pathology of atherosclerosis for undergraduate medical and paramedical students.

1. ATHEROSCLEROSIS
By Dr Utsav Parmar

2. OBJECTIVES
• Definition
• Risk factors
• Pathogenesis
• Outcome
• Clinical effects

3. INTRODUCTION
• Depending upon the calibre and certain
histologic features,
• arteries are divided into 3 types: large (elastic)
arteries,
• medium-sized (muscular) arteries and
• the smallest arterioles

4. Structure of arteries

5. The structure of a medium-sized muscular artery

6. TERMS
• Arteriosclerosis is a general term describing any
hardening (and loss of elasticity) of medium or large arteries
• Arteriolosclerosis is any hardening (and loss of
elasticity) of arterioles (small arteries);
• Atherosclerosis is a hardening of an artery specifically
due to an atheromatous plaque.
• Atherogenic is used for substances or processes that
cause atherosclerosis.
• Atherogenesis is the developmental process of
atheromatous plaques

7. DEFINITION
• Atherosclerosis is a specific form of
arteriosclerosis affecting primarily the intima of
large and medium-sized muscular arteries and is
characterised by fibrofatty 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

8. Causes
Atherosclerosis starts with damage or injury to
the inner layer of an artery. The damage may
be caused by:
• High blood pressure
• High cholesterol
• An irritant, such as nicotine
• Certain diseases, such as diabetes

10. Major risk factors
Dyslipidemia:
i) The atherosclerotic plaques contain cholesterol and cholesterol
esters, largely derived from the lipoproteins in the blood.
ii) The lesions of atherosclerosis can be induced in experimental
animals by feeding them with diet rich in cholesterol.
iii) Individuals with hypercholesterolaemia due to various causes
such as in diabetes mellitus, myxoedema, nephrotic
syndrome, von Gierke’s disease, xanthomatosis and familial
hypercholesterolaemia have increased risk of developing
atherosclerosis and IHD.
iv) Populations having hypercholesterolaemia have higher
mortality from IHD. Dietary regulation and administration
of cholesterol-lowering drugs have beneficial effect on
reducing the risk of IHD.

11. 2. HYPERTENSION.
• Hypertension is a risk factor for all clinical
manifestations of atherosclerosis.
• Hypertension doubles the risk of all forms of
cardiovascular disease.
• It acts probably by mechanical injury to the arterial
wall due to increased blood pressure.
• Elevation of systolic pressure of over 160 mmHg or a
diastolic pressure of over 95 mmHg is associated
with five times higher risk of developing IHD than in
people with blood pressure within normal range
(140/90 mmHg or less).

12. 3. SMOKING
• 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 atherosclerosis in
smokers is due to reduced level of HDL,
• deranged coagulation system and accumulation of
carbon monoxide in the blood that produce
carboxyhaemoglobin and eventually hypoxia in the
arterial wall favouring atherosclerosis

13. 4. DIABETES MELLITUS
Clinical manifestations of atherosclerosis are far more common
and develop at an early age in people with both type 1 and
type 2 diabetes mellitus.
In particular, association of type 2 diabetes mellitus
characterised by metabolic (insulin resistance) syndrome and
abnormal lipid profile termed ‘diabetic dyslipidaemia’ 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.

14. Constitutional risk factors
1. AGE. Atherosclerosis is an age-related disease.
Though early lesions of atherosclerosis 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. SEX. The incidence and severity of atherosclerosis are
more in men than in women and the changes appear a decade
earlier in men (>45 years) than in women (>55 years).
The lower incidence of IHD in women, especially in
premenopausal age, is probably due to high levels of
oestrogen and high-density lipoproteins, both of which have
anti-atherogenic influence.

15. 3. GENETIC FACTORS. Genetic factors play a significant
role in atherogenesis.
Hereditary genetic derangements of lipoprotein
metabolism predispose the individual to high
blood lipid level and familial hypercholesterolaemia.
4. FAMILIAL AND RACIAL FACTORS: The familial
predisposition to atherosclerosis may be related to other
risk factors like diabetes, hypertension and
hyperlipoproteinaemia.
Racial differences too exist; Blacks have generally
less severe atherosclerosis than Whites.

