lesson 2 - atheroscrerosis

8/2/2019 Lesson 2 - Atheroscrerosis

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

ATHEROSCLEROSIS


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Atherosclerosis

o Atherosclerosis is a condition in which an artery

wall thickens as a result of the accumulation of fattymaterials 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 accumulationof macrophage and promoted by low-densitylipoproteins (plasma proteins that carry cholesteroland triglycerides) without adequate removal of fats

and cholesterol from the macrophages by functionalhigh density lipoproteins (HDL),


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Etiology

Risk factorso Age Incidence with age. Slowly progressive

disease.o Hypertension both systolic and diastolic

important. Drug therapy reduces risk.o Hyperlipidaemia a major risk factor.

n LDL cholesterol associated with risk. HDL risk.n HDL mobilizes cholesterol from atheroma and

transports it to liver for excretion into bile.n Exercise and moderate ethanol HDL, obesity

and smoking .


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o Diabetes mellitus induceshypercholesterolemia

o Cigarette smoking increases risk of heartdisease.

o Obesity

o

Sedentary lifestyleo Stressed lifestyle


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Pathogenesis

o The earliest visible lesion of atherosclerosis is

the fatty streak, which is due to an accumulationof lipid-laden foam cells in the intimal layer ofthe artery.

o With time, the fatty streak evolves into a fibrous

plaque, the hallmark of establishedatherosclerosis.

o Ultimately the lesion may evolve to contain

large amounts of lipid; if it becomes unstable,denudation of overlying endothelium, or plaquerupture, may result in thrombotic occlusion ofthe overlying artery.


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o Atherosclerotic lesions are composed of threemajor components.

1. The first is the cellular component comprisedpredominately of smooth muscle cells andmacrophages.

2. The second component is the connective tissuematrix and extracellular lipid.

3. The third component is intracellular lipid thataccumulates within macrophages, thereby

converting them into foam cells.


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o Atherosclerotic lesions develop as a result ofinflammatory stimuli, subsequent release of

various cytokines, proliferation of smoothmuscle cells, synthesis of connective tissuematrix, and accumulation of macrophages andlipid.

o The contemporary view of atherogenesis isexpressed by the response-to-injuryhypothesis.

o This model views atherosclerosis as a chronicinflammatory response of the arterial wall toendothelial injury.


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o Chronic endothelial injury, with resultantendothelial dysfunction, cause increased

permeability, leukocyte adhesion, andthrombosis.


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Steps in the formation of atherosclerosis

o Accumulation of lipoproteins (mainly LDL and its

oxidized forms) in the vessel wallo Monocyte adhesion to the endothelium, followed by

migration into the intima and transformation intomacrophages and foam cells, Platelet adhesion

o Factor release from activated platelets,macrophages, and vascular wall cells, inducingSMC recruitment, either from the media or fromcirculating precursors SMC proliferation and ECM

productiono Lipid accumulation both extracellularly and within

cells (macrophages and SMCs)


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o The accumulation of lipid-containingmacrophages in the initima gives rise to "fatty

streaks (step 4).o With further evolution, a fibrofatty atheroma

(step 5) consisting of proliferated SMC, foamcells, extracellular lipid, and ECM is formed.

o Several aspects of atherogenesis will now beconsidered 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 injury-

whether induced experimentally by mechanical

denudation, hemodynamic forces, immunecomplex deposition, irradiation, or chemicals-results in intimal thickening; in the presence ofhigh-lipid diets, typical atheromas ensue.

o However, early human lesions begin at sites ofmorphologically intact endothelium.


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o Thus, non-denuding endothelial dysfunctionunderlies human atherosclerosis; in the setting of

intact but dysfunctional ECs there is increasedendothelial permeability, enhanced leukocyteadhesion, and altered gene expression.

o The specific causes of endothelial dysfunction inearly atherosclerosis are not completelyunderstood.

o Etiologic culprits include toxins from cigarette

smoke, homocysteine, and even infectiousagents.


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o Inflammatory cytokines (e.g., tumor necrosisfactor, or TNF) can also stimulate the expression

of pro-atherogenic genes in EC.o Nevertheless, the two most important causes of

endothelial dysfunction are hemodynamicdisturbances and hypercholesterolemia.

o Inflammation is also an important contributor.


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o The importance of hemodynamic turbulence inatherogenesis is illustrated by the observation that

plaques tend to occur at ostia of exiting vessels,

branch points, and along the posterior wall of theabdominal aorta, where there are disturbed flow

patterns.

o In vitro studies further demonstrate that

nonturbulent laminar flow in other parts of thenormal vasculature leads to the induction ofendothelial genes whose products (e.g., theantioxidant superoxide dismutase) actuallyprotect

against atherosclerosis.o Such "atheroprotective" genes could explain the

nonrandom localization of early atheroscleroticlesions.


