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Atherosclerosis and ArteriosclerosisROBERT E SARAGIH SPJP, FIHADEPARTEMEN ILMU PENYAKIT JANTUNG DAN PEMBULUH DARAH FK UKIAtherosclerosis Disease of cardiovascular system affecting vessel wall.It leads to the narrowing of arteries or complete blockage.Its main components are endothelial disfunction, lipid deposition, inflammatory reaction in the vascular wall.Remodeling of vessel wall.AtherosclerosisThe term atherosclerosis, which comes from the Greek words atheros (meaning gruel or paste) and sclerosis (meaning hardness), denotes the formation of fibrofatty lesions in the intimal lining of the large and medium-size arteries such as the aorta and its branches, the coronary arteries, and the large vessels that supply the brain.Atherosclerosis contributes to more mortality and more serious morbidity than any other disorder in the western world.

Arterial wallNormally arterial endothelium repels cells and inhibits blood clotting.

The lumen of healthy arterial wall is lined by confluent layer of endothelial cells.Three layers:Intima (subendothelial layer)Media (middle layer) with vascular smooth muscle cells (VSMC)Adventitia (outer layer) with connective tissue and nerves.Arterial wall

Arterial wallEndothelium controls important function: 1. The ability of blood vessels to dilatate (vasodilatation)2. The ability of blood vessels to constrict (vasoconstriction)Endothelium regulates tissue and organ blood flow.Arterial wallEndothelium releases variety substances to control vasomotor tone:Prostacyclines Hyperpolarizing factor Endothelin NOExercise is an important mechanical stimulus mediated by shear stress to increased blood flow.Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall. The flow-dependent dilatation of pre-capillary resistance as well as conductance allows blood flow to increase according metabolic demands.Arterial wallIn the case of intact endothelium, the stimulus for vasodilatation:mechanical stimulation by blood flowcatecholamines, bradykinin, platelets-released serotonin stimulate specific receptorsIn the case of endothelium disfunction:direct vasoconstrictor action of the stimuli on the VSMC outweighs the endothelium-dependent vasodilatator effectthis action leads to paradoxial vasoconstriction (Hypercholesterolemia and other cardiovascular risk factors are associated with endothelial disfunction).

Pathology and pathogenesisThe lesions associated with atherosclerosis are of three types:The fatty streakThe fibrous atheromatous plaqueComplicated lesionThe latter two are responsible for the clinically significant manifestations of the disease.

Pathology and pathogenesisFatty streaks are thin, flat yellow intimal discolorations that progressively enlarge by becoming thicker and slightly elevated as they grow in length.They consist of macrophages and smooth muscle cells that have become distended with lipid to form foam cells.These occurs regardless of geographic setting, gender, or race. They increase in number until about age 20 years, and then they remain static or regress. There is controversy about whether fatty streaks, in and of themselves, are precursors of atherosclerotic lesions.

Fatty Streaks

Pathology and pathogenesisThe fibrous atheromatous plaque is the basic lesion of clinical atherosclerosis. It is characterized by the accumulation of intracellular and extracellular lipids, proliferation of vascular smooth muscle cells, and formation of scar tissue.The lesions begin as a elevated thickening of the vessel intima with a core of extracellular lipid (mainly cholesterol, which usually is complexed to proteins) covered by a fibrous cap of connective tissue and smooth muscle.As the lesions increase in size, they encroach on the lumen of the artery and eventually may occlude the vessel or predispose to thrombus formation, causing a reduction of blood flow.

Fibrous atheromatous plaque

Pathology and pathogenesisThe more advanced complicated lesions are characterized byHemorrhageUlcerationScar tissue deposits Thrombosis is the most important complication of atherosclerosis.It is caused by slowing and turbulence of blood flow in the region of the plaque and ulceration of the plaque.

