Risk factors &

pathogenesis of
atherosclerosis

Objectives :

● Understand the pathogenesis and clinical

consequences of atherosclerosis.

● Be able to discuss pathology and complications of

ischemic heart diseases with special emphasis on
myocardial infarction.

● Know how lifestyle modifications can reduce the risk

of ischemic heart diseases.

Index:
Important
NOTES
Extra Information
 blood vessels
● Large ( elastic ) arteries
e.g: aorta , common carotid, iliac -Large diameter.
-lots of elastic fibers -Thin walls.
● Medium (muscular) arteries - Compressible, penetrable by tumor.
e.g: coronary, renal arteries - Have valves.
-mostly smooth muscle cells
● Small arteries Normal
-all smooth muscle cells Blood
-blood pressure controlled here.

Arteries Veins

Normal blood vessels

Capillaries Lymphatics

-Has same Diameter as RBC.

-Thin walls, slow flow (For gas exchange). -Drains excessive interstitial fluid from
the interstitial tissue.
-Great for exchanging oxygen and nutrients. -Passes through lymph nodes.
-End in the superior vena cava.

It Separate the content of the

blood from the media

( muscle layer)
Regulate the amount of blood that flow
through it

Endothelial cells
The endothelium is a single falt cell thick lining of endothelial cells and it is
the inner lining of the entire cardiovascular system ( arteries, veins and
capillaries) and the lymphatic system.
(It covers the basement membrane completely.)

It is in direct contact with the blood/lymph and

the cells circulating in it.

A normal structure and function of endothelium

is essential for :
● maintenance of vessels wall homeostasis
● Normal circulatory function.

- If the endothelial cell gets injured, the basement membrane gets exposed. This exposure is a
source of trouble and diseases. - Intact endothelial cells are very important for normal physiology.
 blood vessels
Smooth muscle cells (SMC)
SMCs are present in the media of blood vessels that is responsible for vasoconstriction and
vasodilation of blood vessel to regulate the amount of the blood🩸in the vessel

Any vascular injury or dysfunction stimulates [Link] stimulation the SMCs:

1 Migrate from the media to the

intima.

2 In the intima the SMCs lose the capacity to contract and

gain the capacity to divide. So they proliferate as intimal SMCs.
(SMCs changed completely)

3 They synthesize collagen, elastin etc and deposit

extracellular matrix (ECM).

Atherosclerosis

What is atheroma?
An atheroma, or atheromatous plaque ("plaque"), is an abnormal accumulation of material in the inner layer of the wall
of an artery. The material consists of mostly macrophage cells, or debris, containing lipids, calcium and a variable

Definition
amount of fibrous connective tissue. Atheroma is shown in the below gross pathological picture

Atherosclerosis is characterized by intimal lesions called atheromas (also known as

atheromatous plaque or fibrofatty plaque), as it’s growing ,which protrude into and
obstruct vascular lumens and weaken the underlying media.
as the Atheroma grows the vessel became narrower and the blood flow decrease
leading to atherosclerosis.

❖ The most commonly involved vessels are the abdominal aorta than coronary
arteries, the popliteal arteries, the internal carotid arteries, and the vessels of the
circle of Willis (3 arteries come together and meet to form a circle )

AS pulque grow leading to serious complications (depends on the location of AS) In boy’s slide only,consider it extra
information

In Coronary artery disease It blocks the blood flow to heart

Arteriosclerosis (hardening of the arteries) is a
(angina & MI) Leading to MI….etc generic term for thickening and loss of elasticity of
arterial walls.
1. Arteriosclerosis
Carotid atherosclerotic disease 2. Hypertension
(stroke) 3. calcific sclerosis , Mönckeberg medial
4. Atherosclerosis
5. Old age
 The pathogenesis of atherosclerosis
the hypothesis is that AS is a response to injury

Accumulation of lipoproteins
(mainly LDL with its high cholesterol content) in the vessel wall and subtle
chronic endothelial injury
It is the first and most important step in the pathogenesis of atherosclerosis and
will lead to the next following steps.

Will lead to

Increased permeability and leukocyte (monocyte) adhesion.

.

Adhesion of blood leukocytes to the endothelium, followed by migration of leukocytes into

the intima & transformation into macrophages & foam cells

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 production of extracellular matrix ([Link] & proteoglycans).
- Enhanced accumulation of intracellular (macrophages and SMCs) and extracellularly lipids.

