Authors:
K. T. Tan1, H. W. Aw-Yeang2, D. Bakshi2; 1Bristol/UK, 2Liverpool/UK
DOI:
10.1594/ECR05/C-1069
Background
The concept of atherosclerosis as an inflammatory disease was firstpopularised by Ross in the 1990s(1). Since then, there has been countless clinical and basic science studies to support the original hypothesis. Indeed, it has been demonstrated that the degree of the inflammatory response, as measured by high-sensitivity C-reactive protein (hsCRP) levels, can be related to the risk of developing adverse atherosclerotic events(2).
Inflammation is associated with all stages of atherosclerosis(1). An initial pathological insult(e.g. high cholesterol, free radicals, homocysteine) damages the arterial endothelial lining(Figure 1). Persistence of the insult results ina chronic inflammatory reaction in the vessel wall, with the release of proinflammatory molecules. Macrophages are recruited into the vessel wall, where they take up oxidised low-density lipoproteins (LDL) to form foam cells. Subsequent macrophage cell death results in the formation of the so-called lipid core. In addition, there is a proliferation of smooth muscle cells (SMC)over the lipid core to form the fibrous cap. The combination of fibrous cap and lipid core forms the characteristic lesion of atherosclerosis.
The shape and size of the lumen of an atherosclerotic arterymay remain virtually unchangeduntil a relatively late stage of the disease due to remodelling of the blood vessel wall. The symptoms of chronic atherosclerosis often only appear in the late stages of disease when the limit of positive remodelling has been reached and the atherosclerotic plaque begins to cause significant obstruction to blood flow (Figure 2).
Inflammation is also associated with instability of the atherosclerotic plaque(3) . Further recruitment and subsequent death of the lipid-laden macrophages in the plaque leads to enlargement of the lipid core. The further release of pro-inflammatory molecules(e.g. CD40L) can promote cell death (particularly of SMCs) andbreakdown of the local connective tissue, leading to thinning of the fibrous cap. The combination of a large lipid core and thin fibrouscap can lead to plaque instability, resulting in a predisposition to rupture. Plaque rupture results in the symptoms of 'acute atherosclerosis', which may present without prior symptoms of chronic atherosclerosis.
Extravascular plaque rupture can result in haemorrhage and distal ischaemia (e.g. aortic and popliteal aneurysms) (Figure 3). Intravascular plaque rupture exposes the thrombogenic lipid core and sub-endothelium to the blood, resulting in thrombosis and possibly distal ischaemia. The processes of thrombosis and inflammation are closely linked, whereby thrombosis can initiate inflammation and vice versa. Indeed, the inflammatory reaction to an acute thrombotic event can lead to deleterious clinical outcomes, as observed in the brains of patients who have suffered a cerebral infarct(4).