This chapter discusses the causes and effects of hyperlipidemia, as well as treatment strategies for the condition (see accompanying Hurst’s Central Illustration). The two main categories of hyperlipidemia are hypercholesterolemia and hypertriglyceridemia; combined hyperlipidemia indicates an increase in concentration of both cholesterol and triglycerides. An elevated plasma low-density lipoprotein (LDL) level is considered a major risk factor for atherosclerotic cardiovascular disease (ASCVD), and LDL-lowering therapies reduce atherosclerotic plaque progression and the likelihood of plaque rupture and acute ASCVD events. By contrast, high levels of high density lipoprotein (HDL)-cholesterol are associated with reduced risk of ASCVD; however, to date, no convincing randomized controlled trial data have demonstrated that raising HDL-cholesterol levels prevents the condition. Growing evidence indicates that very-low-density lipoprotein (VLDL), and possibly cyclomicron remnants, are also atherogenic. Several genetic defects have been associated with hypercholesterolemia and, in most cases, result in high levels of LDL-cholesterol. Similarly, various genetic abnormalities that affect VLDL, VLDL remnants, and/or chylomicrons have been associated with hypertriglyceridemia. Familial combined hyperlipidemia is likely a polygenic disorder. Secondary causes of hyperlipidemia include diabetes mellitus, nephrotic syndrome, chronic kidney disease, hypothyroidism, human immunodeficiency virus, and various medications. Lifestyle factors, including poor diet, obesity, low physical activity levels, and cigarette smoking, are also risk factors for hyperlipidemia and ASCVD. Therapies shown to lower lipid levels include statins, bile acid resins, ezetimibe, monoclonal antibody inhibitors of PCSK9, mipomersen, lomitapide, fibrates, niacin, and LDL apheresis.
Hurst’s Central Illustration: Causes and Treatment of Hyperlipidemia.
Causes of hyperlipidemia (and, therefore, atherosclerotic cardiovascular disease) and treatment strategies employed. Hypercholesterolemia and hypertriglyceridemia are both types of hyperlipidemia; combined hyperlipidemia indicates an increase in concentration of both cholesterol and triglycerides. High levels of HDL-cholesterol are associated with reduced risk of atherosclerotic cardiovascular disease; however, to date, no convincing randomized controlled trial data have demonstrated that raising HDL-cholesterol levels prevents the condition.
LIPOPROTEIN METABOLISM AND ATHEROSCLEROSIS
The major lipids of plasma, cholesterol and triglyceride, are transported in molecular complexes called lipoproteins. The basic structure of all lipoproteins is similar. They contain a core of neutral lipid (triglyceride and cholesterol ester) that is surrounded by a polar coat containing nonesterified cholesterol, phospholipid, and proteins (called apolipoproteins) (Fig. 29–1). The major categories of lipoproteins consist of low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), high-density lipoprotein (HDL), and chylomicrons. These lipoproteins vary in size and density (Fig. 29–2). Because lipoproteins can be separated by electrophoresis, they also have been named according to their migration relative to serum proteins. LDL is called beta lipoprotein, VLDL is pre-beta lipoprotein, and HDL is alpha lipoprotein.
Lipoprotein structure. Because cholesterol and triglycerides are hydrophobic lipids that are insoluble in plasma, intravascular transport cannot occur with these lipids in their free state. Consequently, cholesterol esters and triglycerides are packaged into spherical lipoprotein particles that span a wide range of particle size ...