ATHEROSCLEROSISAtherosclerosis is characterized by intimal lesions called atheromas (also called atheromatous or atherosclerotic plaques), that protrude into vascular lumina. An atheromatous plaque consists of a raised lesion with a soft, yellow, grumous core of lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap. Besides obstructing blood flow, atherosclerotic plaques weaken the underlying media and can themselves rupture, causing acute catastrophic vessel thrombosis

Epidemiology Atherosclerosis is much less prevalent in Central and South America, Africa, and Asia. The mortality rate for IHD in the United States is among the highest in the world and is approximately five times higher than that in Japan. Multiple risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold. When three risk factors are present (e.g., hyperlipidemia, hypertension, and smoking), the rate of myocardial infarction is increased seven times.

Major Constitutional Risk Factors for IHD

Pathogenesis Atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall. Chronic endothelial injur endothelial dysfunction increased permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing SMC recruitment, either from the media or from circulating precursors SMC proliferation and ECM productionLipid accumulation both extracellularly and within cells (macrophages and SMCs) The accumulation of lipid-containing macrophages in the initima gives rise to "fatty streaks". With further evolution, a fibrofatty atheroma consisting of proliferated SMC, foam cells, extracellular lipid, and ECM is formed. Endothelial Injury Endothelial loss due to any kind of injury-whether induced experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals-results in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. In the setting of intact but dysfunctional ECs there is increased endothelial permeability, enhanced leukocyte adhesion, and altered gene expression. The specific causes of endothelial dysfunction in early atherosclerosis are not completely understood. Etiologic culprits include toxins from cigarette smoke, homocysteine, and even infectious agents. Inflammatory cytokines (e.g., tumor necrosis factor, or TNF) can also stimulate the expression of pro-atherogenic genes in EC. Nevertheless, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia. Inflammation is also an important contributor. Hemodynamic Disturbance

Plaques tend to occur at ostia of exiting vessels, branch points, and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns. Nonturbulent laminar flow in other parts of the normal vasculature leads to the induction of endothelial genes whose products (e.g., the antioxidant superoxide dismutase) actually protect against atherosclerosis.

Lipids Lipids are typically transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes). Dyslipoproteinemias can result from mutations that encode defective apoproteins or alter the lipoprotein receptors on cells, or from some other underlying disorder that affects the circulating levels of lipids (e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus). Common lipoprotein abnormalities include (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol levels, and (3) increased levels of the abnormal Lp(a). The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters. 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 before the age of 20 years. Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk of cardiovascular events. Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair EC function by increasing local production of reactive oxygen species. Among other effects, oxygen free radicals accelerate nitric oxide decay, damping its vasodilator activity and thereby increasing local shear stress. With chronic hyperlipidemia, lipoproteins accumulate within the intima. These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or ECs. Oxidized LDL is ingested by macrophages through a scavenger receptor, distinct from the LDL receptor, resulting in foam-cell formation. In addition, oxidized LDL stimulates the release of growth factors, cytokines, and chemokines by ECs and macrophages that increase monocyte recruitment into lesions. Finally, oxidized LDL is cytotoxic to ECs and SMCs and can induce EC dysfunction. Inflammation Inflammatory cells and mediators are involved in the initiation, progression, and the complications of atherosclerotic lesions. Early in atherogenesis dysfunctional arterial ECs express adhesion molecules that encourage 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. Monocytes transform into macrophages and avidly engulf lipoproteins, including oxidized LDL. Monocyte recruitment and differentiation into macrophages (and ultimately into foam cells) is theoretically protective, since these cells remove potentially harmful lipid particles. Over time, however, progressive accumulation of oxidized LDL drives lesion progression. Thus, macrophage activation (via oxidized LDL or T cells, see below) results in cytokine production (e.g., TNF) that further increases leukocyte adhesion and chemokine production that in turn propel mononuclear inflammatory cell recruitment. Activated macrophages also produce reactive oxygen species, aggravating LDL oxidation.T lymphocytes recruited to the intima interact with macrophages and can generate a chronic immune inflammatory state. Activated T cells in the growing intimal lesions elaborate inflammatory cytokines, (e.g., interferon-), which in turn can stimulate macrophages as well as ECs and SMCs.As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and ECM synthesis. Infection

Herpesvirus, cytomegalovirus, and Chlamydia pneumoniae have all been detected in atherosclerotic plaque but not in normal arteries, and seroepidemiologic studies find increased antibody titers to C. pneumoniae in patients with more severe atherosclerosis. Smooth Muscle Proliferation Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions. Recall that the intimal SMCs have a proliferative and synthetic phenotype distinct from the underlying medial SMCs and, in fact, may substantially derive from the recruitment of circulating precursors. Several growth factors are implicated in SMC proliferation and ECM synthesis, including platelet-derived growth factor (PDGF, released by locally adherent platelets as well as by macrophages, ECs, and SMCs), fibroblast growth factor, and transforming growth factor . The recruited SMCs synthesize ECM (notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas can cause intimal SMC apoptosis, and they also increase ECM catabolism, resulting in unstable plaques.

