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Hyperlipidemia:
Hyperlipidemia is virtually universally acknowledged to be a major risk factor for Atherosclerosis. Most of the evidence specifically implicates hypercholesterolemia but hypertriglyceridemia may also play a role. Large scale epidemiological statistics have demonstrated a significant co-relation between total plasma cholesterol and low density lipoprotein (LPL) level and the severity of AS as judged by mortality rate from IHD.
Hypertrigyceridemia as manifested by the elevated very Low density lipoprotein (VLDL) levels is also associated with some increased rate.
It is important at this point to emphasize the inverse relationship between symptomatic Atherosclerosis and the high density Lipoprotein (HDL) level. HDL participates in reverse transport of cholesterol and is believed to mobilize this lipid from cells and presumably from atherosclerotic plaques and transport it to liver for excretion in the bile. The higher the levels of HDL, the lower are the risk of IHD. Hence there is great interest in dietary levels of lowering serum LDL and raising serum HDL. Non dietary influences may also affect the level of blood lipids.
Hypertension:
Hypertension is major risk factor for atherosclerosis at all ages and may well be more important than hypercholesterolemia after age 45. Men age 45 - 62 whose blood pressure exceeds 160/95mm Hg have more than fivefold greater risk of IHD than those with blood pressure of 140/90 mm of hg or lower. Both systolic and diastolic levels are important in increasing risk.
Smoking:
Smoking another important risk factor thought to account for the relatively recent increase in the incidence and severity of atherosclerosis in women. When one or more packs of cigarettes are smoked per day for several years, the death rate from IHD increases by up to 200%.
Diabetes:
Diabetes induces hypercholesterolemia and a markedly increased predisposition to atherosclerosis.
Other Factors:
These include insufficient regular physical activity, competitive stressful life style with type A personality, obesity, the use of oral contraceptives, hyperuricemia, high carbohydrates intake and hyperhomocysteinemia.
Pathogenesis of Atherosclerosis:
Endothelial Injury:
Chronic or repeated endothelial injury is the corner stone of response to injury hypothesis. Circulating endotoxins, hypoxia, and products derived from cigarette smoke, viruses and specific endothelial toxins such as homocysteine are involved but thought to be much more likely are hemodynamic disturbances shear stress turbulent flow, adverse effects of hypercholesterolemia perhaps acting in concert. Shear stress and turbulent flow cause increased endothelial permeability and cell turnover, enhanced receptor mediated LDL endocytosis and increased endothelial adhesivity to leukocytes.
Hyperlipidemia:
Hyperlipidemia contributes to atherosclerosis in many ways. Chronic hyperlipidemia particularly hypercholesterolemia may itself initiate endothelial dysfunction. With chronic hyperlipidemia, lipoproteins accumulate within the intima at sites of endothelial injury and dysfunction. Most importantly it provides the opportunity for modification of lipid in the arterial wall, largely by oxidative mechanisms, yielding modified LDL. Oxidative modification of LDL is currently thought to be a significant aspect of the atherogenic process. It is proposed that LDL in the microenvironment of interadharent monocytes and endotheial cells is exposed to free radicals generated by these activated cells. Oxidized LDL contributes to atherogenesis in the following ways.
It is readily ingested by macrophages through the scavenger receptor that is distinct from the LDL receptor. It is chemotactic for circulating monocytes. It increases monocytes adhesion, it inhibits the motility of macrophages already in lesions, and thus favoring the recruitment and retention of macrophages in the lesions. It stimulates the release of growth factors and cytokines. It is cytrotoxic to endothelial and SMCs, It is immunogenic.
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