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 fibro fatty plaques or atheromas.
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.
PATHOGENESIS OF ATHEROSCLEROSIS
Put forth by Virchow in 1852 stating that Atherosclerosis 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.
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.
Accumulation of lipoprotein (mainly LDL)
Monocyte adhesion to the endothelium
Transformation of monocytes into macrophages & foam cells
Smooth muscle cell recruitment, proliferation &ECM production
Lipid accumulation both extracellularly &within cells
Endothelial Injury :
Initial triggering event in the development of Atherosclerotic lesion
Caused due to 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.
ROLE OF LIPIDS
The mechanism by which hyperlipidemia contributes to atherogenesis include:
Impairment of EC function through increased production of oxygen free radicals that deactivate NO: the major Endothelial Relaxing Factor
Oxidised lipid generated by free radicals is ingested by by monocytes via the scavenger receptor distinct from the LDL receptor thus forming FOAM cells
Increases monocyte accumulation in lesion
Stimulates release of Growth Factors & Cytokines
Cytotoxic to EC & SMC
ROLE OF SMOOTH MUSCLE
Intimal Smooth Muscle Cell Proliferation
Endothelial injury causes adherence and aggregation of platelet at the site.
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.
ROLE OF BLOOD MONOCYTES
ROLE OF HYPERLIPIDEMIA
4. Role of Hyperlipidaemia
Chronic hyperlipdaemia in itself may initiate endothelial injury.
Increased serum concentration of LDL and VLDL promotes formation of foam cells.
while high serum concentration of HDL has anti-atherogenic effect.
ROLE OF INFLAMATION
Upregulation of endothelial adhesion molecules VCAM which binds monocytes & T cells
After adhering to the endothelial cell, monocytes between the cells stimulated by chemokines & transform into macrophage, that engulf oxidised LDL
Macrophages contribute to the growth of lesion by:
Producing IL-1 & TNF which increases adhesion of leukocytes
Produce chemokines eg:MCP-1
Produce reactive oxygen species which causes oxidation of LDL in the lesion.
ROLE OF 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.
ROLE OF INFECTION
Infection mainly due to CHLAMYDIA PNEUMONIA also lead to atherosclerosis.