High-Density Lipoproteins: Biology, Epidemiology, and Clinical Management

High-density lipoproteins (HDLs) have multiple pleiotropic effects against arteriosclerosis. Most are independent of the cholesterol mass within HDL particles. Yet, HDL cholesterol (HDL-C) remains a biomarker to assess cardiovascular risk. Whereas the epidemiological association between HDL-C and cardiovascular risk is strong, graded and coherent across populations, Mendelian randomization studies cast doubt on whether HDL-C is causally related to atherosclerotic cardiovascular disease. The apparent failure of HDL-C-raising therapies (fibrates, niacin, and cholesteryl ester transfer protein inhibitors) raises questions about the HDL-C hypothesis. HDL particles are heterogeneous in lipid and protein composition, and thus in size and function. Multiple factors related to oxidation and inflammation might render HDL particles malfunctional or proatherogenic. HDL functionality might be a preferred biomarker and therapeutic target. However, most of the beneficial events of HDL particles occur in the subendothelial layer of arteries and not in plasma. In this report, we review the complexity and controversies surrounding HDL and atherosclerotic cardiovascular disease. Importantly, intimal HDL biogenesis, function, and egress from the arterial wall might hold the key to unlocking the therapeutic potential of HDL.