Complicated lesion

MechanismsThere is increasing evidence that atherosclerosis is at least partially the result of:(1) endothelial injury with leukocyte (lymphocyte and monocyte) adhesion and platelet adherence(2) smooth muscle cell emigration and proliferation(3) lipid engulfment of activated macrophages(4) subsequent development of an atherosclerotic plaque with lipid core

MechanismsOne hypothesis of plaque formation suggests that injury to the endothelial vessel layer is the initiating factor in the development of atherosclerosis.Possible injurious agents are:Products associated with smoking;Immune mechanisms;Mechanical stress, such as that associated with hypertension.Hyperlipidemia, particularly LDL with its high cholesterol content, is also believed to play an active role in the pathogenesis of the atherosclerotic lesion.

The development of atherosclerosisThe key event damage to the endothelium caused by excess of lipoproteins, hypertension, diabetes, components of cigarette smoke.Endothelium becomes more permeable to lipoproteins.Lipoproteins move below the endothelial layer (to intima).Endothelium loses its cell-repelent quality.Inflammatory cells move in to the vascular wall.Triggers for inflammation in atherosclerosisLDL retained in the intima (in part by binding to proteoglycan) undergoes oxidative modification.Lipid hydroperoxides, lysophospholipides, carbonyl compounds localize in the lipid fraction.Oxygen free-radicals inactivate NO rapidly.NO + superoxide (O2.-) peroxynitrite (ONOO-).NO has no longer vasoprotective function. The development of atherosclerosisDisfunctional endothelium express adhesion molecules selectins, mediated the rolling interaction of cells.The key molecule - vascular cell addhesion molecule-1 (VCAM-1) promotes monocytes adhesion (precursors of macrophages).Addhering cells are stimulated by monocyte chemoattractant protein-1 (MCP-1).Monocytes cross the endothelium, settle down in the intima.

The process of atherogenesisActivated macrophages produce enzymes lipoxygenases, myeloperoxidase, NADPH oxidase ROSOxidized LDL are cytotoxic to endothelial cells, mitogenic for macrophages.Oxidized LDL apolipoprotein apoB100 bind to the scavenger receptor.Scavenger receptors are not subjected to regulation by intracellular cholesterol level. Macrophages take up oxidized LDL, overload with lipids.The process of atherogenesis

Modern theory of atherosclerosisMultifactor theory:Structural and functional injury of vascular endothelium;Response to injury of immune cells and smooth muscle cells;The role of lipoproteins in initiation and progression of lesions;The role of growth factors and cytokines;The role of repeated thrombosis in lesions progression.

Risk FactorsThe cause or causes of atherosclerosis have not been determined with certainty.Epidemiologic studies have identified predisposing risk factors:Unchangeable risk factorsAgeMale genderMen are at grater risk than are premenopausal women, because of the protective effects of natural estrogens.Family history of premature coronary heart diseaseSeveral genetically determined alterations in lipoprotein and cholesterol metabolism have been identified.

Risk FactorsChangeable risk factors life style risk factors:HyperlipidemiaThe presence of hyperlipidemia is the strongest risk factor for atherosclerosis in persons younger than 45 years of age. Both primary and secondary hyperlipidemia increase the risk.Cigarette smokingHypertensionHigh blood pressure produces mechanical stress on the vessel endothelium.It is a major risk factor for atherosclerosis in all age groups and may be as important or more important than hypercholesterolemia after the age of 45 years.Diabetes mellitusDiabetes elevates blood lipid levels and otherwise increases the risk of atherosclerosis.Insufficient physical activityA stressful lifestyleObesity

Risk FactorsThere are a number of other less well-established risk factors for atherosclerosis, including:High serum homocysteine levelsHomocysteine is derived from the metabolism of dietary methionineHomocysteine inhibits elements of the anticoagulant cascade and is associated with endothelial damage.Elevated serum C-reactive proteinIt may increase the likelihood of thrombus formation;Inflammation marker;Infectious agentsThe presence of some organisms (Chlamydia pneumoniae, herpesvirus hominis, cytomegalovirus) in atheromatous lesions has been demonstrated by immunocytochemistry, but no cause-and-effect relationship has been established. The organisms may play a role in atherosclerotic development by initiating and enhancing the inflammatory response.

