Dislipidemias

Dyslipidemia

Key Points
| • | Patients undergoing screening for dyslipidemia should have a complete fasting lipid profile. |
| • | LDL and non-HDL (total cholesterol − HDL) are atherogenic and have defined targets for therapy based on global risk factor burden. |
| • | LDL-C is currently the primary target of therapy in patients with dyslipidemia, although non-HDL-C or apoB100may become the next primary target of therapy. |
| • | HDL is antiatherogenic, and when less than 40 mg/dL in men and 50 mg/dL in women, therapeutic effort should be made to raise HDL. |
| • | Therapeutic lifestyle changes are an important component of any regimen designed to treat dyslipidemia. |
Causes
Although it is pathogenic, cholesterol is also an important modulator of cellmembrane fluidity and is a substrate for hormone biosynthesis by steroidogenic organs. There is an unequivocal relationship between dyslipidemia and risk for atherogenesis within the coronary, peripheral, renal, and cerebral vasculature. Dyslipoproteinemias develop in response to genetic and environmental factors and are modifiable through lifestyle modification and pharmacologic intervention. Asdemonstrated in the Framingham Study, Multiple Risk Factor Intervention Trial, and the Seven Countries Study, as serum levels of cholesterol increase, the risk for developing CAD increases. The identification and treatment of dyslipidemia lowers the prevalence of atherosclerotic disease and its various clinical manifestations.
Serum very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL)particles deliver cholesterol to peripheral tissues and blood vessel walls. These lipoproteins can cross the endothelial barrier and induce atherogenesis. Atherogenic lipoproteins not taken up by peripheral tissues are cleared from the circulation by hepatic LDL receptors. Therapies targeted at the upregulation of hepatic LDL receptors are antiatherogenic by virtue of their ability to reducecirculating levels of atherogenic lipoproteins.
High-density lipoprotein (HDL) particles are antiatherogenic. With few exceptions, epidemiologic investigation has shown that high HDL levels reduce risk for the development of CAD (Toth, 2001, 2009). Consistent with this finding, patients with familial hypo-α-lipoproteinemia (low HDL) have increased risk for premature CAD, whereas patients with familialhyper-α-lipoproteinemia (high HDL) are relatively resistant to CAD (Toth, 2003, 2004). HDL extracts excess intracellular cholesterol from macrophages and delivers it back to the liver for elimination as bile salts through the gastrointestinal tract in a process referred to as “reverse cholesterol transport” (Fig. 27-1). HDL has also been shown to reduce endothelial CAM expression, augmentendothelial nitric oxide and prostacyclin production, reduce oxidized LDL, decrease platelet aggregability, and inhibit endothelial cell apoptosis (programmed cell death). An HDL greater than 60 mg/dL is a “negative” risk factor. In general, the more elevated the level of serum HDL, the lower is the risk for CAD. Therapeutic interventions should not be targeted at reducing serum HDL. Although emergingevidence suggests that some patients may harbor HDL species that appear to be proinflammatory and pro-oxidative because of alterations in their protein and enzyme cargo (Ansell, 2006), treatment with some types of lipid-modifying agents appears to restore normal functionality to these HDL particles (Heinecke, 2009).
| | Figure 27-1 Molecular and histologic pathways for reverse cholesteroltransport. To deliver peripheral cholesterol back to the liver or steroidogenic organs such as the adrenal glands, placenta, or ovaries, apoA-I and nascent discoidal HDL interact with cells such as macrophages and foam cells within blood vessel walls. The HDL undergoes a series of cell receptor–dependent and serum enzyme–dependent maturation and speciation reactions (HDL speciation). HDL can interact...