© 1997 American Heart Association, Inc.
Articles |
The Role of Triglyceride-Rich Lipoprotein Families in the Progression of Atherosclerotic Lesions as Determined by Sequential Coronary Angiography From a Controlled Clinical Trial
From the Lipid and Lipoprotein Laboratory, Oklahoma Medical Research Foundation (P.A., C.K.-G.), Oklahoma City, Oklahoma, and the Atherosclerosis Research Unit, Division of Cardiology, Departments of Medicine and Preventive Medicine (W.J.M., H.N.H.), University of Southern California, Los Angeles.
Correspondence 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.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract We have demonstrated previously in a subset of Monitored Atherosclerosis Regression Study (MARS) subjects with hypercholesterolemia (190 to 295 mg/dL) and documented coronary artery disease that lovastatin significantly reduces cholesterol-rich lipoprotein B (LpB) but has little effect on complex, triglyceride-rich apolipoprotein (apo) B–containing LpBc (the sum of LpB:C, LpB:C:E and LpA-II:B:C:D:E) particles defined by their apolipoprotein composition. This differential effect of lovastatin on apoB-containing lipoprotein families offered the opportunity to determine in the same subset of MARS subjects the independent relationship of LpB and LpBc with the progression of coronary artery disease. Subjects randomized to either lovastatin (40 mg twice daily) or matching placebo were evaluated by coronary angiography before randomization and after 2 years of treatment, and the overall coronary status was judged by a coronary global change score. In the lovastatin-treated group, there were 22 nonprogressors (69%) and 10 progressors (31%), while in the placebo group 13 subjects (42%) were nonprogressors and 18 (58%) were progressors (P<.03). In the lovastatin-treated group, lipid and lipoprotein parameters did not differ between progressors and nonprogressors except for LpBc and LpA-II:B:C:D:E particle levels, which were statistically higher in progressors (P=.02). In the placebo-treated group, progressors differed from nonprogressors by having significantly higher levels of triglycerides (P=.03) and apoC-III in VLDL+LDL (P=.05), the characteristic constituents of triglyceride-rich lipoproteins. In the placebo- and lovastatin-treated groups combined, progressors had significantly higher on-trial levels of triglycerides (P=.003), VLDL cholesterol (P=.005), apoC-III in VLDL+LDL (P=.008), apoC-III (P=.01), apoB (P=.03), and total cholesterol (P=.04) than nonprogressors. Even after adjustment for treatment group, progressors in the combined placebo- and lovastatin-treated groups had significantly higher levels of LpBc, LpA-II:B:C:D:E, triglycerides, and apoC-III in VLDL+LDL than nonprogressors. Progressors in the placebo-treated, lovastatin-treated, and combined treatment groups had lower levels of LpA-I but not LpA-I:A-II than nonprogressors, and this difference reached statistical significance (P=.047) in the combined sample adjusted for treatment group. Results of this study show that elevated levels of triglyceride-rich LpBc in general and LpA-II:B:C:D:E in particular contribute significantly to the progression of coronary artery disease. Furthermore, they provide additional evidence for the potentially protective role of LpA-I particles in the atherogenic process and suggest that apolipoprotein-defined lipoprotein families may be more specific prognosticators of coronary artery atherosclerosis progression than lipids and apolipoproteins.
Key Words: atherosclerosis • apolipoproteins • clinical trials • lipoprotein particles
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
To determine the effect of lovastatin on the concentrations of apoA- and apoB-containing lipoprotein families, we measured these concentrations in a randomly selected subset of subjects with moderate hypercholesterolemia and coronary artery disease from MARS.1 MARS was a randomized, double-blind, placebo-controlled serial coronary angiographic trial designed to assess the effect of lovastatin on the progression of atherosclerosis.2 Results of this study demonstrated that lovastatin had a differential effect on apoB-containing lipoprotein families.1 After 2 years of treatment, subjects receiving lovastatin had significantly lower concentrations of cholesterol-rich LpB; however, lovastatin- and placebo-treated subjects did not differ in the levels of complex, apoB-containing triglyceride-rich lipoprotein particles (LpBc) encompassing LpB:C, LpB:C:E, and LpA-II:B:C:D:E. Furthermore, lovastatin had very little effect on the levels of LpA-I and LpA-I:A-II particles.
Because of the differential effect of lovastatin on LpB and LpBc particles, MARS has provided the opportunity to study the independent relationship of these apoB-containing lipoprotein families with the progression of coronary artery atherosclerosis. Moreover, because of the lack of any significant effect of lovastatin on LpA-I and LpA-I:A-II and the lack of correlation of these lipoprotein particles with LpB and LpBc, MARS has also provided the opportunity to study the effect of triglyceride-rich lipoproteins on the progression of coronary artery atherosclerosis at practically unchanged concentrations of "protective" HDL particles. With aggressive lowering of LDL and concurrent lowering of LpB, the independent lesion effect of LpBc could thus be studied.
Although results from several randomized serial coronary angiographic trials3 4 have demonstrated combined benefits from reduction of LDL cholesterol and triglyceride levels with concomitant raising of HDL cholesterol levels, none of these trials have specifically evaluated the effects of the lowering of triglyceride-rich lipoproteins on the progression of coronary artery disease. The first compelling evidence of an association between change in triglyceride-rich lipoproteins and coronary artery atherosclerosis originated from the Cholesterol Lowering Atherosclerosis Study (CLAS).5 In this study, the elevated concentration of apoC-III in HDL, indicative of an efficient catabolism of triglyceride-rich lipoproteins,6 was significantly correlated with the stabilization of coronary artery atherosclerotic lesions in subjects randomized to colestipol/niacin treatment. Results from the MARS study have confirmed the association of apoC-III levels and progression of coronary artery disease.7
In the present study of a subpopulation of MARS participants, the role of triglyceride-rich lipoprotein particles in the progression of coronary artery atherosclerosis has been evaluated not only indirectly by measuring the distribution of apoC-III among major lipoprotein density classes7 but also directly by comparing the concentrations of individual apoB-containing triglyceride-rich lipoprotein families and apoA-containing lipoprotein families in subjects with and without progression of coronary artery atherosclerosis after 2 years of treatment with either lovastatin or placebo. Results of the present study demonstrate the significant atherogenicity of triglyceride-rich LpBc particles and provide additional evidence for the protective role of LpA-I particles in the atherogenic process.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
The design and outcome of the MARS study have been described in detail.2 7 8 In brief, the study cohort of 270 subjects (91% men) aged 21 through 67 years with hypercholesterolemia (total cholesterol 190 to 295 mg/dL) and angiographically documented coronary artery disease were randomized to a cholesterol-lowering diet and either lovastatin (40 mg twice daily) or matching placebo tablets twice daily. Baseline and 2-year follow-up coronary angiograms were completed in 247 subjects.
Evaluation of Coronary Angiograms
Coronary angiograms were evaluated by a panel of expert angiographers and a moderator blinded to treatment group assignment and order of angiograms. A coronary GCS based on the consensus of the panel regarding angiographic change was derived.2 5 8 The assigned GCS was a four-point scale ranging from 0 (no change) to 3 (extreme change). The direction of change was applied after the study was completed and ranged from -3 (extreme regression) to +3 (extreme progression).
