Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks
Open accessAbstract
Objective—: Diminished cholesterol efflux activity of apolipoprotein B (apoB)–depleted serum is associated with prevalent coronary artery disease, but its prognostic value for incident cardiovascular events is unclear. We investigated the relationship of cholesterol efflux activity with both prevalent coronary artery disease and incident development of major adverse cardiovascular events (death, myocardial infarction, or stroke). Approach and Results—: Cholesterol efflux activity from free cholesterol–enriched macrophages was measured in 2 case–control cohorts: (1) an angiographic cohort (n=1150) comprising stable subjects undergoing elective diagnostic coronary angiography and (2) an outpatient cohort (n=577). Analysis of media from cholesterol efflux assays revealed that the high-density lipoprotein fraction (1.063< d <1.21) contained only a minority (≈40%) of [ 14 C]cholesterol released, with the majority found within the lipoprotein particle–depleted fraction, where ≈60% was recovered after apolipoprotein A1 immunoprecipitation. Albumin immunoprecipitation recovered another ≈30% of radiolabeled cholesterol within this fraction. Enhanced cholesterol efflux activity from ATP-binding cassette transporter A1–stimulated macrophages was associated with reduced risk of prevalent coronary artery disease in unadjusted models within both cohorts; however, the inverse risk relationship remained significant after adjustment for traditional coronary artery disease risk factors only within the outpatient cohort. Surprisingly, higher cholesterol efflux activity was associated with increase in prospective (3 years) risk of myocardial infarction/stroke (adjusted hazard ratio, 2.19; 95% confidence interval, 1.02–4.74) and major adverse cardiovascular events (adjusted hazard ratio, 1.85; 95% confidence interval, 1.11–3.06). Conclusions—: Heightened cholesterol efflux to apoB-depleted serum was paradoxically associated with increased prospective risk for myocardial infarction, stroke, and death. The majority of released radiolabeled cholesterol from macrophages in cholesterol efflux activity assays does not reside within a high-density lipoprotein particle.
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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 [94]
In another study, cellular efflux was inversely correlated with prevalent atherosclerosis, but not with the long-term risk of cardiovascular events.
“In another study, cellular efflux was inversely correlated with prevalent atherosclerosis, but not with the long-term risk of cardiovascular events [78].”
From HDL cholesterol: reappraisal of its clinical relevance (2017) · cites this paper as [78]
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Markwell, M. A. K., Haas, S. M., BIEBER, L. L., & Tolbert, N. E. (1978) · Analytical Biochemistry · doi:10.1016/0003-2697(78)90586-9 · Cited by 6,460 · see citing works
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Self-citationNiacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
The AIM-HIGH Investigators (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1107579 · Cited by 2,911 · see citing works
Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis
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., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1001689 · Cited by 1,943 · see citing works
Role of cholesterol and lipid organization in disease
Maxfield, F. R., & Tabas, I. A. (2005) · Nature · doi:10.1038/nature04399 · Cited by 1,297 · see citing works
Effect of Torcetrapib on the Progression of Coronary Atherosclerosis
Nissen, S. E., Tardif, J., Nicholls, S. J., Revkin, J. H., Shear, C. L., Duggan, W. T., Rużyłło, W., Bachinsky, W., Lasala, G. P., & Tuzcu, E. M. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa070635 · Cited by 964 · see citing works
Cholesterol Efflux and Atheroprotection: Advancing the Concept of Reverse Cholesterol Transport
