Atherosclerosis

and its complications

Dr. Thin Thin Win @ Safiya Yunus

Pathology Division, IMU
 Arteriosclerosis

Arterio sclerosis: Hardening of the arteries

Thickening and loss of elasticity of arterial walls

3 patterns of arteriosclerosis
Atherosclerosis
Arteriolosclerosis
Monckeberg medial calcific sclerosis

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 Arteriolosclerosis

Affects small arteries and arterioles

2 types:
Hyaline ATS: essential hypertension, DM
Hyperplastic ATS: Malignant hypertension

Thickening of vessel wall with luminal Hyaline arteriolosclerosis in patients with

narrowing leading to downstream diabetes mellitus and hypertension
ischemic injury
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Monckeberg medial calcific sclerosis

Calcified deposits in muscular arteries of older people

Do not encroach vessel lumen
usually not clinically significant

purplish blue calcifications in the

media and the lumen is unaffected
by the process.

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 Atherosclerosis

Pathological disorder of intima of medium & large blood vessels

characterized by formation of fibro-fatty plaques called atheroma
(atheromatous or athero-sclerotic plaque).
Atheroma = Gruel in Greek

Characteristic lesion is the intimal atheromatous plaque obstructing

the lumen and weakening of media
elastic arteries (aorta, carotid, iliac)
Medium-sized muscular arteries (coronary, popliteal)

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 Risk Factors of atherosclerosis

Major Lesser, uncertain,

or non-quantitated
Non-modifiable
Increasing age Obesity
Male gender Physical inactivity
Family history Stress (type A personality)
Genetic abnormalities Postmenopausal estrogen deficiency
High carbohydrate diet
Modifiable/preventable
Lipoprotein Lp(a)
Hyperlipidemia (LDL)
Hardened(trans) unsaturated fat intake
Hypertension
Cigarette smoking
Diabetes
Inflammation
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Risk factors

Age
clinically evident in middle age or later
(between ages 40 & 60 - MI by 5 times)

Sex
Males more prone than females
uncommon in pre-menopausal females (Estrogen improves endothelial
function & play a protective role)
After menopause incidence

Genetics
Familial predisposition of hypertension, DM, hyper-cholesterolemia
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Hyperlipidaemia/hypercholesterolemia

Major risk factor: stimulate development of AS in absence of other RF

LDL: bad cholesterol, HDL: good cholesterol
LDL transports cholesterol to peripheral t/s

HDL mobilizes cholesterol from atheromas & transports it to liver for

excretion in bile (HDL = risk)
HDL after exercise, moderate consumption of alcohol, in obesity
& cessation of smoking
Saturated fat : plasma cholesterol (eg: egg yolk, animal fat, butter)
Polyunsat fat: plasma cholesterol (eg: Omega-3 F/A in fish oil)

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 Hypertension
Major risk factor at all ages
BP >169/95 mm of Hg has 5 fold
greater risk of IHD than normotensive
Antihypertensives reduce the risk of
IHD
Cigarette smoking
Well established risk factor
1 or more pack / day increases
risk by 200%
Cessation of smoking reduces
risk substantially

Diabetes mellitus
Induces hypercholesterolemia increased
predisposition to AS
Risk of MI twice compared to non diabetics
AGEs (Advanced glycosylation end products)
trap LDL in the intima and retard efflux of
LDL
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 Other risk factors
Inflammation C-reactive protein (CRP)
Homocystinurea with premature vascular disease
metabolic syndrome: a number of abnormalities that are associated
with insulin resistance
increased Lipoprotein Lp(a): altered form of LDL increased risk of
ischemic heart & cerebrovascular ds
Type A personality (lack of exercise; competitive, stressful lifestyle)
increased risk
Multiple risk factors have a multiplicative effect

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 Pathogenesis of atheroma

Response to injury hypothesis:

A chronic inflammatory and healing response of arterial wall to
endothelial injury

Interaction between modified lipoproteins, monocyte-derived

macrophages, T-lymphocytes with endothelial cells and smooth
muscle cells of the arterial wall

