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Cindy Chan October 5, 2009 Lecture #1

Atherosclerosis
Atherosclerosis is a disease of muscular arteries in which the inner layer becomes thickened by fatty deposits and fibrous tissue and may produce a plaque with necrotic gruel-like material. Normal Muscular Artery 3 layers intima (closest to arterial wall) media (middle layer) adventitia (outer layer) Intima is composed of a single layer of endothelial cells that rests on a bed of connective tissue. Media is the thickest layer separated from intima and adventitia by internal & e ternal elastic laminae. !he laminae contain openings between the elastic fibers through which cells can pass. !he media is composed of smooth muscle cells in a matri of collagen" elastic and protoglycans. Adventitia is composed of fibroblast and collagen as well as blood vessels (vasovasorum)" nerves and lymphatics.

The pathogenesis of ATHEROSC EROSIS


Atherosclerosis occurs in a patch of intima" often where flow is disturbed. #ey event$ %ocal accumulation of lipid and cells beneath the endothelium. !he pathologic hallmarks of atherosclerosis are the$ fatty streak fibrous plaque complicated plaque

Fatty streak

Fibrous plaque

Complicated plaque
Plaque rupture thrombosis Weakening of wall aneurysm emboli Hemorrhage into plaque Narrowing of lumen
Calcification rigidity of vessel

Fragmentation

!atty Strea" &arliest visible lesion of atherosclerosis Area of yellow discoloration on inner surface of artery 'pots ( )mm in diameter or streaks ) * +mm wide ,oes not protrude into lumen and does not disturb flow -haracteri.ed by subendothelial accumulation of large / !OAM CE S0 filled with intracellular lipid (ma1ority of foam cells derived from macrophages" less from smooth muscle)

!i#rous $la%ue 2ore advanced lesion of atherosclerosis %irm pale gray elevated lesion 2ay pro1ect into lumen and if sufficiently large" may reduce stress-related blood flow -haracteri.ed by subendothelial accumulate of monocytes" lymphocytes" !OAM CE S" (more of smooth muscle cell organ) and connective tissue -ontain necrotic core of cell debris" degenerating foam cells and cholesterol crystals 'eparated from an arterial line by a fibrous cap. !his cap is composed of e tracellular connective tissue matri with embedded smooth muscle cells.

Complicated $la%ue 3upture of ulceration of the fibrous plaque * e posing thrombogenic material to circulating blood" causing a thrombus to form at that site. 'uch an occlusion can suddenly occlude the vessel" resulting in 24 or stroke 5eakening of vessel wall as fibrous plaque are sub1ected to increase pressure provoking loss of elastic tissue and subsequent dilatation of the artery (aneurysm) 6emorrhage from rupture of the fibrous cap or from tiny capillaries resulting in further enlarging of the plaque &mboli.ation of fragments of disrupted atheroma to distal sites (blue toes)" transient ischemic attacks (!4A) -alcification of fibrous plaque" causing pipe-like rigidity of vessel wall

The endothelium is the largest organ in the #ody& The endothelium consists of' Antithrombotic factors$ 3esist thrombosis$ 6eparin sulfate" thrombomodulin" plasminogen activator" etc 7latelet-inhibitors$ 7rostacyclin" nitric o ide" etc 7romotes vasodilatation$ 7rostacyclin" nitric o ide" bradykinin" etc

4nhibits smooth muscle migration and proliferation$ heparin sulfate" nitric o ide" etc !hrombotic factors8 vasoconstrictors$ &ndothelin" angiotensin 44" 9orepinephrine" etc !unction of the Normal Endothelium (& )arrier function' %orms tight barrier that restricts passage of large molecules and cells into the subendothelial space *& Antithrom#otic activity' 3esists thrombosis through actions of heparin sulfate" thrombomodulin" plasminogen activator and secretion of platelet-inhibitors (prostacyclin" nitric o ide (endotheliumderived rela ing factor +& Effect on vascular tone' 7romotes vasodilatation through secretion of prostacycline and 9: (&,3%) ;. Effect on vascular smooth muscle' 4nhibits smooth muscle cell migration and proliferation (heparin sulfate and 9:) of lipid and cells beneath the endothelium In normal state$ &ndothelium provides protective nonthrombogenic surface" is metabolically active and produces vasoactive substances.

