IDL Composition and Angiographically Determined Progression of Atherosclerotic Lesions During Simvastatin Therapy

From the Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Correspondence to Wayne H.F. Sutherland, Department of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand.

	Abstract

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Abstract—Some patients with coronary artery disease experience continued progression of one or more coronary lesions despite treatment with drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and markedly lower plasma cholesterol levels. We examined relationships between the progression of coronary artery lesions and plasma lipoproteins, in particular intermediate density lipoprotein (IDL) and its composition, in 38 patients with coronary artery disease who had been treated with simvastatin for 2 years. Patients were given lipid-lowering dietary advice; 3 months later they were started on simvastatin therapy (10 mg/d) for 1 month, and after review of their plasma cholesterol levels, the dose was increased to 20 mg/d and later to 40 mg/d if the target level of plasma cholesterol had not been attained. Progression of lesions was determined by serial quantitative coronary angiography (variability of 5.5%) and was defined as an increase in percent diameter stenosis (%S)10%; regression was defined as a decrease in %S 10%. The proportions of cholesteryl esters (CEs) and free cholesterol decreased significantly (P<.001), and proportions of protein and triglycerides increased significantly (P<.001) in IDL during simvastatin therapy. The CE content of IDL decreased significantly (-7.2 weight [wt]%, n=20, P<.001) in nonprogressors (patients who did not show progression of any lesions) and did not change significantly (-1.8 wt%, n=14, P=.36) in progressors (patients who showed progression of one or more lesions without regression of any lesion). This decrease in IDL CE content in nonprogressors was significantly (P=.01) different compared with the corresponding change in patients classified as progressors. Mean plasma cholesterol concentration tended to increase in progressors (0.47 mmol/L) and tended to decrease in nonprogressors (-0.39 mmol/L) during the initial 3-month diet period, and these changes were significantly different (P=.02). Furthermore, this change in plasma cholesterol level during the initial diet period was correlated significantly with the change in IDL CE content during the entire study (r=.348, n=38, P=.03). These data suggest that IDL CE content may be a determinant of progression of coronary lesions and may be influenced by compliance with or metabolic response to lipid-lowering dietary advice in patients with coronary artery disease during simvastatin treatment.

Key Words: angiography • diet • IDL • lesions • progression

	Introduction

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There is increasing evidence that IDLs are atherogenic. Plasma IDL levels have been related to the presence and severity of angiographically determined CAD^{1 2 3} and to the progression of arterial lesions.^{4 5 6} Cholesterol enrichment is also believed to increase the atherogenicity of IDL. High levels of cholesterol-enriched IDL are associated with increased atherosclerotic risk.^{7 8}

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) markedly reduce cholesterol levels in plasma apoB-containing lipoproteins, including VLDL, IDL, and LDL.^{9 10} Statin treatment also alters the chemical composition of plasma lipoproteins, and this effect is seen most noticeably in the plasma IDL fraction.¹⁰ In particular, the CE content of IDL is reduced in patients with hypercholesterolemia and symptoms of CAD who are treated with simvastatin.¹⁰ Clinical trials have shown that statins slow the progression of coronary atherosclerosis.^{11 12 13} Nevertheless, in spite of effective lipid lowering with these drugs, progression of coronary artery lesions is not halted entirely in patients with CAD who are treated with statins.^{11 12 13} In one study, 42% of patients treated with lovastatin experienced progression of one or more coronary lesions.¹³ The factors responsible for continued atherosclerotic development during treatment with statins are uncertain. Low baseline levels of plasma HDL₃ mass have been linked to progression of angiographically determined atherosclerosis in patients with CAD who were treated with lovastatin.⁴ However, progression of CAD in relation to IDL composition has not been widely studied. The aim of the present study was to examine plasma IDL cholesterol levels and IDL composition in relation to the progression of angiographically determined CAD in patients treated with simvastatin.