Morphology Fatty Streaks. Fatty streaks are composed of lipid-filled foam cells but are not significantly raised and thus do not cause any disturbance in blood flow. They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer. Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years. Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. Atherosclerotic Plaque. The key processes in atherosclerosis are intimal thickening and lipid accumulation. Atheromatous plaques (also called fibrous or fibrofatty plaques) impinge on the lumen of the artery and grossly appear white to yellow; thrombosis superimposed over the surface of ulcerated plaques is red-brown in color. Plaques vary from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses. In descending order, the most extensively involved vessels are the lower abdominal aorta, the coronary arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the circle of Willis. Vessels of the upper extremities are usually spared, as are the mesenteric and renal arteries, except at their ostia. Atherosclerotic plaques have three principal components: (1) cells, including SMCs, macrophages, and T cells; (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid. Typically, the superficial fibrous cap is composed of SMCs and relatively dense collagen. Beneath and to the side of the cap (the "shoulder") is a more cellular area containing macrophages, T cells, and SMCs. Deep to the fibrous cap is a necrotic core, containing lipid (primarily cholesterol and cholesterol esters), debris from dead cells, foam cells (lipid-laden macrophages and SMCs), fibrin, variably organized thrombus, and other plasma proteins; the cholesterol content is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty "clefts." At the periphery of the lesions, there is usually neovascularization (proliferating small blood vessels). Typical atheromas contain relatively abundant lipid, but some plaques ("fibrous plaques") are composed almost exclusively of SMCs and fibrous tissue. Plaques generally continue to change and progressively enlarge through cell death and degeneration, synthesis and degradation (remodeling) of ECM, and organization of thrombi. Moreover, atheromas often undergo calcification. Patients with advanced coronary calcification appear to be at increased risk for coronary events. Rupture, ulceration, or erosion of the luminal surface of atheromatous plaques exposes the bloodstream to highly thrombogenic substances and induces thrombus formation. Such thrombi can partially or completely occlude the lumen and lead to downstream ischemia. If the patient survives the initial vascular occlusion, thrombi may become organized and incorporated into the growing plaque. Hemorrhage into a plaque. Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; a contained hematoma may expand the plaque or induce plaque rupture. Atheroembolism. Plaque rupture can discharge debris into the bloodstream, producing microemboli composed of plaque contents. Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness of the vessel wall and development of aneurysms that may rupture

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Natural History of Atherosclerosis Atherosclerosis primarily affects elastic arteries (e.g., aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries). In small arteries, atheromas can gradually occlude lumina, compromising blood flow to distal organs and cause ischemic injury. Moreover, atherosclerotic plaques can undergo acute disruption and precipitate thrombi that further obstruct blood flow. In large arteries, plaques are destructive, encroaching on the subjacent media and weakening the affected vessel wall, causing aneurysms that can rupture. Moreover, atheromas can be friable, fragmenting atheroemboli into downstream circulations. It is important to emphasize that atherosclerosis is a slowly evolving lesion usually requiring many decades to become significant. However, acute plaque changes (e.g., rupture, thrombosis, or hematoma formation) can rapidly precipitate clinical sequelae Symptomatic atherosclerotic disease most often involves the arteries supplying the heart, brain, kidneys, and lower extremities. Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysms, and peripheral vascular disease (gangrene of the legs) are the major consequences of atherosclerosis. Atherosclerosis also takes a toll through other consequences of acutely or chronically diminished arterial perfusion, such as mesenteric occlusion, sudden cardiac death, chronic IHD, and ischemic encephalopathy. The effects of vascular occlusion ultimately depend on arterial supply and tissue metabolic demand; details will be discussed in greater detail in subsequent organ-specific chapters.

Prevention of Atherosclerotic Vascular Disease Primary prevention programs aimed at either delaying atheroma formation or encouraging regression of established lesions in persons who have not yet suffered a serious complication of atherosclerosis. Secondary prevention programs intended to prevent recurrence of events such as myocardial infarction or stroke in symptomatic patients. Primary prevention of atherosclerosis-related complications typically involves risk factor identification and modification of those that are amenable to intervention: cessation of cigarette smoking, control of hypertension, weight loss, exercise, and lowering total and LDL blood cholesterol levels while increasing HDL (e.g., by diet or through statins). Interestingly, statin use may also modulate the inflammatory state of the vascular wall. Several lines of evidence suggest that risk factor stratification and reduction should even begin in childhood. Secondary prevention involves the judicious use of aspirin (anti-platelet agent), statins, and beta blockers (to limit cardiac demand), as well as surgical interventions (e.g., coronary artery bypass surgery, carotid endarterectomy). These can successfully reduce recurrent myocardial or cerebral events. Between 1963 (the peak year) and 2000 there has been an approximately 50% decrease in the death rate from IHD and a 70% decrease in deaths from strokes, a reduction in mortality that alone has largely increased the average life expectancy in the United States by 5 years. Three main contributors to this impressive improvement have been (1) prevention of atherosclerosis through recognition of risk factors and changes in life style (e.g., reduced cigarette smoking, reduced consumption of cholesterol, and control of hypertension); (2) improved methods of treatment of myocardial infarction and other complications of IHD; and (3) prevention of recurrences in patients who have previously suffered serious atherosclerosis-related clinical events.

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