Articles |
From the Life Sciences Division, Lawrence Berkeley Laboratory, University of California, Berkeley (H.C., R.M.K.), and the Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montreal, Montreal, Canada (G.O.R., S.L.-C., J.D.).
Correspondence to Ronald M. Krauss, MD, Lawrence Berkeley Laboratory, University of California, Donner Laboratory Room 465, One Cyclotron Rd, Berkeley, CA 94720.
| Abstract |
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Key Words: coronary artery disease LDL subclasses LDL size VLDL cholesterol HDL
| Introduction |
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200
mg/dL) and 42% had "desirable" LDL cholesterol
levels (
130 mg/dL).6 Some of these normolipidemic
patients with CAD had decreased HDL cholesterol
levels.6 7 Other studies have found that a high proportion
of patients with CAD who have normal total and LDL
cholesterol levels have elevated LDL apo B
levels.8 This disorder, hyperapobetalipoproteinemia, is
characterized by an increased number of small, dense, lipid-depleted
LDL particles with abnormal
metabolism.8 9 10 A number of recent studies of CAD risk factors have involved analysis of LDL subclasses.11 12 A high proportion of normocholesterolemic or mildly hypercholesterolemic patients with CAD have been found to have a predominance of smaller, denser LDL particles.13 14 15 16 17 However, the predominance of small LDLs in patients with CAD is found in association with differences in other metabolic parameters, particularly increased plasma triglyceride, reduced HDL, and features of the insulin resistance syndrome18 that may contribute to the observed increased risk of CAD.13 14 15 16 17
To further investigate LDL subclass and other lipoprotein characteristics in normolipidemic men with CAD, we studied 92 patients with angiographically documented CAD, plasma total cholesterol <200 mg/dL, and plasma triglyceride <250 mg/dL. The results were compared with those from a matched population of subjects selected on the basis of health and a normal lipoprotein profile.
| Methods |
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25% stenosis of a major coronary
artery (left main, left anterior descending, circumflex, or right
coronary) as determined by coronary angiography on
multiple projections. More than half of the lesions showed
stenosis of >50%. Eligibility criteria included plasma total
cholesterol level <200 mg/dL, triglyceride
level <250 mg/dL, body mass index (BMI) <30 kg/m2,
absence of hypertension and diabetes, and no use of lipid-altering
medications other than ß-blockers (which 30 subjects with CAD were
taking). Among the 92 men and 7 women recruited on the basis of these
criteria, 91 were symptomatic: 47 had angina alone, 7 had a
history of documented myocardial infarction, and 37 had both.
Twenty-five had prior coronary artery bypass graft surgery, and
12 had prior percutaneous transluminal coronary
angioplasty. Asymptomatic subjects were identified on the
basis of a positive treadmill ECG (4 cases) or of angiography for other
reasons, including valvular heart disease. Because of the small
number of women studied, only the men were included in the present
study. The control population was selected from a sample of white-collar workers employed by Hydro-Quebec, a major utility company in Montreal, Canada. The sample selection and specific procedures have been previously described.19 In brief, control subjects were selected specifically for their health status. They were nonobese (BMI <30 kg/m2), free of cardiovascular disease, hypertension, diabetes, hyperlipidemia, medication use, and thyroid, renal, or liver dysfunction. Control subjects were selected to match the cases as closely as possible for age and BMI. However, because age and BMI were slightly greater in the subjects with CAD than in the controls after the matching procedure, all our analyses were further adjusted for age and BMI.
