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Inflammation and Atherothrombosis

From Population Biology and Bench Research to Clinical Practice

Peter Libby, MD^_*,,_* and Paul M. Ridker, MD, MPH^_*,,

^_* Division of Cardiovascular Medicine, Center for Cardiovascular Disease Prevention
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital
Harvard Medical School, Boston, Massachusetts

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 1 The transition from the normal artery wall to the nascent atherosclerotic lesion. The normal muscular artery has a trilaminar structure. A monolayer of endothelial cells overlies the intimal layer and abuts a basement membrane. In human arteries, the intima normally contains a few resident smooth muscle cells and a layer of extracellular matrix. The internal elastic lamina constitutes the boundary between the intimal layer and the tunica media, normally filled with quiescent smooth muscle cells embedded in an elastin-rich extracellular matrix. When molecules associated with risk factors stimulate oxidative or inflammatory stress, they induce the expression of adhesion molecules for leukocytes and chemoattractants that draw the bound leukocytes into the intimal layer. This diagram does not depict the adventitia, the outermost layer of the blood vessel.

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 2 Formation of the fibrofatty plaque. The transition from the fatty streak to the more fibrous lesion involves the migration of smooth muscle cells (SMCs) from the tunica media through the internal elastic lamina into the intima, where they secrete extracellular matrix molecules such as fibrillar collagen and elastin and can divide in response to mitogenic stimuli. The mononuclear phagocytes will imbibe modified lipoproteins such as oxidized low-density lipoprotein (LDL) through scavenger receptors to form foam cells. The activated mononuclear phagocytes in the lesions release chemoattractant cytokines, proinflammatory mediators including cytokines, and small lipid molecules such leukotrienes and prostaglandins, as well as reactive oxygen species (ROS). When SMCs encounter fibrogenic stimuli such as transforming growth factor-beta, they boost their production of extracellular matrix macromolecules, including fibrillar collagen, depicted by the triple helical structures in the diagram and elastin. OxLDL = oxidized low-density lipoprotein.

View larger version (117K): [in this window] [in a new window] [Download PPT slide]   Figure 3 Maturation of the atherosclerotic plaque. More mature lesions develop a fibrous cap composed of a dense extracellular matrix containing collagen and elastin. Underneath the fibrous cap, a lipid core forms that contains many macrophages, dead or dying macrophages, cellular debris including apoptotic bodies, and extracellular lipid accumulations. Proinflammatory mediators released from activated white cells and endothelial cells and smooth muscle cells (SMC) can potentiate cell death by apoptosis in the advancing lesion. As SMCs die within lesions, fewer remain to renew the extracellular matrix in the plaque's fibrous cap. In addition, the activated cells in the lesion, notably the macrophages, secrete proteinases that can degrade the macromolecules of the extracellular matrix. In particular, interstitial collagenases can attack the triple helical collagen fragments, weakening the fibrous cap. Elastases can break down elastin required for migration of cells within the lesion, and arterial remodeling occurs during compensatory enlargement, and in the extreme, aneurysm formation. During this phase of atherogenesis neovessels form in the intima, often arising as extensions of vasa vasorum that originate in the adventitial layer. IEL = internal elastic lamina; MFC = macrophage foam cell; ROS = reactive oxygen species.

View larger version (98K): [in this window] [in a new window] [Download PPT slide]   Figure 4 The thrombotic complications of atherosclerosis. Thrombi complicating atheroma arise by 2 major mechanisms. The first, depicted in the left panel of this diagram, involves a through-and-through rupture of the plaque's fibrous cap, which has been weakened by the mechanisms described in the text and in the legend to Figure 3. The rent in the fibrous cap permits blood and its coagulation factors to contact tissue factor expressed by macrophages and smooth muscle cell (SMC) and on microparticles elaborated by these cells and endothelial cells (EC). Moreover, the activated cells in the local environment of the plaque, including ECs and SMCs, elaborate large amounts of plasminogen activator inhibitor-1, a potent inhibitor of the endogenous fibrinolytic enzymes also found in the plaque such as urokinase and tissue-type plasminogen activator. A second common mechanism of coronary thrombus formation involves a superficial erosion of the endothelial cells (right panel), perhaps caused by endothelial apoptosis or desquamation.

