Atherosclerosis

1. Atherosclerosis &
Arteriosclerosis
Malik Amonov MD, PhD

2. Definition of atherosclerosis
and arteriosclerosis

3. General patterns of Arteriosclerosis
1. ATHEROSCLEROSIS is the most common and most important form of
arteriosclerosis.
2. HYPERTENSIVE ARTERIOLOSCLEROSIS
a.Hyaline arteriolosclerosis
• Caused by benign HTN and DM→ hyalinization of the wall of arteriole.
• Common locations: visceral arterioles.
• Clinical outcome: benign nephrosclerosis (HTN), microangiopathy (DM).
b. Hyperplastic arteriolosclerosis
• Caused by severe (malignant) HTN → proliferation of smooth muscle cells in
the intima with fibrosis, concentric, laminated thickening (“onion-skin”)
• Common locations: visceral arterioles.

4. HYALINE ARTERIOLOSCLEROSIS HYPERPLASTIC ARTERIOLOSCLEROSIS
ATHEROSCLEROSIS

5. 3. SENILE ARTERIOSCLEROSIS.
• Thickening of media and intima due to increase in elastic and collagen tissue of the arteries seen
due to ageing.
• The changes are non-selective and affect most of the arteries.
• Clinical outcome: age-related elevation of systolic blood pressure..
4. MONCKEBERG MEDIAL CALCIFIC SCLEROSIS
• Calcium deposits only in the middle layer without associated inflammatory reaction.
• Affects medium-sized arteries
• Causes vascular stiffening without obstruction of blood flow; intima not involved.
• Not associated with symptoms unless complicated.
General patterns of Arteriosclerosis (cont.)

7. Atherosclerosis is…
• … accumulation of inflammatory, immune,
and smooth muscle cells; lipids; and
connective tissue in the intima of large and
medium-sized arteries.
• The classic lesion is a fibroinflammatory
lipid plaque known as atheroma.
• Atheroma develops over several decades
and grows continuously, encroaching on
the media of the arterial wall and into the
lumen of the vessel, which narrows its
caliber.

8. Pathogenesis of atherosclerosis
• Several theories proposed for the pathogenesis of atherosclerosis
(e.g. insudation hypothesis, encrustation hypothesis)
• Most widely accepted hypothesis - Response-to-Injury Hypothesis
• According to it atherosclerosis develops as a chronic inflammatory and
healing response of the arterial wall to the endothelial injury.
• Pathogenetic steps: EC dysfunction→ macrophage and LDL accumulation →
foam cell formation → fatty streaks →smooth muscle cell migration (involves
PDGF and FGF), proliferation, and extracellular matrix deposition →fibrous
plaque →complex atheroma

9. 1. Endothelial injury and dysfunction
Major risk factors:
Hypercholesterolemia Inflammation
Plaques tend to locate where blood flow patterns are disturbed:
ostia of vessels, branch points of vessels, along the posterior abdominal aorta
Non-turbulent laminar
flow leads to the induction
of the endothelial genes
such as superoxide
dismutase, Krüppel-like
factor-2, whose products
protect against
atherosclerosis
Turbulent flow causes EC dysfunction → decreased expression of
atheroprotective genes and increased expression of
proinflammatory genes: VCAM-1 and ICAM-1.
Hemodynamic disturbances
2. Migration of monocytes into the intima:
• Monocytes and T lymphocytes adhere at the site of EC injury.
• Locally produced chemokines causes transmigration of
leukocytes into the intima.
• Monocytes are transformed into macrophages.

10. Endothelial injury and dysfunction
Inflammation
Hemodynamic disturbances
3. Lipid accumulation in the intima
• Endothelial dysfunction allows penetration and
accumulation of lipoproteins (mainly LDL) within the
intima of the vessel.
• Accumulated lipoproteins become oxidized by free
radicals produced locally by monocytes/macrophages
and dysfunctional endothelial cells.
Hemodynamic disturbances Hypercholesterolemia

