HDL AND THE ATHEROSCLEROSIS - MYTH OR REALITY


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

Low HDL cholesterol (HDL-C) is an established biomarker for the future development of atherosclerosis and atherosclerotic cardiovascular disease (CVD) events in population-based observational studies and clinical trials of cholesterol-lowering therapies and this includes coronary heart disease (CHD) patients with low levels of LDL cholesterol (LDL-C) on statin therapy. Because multiple clinical trials designed to increase HDL-C and reduce CVD risk have not demonstrated efficacy and instead have shown potential harm, there has been widespread confusion regarding the importance of HDL as a biomarker of risk and as a potential target for therapeutic intervention. Confusion concerning the importance of HDL in atheroprotection has been magnified by a Mendelian randomization study that utilized HDL-C as an intermediary biomarker of CVD risk. In contrast to studies that utilized HDL-C as a surrogate measure of HDL, a genome wide association study (GWAS) that evaluated the associations between phospholipid transpfer protein polymorphisms and CVD risk reported that high concentrations of small HDL particles and total HDL particles were associated with lower CVD risk. Based on the limitations of HDL-C as a biomarker of risk, and misguided attempts to reduce atherosclerosis through effectuating changes in the cholesterol content of HDL particles, future trials that investigate HDL-modifying therapies should assess HDL particle number, and structure function relationships of the HDL proteome and lipidome that are associated with atheroprotective functional measures.