HDL cholesterol concentration or HDL function: which matters?

This editorial refers to ‘Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies’†, by C.M. Madsen et al., on page 2478. The HDLs circulating in human plasma are extremely complex, and their relationship with atherosclerotic cardiovascular disease (ASCVD) is complicated. Human HDLs comprise multiple discrete subpopulations of particles that differ in size, shape, charge, and in composition of both lipids and proteins.1 The individual constituents of HDLs enter the plasma separately and are assembled into HDL particles within the plasma. HDLs are subject to continuous remodelling by multiple plasma factors, and the individual constituents are subsequently removed from plasma separately rather than as an uptake of the intact particle. HDLs have several functions that have the potential to protect against atherosclerosis,2 although how the different functions relate to different HDL subpopulations is not known. It is also uncertain whether any of the known HDL functions directly or indirectly protect against development of ASCVD and associated clinical events.