VASCULAR PATHOLOGY

1. SAMOEI – EGERTON
UNIVERSITY
MBChB
Y3

2. 2
1. ARTERIOSCLEROSIS
1. DEFINATION
2. TYPES
SENILE ARTERIOSCLEROSIS
HYPERTENSIVE
ARTERIOSCLEROSIS
MONCKEBERG’S
ARTERIOSCLEROSIS (MEDIAL
CALCIFIC SCLEROSIS)
ATHEROSCLEROSIS
2. ATHEROSCLEROSIS (AS)
DEFINATION
ETIOLOGY
FRACTIONS OF LIPIDS IN SERUM
PATHOGENESIS OF AS
PROGRESSION OF AS
SYMPTOMS OF AS
PREVENTION OF AVD
SUMMARY
N/B
AVD – ATHEROSCLEROTIC VASCULAR
DISEASE

3. 3
Arteriosclerosis is a general term used to include all conditions with
thickening and hardening of the arterial walls.
TYPES OF ARTERIOSCLEROSIS
1. Senile arteriosclerosis (affects arteries)
2. Hypertensive arteriolosclerosis (affects arterioles)
3. Mönckeberg’s arteriosclerosis (Medial calcific sclerosis) (affects
arteries)
4. Atherosclerosis (affects arteries)
N/B
Atherosclerosis, is the most common and most important form of
arteriosclerosis; if not specified, the two terms are used
interchangeably with each other.

4. 4
• Is the thickening of media and intima of the arteries seen due to ageing.
• Changes are non-selective and affect most of the arteries.
• Possibly induced by stress and strain on vessel wall during life.
MORPHOLOGIC FEATURES
The changes are as under:
1. Fibroelastosis: Intima and media are thickened due to increase in elastic and
collagen tissue.
2. Elastic reduplication: Internal elastic lamina split or reduplicated so that two
wavy layers are seen.
Eventually, the fibrotic changes result in age-related elevation of SBP.

5. 5
Involves 3 morphologic forms of vascular
disease affecting arterioles and small muscular
arteries, these are:
1. Hyaline arteriolosclerosis
2. Hyperplastic arteriolosclerosis
3. Necrotizing arteriolitis.
All the three types are common in hypertension
but may occur due to other causes as well.
HYALINE ARTERIOSCLEROSIS
• May be seen physiologically due to ageing, or
may occur pathologically in:
Benign nephrosclerosis in hypertensives
As a part of microangiopathy in diabetics
MORPHOLOGIC CHANGES
The visceral arterioles are particularly involved. The vascular walls
are thickened and the lumina narrowed or even obliterated.
Microscopically, the thickened vessel wall shows structureless,
eosinophilic, hyaline material in the intima and media.
PATHOGENESIS
The exact pathogenesis is not known.
However, the following hypotheses have been proposed:
1. The lesions result from leakage of components of plasma across
the vascular endothelium. This is substantiated by the
demonstration of Igs, complement, fibrin and lipids in the
lesions. The permeability of the vessel wall is increased, d/t
haemodyanamic stress in HPTN and metabolic stress in diabetes,
so that these plasma components leak out and get deposited in the
vessel wall.
2. The lesions may also be d/t immunologic reaction.
3. It might also be d/t normal aging process exaggerated in HPTN
and DM.

6. 6
HYPERPLASTIC/PROLIFERATIVE
ARTERIOSCLEROSIS
• Is a characteristic lesion of malignant hypertension
• Other causes include HUS, scleroderma and toxemia of
pregnancy.
MORPHOLOGIC FEATURES
The morphologic changes affect mainly the intima,
especially of the interlobular arteries in the kidneys.
Three types of intimal thickening may occur.
1. Onion-skin lesion
2. Mucinous intimal thickening
3. Fibrous intimal thickening
Onion-skin lesion
 Consists of loosely-placed concentric layers of
hyperplastic intimal smooth muscle cells like the bulb of
an onion.
Mucinous intimal thickening
 Is the deposition of amorphous ground substance,
probably proteoglycans, with scanty cells.
Fibrous intimal thickening
 Is less common and consists of bundles of collagen,
elastic fibres and hyaline deposits in the intima.
 Severe intimal sclerosis results in narrowed or
obliterated lumen.
 With time, the lesions become more and more
fibrotic.
PATHOGENESIS
Unclear. Probably, the changes result following:
• Endothelial injury from systemic hypertension,
hypoxia or immunologic damage leading to
increased permeability.
• A healing reaction occurs in the form of
proliferation of smooth muscle cells with fibrosis.

