The notion of atherosclerosis as a chronic inflammatory disease has intensified research on the role of cytokines and the way these molecules act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are expressed by all types of cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects, and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leucocytes, and other vascular residing cells. It is now understood that widely used drugs such as statins, aspirin, methotrexate, and colchicine act in an immunomodulatory way that may beneficially affect atherogenesis and/or cardiovascular disease progression. Moreover, advancement in pharmaceutical design has enabled the production of highly specific antibodies against key molecules involved in the perpetuation of the inflammatory cascade, raising hope for advances in the treatment of atherosclerosis. This review describes the actions and effects of these agents, their potential clinical significance, and future prospects.

/pdf/inflammatory-cytokines-in-atherosclerosis-current-4kab0gb2i4.pdf

Inflammatory cytokines in atherosclerosis: current therapeutic approaches.

The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear.

Statins for acute coronary syndrome

Advanced glycation end products (AGEs) are a heterogeneous group of irreversible adducts resulting from non-enzymatic glycation and oxidation of proteins, lipids and nucleic acids (1,2). AGEs act on cell receptors for AGEs (RAGEs). There are three forms of RAGEs (2–5) – full-length, N-truncated and C-truncated soluble RAGEs (sRAGE). The interaction of full-length RAGE with AGEs leads to increased expression of adhesion molecules, including soluble vascular cell adhesion molecule-1 (sVCAM-1) and the cytokine tumor necrosis factor-alpha (TNF-α) (2,6,7); activation of nuclear factor-kappa B (6), which in turn leads to increased expression of proinflammatory genes for adhesion molecules and cytokines (2); and generation of oxygen radicals (8,9). sRAGE circulates in the plasma (4) and acts as a decoy for RAGE ligands, competing with full-length RAGE for ligand binding (10). It has a protective role by preventing the activation of full-length RAGE.

Adhesion molecules, cytokines and oxygen radicals are involved in atherosclerosis, progression of lesions and lesion instability (11–14). The AGEs and RAGE axis has been implicated in the pathogenesis of atherosclerosis in diabetes (15–17). sRAGE in animal models reduces atherosclerotic lesions, aortic vascular cell adhesion molecule-1 and tissue factor (18–20). The proximate cause of acute coronary syndrome (ACS) is thrombosis and the principal underlying cause is atherosclerosis. Because the combination of AGEs, RAGEs and sRAGE determines the extent of vascular injury, the measurement of these factors is appropriate for determining vascular complications. However, it is not possible to measure RAGE in humans, which is on the cell surface of the artery.

It is hypothesized that non-ST elevation myocardial infarction (NSTEMI) patients have lower levels of serum sRAGE and/or higher levels of AGEs, and a higher ratio of AGEs to sRAGE (AGEs/sRAGE) than healthy subjects. Because the interaction of RAGE with AGEs results in increased expression of cytokines and adhesion molecules, and because sRAGE neutralizes AGEs, low sRAGE levels would be associated with high levels of TNF-α and sVCAM-1. Therefore, the main objectives of the present study are to determine whether levels of serum sRAGE are lower, and whether levels of serum AGEs and AGEs/sRAGE are higher in NSTEMI patients than in healthy subjects; whether low levels of serum sRAGE, and high levels of serum AGEs and AGEs/sRAGE are associated with high levels of serum TNF-α and sVCAM-1; whether the number of diseased coronary arteries is negatively correlated with serum sRAGE and positively correlated with serum TNF-α, sVCAM-1, AGEs and AGEs/sRAGE; and whether the level of sRAGE or AGEs/sRAGE is a better biomarker/predictor of NSTEMI.

/pdf/low-levels-of-soluble-receptor-for-advanced-glycation-end-14250yccxd.pdf

Low levels of soluble receptor for advanced glycation end products in non-ST elevation myocardial infarction patients.

The effects of statin use on inflammatory markers among patients with metabolic syndrome and related disorders: A systematic review and meta-analysis of randomized controlled trials.

Elevated plasma levels of the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 (PAI-1) may contribute to the pathogenesis of atherosclerotic cardiovascular disease. Beyond their lipid-lowering effect, statins have been shown to modulate plasma PAI-1 levels but evidence from individual randomised controlled trials (RCTs) is controversial. Therefore, we aimed to assess the potential effects of statin therapy on plasma PAI-1 concentration through a meta-analysis of RCTs. We searched Medline and SCOPUS databases (up to October 3, 2014) to identify RCTs investigating the effect of statin therapy on plasma PAI-1 concentrations. We performed random-effects meta-analysis and assessed heterogeneity (I² test, subgroup and sensitivity analyses) and publication bias (funnel plot, Egger and “trim and fill” tests). Sixteen RCTs (comprising 19 treatment arms) were included and pooled analyses showed a significant effect of statins in reducing plasma PAI-1 concentrations (weighted mean difference WMD: –15.72 ng/ml, 95 % confidence interval [CI]: –25.01, –6.43,). In subgroup analysis, this effect remained significant in with lipophilic statins (atorvastatin and simvastatin) (WMD: –21.32 ng/ml, 95 % CI: –32.73, –9.91, I²=99 %) and particularly atorvastatin (WMD: –20.88 ng/mL, 95 % CI: –28.79, –12.97, I2=97 %). In the meta-regression analysis, the impact of statins on PAI-1 did not correlate with the administered dose, duration of treatment and changes in plasma LDL-cholesterol concentrations. Finally, evidence of publication bias was observed. In conclusion, taking into account the limit of heterogeneity between studies, the present meta-analysis suggests that statin therapy (mainly atorvastatin) significantly lowers plasma PAI-1 concentrations.

Impact of statin therapy on plasma levels of plasminogen activator inhibitor-1. A systematic review and meta-analysis of randomised controlled trials.

Relationship between whole grain consumption and arterial stiffness. Results of the Corinthia cross-sectional study.

Early initiation of low-dose atorvastatin treatment after an acute ST-elevated myocardial infarction, decreases inflammatory process and prevents endothelial injury and activation

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Relationship between whole grain consumption and arterial stiffness. Results of the Corinthia cross-sectional study.

Early initiation of low-dose atorvastatin treatment after an acute ST-elevated myocardial infarction, decreases inflammatory process and prevents endothelial injury and activation