Chapter 12 Pathophysiology of Atherosclerosis © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 1 Early stages of atherosclerosis development FIGURE 12.1 Early stages of atherosclerosis development. Shown are histologic images of human internal thoracic artery. The internal thoracic artery is normally highly resistant to atherosclerosis, but will develop atherosclerosis later in life. (A) The normal artery has a very thin intima. (B) In intimal thickening/intimal hyperplasia the intima becomes thickened due to the presence of smooth muscle cells (SM) beneath the endothelium. (C) The fatty streak is characterized by the appearance of macrophage foam cells (FC) within the thickened intima. (D) More advanced atherosclerotic lesions are characterized by the appearance of extracellular lipid (Li) which first appears interdigitating between the smooth muscle cells. The arrows indicate the internal elastic lamina, the boundary between the intima and the media. (Reproduced with permission from Cizek SM, Bedri S, Talusan P, Silva N, Lee H, Stone JR. Risk factors for atherosclerosis and the development of pre-atherosclerotic intimal hyperplasia. Cardiovasc Pathol 2007;16:344–50.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 2 Progression of atherosclerotic plaques FIGURE 12.2 Progression of atherosclerotic plaques. (A) The normal vessel is characterized by a lack of inflammation, non-activated endothelium, and balanced levels of circulating lipids. (B) The fatty streak develops in the context of local endothelial dysfunction, lipid accumulation in the intima, and recruitment of monocytes that differentiate into macrophages and subsequently engulf lipid to become foam cells. (C) Plaque progression shows continued accumulation of lipid, macrophages and smooth muscle cells, with recruitment of other inflammatory cells such as lymphocytes. The recruited smooth muscle cells also synthesize collagen and other matrix proteins to form the nascent fibrous cap. (D) The stable fibroatheromatous plaque is characterized by a fibrous cap composed of smooth muscle cells and relatively dense extracellular matrix, separating the necrotic/lipid core from the lumen and a relative paucity of inflammation. Varying degrees of calcification are often present. (Reproduced with permission from Wang T, Palucci D, Law K, Yanagawa B, Yam J, Butany J. Atherosclerosis: pathogenesis and pathology. Diag Histopathol 2012;18:461–7.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 3 Stable atherosclerotic plaque FIGURE 12.3 Stable atherosclerotic plaque. Shown are histologic sections of a stable fibroatheroma in a human coronary artery at autopsy. (A) At low magnification, the lumen (Lu) of the artery is seen to be well demarcated from the necrotic lipid core (NC) by a thick collagenous fibrous cap (FC). (B) On higher magnification, the necrotic lipid core can be seen to contain necrotic debris (ND), red blood cells (arrows), and white spike-like structures due to cholesterol esters (arrowheads). These latter structures are often referred to as cholesterol clefts. Cholesterol itself is extracted from tissue during routine processing leaving the open/white spike-like areas behind. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 4 The vulnerable thin cap fibroatheroma FIGURE 12.4 The vulnerable thin cap fibroatheroma. Shown is a histologic section of a thin cap fibroatheroma from a human coronary artery at autopsy. The necrotic lipid core (NC) is separated from the arterial lumen (Lu) by a relatively thin fibrous cap (FC). Compare with the stable plaque in Figure 12.3. Such thin cap fibroatheromas are considered to be vulnerable to rupture of the fibrous cap and sudden coronary artery occlusion. (Reproduced with permission from Stone JR. Diag Histopathol 2012;18:478–83.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 5 Rupture of a thin cap fibroatheroma FIGURE 12.5 Rupture of a thin cap fibroatheroma. Shown are histologic sections from a coronary artery of a patient who died suddenly and unexpectedly. These sections were stained with Masson trichrome stain; collagen is stained blue. (A) The coronary artery contained areas of thin cap fibroatheroma (TCFA). The necrotic lipid core (NC) was separated from the arterial lumen (Lu) by a fibrous cap (FC), which in some areas was thin (arrow head). (B) In an adjacent section of the same coronary artery, there was acute rupture of the thin fibrous cap, such that the necrotic lipid core (NC) came into contact with the luminal blood, causing the formation of a thrombus (Th). © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 6 Acute plaque rupture FIGURE 12.6 Acute plaque rupture. A thin cap fibroatheroma has ruptured allowing the necrotic lipid core on the left to contact the luminal blood on the right and trigger thrombus formation. Note the cholesterol clefts in the necrotic lipid core. The arrowheads indicate the ruptured thin fibrous cap. This plaque is from a coronary artery examined during the autopsy of a patient who died suddenly. © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 7 Erosion of an inflamed atherosclerotic plaque FIGURE 12.7 Erosion of an inflamed atherosclerotic plaque. Shown are histologic sections of a coronary artery from a man who died suddenly and unexpectedly. (A) At low magnification, there is severe narrowing of the artery due to atherosclerosis. There is focal bluish discoloration of the necrotic lipid core due to the intense infiltration by inflammatory cells (*). (B) At higher magnification the inflamed plaque is associated with surface erosion and luminal thrombus (Th). (Reproduced with permission from Stone JR. Diag Histopathol 2012;18:478–83.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 8 Macrophages and neutrophils in acute plaque erosion FIGURE 12.8 Macrophages and neutrophils in acute plaque erosion. Shown are high power images of the site of plaque erosion in Figure 12.7. (A) A routine hematoxylin and eosin stain shows infiltrating inflammatory cells with the morphology of macrophages and neutrophils. (B) Immunohistochemical stain for the macrophage marker CD68 (brown cells) highlights numerous macrophages. (C) Immunohistochemical stain for the T lymphocyte marker CD3 (brown cells) reveals only rare lymphocytes. (D) Immunohistochemical stain for myeloperoxidase (brown cells) shows numerous myeloperoxidase secreting neutrophils and macrophages. (Reproduced with permission from Stone JR. Diag Histopathol 2012;18:478–83.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 9 Erosion of unstable atherosclerotic plaques FIGURE 12.9 Erosion of unstable atherosclerotic plaques. (A) In some patients, unstable atherosclerotic plaques are characterized by increased amounts of inflammation, typically associated with increased production of matrix metalloproteinases and degradation of the extracellular matrix. (B) Erosion or disruption of the surface endothelium leads to luminal thrombus formation. (C) Disrupted plaques are often associated with hemorrhage into the plaque. The hemorrhage may originate from the luminal surface or from small blood vessels that have migrated into the plaque from the adventitia. (Reproduced with permission from Wang T, Palucci D, Law K, Yanagawa B, Yam J, Butany J. Atherosclerosis: pathogenesis and pathology. Diag Histopathol 2012;18:461–7.) © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease

FIGURE 12. 10 Aortic atherosclerosis and atheroemboli FIGURE 12.10 Aortic atherosclerosis and atheroemboli. The essentially normal aortic wall has a smooth tan inner luminal surface (A). Atherosclerotic plaques in the aorta are often chronically disrupted on the surface, sometimes resulting in a grossly apparent thick carpet of ulcerated material (B). This eroded surface material is prone to embolism, most commonly to the kidneys or lower extremities. Less commonly, eroded atherosclerotic plaques in the ascending aorta can send atheroemboli to the brain or even the heart. Shown at right (C) is a histologic image of the heart from a patient with severe ulcerated ascending aortic atherosclerosis who died suddenly and unexpectedly. Atheroemboli (AE) with cholesterol clefts were identified in multiple small vessels (V) within the myocardium (M). © 2014, Elsevier Inc., Willis, et.al., Cellular and Molecular Pathobiology of Cardiovascular Disease