Alemwosen T.

(MD,pathologist)
 ARTERIOSCLEROSIS
"hardening of the arteries"
Reflects arterial wall thickening and loss of elasticity
Three patterns are recognized, with different clinical
and pathologic consequences:
Atherosclerosis
Mnckeberg medial calcific sclerosis
characterized by calcific deposits in muscular arteries
Arteriolosclerosis
affects small arteries and arterioles
hyaline and hyperplastic
 ATHEROSCLEROSIS
Characterized by intimal lesions called atheromas
Atheromas protrude into & obstruct vascular lumens &
weaken the vascular media
An atheromatous plaque consists of a raised lesion
soft, yellow, grumous core of lipid (mainly cholesterol and
cholesterol esters)
a firm, white fibrous cap
Natural history according to AHA
 Atherosclerosis develops primarily in elastic &
large & medium-sized muscular arteries
Symptomatic atherosclerosis most often involves
the arteries supplying
the heart
Brain
kidneys &
lower extremities
PLAQUE DEPOSIT
ORIGINAL DIAMETER
 Other consquences of atherosclerosis
Sudden cardiac death
Chronic ischemic heart disease & ischemic
encephalopathy
Disruption of Plaques thrombi =obstruct
blood flow
Plaques encroach on the subjacent media -
weaken the vessel wall = aneurysms
Friable Atheromas = emboli
 Morphology
Fatty streaks
earliest lesion of atherosclerosis
Composed of lipid-filled foam cells
Not significantly raised & dont cause any disturbance
in blood flow
Begin as multiple yellow, flat spots less than 1 mm in
diameter that coalesce into elongated streaks, 1 cm
long or longer
 Atherosclerotic Plaque
The key processes in atherosclerosis are intimal
thickening and lipid accumulation
Raised lesion with a soft, yellow, grumous core
of lipid covered by a firm, white fibrous cap
 Atheromatous plaques appear white to whitish
yellow and impinge on the lumen of the artery
Plaques vary from 0.3 to 1.5 cm in diameter but
can coalesce to form larger masses
Usually involve only a partial circumference of
the arterial wall ("eccentric" lesions)
Lesions tend to be much more prominent around
the origins (ostia) of major branches of AA
 The most extensively involved vessels in
descending order are:
lower abdominal aorta
coronary arteries
popliteal arteries
internal carotid arteries,
vessels of the circle of Willis
 Atherosclerotic plaques have three principal
components:
Cells (SMC, macrophages and other WBC)
ECM (collagen, elastin, and PGs)
Lipid = Cholesterol (Intra/extracellular)
These components occur in varying proportions
and configurations in different lesions
 Plaques generally continue to change and
progressively enlarge through
cell death and degeneration
synthesis and degradation (remodeling) of ECM
and
organization of thrombi
Atheromas often undergo calcification
 Atherosclerotic plaques are susceptible to different
pathologic changes with clinical significance:
A.Rupture, ulceration, or erosion of the luminal
surface of atheromatous plaques
Exposes the bloodstream to highly thrombogenic
substances thrombus formation
thrombi can partially or completely occlude the lumen

downstream ischemia
microemboli composed of lesion contents = cholesterol
emboli or atheroemboli
B. Hemorrhage into a plaque
Rupture of the overlying fibrous cap or of the thin-
walled vessels in the areas of neovascularization

