atherosclerosis.pdf

Atherosclerosis ARTERIOSCLEROSIS:hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity. There are three general :patterns, with differing clinical and pathologic consequences Arteriolosclerosis affects small arteries and arterioles. The two ana...

Atherosclerosis ARTERIOSCLEROSIS:hardening of the arteries”; it is a generic term reflecting arterial wall thickening and loss of elasticity. There are three general :patterns, with differing clinical and pathologic consequences Arteriolosclerosis affects small arteries and arterioles. The two anatomic variants, hyaline and hyperplastic, are both associated with vessel wall thickening and luminal narrowing that may.cause downstream ischemic injury Mönckebergmedial calcific sclerosis characterized by calcific deposits in muscular arteries,.typically in persons older than age 50 Atherosclerosis, from Greek root words for "gruel" and "hardening," is the most frequent and clinically important pattern ATHEROSCLEROSIS Atherosclerosis is characterized by intimal lesions called atheromas(also called atheromatousor atherosclerotic plaques), that protrude into vascular lumina. An atheromatousplaque consists of a raised lesion with a soft, yellow, grumouscore of lipid (mainly cholesterol and cholesterol esters) covered by a firm, white fibrous cap Epidemiology Virtually ubiquitous among most developed nations, atherosclerosis is much less prevalent in Central and.South America, Africa, and Asia.Multiple risk factors have a multiplicative effect; two risk factors increase the risk approximately fourfold :Risk factors :Modifiable a)Hyperlipidemia b)Hypertension c)Cigarette smoking d)Diabetes e) Inflammation (C-reactive protein) :Non modifiable a)Increasing age b)Male gender c)Family history d)Genetic abnormalities As many as 20% of all cardiovascular events occur in the absence of hypertension, hyperlipidemia, smoking, or diabetes. Indeed, more than 75% of cardiovascular events in previously healthy women occurred with LDL cholesterol levels below 160 mg/dL(a cutoff generally considered to connote low risk) Inflammation.Inflammation is present during all stages of atherogenesis and is intimately linked with.atherosclerotic plaque formation and rupture Hyperhomocystinemia: Clinical and epidemiologic studies show a strong relationship between total serum homocysteine levels and coronary artery disease, peripheral vascular disease, stroke, and venous thrombosis Metabolic syndrome: The metabolic syndrome is characterized by a number of abnormalities that are.associated with insulin resistance.Lipoprotein (a) Factors affecting hemostasis. Several markers of hemostatic and/or fibrinolytic function (e.g., elevated plasminogen activator inhibitor 1) are predictors of risk for major atherosclerotic events.Other factors PATHOGENESIS OF ATHEROSCLEROSIS Called the response-to-injury hypothesis,the model views atherosclerosis as a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through the interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with the normal cellular constituents of the arterial wall :According to this model, atherosclerosis is produced by the following pathogenic events Endothelial injury, which causes (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis ,Accumulation of lipoproteins(mainly LDL and its oxidized.forms) in the vessel wall.Accumulation of lipoproteins(mainly LDL and its oxidized forms) in the vessel wall Platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells, inducing smooth muscle cell recruitment, either from the media or from circulating precursors Lipid accumulation both extracellularly and within cells (macrophages and smooth muscle cells) The major mechanisms of atherogenesis Endothelial Injury injury Endothelial Injury. Endothelial cell injury is the corner stone of the response to hypothesis. Endothelial cell loss due to any kind of injury—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. However, early human atherosclerotic lesions begin at sites of intact, but dysfunctional, endothelium. These dysfunctional endothelial cell exhibit increased permeability, enhanced leukocyte adhesion, and altered gene expression, all of.which may contribute to the development of atherosclerosis Suspected triggers of early atheromatous lesions include hypertension, hyperlipidemia, toxins from cigarette smoke, homocysteine, and even infectious agents. Inflammatory cytokines (e.g., tumor necrosis factor [TNF]) also can stimulate proatherogenic patterns of endothelial cell gene.expression However, the two most important causes of endothelial dysfunction are hemodynamic disturbances and.hypercholesterolemia.Hemodynamic Disturbances The importance of hemodynamic turbulence in atherogenesisis illustrated by the observation that 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.Lipids Lipids are typically transported in the bloodstream