(Circulation. 2000;102:1886.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
VLDL, Apolipoproteins B, CIII, and E, and Risk of Recurrent Coronary Events in the Cholesterol and Recurrent Events (CARE) Trial
From the Department of Nutrition, Harvard School of Public Health, Boston, Mass (F.M.S., M.J.S.); the Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, Mass (F.M.S., M.J.S., M.A.P., E.B.); Oklahoma Medical Research Foundation, Oklahoma City (P.A.); University of Texas School of Public Health, Houston (L.A.M.); Washington University School of Medicine, St Louis, Mo (T.G.C.); and Memorial University of Newfoundland, St John, Newfoundland, Canada (B.S.).
Correspondence to Frank M. Sacks, MD, Nutrition Department, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail fsacks{at}hsph.harvard.edu
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Abstract |
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Background—Plasma triglyceride concentration has been an inconsistent independent risk factor for coronary heart disease, perhaps because of the metabolic heterogeneity among VLDL particles, the main carriers of triglycerides in plasma.
Methods and Results—We conducted a prospective, nested case-control study in the Cholesterol and Recurrent Events (CARE) trial, a randomized placebo-controlled trial of pravastatin in 4159 patients with myocardial infarction and average LDL concentrations at baseline (115 to 174 mg/dL, mean 139 mg/dL). Baseline concentrations of VLDL–apolipoprotein (apo) B (the VLDL particle concentration), VLDL lipids, and apoCIII and apoE in VLDL+LDL and in HDL were compared in patients who had either a myocardial infarction or coronary death (cases, n=418) with those in patients who did not have a cardiovascular event (control subjects, n=370) in 5 years of follow-up. VLDL-cholesterol, VLDL-triglyceride, VLDL-apoB, apoCIII and apoE in VLDL+LDL and apoE in HDL were all interrelated, and each was a univariate predictor of subsequent coronary events. The significant independent predictors were VLDL-apoB (relative risk [RR] 3.2 for highest to lowest quintiles, P=0.04), apoCIII in VLDL+LDL (RR 2.3, P=0.04), and apoE in HDL (RR 1.8, P=0.02). Plasma triglycerides, a univariate predictor of coronary events (RR 1.6, P=0.03), was not related to coronary events (RR 1.3, P=0.6) when apoCIII in VLDL+LDL was included in the model, whereas apoCIII remained significant. Adjustment for LDL- and HDL-cholesterol did not affect these results.
Conclusions—The plasma concentrations of VLDL particles and apoCIII in VLDL and LDL are more specific measures of coronary heart disease risk than plasma triglycerides perhaps because their known metabolic properties link them more closely to atherosclerosis.
Key Words: coronary disease • apolipoproteins • lipoproteins • cholesterol
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Plasma triglyceride concentration is a significant predictor of coronary heart disease (CHD).1 2 3 However, as an independent lipid risk factor, triglycerides is weaker than LDL-cholesterol or HDL-cholesterol. For example, in men, a 30% change in plasma lipid concentration corresponds to a change in coronary risk of 7% for triglycerides1 versus 30% for LDL-cholesterol or HDL-cholesterol.4 5 VLDL, the major carrier of plasma triglycerides, are a diverse group of lipoprotein particles that vary in triglyceride and cholesterol content, apolipoprotein (apo) C and apoE, and in their metabolism.6 7 ApoCIII and apoE are major determinants of the metabolism of VLDL in plasma, and, in animal models, they accelerate8 and protect against9 atherosclerosis, respectively. It has been proposed that the apolipoprotein composition of lipoproteins is more closely linked to CHD than the conventional lipoprotein measurements of lipid content and density.6 In case-control studies, apoCIII concentrations in VLDL+LDL were higher in patients with coronary disease compared with that in control subjects10 11 and were correlated with worsening coronary stenosis on angiography.12 13 14 Surprisingly, patients with CHD have higher apoE concentrations in VLDL+LDL than control subjects.10 11 15 16 Finally, since entire lipoprotein particles enter the arterial intima, perhaps the VLDL concentration or particle size may be the most important variable.17 The present study directly compares major constituents of VLDL and the apoE and apoCIII concentrations in VLDL+LDL as predictors of recurrent coronary events.