),T5hen endothelium become dysfunctional * may lead to atherosclerosis a. permeability of in1ured layer may increase" allowing molecules such as <,< to enter subendothelial space b. in1ured endothelial cells lose antithrombotic properties ( production of 9: and prostacyclin) c. reduced secretion of vasodilatary (9:" prostacyclin) impairs smooth muscle cell rela ation (therefore" one gets relative vasoconstriction d. in1ured cells secrete increased amount of mitogenic substances

A technique to evaluate endothelial function in humans is

)ART .)rachial Artery Reactivity Test/


!he technique involves inflating8deflating a blood pressure cuff on an individual=s arm and using ultrasound to evaluate the change in lumen diameter before and after the test. 9ormal endothelium will respond to the shear force (after deflation) and release vasodilating factors that should increase the lumen by >))?. %actors that have been demonstrated by this technique to cause decreased endothelial function include$ hypercholesterolemia" hypertension" diabetes" age" smoking" <,<" lipoprotein a" small dense <,<" postprandial chylomicrons @<,<" low levels 6,<). %actors that appear to improve a#normal endothelial function include$ lipid lowering" A-& 4nhibitors" diabetic control" <-arginine (a precursor of nitric o ide)" e ercise" antio idants" smoking cessation.
Hyperlipidemia# Hypertension# $moking# %iruses# etc

ndothelial !n&ury

Lumen
ndothelium

L(L L(L

F)+" C LL$

'tracellular matri' synthesis

Proliferation of smooth muscle cells


)'idi*ed L(L

!ntima
!nternal elastic membrane
'tracellular lipids and necrotic cells

"igration of smooth muscle cells

"edia

Normal vessel

Progressive development of atherosclerotic plaque

0hen the endothelium #ecomes dysfunctional1 !here is an increase in adhesion molecules such as vascular endothelium adhesion molecule (@-A2-)). 2onocytes attach to the endothelium (the first visible sign of atherosclerosis) and migrate into the intima becoming macrophages. <,< cholesterol enters the intima" becomes o idi.ed and interacts with the scavenger receptors of the monocyte and is taken up by the macrophage. !he resultant !OAM CE is the pathognomonic cell. !hese cells secrete cytokines and growth factors that attract smooth muscle cells from the media.

!he activated smooth muscle cells proliferate and secrete collagen" elastin and growth factors such as platelet-derived growth factor. %oam cells die * an increase in e tracellular matri and lipids occur. -alcification and capillary in-growth follow. 7,A % 9: B !9%-a 4<-) !A%-b B platelet-derived growth factor nitric o ide B !issue necrosis factor alpha B 4nterleukin -4 B !ransforming growth factor-beta

Foam cells in fatty streak


Cytokinins
,NF-a !L-. ,/F-b

P(/F

Endothelial dysfunction
N) P/!0

,issue factor
,hrombosis# platelet adhesion
heparinase
endothelial heparin sulfate

$mooth muscles cells migrate to intima# proliferate and produce e'tracellular matri'

FIBROUS PLAQUE

7redilectations for certain sites$

Bifurcation/branching of arteries shou!der regions"


proximal coronary arteries (and at bifurcations) proximal cerebral arteries and distal aorta. !here is a progression of atherosclerosis from$ aorta to coronary arteries to peripheral arteries to cerebral arteries. 5hen the atherosclerotic plaque builds up in a coronary artery sufficient to limit blood flow" effort angina pectoris can occur. 5hen the plaque in a coronary artery suddenly ruptures" a 24 can occur. Remodeling' As the plaque compromises the vessel lumen$ compensatory e pansion of the outer wall occurs. !his process termed atherosclerosis. /remodeling0 protects the luminal area in the early stages of

As the plaque continues to e pand" vessel remodeling becomes inadequate and luminal compromise occurs. 4n diabetics" one may see reverse remodelingC

!hat is" in normals as the atherosclerotic plaque builds up" the outer wall stretches out in an attempt to maintain the internal lumen. 4n diabetics" the outer wall may not stretch out but" in fact" may constrict inward. !hus" for the same amount of atherosclerosis" the diabetic may have a smaller internal diameter.

