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(Circulation. 1997;95:2022-2026.)
© 1997 American Heart Association, Inc.

Articles

Intermediate-Density Lipoproteins and Progression of Carotid Arterial Wall Intima-Media Thickness

Howard N. Hodis, MD; Wendy J. Mack, PhD; Meleana Dunn, MS; Chao-ran Liu, MD; Ci-hua Liu, MD; Robert H. Selzer, MS; Ronald M. Krauss, MD

the Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine (H.N.H., W.J.M., M.D., C-r.L., C-h.L., R.H.S.), and the Statistical Consultation and Research Center, Department of Preventive Medicine (H.N.H., W.J.M., M.D.), University of Southern California School of Medicine, Los Angeles; the Jet Propulsion Laboratory, California Institute of Technology (R.H.S.), Pasadena; and Donner Laboratory, Ernest Orlando Lawrence Berkeley National Laboratory, University of California, Berkeley (R.M.K.).

	Abstract

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Background Although LDL cholesterol (LDL-C) is generally accepted to be a major risk factor for progression of atherosclerosis, the traditional measurement of LDL-C includes measurement of IDL. Little is known about the relationship between IDL and progression of atherosclerosis. Therefore, we investigated the association of plasma lipoprotein subclasses with progression of preintrusive carotid artery atherosclerosis in the Monitored Atherosclerosis Regression Study (MARS).

Methods and Results MARS was a randomized, double-blind, placebo-controlled serial arterial imaging trial conducted in subjects 37 to 67 years old with angiographically defined coronary artery disease. Analytical ultracentrifugation was used to determine lipoprotein subclasses, including LDL (S_f 0 to 12), IDL (S_f 12 to 20), VLDL (S_f 20 to 400), and HDL (F_1.20 0 to 9) in 188 subjects. Subjects were randomized to a cholesterol-lowering diet plus placebo or lovastatin 80 mg/d. The outcome measure, the annual progression rate of the distal common carotid artery far wall intima-media thickness determined by high resolution B-mode ultrasonography, was determined at baseline and every 6 months on trial. When the major apolipoprotein B–containing lipoproteins were measured independently, IDL (r=.21, P<.005) but not VLDL (r=-.09, P=.24) or LDL (r=.09, P=.26) was associated with the progression of carotid artery intima-media thickness.

Conclusions These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis and support the evidence that indicates that the risk of atherosclerosis attributable to LDL-C may in part be the result of lipoproteins in the IDL fraction (S_f 12 to 20) that is included within the traditional measurements of LDL-C.

Key Words: atherosclerosis • intima-media thickness • carotid arteries • coronary disease • lipoproteins

	Introduction

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It is generally believed that among the major classes of plasma lipoproteins, those within the low density range (d=1.019 to 1.063 g/mL) have the greatest effect on progression of coronary artery disease.¹ Studies in humans that have identified LDL-C as a risk factor for coronary artery disease generally have been based on the use of two common methods of LDL-C determination: (1) The "indirect" method, in which HDL-C is measured after precipitation of other lipoproteins from plasma and LDL-C is determined from the formula² LDL-C=total cholesterol-(total triglycerides/5+HDL-C), or (2) the "direct" method, in which VLDLs are separated by ultracentrifugation and LDL-C is measured in the infranatant (determined by precipitation) after subtraction of the HDL-C value. In both of these procedures, two classes of apo B–containing lipoproteins other than LDL contribute to the LDL-C measurement: IDL and lipoprotein(a).