	Methods

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Subjects
Thirty-eight patients (aged 36 to 66 years) referred to the Cardiology Department at Dunedin Public Hospital for investigation of suspected CAD were recruited. Patients were eligible for the study if they had at least one lesion with a 25% diameter stenosis on coronary angiography. Patients were excluded if they had unstable symptoms; heart failure; a history of diabetes mellitus, hepatic disease, or renal disease or if they were receiving lipid-lowering drugs. Women with child-bearing potential or those receiving hormone replacement therapy were also excluded. Approximately equal numbers of men (n=20) and women (n=18) were enrolled in the study. All patients were given standard dietary advice aimed at reducing plasma cholesterol levels, and 3 months later they began treatment with simvastatin for 2 years until the final angiogram was recorded. The dose of simvastatin was 10 mg/d for the first month of treatment, and plasma cholesterol levels were reviewed at the end of this period. If levels were above the target value of 4.8 mmol/L, then the dose of simvastatin was increased to 20 mg/d for the following 3 months. Again, plasma cholesterol levels were reviewed, and if necessary, the dose of simvastatin was increased to 40 mg/d. The dose of simvastatin achieved at this time was maintained until the end of the trial. At baseline (at the start of the diet period), clinical data were recorded, and plasma lipids, lipoproteins, apolipoproteins, and IDL composition were measured. These measurements were repeated at the end the study. Patients were monitored monthly for the first 4 months and every 3 months thereafter. At each visit a medical examination was conducted, body weight and blood pressure were recorded, and plasma cholesterol, TG, and HDL cholesterol levels were measured. Baseline coronary angiography was performed within 3 months of the biochemical measurements. In patients who had suffered a myocardial infarction, angiographic variables and blood lipids were measured at least 6 weeks after the event. Angiograms of the left and right coronary arteries were obtained in multiple projections so that all coronary segments were visualized in at least two perpendicular views. The follow-up angiogram was obtained 29±3 (mean±SD) months after the baseline study. The use of nitrates and other vasoactive drugs, the sequence of angiographic projections, catheter size, and field size were duplicated as exactly as possible at the follow-up study. Informed consent was obtained from all patients, and the study was approved by the ethics committee of the Otago Area Health Board.

QCA
The pair of angiograms for each patient was reviewed by two cardiologists who were blinded to the patient's biochemical data. The presence and severity of stenoses were recorded for the 15 proximal coronary artery segments defined by the Ad Hoc Committee on Grading of Coronary Artery Disease of the American Heart Association.¹⁴ All lesions approaching a 25% or greater diameter stenosis by visual estimation were marked on a diagram of the coronary tree for subsequent measurement. QCA was performed blinded with respect to temporal order and biochemical results on all lesions recorded on the coronary diagram. Three end-diastolic frames in the view showing the lesion at its most severe were digitized from the angiographic film. Measurements were performed with the Ancor coronary analysis system (Siemens), with the average of the three frame measurements recorded for each lesion.¹⁵ The view of the angiographic catheter was used to calibrate the measurement system by using the known diameter of the catheter. The region of interest in the target artery was outlined, and a computer-based automatic edge-detection algorithm determined the edges of the lesion. Minimum lumen, proximal, and distal reference diameters were measured and %S was then automatically calculated by the system. Only lesions of 25% or greater diameter stenosis as determined by QCA were accepted as true stenoses. The reproducibility of the QCA system was assessed in 34 lesions. The SD of the difference for repeated measurements of the same view was 3.6% and for the same view in films performed 10 weeks apart 5.5%, which is similar to the variability reported in previous studies.¹⁶ Progression of a lesion was defined^{11 16 17} as an increase in %S 10%, and regression was defined as a decrease in lesion %S10%. The 10% criterion is appropriate because it represents three times the short-term variability and almost twice the medium-term variability of the QCA system that we employed. Progressors were defined as patients with disease progression of one or more lesions without any lesion regression. Nonprogressors were defined as patients with disease regression or no change of any lesion and without any lesions that progressed. Patients who showed both progression and regression of lesions formed a separate group. Categorical definitions of progression or nonprogression were used because they are considered to represent the most conservative approach to angiographic data analysis and use the patient as a unit of analysis, which yields results that are clinically relevant and statistically sound.¹⁸

