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.
Concepts of atherogenesis
Hyperlipideamia, Hypertension,
Smoking, Homocysteine,
Hemodynamic factors, etc
Endothelium (E) Endothelial
Subendothelial space Injury/Dysfunction
Smooth muscle layer (S)
Adventitia
Concepts of atherogenesis
Circulating platelets
adhere to endothelial
surface
Leukocyte
adhesion
Leukocyte migration
Taken from Robbins Pathologic Basis of Disease
Concepts of atherogenesis
Endothelial
Permeability
increased
LDL, VLDL
and leukocyte
accumulation
Smooth muscle migration
Concepts of atherogenesis
Gross appearance of
fatty streaking
Macrophage
and smooth
muscles
engulfing
more and
more LDL
Arrival of
lymphocyte
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
Progression of Atherosclerosis
1. Endothelial Injury:
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 humans, two major risk factors are
haemodynamic stress from hypertension and
chronic hyperlipidaemia.
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-ά.
Proliferation is also facilitated by nitric oxide and
endothelin released from endothelial cells.
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 causing 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.
Infarction
Ischemic necrosis caused by occlusion of arterial or
venous vessles.
Example: MI, cerebral infarction, pulmonary infarct,
bowel infract, gangrene
99% due to thrombosis, mostly arterial
Can be:
o Vasospasm
o External pressure
o Trauma
o Twisting of organs eg. Testicular torsion
o Edema
Venous infarct occurs in organs with single venous
outflow. Eg. Testis, ovary
Types: Red infarct, white infarct, septic infarct
Red infarct:
o Due to venous occlusion
o In loose tissue eg. Lung
o Organs with dual circulation
o In tissues that have be previously congested
White infarct
o Arterial occlusion of solid organs, eg. Heart, kidneys, spleen
Infarction is usually wedge shape surrounded by rim
of hyperemia
Hemosiderin pigment may accumulate following
hemorrhage
Necrosis is of coagulative type (except brain:
liquifactive)
Inflammation within few hours
Repair process
Factors influencing
development of Infarct
1. Nature of the blood supply
a.Dual: lung, liver, hands
b.End-arterial: spleen, kidneys
2.Rate of occlusion:
a.Eg. Atherosclerosis of coronary arteries is
gradual slow process
3. Vulnerability to hypoxia
a. Neuron: 3-4 minutes
b. Heart: 20-30 minutes
c. Fibrous tissue: hours
4. Oxygen content of the blood
a. Eg. Heart failure patient have low oxygen
concentration in blood
TISSUES WITH SINGLE BLOOD SUPPLY
WITH DUAL BLOODTISSUES SUPPLY
Determinants of infarct outcome
Nature of vascular supply
Dual blood supply or collateral vessels
Rate of development of occlusion
Slowly occluded vessels become organized with alternate
perfusion pathways of collateral circulation
Vulnerability to hypoxia
Neurons, 3 – 4 minutes
Myocardial cells, 20 – 30 minutes
Fibroblasts, skeletal muscle, hours
Blood oxygenation
Anemia or cyanosis exacerbates hypoxia
Ischemic coagulative necrosis
Histological changes appear in 4 to 12 hours after
anoxia
Cellular swelling, membrane degradation, nuclear
condensation and breakdown
Inflammation is well defined in 1 to 2 days
Reparation follows
Labile tissues regenerate
Stable tissues scar