Accumulating evidence indicates that IDL is associated with the presence, severity, and progression of coronary artery atherosclerosis.^{3 4 5 6 7 8} Two clinical trials that separately measured LDL and IDL levels have indicated a greater association of IDL than of LDL with the progression of coronary artery disease as determined by serial coronary angiography.^{3 7}

In MARS, progression of coronary artery atherosclerosis assessed by QCA was associated with LDL-C (determined by the indirect method) as well as with levels of plasma apo B and apo C-III.^{9 10} We also have reported that plasma total cholesterol, LDL-C (determined by the indirect method), apo B, apo C-III, and apo E levels each were highly significantly (P<.001) associated with the progression of early preintrusive atherosclerosis, determined by quantitative longitudinal measurement of common carotid artery IMT.¹¹ More recently, we found that masses of both IDL (S_f 12 to 20) and VLDL (S_f 20 to 400) determined by analytical ultracentrifugation also were associated with coronary artery atherosclerosis progression.³ This finding, together with the apparent consistency of the lipoprotein and apolipoprotein correlates of coronary angiographic and carotid IMT progression, prompted us to further investigate the association of plasma levels of VLDL and IDL, as well as LDL, with carotid IMT progression in MARS. The results of these analyses present compelling evidence for the atherogenicity of IDL independent of levels of LDL and VLDL.

	Methods

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MARS Study Design
MARS was a randomized, double-blind, placebo-controlled, serial coronary angiographic and carotid ultrasonographic arterial imaging clinical trial.¹² In all, 270 smoking and nonsmoking subjects (91% male, 19% current smokers) between 37 and 67 years old with plasma total cholesterol levels between 190 and 295 mg/dL were randomized to either lovastatin 80 mg/d or placebo. Treatment groups had identical dietary goals of 250 mg/d cholesterol and 27% of energy as total fat calories, 7% as saturated fat, 10% as monounsaturated fat, and 10% as polyunsaturated fat. All subjects had angiographically defined coronary artery disease in at least two segments, with one or more segments narrowed by 50% diameter stenosis. Sample size requirements were based on coronary angiographic end points.¹² Coronary angiograms were obtained at baseline and 2 and 4 years after randomization under standardized conditions; the 2-year results have been reported.⁹ Of the 270 MARS subjects, 215 (80%) randomized at the University of Southern California underwent B-mode carotid ultrasound examinations from which IMT measurements were made at baseline and every 6 months on trial. Of the 215 subjects, 188 (n=99 lovastatin, n=89 placebo) had a baseline and at least a 2-year follow-up B-mode carotid ultrasound examination: 19 subjects withdrew from the study, and 8 subjects had poor baseline B-mode image quality. Subjects had an average (±SD) of 5.3±1.3 IMT measurements over the 2-year study period.¹¹

Lipoprotein Measurements
Plasma samples for lipoprotein subclasses were obtained from study subjects after an 8-hour fast. Samples were stored at 4°C and transported on wet ice to the Donner Laboratory, Lawrence Berkeley National Laboratory, University of California, Berkeley. The total mass of lipoprotein subclasses was measured by analytical ultracentrifugation, which generates a Schlieren curve representing the distribution of lipoprotein particle mass as a function of particle flotation rate (S_f, where S_f is flotation rate at density 1.063 g/mL [this excludes HDL]). Lipoproteins of flotation rate S_f 0 to 400 were measured in the density <1.063 g/mL fraction of plasma separated by preparative ultracentrifugation.¹³ Computer-based analysis of the resulting Schlieren curves was then used to measure the total mass of VLDL in 14 intervals between S_f 20 and 400, IDL in four intervals between S_f 12 and 20, and LDL in 11 intervals between S_f 0 and 12. HDLs of flotation rate F_1.20 0 to 9 (where F_1.20 is flotation rate at solvent density 1.21 g/mL [this includes HDL]) were measured in the density <1.21 g/mL fraction of plasma.¹³ Specific intervals were combined to obtain measures of total lipoprotein mass of three HDL subclasses (HDL₂ [F_1.20 3.5 to 9], HDL₃ [F_1.20 0 to 3.5], and total HDL [F_1.20 0 to 9]), five LDL subclasses (LDL₄ [S_f 0 to 3], LDL₃ [S_f 3 to 5], LDL₂ [S_f 5 to 7], LDL₁ [S_f 7 to 12], and total LDL [S_f 0 to 12]), one IDL subclass (S_f 12 to 20), and four VLDL subclasses (small VLDL [S_f 20 to 60], intermediate VLDL [S_f 60 to 100], large VLDL [S_f 100 to 400], and total VLDL [S_f 20 to 400]). Samples for measurements of lipoprotein subclasses were obtained at one baseline visit and four on-trial visits (every 6 months on trial).