Rosenson, R. S., Brewer, H. B., Davidson, W. S., Fayad, Z. A., Fuster, V., Goldstein, J., Hellerstein, M., Jiang, X.-C., Phillips, M. C., Rader, D. J., et al. (2012) · Circulation · doi:10.1161/circulationaha.111.066589 · Cited by 953 · see citing works
Protein carbamylation links inflammation, smoking, uremia and atherogenesis
Wang, Z., Nicholls, S. J., Rodríguez, E. R., Kummu, O., Hörkkö, S., Barnard, J., Reynolds, W. F., Topol, E. J., DiDonato, J. A., & Hazen, S. L. (2007) · Nature Medicine · doi:10.1038/nm1637 · Cited by 706 · see citing works
Self-citationHDL and cardiovascular disease: atherogenic and atheroprotective mechanisms
Navab, M., Reddy, S. T., Lenten, B. J. V., & Fogelman, A. M. (2011) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2010.222 · Cited by 656 · see citing works
HDL, ABC transporters, and cholesterol efflux: implications for the treatment of atherosclerosis
Tall, A. R., Yvan-Charvet, L., Terasaka, N., Pagler, T., & Wang, N. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.03.001 · Cited by 540 · see citing works
Effect of ACAT Inhibition on the Progression of Coronary Atherosclerosis
Nissen, S. E., Tuzcu, E. M., Brewer, H. B., Sipahi, İ., Nicholls, S. J., Ganz, P., Schoenhagen, P., Waters, D. D., Pepine, C. J., Crowe, T., et al. (2006) · New England Journal of Medicine · doi:10.1056/nejmoa054699 · Cited by 398 · see citing works
de la Llera-Moya, M., Drazul‐Schrader, D., Asztalos, B. F., Cuchel, M., Rader, D. J., & Rothblat, G. H. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.199158 · Cited by 385 · see citing works
Asztalos, B. F., Cupples, L. A., Demissie, S., Horvath, K. V., Cox, C. E., Batista, M. C., & Schaefer, E. J. (2004) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.0000146325.93749.a8 · Cited by 298 · see citing works
The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis?
Rader, D., & Tall, A. (2012) · Nature Medicine · doi:10.1038/nm.2937 · Cited by 293 · see citing works
Tang, W. H. W., Wang, Z., Cho, L., Brennan, D. M., & Hazen, S. L. (2009) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2009.02.036 · Cited by 221 · see citing works
Self-citationDifferential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux
Asztalos, B. F., de la Llera-Moya, M., Dallal, G. E., Horvath, K. V., Schaefer, E. J., & Rothblat, G. H. (2005) · Journal of Lipid Research · doi:10.1194/jlr.m500187-jlr200 · Cited by 221 · see citing works
The role of cholesterol efflux in regulating the fertilization potential of mammalian spermatozoa
Travis, A. J., & Kopf, G. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16392 · Cited by 211 · see citing works
Zheng, L., Settle, M., Brubaker, G., Schmitt, D., Hazen, S. L., Smith, J. D., & Kinter, M. T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407019200 · Cited by 206 · see citing works
Self-citationThe role of cholesterol efflux in regulating the fertilization potential of mammalian spermatozoa
Travis, A. J., & Kopf, G. S. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216392 · Cited by 206 · see citing works
Tang, W. H. W., Hartiala, J., Fan, Y., Wu, Y., Stewart, A. F. R., Erdmann, J., Kathiresan, S., Roberts, R., McPherson, R., Allayee, H., et al. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.253930 · Cited by 174 · see citing works
Self-citationPlasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., Hindy, G., Hólm, H., Ding, E. L., Johnson, T., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60312-2 · Cited by 148 · see citing works
Targeted Metabolomic Evaluation of Arginine Methylation and Cardiovascular Risks
Wang, Z., Tang, W. H. W., Cho, L., Brennan, D. M., & Hazen, S. L. (2009) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.185645 · Cited by 124 · see citing works
Self-citationFavari, E., Lee, M., Calabresi, L., Franceschini, G., Zimetti, F., Bernini, F., & Kovanen, P. T. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312476200 · Cited by 122 · see citing works
Minimal Lipidation of Pre-β HDL by ABCA1 Results in Reduced Ability to Interact with ABCA1
Mulya, A., Lee, J., Gebre, A. K., Thomas, M. J., Colvin, P. L., & Parks, J. S. (2007) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.142455 · Cited by 113 · see citing works
Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose or in KBr
Ståhlman, M., Davidsson, P., Kanmert, I., Rosengren, B. E., Borén, J., Fagerberg, B., & Camejo, G. (2007) · Journal of Lipid Research · doi:10.1194/jlr.d700025-jlr200 · Cited by 98 · see citing works
Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy
Nicholls, S. J., Tang, W. H. W., Scoffone, H. M., Brennan, D. M., Hartiala, J., Allayee, H., & Hazen, S. L. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m008961 · Cited by 88 · see citing works
Self-citationRelation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease
Guey, L. T., Pullinger, C. R., Ishida, B. Y., O'Connor, P. M., Zellner, C., Francone, O. L., Laramie, J. M., Naya-Vigne, J. M., Siradze, K. A., Deedwania, P., et al. (2011) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2011.03.054 · Cited by 70 · see citing works
Prebeta-1 HDL and coronary heart disease
Kane, J. P., & Malloy, M. J. (2012) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e328353eef1 · Cited by 61 · see citing works
de Vries, R., Groen, A. K., Perton, F. G., Dallinga‐Thie, G. M., van Wijland, M. J. A., Dikkeschei, L. D., Wolffenbuttel, B. H. R., van Tol, A., & Dullaart, R. P. F. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.12.027 · Cited by 57 · see citing works
Red Blood Cells Play a Role in Reverse Cholesterol Transport
Hung, K. T., Berisha, S. Z., Ritchey, B., et al. (2012) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.248971 · Cited by 54 · see citing works
Ha, J., Ha, C., Chao, J.-T., Petersen, C. E., Theriault, A., & Bhagavan, N. V. (2003) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/s0167-4889(03)00027-2 · Cited by 43 · see citing works
The Receptor Model for Transport of Cholesterol in Plasmaa
Brown, M. S., & Goldstein, J. L. (1985) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1985.tb11856.x · Cited by 34 · see citing works
Nestel, P. J., Hoang, A., Sviridov, D., & Straznicky, N. E. (2011) · International Journal of Obesity · doi:10.1038/ijo.2011.170 · Cited by 29 · see citing works
Deckelbaum, R. J., Olivecrona, T., & FAINARU, M. (1980) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39792-3 · Cited by 26 · see citing works
Chirinos, J. A., Zambrano, J. P., Chakko, S. C., et al. (2005) · Circulation · doi:10.1161/circulationaha.104.521815 · Cited by 22 · see citing works
de Vries, R., Perton, F. G., van Tol, A., & Dullaart, R. P. F. (2011) · Clinica Chimica Acta · doi:10.1016/j.cca.2011.11.001 · Cited by 18 · see citing works
Cholesterol Efflux Capacity and Atherosclerosis
de Vries, R., Groen, A. K., & Dullaart, R. P. F. (2011) · New England Journal of Medicine · doi:10.1056/nejmc1101853 · Cited by 17 · see citing works
Brennan, M., Reddy, A., Tang, W. H. W., Wu, Y., Brennan, D. M., Hsu, A., Mann, S. A., Hammer, P. L., & Hazen, S. L. (2010) · Circulation · doi:10.1161/circulationaha.109.881581 · Cited by 16 · see citing works
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2016 ESC/EAS Guidelines for the Management of Dyslipidaemias
Catapano, A. L., Graham, I., De Backer, G., Wiklund, O., Chapman, M. J., Drexel, H., Hoes, A. W., Jennings, C. S., Landmesser, U., Pedersen, T. R., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw272 · Cited by 3,162 · see citing works
Borén, J., Chapman, M. J., Krauss, R. M., Packard, C. J., Bentzon, J. F., Binder, C. J., Daemen, M. J., Demer, L. L., Hegele, R. A., Nicholls, S. J., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz962 · Cited by 1,601 · see citing works
2016 ESC/EAS Guidelines for the Management of Dyslipidaemias
Catapano, A. L., Graham, I., De Backer, G., Wiklund, O., Chapman, M. J., Drexel, H., Hoes, A. W., Jennings, C. S., Landmesser, U., Pedersen, T. R., et al. (2016) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2016.08.018 · Cited by 1,582 · see citing works
HDL cholesterol efflux capacity and incident cardiovascular events
Rohatgi, A., Khera, A., Berry, J. D., Givens, E. G., Ayers, C. R., Wedin, K. E., Neeland, I. J., Yuhanna, I. S., Rader, D. R., de Lemos, J. A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1409065 · Cited by 1,390 · see citing works