7. 7
NECROTIZING ARTERIOLITIS
• In cases of severe HPTN and malignant HPTN, parts
of small arteries and arterioles show changes of
hyaline sclerosis and parts of these show necrosis, or
necrosis may be superimposed on hyaline sclerosis.
• However, hyaline sclerosis may not be always present
in the vessel wall.
MORPHOLOGIC FEATURES
Besides the changes of hyaline sclerosis, the changes of
necrotizing arteriolitis include:
1. Fibrinoid necrosis of vessel wall
2. Acute inflammatory infiltrate of neutrophils in
the adventitia
3. Edema and hemorrhages often surround the
affected vessels.
PATHOGENESIS
Since necrotizing arteriolitis occurs in vessels in
which there is sudden and great elevation of
pressure, the changes are said to result from
direct physical injury to the vessel wall.

8. 8

9. 9
• Is calcification of the media of large and
medium-sized muscular arteries, especially
of the extremities and of the genital tract, in
persons past the age of 50.
• The condition occurs as an age-related
degenerative process, and therefore, an
example of dystrophic calcification, and has
little or no clinical significance.
• However, it also occurs in some pathological
states like pseudoxanthoma elasticum and in
idiopathic arterial calcification of infancy.
MORPHOLOGIC FEATURES
Medial calcification is often an incidental
finding in X-rays of the affected sites having
muscular arteries.
The deposition of calcium salts in the media
produces pipestem-like rigid tubes without
causing narrowing of the lumen.
Microscopically,
It is characterised by deposits of calcium
salts in the media without associated
inflammatory reaction while the intima and
the adventitia are spared.
Often, coexistent changes of atherosclerosis
are present altering the histologic appearance.
PATHOGENESIS
• Unknown, but it is considered as an age-
related physiologic change due to prolonged
effect of vasoconstriction.

10. 10
• Is the thickening and hardening of large and medium-sized muscular arteries, primarily d/t
involvement of tunica intima.
• Characterised by fibro fatty plaques or atheromas.
• The term atherosclerosis is derived from athero-(meaning porridge) referring to the soft lipid-
rich material in the centre of atheroma, and sclerosis (scarring) referring to connective tissue
in the plaques.
• Is the commonest and the most important of the arterial diseases.
• Though any large and medium-sized artery may be involved in atherosclerosis, the most commonly
affected are the aorta, the coronaries and the cerebral arterial systems.
The major clinical syndromes resulting from ischemia d/t atherosclerosis are as under:
1. Heart (angina and MI or heart attacks)
2. Brain (transient cerebral ischemia and cerebral infarcts or strokes)
3. Other sequelae are: peripheral vascular disease, aneurysmal dilatation d/t weakened
arterial wall, chronic IHD, ischemic encephalopathy and mesenteric arterial occlusion.

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I. MAJOR RISK FACTORS
A) Modifiable
1. Dyslipidemia
2. HPTN
3. DM
4. Smoking
B) Constitutional
1. Increasing age
2. Male gender
3. Genetic abnormalities
4. Family history and racial factors
II. EMERGING RISK FACTORS
1. Environmental influences
2. Obesity
3. Hormones: estrogen deficiency, oral
contraceptives
4. Physical inactivity
5. Stressful life (Type A personality)
6. Homocystinuria
7. Role of alcohol
8. Prothrombotic factors
9. Infections (C. pneumoniae, Herpesvirus,
CMV)
10.High CRP

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A. MODIFIABLE BY LIFESTYLE
AND/OR THERAPY
1. DYSLIPIDEMIA
• Abnormalities in plasma lipoproteins is
the most important major risk factor for
atherosclerosis.
• Hypercholesterolemia has directly
proportionate relationship with AS and
IHD.
The following evidences are cited in
support of this:
1. Atherosclerotic plaques contain
cholesterol and cholesterol esters,
derived from the LPs in blood.
2. Lesions of AS can be induced in
experimental animals by feeding them with
diet rich in cholesterol.
3. Individuals with hypercholesterolemia d/t
various causes such as in DM, myxedema,
nephrotic syndrome, von Gierke’s disease,
xanthomatosis and familial
hypercholesterolemia have increased risk of
developing AS and IHD.
4. Populations having hypercholesterolemia
have higher mortality from IHD. Dietary
regulation and administration of cholesterol-
lowering drugs (statins) have beneficial
effect on reducing the risk of IHD.

