20 March 2011
Cholesterol efflux capacity – A metric of HDL function and a strong inverse predictor of risk of atherosclerosis and coronary events
n this study carried out in two independent populations, Khera et al. provide evidence that cholesterol efflux capacity – reflecting the ability of HDL to extract cholesterol from macrophage foam cells – is a strong inverse predictor of both carotid intima-media thickness and future coronary events. Another important finding was that the association between cholesterol efflux capacity and risk of coronary disease remained significant after adjustment for HDL cholesterol levels.
Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ
Comments & References
• To investigate the relationships of cholesterol efflux capacity with subclinical atherosclerosis and obstructive coronary artery disease.
• To test whether the ability of HDL to promote cholesterol efflux from macrophages (cholesterol efflux capacity) reduces the atherosclerotic burden independently of HDL-C levels.
The study was conducted in 2 distinct populations:
- 203 healthy white subjects in whom carotid intima-media thickness was measured (population 1);
- 793 white patients undergoing cardiac catheterization; patients with stenosis > 50% of a major coronary vessel were classified as cases (n=442); others were classified as controls (n=351) (population 2).
In both populations, the efflux of radioactive cholesterol from macrophages was measured ex vivo in blood samples using a technique that quantifies efflux mediated by ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1), scavenger receptor B1, and aqueous diffusion, i.e. pathways of known relevance in cholesterol efflux from macrophages (see box).
Statistical analyses were used to characterize the relationships between efflux capacity and:
- intima-media thickness (population 1): linear regression with age, sex, systolic blood pressure, HbA1c, LDL-C, HDL-C, and Apo A-I as covariates;
coronary artery disease status (population 2): logistic regression with adjustment for age, sex, smoking, diabetes, hypertension; LDL-C, HDL-C, and Apo A-I were added in subsequent models.
- Less than 40% of variation in efflux capacity accounted for by HDL-C and Apo A-I levels;
- No significant relationship between HDL-C levels and carotid intima-media thickness;
- Inverse relationship between efflux capacity and carotid intima-media thickness, even after adjustment for HDL-C level (P=0.003) and Apo A-I level (P=0.005);
- 30% decrease in coronary risk per one standard deviation increase in efflux capacity (adjusted odds ratio, 0.70; 95% confidence interval, 0.59-0.83; P<0.001); 25% decrease after adjustment for HDL-C level (OR, 0.75; 95% CI, 0.63-0.90; P=0.002); 24% decrease after adjustment for Apo A-I level (OR, 0.74; 95% CI, 0.61-0.89; P=0.002);
- 62% decrease in coronary risk between lower and upper quartile of efflux capacity (OR, 0.38; 95% CI, 0.25-0.58; P<0.001);
Landmark epidemiological studies have clearly shown an inverse association between HDL-C levels and the risk of coronary disease, even in patients treated with statins. These studies prompted the development of pharmacological strategies designed to raise low HDL-C levels with the aim of reducing the macrovascular residual risk persisting among patients treated according to current standards of care.
The mechanisms by which HDL may protect against atherosclerostic disease are not fully elucidated. The main hypothesis is that a large part of this effect is due to the ability of the lipoprotein to promote cholesterol efflux from macrophage foam cells within atheromatous vessels wall and to transport directly or indirectly this removed cholesterol to the liver where it is catabolised. The whole process has been labeled “reverse cholesterol transport” or RCT(see box).
However, because HDL particles are heterogeneous in size, lipoprotein composition, cholesterol or triglycerides or apoA-I content, as well as in antiatherogenic functionality, measuring plasma levels of HDL-C is a rather weak surrogate to capture HDL number, turnover and/or function.
Despite the limitations inherent to its cross-sectional design, the study by Khera et al. supports the validity of 2 concepts. First, the cholesterol efflux capacity of HDL is a strong inverse predictor of both early and advanced stages of atherosclerotic disease. Indeed, efflux capacity was strongly and inversely related to subclinical atherosclerosis assessed by measurement of intima-media thickness and to more advanced, clinical coronary artery disease. Second, the association with coronary artery disease remained significant after adjustment for HDL-C levels. Only a small part of the relationship was explained by variation in HDL-C levels.
From a residual risk reduction perspective, these data are in favor of the development of new HDL-directed therapies targeting HDL metabolism and turnover, in order to enhance reverse cholesterol transport.
Cholesterol efflux and reverse cholesterol transport
Cholesterol efflux is the first step of reverse cholesterol transport, the process which extracts and eliminates excess cholesterol from blood vessels. The process starts when excess cholesterol from peripheral cells is transferred to nascent, lipid-poor, small-sized HDL produced by the liver. The initial transfer of a small amount of cholesterol depends on the interaction between Apo A-I, the main apolipoprotein of HDL, and the ATP-binding cassette transporter A1 (ABCA1) transporter on cell surfaces. The larger, more lipid-rich HDL then formed can retrieve and incorporate additional cholesterol from the peripheral cells via ABCA1 and another transporter, ATP-binding cassette transporter G1 (ABCG1).
Inside the HDL particle, unesterified cholesterol is then converted in cholesterylesters by the lecithin:cholesterol acyltransferase (LCAT) enzyme.
Cholesteryl esters thus created may have two fates. One fraction is directly transported by HDL to the liver into which HDL cholesterol enters through the SR-B1 receptor. In the liver, cholesterylesters are transformed into bile salts or directly eliminated through the bile, while Apo A-I returns to the circulation where it contributes to the formation of new HDL particles. Another fraction of transported cholesterol is transferred from HDL to LDL by the cholesterylester transfer protein (CETP) enzyme. Cholesterol from LDL eventually returns to the liver, in which it penetrates after binding of LDL to the LDL receptor.