Laboratory Methods
Subjects fasted overnight, and the next day venous blood was collected from subjects in the supine position into tubes containing disodium EDTA. Plasma was separated by low-speed centrifugation at 4°C. IDLs were separated by sequential ultracentrifugation of plasma between densities of 1.006 and 1.019 g/mL. VLDLs were isolated by ultracentrifugation of the EDTA/plasma adjusted to d=1.006 g/mL in a Beckman type 50.3 Ti rotor for 20 hours at 40 000 rpm and 15°C. The VLDL fraction was isolated in the d<1.006 g/mL fraction. The d>1.006 g/mL fraction was adjusted to d=1.019 g/mL and ultracentrifuged under the same conditions for 24 hours. IDLs were isolated in the d<1.019 g/mL fraction. Recovery of lipoprotein cholesterol from the ultracentrifugal separations was routinely 95%. Densities were checked with a Paar DMA 40 densitometer. LDL₂ cholesterol concentration was calculated by subtracting the plasma HDL cholesterol value from the total cholesterol concentration in the d>1.019 g/mL plasma fraction. Plasma HDL cholesterol was measured in the supernatant after precipitation of apoB-containing lipoproteins with dextran sulfate and MgCl₂.¹⁹ Plasma HDL₃ cholesterol was measured in the supernatant after precipitation of lipoproteins with polyethylene glycol.²⁰ Plasma HDL₂ cholesterol was calculated by subtracting the HDL₃ cholesterol value from the total HDL cholesterol value. Cholesterol, TGs, and phospholipids in plasma and plasma fractions were measured by using commercial enzymatic kits and calibrators. The coefficient of variation was 1.4% for plasma cholesterol measurements and 2.1% for plasma TG measurements. Plasma apoA-I and apoB concentrations were measured by immunoturbidimetry,²¹ and the coefficient of variation was 4.1% for apoA-I and 5.9% for apoB. Protein was measured by the method of Lowry et al.²²

Statistics
Data were loaded onto a Vax mainframe computer and analyzed by using the SPSS-X statistical package. Wilcoxon's rank sign test was used to compare paired data, and the Mann-Whitney U test was used to compare values between groups of unpaired data. Proportions were compared with Fisher's exact test and the ² test (for 3x2 tables). ANOVAs with Tukey's test was used to compare changes in IDL CE content among progressors, nonprogressors, and patients with mixed changes in lesions. ANCOVAs were used to adjust changes in variables for variations in baseline levels. ANOVA with repeated measures was used to compare plasma cholesterol levels between progressors and nonprogressors at several time points during simvastatin therapy. Pearson's product-moment correlation coefficients were used to test for relationships between variables. Two-tailed tests of significance were used, and a value of P <.05 was considered statistically significant.

	Results

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Table 1 shows the clinical characteristics and plasma levels of lipids, lipoproteins, and apolipoproteins in the patients at baseline. There were few current smokers and the majority of patients were former smokers. Approximately half had a previous history of myocardial infarction, half had current angina, and a quarter were hypertensive. Approximately half the patients were taking aspirin, over half were receiving ß-blocking drugs, and a third were using nitrates to control angina symptoms. Baseline clinical characteristics were not significantly different between men (n=20) and women (n=18) except for higher mean±SD plasma levels of apoA-I (women, 1.43±0.28 g/L; men, 1.26±0.23 g/L; P=.05) and HDL₂ cholesterol (women, 0.52±0.28 mmol/L; men, 0.38±0.15 mmol/L; P=.06) in women.

As expected, simvastatin therapy markedly reduced plasma levels of total cholesterol (-24%), VLDL cholesterol (-34%), IDL cholesterol (-45%), LDL₂ cholesterol (-33%), TGs (-11%), and apoB (-32%) and increased the levels of HDL cholesterol (9%) and HDL₂ cholesterol (23%) in the patients overall (n=38). Plasma cholesterol levels during the simvastatin treatment period (from the 4-month point until the end of the study) were not significantly (ANOVA P=.36) different in patients classified as progressors compared with those classified as nonprogressors. In the total study group, men showed a significantly greater mean±SD decrease in VLDL cholesterol (-0.33±0.25 mmol/L, P=.017), IDL cholesterol (-0.33± 0.16 mmol/L, P=.022), total TGs (-0.38±0.51, P=.027), and VLDL TGs (-0.31±0.41 mmol/L, P=.002) than women (VLDL cholesterol, -0.11±0.25 mmol/L; IDL cholesterol, -0.21±0.16 mmol/L; total TGs, 0.03±0.40 mmol/L; and VLDL TGs, 0.10±0.35 mmol/L). Mean±SD body weight did not change significantly (P=.11) in the patients overall during the study (baseline, 74.8±11.1 kg; end of study, 76.4±10.5 kg; n=38).