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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 mutationsthat encode defective apoproteins or alter thelipoprotein receptors on cells, or from someother underlying disorder that affects thecirculating levels of lipids (e.g., nephrotic

syndrome, alcoholism, hypothyroidism, ordiabetes mellitus).


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o Common lipoprotein abnormalities in thegeneral population (indeed, present in many

survivors of myocardial infarction) include (1)increased LDL cholesterol levels, (2) decreasedHDL cholesterol levels, and (3) increased levelsof the abnormal Lp.

o The evidence implicating hypercholesterolemiain atherogenesis includes the followingobservations:n The dominant lipids in atheromatous plaques are

cholesterol and cholesterol esters.n Genetic defects in lipoprotein uptake and

metabolism that cause hyperlipoproteinemia areassociated with accelerated atherosclerosis.


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n Thus, homozygous familial hypercholesterolemia,caused by defective LDL receptors and inadequate

hepatic LDL uptake, can lead to myocardialinfarction before the age of 20 years.n Similarly, accelerated atherosclerosis occurs in

animal models with engineered deficiencies inapolipoproteins or LDL receptors.

o Other genetic or acquired disorders (e.g.,diabetes mellitus, hypothyroidism) that causehypercholesterolemia lead to premature

atherosclerosis.


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o Epidemiologic studies demonstrate a significantcorrelation between the severity of

atherosclerosis and the levels of total plasmacholesterol or LDL.

o Lowering serum cholesterol by diet or drugsslows the rate of progression of atherosclerosis,

causes regression of some plaques, and reducesthe risk of cardiovascular events.


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o The mechanisms by which hyperlipidemiacontributes to atherogenesis include the

following:n Chronic hyperlipidemia, particularly

hypercholesterolemia, can directly impair ECfunction by increasing local production of reactive

oxygen species.n Among other effects, oxygen free radicals

accelerate nitric oxide decay, damping itsvasodilator activity and thereby increasing local

shear stress.n With chronic hyperlipidemia, lipoproteins

accumulate within the intima.


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o These lipids are oxidizedthrough the action ofoxygen free radicals locally generated by

macrophages or ECs.o Oxidized LDL is ingested by macrophages

through ascavenger receptor, distinct from theLDL receptor, resulting in foam-cell formation.

o In addition, oxidized LDL stimulates the releaseof growth factors, cytokines, and chemokines byECs and macrophages that increase monocyte

recruitment into lesions.o Finally, oxidized LDL is cytotoxic to ECs and

SMCs and can induce EC dysfunction.


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o The importance of oxidized LDL inatherogenesis is suggested by its accumulation

within macrophages at all stages of plaqueformation.

o Moreover, antioxidant therapy (-carotene andvitamin E) protects against atherosclerosis in

animal models, but it does not appear to beeffective for preventing IHD.


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Inflammation

o Inflammatory cells and mediators are involved

in the initiation, progression, and thecomplications of atherosclerotic lesions.o Although normal vessels do not bind

inflammatory cells, early in atherogenesis

dysfunctional arterial ECs express adhesionmolecules that encourage leukocyte adhesion;

o Vascular cell adhesion molecule 1 (VCAM-1) inparticular binds monocytes and T cells.

o After these cells adhere to the endothelium, theymigrate into the intima under the influence oflocally produced chemokines.


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o Monocytes transform into macrophages andavidly engulf lipoproteins, including oxidized

LDL.o Monocyte recruitment and differentiation into

macrophages (and ultimately into foam cells) istheoretically protective, since these cells remove

potentially harmful lipid particles.o Over time, however, progressive accumulation

of oxidized LDL drives lesion progression.


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o Thus, macrophage activation (via oxidized LDLor T cells) results in cytokine production (e.g.,

TNF) that further increases leukocyte adhesionand chemokine production that in turn propelmononuclear inflammatory cell recruitment.

o Activated macrophages also produce reactive

oxygen species, aggravating LDL oxidation.o T lymphocytes recruited to the intima interact

with macrophages and can generate a chronic

immune inflammatory state.


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o Activated T cells in the growing intimal lesionselaborate inflammatory cytokines, (e.g.,

interferon-), which in turn can stimulatemacrophages as well as ECs and SMCs.

o As a consequence of the chronic inflammatorystate, activated leukocytes and vascular wall

cells release growth factors that promote SMCproliferation and ECM synthesis.


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Infection Body

o Although there is evidence that infections may drivethe local inflammatory process that results inatherosclerotic plaque, this hypothesis has yet to bedefinitively proven.

o Herpesvirus, cytomegalovirus, and Chlamydiapneumoniae have all been detected inatherosclerotic plaque but not in normal arteries,and seroepidemiologic studies find increasedantibody titers to C. pneumoniae in patients withmore severe atherosclerosis.

o However, a causal link between any of theseinfections and the development or progression ofatherosclerosis 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 andcontribute to the progressive growth ofatherosclerotic lesions.

o The intimal SMCs have a proliferative andsynthetic phenotype distinct from the underlyingmedial SMCs and, in fact, may substantiallyderive from the recruitment of circulating

precursors.