Briefly : fatty streaks taken place in some places on the blood

vessel and then there’s fibrofatty plaque which is growing
bigger and bigger and the vessel became narrower (in this
step the atheroma can rupture or formed thrombus causing
complete occlusion or progressive growth leading to critical
stenosis
 Morphology of AS

Gross morphology of atheroma / atheromatous plaque Fatty streaks

● The key processes in AS is intimal thickening and ● Fatty streaks are the earliest lesion of
lipid accumulation. atherosclerosis, they are a collection of lipid and
● AS plaques impinge on the lumen of the artery. lipid laden foam cells in the intima .
● AS plaques vary in size. ● The do not cause any disturbance in blood flow
● As plaques usually involve only a partial ● Fatty streaks begin as multiple yellow, flat spots
circumference of the arterial wall ( less than 1mm in diameter that coalesce into
“eccentric”lesions )* and are patchy and variable elongated streaks, 1 cm long or longer .
along the vessel length . ● They contain T lymphocytes , extracellular lipid in
*eccentric = in the side , not involving the entire circle of smaller amounts and rare lipid laden foam cells
the vessel . than plaques .

Gross views of atherosclerosis in the

aorta . Photomicrograph of fatty streak in
A. Mild atherosclerosis composed of an experimental
fibrous plaques, one of which is hypercholesterolemic rabbit,
denoted by the arrow . demonstrating intimal
B. Severe disease with diffuse and macrophage-derived foam cells
(arrow)
complicated lesions .
 Morphology
Microscopic

What are you going to see in the AQ pulaque ?

A well established atheroma/AS plaque consists of a raised focal lesion in the intima, with a soft,
yellow, grumous/granular core of lipid ( mainly cholesterol and cholesterol esters), covered by a firm,
white fibrous cap. Atherosclerotic plaques have three principal components :
1- Cells : SMCs “smooth muscle cells”, macrophages & foam cells .
2-Extracellular matrix : including collagen, elastic fibers and proteoglycans
3- Lipid : Typical atheromas contain relatively abundant lipid both intracellular & extracellular lipid .

NOTE : Foam cells are large, lipid-laden macrophages derived from blood
monocytes, but SMCs can also imbibe lipid to become foam cells .

Weak wall

Atheroma

● Typically, the superficial fibrous cap is ● Overall architecture demonstrating

composed of SMCs and extracellular an eccentric lesion with a fibrous cap
and a central lipid core with typical
matrix,With some macrophages and T
cholesterol clefts .
lymphocytes .
● The lumen is moderately narrowed
● Below the fibrous cap is a necrotic core,
containing a lipid deposits (primarily cholesterol
and cholesterol esters), cholesterol clefts, debris
from dead cells, foam cells and fibrin .
● Note:make sure you know the contents of (cap
+ necrotic core)
Complications of AS

Advanced AS Plaque
1-Plaque rupture/ ulceration/ erosion induce thrombus formation OR the AS plaque may discharge
(disruption) Of the AS plaques debris into the bloodstream, producing microemboli composed
(The blood vessel is weak so it may of plaque lipid ( cholesterol emboli or atheroemboli )
ruptur )

Hemorrhage into a plaque due to rupture of the overlying fibrous cap or the
(It can start bleeding inside the the capillaries in the plaque . The hematoma may expand the
atheroma itself ) plaque or induce plaque rupture .

Superimposed thrombosis (and which usually occurs on top of ruptured or ulcerated plaques . It
thromboembolism) is the most feared complication . The thrombus can lead to
endothelial cell gets injured, the partial or complete occlusion of the lumen . The thrombus can
basement membrane gets also embolize .
exposed=thrombosis
There’s 2 masses now = total or sub
blocked the vessel = ischemia

Weakening of the blood vessel wall Atheroma can induce atrophy of the underlying media, causing
with aneurysmal dilation weakness, aneurysm and potential rupture .
(Normally the blood vessel is straight but it
may dilate and plugging out which we call it
aneurysm = ultimately can rupture)

Calcification Atheromas often undergo calcification .

Atheroma is a dead tissue can
undergo Dystrophic calcification

The location of Atheroma determines the

the size of the damage and the chance of
surviving
 Risk factors
Risk factors for atherosclerosis

Major Major Minor risk factors

Non-modifiable risk Modifiable risk factors • Obesity
factors Cannot be changed Can be changed • Physical inactivity
• (Increased age)Aging1 • Hyperlipidemia • Stress ("type A" personality)
• Hypertension • Postmenopausal estrogen
• Male gender2 deficiency
• Family history • Cigarettes smoking
• High carbohydrate intake
• Genetic abnormalities • Diabetes
• Alcohol
• Lipoprotein Lp(a)
• Hardened (trans)unsaturated fat
intake
• Chlamydia pneumoniae

Importance of lipoproteins in hyperlipidemia

High blood levels of the following promotes

atherosclerosis and therefore heart disease:
High density lipoproteins (HDL):

• Low-density lipoproteins (LDLs) Known as “good” cholesterol, high

• Very-low-density lipoproteins (VLDLs) levels of HDL protects against
• Chylomicrons heart attack.
• increased levels of lipoprotein(a)
Low levels of HDL also increase the
risk of heart disease. HDLs help to
reverse the effects of high
cholesterol.