There were, on average, 4 lesions 25%S, 2 lesions 50%S, and 1 lesion 70%S per patient. Eighteen patients showed progression of one or more lesions, 11 showed regression of one or more lesions, 13 showed no change in lesion %S, and 4 showed mixed progression and regression of lesions. Seventy-one percent of lesions that progressed were initially <50%S. New lesions were detected in 3 patients, and the average %S increased significantly (2.8±8.1%, P<.05, n=38, mean±SD) from baseline (51.8±11.4%, mean±SD). The mean±SD change in average lesion %S was 9.7±5.6% in patients classified as progressors and -1.5±7.0% in those classified as nonprogressors.

Table 2 shows baseline levels and changes during simvastatin therapy in plasma lipids, lipoproteins, and apolipoproteins in patients classified as progressors or nonprogressors. There were no significant differences in the levels of these variables between progressors and nonprogressors. Also, on-trial levels of plasma lipids, lipoproteins, and apolipoproteins were not significantly different between progressors and nonprogressors. In patients classified as progressors, 50% were receiving simvastatin at 40 mg/d, 14% at 20 mg/d, and 36% at 10 mg/d. In patients classified as nonprogressors, the corresponding proportions were 35% (40 mg/d), 30% (20 mg/d), and 35% (10 mg/d), and these numbers were not significantly different (P=.52, ² test) when compared with the proportions in patients classified as progressors.

Table 3 indicates baseline levels and changes in IDL composition during simvastatin therapy in all patients and in those classified as progressors or nonprogressors. Composition of IDL at baseline was not significantly different between progressors and nonprogressors. CE content and free cholesterol content decreased significantly and protein content and TG content increased significantly in all patients and in patients who showed nonprogression of any lesion during simvastatin therapy. The decrease in IDL CE content in patients classified as nonprogressors was significantly greater than the corresponding change in those classified as progressors. This difference in the change in IDL CE content between progressors and nonprogressors remained significant (P=.04) when data were adjusted for baseline levels of IDL CE content by ANCOVAs. The mean±SD change in IDL CE content in patients who showed both progression and regression of lesions (-3.7±9.2%, n=4) was intermediate between the corresponding values for progressors and nonprogressors. The change in IDL CE content was significantly (ANOVA P=.03) different among progressors, nonprogressors, and patients with mixed changes in lesions. This difference was mainly due to the significant difference (P<.05, Tukey's test) in the change in IDL CE content between progressors and nonprogressors. The change in IDL content of CEs (P=.18), TGs (P=.64), phospholipids (P=.56), and protein (P=.33) were not significantly different in men (n=20) compared with women (n=18). The decrease in IDL free cholesterol content was greater at a marginal level of significance in men (men, -1.3±1.6%; women, -0.5±1.2%; mean±SD, P=.054).

Mean age (P=.39), baseline body mass index (P=.81), and numbers of months on the study (P=.98) were not significantly different between progressors and nonprogressors. Also, the proportions of men and women (P=.73), never-smokers (P=.72), hypertensives (P=.69), and those receiving ß-blocker (P=.73), nitrate (P=1.00), and aspirin (P=.50) therapies were not significantly different between these groups of patients. Mean±SD change in body weight during the study was not significantly (P=.20) different in patients classified as progressors (1.4±4.1 kg) compared with those classified as nonprogressors (1.1±5.8 kg). ß-Blocker therapy was stopped during the study in 14% (n=2) of patients who were classified as progressors and in 5% (n=1) of patients classified as nonprogressors, and these proportions were not significantly different (P=.56). ß-Blocker therapy was started during the study in 4 patients, all classified as nonprogressors. The mean±SD change in the CE content of IDL in these patients (-5.2±3.5 weight %, n=4) was not significantly different (P=.25) compared with the corresponding change in the remainder of the nonprogressors (-7.7±4.2 weight %, n=16).