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o Several growth factors are implicated in SMCproliferation and ECM synthesis, including

platelet-derived growth factor (PDGF, releasedby locally adherent platelets as well as bymacrophages, ECs, and SMCs), fibroblastgrowth factor, and transforming growth factor .

The recruited SMCs synthesize ECM (notablycollagen), which stabilizes atheroscleroticplaques.

o However, activated inflammatory cells inatheromas can cause intimal SMC apoptosis, andthey also increase ECM catabolism, resulting inunstable 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 significantlyraised and thus do not cause any disturbance inblood flow.

o They begin as multiple minute yellow, flat spotsthat can coalesce into elongated streaks, 1 cmlong or longer.

o Fatty streaks can appear in the aortas of infants

younger than 1 year and are present in virtuallyall children older than 10 years, regardless ofgeography, race, sex, or environment.


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o Coronary fatty streaks begin to form inadolescence, at the same anatomic sites that later

tend to develop plaques.o The relationship of fatty streaks to

atherosclerotic plaques is uncertain; althoughthey may evolve into precursors of plaques, not

all fatty streaks are destined to become advancedatherosclerotic lesions.


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Fatty streak-a collection of foam cells in the intima. Aortawith fatty streaks (arrows), associated largely with theostia of branch vessels


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o Atherosclerotic Plaque. The key processes inatherosclerosis are intimal thickening and lipid

accumulation.


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o Atheromatous plaques (also called fibrous orfibrofatty plaques) impinge on the lumen of the

artery and grossly appear white to yellow;thrombosis superimposed over the surface ofulcerated plaques is red-brown in color.

o Plaques vary from 0.3 to 1.5 cm in diameter but

can coalesce to form larger masses (Fig. 10-9).o Atherosclerotic lesions are patchy, usually

involving only a portion of any given arterial

wall.


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o Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composedof fibrous plaques (arrow). B, Severe disease with diffuse and complicatedlesions, some of which have coalesced.

MILD ADVANCED


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o On cross-section, the lesions therefore appear"eccentric".

o

The focality of atherosclerotic lesions-despite theuniform exposure of vessel walls to such factors ascigarette smoke toxins, elevated LDL, andhyperglycemia-is almost certainly due to the

vagaries of vascular hemodynamics.o Local flow disturbances, such as turbulence at

branch points, leads to certain portions of a vesselwall being more susceptible to plaque formation.

o Although focal and sparsely distributed at first,atherosclerotic lesions become more numerous andmore diffuse with time.


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o Histologic features of atheromatous plaque in the coronary artery.A, Overall architecture demonstrating fibrous cap (F) and a centralnecrotic (largely lipid) core (C). The lumen (L) has been

moderately narrowed. Note that a segment of the wall is plaquefree (arrow), so that there is an eccentric lesion. In this section,collagen has been stained blue (Masson's trichrome stain).


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o B, Higher power photograph of a section ofthe plaque shown inA, stained for elastin

(black), demonstrating that the internal andexternal elastic membranes are destroyedand the media of the artery is thinned underthe most advanced plaque (arrow).

o C, Higher magnification photomicrographat the junction of the fibrous cap and core,showing scattered inflammatory cells,

calcification (arrowhead), andneovascularization (small arrows).


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o In humans, the abdominal aorta is typicallymuch more frequently involved than the thoracic

aorta.o 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 thecircle of Willis.

o Vessels of the upper extremities are usually

spared, as are the mesenteric and renal arteries,except at their ostia.


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o Nevertheless, in an individual case, the severityof atherosclerosis in one artery does not predict

its severity in another.o Moreover, in any given vessel, lesions at various

stages often coexist.


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o Atherosclerotic plaques have three principalcomponents:

1. Cells, including smcs, macrophages, and T cells;2. ECM, including collagen, elastic fibers, and

proteoglycans; and

3. Intracellular and extracellular lipid.

o These components occur in varying proportionsand configurations in different lesions.

o Typically, the superficial fibrous cap iscomposed of SMCs and relatively densecollagen.


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o Beneath and to the side of the cap (the"shoulder") is a more cellular area containingmacrophages, T cells, and SMCs.

o Deep to the fibrous cap is a necrotic core,containing lipid (primarily cholesterol andcholesterol esters), debris from dead cells, foam

cells (lipid-laden macrophages and SMCs),fibrin, variably organized thrombus, and otherplasma proteins;

o The cholesterol content is frequently present as

crystalline aggregates that are washed out duringroutine tissue processing and leave behind onlyempty "clefts."


