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.

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.

Concepts of atherogenesis

Endothelium (E)Subendothelial space

Smooth muscle layer (S)Adventitia

Endothelial Injury/Dysfunction

Hyperlipideamia, Hypertension, Smoking, Homocysteine,

Hemodynamic factors, etc

Concepts of atherogenesisCirculating platelets adhere to endothelial surface

Leukocyte adhesion

Leukocyte migration

Taken from Robbins Pathologic Basis of Disease

Concepts of atherogenesisEndothelial

Permeability increased

LDL, VLDL and leukocyte accumulation

Smooth muscle migration

Concepts of atherogenesisGross appearance of fatty streaking

Macrophage and smooth

muscles engulfing more and more LDL

Arrival of lymphocyte

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

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

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.

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.

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.

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.

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.

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

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

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

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

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

TISSUES WITH SINGLE BLOOD SUPPLY

WITH DUAL BLOODTISSUES SUPPLY

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

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