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AtherosclerosisAtherosclerosis 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.
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AtherosclerosisMost 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.
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Concepts of atherogenesis
Endothelium (E)Subendothelial space
Smooth muscle layer (S)Adventitia
Endothelial Injury/Dysfunction
Hyperlipideamia, Hypertension, Smoking, Homocysteine,
Hemodynamic factors, etc
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Concepts of atherogenesisCirculating platelets adhere to endothelial surface
Leukocyte adhesion
Leukocyte migration
Taken from Robbins Pathologic Basis of Disease
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Concepts of atherogenesisEndothelial
Permeability increased
LDL, VLDL and leukocyte accumulation
Smooth muscle migration
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Concepts of atherogenesisGross appearance of fatty streaking
Macrophage and smooth
muscles engulfing more and more LDL
Arrival of lymphocyte
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Risk Factors in AtherosclerosisMajor 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
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Risk Factors in AtherosclerosisMinor Risk Factors:
1. Environmental influences2. Obesity3. Hormones: Oestrogen deficiency, oral contracep.4. Physical inactivity5. Stressful life6. Infections (C. pneumoniae, Herpes virus, CMV)7. Homocystinuria8. Role of Alcohol
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Progression of Atherosclerosis1. 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.
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Progression of Atherosclerosis2. 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.
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Progression of Atherosclerosis3. 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.
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Progression of Atherosclerosis4. 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.
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Progression of Atherosclerosis5. 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.
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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 arterialCan be:
o Vasospasmo External pressureo Traumao Twisting of organs eg. Testicular torsiono Edema
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Venous infarct occurs in organs with single venous outflow. Eg. Testis, ovary
Types: Red infarct, white infarct, septic infarctRed infarct:
o Due to venous occlusiono In loose tissue eg. Lungo Organs with dual circulationo In tissues that have be previously congested
White infarcto Arterial occlusion of solid organs, eg. Heart,
kidneys, spleen
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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 hoursRepair process
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Factors influencing development of Infarct1.Nature of the blood supply
a.Dual: lung, liver, handsb.End-arterial: spleen, kidneys
2.Rate of occlusion:a.Eg. Atherosclerosis of coronary arteries is gradual slow process
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3. Vulnerability to hypoxiaa. Neuron: 3-4 minutesb. Heart: 20-30 minutesc. Fibrous tissue: hours
4. Oxygen content of the blooda. Eg. Heart failure patient have low
oxygen concentration in blood
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TISSUES WITH SINGLE BLOOD SUPPLY
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WITH DUAL BLOODTISSUES SUPPLY
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Determinants of infarct outcomeNature of vascular supply
Dual blood supply or collateral vesselsRate of development of occlusion
Slowly occluded vessels become organized with alternate perfusion pathways of collateral circulation
Vulnerability to hypoxiaNeurons, 3 – 4 minutesMyocardial cells, 20 – 30 minutesFibroblasts, skeletal muscle, hours
Blood oxygenationAnemia or cyanosis exacerbates hypoxia
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Ischemic coagulative necrosisHistological changes appear in 4 to 12 hours
after anoxiaCellular swelling, membrane degradation,
nuclear condensation and breakdownInflammation is well defined in 1 to 2 daysReparation follows
Labile tissues regenerateStable tissues scar