bound to specific apoproteins(forming lipoprotein complexes). Dyslipoproteinemiascan result from mutations that alter the apoproteinsor the lipoprotein receptors on cells,or from other disorders that affect the circulating levels of lipids (e.g., nephroticsyndrome, alcoholism, hypothyroidism, or diabetes mellitus).Common lipoprotein abnormalities in the general population (indeed, present in many myocardial infarction survivors) include ,increased LDL cholesterol levels (1) ,decreased HDL cholesterol levels (2) increased levels of the abnormal lipoprotein (a) (3) Lipoproteins are large macromolecular complexes that transport hydrophobic lipids (primarily triglycerides,cholesterol, and fat-soluble vitamins) through body fluids(plasma, interstitial fluid, and lymph) to and from tissues. Lipoproteins play an essential role in the absorption of dietary cholesterol, long-chain fatty acids, and fat soluble vitamins; the transport of triglycerides, cholesterol, and fat-soluble vitamins from the liver to peripheral tissues; and the transport of cholesterol from peripheral tissues to the.liver Lipoproteins contain a core of hydrophobic lipids (triglycerides and cholesteryl esters) surrounded by hydrophilic lipids (phospholipids, unesterified cholesterol) and proteins that interact with body fluids. The plasma lipoproteins are divided into five major classes based on their relative density : chylomicrons, very low density lipoproteins (VLDLs), intermediate density lipoproteins (IDLs), low-density lipoproteins (LDLs), and high-density.lipoproteins (HDLs) The proteins associated with lipoproteins, called apolipoproteins, are required for the assembly, structure, and function of lipoproteins The evidence implicating hypercholesterolemia in atherogenesis includes the following :observations.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 Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause.hypercholesterolemia lead to premature atherosclerosis Epidemiologic analyses demonstrate a significant correlation between the severity of..atherosclerosis and the levels of total plasma cholesterol or LDL 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 The mechanisms by which hyperlipidemia contributes to atherogenesis include the following Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair endothelial cell function by increasing local oxygen free radical production; oxygen free radicals can injure vasodilator tissues and accelerate nitric oxide decay, reducing its.activity With chronic hyperlipidemia, lipoproteins accumulate within the intima. These lipids are oxidized through the action of oxygen free radicals locally generated by macrophages or endothelial cells and ingested by macrophages through the.scavenger receptor, resulting in foam cell formation 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 Morphology Fatty Streaks. Fatty streaks are the earliest lesions in atherosclerosis. They are composed of lipid filled foamy macrophages. Beginning as multiple minute flat yellow spots, they eventually coalesce into elongated streaks1cm or more in length. Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to.develop plaques Atherosclerotic Plaque. 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 have three principal components cells, including smooth muscle cells, macrophages, and T (1) ;cells extracellular matrix, including collagen, elastic fibers, and (2) ;proteoglycans.intracellular and extracellular lipid (3) Plaques generally continue to change and progressively enlarge due to cell death and degeneration, synthesis and degradation(remodeling)of ECM, and organization of thrombus. Moreover, atheromas often undergo calcification Atherosclerotic plaques are susceptible to the following clinically important changes Rupture, ulceration, or erosion of the intimal surface of atheromatous plaques exposes the blood to highly thrombogenic substances and induces.thrombosis.Hemorrhage into a plaque.Atheroembolism Aneurysm formation Aorta with fatty streaks (arrows), associated largely with the ostia of branch vessels Fatty streak. Gross photo of yellow fatty streaks (arrows) in the thoracic aorta Fatty streak. Microscopic features of fatty streak in artery wall with intimal foam cells Fibroinflammatory lipid plaques. Focal elevated plaques in thoracic aorta Photomicrograph of fatty streak  Schematic depiction of the major components of well-developed intimal atheromatous plaque overlying an intact media Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow Severe disease with diffuse and complicated lesions Histologic features of atheromatousplaque in the coronary artery. A,Overall architecture demonstrating fibrous cap (F) and a central necrotic (largely lipid) core (C). The lumen (L) has been moderately narrowed. Note that a segment of the wall is plaque free (arrow Higher-power photograph of a section of the plaque ,stained for elastin (black), demonstrating that the internal and external elastic membranes are destroyed.and the media of the artery is thinned under the most advanced plaque (arrow) Higher-magnification photomicrograph at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (broad arrow),and neovascularization (small arrows CONSEQUENCES OF ATHEROSCLEROTIC DISEASE Large elastic arteries(e.g. The aorta,carotid,and iliac arteries)and large and medium-sized muscular arteries(e.g. Coronary and popliteal arteries)are the major targets of atherosclerosis. 