Laboratory Analyses
After a 12-hour fast, blood samples were collected into tubes
containing 1.5 mg/mL EDTA and centrifuged at 4°C within 2
hours to separate plasma. Plasma was subjected to
ultracentrifugation under standard
conditions20 and the d=1.006 g/mL supranatant
and infranatant fractions were obtained. LDL and HDL concentrations
were obtained after heparin-manganese precipitation of apo
Bcontaining lipoproteins in the d=1.006 g/mL infranatant
according to the Lipid Research Clinics protocol.20
HDL2 and HDL3 cholesterol
were determined after precipitation of HDL2 with
dextran sulfate.21 Plasma, HDL, HDL3,
and 1.006 g/mL supranate and infranate
cholesterol22 as well as plasma and 1.006 g/mL
supranate triglyceride23 were measured on an
automated analyzer (Abbott Bichromatic Analyzer model
100, Abbott Laboratories) by use of enzymatic reagents. Apo B was
measured in plasma and in the 1.006 g/mL infranate fraction by
electroimmunoassay as previously described.24
LDL Subclass Analysis
Particle diameters of the predominant LDL size species were
determined after electrophoresis of the d>1.006 g/mL plasma
fraction on nondenaturing 2% to 16% polyacrylamide gradient
gels (Pharmacia Fine Chemicals) stained for lipid with oil red O as
previously described.11 25 Stained gels were scanned with
a Transidyne RFT scanning densitometer (Transidyne Corp), and LDL
particle diameters were estimated from calibration curves made by using
latex beads and Pharmacia highmolecular weight standards for
reference. Three subgroups of the studied population were defined by
the 25th and 75th percentiles of peak LDL diameter in the control
group: large LDL group, >26.8 nm; intermediate LDL group,
26.0 and
26.8 nm; and small LDL group: <26.0 nm. The size ranges for these
groups include the intervals previously used to define LDL subclasses
I, II, and III, respectively.25 26
Statistical Analyses
Case-control comparisons of plasma lipoprotein concentration and
LDL particle diameter were determined by use of multiple linear
regression to adjust for the effects of age (mean, 52 years) and BMI
(mean, 24.9 kg/m2). Two-way ANOVA was used to compare the
effects of LDL subclass and case-control status on plasma lipoproteins.
Logistic regression was used to determine the independent plasma
lipoprotein determinants of disease status (CAD compared with
control).
| Results |
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The distributions of predominant LDL particle diameters in subjects
with and without CAD are shown in the Figure
. Subjects
with CAD were characterized by having a predominance of large LDL
particles: 43% had LDL particle diameters >26.8 nm, the 75th
percentile for the control population. Moreover, only 14% of the
subjects with CAD had a predominance of small LDL particles (<26.0 nm)
corresponding to the 25th percentile for the control population. The
prevalence of a predominance of intermediate-size LDL was very similar
in subjects with and without CAD (42% and 51%, respectively).
Overall, LDL particle size distribution was significantly different
between subjects with and without CAD (
2=14.6,
P<.002). Mean LDL particle diameters within each LDL
particle size group were similar in subjects with and without CAD
(27.4, 26.6, and 25.5 nm and 27.3, 26.5, and 25.5 nm,
respectively).
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Age- and BMI-adjusted lipoprotein concentrations for subjects with and
without CAD are presented in Table 2
. Particle
diameters of the predominant LDL species remained significantly greater
(P=.001) in the subjects with CAD than in the control
subjects after adjustment for age and BMI. Levels of HDL and
HDL2 cholesterol were significantly
lower (P<.01) in subjects with CAD than in control
subjects, but mean HDL3 cholesterol values were
identical. Subjects with CAD also had significantly higher VLDL apo B
levels (P=.05) and LDL/HDL cholesterol ratios
(P=.02) than control subjects. Total
triglyceride, VLDL triglyceride, VLDL
cholesterol, and LDL apo B concentrations were similar in
the two groups. Total cholesterol, VLDL
cholesterol, and LDL cholesterol concentrations
were somewhat higher among the subjects with CAD, but the differences
were not statistically significant.
