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

doi:10.1016/S0140-6736(02)07277-X

The Lancet

Volume 359, Issue 9300, 5 January 2002, Pages 37-41

https://doi.org/10.1016/S0140-6736(02)07277-X Get rights and content

Summary

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.

Findings

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.

Interpretation

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.

Introduction

Atherosclerotic cardiovascular disease (CVD) is the worldwide leading cause of death.¹ Disorders of lipoprotein metabolism constitute a frequent cause of premature CVD, with decreased HDL cholesterol concentrations being the most frequent abnormality.2, 3 One theory to explain this relation is that HDL mediates the flux of cholesterol from macrophage-derived foam cells in the arterial wall back to the liver, where it is excreted into the bile—a process called reverse cholesterol transport.⁴ However, evidence that definitely establishes the relation between HDL, reverse cholesterol transport, and early atherogenesis in humans has been unavailable until now.⁵ The elucidation of the molecular basis of tangier disease and familial hypoalphalipoproteinaemia has substantially changed this situation.6, 7, 8, 9, 10 Both diseases are characterised by an increased risk of premature CVD, and the molecular defects for both disorders have proven to be mutations in an atp-binding-cassette transporter, ABCA1.6, 7, 8, 9, 10

ABCA1 stimulates efflux of cholesterol and phospholipid (figure 1), particularly to lipid-poor apolipoprotein ai, the initial step in the formation of nascent HDL particles. This discovery has provided the scientific basis for the establishment of the link between defective cholesterol efflux, decreased HDL, and defined endpoints of coronary-artery disease. We have provided further evidence of this relation in a substantial number of ABCA1-deficient kindreds in whom we could show a reduction of HDL cholesterol and apolipoprotein AI concentrations and a more than three-fold excess of CVD in individuals with ABCA1 mutations compared with unaffected family members.¹¹ Additionally, we discovered that variation in ABCA1 function, as assessed by cholesterol efflux in a cellular assay, correlates with HDL concentrations.¹¹ Furthermore, in transgenic mice, we and others have shown a direct correlation between ABCA1 expression and concentrations of HDL cholesterol.12, 13 However, in the previous study of heterozygotes for ABCA1 deficiency, the number of CVD endpoints was small and might have been further confounded by selection bias, since only patients with established coronary endpoints were studied.

Carotid ultrasound measurements of intima-media thickness are a validated surrogate marker for atherosclerosis.¹⁴ In cross-sectional and prospective studies, this variable has emerged as a predictor of future endpoints for coronary-artery disease,15, 16, 17, 18, 19 and is increasingly used to assess the effects of intervention strategies in cardiovascular disease.²⁰ To explore the relation between cholesterol efflux, HDL cholesterol, and early atherogenesis, we measured apolipoprotein-AI-mediated and HDL-particle-mediated cholesterol efflux in skin fibroblasts and assessed carotid arterial-wall thickness in unselected individuals with defined mutations in the ABCA1 gene and in controls.

Section snippets

Participants

We made exhaustive efforts to find all available family members of four Dutch kindreds with known mutations in the ABCA1 gene. Two index patients have been described previously.6, 9 No selection was made on the basis of HDL cholesterol concentrations or coronary-artery disease status. The control cohort represented ethnically matched, normolipidaemic, normotensive individuals free of clinical signs or symptoms of CVD. All participants gave their written informed consent for participation, and

Results

Our cohort of patients consisted of 30 individuals carrying ABCA1 mutations who were identified by active screening efforts in four unrelated families (NL-014 [n=8] and NL-027 [n=9] with Tangier disease, and NL-016 [n=4] and NL-020 [n=9] with familial hypoalpha-lipoproteinaemia). The ABCA1 mutations in NL-014 and NL-016, which have been previously described, consist of 4369T→C (C1477R) and 3212T→C (M1091T), respectively.6, 9 Mutation carriers from the two newly discovered families with familial

Discussion

This study shows that heterozygotes for ABCA1 mutations possess significantly larger mean intima-media thicknesses than controls, and therefore have an increased arterial-wall thickness. These individuals were expected to reach the upper limit of normal intima-media thickness at the age of 55 years, compared with 80 years in controls. Even more strikingly, a strong correlation was seen between levels of cholesterol efflux in skin fibroblasts and mean arterial wall intima-media thicknesses.

