Association between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study

• Published in: The Lancet (British edition) Vol. 359; no. 9300; pp. 37 - 41
• Main Authors: van Dam, Marjel J, de Groot, Eric, Clee, Susanne M, Hovingh, G Kees, Roelants, Roosje, Brooks-Wilson, Angie, Zwinderman, Aeilko H, Smit, Andries J, Smelt, August HM, Groen, Albert K, Hayden, Michael R, Kastelein, John JP
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 05.01.2002; Lancet; Elsevier Limited
• Subjects: ABCA1 protein; Adult; Age; Aging - metabolism; Apolipoproteins; Arteries; Arteriosclerosis; Arteriosclerosis - etiology; Atherosclerosis; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP-Binding Cassette Transporters - genetics; ATP-binding protein; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular disease; Cardiovascular diseases; Carotid arteries; Carotid Arteries - diagnostic imaging; Carotid Arteries - pathology; Carotid artery; Case-Control Studies; Cholesterol; Cholesterol, HDL - blood; Consent; Efflux; Female; Fibroblasts; Genetics; Health risks; Heterozygotes; High density lipoprotein; Humans; Internal medicine; Laboratories; Lipids; Low density lipoprotein; Male; Medical research; Medical sciences; Medicine; Mutation; Observational studies; Skin; Smoking - adverse effects; Software; Ultrasonic imaging; Ultrasonography; Ultrasound; Wall thickness; Canada; United States > US; Sonography; Human; Wall; Cardiovascular disease; Artery; Blood plasma; Vascular disease; Symptomatology; Gene; Cholesterol HDL; Atherosclerosis; Echography; Risk factor; Mutation; Fibroblast; Quantitative analysis
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(02)07277-X

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. 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. 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. 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.