Systemic inflammation and early atheroma formation: are they related?

Abstract

Atherosclerosis is a chronic inflammatory disease started by endothelial injury and defined by arterial wall load with free and esterified cholesterol, followed by subintimal focal recruitment of circulating monocytes and T-lymphocytes that heals by fibrosis and calcification. Inflammation plays a crucial role in atherogenesis either by local cellular mechanisms or humoral consequences easily measurable in plasma. In most cases inflammation and endothelial dysfunction are triggered by cardiovascular risk factors: hypercholesterolemia, hypertension, smoking or diabetes. In other cases inflammation precedes atherosclerotic changes that occur in autoimmune diseases, as systemic lupus erythematosus and rheumatoid arthritis. In these diseases atherogenesis is mostly independent from conventional risk factors. Irrespective of its cause systemic inflammation is correlated with cardiovascular events, but currently there are controversial results regarding inflammatory markers and early atherosclerotic process. We designed a study to identify if the amplitude of inflammation expressed by multiple serum markers is correlated with the severity of the atherosclerotic process measured by coronary atheroma volume and carotid intima-media thickness. The selected inflammatory markers are associated with different pathogenic steps in atherogenesis: acute phase reactants (C-reactive protein); pro-inflammatory cytokines (TNF-alpha, interleukin-6 and -18); endothelium activation markers (soluble VCAM-1, ICAM-1); and specific factors (anticardiolipinic antibodies). We aim to enrol the two different patient subsets with early atherosclerosis: one with conventional risk factors and one with autoimmune diseases without traditional risk factors, in whom inflammation is part of the systemic disease progression.

Keywords: early atheroma formation; systemic inflammation.

Figure 1. The connections between risk factors, endothelial dysfunction and atherogenesis that promote systemic inflammation.

Ang-II: angiotensin-II; AGE: advanced glycation end-products; ROS: reactive oxygen species; NO: nitric oxyde; MMP: matrix metalloproteinases; MCP-1: monocyte chemotactic protein-1; TNF: tumor necrosis factor; Il: interleukins; SAA: serum amyloid A

Figure 2. The pathogenic role of CRP in the mechanisms of atherogenesis. CRP is fixed on platelets as a pentameric integrin and it is transformed in a monomer that atracts monocytes and stimulates their adhesion and transmigration in the subendothelial space. Here CRP co-localizes with LDL and it is specifically uptaken in the macrophages by specific receptors. Macrophages subsequently upregulate adhesion molecules, sinthesize tissue factor and activate complement. Interleukin-6 is the main citokyne responsible for increased liver synthesis of CRP

Figure 3. Practical way to assess the surface of coronary atheroma by IVUS planimetry of the blood-vessel interface (lumen surface) and vessel surface at the level of external elastic membrane (EEM)

A.

B.

B.

B.