intra-plaque hemorrhage

expand the plaque

plaque rupture
 C. 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
 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 (the so-called "clinical
horizon)
Natural history, morphologic features, main pathogenetic events, and clinical
complications of atherosclerosis in the coronary arteries.
 Epidemiology & Risk factors
Virtually ubiquitous among most developed nations
but now..
Epidemiologic data on atherosclerosis is usually
presented in terms of deaths caused by ischemic
heart disease
The prevalence and severity of atherosclerosis and
IHD among individuals and groups are related to
several risk factors: constitutional or acquired or
related to behaviors
NB: Multiple risk factors have a multiplicative effect
Constitutional risk factors
Age
Age is a dominant influence
Death rates from IHD rise with each decade
Atherosclerosis is not usually clinically evident
until middle age or later
Gender
Males are much more prone to atherosclerosis and
its consequences than are females
After menopause, however, the incidence of
atherosclerosis-related diseases increases
 Genetics
The well-established familial predisposition to
atherosclerosis and IHD is multifactorial
Relates to familial clustering of other risk factors,
such as hypertension or diabetes, or
well-defined genetic derangements in lipoprotein
metabolism, such as familial
hypercholesterolemia
Major Modifiable Risk Factors
Hyperlipidemia
Hyperlipidemia- more specifically, hypercholesterolemia
Even in the absence of other risk factors,
hyercholesterolemia is sufficient to stimulate lesion
development
The major component of serum cholesterol associated with
increased risk is low-density lipoprotein (LDL) cholesterol
Exercise and moderate consumption of ethanol both raise
the HDL level, whereas obesity and smoking lower it
 Hypertension
HTN can increase the risk of IHD by approximately 60%
in comparison with normotensive populations,other
factors being controled
Both systolic and diastolic levels are important in
increasing risk
Left untreated, roughly half of hypertensive patients
will die of IHD or CHF, and another third will die of
stroke
 Cigarette Smoking
Prolonged (years) smoking of one pack of cigarettes or
more daily increases the death rate from IHD by 200%
Smoking cessation reduces that risk substantially
Diabetes Mellitus
Induces hypercholesterolemia as well as a markedly
increased predisposition to atherosclerosis
The incidence of MI is twice as high in diabetic as in
nondiabetic individuals other factors being equal
There is also an increased risk of strokes and a 100-
fold increased risk of atherosclerosis-induced
gangrene of the lower extremities
 Other factors
Inflammation
Inflammation is present during all stages of atherogenesis and is
intimately linked with atherosclerotic plaque formation and
rupture
Assessing systemic inflammatory status has become important in
overall risk stratification.
Eg. C-reactive protein (CRP) strongly and independently predicts the
risk of MI, stroke, PAD, and SCD, even among apparently healthy
Lipoprotein a-Lp(a)
Homocystinuria
Lack of exercise;competitive, stressful lifestyle ("type A"
personality); and obesity
Epidemiologic data indicate a protective role for
moderate intake of alcohol
 Pathogenesis
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
Lesion progression occurs through interactions of modified
lipoproteins, monocyte-derived macrophages, T
lymphocytes, and the normal cellular constituents of the
arterial wall
 Central tenets of response-to-injury hypothesis
Chronic endothelial injury (subtle) endothelial
dysfunction increased permeability, leukocyte
adhesion, and thrombosis
Accumulation of lipoproteins, mainly LDL
Modification of lesional lipoproteins by oxidation
Adhesion of blood monocytes (and other leukocytes)
to the endothelium, followed by their migration into
the intima and their transformation into macrophages
and foam cells
 Central tenets of response-to-injury hypothesis.ctd
Adhesion of platelets
Release of factors from activated platelets,
macrophages, or vascular cells that cause migration of
SMCs from media into the intima
Proliferation of smooth muscle cells in the intima, and
elaboration of extracellular matrix, leading to the
accumulation of collagen and proteoglycans
Enhanced accumulation of lipids both within cells
(macrophages and SMCs) and extracellularly.
 Summary of Pathogenesis of atherosclerosis
The contemporary view of the pathogenesis:
Atherosclerosis is a chronic inflammatory response of
arterial wall initiated by some form of endothelial injury!!
chronic endothelial injury,
insudation of lipoproteins (mainly LDL and VLDL) into the
vessel wall,
modification of such lipoproteins by oxidation,
adhesion of blood monocytes to the endothelium,
migration of monocytes into the intima and their
transforamtion into macrophages and foam cells,
adhesion of platelets to focal areas of denudation or to
adherent leukocytes
Summary of Pathogenesis of atherosclerosis..ctd:
release of factors from activated platelets,
macrophages or vascular cells,
migration of smooth muscle cells from media into
intima,
proliferation of smooth muscle cells in the intima and
elaboration of extracellular matrix,
accumulation of collagen anf proteoglycans,
enhanced accumulation of lipids within macrophages,
smooth muscle cells and extracellularly.
 Prevention of Atherosclerotic Vascular Disease
Primary prevention
either delaying atheroma formation or
encouraging regression of established lesions in persons who
have not yet suffered a serious complication of
atherosclerosis
Risk factor identification and modification of those that
are amenable to intervention:
cessation of cigarette smoking
control of hypertension
weight loss
Exercise
lowering total and LDL blood cholesterol levels while
increasing HDL
 Secondary prevention
Programs intended to prevent recurrence of events such as
MI or stroke in symptomatic patients
Involves the judicious use of
Aspirin (anti-platelet agent)
Beta blockers (to limit cardiac demand)
Surgical interventions (e.g., coronary artery bypass
surgery, carotid endarterectomy)
These can successfully reduce recurrent myocardial or
cerebral events