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Lipids and Lipoproteins |
1
Lipid Research Laboratory, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center, and Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111.
2
Otsuka America Pharmaceutical, Inc., Rockville, MD
20850.
3
Department of Epidemiology and Biostatistics, Boston
University School of Public Health, Boston, MA 02118.
4
National Heart, Lung, and Blood Institute's Framingham
Heart Study, National Institutes of Health, Framingham, MA 01701.
a Address correspondence to this author at: Lipid Metabolism Laboratory Jean Mayer, USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington St., Boston, MA 02111. Fax 617-556-3103; e-mail McNamara_LI{at}HNRC.Tufts.edu.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The liver also produces TRLs, known as VLDLs. Like chylomicrons, VLDLs have a density of <1.006 kg/L. Newly formed VLDLs also undergo lipolysis, losing much of their triglyceride and apo C and gaining a cholesteryl ester and apo E. They are then known as VLDL remnants and contain apo B-100 and apo E as their major protein components. VLDL remnants can undergo additional metabolism to form intermediate density lipoproteins (density 1.006–1.019 kg/L) and LDLs (density 1.019–1.063 kg/L). Alternatively, they can be taken up directly by the liver. Like intermediate density lipoproteins and LDLs, both chylomicron remnants and VLDL remnants are thought to be atherogenic (4)(5)(6)(7)(8)(9)(10).
Although assays for direct measurement for LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) are routinely available (11)(12)(13)(14)(15), assays for measurement of remnant lipoproteins have not been available until recently (16)(17)(18). Remnant isolation offers the potential benefit of allowing for the measurement of atherogenic particles within TRLs without measuring newly formed TRLs that are possibly nonatherogenic. In the past, remnant lipoproteins past have been difficult to isolate because they are extremely heterogeneous in size, co-migrate in the same density region as other TRLs, and contain the same lipid and apolipoprotein composition. Studies have shown, however, that these particles can remain in the circulation for an extended period of time, postprandially, even in individuals with low fasting triglyceride concentrations (19)(20)(21)(22)(23). Moreover, these remnant particles can increase dramatically in the nonfasting state, and there may be a wide degree of variability in this postprandial response among individuals.
Methodology developed by Nakajima and co-workers (16)(17)(18) uses antibodies to isolate a subset of TRLs that are enriched in apo E and display remnant-like characteristics. In this study, we evaluated measurements of these remnant-like particles (RLPs) in a large American population for the purpose of generating reference ranges and examining the effects of gender, age, and menopause as a basis for additional case-control and prospective evaluations of RLP-cholesterol (RLP-C) and -triglyceride (RLP-TG) concentrations as markers of CHD risk.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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lipoprotein analyses
Blood from FHS participants was drawn from each subject at the
time of the exam, after a 12-h overnight fast, into tubes containing
EDTA (final concentration, 1.5 g/L). Plasma was separated by
centrifugation (1000g, 4 °C, 20 min). Plasma lipid and
lipoprotein concentrations (total cholesterol, triglycerides, and
HDL-C) were measured fresh, using established enzymatic methods,
essentially as previously described (25). These values have
been previously reported (26)(27).
rlp analyses
RLP isolation was based on the removal of apo A-I-containing
particles (HDL) and most apo B-containing particles (LDL, nascent VLDL,
and nascent chylomicrons), using an immunoseparation technique [Japan
Immunoresearch Laboratories (JIMRO) described previously
(16)(17)(18)], which has been shown to leave remnants of both
intestinal and hepatic origin in the unbound fraction. Briefly,
monoclonal antibodies (Mabs) to apo A-I and specific Mabs to apo B
(JI-H), which do not recognize partially hydrolyzed, apo E-enriched
lipoprotein remnants, were immobilized on agarose gel. RLP-C and RLP-TG
concentrations were measured in the FHS plasma aliquots that had been
frozen at -80 °C until the time of analysis. Plasma was incubated
with the gel for 2 h on a JIMRO incubator in Hitachi sample cups
(Boehringer Mannheim Diagnostics), after which the gel, containing the
bound (non-RLP) lipoproteins, was precipitated by low-speed
centrifugation (5 min, 135g). Cholesterol and triglyceride
concentrations (RLP-C and RLP-TG, respectively) were then measured in
the unbound supernates, using two-reagent enzymatic assays with a
sensitive chromophore (Kyowa Medex) for both the RLP-C and RLP-TG
measurements on an Abbott Spectrum analyzer (Abbott Diagnostics). The
sensitive chromophore is necessary because remnant concentrations are
very low in most individuals, particularly in the fasting state, and
the final supernate dilution of the assay is 1:61 (by volume).
