HDL Particle Size and Functional Heterogeneity.

Classic clinical and epidemiological studies have long ago established the presence of an inverse relationship between high-density lipoprotein cholesterol (HDLC) levels and cardiovascular disease (CVD) risk, and thus, it was assumed that measures that increase HDLC levels would afford protection against atherosclerosis-based CVD. However, trials of drugs, such as cholesterol ester transfer protein inhibitors and niacin, have failed to provide evidence of cardiovascular benefit in patients on statin therapy, indicating that HDLC increases from 30% to 120% are not able to modify risk when low-density lipoprotein is kept very low. Moreover, genetic polymorphisms that associate with increased HDLC do not predict reduced CVD risk, and isolated low HDL does not predict risk when low-density lipoprotein and triglyceride levels are completely normal. Therefore, although a causal role for HDL in arterial homeostasis is still widely accepted, current discussions highlight the necessity to identify novel HDL metrics linked to CVD risk and targetable for diagnostic or therapeutic development.