Ultrasound Imaging and Image Analysis
Ultrasound imaging and IMT image analysis methods and reproducibility have been described previously.^{14 15} B-mode scanning was performed with a Diasonics CV400 ultrasound system using a 7.5-MHz probe. Longitudinal views of the far wall of the right distal common carotid artery were recorded with minimum gain necessary for clear visualization of structures.

With treatment assignment masked, an image analyst measured IMT by automated computerized edge detection using a 386/33 PC equipped with a Data Translation DT 2862 image processing board. Our automated computerized edge-finding algorithm results in closely spaced measurements of IMT, 100 points per centimeter, from which average IMT is determined. The distance between the echoes arising from the blood-intima interface and the media-adventitia interface was taken as the measure of the IMT complex.¹⁶ The automated computerized edge-detection method has been described.¹⁵

Statistical Analysis
For subjects with carotid IMT end points, treatment group comparisons were made on baseline and on-trial change from baseline for all levels of the lipoprotein subclasses with a Wilcoxon rank-sum test. On-trial levels of the subclasses were computed as an average over all on-trial measures. Of the 188 subjects with carotid IMT end points, lipoprotein subclass data were not available for 7 subjects at baseline and 1 subject on trial, leaving 180 subjects for this analysis.

A least-squares regression line relating IMT to time since baseline ultrasound was determined for each subject to provide a subject-specific estimate of the annual carotid IMT progression rate. On-trial levels of the lipoprotein subclasses were correlated with carotid IMT progression rate by use of Pearson correlation coefficients. Prior analyses had indicated a strong correlation between baseline levels of IMT and IMT progression rate in the drug (r=-.51) but not the placebo (r=-.06) group.¹¹ For this reason, all correlations between on-trial lipoprotein subclasses and IMT progression rate were computed as partial correlations, with adjustment for baseline IMT and baseline levels of the lipoprotein subclasses. These partial correlations were computed within each treatment group; partial correlation coefficients, with adjustment for treatment group and baseline levels of carotid IMT and lipoprotein subclasses, were computed over the combined sample.

To determine whether the relationship between particular lipoprotein subclasses and IMT progression rate varied by treatment group, correlations computed by treatment group were tested for differences by a Fisher's Z transformation.¹⁷

Stepwise linear regression models were used to determine statistically independent correlates of carotid IMT progression rate. Treatment group and baseline carotid IMT were initially forced into the model. Additional independent variables that were allowed to enter into a forward stepwise selection procedure included univariately significant lipoprotein subclasses and specific apolipoproteins and lipoproteins that had been found to be related to carotid IMT progression in previous analyses.¹¹ These variables included apo B, apo C-III, apo E, LDL-C, and IDL mass (S_f 12 to 20).

	Results

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Baseline and On-Trial Changes in Lipoprotein Subclasses
Table 1 summarizes baseline and on-trial changes in the lipoprotein subclasses for the study cohort. There were no significant differences in any of the baseline lipoprotein subclass levels between treatment groups. The lovastatin-treated group showed statistically significant on-trial decreases in all LDL, IDL, and VLDL subclasses relative to the placebo-treated group; HDL₂ but not HDL₂ showed a significant on-trial increase in the lovastatin-treated group.

View this table: [in this window] [in a new window]   Table 1.

Lipoprotein Subclass Relationship to Progression of Carotid IMT
Table 2 shows the partial correlations between major lipoprotein subclasses and the annual progression rate of carotid IMT. In the two treatment groups combined and within each treatment group individually, the on-trial total IDL (S_f 12 to 20) level was the only lipoprotein variable significantly correlated (after adjustment for treatment group, baseline IMT, and baseline IDL level) with progression of carotid IMT.

