Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis

Khera, Amit V.; Cuchel, Marina; de la Llera-Moya, Margarita; Rodrigues, Amrith; Burke, Megan F.; Jafri, Kashif; French, Benjamin C.; Phillips, Julie A.; Mucksavage, Megan L.; Wilensky, Robert L.; Mohler, Emile R.; Rothblat, George H.; Rader, Daniel J.

doi:10.1056/nejmoa1001689

Cited by 1,943Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthParaoxonase enzyme and polymorphisms

Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis

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Khera, Amit V., Cuchel, Marina, de la Llera-Moya, Margarita, Rodrigues, Amrith, Burke, Megan F., Jafri, Kashif, French, Benjamin C., Phillips, Julie A. +5 more·2011·New England Journal of Medicine

DOI 10.1056/nejmoa1001689PMC PMC3030449

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Abstract

BACKGROUND: High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden. METHODS: We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima-media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B-depleted serum from the study participants. RESULTS: The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima-media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P=0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P=0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins. CONCLUSIONS: Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.).

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Recent studies suggest HDL has a complex role in atherogenesis and dysfunctional HDL may be more relevant to atherosclerosis than the HDL-C level.
“Recent studies suggest that HDL has a complex role in atherogenesis and that the presence of dysfunctional HDL may be more relevant to the development of atherosclerosis than the HDL-C level. 93-95”
From 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias (2016) · cites this paper as [93]
The function and cholesterol efflux capacity of HDL are the crucial factors associated with its atheroprotective effects, as simply increasing serum HDL levels does not necessarily reduce cardiovascular event risk.
“The function and cholesterol efflux capacity of HDL are the crucial factors associated with its atheroprotective effects52, as indicated in a meta-analysis that showed that simply increasing serum HDL levels does not necessarily reduce the risk of cardiovascular events53.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [52]
The rate of cholesterol efflux has been associated with the prevalence of CHD, independent of the HDL-C concentration.
“The rate of cholesterol efflux has been associated with the prevalence of CHD, independent of the HDL-C concentration [24], with cardiovascular events and deaths (Fig. 4) [25, 26].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [24]
HDL function may be more predictive of CVD risk compared with its cholesterol content (HDL-C levels).
“Indeed recent studies suggest that HDL function may be more predictive of CVD risk compared with its cholesterol content35, as reflected by HDL-C levels.”
From Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor?: New Insights From the Framingham Offspring Study (2016) · cites this paper as [35]

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Authors: Khera, A. V., Cuchel, M., de la Llera-Moya, M., Rodrigues, A., Burke, M. F., Jafri, K., French, B. C., Phillips, J. A., Mucksavage, M. L., Wilensky, R. L., Mohler, E. R., Rothblat, G. H., & Rader, D. J.
Affiliations: University of Pennsylvania (US)
Rutgers, The State University of New Jersey (US)
Children's Hospital of Philadelphia (US)
ORCID: Khera, Amit V.
Cuchel, Marina
Burke, Megan F.
Jafri, Kashif
French, Benjamin C.
Phillips, Julie A.
Rader, Daniel J.
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2011-01-13
Volume: 364
Issue: 2
Pages: 127-135
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1001689
PMC: PMC3030449
OpenAlex: W2055823448
Cited by: 1,943
References: 39
Citations by year: 2026: 51 · 2025: 81 · 2024: 87 · 2023: 76 · 2022: 95 · 2021: 113 · 2020: 130 · 2019: 121 · 2018: 153 · 2017: 153 · 2016: 145 · 2015: 177 · 2014: 160 · 2013: 180 · 2012: 120
FWCI: 183.19
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Howard Hughes Medical Institute
National Heart, Lung, and Blood Institute (P50-HL70128, K23HL077146, HL22633, P01HL022633, P50HL070128)
National Center for Research Resources (M01-RR-00040, M01RR000040, UL1RR024134)
Topics: Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
Keywords: cholesterol efflux capacity, HDL function, HDL cholesterol, apolipoprotein A-I, macrophages, reverse cholesterol transport, atherosclerosis, carotid intima-media thickness, coronary artery disease, metabolic syndrome, pioglitazone, statins, hypercholesterolemia
MeSH terms: Pioglitazone, Aged, Biological Transport, Carotid Arteries, Cholesterol, Coronary Artery Disease, Foam Cells, Humans, Hypoglycemic Agents, Lipoproteins, HDL, Middle Aged, Radiography, Smoking, Logistic Models, Case-Control Studies, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Thiazolidinediones

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Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis

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