Aernoud Fiolet

24 Chapter 1 THE SHARPLY SPIKED LINKING COMPONENTS: CHOLESTEROL CRYSTALS As we now know, there certainly is a great pool of evidence for the causal and essential role of these cytokines in many inflammatory diseases—and as such they are a conditio sine qua non for atherothrombosis. The next crucial mechanism is that of plaque destabilisation. The relation of cholesterol, inflammation and plaque destabilisation is described below. Plaque destabilisation Three different mechanism can compromise the integrity of the cap covering the lipid core of the atheroma: erosion, rupture, and haemorrhage. Data from large histopathological series indicate a contemporary change in ratio in favour of the former. 68,69 These phenomena and the subsequent thrombotic sequelae may cause partial or complete luminal obstruction leading to distal ischaemia. This will contribute to tissue injury, clinical symptomatology and eventually tissue damage with functional impairment of the corresponding organ. The haemostasis, aimed to be of a protective effect of the local vascular damage, thus comes at high costs when it compromises luminal patency and distal tissue viability. The cap of the fibroatheroma is formed after relocalisation of smooth vascular muscle cells and consists of collagen structures. (Figure 1) Classically, ruptured caps are often thin (the “thin-capped fibroatheroma”) and showhigh levels of matrix metalloproteinases, that have collagenase properties. 70,71 An important role in the loss of cap integrity has thus been assigned to the presence of these enzymes. 72 The matrix- metalloproteinases are unique in their interstitial collagenase activity and are produced in plaques by macrophages. In vulnerable or ruptured plaques predominantly matrix metalloproteinases 1, 8, and 18 are found. The expression of these matrix metalloproteinases by macrophages is regulated by, among others, T‑cells and increased in regions with low shear stress. 73,74 The degraded, thin cap will further disintegrate in these circumstances, ultimately initiating the unfortunate thrombotic cascade.