Tuesday, November 13, 2012

The development and progression of Atherosclerosis:


Atherosclerosis is a chronic inflammatory, degenerative disease affecting medium and large arteries. It is associated with narrowing of vessel wall by deposition of lipids which causes reduced blood supply, ischaemia or necrosis. Clinical events occur due to unstable lesion that breaks off leading to thrombosis that ultimately cause MI. The inflammation damages endothelium of blood vessels, which facilitates the egress of lipid into subendothelial space. Once damaged LDL can cross into the vessel easily in NADPH oxidase mediated fashion and here LDL is oxidized. This oxidized LDL is ingested by macrophages and form foam cells. This is followed by recruitment of lymphocytes, monocytes, macrophages and smooth muscle cells. The inflammatory milieu is mediated by CD40L, CRP, IL-1,6,8, etc. 

There is also increased adherence of WBC to damaged endothelial surface with subsequent degranulation and elaboration of myeloperoxidase. There is also a procoagulant component due to presence of tissue factor, which is localized under the plaque. During inflammation and cellular infiltration thick cap on plaque is ruptured making plaques vulnerable to fragment. Rupture of this plaque leads to unstable angina, that can proceed to AMI. Platelet aggregated in the plaque gets activated and secrete vasoconstricting substance that expressed adhesive receptors (CAMs). They also activate thrombin, which converts fibrinogen to insoluble fibrin clot. This, in addition to stagnant blood flow causes platelet and WBC to adhere to the surface of the vessels. In many patients platelets adhere and enhance vasoconstriction and then break off, causing small vessel emboli.

Atherosclerosis is present in early in life but it increases with age. Dyslipidemia, specifically elevated Tg, LDL-C and reduced HDL-C have strong association with AMI. Risk factors for atherosclerosis include age, sex, race, familial history, genetic factors (non modifiable risk factors), hypercholesterolemia, smoking oxidized LDL, low HDL, hypertension, dyslipidemia inflammation (modifiable risk factors) and microabluminuria, diabetes, stress, lipoprotein (a) (partially modifiable risk factors).

The wall of arteries consists of 3 layers, innermost tunica intima overlaid by single layer of endothelial cells subendothelial layer has smooth muscle cells, middle tunica media mainly consisting of smooth muscle cells and the outermost tunica adventitia which consists of connective tissue and fibroblasts.

Endothelium maintains vascular tone, and inhibiting leukocyte adhesion and platelet aggregation, through its release of nitric oxide (NO) and prostacyclin which are vasodilator (by increasing smooth muscle cell cGMP). NO is derived from arginine by constitutive enzyme NO synthase. NO inhibits platelet aggregation and adhesion, modulates smooth muscle cell proliferation, generates endothelin (vasoconstrictor) and reduces leukocyte adhesion to endothelium. Circulation also contains tissue plasminogen activator and plasminogen activator inhibitor that controls relative balance between prothrombotic and fibrinolytic activity.

Athere is Greek for gruel, and describes fatty contents of the fibrofatty lesion. There are several hypotheses for atherosclerosis.

The response to injury hypothesis: This hypothesis proposed by Ross is probably the most widely accepted. This focused the role of platelet as possible source of growth factors, and their interaction with the damaged artery wall. Later it was proposed that a number of different risk factors contribute to endothelial injury, including smoking hypertension, hyperlipidaemia and viral infection, insulin resistance, etc.

Lipid oxidation hypothesis: This theory provided another mechanism of endothelial injury and explanation for the formation of macrophage derived foam cells. Oxidant and inflammatory environment activate circulating monocyte to macrophages, this is process LDL is also oxidized to form oxidized LDL. Due to activation of leukocytes, formation of ox-LDL and inflammatory environment, this induces endothelium to express adhesion molecules and also increases endothelial permeability, increase chemotactic factors (MCP-1). This process causes transmigration of leukocytes (macrophages, lymphocytes) to the subendothelial layer. 

Activated macrophages can uptake normal LDL and oxidized LDL via scavenger receptors and gets converted to lipid laden foam cells and give a lesion termed fatty streak. Activation of Th1 cells induces proinflammatory cytokines. Excessive uptake of cholesterol by smooth muscle cells and macrophages, sufficient to lead to the formation of foam cells that are characteristic of fatty streak occur by scavenger receptors which allows unregulated cholesterol uptake in the form of modified LDL. LDL when oxidized produces MDA, 4-hydroxynonenol and lipid peroxides which in turn react with apo-B 100 within LDL particles, cross linking and altered antigen expression, there is production of neo antigens which elicit autoimmune response and autoantibodies to ox-LDL occurring within the atherosclerotic lesion.

The conversion of fatty streak into a fibrous plaque requires the recruitment and proliferation of vascular smooth muscle cells. This is driven by several growth factors like platelet-derived growth factor, IGF and basic fibroblast growth factor as they are smooth muscle cell mitogen. Activated smooth muscle cells and fibroblast produce collagenous cap. The mature plaque is characterized by fibrous cap composed of smooth muscle cells and extracellular matrix, overlying a pool of lipid, cholesterol crystals and inflammatory cells. 




Unstable plaques are prone to fissuring and rupture. Such plaques contain large lipid pool, thin fibrous cap, few smooth muscle and larger number of inflammatory cells. Activated macrophages within plaques are rich source of matrix metalloproteinase which can degrade extracellular matrix and has potential to destabilize the plaque. Rupture of plaque exposes thrombogenic collagen and tissue factor leading to thrombus formation. Some plaques are stabilized through the development of thick fibrous cap which will become calcified.
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