The mean change in plasma cholesterol concentration between baseline and the end of the initial 3-month lipid-lowering diet period in progressors compared with nonprogressors is shown in the Figure. Plasma cholesterol concentration tended to increase in progressors and to decrease in nonprogressors during the diet period, and these changes were significantly (P=.023) different. The change in plasma cholesterol level during the diet period remained significantly (P=.02) different between progressors and nonprogressors when it was adjusted for baseline plasma cholesterol concentration by ANCOVAs. The mean±SD change in plasma cholesterol concentration at the end of the diet period in the total study population (-0.18±1.07 mmol/L, n=38) was not statistically significant (P=.29). The change in plasma cholesterol concentration at the end of the lipid-lowering diet period was correlated significantly (r=.348, n=38, P=.03) with the change in IDL CE content during the total duration of the study. Essentially similar findings were obtained when the average of plasma cholesterol concentrations at months 1, 2, and 3 was used to determine the change in plasma cholesterol during the diet period. The average plasma cholesterol value decreased significantly from baseline in nonprogressors (-0.46±0.81 mmol/L, n=20, P=.02, mean±SD) but did not change significantly in progressors (0.06±0.81 mmol/L, n=14, P=.78, mean±SD), and these changes tended to be different (P=.09). In all patients combined, the average plasma cholesterol level was significantly decreased during the diet period (-0.40± 0.96 mmol/L, n=38, P=.02, mean±SD). The correlation between this change in plasma cholesterol and the change in IDL CE content during the entire study approached statistical significance (r=.284, P=.08). The mean±SD changes in plasma TGs (P=.18), HDL cholesterol (P=.78), and body weight (P=.53) between baseline and at the end of the diet period were not significantly different between progressors (TGs, 0.12±0.49 mmol/L; HDL cholesterol, 0.01±0.32 mmol/L; and body weight, 1.5±3.7 kg; n=14) and nonprogressors (TGs, -0.13±0.49 mmol/L; HDL cholesterol, 0.06± 0.12 mmol/L; and body weight, -0.5±3.3 kg; n=20). The changes in plasma TGs and HDL cholesterol during the diet period were not correlated significantly with the changes in IDL composition in the patients (n=38) during this 2.5-year study.

View larger version (29K): [in this window] [in a new window]   Figure 1. Bar graph shows mean±SEM change in plasma cholesterol concentration between baseline and the end of the initial 3-month lipid-lowering diet period in patients treated with simvastatin who were classified as progressors (n=14) or nonprogressors (n=20). Progressors showed progression (increase percent lesion stenosis10%) of one or more lesions without regression (decrease in percent lesion stenosis10%) of any lesion. Nonprogressors did not show progression of any lesion. The changes in plasma cholesterol during the diet period were marginally significant in the progressors (P=.06) and nonprogressors (P=.08).

	Discussion

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Simvastatin therapy markedly lowers plasma levels of apoB-containing lipoproteins, increases plasma HDL cholesterol levels, slows the progression of coronary lesions, reduces the formation of new lesions, and reduces mortality from coronary heart disease.²³ However, in some patients, progression of lesions still occurs during statin treatment. Our data suggest that changes within the plasma IDL fraction may influence the changes in lesion size in patients treated with simvastatin. Specifically, a decrease in IDL CE content appears to characterize patients who do not show progression of lesions during simvastatin therapy. A decrease in CE content is consistent with a reduced atherogenicity of IDL, which may delay progression of arterial lesions.