1
Because women’s estrogen levels decrease after menopause .
2
Because women have higher estrogen levels which protect against
atherosclerosis.
 Stroke / cerebrovascular accident

Ischemic stroke occurs when oxygen-rich blood

flow to the brain is restricted .
(Type of stroke depend on the involved site)

atherosclerosis
Angina

Coronary artery disease Heart disease

heart attack
cerebrovascular stroke

Leg blood clot

peripheral arterial disease
Intermittent claudication

Atherosclerosis in

Internal carotid may lead to

Ischemia,stroke and cerebral infarction.
Angioplasty

Middle cerebral & Internal carotid It is a procedure to restore blood flow through
may lead to stroke and cerebral atrophy.
the artery. You have angioplasty in a hospital.
(treatment of Atherosclerosis)

Anterior descending coronary

artery may lead to myocardial infarction.

Renal artery May lead to renal ischemia.

Femoral Artery may lead to

intermittent claudication.

Popliteal artery may lead to peripheral

ischemia which may lead to gangrene and
claudication (cramping pain in the leg induced by
exercise).

Superior mesenteric may lead to

infarction of the small intestines.
 Quiz
1- A 66-year-old woman has sudden paralysis of the left side of her body. She has been smoking
a pack of cigarettes daily for the past 45 years. Vital signs: temp: 37.1 C. heart rate 80/minute,
respiratory rate 16/minute, and BP 160/100 mm Hg. A cerebral angiogram reveals occlusion of a
branch of her middle cerebral artery. Laboratory findings include a hemoglobin A1C of 9%.
- Which of the following components of blood lipids is most important in contributing to her
Disease ?

A- HDL B- Chylomicrons C- Oxidized LDL D- VLDL

2- A 63-year-old man has had insulin dependent diabetes mellitus for over two decades. The
degree of control of his disease is characterized by the laboratory finding of a hemoglobin A1C of
10.1%. He has noted episodes of abdominal pain following meals. These episodes have worsened
over the past year. On physical examination, there are no masses and no organomegaly of the
abdomen, and he has no tenderness to palpation.
- Which of the following pathologic findings is most likely to be present in this man?

A- Ruptured aortic B- Chronic renal failure C- Mesenteric artery D- Acute pancreatitis

aneurysm occlusion

3- A group of pathologists are analyzing tissue samples of adolescents age 13-18 to study the
aging process. Autopsy of a 14-year-old boy who died in a motor vehicle accident shows several
minimally raised yellow spots on the inner surface of the abdominal aorta. The rest of the
cardiovascular findings during the autopsy are unremarkable. He had no known medical
problems. There was no family history of cardiovascular disease or sudden cardiac death. Which
of the following is most likely to be the predominant cell type in these lesions on light
microscopy?

A- Macrophages B- Fibroblasts C- Neutrophils D- Mast cells

4-:A 42-year-old man is found dead at home. His medical problems included hypertension and
dyslipidemia, but he had been noncompliant with his medications. The patient had a lengthy
smoking history and, despite constant urging from his physicians to stop smoking, he had only
quit recently. An autopsy is requested by the family. Pathological examination shows complete
thrombotic occlusion of the left main coronary artery and diffuse atherosclerotic vascular
disease characterized by multiple atheromas. Along with a lipid core, these atheromas have a
fibrous cap formed from dense deposition of collagen. Which of the following cells are directly
responsible for synthesizing this fibrous cap?

A- Interstitial fibroblasts B- Macrophages C- Smooth muscle cells D- Endothelial cells

4-C
3-A
2-C
1-C
 Summary

Atherosclerosis

Definition characterized by atheromas (intimal thickening + lipid accumulation), which protrude into
and obstruct vascular lumens and weakens the underlying media

Morphology Microscopic Gross

:Components of Atherosclerotic plaques • Early lesion → Fatty streaks
cells: SMCs, macrophages, lymphocytes and foam • Eccentric lesions, patchy, and
.cell variable AS plaques along the
Extracellular matrix: including collagen, elastic vessel length.
.fibers, and proteoglycans
. Lipid: intracellular and extracellular lipid
.Fibrous cap -
.Central Necrotic core -

Major Non modifiable Modifiable

age ↑ Hyperlipidemia
risk factors Male gender Hypertension
(Minor risk factors page 9)
Family history Cigarette Smoking
Genetic abnormalities Diabetes
Inflammation

Pathogenesis Chronic endothelial injury → endothelial dysfunction (↑ permeability + leukocyte adhesion)

→ smooth muscle emigration from media to intima → macrophages & SMC engulf lipid →
smooth muscle proliferation, collagen & other ECM deposition, extracellular lipid

Complications • Calcification: renal artery stenosis, angina, peripheral vascular disease

• Rupture: MI, thrombotic stroke.
• Hemorrhage
• Embolic stroke
• Aneurysm of abdominal aorta (AAA)
• Weakening of the blood vessel wall with aneurysmal dilation
Summary
 ‫‪Team Leaders‬‬

‫‪- Rania Almutairi‬‬

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