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Table 3
shows correlations of LDL particle size with
plasma lipoprotein measurements in subjects with and without CAD. LDL
particle size was strongly inversely related with plasma
triglyceride and positively correlated with HDL,
HDL2, and HDL3
cholesterol. Somewhat stronger associations with
HDL2 cholesterol were observed in the
control subjects than in the subjects with CAD (r=.59 and
.37, respectively). VLDL triglyceride, VLDL
cholesterol, and VLDL apo B levels were also inversely
correlated with LDL particle size in both subjects with CAD and control
subjects, with stronger associations among the control subjects for the
three parameters. LDL apo B levels were inversely related
to LDL particle size in the control group only. It is interesting to
note that the correlations between LDL particle size are stronger with
VLDL apo B levels than with LDL apo B levels, reflecting the strong
inverse association consistently found between plasma
triglyceride concentration and LDL particle
size.14 15 27
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Table 4
shows an analysis of plasma lipoprotein
parameters as a function of LDL size group and case-control
status. Both LDL subclass and disease status were significantly
associated with HDL cholesterol levels
(P=.0001). These differences in HDL cholesterol
between subjects with and without CAD were due to differences in
HDL2 but not HDL3
cholesterol. For HDL2 there was a
significant interaction between LDL subclass and disease status. The
highest HDL2 cholesterol levels were
found in control subjects with a predominance of large LDL particles
(mean, 22 mg/dL). HDL2 cholesterol
levels decreased with decreasing size to 9 mg/dL in control subjects
with a predominance of small LDL. Subjects with CAD who had a
predominance of large and intermediate LDL had 45% and 29% lower
(P<.01) HDL2 cholesterol
levels than control subjects in the same groups. No differences in
HDL2 cholesterol were found between
subjects with and without CAD who had a predominance of small LDL.
HDL3 cholesterol levels also decreased
significantly with decreasing LDL particle size, but there were no
significant differences between subjects with and without CAD.
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Also shown in Table 4
is a significant LDL size group effect on VLDL
constituents (P=.0001). VLDL triglyceride, VLDL
cholesterol, and VLDL apo B increased with decreasing LDL
particle size in both subjects with CAD and control subjects. A
significant interaction between LDL subclass and disease status was
found for VLDL cholesterol (P=.005). Subjects
with CAD who had a predominance of large and intermediate LDL had
significantly higher (P<.05) VLDL cholesterol
and apo B levels than control subjects with the same LDL subclass.
There was no significant difference between subjects with and without
CAD in the groups with small LDL. No significant LDL size or disease
status effect was detected on LDL cholesterol or LDL apo B
levels, but subjects with CAD who had intermediate-size LDL had
significantly higher (P<.05) LDL cholesterol
levels than control subjects in the same group.
As shown in Table 5
, the strongest association with CAD
risk among these normolipidemic men was found with large LDL particle
diameter (
2=29.4, P=.0001). Low
HDL2 cholesterol concentrations were
also significantly associated with disease risk in this study, as in
previous studies.6 7 High VLDL cholesterol
levels were positively associated with disease risk, but this
relationship was of borderline significance (P=.06).
Increased LDL diameter was the best predictor of CAD risk among
normolipidemic men after adjustments were made for other factors
including low HDL cholesterol, high VLDL
cholesterol, age, and BMI.
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| Discussion |
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With regard to other lipoprotein variables, our findings are consistent with previous reports of reduced HDL cholesterol levels in normolipidemic subjects with CAD compared with control subjects6 7 and with a recent prospective study that indicates that the protective effect of high HDL cholesterol levels is more pronounced among subjects with lower plasma total cholesterol levels.29 The observed association between large LDL particles and CAD risk was not altered when the analysis was adjusted for HDL or HDL2 cholesterol levels and other CAD risk factors. Plasma triglyceride, total cholesterol, and LDL cholesterol levels were similar in subjects with and without CAD, probably because of the selection criteria for this study. Moreover, we did not find increases in LDL apo B, LDL cholesterol, or LDL apo B/LDL cholesterol ratio in the subjects with CAD compared with the control subjects. These findings are in contrast to those of other studies in which the LDL apo B/cholesterol ratio was increased in normolipidemic patients with CAD (indicating hyperapobetalipoproteinemia).8 9 10 Because small LDL particles are associated with increased plasma apo B relative to LDL cholesterol, we feel it is likely that, as noted above, the selection criteria tending to exclude subjects with smaller LDL also led to a lower prevalence of subjects with hyperapobetalipoproteinemia.