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o At the periphery of the lesions, there is usuallyneovascularization (proliferating small bloodvessels).

o Typical atheromas contain relatively abundant lipid,but some plaques ("fibrous plaques") are composedalmost exclusively of SMCs and fibrous tissue.

o Plaques generally continue to change andprogressively enlarge through cell death anddegeneration, synthesis and degradation(remodeling) of ECM, and organization of thrombi.

o Moreover, atheromas often undergo calcification.

o Patients with advanced coronary calcificationappear to be at increased risk for coronary events.


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Atherosclerotic plaques are susceptible to thefollowing pathologic changes with clinical

significance:o Rupture, ulceration, or erosion of the luminal

surface of atheromatous plaques exposes thebloodstream 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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o If the patient survives the initial vascularocclusion, thrombi may become organized and

incorporated into the growing plaque.o Hemorrhage into a plaque. Rupture of the

overlying fibrous cap or of the thin-walledvessels in the areas of neovascularization can

cause intra-plaque hemorrhage; a containedhematoma may expand the plaque or induceplaque rupture.

o

Atheroembolism. Plaque rupture can dischargedebris into the bloodstream, producingmicroemboli composed of plaque contents.


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o Aneurysm formation. Atherosclerosis-inducedpressure or ischemic atrophy of the underlying

media, with loss of elastic tissue, causesweakness of the vessel wall and development ofaneurysms that may rupture.


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Natural History of Atherosclerosis

o The natural history, morphologic features, and

main pathogenic events of atherosclerosis aresummarised as below.

o It primarily affects elastic arteries (e.g., aorta,carotid, and iliac arteries) and large andmedium-sized muscular arteries (e.g., coronaryand popliteal arteries).

o In small arteries, atheromas can gradually

occlude lumina, compromising blood flow todistal organs and cause ischemic injury.

o "clinical horizon";


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o Atherosclerotic plaques can undergo acutedisruption and precipitate thrombi that further

obstruct blood flow.o In large arteries, plaques are destructive,

encroaching on the subjacent media andweakening the affected vessel wall, causing

aneurysms that can rupture.o Moreover, atheromas can be friable, fragmenting

atheroemboli into downstream circulations.


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o Atherosclerosis is a slowly evolving lesionusually requiring many decades to become

significant.o However, acute plaque changes (e.g., rupture,

thrombosis, or hematoma formation) can rapidlyprecipitate clinical sequelae called clinical

horizon.o 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 majorconsequences of atherosclerosis.

o Atherosclerosis also takes a toll through otherconsequences of acutely or chronicallydiminished arterial perfusion, such as

n mesenteric occlusion,n sudden cardiac death,n chronic IHD, and ischemic encephalopathy.


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Prevention of Atherosclerotic Vascular Disease

o Prevention include;n Primary prevention programs aimed at either

delaying atheroma formation or encouragingregression of established lesions in persons whohave not yet suffered a serious complication of

atherosclerosis.n It involves risk factor identification and

modification of those that are amenable tointervention such as cessation of cigarette smoking,control of hypertension, weight loss, exercise, andlowering total and LDL blood cholesterol levelswhile increasing HDL (e.g., by diet or throughstatins).


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n Secondary prevention programs intended toprevent recurrence of events such as myocardialinfarction or stroke in symptomatic patients.

n It involves the use of aspirin (anti-platelet agent),statins, and beta blockers (to limit cardiac demand),as well as surgical interventions (e.g., coronaryartery bypass surgery, carotid endarterectomy).

These can successfully reduce recurrent myocardialor cerebral events.

C li ti


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Complications

W.B. Saunders Co. 1999


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Interventional Procedures

o

Angioplasty (PCI)o Atherectomyo Stentso

Lasero Revascularization

n gene therapyn

stem cells


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Angioplasty - PCI

HeartPoint, 1997

Percutaneous Coronary Intervention


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Percutaneous Coronary Intervention(PCI)

Restenosis


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Restenosis

St t


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Stents

St t


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Stents

Di ti l Ath t


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Directional Atherectomy

Ath t Bi i


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Atherectomy Biopsies

Rotoblater


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Rotoblater

L


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Laser



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o

Pron Relatively nonivasiven Cheap

o Conn Restenosis 25%n Drug coated stents restenosis rate to


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Coronary Artery Bypass Surgery

o

Saphenous vein graftso Internal mammary artery

CABG

CABG


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CABG

HeartPoint, 1997


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CABG - Saphenous Vein Grafts


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p

CABG S


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CABG Surgery

o

Pron Good revascularization

o Conn

Restenosis in 10-15 yrsn Invasiven Expensive


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END OF PRESENTION

lesson 2 - atheroscrerosis

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