-omplicated plaque 3upture of an atherosclerotic plaque$


An atherosclerotic plaque contains a soft core of necrotic and fatty material. !he core is covered with a fibrous cap. !he plaque may either be hard1 fi#rous and sta#le or it may #e soft and unsta#le. -hronic symptoms are related to a fibrous plaque with a small residual lipid core and much connective tissue matri " eventually narrowing the lumen enough to cause a limitation of blood supply. !his may cause stable angina. Acute symptoms are related to a plaque with a large lipid core and a thin fibrous plaque that ruptures e posing thrombogenic material to the blood resulting in thrombus formation. !he sudden occlusion by the thrombus may cause an acute coronary syndrome (acute myocardial infarction or unstable angina).

!he vulnerable plaque usually has a substantial lipid core and a thin fibrous plaque separating the thrombogenic foam cells (bearing tissue factor" a powerful procoagulant) from the blood. At sites of disruption" smooth muscle cells ('2-) are often activated" releasing metalloproteinases and other proteolytic en.ymes that degrade collagen in the fibrous cap. !he shoulder region is most susceptible to mechanical disruption and rupture. 7laques that rupture tend to be the earlier softer plaques that may only mildly decrease the luminal diameter. There may li"ely #e an inflammatory process that plays a ma2or role in the disruption of the pla%ue& 4n contrast" the stable plaque has a thick cap protecting the lipid core from contact with the blood. !he stable plaques more often show luminal narrowing detectable on an angiogram than do vulnerable plaques. 3upture is more likely in soft plaques with$ <arge lipid core !hin fibrous plaque 6igh stress at plaque margin <ipid-laden macrophages DE&'!4:9$ 4f a patient has a FG? narrowing of the left anterior descending coronary artery on a coronary angiogram and has a subsequent myocardial infarction" where is the /culprit0 lesionH

RIS3 !ACTORS
Ma2or Nonmodifia#le %amily history of premature disease 4ncreasing age 2ale gender Aenetic abnormalities $otentially Controlla#le 6yperlipidemia 6ypertension 'moking ,iabetes esser1 ,ncertain or Non%uantified O#esity $hysical inactivity 'tress (!ype A personality) 6omocysteine ('&& 9&I! 7AA&) 7ostmenopausal estrogen deficiency <ipoprotein (a) 6ardened (trans) unsaturated fat intake -hlamydia pneumoniae 6igh carbohydrate intake

#$%$%B$#& %O'( )*+L( C)#*,O-)'C+L)# *,'$)'$ ,' .,/.L0 1#$-$2()BL$3

.o4ocysteine is an inter4ediate in the 4ethy!ation cyc!e, !eading to the 5roduction of 6arious 4ethy!ated 5roducts 7*2), 4ye!in basic 5rotein, 4ethy!ated !i5ids8. (hose born 9ith en:y4e deficiencies a!ong this 5ath9ay suffer fro4 6ascu!ar disease. $!e6ated !e6e! of ho4ocysteine ha6e sho9n to be associated 9ith coronary heart disease 7a!ong 9ith cerebro6ascu!ar and 5eri5hera! 6ascu!ar disease8. 1re6ious tria!s atte45ting to !o9er ho4ocysteine !e6e!s, ho9e6er, ha6e not sho9n a reduction of cardio6ascu!ar e6ents. 'tudies are ongoing;.