Initially, calibration was established with serial dilutions of a 1.29
mmol/L (50 mg/dL) cholesterol calibrator and a 0.56 mmol/L (50 mg/dL)
glycerol calibrator, with final cholesterol calibrator concentrations
of 1.617 x 10-3, 3.234 x 10-3,
6.468x 10-3, 12.937 x 10-3, and
25.873 x 10-3 mmol/L (0.0625, 0.125, 0.250, 0.500,
and 1.000 mg/dL); and final triglyceride calibrator concentrations of
1.412 x 10-3, 2.825 x 10-3,
5.650 x 10-3, 11.299 x 10-3, and
22.599 x 10-3 mmol/L (0.125, 0.250, 0.500, 1.000,
and 2.000 mg/dL). These were subsequently replaced by calibration
factors to obtain more consistent and accurate performance on the
Abbott Spectrum. Because the working calibrators were large, serial
dilutions of the stock calibrators, they were by definition linear but
did not necessarily provide accurate, reproducible calibration. Very
small differences in calibrator absorbances corresponded to relatively
large differences in concentration in the resulting analyses and
thereby led to the the need to manually evaluate the calibrator
absorbances to determine acceptance or rejection on the basis of a very
narrow acceptable absorbance range for each calibrator. The change to
the use of a calibration factor essentially performed the same
function. More recently, a set of calibrators that requires no
manipulation has been developed at Pacific Biometrics Research
Foundation (Seattle, WA) to prevent such problems, but these
calibrators were not available at the time the present study samples
were analyzed. Cross-over comparisons between the calibration factor
and the preset calibrators produced equivalent sample results.
evaluation of frozen plasma
Before analysis of the FHS samples, the relationship between
paired fresh and frozen samples was evaluated in a separate set of
samples. In the initial fresh/frozen comparison, 40 fasting samples
were analyzed for RLP-C and RLP-TG in the fresh state and were then
frozen at -80 °C in multiple aliquots for subsequent analysis at
multiple time points. A single aliquot of each sample was removed from
the freezer for isolation and analysis at 1-, 2-, 3-, and 6-week (no
RLP-TG) intervals and at 3- and 6-month intervals. These thawed samples
were analyzed under the same preoptimization conditions as the original
fresh aliquots, using Kyowa Medex cholesterol reagent, but a
non-blanked triglyceride reagent generally used for serum triglyceride
measurements; isolations also used Abbott wide-mouthed sample cups. A
second comparison, under final, optimized conditions, used 61 fasting
samples in which RLP-C and RLP-TG were each measured fresh and at a
single frozen time point (frozen 1 week to 3 months). Optimized
conditions included incubation in Hitachi sample cups, which provided
better mixing characteristics, calibration with the use of calibration
factors, and RLP-TG measurements with a sensitive, blanked triglyceride
reagent (Kyowa Medex).
