Original ArticleHigh-density lipoproteins: A consensus statement from the National Lipid Association
Section snippets
HDL-C as an independent risk factor for CVD
The epidemiologic evidence in support of HDL-C as an inverse predictor of CVD has been appreciated for >50 years. Gofman et al13 first reported an inverse association between HDL-C levels and risk of ischemic heart disease. Subsequently, an inverse association between HDL-C and CVD risk was found in the Norwegian Tromsø Heart Study,14 and this was soon followed by US longitudinal data available from the Honolulu Heart Study and the Framingham Heart Study (FHS).15, 16 Both of those studies found
Analytical methods
A need is increasing to characterize and quantify the diverse roles of HDL particles in atherogenesis to improve the diagnosis, prevention, and treatment of CVD.60, 61 This information provides a foundation for fostering improved understanding of the pathophysiology of atherosclerosis, direct the future course of research, and design interventions that effectively reduce CVD risk in various patient populations. This section describes features of the major analytic procedures used to assess HDL
HDL-targeted intervention studies in animals
Many studies have investigated the effects of increasing HDL concentration on atherosclerosis animal models. It should be emphasized, however, that all of these models have their limitations and that none is a true model for human disease. However, with this reservation, the animal studies have, with very few exceptions, provided powerful evidence that increasing HDL-C concentration does protect against atherosclerosis.
Badimon et al4 were the first to report direct antiatherogenic effects of
Dal-OUTCOMES
This was a multicenter, randomized, double-blind, placebo-controlled trial designed to test the hypothesis that CETP inhibition with dalcetrapib reduces CVD morbidity and mortality in patients with recent ACS. More than 15,000 patients, all of whom were being treated with statins to achieve recommended levels of LDL-C, were randomly assigned to receive dalcetrapib or matching placebo. The primary outcome was time to first occurrence of a composite CV end point. The trial was planned to continue
AIM-HIGH
This trial tested the hypothesis that treatment with niacin would reduce CVD events in statin-treated humans who had low levels of HDL-C. The rationale for AIM-HIGH was that niacin increases the level of HDL-C by up to 30% and also reduces the level of LDL-C by approximately 15%. When given as monotherapy, niacin has been shown to reduce clinical CVD events. Furthermore, when given in combination with a statin, niacin promotes regression of atherosclerosis as assessed by measuring cIMT.
AIM-HIGH
Intravenous infusion of reconstituted HDLs
rHDL-like particles consist of complexes of phospholipids with the main HDL apolipoprotein, apoA-I. Intravenous infusions of rHDLs have been shown consistently in a variety of animal models to inhibit experimental atherosclerosis.5, 88 Two proof-of-concept studies suggest a similar antiatherogenic effect of infusing rHDLs into humans.9, 10
ApoA-IMilano is a mutant form of apoA-I that was discovered in Italian families with low HDL-C but apparently decreased CV risk. In a small study in humans
Role of HDL in RCT
Plasma levels of HDL-C are inversely associated with incident CAD and CVD events such as MI and mortality. This highly consistent observation led to the HDL hypothesis that interventions to raise HDL-C will result in reduced risk of CAD. However, recent findings have raised serious questions about the validity of this hypothesis or the emphasis on whole body cholesterol excretion vs a focus on macrophage cholesterol efflux.73 A number of genetic polymorphisms associated with HDL-C have no
HDL consensus summary of conclusions and recommendations
- A.
Epidemiology
- 1.
Low serum levels of HDL-C have been found repeatedly to be the best predictor of CHD in observational studies, especially in men older than 50 years. After adjustment for established covariates, high levels of HDL-C in general correlate with low risk, whereas low levels correlate with higher risk of CHD. This is established from cohorts around the world and independent of race, ethnicity, and sex. However, most studies did not adjust for LDL particle concentration or apoB levels
- 1.
Acknowledgments
Each author contributed in writing this consensus statement and each is responsible for the content. The chair (Dr Toth) and co-chairs (Drs Barter and Rosenson) were also responsible for reviewing and editing throughout the development of this article. We thank Mary R. Dicklin, PhD, Chad C. Cook, PhD, and Kevin C. Maki, PhD, with Biofortis Clinical Research for providing editorial assistance. The paper “High-Density Lipoproteins: A Consensus Statement from the National Lipid Association” has
References (268)
- et al.
The metabolism and anti-atherogenic properties of HDL
J Lipid Res
(2009) - et al.
Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein[a] in transgenic mice
J Lipid Res
(1994) - et al.
Plasma-high-density-lipoprotein concentration and development of ischaemic heart-disease
Lancet
(1975) - et al.
High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study
Am J Med
(1977) - et al.
High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport
Atherosclerosis
(1996) - et al.
A population at risk. Prevalence of high cholesterol levels in hypertensive patients in the Framingham Study
Am J Med
(1986) Epidemiology of coronary heart disease: the Framingham study
Am J Med
(1984)- et al.
Dyslipidemias with desirable plasma total cholesterol levels and angiographically demonstrated coronary artery disease
Am J Cardiol
(1990) - et al.
Frequency of low serum high-density lipoprotein cholesterol levels in hospitalized patients with “desirable” total cholesterol levels
Am J Cardiol
(1991) - et al.
Prevalence of risk factors in men with premature coronary artery disease
Am J Cardiol
(1991)
Relation of serum lipoprotein cholesterol levels to presence and severity of angiographic coronary artery disease
Am J Cardiol
Should both HDL-C and LDL-C be targets for lipid therapy? A review of current evidence
J Clin Lipidol
Efficacy of lipid profiles in prediction of coronary disease
Am Heart J
Familial hyper-alpha-lipoproteinemia: studies in eighteen kindreds
Metabolism
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Lancet
The protein cargo of HDL: implications for vascular wall biology and therapeutics
J Clin Lipidol
Factors influencing coronary risk in low HDL syndromes
Atherosclerosis
Metabolic origins and clinical significance of LDL heterogeneity
J Lipid Res
High density lipoprotein distribution. Resolution and determination of three major components in a normal population sample
Atherosclerosis
Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman's Livermore Cohort
Atherosclerosis
Characterization of human high-density lipoproteins by gradient gel electrophoresis
Biochim Biophys Acta
A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum
J Lipid Res
Computerized rapid high resolution quantitative analysis of plasma lipoproteins based upon single vertical spin centrifugation
J Lipid Res
Quantification of HDL2 and HDL3 cholesterol by the Vertical Auto Profile-II (VAP-II) methodology
J Lipid Res
Cholesterol profile measurement by vertical auto profile method
Clin Lab Med
Two-dimensional electrophoresis of plasma lipoproteins: recognition of new apo A-I-containing subpopulations
Biochim Biophys Acta
Differential effects of HDL subpopulations on cellular ABCA1- and SR-BI-mediated cholesterol efflux
J Lipid Res
Lipoprotein particle analysis by nuclear magnetic resonance spectroscopy
Clin Lab Med
Separation and analysis of lipoproteins by gel filtration
Methods Enzymol
Characterization of subfractions of triglyceride-rich lipoproteins separated by gel chromatography from blood plasma of normolipemic and hyperlipemic humans
J Lipid Res
Protein heterogeneity of lipoprotein particles containing apolipoprotein A-I without apolipoprotein A-II and apolipoprotein A-I with apolipoprotein A-II isolated from human plasma
J Lipid Res
Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits
J Biol Chem
Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits
J Lipid Res
Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy
J Am Coll Cardiol
Distribution of lipids in 8,500 men with coronary artery disease. Department of Veterans Affairs HDL Intervention Trial Study Group
Am J Cardiol
Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease
J Am Coll Cardiol
Major lipids, apolipoproteins, and risk of vascular disease
JAMA
Biological, clinical and population relevance of 95 loci for blood lipids
Nature
Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit
J Clin Invest
Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI
Nature
Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient mouse
Proc Natl Acad Sci U S A
Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial
JAMA
Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial
JAMA
Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy
N Engl J Med
Effects of dalcetrapib in patients with a recent acute coronary syndrome
N Engl J Med
Effects of torcetrapib in patients at high risk for coronary events
N Engl J Med
Ischemic heart disease, atherosclerosis, and longevity
Circulation
Serum lipoproteins and coronary heart disease in a population study of Hawaii Japanese men
N Engl J Med
HDL metabolism and atherosclerosis
J Cardiovasc Pharmacol
High density lipoprotein cholesterol and incidence of coronary heart disease–the Israeli Ischemic Heart Disease Study
Am J Epidemiol
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The paper, ‘‘High-density lipoproteins: A consensus statement from the National Lipid Association” has been endorsed by the American Society for Preventive Cardiology, the International Atherosclerosis Society, the Association of Black Cardiologists and the Preventive Cardiovascular Nurses Association.