This is an educational presentation on pathogenesis of Atherosclerosis. Risk factors are explained in detail. Pathophysiology is described in detail.

1. Atherosclerosis
(Risk factors & Pathogenesis)
Dr. Mantasha Binth Siraj
Assistant Professor
Dept. of Mahiyatul Amraz (Pathology )
Hayat Unani Medical College and Research Center,
Lucknow

2. Introduction
• Atherosclerosis is a specific form of arteriosclerosis (thickening & hardening of
arterial walls) affecting mainly the intima of large and medium-sized muscular
arteries and is characterized by the presence of fibrofatty plaques or atheroma's.
• The term atherosclerosis is derivative of athero (meaning porridge) refers to the
soft lipid-rich material in the center of atheroma, and sclerosis (scarring) referring to
connective tissue in the plaques.
• Most commonly affected arteries by atherosclerosis include large and medium
sized arteries like aorta, coronary, popliteal and cerebral arteries.
• Major complications resulting from ischemia due to atherosclerosis include
myocardial infarction leading to heart attacks and cerebral infarction leading to
strokes.
• Less common complications include peripheral vascular disease, aneurysmal
dilatation due to weakened arterial wall, chronic ischemic heart disease, ischemic
encephalopathy and mesenteric occlusion.

3. Etiology &
Pathogenesis

4. Risk Factors

 Major risk factors
 Major Constitutional risk
factors:
• Age
• Sex
• Genetic factors iv.
• Familial and racial
factors
 Major Acquired risk
factors
• Hyperlipidemia
• Hypertension
• Diabetes mellitus
• Smoking
• Hyperhomocysteinemia
 Minor Risk Factors
 Environmental
influences
 Obesity
 Hormones:
 Estrogen deficiency,
 Oral contraceptives
 Physical inactivity
 Stressful life
 Infections (C.
pneumoniae, Herpes
virus, CMV)
 Homocystinuria
 Role of Alcohol

5. Major Constitutional Risk Factors
AGE
o Atherosclerosis is an age-related disease.
o Clinically significant lesions are found with increasing age.
o Fully-developed atheromatous plaques usually appear in 40s and beyond.
o Evidence in support comes from the high death rate from IHD in this age group.
SEX
o Incidence and severity of atherosclerosis is seen more in males as compared to
females .
o Prevalence of atherosclerotic IHD is about three times higher in men in 4th decade
than in women.
o Lower incidence of IHD in women, especially in premenopausal age is probably
due to high levels of estrogens and high-density lipo- proteins, both of which have
anti-atherogenic influence.

6. GENETIC FACTORS
o Hereditary genetic derangements of lipoprotein metabolism predispose the
individuals to high blood lipid level and familial hypercholesterolemia
FAMILIAL AND RACIAL FACTORS
o Familial predisposition to atherosclerosis may be related to other risk factors like
diabetes, hypertension and hyperlipoproteinemia
o Racial differences too exist. Blacks have less severe atherosclerosis than Whites

7. Major Acquired Risk Factors
HYPERLIPIDAEMIA
Hypercholesterolemia has directly proportionate relationship with atherosclerosis and
IHD as :
• The atherosclerotic plaques contain cholesterol and cholesterol esters largely
derived from the lipoproteins in the blood
• The lesions of atherosclerosis can be induced in experimental animals by feeding
them cholesterol-rich diet
• Individuals with hypercholesterolemia due to various causes such as diabetes
mellitus, myxedema, nephrotic syndrome and familial hypercholesterolemia have
increased risk of developing atherosclerosis and IHD
• Populations having hypercholesterolemia have higher mortality from IHD. Dietary
regulation and administration of cholesterol-lowering drugs have beneficial effect
on reducing the risk of IHD

8. • Virchow in 19th century first identified cholesterol crystals in the atherosclerotic
lesions
• An elevation of serum cholesterol levels above 260mg/dl in men and women
between 30 and 50 years of age has three times higher risk of developing IHD as
compared with people with normal serum cholesterol levels (140-200 mg/dl)
• Low-density lipoproteins (LDL) is richest in cholesterol and has maximum
association with atherosclerosis
• VLDL carries much of triglycerides & has less marked effect than LDL
• HDL is protective good cholesterol against atherosclerosis
• Diet rich in saturated fats e.g., eggs, meat, milk, butter etc. raises the plasma
cholesterol level while the diet rich in poly-unsaturated fats and omega-3 fatty
acids e.g., fish, fish oils lowers its level
Cont…

9. HYPERTENSION
• Hypertension causes mechanical injury to the arterial wall due to increased blood
pressure leading to IHD and cerebrovascular disease
• Endothelial injury owing to persistent high B.P leads to plaque formation as per
response to injury hypothesis
• A systolic pressure of over 160 mmHg or a diastolic pressure of over 95 mmHg
leads to 5 times higher risk of developing IHD than in people with normal B.P.
(140/90 mmHg or less)
SMOKING
• The extent and severity of atherosclerosis are much greater in smokers than in
non-smokers
• Cigarette smoking is associated with higher risk of atherosclerosis, IHD and
sudden cardiac death
• Increased risk is due to reduced level of HDL and accumulation of carbon
monoxide in the blood that produces carboxy- Hb and eventually hypoxia in the
arterial wall favoring atherosclerosis