statistical analysis
Statistical analyses were conducted with the SAS statistical
program (SAS Institute). Student's t-test was used to
compare mean values between groups. Categorical values were compared by
analysis. Percentiles were determined with the Proc
Univariate procedure. The fresh/frozen sample comparisons were analyzed
by paired Student's t-test and correlation analyses. Bias
and percentage bias determinations were calculated for each pair and
averaged. Because analyses in most clinical laboratories would be
performed on fresh samples, the equations for bias derived from the
fresh/frozen comparison were applied to results obtained on the FHS
samples to provide fresh-equivalent reference ranges.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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5.65 mmol/L
(500 mg/dL) was not directly related to the duration of freezing,
because samples frozen for 1 week to 6 months were not different from
each other: mean RLP-C at 1 week, 0.223 ± 0.111 mmol/L (8.62
± 4.30 mg/dL); mean RLP-C at 6 months, 0.230 ± 0.138 mmol/L
(8.90 ± 5.33 mg/dL); mean RLP-TG at 1 week, 0.537 ± 0.467
mmol/L (47.53 ± 41.37 mg/dL); and mean RLP-TG at 6 months,
0.485 ± 0.409 mmol/L (42.93 ± 36.21 mg/dL) (28).
Results of the second fresh/frozen comparison, performed under the
optimized conditions used for the FHS samples, indicated a small mean
bias for RLP-C of 0.013 mmol/L (0.5 mg/dL; 3.5%; r =
0.86; P = 0.097), which did not reach significance, and
a small but significant mean bias for RLP-TG of -0.032 mmol/L (-2.8
mg/dL; -7%; r = 0.96; P <0.001). The
derived-fit equations were y = 1.22x -
0.032 (1.22) for RLP-C and y = 0.95x -
0.013 (1.14) for RLP-TG (Fig. 1
); these equations were used to adjust the measurements obtained
from the frozen FHS samples to provide fresh-equivalent concentrations.
At an RLP-C concentration of 0.25 mmol/L (10 mg/dL), there was a
positive bias of 0.023 mmol/L (0.89 mg/dL), producing a concentration
of 0.273 mmol/L (10.6 mg/dL), with 95% confidence limits of 0.270 and
0.276 mmol/L (10.4 and 10.7 mg/dL), respectively. At an RLP-TG
concentration of 0.40 mmol/L (35 mg/dL), the bias was -0.032 mmol/L
(-2.8 mg/dL), yielding a concentration of 0.368 mmol/L (32.6 mg/dL),
with 95% confidence limits of 0.366 and 0.370 mmol/L (32.4 and 32.7
mg/dL), respectively.
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Technically, measurement of RLP-C and RLP-TG is very demanding because of low plasma remnant concentrations in most individuals [generally <0.25 mmol/L (<10 mg/dL) and <0.40 mmol/L (<35 mg/dL), respectively] and the relatively high supernatant dilution factor of 1:61, yielding actual measured raw concentrations generally of <0.005 mmol/L (<0.2 mg/dL) and <0.007 mmol/L (<0.6 mg/dL), respectively. Through use of the sensitive chromophore-containing cholesterol and triglyceride reagents, however, within-run precision for duplicate analyses of samples was typically within 10% for RLP-C and within 15% for RLP-TG. Two concentrations of control materials, isolated and measured in the same manner as the plasma samples, yielded average imprecision values for RLP-C duplicates (in 20 sets of pairs) of 3.9% at 0.18 mmol/L (7 mg/dL) and 4.8% at 0.62 mmol/L (24 mg/dL). The same control materials yielded RLP-TG imprecision values among pairs of 9.5% at 0.25 mmol/L (22 mg/dL) and 6.5% at 1.23 mmol/L (109 mg/dL). Two other control materials, used only to monitor the cholesterol and triglyceride assays, yielded mean paired RLP-C imprecision values of 8.2% at 0.21 mmol/L (8 mg/dL) and 5.4% at 0.57 mmol/L (22 mg/dL) and RLP-TG imprecision values of 16.3% at 0.14 mmol/L (12 mg/dL) and 7.4% at 0.64 mmol/L (57 mg/dL). The among-run RLP-C imprecision values for two concentrations of RLP-isolation control materials over 20 analytical runs was 9.1% at 0.18 mmol/L (7 mg/dL) and 7.3% at 0.62 mmol/L (24 mg/dL). Among-run RLP-TG imprecision values for the same control materials was 8.3% at 0.25 mmol/L (22 mg/dL) and 5.0% at 1.23 mmol/L (109 mg/dL). Among-run imprecision values for the two control materials with low cholesterol and triglyceride concentrations in the same 20 analytical runs were 10.9% and 7.4%, respectively, for RLP-C and 15.3% and 12.0%, respectively, for RLP-TG.
age and gender differences with respect to rlp-c and rlp-tg
Relevant biochemical and anthropomorphic characteristics for the
FHS participants are presented in Table 1
. Although all of the parameters except for RLP-C and RLP-TG
have been previously reported (26)(27), they are
included here for comparison with RLP-C and RLP-TG concentrations.