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Total cholesterol
Desirable normal serum level is 140- 200
mg/dl
Levels of borderline high are 200-240 mg/dl.
Levels above 260 mg/dl in men and women
between 30 and 50 years has three times
higher risk of developing IHD as compared
with people with cholesterol levels within
normal limits.
Triglycerides
Normal serum level is below 150 mg/dl.
Low-density lipoproteins (LDL) cholesterol
Optimal serum level is <100 mg/dl.
LDL is richest in cholesterol and has the
maximum association with atherosclerosis.
Very-low-density lipoprotein (VLDL)
Carries much of the TGs and its blood levels
therefore parallel with that of TGs;
VLDL has less marked effect than LDL.
High-density lipoproteins (HDL) cholesterol
Normal desirable serum level is <50 mg/dl.
It’s protective (‘good cholesterol’) against
atherosclerosis.
N/B
1. Total cholesterol – <200mg/dl
2. TGs/VLDL – <150mg/dl
3. LDL – <100mg/dl
4. HDL - <50mg/dl

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PLASMA CHOLESTROL LEVELS ELEVATED
BY:
1. Diet containing large quantities of saturated fats
(e.g. in eggs, meat, milk, butter etc)
2. Diet containing large quantities of trans fats (i.e.
unsaturated fats produced by artificial
hydrogenation of polyunsaturated fats)
3. High intake of total number of calories from
carbohydrates, proteins, alcohol & sweets.
4. Familial hypercholesterolemia, an autosomal
codominant disorder, characterised by elevated
LDL cholesterol and normal TGs and occurrence
of xanthomas and premature CAD. It occurs d/t
mutations in LDL receptor gene.
N/B
 High serum cholesterol levels increases the risk of
AS
PLASMA CHOLESTEROL LEVELS
LOWERED BY:
 Diet low in saturated fats and high in poly-
unsaturated fats
 Diet having omega-3 fatty acids (e.g. in fish,
fish oils etc).
 Use of statins, to lower LDL in particular, and
total cholesterol in general, in the management
of dyslipidemia (Inhibits HMG-CoA reductase)
 Weight loss, exercise and use of nicotinic acid to
raise HDL
 Moderate consumption of ethanol to raise HDL
N/B
Currently, preferred term for hyperlipidemia is
dyslipidemia because one risky plasma lipoprotein
(LDL) is elevated and needs to be brought down,
while the other good plasma lipoprotein (HDL)
when low requires to be raised.

15. 15
2. HYPERTENSION
• Is a risk factor for all clinical manifestations of
AS.
• Doubles the risk of all forms of cardiovascular
disease.
• Acts probably by mechanical injury to the
arterial wall d/t increased BP.
• Elevation of SBP over160 mmHg or DBP over
95 mmHg is associated with five times higher
risk of developing IHD than in people with BP
within normal range (140/90 mmHg or less)
3. SMOKING
• The extent and severity of AS are much
greater in smokers than in non-smokers.
• Cigarette smoking is associated with
higher risk of atherosclerotic IHD and
sudden cardiac death.
• Men who smoke a pack of cigarettes a
day are 3-5 times more likely to die of
IHD than non-smokers.
• The increased risk and severity of AS
in smokers is d/t:
• Reduced level of HDL
• Deranged coagulation system
• Accumulation of carbon monoxide in
the blood that produces carboxyHb
and eventually hypoxia in the arterial
wall favouring AS.

16. 16
4. DIABETES MELLITUS
Clinical manifestations of AS are far more common and develop at an early age in
people with both type 1 and type 2 DM.
In particular, association of type 2 DM characterised by metabolic (insulin
resistance) syndrome and abnormal lipid profile termed ‘diabetic dyslipidemia’ is
common and heightens the risk of cardiovascular disease.
The risk of developing IHD is doubled, tendency to develop cerebrovascular
disease is high, and frequency to develop gangrene of foot is about 100 times
increased.
The causes of increased severity of AS are complex and numerous which include
endothelial dysfunction, increased aggregation of platelets, increased LDL and
decreased HDL.