Determination of Lipids, Apolipoproteins, and Lipoprotein Families
ApoA- and apoB-containing lipoprotein families were measured in a subset of 63 subjects who were randomly selected from the total 270 randomized MARS subjects.1 Lipids and apolipoproteins were determined in all MARS subjects at the time of randomization (baseline levels) and every 4 months on trial. The apoA- and apoB-containing lipoprotein families were analyzed after 2 years of treatment. Blood drawing and the preparation and storage of plasma samples have been previously described.1 7
The determination of lipids (total cholesterol, triglycerides, and HDL cholesterol), apolipoproteins (A-I, B, C-III, and E), and apoC-III in heparin-Mn2+ supernatants (apoC-III–HS) and precipitates (apoC-III–HP) was performed according to previously described procedures.1 ApoC-III–HS is equivalent to the concentration of apoC-III in HDL, and apoC-III–HP to that of apoC-III in VLDL+LDL. The apoA-containing lipoprotein families, LpA-I and LpA-I:A-II, were measured by immunoaffinity chromatography on an anti–apoA-II immunosorber. The apoB-containing lipoprotein families, including LpB, LpBc (the sum of LpB:C, LpB:C:E, and LpA-II:B:C:D:E particles), LpB:C+LpB:C:E, and LpA-II:B:C:D:E, were quantified by immunoaffinity chromatography using anti–apoA-II and anti–apoC-III immunosorbers. The concentrations of LpA-I and LpA-I:A-II families are expressed in terms of apoA-I values, and those of LpB and LpBc families in terms of apoB values. A detailed description of procedures used for the preparation of immunosorbers and performance of immunoaffinity chromatography of both the apoA- and apoB-containing lipoprotein families has been previously reported.1
Statistical Analysis
Coronary angiographic progression was defined using the coronary GCS, with a GCS >0 representing overall coronary angiographic lesion progression and a GCS 
0 representing nonprogression. Treatment group comparisons on GCS-defined progressors were performed with a 
2 test. Within the treatment group and in the combined sample, on-trial lipids, lipoproteins, apolipoproteins, and lipoprotein families were tested for differences between progressors and nonprogressors by using the nonparametric Wilcoxon rank sum test. In the combined sample, on-trial lipids, lipoproteins, apolipoproteins, and lipoprotein particles were regressed against treatment group. The residuals from those regressions were then compared between progressors and nonprogressors by Wilcoxon rank sum tests, thereby providing additional comparisons in the combined sample, adjusted for treatment group. Logistic regression analyses were used to compute odds ratios as estimates of the relative risk for coronary angiographic progression by tertiles of relevant lipoprotein families. The lipoprotein particle distribution in the entire sample was used to define the tertiles. Tests for trend in the relative risk used lipoprotein families as continuous variables. A two-sided alpha level of .05 was used for all significance testing.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Clinical Characteristics of the MARS Cohort
As shown previously, there were no differences in the clinical characteristics and lipid, lipoprotein, and apolipoprotein profiles between the subset of 63 randomly selected subjects and the total randomized 270 MARS subjects, except for lower baseline apoB levels.1 The 31 placebo-treated and 32 lovastatin-treated subjects of the MARS subset population were well matched with respect to age, weight, systolic and diastolic blood pressure, gender, and smoking habits; there were no significant differences between the two treatment groups in baseline lipid, lipoprotein, and apolipoprotein values.1 After 2 years of treatment, the lovastatin-treated group had significantly reduced levels of total cholesterol (33%, P<.0001), triglycerides (30%, P<.02), VLDL cholesterol (36%, P<.002), LDL cholesterol (43%, P<.0001), apoB (36%, P<.0001), apoC-III (18%, P<.008), and apoE (17%, P<.02) in comparison with the placebo-treated group. Levels of HDL cholesterol (6%) and apoA-I (1%) were slightly raised but were not significantly different between treatment groups. Comparing lipoprotein families after 2 years of randomized treatment, the main effect of lovastatin was a significant reduction in the levels of cholesterol-rich LpB particles (40%, P<.0001), with very little effect on the levels of intact and/or partially delipidized triglyceride-rich LpB:C+LpB:C:E and LpA-II:B:C:D:E particles. Lovastatin treatment slightly increased the concentration of LpA-I (4%) and LpA-I:A-II (8%) particles; these changes were not statistically significant.1
Effect of Lovastatin Treatment on the Progression of Coronary Artery Lesions
After 2 years of treatment, 10 subjects (31%) receiving lovastatin progressed (GCS>0) and 22 subjects (69%) treated with lovastatin regressed or showed no change in their coronary artery status (GCS0). In comparison, 18 subjects (58%) receiving placebo progressed and 13 placebo subjects (42%) regressed or showed no change (P<.03).
Relationship of Lipoprotein Variables to the Progression of Coronary Artery Lesions
In the placebo-treated group, progressors had significantly higher levels of triglycerides (P<.03) and apoC-III–HP (P<.05) than did nonprogressors. There were no significant differences in other measured lipids, lipoproteins, and apolipoproteins (Table 1
). The evaluation of apoA-containing lipoprotein families showed that progressors had lower concentrations of LpA-I (P=.06) and nonsignificantly higher concentrations of LpA-I:A-II than nonprogressors (Table 2). Although progressors in the placebo-treated group had higher levels of LpA-II:B:C:D:E and LpBc particles than nonprogressors, these differences were not statistically significant, presumably due to a relatively small number of subjects (Table 2).
|
|
In the lovastatin-treated group, there were no significant differences between progressors and nonprogressors in the concentrations of measured lipids, lipoproteins, and apolipoproteins (Table 1
). Similar to the placebo-treated group, the concentrations of LpA-I were lower and those of LpA-I:A-II higher in progressors than nonprogressors, but statistical significance was not reached (Table 2). There was no difference between progressors and nonprogressors in the level of cholesterol-rich LpB. However, progressors were characterized by significantly elevated concentrations of LpBc (P=.02), representing the sum of the three major triglyceride-rich lipoprotein families. Among the individual triglyceride-rich lipoproteins comprising LpBc, the significantly increased concentration of LpA-II:B:C:D:E particles (P=.02) was found to be the main contributor to the elevated concentration of LpBc particles; the increased concentration of the LpB:C+LpB:C:E particles did not reach statistical significance.
In the placebo- and lovastatin-treated groups combined, there were 35 nonprogressors (56%) and 28 progressors (44%) (Table 3). Progressors had significantly higher on-trial concentrations of triglycerides (P=.003), VLDL cholesterol (P=.005), apoC-III–HP (P=.008), and apoC-III (P=.01) than nonprogressors. In addition to these typical constituents of triglyceride-rich lipoproteins, progressors also had significantly higher levels of apoB (P=.03) and total cholesterol (P=.04) in comparison with nonprogressors. However, there was no significant difference between progressors and nonprogressors in the on-trial levels of LDL cholesterol, apoC-III–HS, and apoE. These results were clearly reflected in directly measured apoB-containing lipoprotein families: progressors had significantly higher concentrations of LpBc (P=.02) and LpA-II:B:C:D:E (P=.01) lipoprotein families than nonprogressors. On the other hand, the levels of cholesterol-rich LpB particles, albeit slightly higher in progressors than nonprogressors, were not statistically significant (P=.07). After adjusting lipid, lipoprotein, apolipoprotein, and lipoprotein family data for treatment group, progressors still had significantly higher concentrations of triglycerides (adjusted mean±SD=195±84 versus 132±84 mg/dL, P=.05) and apoC-III–HP (6.0±2.4 versus 4.7±2.4 mg/dL, P=.05) than nonprogressors. Progressors also had higher levels of apoC-III and VLDL cholesterol of borderline significance (P=.08 and P=.09, respectively). Whereas the concentrations of LpBc (11.8±5.5 versus 7.3±5.5 mg/dL, P=.003) and LpA-II:B:C:D:E (7.9±4.3 versus 5.3±4.3 mg/dL, P=.008) particles remained significantly higher in progressors than nonprogressors, the concentrations of LpB particles were almost identical (90.0±17.7 versus 89.7±17.7, not significant) after adjustment for treatment group.
|
Progressors had nonsignificantly lower levels of LpA-I particles than nonprogressors despite similar HDL cholesterol and apoA-I levels (Table 3). After adjustment for treatment group, the concentrations of LpA-I particles were significantly lower in progressors than nonprogressors (19.5±14.3 versus 31.3±14.3 mg/dL, P<.05). There was no difference between progressors and nonprogressors in the concentration of LpA-I:A-II particles whether unadjusted or adjusted for treatment group.
The progression/nonprogression of coronary artery atherosclerosis in the subset of MARS subjects was also determined by QCA, which was the primary end point in the total MARS cohort.2 However, due to a smaller number of subjects evaluated by QCA, data presented in the present study are based on GCS as a means of defining the progression of coronary artery atherosclerosis. The results for QCA progression are strikingly similar to those determined by GCS, with some loss of statistical significance due to a smaller sample size. The significant variables included triglycerides (P=.003), VLDL cholesterol (P=.02), LpA-II:B:C:D:E (P=.03), and apoA-I (P=.02).
To further evaluate the significance of triglyceride-rich LpBc particles for the progression of atherosclerosis, the LpBc levels in the total sample subpopulation of MARS subjects were subdivided into tertiles. The percentages of subjects with coronary artery lesion progression and odds ratios for progression were computed for each tertile (Table 4). The lovastatin-treated group clearly illustrates the effect of increasing concentrations of triglyceride-rich LpBc particles on the relative risk of coronary artery lesion progression, since the significantly reduced levels of cholesterol-rich LpB particles unmask this association. There were no statistically significant differences between the lowest and highest LpBc tertiles in the levels of LpB (mean±SD=62.7±4.1, 67.4±7.6, and 73.3±9.3 mg/dL, respectively) or LDL cholesterol (78.8±5.9, 79.4±11.7, and 89.2±13.4 mg/dL). This effect was also independent of HDL cholesterol levels, which were essentially the same for each tertile (43.5±2.3, 43.8±3.7, and 43.3±6.4 mg/dL). The increasing trend in the relative risk for coronary artery lesion progression with increasing levels of LpBc particles was significant in the lovastatin-treated group and in the combined sample even after adjustment for treatment group. Because of the still-unresolved question regarding the atherogenic potential of Lp(a), we have not measured the levels of these lipoprotein particles in this study. It should be pointed out that apoB contents of LpBc and LpA-II:B:C:D:E particles did not encompass the apoB contents of Lp(a) particles, since Lp(a) is not retained on anti–apoC-III or anti–apoA-II immunosorbers. The apoB contents of Lp(a) particles were actually present in the unretained fraction from these two immunosorbers and codetermined with the LpB particles.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Because of its specific reducing effect on the levels of cholesterol-rich LpB particles, the main lipoprotein family of LDL, and a minimal effect on the concentrations of LpA-I and LpA-I:A-II, the major lipoprotein families of HDL, the use of lovastatin as a hypolipidemic drug in the MARS study2 offered a unique opportunity for studying the role of triglyceride-rich lipoproteins in the progression of atherosclerosis. Results have shown that in the presence of significantly reduced levels of LpB particles and minimal changes in the concentrations of LpA-I and LpA-I:A-II particles, increased concentrations of triglyceride-rich LpBc particles contribute significantly to coronary artery lesion progression. Furthermore, among these complex, triglyceride-rich lipoproteins, increased levels of LpA-II:B:C:D:E particles appear to be the main individual triglyceride-rich lipoprotein contributing to lesion progression. By direct measurement of individual apoB-containing lipoprotein families, this study has provided direct evidence for the atherogenic potential of triglyceride-rich lipoproteins and their role in the progression of coronary artery atherosclerosis.
A number of epidemiological, clinical, and metabolic studies have demonstrated that abnormalities in the metabolism of plasma lipoproteins are one of the major risk factors for development of coronary artery disease.9 10 Most epidemiological studies have concluded that hypercholesterolemia is more independently associated with coronary artery disease than hypertriglyceridemia and that cholesterol-rich LDL and thus LpB particles have a greater atherogenic potential than the triglyceride-rich lipoproteins (VLDL and IDL) or LpBc particles. Although most case-control studies have shown a strong univariate association between plasma triglyceride levels and coronary heart disease,11 prospective studies have provided little evidence that triglyceride levels represent an independent predictor of coronary artery disease after adjusting for other risk factors including plasma cholesterol, HDL cholesterol, and hypertension.12 However, more recent studies have indicated that in some populations, increased levels of triglycerides are an independent risk factor for coronary heart disease13 14 15 16 17 18 19 20 and that, in general, hypertriglyceridemia with or without associated hypercholesterolemia occurs more frequently in subjects with premature coronary artery disease than does hypercholesterolemia alone.21
Impaired lipolytic degradation of triglyceride-rich lipoproteins of intestinal and hepatic origin leads to the accumulation of remnant lipoprotein particles of intermediate densities (IDL, d=1.006 to 1.019 g/mL, Sf 12-20) that are only partially depleted of triglycerides but enriched in cholesterol esters.22 23 24 25 Several clinical26 27 28 29 30 and metabolic24 25 31 32 33 studies have suggested that these triglyceride-rich lipoproteins may have atherogenic potential similar if not equal to that of cholesterol-rich LDL. These claims, irrespective of whether they are made with respect to lower- or higher-density segments of LDLs, raise the question regarding the chemical and physical nature of "atherogenic" lipoproteins. ApoB as the main structural apolipoprotein of lipoproteins with d<1.063 g/mL has also been considered as a marker of atherogenic lipoproteins. There is a great variety of apoB-containing lipoproteins consisting of nascent and metabolically modified lipoprotein particles differing in sizes, densities, and lipid and apolipoprotein composition. Although the exact physical-chemical makeup of an atherogenic lipoprotein has not been unequivocally established, the circumstantial evidence suggests that size and a specific structural arrangement of lipids and apolipoproteins may be the main factors determining the atherogenicity of apoB-containing lipoproteins. Studies on the interactions of plasma lipoproteins and arteries in animals31 33 34 35 and humans31 36 37 have consistently shown an inverse relationship between lipoprotein particle diameter and extent of arterial influx. Accordingly, chylomicrons and large VLDL (Sf 60-400) do not seem to have the capacity to enter the arterial intima. On the other hand, small VLDL (Sf 20-60), IDL, and LDL seem to share a similar potential and mechanism for penetrating and leaving the arterial intima36 37 and thus promoting the atherogenic process when present in increased concentrations. It appears that other than size, plasma concentrations and extent of already present atherosclerotic lesions are additional factors that determine the magnitude of arterial influx of VLDL, IDL, and LDL.35 37 Several investigators have isolated cholesterol ester–rich VLDL+IDL and LDL from human aortas and identified apolipoproteins B, C, and E as their protein constituents.38 39 40 Recently, Rapp et al41 isolated immunoreactive apoB-containing lipoproteins from human atherosclerotic plaques and established that one third of the total apoB-associated lipoprotein cholesterol occurred in the VLDL+IDL fraction. The isolated VLDL+IDL fraction was enriched in apoE in comparison with the corresponding plasma fraction and contained predominantly triglycerides when isolated from hypertriglyceridemic patients and cholesterol esters when isolated from normotriglyceridemic patients. These findings have demonstrated the ability of some intact or partially delipidized triglyceride-rich lipoproteins (Sf 12-60) to enter and accumulate in atherosclerotic lesions and have disclosed that atherosclerotic plaques may contain, in addition to cholesterol esters, undegraded triglycerides in subjects with increased plasma concentrations of triglyceride-rich lipoproteins.
