Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study.
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.
van Dam
Marjel J
MJ
Departments of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
de Groot
Eric
E
Clee
Susanne M
SM
Hovingh
G Kees
GK
Roelants
Roosje
R
Brooks-Wilson
Angie
A
Zwinderman
Aeilko H
AH
Smit
Andries J
AJ
Smelt
August H M
AH
Groen
Albert K
AK
Hayden
Michael R
MR
Kastelein
John J P
JJ
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
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL