Aernoud Fiolet

14 Chapter 1 initiation and development of atherothrombotic plaque. Moreover, both play a crucial role in the metamorphosis of a chronic-stable disease to an acute-unstable disease. Inflammation in atherothrombosis is complex, and to understand how to modulate such mechanisms, one first needs to establish the basic elements of the immunological response that follow the many vascular threats experienced during lifetime. The understanding of this interplay of protective mechanisms has been slowly unravelled by years of experimental and clinical research. Paradoxically, the more actors that are identified, the more limited our actual understanding seems. However, when accurately aligning the windows of insights offered to us by preceding scientists, we may still glimpse ways to intervene—albeit these insights always come with new biological and methodological challenges. We then may come to realise, freely paraphrasing Sir William Osler, that he who understands inflammation, understands medicine. THE BIOLOGICAL PERSPECTIVE: BASIC ELEMENTS OF THE IMMUNOLOGICAL RESPONSE IN ATHEROTHROMBOSIS Endothelial dysfunction A hallmark in the origin of atherothrombosis is endothelial dysfunction, which comprises increased endothelial permeability to lipoproteins, leukocyte adherence, a prothrombotic state, and decreased vasomotor function. 4,6,7 These alterations in endothelial state first occur in predisposing regions. These are the regions that have calibre changes or bifurcations that lead to the disruption of the laminar blood flow, resulting in a more turbulent flowwith lower shear stress encountered by the endothelium. 8 Hypertension, oxidative stress, and hypercholesterolaemia further induce the endothelial changes, which are mediated by transcriptional factors such as nuclear factor kB. 9 Although endothelial dysfunction denotes impairment of any of its properties, its inability to adequately maintain vascular tone is used clinically as an objective measure and is associated with future development of atherothrombosis. 10 Initiation of the fatty streak and fibroatheroma Following the increased permeability of the endothelium, ApoB-containing lipoproteins will enter the extracellular matrix of the intima. Most notably are