Cross-sectional studies in mildly hypercholesterolemic patients have consistently found a significant univariate association between small LDL particles and CAD.13 14 15 16 17 However, this association was not statistically significant in multivariate analyses in which triglyceride,13 14 17 triglyceride and HDL cholesterol,15 or LDL cholesterol, HDL cholesterol, and other known risk factors were included in the analysis.15 16 17 Differences between our findings and those from previous studies may be due to the selection criteria in our study (disease status and lipoprotein profile), genetic differences, or environmental differences such as dietary intake. Increased dietary fat and reduced carbohydrate intake and other environmental factors have been associated with increased LDL particle size.27 30 31 Therefore, cross-sectional studies should be interpreted with caution, because behavior modification and disease status itself may alter the LDL size profile. Our current finding of a strong association between large LDL particles and CAD risk is consistent with studies in nonhuman primates in which large LDL particles were strongly independently related to extent of atherosclerosis.32 33 Consistent with human cross-sectional studies,27 30 these animal models suggest that diets high in saturated fat and cholesterol increase LDL particle size. It is possible that large LDL particles are predictors of atherosclerosis in some human populations as well, particularly those with normal lipoprotein profiles and reduced HDL2 cholesterol levels.
As other studies have shown,14 15 27 LDL particle size in this normolipidemic population was strongly inversely related to triglyceride levels. A positive correlation was also observed between HDL cholesterol levels and LDL particle size in both subjects with CAD and control subjects, as previously reported.14 15 27 The somewhat weaker association between LDL particle size and HDL2 cholesterol levels among the subjects with CAD compared with control subjects was primarily due to significantly lower HDL2 cholesterol among the subjects with CAD who had large LDL particles compared with controls. We also observed stronger inverse associations of LDL particle size with VLDL cholesterol and VLDL apo B in control subjects than in subjects with CAD. This may have resulted from the substantially higher levels of VLDL constituents in subjects with CAD who had large LDL particles than in the control subjects. Because there is one apo B molecule per VLDL particle, the difference in VLDL between subjects with and without CAD who had large LDL particles is due to increased VLDL particle number. It is possible that in control subjects, the observed profile results from metabolic factors that result in coordinate regulation of VLDL, HDL2, and LDL particle size,34 whereas in the subjects with CAD, other factors may override these effects to raise VLDL and lower HDL2 independent of LDL particle size.
In general, subjects with a predominance of large LDL particles have been characterized as having the highest HDL cholesterol levels and lowest triglyceride levels, compared with individuals with smaller LDL particles.27 Therefore, it is possible that large LDL particles can be atherogenic but that the risk associated with this trait is usually attenuated or eliminated by virtue of associations with low VLDL and particularly high HDL cholesterol levels in most individuals. Alternatively, it can be speculated that the chemical composition or metabolic properties of large LDL particles from the subjects with CAD in this study are different from those in healthy subjects with a predominance of large LDL particles (eg, women and endurance athletes).27 35
There is some evidence to support the hypothesis that certain forms of large LDL particles may be atherogenic, possibly because of alterations in cholesteryl ester fatty acid composition.32 33 36 For example, studies in nonhuman primates indicate that large LDL particles are higher in cholesteryl ester in the liquid crystalline state at body temperature, deliver more cholesteryl ester per particle to cells in the arterial wall, and are associated with increased stenosis.32 33 It has also been shown in humans that large LDL particles have a reduced affinity for the LDL receptor37 compared with intermediate-size LDL. This property of large LDL particles might enhance their uptake by non-receptormediated pathways and thus increase their atherogenic potential. It is of interest to note that estrogen supplementation in postmenopausal women reduces levels of large LDL particles.38 If under certain circumstances large LDL particles can be relatively more atherogenic, as suggested by the results of the present study, it is possible that lower levels of such particles contribute to the overall improvement in the lipoprotein risk factor profile that is observed with estrogen use.39 In the present study, the association between large LDL particles and CAD risk was independent of HDL2 cholesterol levels and other CAD risk factors. Although there may be other metabolic factors, not measured here, that could be responsible for this finding, the present results raise the possibility that some large LDL particles are atherogenic in humans.
| Acknowledgments |
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Received December 22, 1994; accepted May 8, 1995.