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 Normal histology of blood vessel wall

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Chronic endothelial injury
1
Hyperlipidemia
Hypertension
Smoking Endothelium
Homocysteine
Viruses
Toxins
Immune reactions
Hemodynamic factors Intima

Media Adventitia
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 Endothelial Dysfunction:
Increased permeability & Leukocyte adhesion 2
Monocyte adhesion & emigration
Platelet adhesion Response to injury

platelet
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monocyte
 Smooth muscle emigration from media to intima
(d/t released factors from activated platelet,
macrophage & endothelial cells) 3
Macrophage activation

Smooth muscle cell

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 4
Macrophages & smooth muscle cells engulf lipid
resulting foam cells

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 Smooth muscle proliferation
5
Collagen & other ECM deposition
Accumulation of lipid intracellularly &
extracellularly

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Role of endothelial injury

Chronic/repetitive injury
Mechanical denudation, hemodynamic force, immune complex
deposition, irradiation, chemicals, hyperlipidemia
non-denuding endothelial dysfunction:
- increased permeability
- enhanced leukocyte adhesion
- alteration of gene products

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Role of inflammation

Initiate, progression and development of complications of AS lesions

Early AS endothelial cells express VCAM- 1 (vascular cell adhesion
molecule -1) which binds leukocytes, monocytes and lymphocytes
Monocytes differentiate to macrophages and foam cells
Elaborate growth factors leading to SMC proliferation
T lymphocytes leads to activation of cellular and humoral
immunity

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Role of lipids

Major lipids in atheromatous plaque plasma derived cholesterol &

cholesterol ester
Genetic/acquired defects (DM, hypothyroidism) in lipoprotein
metabolism lead to premature ATH
Lowering of serum cholesterol by diet or drugs: slow the progression
of AS and reduce risk of CV events
Anti-oxidants ( carotene, Vit E) protects AS formation

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Role of smooth muscle cells
Smooth muscle cells migrate from media to intima, where they
proliferate and deposit ECM components, converting fatty streak into
a mature atherosclerotic lesions stabilize the AS plaques
Smooth m/s proliferation by growth factors (PDGF, FGF, TGF-)

Infection
Herpes virus, cytomegalovirus, Chlamydia pneumoniae: detected in
AS plaques but not in normal arteries -
contribute to the local prothrombotic state.

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 Cellular interaction in atherosclerosis

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Morphology of Atherosclerotic plaque

Common Sites ( in descending order)

Aorta (abdomen>thoracic)
Coronary arteries
Popliteal arteries
Internal carotid arteries & vessels of circle of Willis
Spare vessels of upper extremities, mesenteric arteries, renal
arteries except at their ostia

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Morphology of Atherosclerotic plaque

Fatty streaks
Earliest lesions of AS
Composed of lipid-filled foam cells
Begin as multiple yellow, flat spots <1mm in diameter that coalesce
into elongated streaks, 1cm long or longer
Contain smaller amounts of T lymphocytes and extra cellular lipids
Commonly found in children, as early as < 1 year of age

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 Fatty Streaks

Lipid laden macrophages

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Atherosclerotic plaque
Key processes in AS - Intimal thickening
- Lipid accumulation
Atheromatous plaque: a raised focal lesion in intima having soft yellow
grumous core of lipid covered by a firm white fibrous capsule

Key components of Atheromatous plaque

Cells: Smooth muscle cell, macrophage, leukocytes
ECM: Collagen, elastic fibers, proteoglycans
Intracellular and extra cellular lipid deposits

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 Microscopic appearance of an athroma

Fibrous Cap smooth muscle cell (SMC), elastin,

macrophage, foam cells, lymphocyte, collagen

Monocyte Smooth muscle cell

Cholesterol cleft
Foam cell

Necrotic center cell debris, Revascularization

cholesterol crystals, foam cells,
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 Atheroma Coronary Artery