Previously reported parameters that differed significantly between
women and men were blood pressure, serum glucose, triglycerides, HDL-C,
and LDL-C. However, in the present study we also found significant age-
and gender-associated differences in concentrations of both RLP-C and
RLP-TG (Table 1
). Women consistently had lower mean concentrations of
both RLP-C and RLP-TG than men [RLP-C, 0.176 ± 0.058 mmol/L
(6.8 ± 2.3 mg/dL) vs 0.208 ± 0.096 mmol/L (8.0 ± 3.7
mg/dL), P <0.0001; RLP-TG, 0.204 ± 0.159 mmol/L
(18.1 ± 14.1 mg/dL) vs 0.301 ± 0.261 mmol/L (26.7
± 23.1 mg/dL), P <0.0001]. Concentrations increased with age
(Tables
2 and
3), and gender differences for both RLP-C and RLP-TG were evident
throughout all age categories. Smoking was positively associated with
RLP-C (P <0.02) and RLP-TG (P <0.04)
concentrations in women, but there was no association in men. Alcohol
intake was not associated with RLP concentrations in women or men.
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We also assessed the influence of menopause on RLP concentrations and
found that postmenopausal women (n = 718) had significantly higher
RLP-C values than premenopausal women [n = 667; 0.188
± 0.063 mmol/L (7.3 ± 2.5 mg/dL) vs 0.163 ± 0.049 mmol/L
(6.3 ± 1.9 mg/dL), P <0.0001]. Postmenopausal women
also had significantly higher RLP-TG concentrations than premenopausal
women (0.225 ± 0.179 mmol/L (19.9 ± 15.8 mg/dL) vs
0.181 ± 0.130 mmol/L (16.0 ± 11.5 mg/dL), P
= 0.0001; Table 4
].
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Univariate correlation coefficient analysis indicates that both RLP-C
and RLP-TG are significantly positively correlated with total
cholesterol, triglyceride, and LDL-C concentrations, and inversely
correlated with HDL-C concentrations (Table 5
).
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From the RLP-C and RLP-TG data that were generated, we have developed
age- and gender-specific distribution ranges (Tables 2
and 3
), based on
10-year intervals for men and women. From these distribution ranges, we
have also calculated cutoff points for low, normal, and increased
concentrations. Ranges set for RLP-C were: low, <0.15 mmol/L (<6
mg/dL); normal, 0.15–0.25 mmol/L (6–10 mg/dL); and increased, >0.25
mmol/L (>10 mg/dL). Corresponding RLP-TG cutoff points were also set:
<0.15 mmol/L (15 mg/dL), 0.15–0.40 mmol/L (15–35 mg/dL), and >0.40
mmol/L (>35 mg/dL), respectively.
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Women with increased RLP-C (>0.25 mmol/L, >10 mg/dL) and RLP-TG
(>0.40 mmol/L, >35 mg/dL) had mean RLP-C and RLP-TG concentrations of
0.325 ± 0.095 and 0.615 ± 0.250 mmol/L (12.5 ± 3.2
and 54.3 ± 23.0 mg/dL), respectively, whereas women with
concentrations 0.25 and 0.40 mmol/L, respectively, had mean RLP-C and
RLP-TG concentrations of 0.165 ± 0.35 and 0.170 ± 0.080
mmol/L (6.4 ± 1.4 and 15.0 ± 7.0 mg/dL), respectively.