Although there are no systematic studies exploring the possible role of apolipoproteins in the atherogenicity of lipoproteins, it appears that the structural arrangements of minor apolipoproteins, especially apoC peptides and apoE, may be of significant importance in modulating the interaction of apoB-containing lipoproteins with the arterial wall.24 33 41 42 Preliminary results from our laboratory43 have shown a differential uptake by THP-1 macrophages of apoB-containing lipoprotein particles; the highest accumulation of neutral lipids and apoB resulted from the uptake of LpB:C:E followed in decreasing order by LpB:C and LpA-II:B:C:D:E particles, with the lowest uptake occurring for the cholesterol ester–rich LpB particles. Although these findings need to be confirmed and expanded by additional experiments, they suggest that on an apoB molar basis, various apoB-containing lipoproteins might differ in their atherogenic potential, with complex triglyceride-rich particles possibly exceeding cholesterol ester–rich LpB particles.
In the present study, the concentration of LpA-II:B:C:D:E particles exceeded the concentration of LpB:C:E and LpB:C particles in both the placebo and drug groups. There are several differences in the metabolic properties between these three major complex, triglyceride-rich lipoproteins.8 44 One of the most characteristic among these properties is their reactivity toward lipoprotein lipase.45 Despite similar triglyceride and apoC-III contents, LpB:C:E and LpB:C particles were shown to be more efficient substrates for lipoprotein lipase than LpA-II:B:C:D:E particles. Consequently, the latter particles may have longer residence time, higher concentrations, and greater exposure to monocyte-derived macrophages than the former particles, which under normal circumstances may be rapidly hydrolized to LpB particles46 and thus occur in plasma in low concentrations.
The density range of triglyceride-rich LpBc or LpA-II:B:C:D:E particles has not been determined in the present study. However, on the basis of circumstantial evidence, it appears that the major part of these lipoprotein particles was present in their partially delipidized forms as smaller VLDL and IDL. It has been shown previously1 7 that lovastatin decreased the levels of triglycerides and apolipoproteins B, E, C-III, and apoC-III–HP and slightly increased the apoC-III ratio, a useful measure of the lipolytic degradation and/or uptake of triglyceride-rich lipoproteins. However, it appears that this treatment has resulted only in a partial degradation of triglyceride-rich lipoprotein particles, as evidenced by increased levels of these lipoproteins and their constituents in lovastatin-treated progressors. In addition, the measurement of lipoprotein density subclasses in the MARS study indicated that small VLDL (Sf 20-60) and IDL (Sf 12-20) masses were significantly associated with the progression of coronary artery atherosclerosis.47
These findings, in conjunction with results of the present study, indicate that in the MARS subjects, progression of coronary artery atherosclerosis is associated with increased levels of LpBc and LpA-II:B:C:D:E particles of small VLDL- and/or IDL-like sizes. In contrast, it appears that the cholesterol-rich LpB particles contribute only marginally to the progression of coronary artery atherosclerosis, as evidenced by a lack of statistically significant differences in the levels of total cholesterol, LDL cholesterol, and LpB particles between placebo-treated progressors and nonprogressors (Tables 1 and 2). These findings are in agreement with results of a recent clinical study by Phillips et al30 who have shown that the progression of coronary artery atherosclerosis and subsequent clinical events are promoted by increased levels of VLDL and IDL remnants and decreased levels of HDL but are unrelated to the levels of LDL components. This does not necessarily argue against the atherogenicity of LpB particles but merely suggests that its potential may be of a lesser degree than previously considered or anticipated, especially in comparison with atherogenic capacities of intact or partially delipidized triglyceride-rich lipoproteins. It is quite possible that the atherogenic threshold concentration of LpB particles is higher than that of LpBc in the majority of MARS subjects and thus a less important factor in differentiating progression versus nonprogression of atherosclerotic lesions. Whether the reduction of the number of progressors by lovastatin was mediated through a lowering effect on the levels of LpB particles or some other mechanism(s) remains to be explored in future studies. In any case, the lowering of LpB levels by lovastatin facilitated the recognition of LpBc and LpA-II:B:C:D:E as the lipoprotein particles mainly responsible for the progression of atherosclerosis in the present study.
If the atherogenic potential of triglyceride-rich lipoprotein particles increases with the partial loss of triglycerides and minor apolipoproteins, the term "triglyceride-rich lipoproteins" may be somewhat misleading. It may be preferable to refer to triglyceride-rich lipoproteins as complex apoB-containing lipoproteins characterized by their specific complement of minor apolipoproteins and to refer to cholesterol-rich lipoproteins as simple apoB-containing lipoproteins with apoB as their sole apolipoprotein constituent.
Puchois et al48 have suggested that LpA-I particles might represent the "antiatherogenic" fraction of HDL. Further studies have substantiated this view by showing that subjects with coronary artery disease have significantly lower concentrations of LpA-I than LpA-I:A-II particles in comparison with controls49 and that adolescents with a family history of myocardial infarction have lower levels of LpA-I than control subjects.50 However, several other studies found no significant difference between levels of LpA-I and LpA-I:A-II in subjects with coronary artery disease.51 52 53 54 55 Results of the present study have shown that progressors in the placebo-treated, lovastatin-treated, and combined treatment groups have lower levels of LpA-I but not LpA-I:A-II than nonprogressors and that this difference tended to reach statistical significance in the combined sample adjusted for treatment group. This finding, suggestive of a protective role of LpA-I particles in the progression of atherosclerotic lesions, is in agreement with a recent report of a cardioprotective effect of this lipoprotein family55 and lends further support to the view that LpA-I may be the antiatherogenic or protective factor of HDL.