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Methods |
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We used a prospective, nested, case-control design in the Cholesterol and Recurrent Events (CARE) trial. CARE was a randomized, placebo-controlled trial of pravastatin in 4159 patients who had acute myocardial infarction 3 to 20 months before enrollment.18 The institutional review board at each participating clinical center approved the study, subjects gave informed consent, and all procedures followed were in accordance with institutional guidelines. Baseline total cholesterol was <240 mg/dL, LDL-cholesterol 115 to 174 mg/dL, and triglycerides <350 mg/dL. The median follow-up duration was 5 years. During the trial, 486 patients had a primary end point, coronary death, or myocardial infarction.18 Sufficient plasma for analysis was available from both screening visits for 418 of these "cases." The baseline characteristics of these 418 patients were similar to the 68 patients for whom sufficient plasma was not available. Patients who did not have a primary end point that matched the cases for decade of age (eg, 40 to 49, 50 to 59 years) and sex were randomly selected. Among the 418 matches, 370 did not have coronary bypass surgery, coronary angioplasty, or stroke (or a primary end point) after randomization during the follow-up and were selected as the control subjects. We excluded these 48 patients because the results of the trial demonstrated that pravastatin reduced coronary revascularization and stroke,18 and patients who had these clinical cardiovascular end points should not be considered as event-free control subjects.
Fasting venous blood was taken from each patient on each of 2 screening
visits, 
1 week apart, and sent by overnight delivery in cooled
containers to the core laboratory in St Louis, Missouri. Edetic acid
was used as an anticoagulant and preservative. Plasma was separated in
a refrigerated centrifuge, and 1-mL aliquots were placed in
polypropylene vials and stored continuously at -80°C until
analysis. After the trial concluded, vials containing frozen
plasma from the 2 screening visits were shipped on solid
CO2 by overnight delivery from the core
laboratory to the laboratories of Dr Alaupovic (Oklahoma Medical
Research Foundation, Oklahoma City) for apoCIII and apoE measurements
and of Dr Sacks (Harvard School of Public Health, Boston, Mass) for
VLDL lipid and apoB measurements. The average time between collection
of samples and these analyses was 8 years, with a range of 7 to
9 years. The mean concentrations and ranges of the total
cholesterol, LDL-C, HDL-C and triglycerides in
the present study were similar to those measured on the same
patients with fresh plasma.18 Apolipoprotein measurements
have been affected minimally by long-term frozen storage (P. Alaupovic,
unpublished findings). For example, mean apoCIII in VLDL+LDL in 20
patients was 2.4±0.8 mg/dL in fresh plasma versus 2.7±1.0 mg/dL after
2.5 years storage at -70°C, which included a thawing and refreezing.
ApoB decreased by 4.5% (NS) during this time. Total plasma apoCIII in
44 patients was 19±7 mg/dL in fresh plasma versus 21±7 mg/dL after 5
years of continuous storage at -20°C; apo B was 137±25 versus
117±22 mg/dL (P<0.001). The reduction in apoB after 5
years of storage at -20°C was uniform across samples, ranging from
14% to 22% of initial values. Thus, we expect that any changes in
apoB in the present study in which the samples were stored at
-80°C would have been minimal. For each patient, an equal volume of
plasma from the 2 screening visits was combined for analysis to
reduce the influence of biological variation. Analysis was
conducted with the matched cases and control subjects in each
laboratory batch so that run-to-run variation would not add imprecision
to the case-control differences in the measurements. All personnel at
the laboratories were blinded to the case-control code, which was
maintained at the Data Coordinating Center, University of Texas School
of Public Health, Houston.
VLDL was prepared by ultracentrifugation of plasma overlayered with 0.9 mol/L sodium chloride. In VLDL, cholesterol, unesterified cholesterol, and triglyceride were measured by enzymic methods, and apoB by ELISA. Polyclonal anti-apoB was used for capture and detection. LDL-cholesterol was measured directly in the LDL fraction isolated by ultracentrifugation within a density range of 1.006 to 1.063 g/mL. Within-run coefficients of variation were 3% for VLDL-cholesterol, 4% for VLDL-triglycerides, 4% for VLDL-apoB, and 2% for LDL-cholesterol.
Plasma (1 mL) was precipitated with heparin manganese to remove apoB-containing lipoproteins (VLDL+LDL).19 The supernatant containing HDL was removed, and the precipitate was dissolved in PBS containing 0.025% Tween 20. ApoCIII20 and apoE21 were measured in plasma, and the supernatant (HDL) and precipitate (VLDL+LDL) by immunoturbidimetry. The within-run assay coefficients of variation were 7% for apoCIII in the supernatant, 3% for apoCIII in the precipitate, 9% for apoE in the supernatant, and 7% for apoE in the precipitate.