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 Smaller vessels can become occluded, compromising distal tissue.perfusion Ruptured plaque can embolize atherosclerotic debris and cause distal vessel obstruction, or can lead to acute(and frequently.catastrophic)vascular thrombosis Destruction of the underlying vessel wall can lead to aneurysm formation, with secondary rupture and/or thrombosis.Atherosclerotic Stenosis In small arteries, atherosclerotic plaques can gradually occlude vessel lumens, compromising.blood flow and causing ischemic injury Critical stenosis is the Rubicon at which chronic occlusion significantly limits flow, and demand begins exceeding supply. In the coronary(and other) circulations, this typically occurs at approximately 70% fixed occlusion(i.e., loss of are through which blood can flow);at this degree ;of stenosis, patients classically develop chest pain(angina)on exertion(so-called stable angina mesenteric occlusion and bowel ischemia ,chronic IHD, ischemic encephalopathy, and intermittent claudication(diminished extremity perfusion)are all consequences off low limiting.stenosis.Acute Plaque Change Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis resulting in acute tissue infarction (e.g., myocardial or.cerebral infarction) :Plaque changes fall into three general categories Rupture/fissuring, exposing highly thrombogenic plaque constituents.1 Erosion/ulceration,exposing the thrombogenic subendothelial basement membrane.2 to blood Hemorrhage into the atheroma, expanding its volume3. now recognized that the precipitating lesion in patients who develop myocardial infarction and other acute coronary syndromes is not necessarily a severely stenotic and hemodynamically significant lesion before.its acute change The events that trigger abrupt changes in plaque configuration and superimposed thrombosis are complex and include both intrinsic factors(e.g. Plaque structure and composition)and extrinsic factors e.g.,blood pressure, platelet reactivity It is also important to note that not all plaque ruptures result in occlusive thrombosis with catastrophic consequences. Indeed, plaque disruption and ensuing platelet aggregation and thrombosis are probably common, repetitive, and often clinically silent complications of atheroma. Healing of these subclinical plaque disruptions—with their overlying thrombosis—is an important mechanism in the growth.of atherosclerotic lesions It is also established that the fibrous cap undergoes continuous remodeling that may make the plaque.susceptible to acute alterations In general, plaque inflammation results in a net increase in collagen degradation and reduces collagen synthesis, there by destabilizing the mechanical integrity of the fibrous cap Influences extrinsic to plaques are also important. Thus, adrenergic stimulation can increase systemic.blood pressure or induce local vasoconstriction It is also important to note that not all plaque ruptures result in occlusive thrombosis with catastrophic consequences.Thrombosis partial or total thrombosis associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. In the most serious form, thrombus superimposed on a disrupted but previously only partially stenotic plaque converts it to a total occlusion. In contrast, in other coronary syndromes, luminal obstruction by thrombosis is usually.incomplete, and can even wax and wane with time.Vasoconstriction Vasoconstriction compromises lumen size, and, by increasing the local mechanical forces can potentiate plaque disruption. Vasoconstriction at sites of atheroma is stimulated by ,Circulating adrenergic agonists(1) ,Locally released platelet contents(2) Impaired secretion of endothelial cell relaxing factors(nitric(3) oxide) relative to contracting factors(endothelin) as a result of endothelial cell dysfunction, and possibly Mediators released from perivascular inflammatory cells(4) Fibroinflammatory lipid plaque. Microscopic features of.plaque erosion (arrowheads) and fissure formation (arrow) Fibroinflammatory lipid plaque with occlusive luminal thrombosis.(arrow) Abdominal aortic aneurysm with thrombus Rupture of fibrous cap and occlusive luminal thrombosis Treatment: LIPOPROTEIN DISORDERS Diet Dietary modification is an important.component in the management of dyslipidemia Weight Loss and Exercise PHARMACOLOGIC TREATMENT