10. Smoking also promotes Atherosclerosis by means of increasing platelet
adhesiveness, raised endothelial permeability, sympathetic nervous system
stimulation by nicotine
DIABETES MELLITUS
• Atherosclerosis develops at an early age in people with both insulin-dependent
and non-insulin dependent diabetes mellitus
• The risk of cerebrovascular disease is high and frequency to develop gangrene of
foot is about 100 times increased
• Causes of increased severity of atherosclerosis are complex and include
increased aggregation of platelets, increased LDL and decreased HDL

11. Minor Risk Factors
• Higher incidence in developed countries is because of environmental influences
• Obesity as risk is increased if a person is overweight by 20% or more
• Use of exogenous hormones like oral contraceptives by women or endogenous
estrogen deficiency e.g., in post-menopausal women leads to increased risk
• Physical inactivity and lack of exercise increases risk
• Stressful life style led by aggressiveness, competitive drive, over-ambitiousness
and a sense of urgency is associated with enhanced risk of IHD
• Infections particularly Chlamydia pneumoniae and viruses such as- herpes virus
and cytomegalovirus increases coronary atherosclerotic lesions.
• Patients with homocystinuria
• Moderate consumption of alcohol has slightly beneficial effect by raising the level
of HDL cholesterol and by causing vasodilation, However, persistent consumption
of alcohol in large quantities causes more damage

12. Pathogenesis

13. INSUDATION HYPOTHESIS
Virchow in 1852 states that Atherosclerosis is a form of cellular proliferation of the
intimal cells resulting from increased imbibing of lipids from the blood
ENCRUSTATION HYPOTHESIS
Put forth by Rokitansky in 1852 stating that atheroma represented a form of
encrustation on the arterial wall from the components in the blood forming thrombi
composed of platelets, fibrin and leucocytes
Response to Injury Theory
• Original Theory: Initial event in atherogenesis is endothelial injury followed by
smooth muscle cell proliferation
• Modified theory describes lipoprotein entry into the intima as the initial event
followed by lipid accumulation in the macrophages (now foam cells) which
according to modified theory are the dominant cells in early lesions

14. Monoclonal Hypothesis
• Based on the postulate that proliferation of smooth muscle cells is the primary
event and that this proliferation is monoclonal in origin similar to cellular
proliferation in neoplasms
• Evidence in support of this hypothesis is the presence of proliferated smooth
muscle cells in atheromatous plaques which have only one of the two forms of
G6PD isoenzymes, suggesting monoclonality in origin. Monoclonal proliferation of
smooth muscle cells may be initiated by mutations caused by exogenous
chemicals like cigarette smoke or endogenous metabolites like lipoproteins or
some viruses like herpesvirus

15. STAGES OF DEVELOPMENT OF ATHEROSCLEROSIS

16. Progression of Atherosclerosis
Endothelial Injury:
• Initial triggering event in the development of Atherosclerotic lesions causes
ascribed to endothelial injury in experimental animals include mechanical trauma,
hemodynamic forces, immunological and chemical mechanisms, metabolic agents
like chronic hyperlipidemia, homocysteine, circulating toxins from systemic
infections, viruses, hypoxia, radiation, carbon monoxide and tobacco products
• In man, two major risk factors are hemodynamic stress from hypertension and
chronic Intimal Smooth Muscle Cell Proliferation
• Endothelial injury causes adherence aggregation and platelet release reaction at
the site of exposed subendothelial connective tissue
• Proliferation of intimal smooth muscle cells is stimulated by various mitogens
released from platelets adherent at the site of endothelial injury
• These mitogens include PDGF, fibroblast growth factor, TGF-ά. Proliferation is
also facilitated by nitric oxide and endothelin released from endothelial cells

17. 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. Oxidized LDL formed
in the intima performs following two important functions :
 For monocytes, oxidized LDL acts to attract, proliferate, immobilize and
activate them and is readily taken up by scavenger receptor on the
monocyte to transform it to a lipid laden foam cell.
 For endothelin, oxidized LDL is cytotoxic.
Role of Hyperlipidemia
• Chronic hyperlipidemia in itself may initiate endothelial injury and dysfunction by
casing increased permeability
• Increased serum concentration of LDL and VLDL promotes formation of foam
cells, while high serum concentration of HDL has anti-atherogenic effect.

18. Thrombosis
Endothelial injury exposes sub-endothelial connective tissue resulting in platelet
aggregation at the site besides proliferation of smooth muscle cells. .This causes
mild inflammatory reaction which together with foam cells is incorporated into
atheromatous plaque. Lesions enlarge by attaching fibrin and blood cells causing
thrombus formation which becomes a part of atheromatous plaque.

21. THANK YOU