11. Endothelial injury and dysfunction
Hemodynamic disturbances
•Chronic hyperlipidemia impairs EC function and increases the production of ROS.
•Lipoproteins accumulate in the intima and may become oxidized by free radicals.
•Modified LDL is taken up by macrophages and SMCs, forming foam cells.
•Fatty streaks, early lesions containing lipid-filled macrophages, are formed as a result
of chronic ingestion of modified lipids.
•The modified lipoproteins are toxic to ECs, SMCs, and macrophages, and their binding
and uptake also stimulate the release of growth factors, cytokines, and chemokines
that create an inflammatory cycle.
•Atheromatous plaques contain mainly cholesterol and cholesterol esters.
Hemodynamic disturbances Hypercholesterolemia Inflammation
4. Formation of foam cells and activation of macrophages:
Modified LDL is taken up by macrophages and SMCs, forming
foam cells.
Macrophage engulfs oxidized LDL → triggers the
inflammatory response
Activated macrophages produce:
i. Cytokine (IL-1, TNF)—increases leukocyte adhesion.
ii. Chemokines (e.g. monocyte chemotactic protein 1)—
accumulation of monocytes.
iii. iv. Growth factors (PDGF, FGF)—stimulate smooth
muscle cell proliferation and ECM synthesis.

12. Fatty streaks
Fatty streaks are early lesions
containing foam cells.
Beginning as small flat yellow
macules, can eventually coalesce
into elongated streaks 1 cm long
or longer.
• Do not cause any significant
flow disturbance.
• Not all are destined to become
advanced lesions.
• Present in virtually all
adolescents.

13. 5. Migration of smooth muscle cells into the intima:
Growth factor from
activated platelets,
macrophages, and ECs
causes migration of
smooth muscle cells
either from the
arterial media or from
circulating precursors.

14. 6. Smooth muscle cell
proliferation in the
intima and ECM
production:
• Growth factors (FGF, PFGF, TGF-α)
cause smooth muscle cells
proliferate, and produce ECM
(mainly collagen and
proteoglycans) which stabilizes
atherosclerotic plaques.
• This converts a fatty streak into a
mature atheroma and contribute
to the progressive growth of
atherosclerotic lesions.
Fibroinflammatory lipid plaques. Fibrous cap
(asterisks) separating lumen (L) from central
necrotic core (bracket).

15. 7. Lipid accumulation
• Occurs both intracellularly
(within macrophages and
smooth muscle cells) and
extracellularly.
• Extracellular lipid is
derived from insudation
from the vessel lumen and
also from necrotic foam
cells.
Fully-developed atheroma.

16. Initial to
complicated
lesions of
atherosclerosis

17. Complicated lesions of atherosclerosis
• 1. Rupture, ulceration, or erosion: Plaque protrudes into the lumen and can
disturb the blood flow → resulting in turbulent flow of blood → which can
damage the endothelium → cause rupture, ulceration or erosion of the intimal
surface of plaques.
• 2. Thrombosis and embolism: Ulceration of endothelial surface → exposes the
blood to highly thrombogenic subendothelial collagen → favors thrombus
formation → can partially or completely occlude the lumen → lead to ischemia.
The thrombus may become fragmented to form thromboemboli.
• 3. Hemorrhage into a plaque: It may occur due to rupture of the fibrous cap of
the plaque or of the thin-walled vessels formed due to neovascularization.

19. Schematic comparing vulnerable and stable atherosclerotic plaque. Whereas
stable plaques have densely collagenous and thickened fibrous caps with
minimal inflammation and negligible underlying atheromatous core, vulnerable
plaques (prone to rupture) are characterized by thin fibrous caps, large lipid
cores, and increased inflammation.

20. Complicated lesions of atherosclerosis
• 4. Atheroembolism: Plaque rupture → discharge atherosclerotic
debris into the bloodstream → results in atheroemboli.
• 5. Aneurysm formation: Atherosclerosis even though an intimal
disease may cause pressure or ischemic atrophy of the underlying
media. It may also damage the elastic tissue and cause weakening the
wall → result in aneurysmal dilation → which may rupture.
• 6. Calcification: It may occur in the central necrotic area of the plaque
(dystrophic calcification).