Statistical analyses were performed at the University of Texas Public Health School. The distribution of lipid measurements of the control subjects was used to compute quintiles, and the number of cases and control subjects in each quintile were determined. Multiple logistic regression computed odds ratios for case status for the second through fifth quintiles compared with the first quintile. Tests for linear trend were performed on the relative risks across quintiles, with the median value for each of the quintiles. The primary model included covariates of age, smoking, hypertension, and left ventricular ejection fraction. In additional models, other lipid and nonlipid covariates were added as described. The primary analysis included all cases and control subjects regardless of treatment assignment in the trial to placebo or pravastatin. In additional analyses, lipoprotein variables were investigated in each treatment group separately, and tests for interaction between treatment assignment and relative risk of coronary events for a lipoprotein concentration were conducted. A probability value of 0.05 (2-sided) was considered significant.
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Results |
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Compared with the control subjects, the cases had a higher mean body mass index and waist circumference; more of them were current smokers, hypertensive, or diabetic, and more used ß-blockers and diuretics (Table 1
).
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Triglycerides, VLDL-apoB, VLDL-cholesterol,
VLDL-triglycerides, and apoCIII and apoE in VLDL+LDL were
strongly correlated with one another (r=0.63 to 0.92),
moderately inversely correlated with HDL cholesterol
(r=-0.33 to -0.48), and weakly inversely correlated with
LDL cholesterol (r=-0.10 to -0.24) (Table 2). Triglycerides, VLDL-apoB,
VLDL-cholesterol, and VLDL-triglycerides were
moderately correlated with apoE and apoCIII in HDL (r=0.32
to 0.52).
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VLDL-apoB, VLDL-cholesterol, and
VLDL-triglycerides were predictors of recurrent
coronary events, comparing the highest and lowest quintiles,
and the test for linear trend was significant for VLDL-apoB and
VLDL-triglycerides (Table 3).
The VLDL measurements were studied together in multiple logistic
regression to determine which were independent. VLDL-apoB was the
strongest predictor of recurrent events (relative risk [RR] 3.2,
P=0.04) for the highest compared with the lowest quintile,
whereas VLDL-cholesterol trended toward an inverse relation
with simultaneous adjustment (P=0.10) (Figure 1). In this model,
LDL-cholesterol remained a significant predictor (RR 1.7,
P=0.03), whereas HDL-cholesterol (RR 0.97) and
triglycerides (RR 1.8, P=0.25) were not
significant. When VLDL-triglyceride was substituted for
total triglyceride, the results were similar.
VLDL-cholesterol ester and VLDL-unesterified
cholesterol had a similar relation to coronary
events as VLDL-cholesterol (cholesterol
ester+unesterified cholesterol) (data not shown). The
number of triglyceride molecules in VLDL, the major
determinant of VLDL size, was not associated with coronary
events (Table 3).
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0.10.
ApoCIII in VLDL+LDL was a strong significant predictor of
coronary events (RR 2.25, P=0.001), whereas apoE in
VLDL+LDL was less so (RR 1.68, P=0.03) (Table 3
).
When both were included in the logistic regression model, apoCIII
remained a significant predictor, whereas apoE lost its association
with coronary events (Figure 2).
The amount of apoCIII per VLDL/LDL particle (apoCIII/apoB ratio) was a
significant predictor, whereas the apoE/apoB ratio had no relation to
coronary events (Table 3). ApoCIII in VLDL+LDL (RR 2.3,
P=0.04) and VLDL-apoB (RR 3.2, P=0.04) were both
significant independent predictors of coronary events in a
single model that included LDL cholesterol, VLDL
cholesterol, triglycerides, and HDL
cholesterol (Figure 3).
However, the predictive value for triglycerides,
significant in univariate analysis (RR 1.58,
P=0.03) (Table 3), was lost (RR 1.3, P=0.6
for fifth versus first quintile) (Figure 3).
