Measurement issues related to lipoprotein heterogeneity

doi:10.1016/S0002-9149(02)02632-2

The American Journal of Cardiology

Volume 90, Issue 8, Supplement, 17 October 2002, Pages 22-29

https://doi.org/10.1016/S0002-9149(02)02632-2 Get rights and content

Abstract

In clinical practice, the coronary artery disease (CAD) risk associated with high levels of low-density lipoprotein (LDL) or low levels of high-density lipoprotein (HDL) is assessed not by measuring LDL and HDL particles directly, but by measuring the amount of cholesterol carried by these lipoproteins. It is not generally appreciated how much the amount of cholesterol per particle varies from person to person, especially for LDL, because of differences in the relative amounts of cholesterol ester and triglycerides in the particle core as well as differences in particle diameter. As a consequence of the magnitude and prevalence of this lipid compositional variability, even the most accurate lipoprotein cholesterol measurements will, for many individuals, provide an inaccurate measure of the number of circulating lipoprotein particles and the CAD risk they confer. Nuclear magnetic resonance (NMR) spectroscopy offers an efficient new means of measuring lipoprotein levels in plasma, with quantification based not on cholesterol content, but on the amplitudes of spectral signals emitted by lipoprotein subclasses of different size. Because the subclass signal amplitudes are not influenced by cholesterol compositional variability, they provide a direct measure of lipoprotein particle concentrations. NMR data from the Framingham Offspring Study demonstrate a significant “disconnect” between LDL cholesterol and LDL particle concentrations in patients with low levels of HDL cholesterol. The results imply that a substantial portion of the excess CAD risk of patients with low HDL stems from an unrecognized excess of LDL particles containing less cholesterol than normal. Patients with this abnormality would benefit from LDL-lowering therapy but are not identified as candidates for such treatment on the basis of traditional LDL cholesterol tests.

Section snippets

Prevalence and metabolic origins of low-density lipoprotein cholesterol compositional variability

LDL cholesterol has been used for so long as the basis of quantifying LDL that physicians and patients rarely bother to note the distinction. For example, it is common for someone to express concern about “my LDL of 160 mg/dL” without worrying about the fact that it is a cholesterol concentration they are talking about, not an LDL concentration. Why is this distinction important? Because LDL particles from different individuals vary tremendously in the amount of cholesterol they contain. As a

Lipoprotein quantification by NUCLEAR MAGNETIC RESONANCE spectroscopy

NMR spectroscopic analysis of lipoprotein subclasses is considerably more efficient than traditional electrophoretic or ultracentrifugal methods, because no physical fractionation of the lipoproteins is required. However, potentially more important in terms of clinical utility is the fact that NMR provides direct access for the first time to lipoprotein particle data. Instead of basing lipoprotein quantification on cholesterol or apolipoprotein measurements, the NMR method employs the

Clinical implications of the disconnect between LDL cholesterol and LDL particles in patients with low HDL cholesterol

NMR analyses conducted on >3,400 frozen plasma samples from the Framingham Offspring Study cohort²⁶ provide an opportunity to take a fresh look at the reasons for the enhanced CAD risk of patients whose primary lipid abnormality is not high LDL cholesterol, but low HDL cholesterol. Prospective epidemiologic studies have consistently shown low HDL cholesterol to be a strong CAD risk factor, independent of the level of LDL cholesterol.⁴ With clinical trial support coming from the recent VA-HIT

Prevalence of the disconnect between LDL cholesterol and LDL particles

The ATP III guidelines recommend LDL cholesterol targets of <100 mg/dL for patients with CAD or CAD risk equivalents, <130 mg/dL for patients with ≥2 risk factors and a 10-year Framingham risk ≤20%, and <160 mg/dL for patients with 0 to 1 risk factors.³⁰ As shown in Figure 5, these targets correspond to the 20th, 50th, and 80th percentile values in the Framingham Offspring population. The LDL particle concentration distribution, also given in Figure 5, shows that the corresponding 20th, 50th,

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Regular paperMeasurement issues related to lipoprotein heterogeneity

Abstract

Section snippets

Prevalence and metabolic origins of low-density lipoprotein cholesterol compositional variability

Lipoprotein quantification by NUCLEAR MAGNETIC RESONANCE spectroscopy

Clinical implications of the disconnect between LDL cholesterol and LDL particles in patients with low HDL cholesterol

Prevalence of the disconnect between LDL cholesterol and LDL particles

Am J Cardiol

Am J Cardiol

Atherosclerosis

Clin Chim Acta

J Lipid Res

Atherosclerosis

Fat transport in lipoproteins—an integrated approach to mechanisms and disorders

N Engl J Med

An emerging understanding of the interactions of plasma lipoproteins with the arterial wall that leads to the development of atherosclerosis

Curr Opin Lipidol

The response-to-retention hypothesis of early atherogenesis

Arterioscler Thromb Vasc Biol

Incidence of coronary heart disease and lipoprotein cholesterol levelsthe Framingham Study

JAMA

The association of coronary atherosclerosis and hyperapobetalipoproteinemia (increased protein but normal cholesterol content in human plasma low density lipoprotein)

Proc Natl Acad Sci USA

Apolipoprotein concentrations during treatment and recurrent coronary artery disease events

Arterioscler Thromb Vasc Biol

Relation between baseline and on-treatment lipid parameters and first acute major coronary events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

Circulation

High apolipoprotein B, low apolipoprotein A-1, and improvement in the prediction of fatal myocardial infarction (AMORIS study)a prospective study

Lancet

Measurement of apoproteinstime to improve the diagnosis and treatment of the atherogenic dyslipoproteinemias

Clin Chem

Regular paper
Measurement issues related to lipoprotein heterogeneity