Consistent with the correlation coefficient analysis, women with
increased concentrations of RLP-C and RLP-TG were older (55 vs 51
years) and had higher body-mass index values (30 vs 26
kg/m), higher systolic blood pressure (138 vs 125
mmHg), higher diastolic blood pressure (83 vs 77 mmHg), increased
glucose (6.2 vs 5.0 mmol/L, 112 vs 91 mg/dL), increased total
cholesterol (6.0 vs 5.2 mmol/L, 235 vs 203 mg/dL), increased LDL-C (3.8
vs 3.3 mmol/L, 148 vs 128 mg/dL), and increased triglycerides (2.6 vs
1.0 mmol/L, 228 vs 91 mg/dL); they also had lower concentrations of
HDL-C (1.1 vs 1.5 mmol/L, 42 vs 57 mg/dL) and included a larger
percentage of current smokers (31% vs 25%).
Men with increased RLP-C and RLP-TG concentrations had mean concentrations of 0.360 ± 0.120 and 0.725 ± 0.315 mmol/L (14.0 ± 4.7 and 64.2 ± 28.3 mg/dL), respectively, compared with men with low to unaffected concentrations, who had mean RLP-C and RLP-TG concentrations of 0.173 ± 0.035 and 0.202 ± 0.095 mmol/L (6.7 ± 1.4 and 17.9 ± 8.0 mg/dL), respectively. Unlike what was seen in the women, however, the lipid profiles of the men with increased concentrations were not very different from the men with lower concentrations. There were no differences in age (53 vs 52 years) or percentage of smokers (24% vs 23%), and there were only modest differences in body mass index (29 vs 27 kg/m), systolic blood pressure (134 vs 129 mmHg), diastolic blood pressure (85 vs 81 mmHg), glucose (5.7 vs 5.3 mmol/L, 106 vs 97 mg/dL), and LDL-C (3.6 vs 3.4 mmol/L, 140 vs 134 mg/dL). Somewhat larger differences were seen for total cholesterol (5.7 vs 5.2 mmol/L, 224 vs 200 mg/dL), triglycerides (2.7 vs 1.2 mmol/L, 238 vs 103 mg/dL), and HDL-C (0.95 vs 1.15 mmol/L, 36 vs 45 mg/dL). No differences were seen in alcohol intake between groups for either men or women.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Increases in serum triglycerides are frequently seen in patients diagnosed with CHD and also in segments of the general population that are at highest risk for the development of CHD. However, triglycerides are not significantly and independently associated with CHD in most prospective studies. The difficulty with using plasma or serum triglyceride measurements to assess CHD risk may stem from the variability within the subspecies of TRL particles, as well as the inverse association with HDL-C. It is not possible to distinguish TRLs that are atherogenic from those that are nonatherogenic simply by measuring triglyceride content. It has been hypothesized for many years that lipoprotein remnants are atherogenic (37)(41)(42)(43). These particles have been difficult to isolate and quantitate, however, because they have so few distinguishing characteristics and come in widely varying sizes that overlap with other similarly composed lipoproteins. Remnants have been separated primarily by density and charge (5)(44), and studies that have tried to analyze the impact of remnants have often had to rely on indirect methods (43). Each method that is used to separate the particles called "remnants" will probably isolate slightly different populations. The immunoseparation technique used for the current study is no exception.
The RLP assay relies on two Mabs to bind and sequester all lipoproteins except apo E- and cholesteryl-ester-enriched, apo C-poor TRLs, generally considered to be remnants. HDLs are bound by an anti-apo A-I, whereas the apo B-containing lipoproteins are bound by the specific anti-apo B, Mab JI-H (16)(17). The unbound lipoproteins after incubation with Mab JI-H were carefully characterized by agarose electrophoresis, ultracentrifugation, immunoaffinity chromatography, and electron photomicrography. Their characteristics were consistent with the results of previous studies describing remnants in both rats (44) and humans (45).
