Reconstituted High-Density Lipoprotein Therapies
A Cause for Optimism
Despite epidemiological studies showing that increased levels of high-density lipoprotein cholesterol (HDL-C) are associated with a reduced risk of future coronary heart disease, neither monogenic diseases characterized by extreme HDL-C levels nor genetic variants associated with higher HDL-C levels are associated with coronary heart disease risk reduction.1,2 Most importantly, increasing HDL-C levels as a therapeutic approach to reduce cardiovascular risk has been called into question by the recent failure of several randomized trials in which therapies aimed at increasing HDL-C levels, such as niacin and cholesteryl ester transferase protein inhibitors, have failed to improve cardiovascular outcomes.3–5
See accompanying article on page 2106
However, it remains clear that HDL has multiple potential antiatherogenic functions,6 including its well-described role in reverse cholesterol transport (RCT)7 (Figure [A]). Thus, a novel approach toward coronary heart disease prevention and HDL-targeting therapies focuses on enhancing HDL function rather than HDL-C levels. That cholesterol efflux capacity of HDL isolated from human subjects is inversely correlated with coronary heart disease status8 reinforces the concept that atheroprotection is associated with HDL function rather than HDL-C levels. In this issue of Arteriosclerosis Thrombosis and Vascular Biology, Gille et al9 present evidence that in healthy volunteers, infusion of CSL112, a reconstituted HDL (rHDL) containing apolipoprotein AI (apoAI) and phospholipids improves biomarkers of RCT and cholesterol efflux when measured ex vivo.