16. PATHOGENESIS
• Insudation hypothesis.
• The concept hypothesised by Virchow in 1856 that
atherosclerosis is a form of
• Cellular proliferation of the intimal cells resulting
from increased imbibing of lipids from the blood
came to be called the ‘lipid theory’.
• Modified form of this theory is currently known as
‘response to injury hypothesis’ and is now-a-days the
most widely accepted theory

17. Encrustation hypothesis
The proposal put forth by Rokitansky in 1852
that atheroma represented a form of
encrustation on the arterial wall from the components
in the blood forming thrombi composed of platelets,
fibrin andleucocytes, was named as ‘encrustation
theory’ or ‘thrombogenic theory’.
this theory has now been
incorporated into the response-to-injury hypothesis
mentioned above.

18. The role of four key factors
1. Arterial smooth muscle cells,
2. Endothelial cells,
3. Blood monocytes
4. Dyslipidaemia,
Currently, pathogenesis of atherosclerosis is explained
on the basis of the following two theories:
• 1. Reaction-to-injury hypothesis,
• 2. Monoclonal theory, based on neoplastic
proliferation of smooth muscle cells

19. REACTION-TO-INJURY HYPOTHESIS

20. i) Endothelial injury
The initial triggering event
Actual endothelial denudation is not an essentia
lrequirement, but endothelial dysfunction may initiate the
sequence of events.
causes of endothelial injury in experimental animals are:
mechanical trauma, haemodynamic forces, immunological
and chemical mechanisms, metabolic agent as chronic
dyslipidaemia, homocystine, circulating toxins from systemic
infections, viruses, hypoxia, radiation, carbon monoxide and
tobacco products.
In man, two of the major risk factors which act together
to produce endothelial injury are: haemodynamic stress from
hypertension and chronic dyslipidaemia

21. ii) Intimal smooth muscle cell proliferation
• injury causes adherence, aggregation and platelet
release reaction at the site of exposed subendothelial
connective tissue and infiltration by inflammatory cells.
• Proliferation stimulated by
• IL-1,
• TNF-α,
• Platelet-derived growth factor (PDGF) ,
• fibroblast growth factor (FGF) ,
• Transforming growth factor-β (TGF-β) and interferon-
(IFN-γ) derived from activated T lymphocytes

22. iii) Role of blood monocytes
• LDL does appear in the monocyte cytoplasm
to form foam cell
• For monocytes: Oxidised LDL acts to attract,
proliferate, immobilise and activate them as
well as is readily taken up by scavenger
receptor on the monocyte to transform it to a
lipid-laden foam cell

23. Mechanism of foam cell formation

24. iv) Role of dyslipidaemia
• Chronic dyslipidaemia in itself may initiate
endothelial injury and dysfunction by causing
increased permeability.
• In particular, hypercholesterolaemia with
increased serum concentration of LDL
promotes formation of foam cells,
• while high serum concentration of HDL has
anti-atherogenic effect.

25. Schematic evolution of lesions in atherosclerosis

27. MORPHOLOGIC FEATURES
Early lesions in the form of diffuse intimal
thickening,
Fatty streaks and gelatinous lesions are often the
forerunners in the evolution of atherosclerotic
lesions.
However, the clinical disease states due to
luminal narrowing in atherosclerosis are caused
by fully developed
Atheromatous plaques and complicated plaques

28. Histological appearance of plaque

29. COMPLICATED PLAQUES
• Calcification
• Thrombosis
• Ulceration
• Hemorrhage
• Aneurysm formation

30. Clinical effects
• Depend upon the size and type of arteries affected.
• 1. Slow luminal narrowing causing ischaemia and
atrophy.
• 2. Sudden luminal occlusion causing infarction
necrosis.
• 3. Propagation of plaque by formation of thrombi
and emboli.
• 4. Formation of aneurysmal dilatation and eventual
rupture

31. Major sites of atherosclerosis (serially numbered) in
descending order of frequency

32. Major effects on organs
• i) Aorta—Aneurysm formation, thrombosis and
embolisation to other organs.
• ii) Heart—Myocardial infarction, ischaemic heart
disease.
• iii) Brain—Chronic ischaemic brain damage, cerebral
infarction.
• iv) Small intestine—Ischaemic bowel disease,
infarction.
• v) Lower extremities—Intermittent claudication,
gangrene.