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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1995;15:1043-1048.)
© 1995 American Heart Association, Inc.

Articles

Predominance of Large LDL and Reduced HDL₂ Cholesterol in Normolipidemic Men With Coronary Artery Disease

Hannia Campos; Ghislaine O. Roederer; Suzanne Lussier-Cacan; Jean Davignon; Ronald M. Krauss

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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Abstract Previous studies have indicated that a predominance of small, dense LDL particles is associated with coronary artery disease (CAD) risk. In the present study we examined the LDL peak particle diameter (determined by lipid-stained 2% to 16% gradient gel electrophoresis) in 92 normolipidemic men with CAD (total cholesterol <200 mg/dL and triglyceride <250 mg/dL) and 92 matched healthy controls. Plasma triglyceride, LDL cholesterol, and apo B levels were similar in subjects with CAD and in control subjects, whereas subjects with CAD had decreased HDL₂ cholesterol levels (mean±SEM, 10±0.7 compared with 15±0.7 mg/dL in control subjects; P<.0002). Mean LDL particle diameter (±SEM) was increased in the subjects with CAD compared with control subjects (26.8±0.08 and 26.4±0.08 nm, respectively; P<.001). The association between large LDL size and CAD was significant (P<.0001) after adjustments were made for age, body mass index, HDL cholesterol levels, and VLDL cholesterol levels. An LDL particle size distribution characterized by a predominance of the largest of three classes of LDL particles (>26.8 nm) was more prevalent among subjects with CAD (43%) than among control subjects (25%) (P<.002). Among subjects with this LDL size profile, subjects with CAD had significantly higher (P<.05) VLDL triglyceride, VLDL cholesterol, and VLDL apo B levels and significantly lower (P<.0001) HDL₂ cholesterol levels than controls. Thus, in this normolipidemic population with CAD, a predominance of very large rather than small LDL particles was associated with increased VLDL and reduced HDL₂ cholesterol levels and with increased CAD risk, independent of other plasma lipid and lipoprotein levels.

Key Words: coronary artery disease • LDL subclasses • LDL size • VLDL cholesterol • HDL

	Introduction

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Despite strong independent associations between plasma lipoprotein fractions and coronary artery disease (CAD),^{1 2 3} several studies have shown that about 30% of patients with premature atherosclerosis have normal plasma total and LDL cholesterol levels,^{4 5} as defined by the National Cholesterol Education Program guidelines.² Recently it was reported that 46% of middle-aged men with premature CAD had "desirable" total cholesterol levels (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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Subjects
Subjects with CAD were recruited at the time of admission for coronary angiography to one of three Montreal hospitals, and were sampled within 3 months of the angiogram or at 3 months if they had undergone major surgery or had sustained a myocardial infarction at the time of the angiographic admission. Coronary artery disease was defined as 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 B–containing 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 high–molecular 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

Top Abstract Introduction Methods Results Discussion References

 
Although significant effects of ß-blockers on plasma lipoproteins and LDL particle size have been reported for mildly hypercholesterolemic patients with CAD,¹⁵ we found that plasma lipoprotein levels and LDL particle diameter in normolipidemic subjects with CAD who were taking this medication were very similar to those not taking them (Table 1). Therefore, we included all the patients with CAD in our case-control comparisons.

View this table: [in this window] [in a new window]   Table 1. Lipoprotein Parameters in Normolipidemic Men With Coronary Artery Disease According to ß-Blocker Use

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).

View larger version (36K): [in this window] [in a new window]   Figure 1. Bar graphs indicate the LDL particle diameter frequency distribution in normolipidemic men with coronary artery disease (CAD) and control subjects. The arrows indicate the percentiles for the control population. The corresponding LDL diameters for each LDL subclass group are: LDL I >26.8 nm (268 Å), LDL II 26.8 and 26.0 nm (268 and 260 Å, respectively), and LDL III <26.0 nm (260 Å). In the group of men with CAD 14% were below the 25th percentile for LDL particle size and 43% were above the 75th percentile, compared with 24% and 25%, respectively, in the control group. The frequency distribution was significantly different between subjects with and without CAD (2=14.6, P=.002).

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.

View this table: [in this window] [in a new window]   Table 2. Lipoprotein Parameters in Normolipidemic Men With Coronary Artery Disease and Control Subjects

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}

View this table: [in this window] [in a new window]   Table 3. Pearson Correlation Coefficients Between Plasma Parameters and LDL Particle Size in Normolipidemic Men With Coronary Artery Disease and Control Subjects

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.

View this table: [in this window] [in a new window]   Table 4. Triglyceride and HDL Cholesterol Levels by LDL Subclass in Normolipidemic Men With Coronary Artery Disease and Control Subjects

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.

View this table: [in this window] [in a new window]   Table 5. Discriminators for Coronary Artery Disease Risk in Normolipidemic Men

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study afforded the opportunity to examine the relation of LDL particle size to risk for CAD in a subset of subjects selected to be normolipidemic and free of obesity, diabetes, and hypertension. It is highly likely that the exclusion criteria, particularly triglyceride >250 mg/dL, resulted in the finding of a much lower prevalence of men with small LDL peak particle diameter than that described for unselected populations.^{14 27 28} If a cutoff of 25.5 nm is used to define small LDL (subclass pattern B) as previously reported,²⁸ the prevalence in our study was 7% for the patients with CAD and 11% for the control group, compared with results from other studies indicating prevalences of 48% to 54% among patients with CAD or myocardial infarction^{14 15} and 25% to 33% among free-living men in the United States.^{14 27 28} In the selected population of the present study, we found that a predominance of large LDL particles was significantly positively associated with CAD risk.

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 subjects^{6 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-receptor–mediated 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

 
This work was supported in part by National Institutes of Health grants HL-18574 and HL-33577 from the National Heart, Lung, and Blood Institute and a grant from the National Dairy Promotion and Research Board administered in cooperation with the National Dairy Council, and was conducted in part at the Lawrence Berkeley Laboratory through the US Department of Energy under contract DE-AC03-76SF00098. This work was also sponsored in part by grants from the Medical Research Council of Canada (MA-5427) and the Medical Research Council of Canada/CIBA-GEIGY Canada Ltd (UI-11407). We wish to thank Patricia Blanche and Laura Holl for performing gradient gel electrophoresis.

Received December 22, 1994; accepted May 8, 1995.

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