17. 17
B. CONSTITUTIONAL FACTORS
1. INCREASING AGE
• AS is an age-related disease.
• Though early lesions of AS may be present in
childhood, clinically significant lesions are
found with increasing age.
• Fully-developed atheromatous plaques usually
appear in the 4th decade and beyond.
• Evidence in support comes from the high
death rate from IHD in this age group.
2. MALE GENDER
• Premenopausal women are relatively protected
against atherosclerosis and its consequences
compared with men of the same age
• MI and other complications of AS are uncommon in
premenopausal women unless otherwise predisposed by
diabetes, hyperlipidemia, or severe HPTN.
• After menopause, the incidence of AS-related diseases
increases and with greater age exceeds that of men.
• The lower incidence of AS in women of premenopausal
age, is probably d/t high levels of estrogen and HDLs,
both of which have anti-atherogenic influence.
3. GENETIC ABNORMALITIES
• Hereditary derangements of LP metabolism predispose
individual to high blood lipid level and familial
hypercholesterolemia.
4. FAMILY Hx AND RACIAL FACTORS
• Familial predisposition is related to risk factors like
diabetes, HPTN and hyperlipoproteinemia.
• Racial differences also exist; Blacks have generally less
severe AS than Whites.

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1. Environmental influences; Theris higher incidence
of AS in developed countries and low prevalence in
underdeveloped countries.
2. Metabolic syndrome characterised by abdominal
obesity, glucose intolerance, insulin resistance,
dyslipidemia and HPTN, is associated with increased
risk.
3. Use of exogenous hormones (oral contraceptives) or
endogenous estrogen deficiency (in postmenopausal
women) increases the risk of developing MI or stroke.
4. Physical inactivity and lack of exercise increases the
risk of developing AS and its complications.
5. Stressful life style, termed as ‘type A’ behavior
pattern, characterised by aggressiveness, competitive
drive, ambitiousness and a sense of urgency, is
associated with enhanced risk of IHD compared with
‘type B’ behavior of relaxed and happy go-lucky type.
6. Hypercystinemia d/t elevated serum homocysteine
level from low folate and vit B12 have a relationship
with CAD and its consequences.
7. Homocystinuria, an uncommon inborn error of
metabolism, having hypercystinemia have early AS and
CAD.
8. Prothrombotic factors and elevated fibrinogen
levels favour formation of thrombi; the gravest
complication of AS.
9. Role of infections, particularly of Chlamydia
pneumoniae, herpesvirus and CMV, has been found in
coronary atherosclerotic lesions by causing
inflammation. Possibly, infections may be acting in
combination with some other factors.
10. Elevated CRP, an acute phase reactant & a marker
of inflammation, correlate with risk of developing AS.

19. 19
The contemporary view of atherogenesis is
expressed by the response-to-injury
hypothesis.
This model views AS 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.
Endothelial injury
 Endothelial injury is the initial triggering event
in the development of lesions of AS.
 This leads to endothelial dysfunction which
initiate sequence of events.
 Two of the major risk factors which act
together to produce endothelial injury are:
hemodynamic stress from HPTN and
chronic dyslipidemia.
 Other risk factors include: mechanical trauma,
hemodynamic forces, immunological and
chemical mechanisms, metabolic agent as
chronic dyslipidemia, homocysteine,
circulating toxins from systemic infections,
viruses, hypoxia, radiation, carbon monoxide
and tobacco products.
 The role of hemodynamic forces in causing
endothelial injury is supported by the
distribution of atheromatous plaques at points
of bifurcation of blood vessels which are
under greatest shear stress.

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Intimal smooth muscle cell proliferation
 Endothelial injury causes adherence,
aggregation and platelet release reaction
at the site of exposed subendothelial CT
and infiltration by inflammatory cells.
 Proliferation of intimal SMCs and
production of ECM are stimulated by IL-
1 and TNF-α released from invading
monocyte-macrophages and by activated
platelets at the site of endothelial injury.
 These cytokines lead to local synthesis of
PDGF & FGF which stimulate
proliferation and migration of SMCs from
their usual location in the media into the
intima.
• TGF-β & IFN-γ derived from
activated T lymphocytes within lesions
regulate the synthesis of collagen by
SMCs.
• SMC proliferation is also facilitated by
NO and endothelin released from
endothelial cells.
• Intimal proliferation of SMCs is
accompanied by synthesis of matrix
proteins - collagen, elastic fibre
proteins and proteoglycans.

