Atherosclerosis

As many as 20% of all cardiovascular events occur in the absence of overt risk factors (e.g. hypertension, hyperlipidemia, smoking or diabetes). Clearly other factors also contribute to risk:

• Inflammation is present during all stages of atherogenesis and intimately linken with atherosclerotic plaque formation and rupture. C-reactive protein (CRP) is one the most sensitive way to measure inflammation correlated with ischemic heart disease. CRP is an acute phase reactant synthesized primarily by the liver. Its expression is increased by a number of inflammatory mediators (IL-6). It is established that plasma CRP is a strong, independent marker of risk for myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy individuals.
• Hyperhomocystinemia makes a person more prone to endothelial cell injury, which leads to inflammation in the blood vessels.Serum homocysteine levels correlate with coronary atherosclerosis, peripheral vascular disease, stroke and venous thrombosis.
• Metabolic syndrome. Associated with central obesity,metabolic syndrome is characterized by insulin resistance, hypertension, dyslipidemia (elevated LDL and depressed HDL), hypercoagulability and proinflammatory state.
• Lipoprotein a [Lp(a)] is an altered from of LDL. Lp(a) levels are associated with coronary and cerebrovascular disease risk, independent of total cholesterol or LDL levels.
• Factors affecting homeostasis. Several markers of hemostatic and/or fibrinolytic function are potent predictors of risk for major atherosclerotic events.
• Other factors. Factors associated with a less pronounced and/or difficult-to-quantitate risk include lack of exercise, competitive/stressful lifestyle (type A personality) and obesity.

Pathogenesis of atherosclerosis
Atherosclerosis is a chronic inflammatory and healing response of the arterial wall to endothelial injury. Lesion progression occurs through interaction of modified lipoproteins, monocyte-derived macrophages, and T lymphocytes with endothelial cells and smooth muscle cells of the arterial wall.
Atherosclerosis progresses in the following sequence:

1. Endothelial injury and dysfunction
2. Accumulation of lipoprotein
3. Monocyte adhesion to the endothelium
4. Platelet adhesion
5. Factor release from activated platelets, macrophages and vascular wall cells
6. Smooth muscle cell proliferation, extracellular matrix production and recruitment of T cells.
7. Lipid accumulation

Atherosclerosis progress

Endothelial injury
Endothelial loss due to any kind of injury results in intimal thickening. The two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.
Hemodynamic disturbances
The importance is hemodynamic turbulence in atherogenesis is illustrated by the observation that plaques tend to occur at Ostia of exiting vessels, branch points and along the posterior wall of the abdominal aorta, where there are disturbed flow patterns.
Lipids
The evidence implicating hypercholesterolemia in atherogenesis includes:

• The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters
• Genetic defects that cause hyperlipoproteinemia/hypercholesterolemia are associated with accelerated/premature atherosclerosis.
• Epidemiologic analyses demonstrate a significant correlation between the severity of atherosclerosis and the levels of total plasma cholesterol or LDL.

The mechanisms by which hyperlipidemia contributes to atherogenesis include the following:

• Chronic hyperlipedmia can directly impair endothelial cell function by increasing local reactive oxygen species production. Beside causing membrane and mitochondrial damage, oxygen free radicals accelerate nitric oxide decay, damping it vascular activity.
• With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they may aggregate or become oxidized by free radicals produced by inflammatory cells. Chronic ingestion of lipids by machrophages leads to foam cells formation. Smooth muscle cells can similarly transform into lipid laden foams cells by ingesting modified lipids through LDL-receptor related proteins.

Inflammation
It is believed that inflammation is triggered by the accumulation cholesterol crystals and free fatty acids in macrophages and other cells. The net result of macrophage and T cell activation is the local production a\of cytokines and chemokines that recruit and activate more inflammatory cells.
Smooth muscle proliferation and matrix synthesis
Intimal smooth muscle cell proliferation and extracellular matrix deposition convert a fatty streak into a mature atheroma and contribute to the progressive growth of atherosclerotic lesions.

Consequences of atherosclerotic disease
Myocardial infarction, cerebral infarction, aortic aneurysms and peripheral vascular disease are the major consequences of atherosclerosis

Consequence of atherosclerosis

Atherosclerotic stenosis
In small arteries, atherosclerotic plaques can gradually occlude vessel lumina, compromising blood flow and causing ischemic injury. Critical stenosis is the stage at which the occlusion is sufficiently severe to produce tissue ischemia.
Acute plaque change
Plaque erosion or rupture is typically promptly followed by partial or complete vascular thrombosis resulting in acute tissue infarction. Plaque change fall into three general changes:

• Rupture/fissuring
• Erosion/ulceration
• Hemorrhage into the atheroma