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The apoE concentration in HDL significantly predicted recurrent
coronary events when studied in several models (1) as a
univariate lipoprotein measurement in the standard model
(RR 2.05, P=0.002) (Table 3), (2) with
LDL-cholesterol, HDL-cholesterol, and
triglycerides (RR 1.9, 0.009), and (3) together with
apoCIII in VLDL+LDL (RR 1.8, P=0.02). The significant
positive univariate association between
triglycerides and coronary events (Table 3)
was not present when apoE in HDL was included (RR 1.2,
P=0.5), whereas LDL-C remained significant (RR 1.8,
P=0.01). Including apoE in VLDL+LDL did not alter the
relative risk for apoE in HDL. The apoCIII concentration in HDL was not
significant in any of the models.
The relative risks for the significant lipoprotein predictors were
similar with or without adjustment for diabetes in
multivariate analysis; the relative risks for
the highest compared with the lowest quintile of VLDL-apoB was 1.85
compared with 1.95 (Table 3) with and without adjustment,
respectively, for apoCIII in VLDL+LDL (RR 2.07 versus 2.25) and for
apoE in HDL (RR 1.95 versus 2.05). The relative risks were also similar
in an analyses that excluded the diabetic patients. For
example, in the full multivariate model shown in Figure 3, the relative risk for VLDL-apoB was 3.2 in the full cohort
(Figure 3) versus 3.4 in the nondiabetics, and for apoCIII in
VLDL+LDL the relative risk was 2.3 versus 1.8, respectively. Thus, the
larger number of diabetics among the cases did not account for the
predictive association of these lipoprotein measurements with
coronary events. The relative risks were slightly attenuated
when additional covariates, waist circumference, and use of
ß-blockers or diuretics were added with diabetes together to
the standard model.
The relative risks for VLDL measurements and apoCIII and apoE in VLDL+LDL tended to be higher in the pravastatin group than in the placebo group. For example, the univariate relative risks for the highest compared with the lowest quintile of VLDL-apoB were 1.6 (95% CI 0.4 to 3.0) in the placebo group compared with 2.7 (1.3 to 5.6) in the pravastatin group and for apoCIII in VLDL+LDL 1.5 (0.8 to 2.8) in placebo versus 2.7 (1.3 to 5.7) in the pravastatin group. However, these differences in the relative risks between the placebo and pravastatin groups were not significant by test of interaction (P=0.09 for VLDL-apoB, P=0.25 for apoCIII in VLDL+LDL).
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Discussion |
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Difficulty in establishing the independent relation between plasma triglycerides and CHD may have been due in part to the lack of specificity of a plasma triglyceride measurement to indicate levels of atherogenic lipoproteins. Triglycerides are carried in lipoproteins, mainly VLDL, which are heterogeneous in size, density, composition, and function.6 7 We found that the risk of a recurrent coronary event associated with plasma triglycerides could be explained by 2 specific and related measurements, VLDL-apoB (which indicates the concentration of VLDL particles in plasma since each VLDL particle has 1 apoB molecule) and the apoCIII concentration of VLDL+LDL. VLDL-apoB concentration therefore may represent the concentration of potentially atherogenic VLDL particles to which the arterial wall is exposed. Excessive apoCIII may contribute to the atherogenicity of VLDL particles, since apoCIII delays the lipolysis of VLDL22 and inhibits its uptake and clearance from plasma by normal, high-affinity receptors on hepatocytes.23 Approximately 30% to 70% of VLDL particles contain apoCIII, compared with only a few percent of LDL particles.24 Inhibition of rapid clearance of VLDL by the liver may be atherogenic if it results in uptake by low-affinity, high-capacity pathways in cells involved in atherosclerosis. Therefore, the relation between the apoCIII concentration in VLDL+LDL and coronary events in the present study gains plausibility from the deleterious metabolic properties of this apolipoprotein.
These findings are consistent with studies that found that apoCIII concentrations in VLDL+LDL were increased in survivors of myocardial infarction11 and in patients before undergoing bypass surgery10 compared with control populations. ApoCIII concentrations in VLDL+LDL also were significant markers of progression of coronary atherosclerosis measured by angiography.12 13 14 The present study is applicable to the majority of patients in the United States with CHD because it included patients with average LDL-cholesterol concentrations (115 to 174 mg/dL)18 and excluded those with hypercholestesterolemia (total cholesterol >240 mg/dL), or hypertriglyceridemia (triglycerides >350 mg/dL).