21. 21
Role of blood monocytes
• Though blood monocytes do not possess
receptors for normal LDL, LDL does appear
in the monocyte cytoplasm to form foam cell.
• Plasma LDL on entry into the intima
undergoes oxidation.
• Oxidised LDL attracts, proliferates,
immobilizes and activate monocytes
• Also, oxidized LDL is readily taken up by
scavenger receptor on the monocyte to
transform the monocyte to a lipid laden foam
cell.
• Oxidised LDL is cytotoxic to ECs & SMCs.
• Death of foam cell by apoptosis releases lipid
to form lipid core of plaque
Role of dyslipidemia
• Chronic dyslipidemia in itself may initiate endothelial
injury and dysfunction by causing increased permeability.
• Hypercholesterolemia with increased serum concentration
of LDL promotes formation of foam cells, while high
serum concentration of HDL has anti-atherogenic effect.
Thrombosis
• Endothelial injury exposes subendothelial CT resulting in
formation of small platelet aggregates at the site and
causing proliferation of SMCs.
• This causes mild inflammatory reaction which together
with foam cells is incorporated into the atheromatous
plaque.
• The lesions enlarge by attaching fibrin and cells from the
blood so that thrombus becomes a part of atheromatous
plaque.

22. 22
• Atherosclerotic Plaque-The key processes in AS are
intimal thickening and lipid accumulation
• Atheromatous plaques (also called fibrous or fibro
fatty plaques) impinge on the lumen of the artery and
grossly appear white to yellow
• Plaques vary from 0.3 to 1.5 cm in diameter but can
coalesce to form larger masses.
Components of Atherosclerotic plaque
Have three principal components:
1. Cells; SMCs, macrophages, and T cells
2. ECM; collagen, elastic fibers, and
proteoglycans
3. Intracellular and extracellular lipid
• These components occur in varying proportions and
configurations in different lesions.
Changes in Atherosclerotic Plaque
Atherosclerotic plaques are susceptible to the
following pathologic changes with clinical
significance:
1. Rupture, ulceration, or erosion
2. Hemorrhage
3. Atheroembolism
4. Aneurysm formation
• AS 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“)

23. 23

24. 24
1. Heart - MI, IHD.
2. Brain - Chronic ischemic brain damage, cerebral infarction and
stroke.
3. Aorta - Aneurysm formation, thrombosis and embolization to other
organs.
4. Small intestine - Ischemic bowel disease, infarction.
5. Lower extremities - Intermittent claudication, gangrene (peripheral
vascular disease).

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Primary prevention of AS
Aims at the following, in persons who have not yet
suffered a serious complication of AS;
 Delaying atheroma formation
 Encouraging regression of established lesions
Involves:
 Cessation of cigarette smoking
 Control of hypertension
 Weight loss
 Exercise, and lowering total and LDL blood
cholesterol levels while increasing HDL (e.g., by
diet or through statins).
 Statin use may also modulate the inflammatory
state of the vascular wall.
Risk factor stratification and reduction should even
begin in childhood.
Secondary prevention of AS
Is intended to;
Prevent recurrence of events such as MI
or stroke in symptomatic patients
Involves use of:
 Aspirin (anti-platelet agent),
 Statins, and 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.
N/B
Atherosclerotic Vascular Disease (AVD)

26. 26
Atherosclerosis is an intima-based lesion organized into a fibrous cap and an
atheromatous (gruel-like) core and composed of SMCs, ECM, inflammatory cells,
lipids, and necrotic debris.
Atherogenesis is driven by an interplay of inflammation and injury to vessel wall
cells.
Atherosclerotic plaques accrue slowly over decades but may acutely cause
symptoms d/t rupture, thrombosis, hemorrhage, or embolization.
Risk factor recognition and reduction can reduce the incidence and severity of
atherosclerosis-related disease.

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