HDL and cardiovascular disease
Rader, D. J., & Hovingh, G. K. (2014) · The Lancet · doi:10.1016/s0140-6736(14)61217-4 · Cited by 870 · see citing works
Dysfunctional HDL and atherosclerotic cardiovascular disease
Rosenson, R. S., Brewer, H. B., Ansell, B. J., Barter, P., Chapman, M. J., Heinecke, J. W., Kontush, A., Tall, A. R., & Webb, N. R. (2016) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2015.124 · Cited by 822 · see citing works
HDL cholesterol: reappraisal of its clinical relevance
März, W., Kleber, M. E., Scharnagl, H., Speer, T., Zewinger, S., Ritsch, A., Parhofer, K. G., von Eckardstein, A., Landmesser, U., & Laufs, U. (2017) · Clinical Research in Cardiology · doi:10.1007/s00392-017-1106-1 · Cited by 275 · see citing works
From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk
Shapiro, M. D., & Fazio, S. (2016) · Circulation Research · doi:10.1161/circresaha.115.306471 · Cited by 217 · see citing works
Nonfasting versus fasting lipid profile for cardiovascular risk prediction
Langsted, A., & Nordestgaard, B. G. (2019) · Pathology · doi:10.1016/j.pathol.2018.09.062 · Cited by 191 · see citing works
High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality
Silbernagel, G., Schottker, B., Appelbaum, S., Scharnagl, H., Kleber, M. E., Grammer, T. B., Ritsch, A., Mons, U., Holleczek, B., Goliasch, G., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht343 · Cited by 123 · see citing works
Determinants of cholesterol efflux capacity in humans
Talbot, C. P. J., Plat, J., Ritsch, A., & Mensink, R. P. (2018) · Progress in Lipid Research · doi:10.1016/j.plipres.2017.12.001 · Cited by 99 · see citing works
Annema, W., & von Eckardstein, A. (2016) · Translational Research · doi:10.1016/j.trsl.2016.02.008 · Cited by 94 · see citing works
Update on the laboratory investigation of dyslipidemias
Ramasamy, I. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.01.015 · Cited by 50 · see citing works
von Eckardstein, A., & Rohrer, L. (2016) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000294 · Cited by 33 · see citing works
Ljunggren, S. A., Levels, J. H. M., Hovingh, K., Holleboom, A. G., Vergeer, M., Argyri, L., Gkolfinopoulou, C., Chroni, A., Sierts, J. A., Kastelein, J. J., et al. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2015.09.006 · Cited by 19 · see citing works
- Authors
- Li, X.-M., Tang, W. H. W., Mosior, M. K., Huang, Y., Wu, Y., Matter, W., Gao, V., Schmitt, D., DiDonato, J. A., Fisher, E. A., Smith, J. D., & Hazen, S. L.
- Affiliations
- Cleveland State University (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2013-07
- Volume
- 33
- Issue
- 7
- Pages
- 1696-1705
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC3743250
- OpenAlex
- W2155110384
- Cited by
- 301
- References
- 38
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 5 · 2023: 8 · 2022: 13 · 2021: 24 · 2020: 20 · 2019: 23 · 2018: 31 · 2017: 26 · 2016: 30 · 2015: 45 · 2014: 38 · 2013: 23
- FWCI
- 44.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R01HL103931, P20HL113452, P01HL076491, P01HL098055, R01HL103866)
- National Center for Advancing Translational Sciences
- 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, apolipoprotein A-I, ABCA1, macrophages, coronary artery disease, major adverse cardiovascular events, myocardial infarction, stroke, high-density lipoprotein, apolipoprotein B, free cholesterol, cardiovascular risk prediction
- MeSH terms
- Serum Albumin, Human, Aged, Animals, Apolipoproteins B, Cardiovascular Diseases, Cell Line, Cholesterol, Coronary Artery Disease, Female, Humans, Cholesterol, HDL, Macrophages, Male, Middle Aged, Myocardial Infarction, Ohio, Predictive Value of Tests, Prognosis, Risk Factors, Serum Albumin, Time Factors, Biomarkers, Incidence, Multivariate Analysis, Logistic Models, Proportional Hazards Models, Case-Control Studies, Apolipoprotein A-I, Coronary Angiography, ATP-Binding Cassette Transporters, Risk Assessment, Stroke, Immunoprecipitation, Mice, ATP Binding Cassette Transporter 1
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