In this study, the complex interaction of lipoproteins with the arterial wall both in the placebo and drug groups was monitored not only by measuring lipids, lipoprotein cholesterol, and apolipoproteins but also by analyzing individual apoA- and apoB-containing lipoprotein families, as defined by their apolipoprotein composition. These latter analyses proved to be more significant as predictors of lesion progression than those of lipids and apolipoproteins in this subsample of 63 MARS subjects. Because individual apoA- and apoB-containing lipoprotein families differ in their metabolic properties8 44 45 and possibly in their nonatherogenic and atherogenic potentials,30 37 43 48 their measurement may provide more specific information about the metabolic defect(s) and/or magnitude of atherosclerotic risk in individual subjects than does the estimation of total lipid and apolipoprotein constituents of plasma or major lipoprotein density classes. Furthermore, due to the selective effect on lipoprotein families by hypolipidemic drugs,1 56 57 58 59 60 61 it may be possible to select, on the basis of lipoprotein family profile, a more appropriate therapy targeted at decreasing undesirable and/or increasing desirable lipoprotein particles.
In conclusion, the results of this study indicate that elevated levels of triglyceride-rich complex apoB-containing lipoproteins (LpBc in general and the LpA-II:B:C:D:E family of particles in particular) contribute significantly to the progression of coronary artery disease. Furthermore, this study provides additional evidence for the protective role of LpA-I particles in the atherogenic process and suggests that apolipoprotein-defined lipoprotein families may be more specific prognosticators of coronary artery atherosclerosis progression than lipids and apolipoproteins.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This study was supported in part by US Public Health Service grant HL-49885, Merck Research Laboratories, and resources of the Oklahoma Medical Research Foundation. We wish to thank Carmen Quiroga, Sandra Bryant, Jim Fesmire, and Randy Whitmer for their skillful technical assistance and Margo French for her assistance in the preparation of this manuscript.
Received September 11, 1995; accepted July 18, 1996.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Alaupovic P, Hodis HN, Knight-Gibson C, Mack WJ, LaBree L, Cashin-Hemphill L, Corder CN, Kramsch DM, Blankenhorn DH. Effects of lovastatin on apoA- and apoB-containing lipoprotein families in a subpopulation of patients participating in the Monitored Atherosclerosis Regression Study (MARS). Arterioscler Thromb. 1994;14:1906-1914.
2.
Blankenhorn DH, Azen SP, Kramsch DM, Mack WJ, Cashin-Hemphill L, Hodis HN, DeBoer LWV, Mahrer PR, Masteller MJ, Vailas LI, Alaupovic P, Hirsch LJ, and the MARS Research Group. Coronary angiographic changes with lovastatin therapy: the Monitored Atherosclerosis Regression Study (MARS). Ann Intern Med. 1993;119:969-976.
3.
Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation. 1993;87:1781-1791.
4.
Blankenhorn DH, Hodis HN. Arterial imaging and atherosclerosis reversal. Arterioscler Thromb. 1994;14:177-192.
5.
Blankenhorn DH, Alaupovic P, Wickham E, Chin HP, Azen SP. Prediction of angiographic change in native human coronary arteries and aortocoronary bypass grafts: lipid and nonlipid factors. Circulation. 1990;81:470-476.
6. Alaupovic P. David Rubenstein Memorial Lecture: the biochemical and clinical significance of the interrelationship between very low density and high density lipoproteins. Can J Biochem. 1981;59:565-579.[Medline] [Order article via Infotrieve]
7.
Hodis HN, Mack WJ, Azen SP, Alaupovic P, Pogoda JM, LaBree L, Hemphill LC, Kramsch DM, Blankenhorn DH. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild to moderate/severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Circulation. 1994;90:42-49.
8. Cashin-Hemphill L, Kramsch DM, Azen SP, DeMets D, DeBoer L, Hwang I, Vailas L, Hirsch LJ, Mack WJ, Hodis HN, Mahrer PR, Selzer RH, Alaupovic P, Blankenhorn DH. The Monitored Atherosclerosis Regression Study (MARS): design, methods and baseline results. Online J Curr Clin Trials. 1992;264:3047-3052.
9.
Steinberg D, Witztum JL. Lipoproteins and atherogenesis: current concepts. JAMA. 1990;264:3047-3052.
10.
Wallace RB, Anderson RA. Blood lipids, lipid-related measures and the risk of atherosclerotic cardiovascular disease. Epidemiol Rev. 1987;9:95-119.
11.
Austin MA. Plasma triglyceride as a risk factor for coronary heart disease: the epidemiologic evidence and beyond. Am J Epidemiol. 1989;129:249-259.
12. Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical decisions: the association between triglyceride and coronary heart disease. N Engl J Med. 1980;302:1383-1389.[Abstract]
13. Heyden S, Heiss G, Hames CG, Bartel AG. Fasting triglycerides as predictors of total and CHD mortality in Evans County, Georgia. J Chron Dis. 1980;33:275-282.[Medline] [Order article via Infotrieve]
14. Lapidus L, Bengtsson C, Lindquist O, Sigurdsson JA, Rybo E. Triglycerides: main lipid risk factor for cardiovascular disease in women? Acta Med Scand. 1985;217:481-489.[Medline] [Order article via Infotrieve]
15. Carlson LA, Böttiger LE. Risk factors for ischemic heart disease in men and women: results of the 19-year follow-up of the Stockholm Prospective Study. Acta Med Scand. 1985;218:207-211.[Medline] [Order article via Infotrieve]
16.
Cambien F, Jacqueson A, Richard JL, Warnet JM, Ducimetière P, Claude JR. Is the level of serum triglyceride a significant predictor of coronary death in `normocholesterolemic' subjects? Am J Epidemiol. 1986;124:624-632.
17. Castelli WP. Epidemiology of triglycerides: a view from Framingham. Am J Cardiol. 1992;70:3H-9H.[Medline] [Order article via Infotrieve]
18.
Bainton D, Miller NE, Bolton CH, Yarnell JWG, Sweetnam PM, Baker IA, Lewis B, Elwood PC. Plasma triglyceride and high density lipoprotein cholesterol as predictors of ischaemic heart disease in British men: the Caerphilly and Speedwell Collaborative Heart Disease Studies. Br Heart J. 1992;68:60-66.
19.
Bass KM, Newschaffer CJ, Klag MJ, Bush TL. Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med. 1993;153:2209-2216.
20. Stensvold I, Tverdal A, Urdal P, Graff-Iversen S. Non-fasting serum triglyceride concentration and mortality from coronary heart disease and any cause in middle aged Norwegian women. Br Med J. 1993;307:1318-1322.
21. Schaefer EJ, McNamara JR, Genest JJ, Ordovas JM. Clinical significance of hypertriglyceridemia. Semin Thromb Hemost. 1988;14:143-148.[Medline] [Order article via Infotrieve]
22. Eisenberg S, Sehayek E. Cellular metabolism of triglyceride-rich lipoproteins and their remnants. In: Gotto AM Jr, Mancini M, Richter WO, Schwandt P, eds. Treatment of Severe Dyslipoproteinemia in the Prevention of Coronary Heart Disease, 4. Basel, Switzerland: Karger; 1993:27-36.
23.
Havel R. McCollum Award Lecture, 1993: triglyceride-rich lipoproteins and atherosclerosis: new perspectives. Am J Clin Nutr. 1994;59:795-799.
