plasma levels of MCP-4 compared with healthy controls (n = 20); (ii) in vitro, releasate from activated platelets markedly increased the expression of MCP-4 and CCR2 in THP-1 monocytes, and enhanced the MCP-4-mediated effect on interleukin-8 secretion in these cells, involving the platelet-derived chemokine RANTES; (iii) while MCP-1 had no effect on the release of RANTES and interferon-inducible protein of 10 kDa in tumour necrosis factor alpha-pre-activated THP-1 monocytes, MCP-4 profoundly enhanced the release of these pro-atherogenic chemokines; and (iv) the data indicate an inflammatory interaction between RANTES and MCP-4, involving CCR2, and mRNA levels of these mediators were markedly up-regulated within symptomatic atherosclerotic carotid plaque (n = 81). CONCLUSION: Our findings suggest that the pro-atherogenic effects of CCR2 may not be restricted to interaction with MCP-1, but could also involve activation by MCP-4, being an inflammatory link between platelet and monocyte activation.

The chemokine network in relation to infarct size and left ventricular remodeling following acute myocardial infarction.

Increased circulating chemokines have been reported during acute myocardial infarction and might give prognostic information about future ischemic events. However, data on the chemokine network in relation to infarct size and measures of left ventricular remodeling after successful percutaneous coronary intervention (PCI) are lacking. A total of 42 patients with first-time ST-segment elevation acute myocardial infarction with a single occluded vessel were recruited, and cardiac magnetic resonance was used for serial assessment (2, 7, and 60 days) of infarct size and left ventricular remodeling. The chemokines were analyzed before and after PCI. After PCI, high levels of CCL4, CXCL16, CXCL10, and, in particular, CXCL8 within the first week after PCI correlated positively with the degree of myocardial damage, as reflected by correlations with the maximum troponin T levels and infarct size after 2 months, as assessed by cardiac magnetic resonance, and with impaired myocardial function after 2 months as assessed by cardiac magnetic resonance and neurohormonal methods. In contrast, the plasma levels of CCL3 and CXCL7 during the first week correlated negatively with myocardial dysfunction after 2 months. In conclusion, our findings suggest a role for chemokines in both adaptive and maladaptive responses after myocardial infarction and might support a role for CCL4, CXCL16, CXCL10, and, in particular, CXCL8 in postmyocardial infarction reperfusion and remodeling.