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M. Kratz, E. Gulbahce, A. von Eckardstein, P. Cullen, A. Cignarella, G. Assmann, and U. Wahrburg Dietary Mono- and Polyunsaturated Fatty Acids Similarly Affect LDL Size in Healthy Men and Women J. Nutr., April 1, 2002; 132(4): 715 - 718. [Abstract] [Full Text] [PDF] |
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L. Chancharme, P. Therond, F. Nigon, S. Zarev, A. Mallet, E. Bruckert, and M. J. Chapman LDL particle subclasses in hypercholesterolemia: molecular determinants of reduced lipid hydroperoxide stability J. Lipid Res., March 1, 2002; 43(3): 453 - 462. [Abstract] [Full Text] [PDF] |
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R. M. Krauss, H. Campos, and F. M. Sacks Is the Size of Low-Density Lipoprotein Particles Related to the Risk of Coronary Heart Disease? JAMA, February 13, 2002; 287(6): 712 - 713. [Full Text] [PDF] |
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H. Campos, L. A. Moye, S. P. Glasser, M. J. Stampfer, and F. M. Sacks Low-Density Lipoprotein Size, Pravastatin Treatment, and Coronary Events JAMA, September 26, 2001; 286(12): 1468 - 1474. [Abstract] [Full Text] [PDF] |
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A. Pedersen, M. W. Baumstark, P. Marckmann, H. Gylling, and B. Sandström An olive oil-rich diet results in higher concentrations of LDL cholesterol and a higher number of LDL subfraction particles than rapeseed oil and sunflower oil diets J. Lipid Res., December 1, 2000; 41(12): 1901 - 1911. [Abstract] [Full Text] |
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T. P. Carr, G. Cai, J.-Y. Lee, and C. L. Schneider Cholesteryl Ester Enrichment of Plasma Low-Density Lipoproteins in Hamsters Fed Cereal-Based Diets Containing Cholesterol Experimental Biology and Medicine, January 1, 2000; 223(1): 96 - 101. [Abstract] [Full Text] |
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L. Berglund, E. H Oliver, N. Fontanez, S. Holleran, K. Matthews, P. S Roheim, H. N Ginsberg, R. Ramakrishnan, and M. Lefevre HDL-subpopulation patterns in response to reductions in dietary total and saturated fat intakes in healthy subjects Am. J. Clinical Nutrition, December 1, 1999; 70(6): 992 - 1000. [Abstract] [Full Text] [PDF] |
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A. M. Dart and B. Cooper Independent Effects of Apo E Phenotype and Plasma Triglyceride on Lipoprotein Particle Sizes in the Fasting and Postprandial States Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2465 - 2473. [Abstract] [Full Text] [PDF] |
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K. A. Greaves, J. S. Parks, J. K. Williams, and J. D. Wagner Intact Dietary Soy Protein, but Not Adding an Isoflavone-Rich Soy Extract to Casein, Improves Plasma Lipids in Ovariectomized Cynomolgus Monkeys J. Nutr., August 1, 1999; 129(8): 1585 - 1592. [Abstract] [Full Text] |
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M. C. Mahaney, J. Blangero, D. L. Rainwater, G. E. Mott, A. G. Comuzzie, J. W. MacCluer, and J. L. VandeBerg Pleiotropy and Genotype by Diet Interaction in a Baboon Model for Atherosclerosis : A Multivariate Quantitative Genetic Analysis of HDL Subfractions in Two Dietary Environments Arterioscler Thromb Vasc Biol, April 1, 1999; 19(4): 1134 - 1141. [Abstract] [Full Text] [PDF] |
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H. Campos, B. W. Walsh, H. Judge, and F. M. Sacks Effect of Estrogen on Very Low Density Lipoprotein and Low Density Lipoprotein Subclass Metabolism in Postmenopausal Women J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 3955 - 3963. [Abstract] [Full Text] [PDF] |
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A. T.K. Singh, D. L. Rainwater, C. M. Kammerer, R. M. Sharp, M. Poushesh, W. R. Shelledy, and J. L. VandeBerg Dietary and Genetic Effects on LDL Size Measures in Baboons Arterioscler Thromb Vasc Biol, December 1, 1996; 16(12): 1448 - 1453. [Abstract] [Full Text] |
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G. L. Vega and S. M. Grundy Hypercholesterolemia With Cholesterol-Enriched LDL and Normal Levels of LDL–Apolipoprotein B : Effects of the Step I Diet and Bile Acid Sequestrants on the Cholesterol Content of LDL Arterioscler Thromb Vasc Biol, April 1, 1996; 16(4): 517 - 522. [Abstract] [Full Text] |
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