24. Bradley WA, Gianturco SH. Triglyceride-rich lipoproteins and atherosclerosis: pathophysiological considerations. J Intern Med. 1994;236:33-39.
25.
Zilversmit DB. Atherogenic nature of triglycerides, postprandial lipidemia, and triglyceride-rich remnant lipoproteins. Clin Chem. 1995;41:153-158.
26.
Tatami R, Mabuchi H, Ueda K, Ueda R, Haba T, Kametani T, Ito S, Koizumi J, Ohta M, Miyamoto S, Nakayama A, Kanaya H, Oiwake H, Genda A, Takeda R. Intermediate-density lipoprotein and cholesterol-rich very-low-density lipoprotein in angiographically determined coronary artery disease. Circulation. 1981;64:1174-1184.
27.
Reardon MF, Nestel PJ, Craig IH, Harper RW. Lipoprotein predictors of the severity of coronary artery disease in men and women. Circulation. 1985;71:881-888.
28. Simons LA, Dwyer T, Simons J, Bernstein L, Mock P, Poonia NS, Balasubramaniam S, Baron D, Branson J, Morgan J, Roy P. Chylomicrons and chylomicron remnants in coronary artery disease: a case-control study. Atherosclerosis. 1987;65:181-189.[Medline] [Order article via Infotrieve]
29. Krauss RM, Williams PT, Brensike J, Detre KM, Lindgren FT, Kelsey SF, Vranizan K, Levy RI. Intermediate-density lipoproteins and progression of coronary artery disease in hypercholesterolaemic men. Lancet. 1987;2:62-66.[Medline] [Order article via Infotrieve]
30.
Phillips NR, Waters D, Havel RJ. Plasma lipoproteins and progression of coronary artery disease evaluated by angiography and clinical events. Circulation. 1993;88:2762-2770.
31.
Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation. 1979;60:473-485.
32. Florèn CH, Albers JJ, Bierman EL. Uptake of chylomicron remnants causes cholesterol accumulation in cultured human arterial smooth muscle cells. Biochim Biophys Acta. 1981;663:336-349.[Medline] [Order article via Infotrieve]
33. Weisgraber KH, Innerarity TL, Rall SCJ, Mahley RW. Atherogenic lipoproteins resulting from genetic defects of apolipoproteins B and E. Ann N Y Acad Sci. 1990;598:37-48.[Medline] [Order article via Infotrieve]
34. Nordestgaard BG, Lewis B. Intermediate density lipoprotein levels are strong predictors of the extent of aortic atherosclerosis in the St Thomas's Hospital rabbit strain. Atherosclerosis. 1991;87:39-46.[Medline] [Order article via Infotrieve]
35.
Nordestgaard BG, Tybjærg-Hansen A, Lewis B. Influx in vivo of low-density, intermediate-density, and very-low-density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits: roles of plasma concentration, extent of aortic lesion, and lipoprotein particle size as determinants. Arterioscler Thromb. 1992;12:6-18.
36. Nordestgaard BG, Tybjærg-Hansen A. IDL, VLDL, chylomicrons and atherosclerosis. Eur J Epidemiol. 1992;8:92-98.
37.
Shaikh M, Wootton R, Nordestgaard BG, Baskerville P, Lumley JS, La Ville AE, Quincy J, Lewis B. Quantitative studies of transfer in vivo of low density, Sf 12-60, and Sf 60-400 lipoproteins between plasma and arterial intima in humans. Arterioscler Thromb. 1991;11:569-577.
38. Hollander W, Combo M, Paddock J. Lipoproteins in human atherosclerotic vessels, II: biochemical properties of the major apolipoproteins of arterial low density and very low density lipoproteins. Exp Mol Pathol. 1979;30:172-189.[Medline] [Order article via Infotrieve]
39. Hoff HF, Bradley WA, Heideman CL, Gaubatz JW, Karagos MD, Gotto AM Jr. Characterization of low density lipoprotein–like particle in human aorta from grossly normal and atherosclerotic regions. Biochim Biophys Acta. 1979;573:361-374.[Medline] [Order article via Infotrieve]
40. Ylä Herttuala S, Jaakkola O, Ehnholm C, Tikkanen MJ, Solakivi T, Särkioja T, Nikkari T. Characterization of two lipoproteins containing apolipoproteins B and E from lesion-free human aortic intima. J Lipid Res. 1988;29:563-572.[Abstract]
41.
Rapp JH, Lespine A, Hamilton RL, Colyvas N, Chaumeton AH, Tweedie-Hardman J, Kotite L, Kunitake ST, Havel RJ, Kane JP. Triglyceride-rich lipoproteins isolated by selected-affinity anti–apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994;14:1767-1774.
42. Hamsten A. Hypertriglyceridaemia, triglyceride-rich lipoproteins and coronary heart disease. Baillieres Clin Endocrinol Metab. 1990;4:895-922.[Medline] [Order article via Infotrieve]
43. Koren E, Koscec M, Corder C, Knight-Gibson C, Lee DM, Alaupovic P. Differential atherogenicity of complex apoB-containing lipoprotein particles. Atherosclerosis. 1994;109:217-218. Abstract.
44.
Agnani G, Bard JM, Candelier L, Delattre S, Fruchart J-C, Clavey V. Interaction of LpB, LpB:E, LpB:C-III, and LpB:C-III:E lipoproteins with the low-density lipoprotein receptor of HeLa cells. Arterioscler Thromb. 1991;11:1021-1029.
45. Alaupovic P, Knight-Gibson C, Wang C-S, Downs D, Koren E, Brewer HB Jr, Gregg RE. Isolation and characterization of an apoA-II–containing lipoprotein (LP-A-II:B complex) from plasma very low density lipoproteins of patients with Tangier disease and type V hyperlipoproteinemia. J Lipid Res. 1991;32:9-19.[Abstract]
46. Alaupovic P, Wang C-S, McConathy WJ, Weiser D, Downs D. Lipolytic degradation of human very low density lipoproteins by human milk lipoprotein lipase: the identification of lipoprotein B as the main lipoprotein degradation product. Arch Biochem Biophys. 1986;244:226-237.[Medline] [Order article via Infotrieve]
47.
Mack WJ, Krauss RM, Hodis HN. Lipoprotein subclasses in the Monitored Atherosclerosis Regression Study (MARS): treatment effects and relation to coronary angiographic progression. Arterioscler Thromb Vasc Biol. 1996;16:697-704.
48. Puchois P, Kandoussi A, Fievet P, Fourrier JL, Bertrand M, Koren E, Fruchart JC. Apolipoprotein A-I containing lipoproteins in coronary artery disease. Atherosclerosis. 1987;68:35-40.[Medline] [Order article via Infotrieve]
49.
Parra HJ, Arveiler D, Evans AE, Cambou JP, Amouyel P, Bingham A, McMaster D, Schaffer P, Douste-Blazy Ph, Luc G, Richard JL, Ducimetière P, Fruchart JC, Cambien F. A case-control study of lipoprotein particles in two populations at contrasting risk for coronary heart disease: the ECTIM study. Arterioscler Thromb. 1992;12:701-707.
50.
