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2286 Part XII: Hemostasis and Thrombosis Chapter 134: Atherothrombosis: Disease Initiation, Progression, and Treatment 2287

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B1 cells, express a restricted set of germline–encoded antigen receptors inhibition of endothelial NO production. Although originally desig-
that may bind oxidized LDL. nated as platelet-activating factor acetylhydrolase because of its abil-
ity to degrade platelet-activating factor, the clinical importance of this
Adaptive Immunity and Atherosclerosis effect is not thought significant. Numerous epidemiologic studies show
Compared to innate immunity, adaptive immunity is slower but more that Lp-PLA is a significant biomarker associated with cardiovascular
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precise (Chap. 77). T cells can be activated by dendritic cells and events. The selective inhibition of Lp-PLA with the drug darapladib
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macrophages, whereas most antigens cannot stimulate B cells with- reduced development of advanced coronary atherosclerosis in diabetic
out assistance from CD4+ T cells, which recognize the peptide–major and hypercholesterolemic swine. A phase 2 clinical study of patients
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histocompatibility complex (MHC) complexes on B cells. By genetic with cardiovascular disease showed that sustained inhibition of plasma
recombination, the number of T-cell and B-cell receptors that can be Lp-PLA activity with background of intensive atorvastatin therapy
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formed is almost unlimited and far exceed the number of pattern rec- resulted in reduction in IL-6 and hsCRP after 12 weeks of darapladib
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ognition receptors used by the innate immune system. Most CD4+ 160 mg, suggesting a possible reduction in inflammatory burden.
cells are cytokine-secreting T-helper (Th) cells and express αβ–T-cell However, a prospective double-blind phase III trial of 15,828 patients,
receptors, which interact with MHC class II molecules. A smaller darapladib did not reduce the composite end point of cardiovascular
number of Th cells express γδ–T-cell receptors, which interact with death, MI, or stroke. There was a significant reduction in major coro-
the nonpolymorphic, nonclassic MHC molecules, CD1, which present nary events and total coronary events. 91
certain antigens (particularly lipids and glycolipids). Th cells are classi-
fied according to the cytokines they secrete. Th1 cells secrete interferon Immune Cells and Atherosclerosis
(IFN)-γ and IL-2 and promote cell-mediated immunity (Chap. 78). Macrophages are essential for the clearance of modified lipoproteins
Th2 cells secrete IL-4, IL-5, IL-10, and IL-13, and help B cells produce and the efflux of lipoprotein-derived cholesterol to HDL receptors for
antibodies. CD8+ T cells are primarily cytotoxic killer cells, although reverse cholesterol transport, the process by which HDL removes cho-
they can secrete cytokines, such as tumor necrosis factor-α, IFN-γ, lesterol from cells. Multiple lines of evidence indicate that macrophages
and lymphotoxin. Some thymus-independent antigens can activate promote lesion initiation and progression. For example, hypercholes-
these cells without the help of T cells. Oxidized LDL is considered such terolemic mice become markedly resistant to atherosclerosis if they are
an antigen because it expresses multiple copies of oxidation-specific bred to macrophage-deficient animals. 92
epitopes on a single LDL particle. The earliest grossly visible sign of atherosclerosis is the fatty streak,
which is composed mainly of macrophage foam cells containing rel-
Adhesion Molecules and Atherosclerosis atively large amounts of cholesterol. Foam cells also can derive from
Monocyte recruitment to inflammatory foci initially involves the smooth muscle cells, as these cells can express scavenger receptors when
expression of endothelial cell selectins, which mediate monocyte roll- appropriately activated. 93,94 Formation of the fatty streak is thought to
ing on the endothelium (see Fig. 134–3). The rolling phenomenon is begin with adherence of circulating monocytes to activated endothelial
followed by a firmer attachment to endothelial cells mediated by integ- cells at sites in the arterial system prone to atherosclerotic disease, such
rins. Perhaps the most important of these is VCAM-1, which is upregu- as at branch points in vessels. Multiple chemoattractant molecules have
lated in cultured endothelial cells in the presence of oxidized LDL. The been identified in these nascent lesions, which recruit monocytes and
appearance of this molecule before the development of grossly visible induce their diapedesis into the subendothelial space where they further
atherosclerotic lesions supports oxidized LDL as an initial recruiter differentiate into macrophages. As noted above, however, more recent
of macrophages. The finding of reduced atherosclerosis in VCAM- evidence indicates that microenvironment-supported macrophage pro-
1–deficient mice further supports the important role of macrophages liferation in situ within the atherosclerotic lesion is likewise a key event
and VCAM-1 in the pathogenesis of atherosclerosis. 81,82 Other adhesion in atherogenesis. 84
molecules, such as P-selectin and intracellular cell adhesion molecule-1, The chemoattractant CCL2 (MCP-1) facilitates recruitment of
also may be involved in monocyte adhesion at sites of lesion forma- monocytes to atherosclerotic lesions, as noted in studies of mouse mod-
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tion. The entry of monocytes into the vascular intima leads to their els of atherosclerosis, such as apoE–/– or LDL receptor (LDLR–/–)–
differentiation into resident macrophages. Here they take up cholesterol deficient mice fed a Western-style diet. When these mice are crossed
that has also accumulated in the vascular intima, thereby becoming to the model lacking CCL2, or its receptor CCR-2, lesion development
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cholesterol-engorged foam cells. It has been demonstrated that the decreases significantly. 95–97
accumulation of macrophage foam cells in established atherosclerotic Macrophages and T cells were once thought to be the only inflam-
lesions actually originates mainly from the proliferation of macrophages matory cells to significantly promote angiogenesis. More recent data
within the lesion rather than from the recruitment of circulating mono- showing that neutrophils are found at sites of plaque rupture or erosion
cytes. Platelet-derived EVs contain and deliver the chemokine “regu- and in thrombus from patients with acute coronary artery syndromes
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lated upon activation, normal T-cell expressed and secreted” (RANTES) indicate that they also have an important role in atherothrombosis.
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to activate endothelium in atherosclerosis to promote attraction of Mast cells have been found in the adventitia of lesions and in areas of
monocytes. 86 plaque hemorrhage; they have been implicated in macrophage apopto-
sis, increased vascular permeability, degradation of HDL and reduced
Lipoprotein Phospholipase A and Atherosclerosis cholesterol efflux. Neutrophils and mast cells are recruited to athero-
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Lipoprotein phospholipase A (Lp-PLA ) is an inflammatory enzyme sclerotic lesions in response to CXC-chemokine receptor 2 (CXCR2)
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belonging to the large family of phospholipases that are capable of signals. The mobilization of neutrophils to atherosclerotic lesions
hydrolyzing the sn-2 ester bond of phospholipids of cell membranes is inhibited by CXC-chemokine receptor 4 (CXCR4) and its ligand
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and lipoproteins. This enzyme, produced by macrophages, circulates CXC-chemokine ligand 12 (CXCRL12; also known as stromal-derived
bound to LDL and in the intimal space of the artery can produce oxi- factor (SDF) 1. A subset of CD31+ T cells, so called T cells, was shown
ang
dized fatty acids and lysophosphatidyl choline. These molecules have to promote endothelial repair and revascularization, and to be inversely
a range of potentially atherogenic effects, including chemoattrac- correlated with age and cardiovascular disease (CVD) risk in patients
tion of monocytes, increased expression of adhesion molecules, and undergoing coronary angiography. 98

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