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The plaques in the arterial walls of patients with atherosclerosis contain large amounts of cholesterol. The higher the level of low-density lipoproteins (LDL) cholesterol, the greater the risk of atherosclerotic heart disease; conversely, the higher the high-density lipoproteins (HDL) cholesterol, the lower the risk of coronary heart disease (CHD). This is true in men and women, in different racial and ethnic groups, and at all ages up to at least age 75 years. Because most cholesterol in serum is LDL, high total cholesterol levels are also associated with an increased risk of CHD. Middle-aged men whose serum cholesterol levels are in the highest quintile for age (above about 230 mg/dL or 5.95 mmol/L) have a risk of coronary death before age 65 years of about 10%; men in the lowest quintile (below about 170 mg/dL or 4.40 mmol/L) have a 3% risk. Death from CHD before age 65 years is less common in women, with equivalent risks one-third those of men. In men, each 10-mg/dL or 0.26-mmol/L increase in cholesterol (or LDL cholesterol) increases the risk of CHD by about 10%; each 5-mg/dL or 0.13-mmol/L increase in HDL is associated with reduced risk of about 10%. The association of HDL cholesterol with reduced risk is greater in women, whereas the effects of total and LDL cholesterol are smaller.

The exact mechanism by which apolipoprotein B–containing LDL particles, as well as VLDL and IDL remnants (remnant lipoproteins), result in the formation of atherosclerotic plaques—or the means whereby HDL particles protect against their formation—is incompletely described. The model of LDL carrying cholesterol into the walls of arteries with HDL removing it is likely oversimplified. After uptake of apolipoprotein B–carrying lipoproteins into the arterial wall, oxidation makes them particularly atherogenic. Receptors on the surface of macrophages within atherosclerotic plaques bind and accumulate oxidized LDL and remnant lipoproteins. The formation of antibodies to oxidized LDL may also be important in plaque formation. The size of the LDL molecule may also influence atherogenesis; at the same LDL concentrations, individuals with large numbers of smaller particles appear to be at higher risk for CHD.

The relationship of VLDL cholesterol to atherogenesis is less certain, although remnant lipoproteins (derived from VLDL metabolism) are thought to be at least as atherogenic as LDL particles. The number, size, or subtype of VLDL particles—in addition to the total amount in serum—may be important. In addition, HDL and VLDL levels are inversely related via their associations with insulin resistance. Patients with a high VLDL level are likely to have a low HDL level.

There are several genetic disorders that provide insight into the pathogenesis of lipid-related diseases. Familial hypercholesterolemia, rare in the homozygous state (about one per million), causes markedly high low-density lipoprotein (LDL) levels and early CVD. The most common genetic defects involve absent or defective LDL receptors, resulting in unregulated LDL metabolism, genetic mutations of apolipoprotein B, or gain of function in proprotein convertase subtilisin/kexin type 9 ...

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