The well-known changes in plasma levels of lipids, lipoproteins, and apolipoproteins during simvastatin therapy were observed in the present simvastatin-treated patients. The 24% reduction in plasma cholesterol level is comparable with those achieved in previous studies using monotherapy with a statin.^{12 13} The angiographic findings, including a small number of patients with new lesions (8%), progression of small to moderate lesions in 40% of patients, regression of one or more lesions in 30% of patients, and no change in lesion stenosis in the remaining 30%, were also comparable with previously reported data in patients with CAD during statin treatment.^{11 12 13}

The decrease in plasma IDL cholesterol concentration, the reductions in IDL CE content and free cholesterol, and the increase in IDL TG content during simvastatin therapy in this study are in line with previous findings.^{4 10} The decrease in plasma IDL levels during simvastatin treatment is almost entirely due to an increase in fractional catabolism of the IDL pool.¹⁰ Gaw and coworkers¹⁰ have suggested that the decrease in IDL CE content is most likely due to selective removal of cholesterol-enriched IDL, which may bind more effectively to hepatic LDL receptors than do other IDL species. Thus, the marked decrease in IDL CE content in patients who were classified as nonprogressors during simvastatin treatment in the present study may reflect increased removal of circulating cholesterol-rich IDL by the liver.

Compliance with lipid-lowering dietary advice or response to dietary changes may also have influenced IDL CE content and the progression of coronary lesions. There was evidence that patients classified as progressors may not have complied with lipid-lowering dietary advice or that their plasma cholesterol levels did not respond to any dietary changes. Plasma cholesterol levels during the initial 3-month diet-only period of the study tended to increase in these patients. In contrast, there was a clearly different trend toward a decrease in plasma cholesterol during the diet period in patients who were classified as nonprogressors, which may suggest that they followed dietary instructions and/or that their plasma cholesterol levels responded to the diet. Furthermore, the correlation between the change in plasma cholesterol during the initial diet period and the decrease in IDL CE content over the 2.5-year trial period suggests that dietary changes may have modified IDL CE content during the study. An effect of diet on plasma IDL is consistent with previous studies, which have reported that dietary cholesterol²⁴ and polyunsaturated fat²⁵ intakes influence IDL levels. However, we are not aware of any published information on the effect of diet on IDL composition.

The stabilization or regression of lesions appears to be consistent with the decrease in IDL CE content in patients classified as nonprogressors during simvastatin treatment. There is evidence that cholesterol-rich IDL is atherogenic.⁸ Increased levels of particles similar to cholesterol-enriched IDL may contribute to the accelerated atherosclerosis in patients with familial dysbetalipoproteinemia.^{7 26} Also, particles similar to IDL have been isolated from human atherosclerotic lesions.²⁷ The human arterial intima retains IDL,²⁸ which may facilitate transfer of cholesterol into arterial cells, including macrophages, that are associated with atherosclerotic plaques.²⁹ Thus, a reduced CE content in IDL may conceivably reduce the delivery of CEs to arterial lesions and thereby limit their growth. According to current theories,²⁹ alteration of the lipid core of small to moderate lesions by IDL lipids may also influence the risk of plaque fissure, thrombus formation, and rapid lesion growth. The present finding that in patients who showed progression of lesions during simvastatin treatment had failed to reduce their IDL CE content tends to support the notion that elevated levels of cholesterol-rich IDL may be important for the continuing enlargement of atherosclerotic lesions. In accord with this hypothesis, unchanged IDL CE content was accompanied by progression of one or more lesions in 88% of patients during the 2.5-year trial in a small, placebo-treated group of patients with CAD (data not shown).

Although IDL and LDL are atherogenic lipoproteins, the changes in and on-trial levels of plasma IDL and LDL₂ cholesterol were not appreciably different between patients classified as progressors compared with those classified as nonprogressors during simvastatin treatment in the current study. This finding is consistent with a previous study, which reported that plasma levels of IDL mass and LDL mass were unrelated to angiographically determined change in lesion size in patients with CAD during lovastatin therapy.⁴ In the placebo group, the on-trial masses of IDL, dense LDL, and VLDL subfractions were related to progression of arterial lesions,⁴ which suggests that statin therapy may alter the relationships between plasma lipoproteins and progression of atherosclerotic disease. While on-trial levels of IDL do not appear to determine change in intrusive coronary lesions during statin therapy, they may influence earlier stages of lesion development. Hodis and coworkers³⁰ have reported that on-trial levels of plasma IDL mass are associated with the annual rate of change in carotid artery intima-media thickness, as measured by ultrasound techniques in patients with CAD who were treated with lovastatin or placebo.³⁰ In contrast, on-trial levels of plasma LDL₂ (Svedberg flotation units 0 to 12) do not appear to influence preintrusive atherosclerosis in patients treated with statins. Further studies are required to clarify the roles of IDL and LDL in the development of atherosclerosis.