In the present and in previous studies, apoE concentrations in plasma or in VLDL+LDL were associated with CHD,10 11 15 16 a counterintuitive finding, in view of the necessity for apoE for normal rapid removal of VLDL by the liver.9 25 Since most VLDL and LDL particles that contain apoE also contain apoCIII,24 apoE in VLDL+LDL may be simply a marker for apoCIII and not a direct cause of atherosclerosis. This explanation is supported by multivariate analysis showing that apoCIII in VLDL+LDL was the independent risk factor of the two. Perhaps apoCIII is the dominant of these two metabolically antagonistic apolipoproteins in VLDL and LDL in influencing coronary events in humans.
However, subordinance of apoE to the actions of apoCIII does not explain the finding that HDL-apoE but not HDL-apoCIII was an independent risk factor for coronary events. In a previous study, HDL-apoE independently discriminated patients with coronary bypass surgery from normal control subjects.10 In the present study, high HDL-apoE concentration was correlated with low HDL-cholesterol and high triglycerides, VLDL-apoB, and VLDL/LDL apoCIII concentrations. Recently, this lipoprotein pattern was produced by overexpression of human apoE in transgenic mice.26 The mechanism was stimulation by apoE of VLDL production by the liver and inhibition by apoE of VLDL lipolysis by lipoprotein lipase. Thus, the association between HDL-apoE and an atherogenic lipid profile and risk of coronary events could be directly related to the actions of apoE itself.
The VLDL cholesterol concentration, a significant positive predictor of coronary events in univariate analysis, became an inverse predictor when VLDL-apoB was included in the multivariate model. Consistent with this unexpected finding, the cholesterol enrichment of VLDL particles was inversely related to risk of coronary events. Cholesterol-rich VLDL particles are taken up rapidly by LDL receptors on cultured fibroblasts and macrophages.27 Although this may appear to be an atherogenic characteristic of VLDL, rapid uptake of cholesterol-rich VLDL by LDL receptors in the liver is the normal route for VLDL clearance, which could protect against their entry into the arterial intima.
The primary analysis of this study included the total cohort of patients who had a recurrent event, whether treated with pravastatin or placebo. The relative risks associated with VLDL-apo B, and apoCIII in VLDL+LDL appeared to be stronger in the pravastatin group than in the placebo group. However, this apparent difference was not statistically significant and therefore may have been due to chance. We recently reported that pravastatin reduced the concentrations of these apolipoprotein measurements (Sacks FM, et al, 1999 AHA Scientific Sessions). Nonetheless, statin therapy, by diminishing the influence of LDL on CHD, could "unmask" the influence of atherogenic VLDL particles or have differential effects on VLDL particle types with distinct atherogenic potential.
In summary, we found that the VLDL-apoB concentration, the apoCIII concentration of VLDL+LDL, and apoE in HDL are independent predictors of recurrent coronary events and explain the weaker relation between plasma triglycerides and coronary events. The results are consistent with the known metabolic properties of apoCIII and VLDL particles, which link them to atherosclerosis, and with newly recognized properties of apoE and suggest that plasma triglyceride level is an imperfect marker for these specific lipoprotein particle measurements. The apolipoprotein measurements are not technically difficult. These prospective findings need to be explored in other populations, and if confirmed could be applied clinically.
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Acknowledgments |
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This study was supported by an investigator-initiated grant from Bristol-Myers Squibb, Co.
Received April 28, 2000; revision received May 31, 2000; accepted June 3, 2000.
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References |
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 D. C. Chan, G. F. Watts, E. M.M. Ooi, J. Ji, A. G. Johnson, and P. H. R. Barrett Atorvastatin and Fenofibrate Have Comparable Effects on VLDL-Apolipoprotein C-III Kinetics in Men With the Metabolic Syndrome Arterioscler Thromb Vasc Biol, October 1, 2008; 28(10): 1831 - 1837. [Abstract] [Full Text] [PDF]
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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]
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 P. G. Scheffer, T. Teerlink, J. M. Dekker, G. Bos, G. Nijpels, M. Diamant, P. J. Kostense, C. D. A. Stehouwer, and R. J. Heine Increased Plasma Apolipoprotein C-III Concentration Independently Predicts Cardiovascular Mortality: The Hoorn Study Clin. Chem., August 1, 2008; 54(8): 1325 - 1330. [Abstract] [Full Text] [PDF]
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M. Stahlman, P. Davidsson, I. Kanmert, B. Rosengren, J. Boren, B. Fagerberg, and G. Camejo Proteomics and lipids of lipoproteins isolated at low salt concentrations in D2O/sucrose or in KBr J. Lipid Res., February 1, 2008; 49(2): 481 - 490. [Abstract] [Full Text] [PDF]
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 D. C. Chan, M. N. Nguyen, G. F. Watts, and P. H. R. Barrett Plasma Apolipoprotein C-III Transport in Centrally Obese Men: Associations with Very Low-Density Lipoprotein Apolipoprotein B and High-Density Lipoprotein Apolipoprotein A-I Metabolism J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 557 - 564. [Abstract] [Full Text] [PDF]
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 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]
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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]
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A. Kawakami, M. Aikawa, N. Nitta, M. Yoshida, P. Libby, and F. M. Sacks Apolipoprotein CIII-Induced THP-1 Cell Adhesion to Endothelial Cells Involves Pertussis Toxin-Sensitive G Protein- and Protein Kinase C{alpha}-Mediated Nuclear Factor-{kappa}B Activation Arterioscler Thromb Vasc Biol, January 1, 2007; 27(1): 219 - 225. [Abstract] [Full Text] [PDF]
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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]
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M. N. Nguyen, D. C. Chan, K. P. Dwyer, P. Bolitho, G. F. Watts, and P. H. R. Barrett Use of Intralipid for kinetic analysis of HDL apoC-III: evidence for a homogeneous kinetic pool of apoC-III in plasma J. Lipid Res., June 1, 2006; 47(6): 1274 - 1280. [Abstract] [Full Text] [PDF]
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C.-Q. Lai, D. Corella, S. Demissie, L. A. Cupples, X. Adiconis, Y. Zhu, L. D. Parnell, K. L. Tucker, and J. M. Ordovas Dietary Intake of n-6 Fatty Acids Modulates Effect of Apolipoprotein A5 Gene on Plasma Fasting Triglycerides, Remnant Lipoprotein Concentrations, and Lipoprotein Particle Size: The Framingham Heart Study Circulation, May 2, 2006; 113(17): 2062 - 2070. [Abstract] [Full Text] [PDF]
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Y. Fang, E. R. Mohler III, E. Hsieh, H. Osman, S. M. Hashemi, P. F. Davies, G. H. Rothblat, R. L. Wilensky, and I. Levitan Hypercholesterolemia Suppresses Inwardly Rectifying K+ Channels in Aortic Endothelium In Vitro and In Vivo Circ. Res., April 28, 2006; 98(8): 1064 - 1071. [Abstract] [Full Text] [PDF]
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D. C. Chan, G. F. Watts, M. N. Nguyen, and P. H. R. Barrett Apolipoproteins C-III and A-V as Predictors of Very-Low-Density Lipoprotein Triglyceride and Apolipoprotein B-100 Kinetics Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 590 - 596. [Abstract] [Full Text] [PDF]
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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]
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C. Imke, B. L. Rodriguez, J. S. Grove, J. R. McNamara, C. Waslien, A. R. Katz, B. Willcox, K. Yano, and J. D. Curb Are Remnant-Like Particles Independent Predictors of Coronary Heart Disease Incidence?: The Honolulu Heart Study Arterioscler Thromb Vasc Biol, August 1, 2005; 25(8): 1718 - 1722. [Abstract] [Full Text] [PDF]
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 E. M. Stuveling, S. J. L. Bakker, H. L. Hillege, P. E. de Jong, R. O. B. Gans, and D. de Zeeuw Biochemical risk markers: a novel area for better prediction of renal risk? Nephrol. Dial. Transplant., March 1, 2005; 20(3): 497 - 508. [Full Text] [PDF]
