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ATHEROSCLEROSIS

PRESENTER: CHAPIMA F. BSc (UNZA) MSc. PTH (CLINICAL)


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Atherosclerosis o Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol. o It is a syndrome affecting arterial blood vessels. o There is a chronic inflammatory response in the walls of arteries, caused largely by the accumulation of macrophage and promoted by low-density lipoproteins (plasma proteins that carry cholesterol and triglycerides) without adequate removal of fats and cholesterol from the macrophages by functional high density lipoproteins (HDL),

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Etiology Risk factors o Age Incidence with age. Slowly progressive disease. o Hypertension both systolic and diastolic important. Drug therapy reduces risk. o Hyperlipidaemia a major risk factor.
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LDL cholesterol associated with risk. HDL risk. HDL mobilizes cholesterol from atheroma and transports it to liver for excretion into bile. Exercise and moderate ethanol HDL, obesity and smoking .

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Diabetes mellitus induces hypercholesterolemia Cigarette smoking increases risk of heart disease. Obesity Sedentary lifestyle Stressed lifestyle

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Pathogenesis o The earliest visible lesion of atherosclerosis is the fatty streak, which is due to an accumulation of lipid-laden foam cells in the intimal layer of the artery. o With time, the fatty streak evolves into a fibrous plaque, the hallmark of established atherosclerosis. o Ultimately the lesion may evolve to contain large amounts of lipid; if it becomes unstable, denudation of overlying endothelium, or plaque rupture, may result in thrombotic occlusion of the overlying artery.
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Atherosclerotic lesions are composed of three major components. The first is the cellular component comprised predominately of smooth muscle cells and macrophages. The second component is the connective tissue matrix and extracellular lipid. The third component is intracellular lipid that accumulates within macrophages, thereby converting them into foam cells.

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Atherosclerotic lesions develop as a result of inflammatory stimuli, subsequent release of various cytokines, proliferation of smooth muscle cells, synthesis of connective tissue matrix, and accumulation of macrophages and lipid. The contemporary view of atherogenesis is expressed by the response-to-injury hypothesis. This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury.

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Chronic endothelial injury, with resultant endothelial dysfunction, cause increased permeability, leukocyte adhesion, and thrombosis.

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Steps in the formation of atherosclerosis o Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall o Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells, Platelet adhesion o 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 production o Lipid accumulation both extracellularly and within cells (macrophages and SMCs)
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The accumulation of lipid-containing macrophages in the initima gives rise to "fatty streaks (step 4). With further evolution, a fibrofatty atheroma (step 5) consisting of proliferated SMC, foam cells, extracellular lipid, and ECM is formed. Several aspects of atherogenesis will now be considered in detail.

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Endothelial Injury o Chronic or repetitive endothelial injury is the cornerstone of the response-to-injury hypothesis. o Endothelial loss due to any kind of injurywhether induced experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicalsresults in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. o However, early human lesions begin at sites of morphologically intact endothelium.
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Thus, non-denuding endothelial dysfunction underlies human atherosclerosis; 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.

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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.

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The importance of hemodynamic turbulence in atherogenesis is 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. In vitro studies further demonstrate that 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. Such "atheroprotective" genes could explain the nonrandom localization of early atherosclerotic lesions.
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Lipids o Lipids are typically transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes). o 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).
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Common lipoprotein abnormalities in the general population (indeed, present in many survivors of myocardial infarction) include (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol levels, and (3) increased levels of the abnormal Lp. The evidence implicating hypercholesterolemia in atherogenesis includes the following observations:
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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.

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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. Similarly, accelerated atherosclerosis occurs in animal models with engineered deficiencies in apolipoproteins or LDL receptors.

Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis.

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Epidemiologic studies 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.

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The mechanisms by which hyperlipidemia contributes to atherogenesis include the following:


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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.

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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.

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The importance of oxidized LDL in atherogenesis is suggested by its accumulation within macrophages at all stages of plaque formation. Moreover, antioxidant therapy (-carotene and vitamin E) protects against atherosclerosis in animal models, but it does not appear to be effective for preventing IHD.

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Inflammation o Inflammatory cells and mediators are involved in the initiation, progression, and the complications of atherosclerotic lesions. o Although normal vessels do not bind inflammatory cells, early in atherogenesis dysfunctional arterial ECs express adhesion molecules that encourage leukocyte adhesion; o Vascular cell adhesion molecule 1 (VCAM-1) in particular binds monocytes and T cells. o After these cells adhere to the endothelium, they migrate into the intima under the influence of locally produced chemokines.
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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.

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Thus, macrophage activation (via oxidized LDL or T cells) 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.

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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.

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Infection Body o Although there is evidence that infections may drive the local inflammatory process that results in atherosclerotic plaque, this hypothesis has yet to be definitively proven. o 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. o However, a causal link between any of these infections and the development or progression of atherosclerosis remains to be established.
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Smooth Muscle Proliferation o Intimal SMC proliferation and ECM deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions. o 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.