Amouyel P, Isorez D, Bard J-M, Goldman M, Lebel P, Zylberberg G, Fruchart J-C. Parental history of early myocardial infarction is associated with decreased levels of lipoparticle A-I in adolescents. Arterioscler Thromb. 1993;13:1640-1644.
51. Coste-Burel M, Mainard F, Chivot L, Auget JL, Madec Y. Study of lipoprotein particles LpAI and LpAI:AII in patients before coronary bypass surgery. Clin Chem. 1990;36:1889-1891.[Abstract]
52. Cheung MC, Brown BG, Wolf AC, Albers JJ. Altered particle size distribution of apolipoprotein A-I–containing lipoproteins in subjects with coronary artery disease. J Lipid Res. 1991;32:383-394.[Abstract]
53. Genest JJ Jr, Bard JM, Fruchart J-C, Ordovas JM, Wilson PFW, Schaefer EJ. Plasma apolipoprotein A-I, A-II, B, E and C-III containing particles in men with premature coronary artery disease. Atherosclerosis. 1991;90:149-157.[Medline] [Order article via Infotrieve]
54.
Montali A, Vega GL, Grundy SM. Concentrations of apolipoprotein A-I–containing particles in patients with hypoalphalipoproteinemia. Arterioscler Thromb. 1994;14:511-517.
55.
O'Brien T, Nguyen TT, Hallaway BJ, Hodge D, Bailey K, Holmes D, Kottke BA. The role of lipoprotein A-I and lipoprotein A-I/A-II in predicting coronary artery disease. Arterioscler Thromb Vasc Biol. 1995;15:228-231.
56. Atmeh RF, Shepherd J, Packard CJ. Subpopulations of apolipoprotein A-I in human high-density lipoproteins: their metabolic profiles and response to drug therapy. Biochim Biophys Acta. 1983;751:175-188.[Medline] [Order article via Infotrieve]
57. Corder C, Tavella M, Alaupovic P. Effect of gemfibrozil on discrete ApoB-containing lipoproteins in patients with type V hyperlipoproteinemia. Arteriosclerosis. 1987;7:515a. Abstract.
58. Bard JM, Parra HJ, Douste-Blazy Ph, Fruchart JC. Effect of pravastatin, an HMG CoA reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by their apolipoprotein composition. Metabolism. 1990;39:269-273.[Medline] [Order article via Infotrieve]
59. Bard JM, Parra HJ, Camare R, Luc G, Ziegler O, Dachet C, Bruckert E, Douste-Blazy Ph, Drouin P, Jacotot B, DeGennes JL, Keller U, Fruchart JC. A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition. Metabolism. 1992;41:498-503.[Medline] [Order article via Infotrieve]
60. Bard JM, Fruchart JC. HDL particle measurements: impact for diagnosis and therapy. Clin Biochem. 1993;26:65-68.[Medline] [Order article via Infotrieve]
61. Kahri J, Vuorinen-Markkola H, Tilly-Kiesi M, Lahdenperä S, Taskinen MR. Effect of gemfibrozil on high density lipoprotein subspecies in non–insulin dependent diabetes mellitus: relations to lipolytic enzymes and to the cholesteryl ester transfer protein activity. Atherosclerosis. 1993;102:79-89.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  J.-C. Fruchart, F. M Sacks, M. P Hermans, G. Assmann, W V. Brown, R. Ceska, M J. Chapman, P. M Dodson, P. Fioretto, H. N Ginsberg, et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients Diabetes and Vascular Disease Research, November 1, 2008; 5(4): 319 - 335. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Kawakami, M. Osaka, M. Tani, H. Azuma, F. M. Sacks, K. Shimokado, and M. Yoshida Apolipoprotein CIII Links Hyperlipidemia With Vascular Endothelial Cell Dysfunction Circulation, August 12, 2008; 118(7): 731 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Mallika, B. Goswami, and M. Rajappa Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective Angiology, November 1, 2007; 58(5): 513 - 522. [Abstract] [PDF]
|
|
|
|
|
|
R. S. Birjmohun, G. M. Dallinga-Thie, J. A. Kuivenhoven, E. S.G. Stroes, J. D. Otvos, N. J. Wareham, R. Luben, J. J.P. Kastelein, K.-T. Khaw, and S. M. Boekholdt Apolipoprotein A-II Is Inversely Associated With Risk of Future Coronary Artery Disease Circulation, October 30, 2007; 116(18): 2029 - 2035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-J. Shin, P. J Blanche, R. S Rawlings, H. S Fernstrom, and R. M Krauss Increased plasma concentrations of lipoprotein(a) during a low-fat, high-carbohydrate diet are associated with increased plasma concentrations of apolipoprotein C-III bound to apolipoprotein B-containing lipoproteins Am. J. Clinical Nutrition, June 1, 2007; 85(6): 1527 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Zheng, C. Khoo, K. Ikewaki, and F. M. Sacks Rapid turnover of apolipoprotein C-III-containing triglyceride-rich lipoproteins contributing to the formation of LDL subfractions J. Lipid Res., May 1, 2007; 48(5): 1190 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F Hilpert, S. G West, P. M Kris-Etherton, K. D Hecker, N. M Simpson, and P. Alaupovic Postprandial effect of n-3 polyunsaturated fatty acids on apolipoprotein B-containing lipoproteins and vascular reactivity in type 2 diabetes Am. J. Clinical Nutrition, February 1, 2007; 85(2): 369 - 376. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kawakami, M. Aikawa, P. Alcaide, F. W. Luscinskas, P. Libby, and F. M. Sacks Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells Circulation, August 15, 2006; 114(7): 681 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kawakami, M. Aikawa, P. Libby, P. Alcaide, F. W. Luscinskas, and F. M. Sacks Apolipoprotein CIII in Apolipoprotein B Lipoproteins Enhances the Adhesion of Human Monocytic Cells to Endothelial Cells Circulation, February 7, 2006; 113(5): 691 - 700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Park, P. G Jones, and W. S Harris Triacylglycerol-rich lipoprotein margination: a potential surrogate for whole-body lipoprotein lipase activity and effects of eicosapentaenoic and docosahexaenoic acids Am. J. Clinical Nutrition, July 1, 2004; 80(1): 45 - 50. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Carmena, P. Duriez, and J.-C. Fruchart Atherogenic Lipoprotein Particles in Atherosclerosis Circulation, June 15, 2004; 109(23_suppl_1): III-2 - III-7. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. M. Dallinga-Thie, I. I.L. Berk-Planken, A. H. Bootsma, and H. Jansen Atorvastatin Decreases Apolipoprotein C-III in Apolipoprotein B-Containing Lipoprotein and HDL in Type 2 Diabetes: A potential mechanism to lower plasma triglycerides Diabetes Care, June 1, 2004; 27(6): 1358 - 1364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Chiuve, L. A. Martin, H. Campos, and F. M. Sacks Effect of the Combination of Methyltestosterone and Esterified Estrogens Compared with Esterified Estrogens Alone on Apolipoprotein CIII and Other Apolipoproteins in Very Low Density, Low Density, and High Density Lipoproteins in Surgically Postmenopausal Women J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2207 - 2213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.J Chapman and M Caslake Non-high-density lipoprotein cholesterol as a risk factor: addressing risk associated with apolipoprotein B-containing lipoproteins Eur. Heart J. Suppl., March 1, 2004; 6(suppl_A): A43 - A48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Frohlich and M. Dobiasova Fractional Esterification Rate of Cholesterol and Ratio of Triglycerides to HDL-Cholesterol Are Powerful Predictors of Positive Findings on Coronary Angiography Clin. Chem., November 1, 2003; 49(11): 1873 - 1880. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-J. Lee, H. Campos, L. A. Moye, and F. M. Sacks LDL Containing Apolipoprotein CIII Is an Independent Risk Factor for Coronary Events in Diabetic Patients Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 853 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Park and W. S. Harris Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance J. Lipid Res., March 1, 2003; 44(3): 455 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]
