title: Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.
abstract: BACKGROUND
  Decreased concentrations of HDL cholesterol are associated with increased cardiovascular risk. These concentrations are directly related to cholesterol efflux from cells-the first step and a key process in reverse cholesterol transport. Cholesterol efflux is mediated by the ATP-binding cassette A1 transporter (ABCA1), the rate-limiting step in the production of HDL. We aimed to assess the relation between cholesterol efflux, HDL concentrations, and arterial-wall changes in individuals with impaired ABCA1 function.
  
  
  METHODS
  We investigated 30 individuals from families with ABCA1 mutations, and 110 controls matched for age, sex, and ethnic origin. We measured concentrations of HDL cholesterol in plasma and intima-media thickness of the carotid arteries by B-mode ultrasonography in all participants. We also measured cholesterol efflux from skin fibroblasts in nine individuals with ABCA1 mutations and in ten controls.
  
  
  RESULTS
  Individuals with ABCA1 mutations had lower amounts of cholesterol efflux, lower HDL cholesterol concentrations, and greater intima-media thicknesses than controls. An intima-media thickness at the upper limit of normal (0.80 mm) was reached by age 55 years in the ABCA1 heterozygotes, and at age 80 years in unaffected controls (p<0.0001). Additionally, strong positive correlations were seen between HDL cholesterol concentrations and cholesterol efflux (r=0.90, p=0.001), and negative correlations between apolipoprotein-AI-mediated (r=-0.61, p=0.030) and HDL-particle-mediated (r=-0.60, p=0.018) efflux and intima-media thickness in the ABCA1 mutation carriers.
  
  
  CONCLUSIONS
  These results show a direct relation between ABCA1-mediated cellular cholesterol efflux and arterial-wall thickness, and therefore suggest that increasing efflux could inhibit atherosclerosis progression before the manifestation of symptomatic cardiovascular disease.
authors.affiliation: Departments of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Marjel J
authors.initials: MJ
authors.lastname: van Dam
authors.forename: Eric
authors.initials: E
authors.lastname: de Groot
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
authors.forename: Roosje
authors.initials: R
authors.lastname: Roelants
authors.forename: Angie
authors.initials: A
authors.lastname: Brooks-Wilson
authors.forename: Aeilko H
authors.initials: AH
authors.lastname: Zwinderman
authors.forename: Andries J
authors.initials: AJ
authors.lastname: Smit
authors.forename: August H M
authors.initials: AH
authors.lastname: Smelt
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000375:Aging / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology; D002339:Carotid Arteries / Q000000981:diagnostic imaging / Q000473:pathology*; D016022:Case-Control Studies; D008076:Cholesterol, HDL / Q000097:blood*; D005260:Female; D006801:Humans; D008297:Male; D012907:Smoking / Q000009:adverse effects; D014463:Ultrasonography
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL