TRANSLATION OF HDL FUNCTIONALITY INTO CLINICAL PRACTICE


Robert S. Rosenson, M.D., School of Medicine at Mount Sinai, New York, NY, USA

HDL is conventionally quantified by the cholesterol cargo transported in these protein rich lipoprotein particles. In prospective population studies and clinical trials with low to moderate intensity statins, HDL cholesterol (HDL-C) is biomarker of atherosclerotic cardiovascular disease (ASCVD) risk. However, the reduced CVD risk associated with high HDL-C levels is attenuated in models that adjust for associated excess apolipoprotein (apo) B-containing lipoproteins or in trials that use high-potency statins, which are more effective in lowering apoB levels than low to moderate intensity statins. In these analyses, NMR-measured HDL particles retain their inverse association with ASCVD risk. Thus, the concentration of HDL particles is a more robust measure of ASCVD risk than the cholesterol content transported by HDL particles. HDL particles are heterogeneous in their protein (proteome) and lipid (lipidome) constituents. Small HDL particles contain proteins that contribute to the HDL functions in protecting LDL against oxidation, suppression of proinflamamtory pathways, endothelial protection and repair, reduced apoptosis and reduced prothrombotic state. When the HDL particles increase in size due to increased cholesterol content, the proteome is altered resulting in atheroprotective particles. Therapeutic interventions directed at increasing HDL have been directed to increasing the cholesterol carried in HDL particles rather than expanding the number of HDL particles and the functionality of those particles. Future investigations into HDL therapies need to be directed towards increasing the numbers of atheroprotective HDL particles or preventing the formation of dysfunctional HDL particles. Currently, delipidation of HDL particles or infusions of apo A-I/phospholipid complexes hold the most promise to reducing HDL associated residual risk.