Baseline levels of plasma HDL₃ mass have been previously linked with the progression of atherosclerosis in patients treated with lovastatin.⁴ In contrast, baseline plasma HDL₃ cholesterol levels were not clearly different in progressors compared with nonprogressors in our study. Part of the explanation for this finding may be that most of the lesions that progressed in the patients we studied were initially small to moderate. Mack and coworkers⁴ have reported that when only small to moderate lesions are considered, baseline levels of plasma HDL₃ mass are no longer related to the progression of atherosclerosis. In addition, we cannot exclude the possibility that measurement of HDL₃ cholesterol by the precipitation techniques used in the present study may not be indicative of HDL₃ mass as measured previously by ultracentrifugation.⁴

There are limitations to the present study. The study population was relatively small, which increases the risk of an unusual and unrepresentative sample of patients with CAD. Thus, care must be taken in extrapolating our findings to other populations. However, apart from the absence of diabetes, the characteristics of the current patients were comparable with those in patients with CAD in previous larger studies. Lipoprotein composition was not determined in fractions other than IDL, and theoretically, this may have excluded important information on the relationship between lipoprotein composition and progression of arterial lesions. On the other hand, increasing evidence that IDL is important in the progression of arterial disease^{4 5 30} and the more pronounced effect of simvastatin therapy on the composition of IDL compared with other lipoproteins¹⁰ justify our present focus on IDL composition in relation to the progression of arterial lesions.

Plasma levels of IDL cholesterol in the patients in the present study were comparable with those in men and women with CAD as reported by Reardon and coworkers² but were higher than those in a study of Japanese patients with CAD¹ and markedly higher than those in middle-aged men referred for coronary angiography.³¹ Plasma cholesterol levels, however, were lower in the previous studies, which also reported lower plasma IDL cholesterol levels^{1 31} than in the present study. Factors responsible for these lower plasma cholesterol levels may also underlie the corresponding lower plasma IDL cholesterol levels in previous studies.^{1 31} The IDL that we isolated was richer in TGs and poorer in CEs and phospholipids than was the IDL obtained from 7 moderately hypercholesterolemic subjects¹⁰ and from 6 normolipidemic subjects³² in previous studies. It is conceivable that the d=1.006 to 1.019 g/mL plasma fraction in the present study may have also contained cholesterol-enriched VLDL (ie, VLDL₂), which is richer in TGs and poorer in CEs and phospholipids than IDL. Simvastatin treatment is known to reduce the CE content of VLDL₂,¹⁰ a potentially atherogenic lipoprotein subspecies.⁴

In conclusion, this study has identified IDL CE content as a possible determinant of progression of coronary lesions in nondiabetic patients with CAD during simvastatin therapy. Furthermore, our data suggest that the degree of compliance with lipid-lowering diet instructions or the metabolic response to this type of diet may conceivably influence IDL CE content and the progression of lesions in these patients. Thus, it may be important that CAD patients who are treated with simvastatin adhere to lipid-lowering dietary advice to delay progression of atherosclerotic disease. Factors that influence progression of coronary lesions may influence the risk of future clinical events. Substantial progression of at least one coronary lesion has been previously associated with a markedly higher risk of cardiac death.³³ Finally, the results of our study need confirmation in larger numbers of patients with CAD.

	Selected Abbreviations and Acronyms

 

CAD = coronary artery disease CE = cholesteryl ester QCA = quantitative coronary angiography %S = percent stenosis TG = triglyceride

	Acknowledgments

 
This study was supported by a grant from the National Heart Foundation of New Zealand (to E.R.N., N.J.R., and W.H.F.S.). M.J.A.W. was supported by the Southland Medical Foundation as the W&GS Dick Research Fellow. The authors are grateful to the participants in the study and to Maree McCormick for technical assistance. Also, the authors thank Merck Sharp and Dohme (NZ Ltd) for supplying simvastatin.

Received July 14, 1997; accepted November 14, 1997.

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