title: Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks.
abstract: 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).
  
  
  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.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xin-Min
authors.initials: XM
authors.lastname: Li
authors.forename: Wai Hong Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Marian K
authors.initials: MK
authors.lastname: Mosior
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: William
authors.initials: W
authors.lastname: Matter
authors.forename: Vivian
authors.initials: V
authors.lastname: Gao
authors.forename: David
authors.initials: D
authors.lastname: Schmitt
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Didonato
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000368:Aged; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology* / Q000401:mortality; D016022:Case-Control Studies; D002460:Cell Line; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000097:blood / Q000453:epidemiology; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D015994:Incidence; D016015:Logistic Models; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood / Q000453:epidemiology; D009820:Ohio / Q000453:epidemiology; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D012709:Serum Albumin / Q000378:metabolism; D000075462:Serum Albumin, Human; D020521:Stroke / Q000097:blood / Q000453:epidemiology; D013997:Time Factors
chemical_list: C422455:ALB protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D015415:Biomarkers; D008076:Cholesterol, HDL; D012709:Serum Albumin; D002784:Cholesterol; D000075462:Serum Albumin, Human
keywords: cholesterol efflux; high-density lipoprotein-cholesterol; macrophage; prognosis