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a. CRP = acute-phase reactant synthesized primarily by the liver
b. Plays a role in the innate immune response by opsonizing bacteria and activating complement
c. Activates endothelial cells, induces a pro-thrombotic state and increases the adhesiveness of endothelium for leukocytes
d. IMPORTANT: strong independent predictor of the risk of MI, stroke, peripheral arterial disease, and sudden cardiac death even among apparently healthy individuals
e. Smoking cessation, weight loss and exercise reduce CRP levels
f. Statins reduce CRP levels independent of their effects on LDL cholesterol
g. Locally, CRP secreted by cells within atherosclerotic plaques can activate endothelial cells, increasing adhesiveness and inducing a prothrombotic state. Its clinical importance lies in its value as a circulating biomarker: CRP levels strongly and independently predict the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy persons. While there is no direct evidence that lowering CRP diminishes cardiovascular risk, it is of interest that CRP is reduced by smoking cessation, weight loss, and exercise. Moreover, statins reduce CRP levels independent of their LDL cholesterol-lowering effects, suggesting a possible anti-inflammatory action of these agents. 1. Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair endothelial cell function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.
2. With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives, oxidized LDL and cholesterol crystals.
3. LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or endothelial cells and ingested by macrophages through the scavenger receptor, resulting in foam cell formation.
4. Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to endothelial cells and smooth muscle cells. More recently, it has been shown that minute extracellular cholesterol crystals found in early atherosclerotic lesions serve as "danger" signals that activate innate immune cells such as monocytes and macrophages.
*Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by age 20.
*Other genetic or acquired disorders (e.g., diabetes melli- tus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis. 1. Inflammation contributes to the initiation, progression, and complications of atherosclerotic lesions. Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional endothelial cells express adhesion molecules that promote leukocyte adhesion; vascular cell adhesion molecule-1 (VCAM-1), in particular, binds monocytes and T cells. After these cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines.
2. Monocytes differentiate into macrophages and avidly engulf lipoproteins, including oxidized LDL and small cholesterol crystals. Cholesterol crystals appear to be par ticularly important instigators of inflammation through activation of the inflammasome and subsequent release of IL-1. Activated macrophages also produce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate smooth muscle cell proliferation.
3. T lymphocytes recruited to the intima interact with the macrophages and also contribute to a state of chronic inflammation. It is not clear whether the T cells are responding to specific antigens (e.g., bacterial or viral anti- gens, heat-shock proteins [see further on], or modified arterial wall constituents and lipoproteins) or are nonspe- cifically activated by the local inflammatory milieu. Never- theless, activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, endothelial cells, and smooth muscle cells.
4. As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote smooth muscle cell proliferation and matrix synthesis. • Intimal smooth muscle cell proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions.
• Intimal smooth muscle cells can originate from the media or from circulating precursors; regardless of their source, they have a proliferative and synthetic phenotype distinct from that of the under- lying medial smooth muscle cells.
• Several growth factors are implicated in smooth muscle cell proliferation and matrix synthesis, including platelet-derived growth factor (released by locally adherent platelets, macrophages, endothelial cells, and smooth muscle cells), fibroblast growth factor, and TGF- α.
• The recruited smooth muscle cells synthesize ECM (most notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas also can cause intimal smooth muscle cell apoptosis and breakdown of matrix, leading to the development of unstable plaques (see later). 1. Fibrous cap: smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization
2. Necrotic center: cell debris, cholesterol crystals, foam cells, Ca+
3. Media
• The key features of these lesions are intimal thickening and lipid accumulation
• Atheromatous plaques are white to yellow raised lesions; they range from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses.
• Thrombus superimposed on ulcerated plaques imparts a red-brown color
• Atherosclerotic plaques are patchy, usually involving only a portion of any given arterial wall; on cross-section, therefore, the lesions appear "eccentric" • REPERFUSION INJURY = Myocardial, vascular, or electrophysiological dysfunction that is induced by the restoration of blood flow to previously ischemic tissue.
- For approximately 30 min after the onset of even the most severe ischemia, myocardial injury is potentially reversible. Thereafter, progressive loss of viability occurs that is complete by 6 to 12 hours. The benefits of reperfusion are greatest when it is achieved early, and are progressively lost when reperfusion is delayed.
• Such reperfusion is achieved by thrombolysis (dissolution of thrombus by tissue plasminogen activator), angioplasty, or coronary arterial bypass graft.
Following coronary occlusion, contractile function is lost within 2 minutes and viability begins to diminish after approximately 20 minutes. If perfusion is not restored, then nearly all myocardium in the affected region will die.
If flow is restored, then some necrosis is prevented, myocardium is salvaged, and at least some function will return. The earlier reperfusion occurs, the greater the degree of salvage. However, the process of reperfusion itself may induce some damage (reperfusion injury), and return of function of salvaged myocardium may be delayed for hours to days (post-ischemic ventricular dysfunction). 