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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.

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Classifications of Atherosclerosis

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Morphology o 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. o They begin as multiple minute yellow, flat spots that can coalesce into elongated streaks, 1 cm long or longer. o Fatty streaks can appear in the aortas of infants younger than 1 year and are present in virtually all children older than 10 years, regardless of geography, race, sex, or environment.
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Coronary fatty streaks begin to form in adolescence, at the same anatomic sites that later tend to develop plaques. The relationship of fatty streaks to atherosclerotic plaques is uncertain; although they may evolve into precursors of plaques, not all fatty streaks are destined to become advanced atherosclerotic lesions.

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Fatty streak-a collection of foam cells in the intima. Aorta with fatty streaks (arrows), associated largely with the ostia of branch vessels
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Atherosclerotic Plaque. The key processes in atherosclerosis are intimal thickening and lipid accumulation.

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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 (Fig. 10-9). Atherosclerotic lesions are patchy, usually involving only a portion of any given arterial wall.

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MILD
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ADVANCED

Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques (arrow). B, Severe disease with diffuse and complicated lesions, some of which have coalesced.
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On cross-section, the lesions therefore appear "eccentric". The focality of atherosclerotic lesions-despite the uniform exposure of vessel walls to such factors as cigarette smoke toxins, elevated LDL, and hyperglycemia-is almost certainly due to the vagaries of vascular hemodynamics. Local flow disturbances, such as turbulence at branch points, leads to certain portions of a vessel wall being more susceptible to plaque formation. Although focal and sparsely distributed at first, atherosclerotic lesions become more numerous and more diffuse with time.
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Histologic features of atheromatous plaque 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), so that there is an eccentric lesion. In this section, collagen has been stained blue (Masson's trichrome stain).
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B, Higher power photograph of a section of the plaque shown in A, 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). C, Higher magnification photomicrograph at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (arrowhead), and neovascularization (small arrows).

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In humans, the abdominal aorta is typically much more frequently involved than the thoracic aorta. 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.

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Nevertheless, in an individual case, the severity of atherosclerosis in one artery does not predict its severity in another. Moreover, in any given vessel, lesions at various stages often coexist.

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Atherosclerotic plaques have three principal components:


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Cells, including smcs, macrophages, and T cells; ECM, including collagen, elastic fibers, and proteoglycans; and Intracellular and extracellular lipid.

These components occur in varying proportions and configurations in different lesions. Typically, the superficial fibrous cap is composed of SMCs and relatively dense collagen.

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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."

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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.

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Atherosclerotic plaques are susceptible to the following pathologic changes with clinical significance: o Rupture, ulceration, or erosion of the luminal surface of atheromatous plaques exposes the bloodstream to highly thrombogenic substances and induces thrombus formation. o Such thrombi can partially or completely occlude the lumen and lead to downstream ischemia.

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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.

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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 o The natural history, morphologic features, and main pathogenic events of atherosclerosis are summarised as below. o It primarily affects elastic arteries (e.g., aorta, carotid, and iliac arteries) and large and medium-sized muscular arteries (e.g., coronary and popliteal arteries). o In small arteries, atheromas can gradually occlude lumina, compromising blood flow to distal organs and cause ischemic injury. o "clinical horizon";
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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.

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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 called clinical horizon. Symptomatic atherosclerotic disease most often involves the arteries supplying the heart, brain, kidneys, and lower extremities.

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Major consequences of atherosclerosis o Myocardial infarction (heart attack), o cerebral infarction (stroke), o aortic aneurysms, and peripheral vascular disease (gangrene of the legs) are the major consequences of atherosclerosis. o Atherosclerosis also takes a toll through other consequences of acutely or chronically diminished arterial perfusion, such as
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mesenteric occlusion, sudden cardiac death, chronic IHD, and ischemic encephalopathy.

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Prevention of Atherosclerotic Vascular Disease o Prevention include;


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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. It involves risk factor identification and modification of those that are amenable to intervention such as 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).

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Secondary prevention programs intended to prevent recurrence of events such as myocardial infarction or stroke in symptomatic patients. It involves the 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.

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Complications

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W.B. Saunders Co. 1999

Interventional Procedures
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Angioplasty (PCI) Atherectomy Stents Laser Revascularization


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gene therapy stem cells

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Angioplasty - PCI

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HeartPoint, 1997

Percutaneous Coronary Intervention (PCI)

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Restenosis

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Stents

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Stents

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Directional Atherectomy

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Atherectomy Biopsies

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Rotoblater

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Laser

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Interventional Procedures
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Pro n Relatively nonivasive n Cheap Con n Restenosis 25% n Drug coated stents restenosis rate to <10%

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Coronary Artery Bypass Surgery

CABG
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Saphenous vein grafts Internal mammary artery

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CABG

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HeartPoint, 1997

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CABG - Saphenous Vein Grafts

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CABG Surgery
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Good revascularization Restenosis in 10-15 yrs Invasive Expensive

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END OF PRESENTION

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