|
|
|
|
|
|
M. Guerin, P. Egger, W. Le Goff, C. Soudant, R. Dupuis, and M. J. Chapman Atorvastatin Reduces Postprandial Accumulation and Cholesteryl Ester Transfer Protein-Mediated Remodeling of Triglyceride-Rich Lipoprotein Subspecies in Type IIB Hyperlipidemia J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4991 - 5000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Blanco-Vaca, J. C. Escola-Gil, J. M. Martin-Campos, and J. Julve Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein J. Lipid Res., November 1, 2001; 42(11): 1727 - 1739. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. H. McGladdery and J. J. Frohlich Lipoprotein lipase and apoE polymorphisms: relationship to hypertriglyceridemia during pregnancy J. Lipid Res., November 1, 2001; 42(11): 1905 - 1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tomiyasu, B. W. Walsh, K. Ikewaki, H. Judge, and F. M. Sacks Differential Metabolism of Human VLDL According to Content of ApoE and ApoC-III Arterioscler Thromb Vasc Biol, September 1, 2001; 21(9): 1494 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Campos, D. Perlov, C. Khoo, and F. M. Sacks Distinct patterns of lipoproteins with apoB defined by presence of apoE or apoC-III in hypercholesterolemia and hypertriglyceridemia J. Lipid Res., August 1, 2001; 42(8): 1239 - 1249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Park, W. J. Grellner, W. S. Harris, and J. M. Miles A new method for the study of chylomicron kinetics in vivo Am J Physiol Endocrinol Metab, December 1, 2000; 279(6): E1258 - E1263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Sacks, P. Alaupovic, L. A. Moye, T. G. Cole, B. Sussex, M. J. Stampfer, M. A. Pfeffer, and E. Braunwald VLDL, Apolipoproteins B, CIII, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial Circulation, October 17, 2000; 102(16): 1886 - 1892. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Escolà-Gil, J. Julve, A. Marzal-Casacuberta, J. Ordóñez-Llanos, F. González-Sastre, and F. Blanco-Vaca Expression of human apolipoprotein A-II in apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia J. Lipid Res., August 1, 2000; 41(8): 1328 - 1338. [Abstract] [Full Text]
|
|
|
|
|
|
S. M. Haffner Secondary Prevention of Coronary Heart Disease : The Role of Fibric Acids Circulation, July 4, 2000; 102(1): 2 - 4. [Full Text] [PDF]
|
|
|
|
 |
|
 T. A. Jacobson, G. G. Griffiths, C. Varas, D. Gause, J. C. Y. Sung, and C. M. Ballantyne Impact of Evidence-Based "Clinical Judgment" on the Number of American Adults Requiring Lipid-Lowering Therapy Based on Updated NHANES III Data Arch Intern Med, May 8, 2000; 160(9): 1361 - 1369. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Clee, N. Bissada, F. Miao, L. Miao, A. D. Marais, H. E. Henderson, P. Steures, J. McManus, B. McManus, R. C. LeBoeuf, et al. Plasma and vessel wall lipoprotein lipase have different roles in atherosclerosis J. Lipid Res., April 1, 2000; 41(4): 521 - 531. [Abstract] [Full Text]
|
|
|
|
|
|
R. van Antwerpen, M. La Belle, E. Navratilova, and R. M. Krauss Structural heterogeneity of apoB-containing serum lipoproteins visualized using cryo-electron microscopy J. Lipid Res., October 1, 1999; 40(10): 1827 - 1836. [Abstract] [Full Text]
|
|
|
|
|
|
J. S. Cohn, C. Marcoux, and J. Davignon Detection, Quantification, and Characterization of Potentially Atherogenic Triglyceride-Rich Remnant Lipoproteins Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2474 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. N. Hodis Triglyceride-Rich Lipoprotein Remnant Particles and Risk of Atherosclerosis Circulation, June 8, 1999; 99(22): 2852 - 2854. [Full Text] [PDF]
|
|
|
|
|
|
C. Lee, F. Sigari, T. Segrado, S. Horkko, S. Hama, P. V. Subbaiah, M. Miwa, M. Navab, J. L. Witztum, and P. D. Reaven All ApoB-Containing Lipoproteins Induce Monocyte Chemotaxis and Adhesion When Minimally Modified : Modulation of Lipoprotein Bioactivity by Platelet-Activating Factor Acetylhydrolase Arterioscler Thromb Vasc Biol, June 1, 1999; 19(6): 1437 - 1446. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Boisfer, G. Lambert, V. Atger, N. Q. Tran, D. Pastier, C. Benetollo, J.-F. Trottier, I. Beaucamps, M. Antonucci, M. Laplaud, et al. Overexpression of Human Apolipoprotein A-II in Mice Induces Hypertriglyceridemia Due to Defective Very Low Density Lipoprotein Hydrolysis J. Biol. Chem., April 23, 1999; 274(17): 11564 - 11572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Ballantyne, J. A. Herd, L. L. Ferlic, J. K. Dunn, J. A. Farmer, P. H. Jones, J. R. Schein, and A. M. Gotto Jr Influence of Low HDL on Progression of Coronary Artery Disease and Response to Fluvastatin Therapy Circulation, February 16, 1999; 99(6): 736 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. T. Leary, T. Wang, D. J. Baker, D. D. Cilla, J. Zhong, G. R. Warnick, K. Nakajima, and R. J. Havel Evaluation of an immunoseparation method for quantitative measurement of remnant-like particle-cholesterol in serum and plasma Clin. Chem., December 1, 1998; 44(12): 2490 - 2498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ruotolo, C.-G.o. Ericsson, C. Tettamanti, F. Karpe, L. Grip, B. Svane, J. Nilsson, U. de Faire, and A. Hamsten Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) J. Am. Coll. Cardiol., November 15, 1998; 32(6): 1648 - 1656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Syvanne, M. S. Nieminen, M. H. Frick, H. Kauma, S. Majahalme, V. Virtanen, Y. A. Kesaniemi, A. Pasternack, C. Ehnholm, and M.-R. Taskinen Associations Between Lipoproteins and the Progression of Coronary and Vein-Graft Atherosclerosis in a Controlled Trial With Gemfibrozil in Men With Low Baseline Levels of HDL Cholesterol Circulation, November 10, 1998; 98(19): 1993 - 1999. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Gotto Jr Triglyceride : The Forgotten Risk Factor Circulation, March 24, 1998; 97(11): 1027 - 1028. [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||