BYSRUTI MARY JOSEPH

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 fibro fatty plaques or atheromas.

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, ischemic encephalopathy and mesenteric occlusion.

PATHOGENESIS OF ATHEROSCLEROSISINSUDATION HYPOTHESIS

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.

ENCRUSTATION HYPOTHESISPut 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 THEORYOriginal 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.

EVENTSEndothelial injuryAccumulation of lipoprotein (mainly LDL)Monocyte adhesion to the endotheliumTransformation of monocytes into

macrophages & foam cellsPlatelet adhesionSmooth muscle cell recruitment, proliferation

&ECM productionLipid accumulation both extracellularly

&within cells

ENDOTHELIAL INJURY1. 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 LIPIDSThe 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

CONT’DIncreases monocyte accumulation in lesion Stimulates release of Growth Factors &

CytokinesCytotoxic to EC & SMC

ROLE OF SMOOTH MUSCLE2. 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 HYPERLIPIDEMIA4. 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 INFLAMATIONUpregulation 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

CONT’DProduce chemokines eg:MCP-1Produce 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 INFECTIONInfection mainly due to CHLAMYDIA

PNEUMONIA also lead to atherosclerosis.