Dr Geer Mohammad Ishaq

Senior Assistant Professor

Department of Pharmaceutical Sciences
University of Kashmir

July 31, 2010 For the exclusive use of Kashvarsity e-group members
Atherosclerosis
Atherosclerosis is a specific form of arteriosclerosis
(thickening & hardening of arterial walls) affecting
primarily the intima of large and medium-sized
muscular arteries and is characterized by the presence
of 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.
Atherosclerosis
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,
ischaemic encephalopathy and mesenteric occlusion.
Etiology
Atherosclerosis is the cause of more than half of all deaths
in the western industrialized nations.
Incidence progressively increasing in developing nations
too in an epidemic proportion over the last few decades
due to fast changing lifestyles.
Deaths from myocardial infarction (20-25 % of all deaths)
are mostly related to underlying atherosclerosis.
Cardiovascular disease related to atherosclerotic coronary
heart disease (CHD) or ischaemic heart disease (IHD) is
the most common cause of death in the developed
countries of the world.
Risk Factors in Atherosclerosis
Major risk factors
1) Major Constitutional risk factors:
i. Age ii. Sex iii. Genetic factors
iv. Familial and racial factors
2) Major Acquired risk factors:
i. Hyperlipidaemia ii. Hypertension
iii. Diabetes mellitus iv. Smoking
v. Hyperhomocysteinemia
Risk Factors in Atherosclerosis
Minor Risk Factors:
1. Environmental influences
2. Obesity
3. Hormones: Oestrogen deficiency, oral contracep.
4. Physical inactivity
5. Stressful life
6. Infections (C. pneumoniae, Herpes virus, CMV)
7. Homocystinuria
8. Role of Alcohol
Major Constitutional Risk Factors
AGE
Atherosclerosis is an age-related disease.
Clinically significant lesions are found
with increasing age.
Fully-developed atheromatous plaques
usually appear in 40s and beyond.
Evidence in support comes from the high
death rate from IHD in this age group.
Major Constitutional Risk Factors
SEX
Incidence and severity of atherosclerosis is more
in men than in women.
Prevalence of atherosclerotic IHD is about three
times higher in men in 4th decade than in women.
Lower incidence of IHD in women, especially in
premenopausal age is probably due to high levels
of oestrogens and high-density lipo- proteins,
both of which have anti-atherogenic influence.
Major Constitutional Risk Factors
GENETIC FACTORS
Hereditary genetic derangements of lipoprotein
metabolism predispose the individuals to high
blood lipid level and familial
hypercholesterolaemia.
FAMILIAL AND RACIAL FACTORS
Familial predisposition to atherosclerosis may
be related to other risk factors like diabetes,
hypertension and hyperlipoproteinaemia.
Racial differences too exist. Blacks have less
severe atherosclerosis than Whites.
Major Acquired Risk Factors
HYPERLIPIDAEMIA
Hypercholesterolaemia has directly proportionate relationship
with atherosclerosis and IHD because:
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 hypercholesterolaemia due to various causes
such as diabetes mellitus, myxoedema, nephrotic syndrome and
familial hypercholesterolaemia have increased risk of developing
atherosclerosis and IHD.
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
Major Acquired Risk Factors
HYPERLIPIDAEMIA
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 athersc
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 etc lowers its level.
Major Acquired Risk Factors
HYPERTENSION
Hypertension causes mechanical injury to the arterial
wall due to increased blood pressure leading to athero-
sclerotic IHD and cerebrovascular disease.
Endothelial injury due 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).
Major Acquired Risk Factors
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-haemoglobin and eventually hypoxia in
the arterial wall favouring atherosclerosis.
Smoking also promotes Athr. by increased platelet
adhesiveness, raised endothelial permeability,
symapathetic nervous system stimulation by nicotene.
Major Acquired Risk Factors
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 Ath. are complex and
include increased aggregation of platelets, increased
LDL and decreased HDL.
Minor Risk Factors
1. Higher incidence of Athr. in developed countries is
primarily because of environmental influences.
2. Obesity: Risk is increased if a person is overweight
by 20% or more.
3. Use of exogenous hormones like oral contraceptives
by women or endogenous oestrogen deficiency e.g.,
in post-menopausal women leads to increased risk.
4. Physical inactivity and lack of exercise increases risk
5. Stressful life style led by aggressiveness, competitive
drive, over-ambitiousness and a sense of urgency is
associated with enhanced risk of IHD.
Minor Risk Factors
6. Infections particularly Clamydia pneumoniae and
viruses such as herpesvirus and cytomegalovirus
increases coronary atherosclerotic lesions.
7. Patients with homocystinuria, an inborn error of
metabolism have early athr and CAD.
8. Moderate consumption of alcohol has slightly
beneficial effect by raising the level of HDL cholesterol
and by causing vasodilation.
9.However persistent consumption of alcohol in large
quantities causes more damage.
Pathogenesis of Atherosclerosis
Pathogenesis of Atherosclerosis
INSUDATION HYPOTHESIS
Put forth by Virchow in 1852 stating that Ath is a form of
cellular proliferation of the intimal cells resulting from
increased imbibing of lipids from the blood. Earlier known
as lipid theory is now called response to injury
hypothesis and is the most widely accepted theory.
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, and was
earlier named as thrombogenic theory.
Response to Injury Theory
Original theory put forth in 1973 modified in 1993.
Original Theory: Initial event in atherogenesis is
endothelial injury followed by smooth muscle cell
proliferation. As per this theory early lesions mainly
consist of smooth cells.
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.
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 in Ath.
may be initiated by mutations caused by exogenous
chemicals like cigarette smoke or endogenous metabolites
like lipoprotiens or some viruses like herpesvirus.
Progression of Atherosclerosis
1. Endothelial Injury:
Initial triggering event in the development of
Atherosclerotic lesions
Causes ascribed to endothelial injury in experimental
animals include mechanical trauma, haemodynamic
forces, immunological and chemical mechanisms,
metabolic agents like chronic hyperlipidaemia,
homocystine, circulating toxins from systemic
infections, viruses, hypoxia, radiation, carbon
monoxide and tobacco products.
In man, two major risk factors are haemodynamic
stress from hypertension and chronic hyperlipidaemia.
Pathogenesis of Atherosclerosis
Progression of Atherosclerosis
2. 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-.
Proliferation is also facilitated by nitric oxide and
endothelin released from endothelial cells.
Pathogenesis of Atherosclerosis
Progression of Atherosclerosis
3. 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 formed in the intima performs
following two important functions :
For monocytes, oxidized LDL acts to attract, proliferate,
immobilise 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.
Progression of Atherosclerosis
4. Role of Hyperlipidaemia
Chronic hyperlipdaemia 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.
Progression of Atherosclerosis
5. 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.