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.
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.
Authors: Bela F Asztalos; L Adrienne Cupples; Serkalem Demissie; Katalin V Horvath; Caitlin E Cox; Marcelo C Batista; Ernst J Schaefer Journal: Arterioscler Thromb Vasc Biol Date: 2004-09-23 Impact factor: 8.311
Authors: R de Vries; A K Groen; F G Perton; G M Dallinga-Thie; M J A van Wijland; L D Dikkeschei; B H R Wolffenbuttel; A van Tol; R P F Dullaart Journal: Atherosclerosis Date: 2007-02-01 Impact factor: 5.162
Authors: Steven E Nissen; Jean-Claude Tardif; Stephen J Nicholls; James H Revkin; Charles L Shear; William T Duggan; Witold Ruzyllo; William B Bachinsky; Gabriel P Lasala; Gregory P Lasala; E Murat Tuzcu Journal: N Engl J Med Date: 2007-03-26 Impact factor: 91.245
Authors: Lemin Zheng; Megan Settle; Gregory Brubaker; Dave Schmitt; Stanley L Hazen; Jonathan D Smith; Michael Kinter Journal: J Biol Chem Date: 2004-10-21 Impact factor: 5.157
Authors: Julio A Chirinos; Juan P Zambrano; Simon Chakko; Alan Schob; Ronald B Goldberg; Guido Perez; Armando J Mendez Journal: Circulation Date: 2005-10-18 Impact factor: 29.690
Authors: Zeneng Wang; Stephen J Nicholls; E Rene Rodriguez; Outi Kummu; Sohvi Hörkkö; John Barnard; Wanda F Reynolds; Eric J Topol; Joseph A DiDonato; Stanley L Hazen Journal: Nat Med Date: 2007-09-09 Impact factor: 53.440
Authors: Marcus Ståhlman; Pia Davidsson; Ida Kanmert; Birgitta Rosengren; Jan Borén; Björn Fagerberg; Germán Camejo Journal: J Lipid Res Date: 2007-11-18 Impact factor: 5.922
Authors: Anny Mulya; Ji-Young Lee; Abraham K Gebre; Michael J Thomas; Perry L Colvin; John S Parks Journal: Arterioscler Thromb Vasc Biol Date: 2007-05-17 Impact factor: 8.311
Authors: Steven E Nissen; E Murat Tuzcu; H Bryan Brewer; Ilke Sipahi; Stephen J Nicholls; Peter Ganz; Paul Schoenhagen; David D Waters; Carl J Pepine; Tim D Crowe; Michael H Davidson; John E Deanfield; Lisa M Wisniewski; James J Hanyok; Laurent M Kassalow Journal: N Engl J Med Date: 2006-03-23 Impact factor: 91.245
Authors: Mark S Borja; Kit F Ng; Angela Irwin; Jaekyoung Hong; Xing Wu; Daniel Isquith; Xue-Qiao Zhao; Bryan Prazen; Virginia Gildengorin; Michael N Oda; Tomáš Vaisar Journal: J Lipid Res Date: 2015-08-07 Impact factor: 5.922
Authors: Wijtske Annema; Arne Dikkers; Jan Freark de Boer; Robin P F Dullaart; Jan-Stephan F Sanders; Stephan J L Bakker; Uwe J F Tietge Journal: J Am Soc Nephrol Date: 2015-08-28 Impact factor: 10.121
Authors: Ginny L Weibel; Denise Drazul-Schrader; Debra K Shivers; Alisha N Wade; George H Rothblat; Muredach P Reilly; Margarita de la Llera-Moya Journal: Arterioscler Thromb Vasc Biol Date: 2013-11-07 Impact factor: 8.311
Authors: W Sean Davidson; Anna Heink; Hannah Sexmith; John T Melchior; Scott M Gordon; Zsuzsanna Kuklenyik; Laura Woollett; John R Barr; Jeffrey I Jones; Christopher A Toth; Amy S Shah Journal: J Lipid Res Date: 2016-02-23 Impact factor: 5.922
Authors: Joseph A DiDonato; Kulwant Aulak; Ying Huang; Matthew Wagner; Gary Gerstenecker; Celalettin Topbas; Valentin Gogonea; Anthony J DiDonato; W H Wilson Tang; Ryan A Mehl; Paul L Fox; Edward F Plow; Jonathan D Smith; Edward A Fisher; Stanley L Hazen Journal: J Biol Chem Date: 2014-02-20 Impact factor: 5.157