Coronary heart diseaseThe term coronary heart disease (CHD) describes heart disease caused by impaired coronary blood flow. In most cases, it is caused by atherosclerosis.Diseases of the coronary arteries can cause:AnginaMyocardial infarction or heart attackCardiac dysrhythmiasConduction defectsHeart failureSudden death

Coronary circulationBlood flow usually is regulated by the need of the cardiac muscle for oxygen.Even under normal resting conditions, the heart extracts and uses 60% to 80% of oxygen in blood flowing through the coronary arteries, compared with the 25% to 30% extracted by skeletal muscle.Because there is little oxygen reserve in the blood, myocardial ischemia develops when the coronary arteries are unable to dilate and increase blood flow during periods of increased activity or stress.Heart muscle relies primarily on fatty acids and aerobic metabolism to meet its energy needs. Although the heart can engage in anaerobic metabolism, this process relies on the continuous delivery of glucose and results in the formation of large amounts of lactic acid.

Pathogenesis of coronary heart disease (CHD)Atherosclerosis is by far the most common cause of CHD, and atherosclerotic plaque disruption the most frequent cause of myocardial infarction and sudden death.More than 90% of persons with CHD have coronary atherosclerosis.Most, if not all, have one or more lesions causing at least 75% reduction in cross-sectional area, the point at which augmented blood flow provided by compensatory vasodilation no longer is able to assure even moderate increases in metabolic demand.There are two types of atherosclerotic lesions:the fixed or stable plaque, which obstructs blood flowcommonly implicated in chronic ischemic heart disease: stable angina, variant or vasospastic angina, and silent myocardial ischemia;the unstable or vulnerable plaque, which can rupture and cause platelet adhesion and thrombus formationcommonly implicated in unstable angina and myocardial infarction.

Pathogenesis of coronary heart disease (CHD)Plaque disruption may occur with or without thrombosis.Platelets play a major role in linking plaque disruption to acute CHD. As a part of the response to plaque disruption, platelets aggregate and release substances that further propagate platelet aggregation, vasoconstriction, and thrombus formation.Because of the role that platelets play in the pathogenesis of CHD, antiplatelet drugs (e.g., low-dose aspirin) are frequently used for preventing heart attack.Pathogenesis of coronary heart disease (CHD)

Peripheral arterial disease (PAD) PAD refers to the obstruction of large arteries not within the coronary, aortic arch vasculature, or brain. It can result from atherosclerosis, inflammatory processes leading to stenosis, an embolism, or thrombus formation. It causes either acute or chronic ischemia (lack of blood supply). Often PAD is a term used to refer to atherosclerotic blockages found in the lower extremity. Risk factors contributing to PAD are the same as those for atherosclerosis. Risk of PAD also increases in individuals who are over the age of 50, male, obese, or with a family history of vascular disease, heart attack, or stroke. Peripheral arterial disease (PAD)About 20% of patients with mild PAD may be asymptomatic; Symptoms include:Claudication - pain, weakness, numbness, or cramping in muscles due to decreased blood flow; Sores, wounds, or ulcers that heal slowly or not at all ;Noticeable change in color (blueness or paleness) or temperature (coolness) when compared to the other limb ;Diminished hair and nail growth on affected limb and digits.

ArteriolosclerosisArteriolosclerosis is a form of cardiovascular disease affecting the small arteries and arterioles.Types include hyaline arteriolosclerosis and hyperplastic arteriolosclerosis, both associated with vessel wall thickening and luminal narrowing that may cause downstream ischemic injury.Arteriolosclerosis is most often associated with hypertension and/or diabetes mellitus.Arteriosclerosis is a general term describing any hardening (and loss of elasticity) of medium or large arteries (from the Greek arteria, meaning artery, and sclerosis, meaning hardening)Arteriolosclerosis is any hardening (and loss of elasticity) of arterioles (small arteries)Atherosclerosis is a hardening of an artery specifically due to an atheromatous plaque. The term atherogenic is used for substances or processes that cause atherosclerosis.

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