In the present study, we have investigated the use of the RLP assay as a possible means of isolating and measuring potentially atherogenic subspecies of TRLs. If the measurement of remnant lipoproteins were indeed a more sensitive indicator of atherogenic TRLs subspecies and if those measurements could provide additional useful information in terms of risk prediction, diagnosis, and monitoring, then the addition of such an assay to the clinical arena would be very beneficial. Preliminary comparisons between patients with coronary disease and individuals without disease in the FHS population indicate that RLP-C and/or RLP-TG are significantly higher in the coronary disease patients (36). Furthermore, a recent study in postmortem samples by Takeichi et al. showed that individuals that died from sudden cardiac death had significantly higher concentrations of RLP-C and RLP-TG than individuals that died from sudden noncardiac death (46). In addition, studies in patients at risk for CHD, notably diabetics and those with type III hyperlipoproteinemia, have shown similar results (47)(48).
The first step in evaluating the assay with regard to CHD, however, is the development of reliable reference ranges based on a large and representative population. Because most population studies, including the FHS, store plasma or serum at -70 to -80 °C for subsequent biochemical analyses, evaluation of the effects of sample freezing on proposed assays was necessary before developing reference ranges and assessing the clinical utility of the assay in samples stored under these conditions. Previous assay development work by our laboratory has shown that some lipoprotein tests are affected by freezing (11)(49), whereas others are not (40). The issue of most concern is the potential for large systematic biases or for time-dependent variability in concentrations that may result from the freezing process and/or its duration (11). We have documented that, for fasting serum, a single freezing step at -80 °C causes a small increase in RLP-C and a modest concomitant decrease in RLP-TG, compared with fresh serum. Although measurement in fresh samples is preferable, we have determined that the alterations caused by freezing can be adjusted to provide fresh-equivalent values in previously frozen samples; the FHS RLP-C and RLP-TG concentrations in the present study were subjected to these adjustments to provide reference ranges applicable to clinical settings, where samples are generally analyzed fresh.
Our data indicate that, in fresh samples, an RLP-C value 
0.25 mmol/L
(10 mg/dL) and an RLP-TG value 0.40 mmol/L (35 mg/dL) in the fasting
state may be considered increased in this population, and that age,
gender, and menopausal status have significant effects on RLP-C and
RLP-TG concentrations. Abnormal concentrations of RLP-C and RLP-TG are
also associated with abnormal concentrations of other lipoprotein
parameters. With a population base of ~3000 individuals, we
now have sufficient data for comparison of RLP-C and RLP-TG
concentrations in individuals diagnosed with CHD to evaluate the
efficacy of these determinations. Both case control and prospective
comparisons are currently under way.
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Acknowledgments |
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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s OD, Faergeman O, Hamilton RL, Havel RJ. Characterization of remnants produced during the metabolism of triglyceride-rich lipoproteins of blood plasma and intestinal lymph in the rat. J Clin Invest 1975;56:603-615.
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T. G. Redgrave, G. F. Watts, I. J. Martins, P. H. R. Barrett, J. C. L. Mamo, S. B. Dimmitt, and A. D. Marais Chylomicron remnant metabolism in familial dyslipidemias studied with a remnant-like emulsion breath test J. Lipid Res., May 1, 2001; 42(5): 710 - 715. [Abstract] [Full Text]
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C. Marcoux, P. N. Hopkins, T. Wang, E. T. Leary, K. Nakajima, J. Davignon, and J. S. Cohn Remnant-like particle cholesterol and triglyceride levels of hypertriglyceridemic patients in the fed and fasted state J. Lipid Res., September 1, 2000; 41(9): 1428 - 1436. [Abstract] [Full Text]
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D. M. Waterworth, J. A. Hubacek, J. Pitha, J. Kovar, R. Poledne, S. E. Humphries, and P. J. Talmud Plasma levels of remnant particles are determined in part by variation in the APOC3 gene insulin response element and the APOCI;-APOE cluster J. Lipid Res., July 1, 2000; 41(7): 1103 - 1109. [Abstract] [Full Text]
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S. Hirany, D. O'Byrne, S. Devaraj, and I. Jialal Remnant-like Particle-Cholesterol Concentrations in Patients with Type 2 Diabetes Mellitus and End-Stage Renal Dise |