GLOSSARY

cholesterol efflux: Cholesterol efflux is the process whereby peripheral cells, notably macrophages, get rid of excess cholesterol. The rate-limiting step in this process is the transmembrane transporter ABCA1. ABCA1 stimulates efflux of cholesterol and phospholipid particularly to lipid-poor apolipoprotein AI, the initial step in the formation of nascent HDL particles.
apolipoprotein ai: Apolipoprotein AI is the main structural protein of the HDL particle. Concentrations in plasma are inversely

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We enrolled 131 subjects and characterized cardiometabolic risk based on the IDF criteria's for metabolic syndrome (MS). In this population, cholesterol efflux capacity (CEC), Lecithin–cholesterol acyltransferase (LCAT) and ApoA-1 glycation was associated with waist circumference, abdominal visceral fat (VFA) and abdominal subcutaneous fat. In multivariate analyses, VFA was identified as a critical contributor for low CEC and LCAT. When stratified into groups based on the presence of cardiometabolic risk factors, we found a prominent reduction in CEC and LCAT as a function of the progressive increase of cardiometabolic risk from 0–2, 0–3 to 0–4/5, whereas an increase in Pre-β-HDL and ApoA-1 glycation was observed between the lowest and highest risk groups.
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Citation Excerpt :
Several clinical studies have evaluated the association between atherogenesis or CV events and HDL-CEC (Table 1). The first study, published in 2002, used skin fibroblasts from individuals with ABCA1 mutations and controls to evaluate the association of ABCA1-CEC using HDL as the acceptor (HDL/ABCA1-CEC) within atherosclerotic lesions [42]. An inverse correlation between HDL/ABCA1-CEC and arterial-wall thickness was noted, suggesting that increasing efflux could inhibit progression of atherosclerosis prior to the manifestation of symptomatic CVD [43].
Functional assessment of cholesterol efflux capacity (CEC) to high-density lipoprotein (HDL) is an emerging tool for evaluating morbidity and mortality associated with cardiovascular disease (CVD). By promoting macrophage reverse cholesterol transport (RCT), HDL-mediated CEC is believed to play an important role in atherosclerotic lesion progression in the vessel wall. Furthermore, recent evidence indicates that the typical inverse associations between various forms of CEC and CV events may be strongly modulated by environmental systemic factors and traditional CV risk factors, in addition to autoimmune diseases. These factors influence the complex and dynamic composition of HDL particles, which in turn positively or negatively affect HDL-CEC. Herein, we review recent findings connecting HDL-CEC to traditional CV risk factors and cardiometabolic conditions (non-autoimmune diseases) as well as autoimmune diseases, with a specific focus on how these factors may influence the associations between HDL-CEC and CVD risk.
Intracellular cholesterol stimulates ENaC by interacting with phosphatidylinositol‑4,5‑bisphosphate and mediates cyclosporine A-induced hypertension
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Citation Excerpt :
However, it remains unknown whether inhibition of Cho synthesis with statins can attenuate CsA-induced hypertension. In addition, several lines of evidence suggest that impairment of Cho efflux due to reduced ABCA1 function also participates in the pathogenesis of age-related macular degeneration, cardiovascular diseases, and Alzheimer's disease [28–30]. Therefore, elevated ENaC activity due to reduced ABCA1 function may account for the age-related hypertension.
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Mechanisms of DiseaseAssociation between increased arterial-wall thickness and impairment in ABCA1-driven cholesterol efflux: an observational study

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Results

Discussion

GLOSSARY

Lancet

Am J Med

Lancet

Adv Lipid Res

Lancet

Lancet

J Biol Chem

Ultrasound Med Biol

Lancet

J Am Coll Cardiol

Ultrasound Med Biol

Atherosclerosis

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Nat Genet

The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease

Nat Genet

Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1

Nat Genet

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