The Biological Role of Inflammation in Atherosclerosis Brian W. Wong, PhD, Anna Meredith, BSc, David Lin, BMLSc, Bruce M. McManus, PhD, MD  Canadian Journal of Cardiology  Volume 28, Issue 6, Pages 631-641 (November 2012) DOI: 10.1016/j.cjca.2012.06.023 Copyright © 2012 Canadian Cardiovascular Society Terms and Conditions

Figure 1 Evolution of human atherosclerosis. Fatty streaks represent one of the earliest visible lesions in atherogenesis, and have been observed early in life. These fatty streaks often evolve into fibrous plaques, coupled with intimal hyperplasia and accompanying changes to the extracellular matrix. As these fibrous plaques further grow, they may progress toward several outcomes depending on microenvironmental and environmental factors: [i] occlusive thrombosis, as a result of fibrous cap rupture because of the combination of endothelial cell loss revealing the prothrombotic basal lamina, degradation of the fibrous cap as a result of proteases or proteinases or possibly through volume expansion and puncture as a result of cholesterol crystals; [ii] intraplaque hemorrhage, as a result of abnormal neovascularization, vascular permeability, or increasing plaque volume; [iii] stenosis, as a result of progressive luminal reduction by plaques leading to further lipid-richness, fibrosis, and “hardening” of the arteries; or [iv] mural thrombic accretion, as a result of excess subendothelial accumulation of fibrin and platelets. Canadian Journal of Cardiology 2012 28, 631-641DOI: (10.1016/j.cjca.2012.06.023) Copyright © 2012 Canadian Cardiovascular Society Terms and Conditions

Figure 2 Inflammatory mediators in atherosclerosis. (A) Numerous inflammatory cell types play major roles in mediating the inflammatory response which is part of atherosclerosis, including T-cells, monocytes, and neutrophils. Early insudation and retention of lipid and lipoproteins contribute to the initial and continued inflammatory response, especially when the lipids are oxidatively modified. These lipids and lipoproteins are taken up by macrophages, dendritic cells, and smooth muscle cells to form lipid-laden foam cells. Proinflammatory cytokines, chemokines, and growth factors serve to further elaborate this response in the vessel wall. Together, in addition to external factors such as hypoxia, reactive oxygen species (ROS) and nitric oxide (NO) (in excess), inflammation within the atherosclerotic lesion fuels atheroprogression. (B) Early during atherogenesis, monocytes and dendritic cells infiltrate into the vessel wall. (C) During progression of atherosclerosis, infiltrating monocytes differentiate into macrophages and T-cells and other leukocytes enter the vessel wall. (D) As the atherosclerotic lesion further develops, macrophage and foam cells predominate, and further serve to alter the plaque microenvironment, changing extracellular matrix composition and decreasing smooth muscle cell content, predisposing to plaque rupture. Canadian Journal of Cardiology 2012 28, 631-641DOI: (10.1016/j.cjca.2012.06.023) Copyright © 2012 Canadian Cardiovascular Society Terms and Conditions

Figure 3 Progression of atherosclerosis and plaque formation. (A) The subendothelial retention of lipoproteins is an early initiating factor in atherogenesis. (B) This initiating process results in monocyte chemotaxis in response to trapped low-density lipoprotein particles. As well, the intimal layer expands, coupled with changes in extracellular matrix composition, including glycosaminoglycan-rich proteoglycans which have high affinity for apolipoprotein B. (C) Lipoprotein uptake by macrophages results in foam cell formation, further advancing the atherosclerotic lesion. Even minimally modified low-density lipoprotein can lead to cholesterol crystal formation, leading to Nod-like receptor P3 inflammasome priming and macrophage activation. (D) Cholesterol crystals can be found not only within the lipid-rich necrotic core, but also in subendothelial areas both intra- and extracellularly. Resultant macrophage and foam cell death may result directly because of cholesterol crystals, leading to release of intracellular contents including lipoproteins, further expanding the necrotic core. Cholesterol crystals can also further activate Nod-like receptor P3 inflammasomes, maintaining the pathological inflammatory response within the atherosclerotic lesion. SMC, smooth muscle cell. Canadian Journal of Cardiology 2012 28, 631-641DOI: (10.1016/j.cjca.2012.06.023) Copyright © 2012 Canadian Cardiovascular Society Terms and Conditions