Cholesterol efflux capacity as a novel biomarker for incident cardiovascular events: has high-density lipoprotein been resuscitated?

A lthough low levels of high-density lipoprotein cholesterol (HDL-C) represent a strong independent risk marker inversely associated with cardiovascular disease (CVD), large interventional trials have failed to translate the increases in HDL-C into reductions in cardiovascular events. As HDL plasma levels represent a pool of the different HDL subfractions, which may vary in their structure and function, its levels may not capture adequately the dynamic process of reverse cholesterol transport. This has led attention to be focused on markers of HDL function, for example, cholesterol efflux capacity, further supported by a recent population-based cohort study that has related it with incident atherosclerotic cardiovascular events, suggesting HDL hypothesis may need to be revisited. HDL particles are responsible for the reverse cholesterol transport, the physiological mechanism by which the cholesterol in peripheral tissues and cells is transferred to the liver for biliary excretion. Reverse cholesterol transport is considered an important atheroprotective mechanism because it facilitates the removal of excess cholesterol from lipid-laden macrophages in the arterial wall and the subsequent reduction in the proinflammatory responses; in its first steps, the reverse cholesterol transport requires HDL particles to act as extracellular acceptors of cholesterol from these cells. The cholesterol efflux capacity (CEC), that is, the ability of HDL particles to accept cholesterol esters from cholesterol-loaded macrophages, represents, therefore, a key process within the mechanism of reverse cholesterol transport. In animal models , cholesterol efflux can modulate the severity of athero-sclerosis, and in humans, CEC has been related to prevalent coronary artery disease independently of HDL-C levels in cross-sectional studies. 3 In a recent article published by Rohatgi et al in the New England Journal of Medicine, CEC was for the first time reported to be inversely associated with incident atherosclerotic cardiovascular events in a multiethnic population-based co-hort. 4 These authors studied over 2900 individuals free from CVD at baseline from the Dallas Heart Study. Participants were 30 to 65 year of age, 43% males, 49% blacks, and had a median low-density lipoprotein cholesterol and HDL-C at baseline of 104 and 47 mg/dL, respectively. Interestingly, in contrast to HDL-C levels, which were associated with multiple traditional cardiovascular risk factors or metabolic variables and other lipids, the CEC was only weakly or not correlated with these parameters; in fact, traditional risk factors, together with exercise activity and alcohol intake, explained only 3% of the variance in CEC (versus 35% of the variance in HDL-C levels). …