21. Haemorrhage into plaque
Severe atherosclerosis of the aorta

22. Ulcerated
Fibrofatty
Plaque
Complicated lesions of atherosclerosis. The luminal
surface of abdominal aorta and the common iliac arteries
shows numerous fibrous plaques and raised, ulcerated
lesions containing friable, atheromatous debris. Distal
portion of aorta displays a small aneurysmal dilation.

23. • Histological section of the first centimeter
of the left anterior descending artery
showing large lipid-core atherosclerotic
plaque, with internal area of fibrin
deposition and hemorrhage (asterisk).
• Observe the area with marked thinning of
the fibrous cap of the lipid core plaque
(arrow), site of potential rupture and
thrombosis.
Histological section of the second centimeter
of the anterior interventricular artery showing
large lipid-core atherosclerotic plaque with
ruptured area (arrows) and occlusive luminal
thrombosis (asterisk)

24. Risk Factors for
Atherosclerosis
Modifiable
This includes major risk factors which can be controlled by
modifying life style and/or by pharmacotherapy.
Non-modifiable (constitutional)
These are non-modifiable major risk factors that include:
increasing age, male sex, genetic abnormalities, and
familial and racial predisposition.
Non-traditional emerging
This group includes a host of factors whose role in
atherosclerosis is
minimal, and in some cases, even uncertain.

25. Risk factors for atherosclerosis

26. Complications of atherosclerosis
• Depend on the location and size of the affected vessel and the
chronicity of the process
• Acute occlusion
– Thrombosis may occlude the lumen of a muscular artery
– The results is ischaemic necrosis (infarction) of tissue supplied by the
vessel
– Manifested as myocardial infarction, stroke or gangrene of
intestine or lower extremities
– Some occlusive thrombi is dissolved by enzymes that activate plasma
fibrinolytic activity (streptokinase and tissue plasminogen activator)

27. Coronary artery thrombosis
• A microscopic section of a
coronary artery shows severe
atherosclerosis and a recent
thrombus in the narrowed lumen
Major sites of atherosclerosis in descending order of
frequency.

28. Complications of atherosclerosis
• Chronic narrowing of vessel lumen
– Progressively reducing blood flow to the tissue (ischaemia)
– Chronic ischaemia causes atrophy of organ
– Unilateral renal artery stenosis leading to renal atrophy
– Mesenteric artery atherosclerosis causes intestinal stricture
– Ischaemic atrophy of skin occurs in a diabetic with severe peripheral
vascular disease

29. Complications of
atherosclerosis
• Aneurysm formation
• Complicated lesions may
extend into media of elastic
arteries and weaken their
walls
• They allow aneurysm
formation
• Typically in abdominal aorta
• Sudden rupture may
precipitatea vascular
catastrophe

30. Complications of
atherosclerosis
• Embolism
• A thrombus formed over the plaque may
detach and lodge in a distal vessel
• Embolization from a thrombus in abdominal
aortic aneurysm may acutely occlude popliteal
artery, with subsequent gangrene of leg
• Ulceration of the plaque may also
dislodge atheromatous debris and
produce “cholesterol crystal emboli”
(appear as needle-shaped spaces in
tissue; most common in kidney)

31. • Cholesterol crystal embolus
• Needle-shaped clefts
(arrow) are seen in an
atherosclerotic embolus
that has occluded a small
artery

32. Common consequences of atherosclerosis in
specific vessels
• Aorta:
– Aneurysm: abdominal pain, bleeding
– Atheroembolization
– Narrowing of lumen

33. Common consequences of atherosclerosis in
specific vessels
• Coronary artery atherosclerosis:
– MI, heart attack
• Carotid and cerebral circulation:
– Atherosclerosis with thrombosis can lead to brain infarction
(transient ischaemic attack)
• Celiac and mesenteric arteries:
– Narrowing primarily at aorta bifurcation
– Ischaemia can occur if more than 1 artery severely affected

34. Common consequences of
atherosclerosis in specific vessels
• Renal artery:
– Progressive ischaemic atrophy of kidney leads to gradual kidney
failure (nephrosclerosis)
– Renal hypertension
• Iliac and femoral arteries:
– Aneurysms
– Vessel occlusion by plaque and thrombus
• Ischaemia of leg muscles
• Ulcers of skin of leg and feet
• Foot gangrene
• Intermittent claudication

35. Thank you for attention