View this table: [in this window] [in a new window]   Table 2.

No LDL, VLDL, or HDL subclass was significantly associated with progression of carotid IMT for the combined sample. The LDL subclasses showed the following correlations with carotid IMT: LDL₄ (S_f 0 to 3, r=-.04), LDL₃ (S_f 3 to 5, r=.07), LDL₂ (S_f 5 to 7, r=.09), and LDL₁ (S_f 7 to 12, r=.01). Correlations with VLDL and HDL subclasses were as follows: small VLDL (S_f 20 to 60, r=-.05), intermediate VLDL (S_f 60 to 100, r=-.10), large VLDL (S_f 100 to 400, r=-.09), HDL₂ (F_1.20 3.5 to 9, r=.02), and HDL₂ (F_1.20 0 to 3.5, r=.07).

Examined by quartiles of the annual rate of change in carotid IMT, increasing levels of total IDL are clearly associated with a greater progression rate of carotid IMT. As demonstrated in the Figure, subjects at the highest quartile of change in carotid IMT (0.03 to 0.12 mm/y) had a mean total IDL level of 52.0±15.3 mg/dL, whereas subjects at the lowest quartile of annual rate of change in carotid IMT (-0.18 to -0.05 mm/y) had a mean total IDL level of 42.9±14.9 mg/dL (P=.01 between lowest and highest quartiles; P=.01 for test for linear trend in mean IDL by quartiles).

View larger version (15K): [in this window] [in a new window]   Figure 1. On-trial levels of total IDL examined by quartiles of annual rate of change in carotid IMT (P=.01 for test for linear trend in mean IDL by quartiles). IDL reported as least-squares mean±SD adjusted for treatment group, baseline IDL, and baseline IMT.

In the multivariate stepwise model, forcing in treatment group and baseline carotid IMT and allowing apo B, apo E, LDL-C, and IDL mass (S_f 12 to 20) to enter the model, IDL was the first variable to enter. Once IDL entered into the model, no other lipoprotein or apolipoprotein variables remained statistically correlated with the progression of carotid IMT.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Although LDL-C is widely accepted as a major risk factor for the development and progression of coronary artery atherosclerosis, the measurement of LDL-C has generally also included measurement of IDL.¹ Little is known about the relationship between IDL and progression of coronary artery atherosclerosis in general, and there are no reports examining the relationship between IDL and progression of early preintrusive atherosclerosis (IMT) specifically.

In this study, we present compelling evidence that when the major apo B–containing lipoproteins are measured independently, IDL (S_f 12 to 20) but not VLDL (S_f 20 to 400) or LDL (S_f 0 to 12) is associated with the progression of early preintrusive carotid atherosclerosis. The results of this study are striking in that lipoproteins within the narrow IDL range of S_f 12 to 20 are significantly correlated (r=.24, P<.001) with the progression of carotid IMT, whereas the lipoproteins that flank this narrow range of IDL, LDL S_f 0 to 12 and VLDL S_f 20 to 400, are poorly correlated with the progression of carotid IMT, r=-.10 to 0.09. In the same cohort of MARS subjects, we have reported IDL (S_f 12 to 20), VLDL (S_f 20 to 400), and very small dense LDL₄ (S_f 0 to 3) to be risk factors for the progression of coronary artery atherosclerosis, measured by serial QCA.³ Therefore, by two independent measures of atherosclerosis progression, QCA for coronary artery atherosclerosis and IMT for carotid atherosclerosis, the relationship between IDL and progression of atherosclerosis has been demonstrated. Considering the trial inclusion/exclusion criteria that defined the present sample, it is important that these results be confirmed in a more heterogeneous cohort. Furthermore, although the current data relate to total lipoprotein mass, whether IDL-C demonstrates a similar relationship needs to be determined.

The lack of significant relationships of levels of VLDL and small dense LDL with carotid IMT progression may be indicative of a role for these lipoproteins in the more advanced intrusive lesions detected by coronary angiography but not in the progression of early preintrusive atherosclerosis detected by carotid IMT. Alternatively, the specificity of the relationship with IDL alone may be a chance finding and should be reproduced in future studies.