L
F

L: lumen
F: fibrous cap
C: lipid core

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 Coronary narrowing in atherosclerosis

proximal

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Atherosclerotic Stenosis

small arteries: AS plaques gradually occlude lumens, compromising

blood flow and causing ischemic injury

early stages of stenosis: outward remodeling of the vessel media

tends to preserve luminal diameter as the total circumference
expands

Critical stenosis (chronic occlusion) significantly limits flow, and

demand begins exceeding supply when approximately 70% fixed
occlusion (i.e., loss of area through which blood can flow); at this
degree of stenosis, patients classically develop chest pain (angina) on
exertion (so-called stable angina)
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 Complications of atherosclerotic plaques

1. Calcification
2. Rupture/fissuring, Ulceration/erosion - exposure of highly thrombogenic
substance - thrombus formation
3. Thrombosis superimposed thrombus formation, partially or
completely occluded the lumen
4. Atheroembolism rupture plaque discharge atherosclerotic debris
into the blood stream, producing microemboli
5. Haemorrhage into a plaque due to rupture of plaque or thin wall
capillaries that vascularize plaque
6. Aneurysmal dilatation atrophy of underlying media with loss of
elastic tissue causing weakness and potential rupture
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 Calcification

Narrow lumen

calcification

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 Calcification

Gross appearance of severe coronary atherosclerosis, which involves virtually 100% of

the surface of coronary artery. There is extensive calcification, especially at the right
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 Ulceration
Atheroma Aorta
severe atherosclerosis of the aorta in
which the atheromatous plaques have
undergone ulcerations along with
formation of overlying mural thrombus.

Ulceration &
haemorrhage
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 Gross views of atherosclerosis in the aorta.
A, Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow.
B, Severe disease with diffuse and complicated lesions. Plaque rupture (blue arrow) and
superimposed thrombosis(green arrow), some of which have coalesced.

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 Ulceration

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 Hemorrhage into the plaque

Coronary atherosclerosis with the complication of hemorrhage into

atheromatous plaque. Such hemorrhage acutely may narrow the arterial
lumen.
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 Rupture of plaque Thrombosis

Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus,

in a patient who died suddenly. B, Acute coronary thrombosis superimposed on an
atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal
myocardial infarction. In both A and B, an arrow points to the site of plaque
rupture.
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 Thrombosis
Coronary thrombosis
A. a pink to red recent thrombosis in this
narrowed coronary artery. The open,
needle-like spaces in the atheromatous
plaque are cholesterol clefts.
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B
B. Anterior surface of the heart with the left
anterior descending coronary artery opened
longitudinally to show coronary thrombosis, one
of the complications of atherosclerosis. The
occlusive dark red thrombus is seen within the
lumen of the coronary artery. This produces an
acute myocardial infarction. 39
 Thrombosis

At high magnification, the dark red thrombus is apparent in the lumen of the
coronary. The yellow tan plaques of atheroma narrow this coronary
significantly, and the thrombus occludes it completely.
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 Narrowing of coronary artery with Organization & recanalization of previous
atherosclerosis by 60 -70% thrombosis with additional recent thrombus
in small lumen
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 The natural history, morphologic features, main pathogenic events,
and clinical complications of atherosclerosis.

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 Aneurysm

A localized abnormal dilation of a blood vessel or the heart (especially

in abdominal aorta)

Congenital or acquired

True aneurysm: involves an intact attenuated arterial wall or thinned

ventricular wall
False aneurysm: defect in the vascular wall leading to an extravascular
hematoma that freely communicates with the intravascular space

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 Aneurysm

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 Different shapes of aneurysm

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Pathogenesis of Aneurysm

occur when the structure or function of connective t/s within the

vascular wall is compromised
Congenital: Intrinsic quality of the vascular wall connective tissue is
poor (Marfan syndrome)
Altered balance of collagen degradation & synthesis by local
inflammatory infiltrates and the destructive proteolytic enzymes they
produce
The vascular wall is weakened through loss of smooth muscle cells or
the inappropriate synthesis of noncollagenous or nonelastic ECM -
Cystic medial degeneration
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 Aneurysm

Two most important disorders that predispose to aortic aneurysm:

Atherosclerosis abdominal aortic aneurysms
Hypertension aneurysms of the ascending aorta
Other causes which weaken vessel walls: trauma, vasculitis,
congenital defects (eg. berry aneurysms typically in the circle of
Willis), and infections (mycotic aneurysms).
Tertiary syphilis: obliterative endarteritis of vasa vasorum of thoracic
aorta - leads to ischemic injury of the aortic media and aneurysmal
dilation

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 Cystic medial degeneration

Normal elastic media

Aneurysm of abdominal aorta with

formation of blood clot and rupture
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 Abdominal aortic aneurysm

A: large aortic aneurysm that ruptured (arrow)

B: probe show rupture tract. The wall of the
aneurysm is thin & lumen is filled with large
quantity of layered but largely unorganized
thrombus
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Clinical consequences of aneurysm
(Abdominal aortic aneurysms)

Rupture into the peritoneal cavity or retro-peritoneal tissues with

massive, potentially fatal hemorrhage
Obstruction of a branch vessel resulting in ischemic injury of
downstream tissues (iliac, renal, mesenteric, vertebral arteries)
Embolism from atheroma or mural thrombus within the aneurysm
Impingement on an adjacent structure (compression of a ureter or
erosion of vertebrae)
Presentation as an abdominal mass that simulates a tumor

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Clinical consequences of aneurysm
(Thoracic aortic aneurysms)

encroachment on mediastinal structures

respiratory difficulties (encroachment on the lungs and airways)
Dysphagia (compression of the esophagus)
persistent cough (irritation of or pressure on the recurrent laryngeal
nerves)
pain (erosion of bone - ribs & vertebra)
cardiac disease as the aortic aneurysm leads to aortic valve dilation
with valvular insufficiency or narrowing of the coronary ostia causing
myocardial ischemia,
Rupture with fatal haemorrhage

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Aortic dissection

May or may not be associated with dilatation

Dissection of blood between and along the laminar planes of the media to
form a blood-filled channel within the aortic wall
usually initiates with an intimal tear
>90% have antecedent hypertension:
- medial hypertrophy of the vasa vasorum
- degenerative changes in the aortic media
- variable loss of medial smooth muscle cells (pressure
related mechanical injury and/or ischemic injury due
to diminished flow through the vasa vasorum)
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 Aortic dissection (Dissecting aneurysm)

Dissecting
haematoma

Aortic lumen
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 Dissection aneurysm which is filled with red-brown thrombus on both
sides of the section, resulting double lumen. Many atherosclerotic
plugs are seen on the intima surface of aorta.

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Aortic dissection (Dissecting aneurysm)

Classification of dissections

Type A (proximal) involves the

ascending aorta, either as part of a
more extensive dissection (DeBakey
I) or in isolation (DeBakey II).
Type B (distal or DeBakey III)
dissections arise beyond the takeoff
of the great vessels.
The serious complications
predominantly occur in type A
dissections.

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Aortic dissection (Dissecting aneurysm)

Most serious complication: dissections that involve the aorta from the
aortic valve to the arch
Common cause of death: rupture of the dissection outward into the
pericardial, pleural, or peritoneal cavities
sudden onset of excruciating pain, usually beginning in the anterior
chest, radiating to the back between the scapulae, and moving
downward as the dissection progresses; the pain can be confused
with that of myocardial infarction.

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 70

60

50 Myocardial Cerebral Gangrene, Abdominal

Infarct Infarct (extremeties) aortic aneurysm
C L I N I C A L H O R I Z O N
Age in years

40 COMPLICATIONS:
Thrombosis
Plaque rupture
30 Hemorrhage
Wall weakening
Calcification
20
FIBROUS PLAQUE

10 ? ?

FATTY STREAK
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To practice (multiple true false questions)

1 Pathogenesis of atherosclerosis include

A endothelial cell injury
B acute inflammation
C chronic inflammation
D activation of smooth muscle cell
E hypersensitivity reaction

2 Factors associated with atherosclerosis include

A hypertension
B diabetes mellitus
C alcoholism
D cigarette smoking
E high oestrogen level
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