View larger version (55K): [in this window] [in a new window] [Download PPT slide]   Figure 5 An inflammatory pathway links risk factors to altered cellular behavior and elevated inflammatory markers in peripheral blood. The primary proinflammatory risk factors depicted on the top of this diagram activate the various cell types prominent in the atherosclerotic plaque, including the macrophage, endothelial cells (EC), smooth muscle cells (SMC), and in complicated lesions, the activated platelet. These various cell types in turn can secrete inflammatory mediators and reactive oxygen species (ROS). The ECs will express leukocyte adhesion molecules that can be shed and recovered in a soluble form in the peripheral blood. The primary proinflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-alpha, can stimulate large amounts of IL-6 production by intrinsic vascular wall cells. This heightened IL-6 production represents an amplification loop, because 1 molecule of a primary proinflammatory cytokine can beget the expression of many more molecules of IL-6. The IL-6 can function as a messenger, traveling through the peripheral blood to the liver, where it alters the program of gene expression to elicit the acute-phase response. The acute-phase reactants include C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, and plasminogen activator inhibitor-1. Among these acute-phase reactants, CRP has proved to be a robust prospective indicator of cardiovascular events in a wide spectrum of individuals. Activated platelets release a number of inflammatory mediators, including CD40 ligand, which is also shed in a soluble form. The CD40 ligand can activate tissue factor gene expression, providing a positive feedback reinforcement of thrombosis in an inflammatory milieu. AGE = advanced glycation end products; Ang II = angiotensin II; MMPs = matrix metalloproteinases; OxLDL = oxidized low-density lipoprotein; PAI-1 = plasminogen activator inhibitor-1; RANTES = Regulated on Activation, Normal T Cell Expressed and Secreted (also known as chemokine ligand 5, CCL5).

View larger version (28K): [in this window] [in a new window] [Download PPT slide]   Figure 6 Framingham-adjusted relative risks of future cardiovascular events according to baseline levels of high-sensitivity C-reactive protein <1, 1 to 3, and >3 mg/l in 10 major prospective cohort studies. Data from references 56–61,65. *Data from the Reykjavik study are shown in tertiles. ARIC = Atherosclerosis Risk in Communities Study; CHS = Cardiovascular Health Study; EPIC-Norfolk = Evaluation c7E3 for Prevention of Ischemic Complications–Norfolk Study; HPFS = Health Professionals Follow-Up Study; MONICA = Monitoring Trends and Developments in Cardiovascular Disease Study; NHS = National Health Study; PHS = Physicians Health Study; PIMA = Pima Indian Study; WHS = Women's Health Study.

View larger version (23K): [in this window] [in a new window] [Download PPT slide]   Figure 7 Additive value of high-sensitivity C-reactive protein (hsCRP) over and above the total cholesterol (TC):high-density lipoprotein cholesterol (HDLC) ratio (left) and the apolipoprotein (Apo) B:Apo A ratio (right), after adjustment for age, smoking, hypertension, body mass index, and diabetes. Adapted with permission from Ridker et al. (66).

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Figure 8 Odds ratios of cardiovascular disease (CVD) in U.S. patients with diabetes mellitus, metabolic syndrome, and elevated high-sensitivity C-reactive protein (hsCRP) in NHANES (National Health and Nutrition Evaluation Survey). Adapted with permission from Malik et al. (74).

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 9 Prognostic utility of combining high-sensitivity C-reactive protein, troponin, and brain natriuretic peptide in the setting of acute coronary ischemia in the TIMI 16 and TIMI 18 clinical trials. Adapted with permission from Sabatine et al. (91). OPUS-TIMI = Orbofiban in Patients With Unstable Coronary Syndromes–Thrombolysis In Myocardial Infarction Trial; TACTICS = Treat Angina With Aggrastat and Determine Costs of Therapy With Invasive or Conservative Strategies.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 10 Cumulative rate of recurrent myocardial infarction or death from cardiac causes among statin-treated patients according to levels of low-density lipoprotein cholesterol (LDL-C) (left) and levels of C-reactive protein (CRP) (right) both achieved after 30 days in the TIMI 22 trial. Adapted with permission from Ridker et al. (106). TIMI = Thrombolysis In Myocardial Infarction.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Figure 11 Cumulative rate of recurrent myocardial infarction or death from cardiac causes among statin-treated patients according to achieved levels of both low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) in the TIMI 22 trial. Adapted with permission from Ridker et al. (106). TIMI = Thrombolysis In Myocardial Infarction.