Relation of Increased Prebeta-1 High-Density Lipoprotein Levels to Risk of Coronary Heart Disease
ABSTRACT Preβ-1 high-density lipoprotein (HDL) plays a key role in reverse cholesterol transport by promoting cholesterol efflux. Our aims were (1) to test previous associations between preβ-1 HDL and coronary heart disease (CHD) and (2) to investigate whether preβ-1 HDL levels also are associated with risk of myocardial infarction (MI). Plasma preβ-1 HDL was measured by an ultrafiltration-isotope dilution technique in 1,255 subjects recruited from the University of California-San Francisco Lipid and Cardiovascular Clinics and collaborating cardiologists. Preβ-1 HDL was significantly and positively associated with CHD and MI even after adjustment for established risk factors. Inclusion of preβ-1 HDL in a multivariable model for CHD led to a modest improvement in reclassification of subjects (net reclassification index 0.15, p = 0.01; integrated discrimination improvement 0.003, p = 0.2). In contrast, incorporation of preβ-1 HDL into a risk model of MI alone significantly improved reclassification of subjects (net reclassification index 0.21, p = 0.008; integrated discrimination improvement 0.01, p = 0.02), suggesting that preβ-1 HDL has more discriminatory power for MI than for CHD in our study population. In conclusion, these results confirm previous associations between preβ-1 HDL and CHD in a large well-characterized clinical cohort. Also, this is the first study in which preβ-1 HDL was identified as a novel and independent predictor of MI above and beyond traditional CHD risk factors.
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ABSTRACT: Lipid-poor or lipid-free high density lipoprotein (HDL) particles, designated pre ß-HDL, stimulate removal of cell-derived cholesterol to the extracellular compartment, which is an initial step in the reverse cholesterol transport pathway. Pre ß-HDL levels may be elevated in subjects with established cardiovascular disease. We determined the relationship of carotid intima media thickness (IMT), a marker of subclinical atherosclerosis, with pre ß-HDL in subjects without clinically manifest cardiovascular disease. IMT and plasma pre ß-HDL, assayed by crossed immuno-electrophoresis, were determined in 70 non-diabetic subjects (aged 56±9 years; non-smokers only; 27 women). IMT was correlated positively with pre ß-HDL, both expressed as plasma apolipoprotein (apo) A-I concentration (r=0.271, p=0.023) and as% of apo A-I (r=0.341, p=0.004). In contrast, IMT was correlated inversely with HDL cholesterol (r=-0.253, p=0.035). IMT was also related positively to pre ß-HDL after adjustment for age, sex, systolic blood pressure (in apoA-I concentration, ß=0.203, p=0.043; in% of plasma apoA-I, ß=0.235, p=0.023). IMT remained associated with pre ß-HDL after additional adjustment for either body mass index, plasma glucose, cholesterol, triglycerides, HDL cholesterol, apoA-I and apoB. Subclinical atherosclerosis may relate to higher plasma pre ß-HDL independently of apoA-I and HDL cholesterol levels.Clinica chimica acta; international journal of clinical chemistry 11/2011; 413(3-4):473-7. DOI:10.1016/j.cca.2011.11.001 · 2.76 Impact Factor
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ABSTRACT: Mifepristone is a glucocorticoid and progestin antagonist under investigation for the treatment of Cushing's syndrome. Mifepristone decreases high-density lipoprotein (HDL) cholesterol (HDL-C) levels in treated patients, but the clinical significance of this is unclear because recent studies suggest that functional properties of HDL predict cardiovascular disease status better than does HDL-C concentration. The aim of the study was to characterize the impact of mifepristone administration on HDL particle concentration and function. We conducted a double-blind, randomized, placebo-controlled trial at a single-site, clinical research center. Thirty healthy postmenopausal female volunteers participated in the study. Individuals were randomized to receive daily oral mifepristone (600 mg) or placebo for 6 wk. We measured HDL-C, serum HDL particle concentration, and HDL-mediated cholesterol efflux by treatment group. As expected, ACTH, cortisol, estradiol, and testosterone levels increased in the mifepristone group. Mifepristone treatment decreased HDL-C and HDL particle concentration by 26 and 25%, respectively, but did not alter pre-β HDL concentration. In contrast, the serum HDL-mediated cholesterol efflux decreased with mifepristone treatment by only 12%, resulting in an effective increase of the efflux capacity per HDL particle. No changes were observed in cholesterol ester transfer protein or lecithin:cholesterol acyltransferase activity. Treatment with mifepristone reduced HDL-C, HDL particle concentration, and serum HDL cholesterol efflux in postmenopausal women. However, on a per particle basis, the efflux capacity of serum HDL increased. These observations support the concept that a decrease in HDL-C may not represent proportional impairment of HDL function.The Journal of Clinical Endocrinology and Metabolism 03/2012; 97(5):1598-605. DOI:10.1210/jc.2011-2813 · 6.31 Impact Factor
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ABSTRACT: A negative correlation between HDL cholesterol levels and risk of coronary artery disease has long been recognized. Emerging knowledge of the molecular speciation and functional properties of HDL provides an opportunity to study the atheroprotective effects of specific metabolic processes. The discovery of the quantum particle among the molecular species of HDL (prebeta-1 HDL) and its role in cholesterol efflux from the artery wall, offer a means of assessing the efficiency of efflux. This review presents observations on the structure and metabolism of this particle and its emerging role as a predictor of risk for atherosclerotic vascular disease. Prebeta-1 HDL is now recognized as the primary acceptor of cholesterol effluxed by the dominant ATP-binding cassette A1 (ABCA1) transporter in arterial macrophages, a critical step in reverse cholesterol transport. Several studies have revealed an association between high levels of this particle and risk of globally defined coronary artery disease and carotid intima-media thickness. Recently, these findings have been confirmed and extended to include myocardial infarction. High levels of prebeta-1 HDL may serve as an index of functional impairment of cholesterol efflux or esterification, either of which would be expected to impede reverse cholesterol transport. Recent studies underscore the critical role of prebeta-1 HDL in reverse cholesterol transport and its use as a marker of risk for structural coronary disease, myocardial infarction, and cerebral vascular disease.Current opinion in lipidology 04/2012; 23(4):367-71. DOI:10.1097/MOL.0b013e328353eef1 · 5.80 Impact Factor