In a previous report, we demonstrated that among standard lipoprotein and apolipoprotein measurements, apo B was the strongest single significant correlate to the progression of carotid IMT.¹¹ In the multivariate stepwise model, allowing apo B, apo E, LDL-C, and IDL (S_f 12 to 20) to enter the model, IDL mass was the first variable to enter. Once IDL entered into the model, no other lipoprotein or apolipoprotein variables remained statistically correlated with the progression of carotid IMT. This suggests that IDL fully accounted for the relationship between apo B and progression of carotid IMT.

Although no other data examining the relationship between IDL and progression of early preintrusive atherosclerosis (carotid IMT) are available, several studies have examined the relationship between IDL and coronary artery atherosclerosis (intrusive atherosclerosis). Earlier cross-sectional studies have indicated that VLDL and IDL are independent correlates of the presence and severity of coronary artery atherosclerosis.^{4 5 6} In one of these studies, plasma IDL was a stronger correlate of the presence of coronary artery atherosclerosis than were plasma LDL, VLDL, or HDL levels.⁵ Results from the NHLBI type II study using the same analytical ultracentrifugational methodology as that reported here in MARS demonstrated prospectively that change in IDL and the ratios of HDL-C to total cholesterol and HDL-C to LDL-C all predicted coronary artery atherosclerosis progression to a similar degree.⁷ However, these measures were not independently predictive of progression in multivariate models.⁷

Experimental evidence in animals has also indicated that triglyceride-rich lipoproteins in the IDL and small VLDL fraction (S_f 12 to 60) are better predictors of the extent of atherosclerosis than LDL-C.¹⁸ Recent data have demonstrated that human atherosclerotic lesions contain IDL and VLDL,¹⁹ and experimental evidence indicates that the smaller triglyceride-rich lipoproteins, IDL and small VLDL, are retained by the arterial intima.²⁰

In conclusion, our data present compelling evidence that lipoproteins in the IDL fraction (S_f 12 to 20) are associated with progression of atherosclerosis as directly quantified by arterial wall IMT measurements, whereas lipoproteins in the LDL and VLDL density ranges are not associated with progression of carotid IMT. These data provide further evidence for the role of triglyceride-rich lipoproteins in the progression of atherosclerosis²¹ and support the suggestion that the risk of atherosclerosis attributable to LDL-C may be the result of the IDL included within the traditional LDL-C measurements.^{1 7} This notion is further substantiated by the finding that the relationship between apo B and carotid IMT progression noted in the MARS data is fully explained by IDL. These results have important clinical implications, since specific measurements of plasma IDL could improve the identification of individuals at risk for atherosclerotic disease. Moreover, although current lipid-lowering agents are effective in reducing IDL concentrations, treatment strategies as well as pharmacological agents could be developed that more specifically target reduction in IDL levels. Taken together with our earlier studies in coronary artery progression, our data strongly indicate that the involvement of triglyceride-rich lipoproteins in atherogenesis merits greater clinical attention.

	Selected Abbreviations and Acronyms

 

HDL-C = HDL cholesterol IMT = intima-media thickness LDL-C = LDL cholesterol MARS = Monitored Atherosclerosis Regression Study QCA = quantitative coronary angiography Sf = Svedberg flotation rate

	Acknowledgments

 
This study was supported in part by National Heart, Lung, and Blood Institute grant RO1-HL-49885, Program Project Grant HL-18574, a grant from the National Dairy Promotion and Research Board administered in cooperation with the National Dairy Council, and Merck & Co and conducted at the Lawrence Berkeley National Laboratory through the US Department of Energy under contract No. DE-AC03-76SF00098.

	Footnotes

 
Reprint requests to Howard N. Hodis, MD, Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar St, CSC 132, Los Angeles, CA 90033.

Received September 4, 1996; revision received November 18, 1996; accepted November 22, 1996.

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