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O. Olivieri, N. Martinelli, M. Sandri, A. Bassi, P. Guarini, E. Trabetti, F. Pizzolo, D. Girelli, S. Friso, P. F. Pignatti, et al. Apolipoprotein C-III, n-3 Polyunsaturated Fatty Acids, and "Insulin-Resistant" T-455C APOC3 Gene Polymorphism in Heart Disease Patients: Example of Gene-Diet Interaction Clin. Chem., February 1, 2005; 51(2): 360 - 367. [Abstract] [Full Text] [PDF]
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 M. N. Ballesteros, R. M. Cabrera, M. d. S. Saucedo, D. Aggarwal, N. S. Shachter, and M. L. Fernandez High Intake of Saturated Fat and Early Occurrence of Specific Biomarkers May Explain the Prevalence of Chronic Disease in Northern Mexico J. Nutr., January 1, 2005; 135(1): 70 - 73. [Abstract] [Full Text] [PDF]
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 A. S Wierzbicki The role of dyslipidaemia in coronary heart disease The British Journal of Diabetes & Vascular Disease, January 1, 2005; 5(1_suppl): S2 - S6. [Abstract] [PDF]
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J. S. Cohn, C. Rodriguez, H. Jacques, M. Tremblay, and J. Davignon Storage of human plasma samples leads to alterations in the lipoprotein distribution of apoC-III and apoE J. Lipid Res., August 1, 2004; 45(8): 1572 - 1579. [Abstract] [Full Text] [PDF]
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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]
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J.-C. Fruchart, M. C. Nierman, E. S. G. Stroes, J. J. P. Kastelein, and P. Duriez New Risk Factors for Atherosclerosis and Patient Risk Assessment Circulation, June 15, 2004; 109(23_suppl_1): III-15 - III-19. [Abstract] [Full Text]
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 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]
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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]
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 C.C. Shoulders, E.L. Jones, and R.P. Naoumova Genetics of familial combined hyperlipidemia and risk of coronary heart disease Hum. Mol. Genet., April 1, 2004; 13(90001): R149 - 160. [Abstract] [Full Text] [PDF]
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O. Olivieri, A. Bassi, C. Stranieri, E. Trabetti, N. Martinelli, F. Pizzolo, D. Girelli, S. Friso, P. F. Pignatti, and R. Corrocher Apolipoprotein C-III, metabolic syndrome, and risk of coronary artery disease J. Lipid Res., December 1, 2003; 44(12): 2374 - 2381. [Abstract] [Full Text] [PDF]
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 O. Ziouzenkova, L. Asatryan, D. Sahady, G. Orasanu, S. Perrey, B. Cutak, T. Hassell, T. E. Akiyama, J. P. Berger, A. Sevanian, et al. Dual Roles for Lipolysis and Oxidation in Peroxisome Proliferation-Activator Receptor Responses to Electronegative Low Density Lipoprotein J. Biol. Chem., October 10, 2003; 278(41): 39874 - 39881. [Abstract] [Full Text] [PDF]
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J. S. Cohn, R. Batal, M. Tremblay, H. Jacques, L. Veilleux, C. Rodriguez, O. Mamer, and J. Davignon Plasma turnover of HDL apoC-I, apoC-III, and apoE in humans: in vivo evidence for a link between HDL apoC-III and apoA-I metabolism J. Lipid Res., October 1, 2003; 44(10): 1976 - 1983. [Abstract] [Full Text] [PDF]
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 E. Rizos, E. Bairaktari, A. Kostoula, G. Hasiotis, A. Achimastos, E. Ganotakis, M. Elisaf, and D. P. Mikhailidis The Combination of Nebivolol plus Pravastatin is Associated with a More Beneficial Metabolic Profile Compared to that of Atenolol plus Pravastatin in Hypertensive Patients with Dyslipidemia: A Pilot Study Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 127 - 134. [Abstract] [PDF]
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 J. Sabate, E. Haddad, J. S Tanzman, P. Jambazian, and S. Rajaram Serum lipid response to the graduated enrichment of a Step I diet with almonds: a randomized feeding trial Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1379 - 1384. [Abstract] [Full Text] [PDF]
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C. Couillard, M.-C. Vohl, J. C. Engert, I. Lemieux, A. Houde, N. Almeras, D. Prud'homme, A. Nadeau, J.-P. Despres, and J. Bergeron Effect of apoC-III gene polymorphisms on the lipoprotein-lipid profile of viscerally obese men J. Lipid Res., May 1, 2003; 44(5): 986 - 993. [Abstract] [Full Text] [PDF]
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L. Mabile, J.-B. Ruidavets, J. Fauvel, B. Perret, and J. Ferrieres Differential Levels of {gamma}-Glutamyl Transferase Activity and Apolipoprotein CIII in Men on Either Statin or Fibrate Therapy Diabetes Care, May 1, 2003; 26(5): 1652 - 1653. [Full Text] [PDF]
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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]
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 O. Ziouzenkova, S. Perrey, L. Asatryan, J. Hwang, K. L. MacNaul, D. E. Moller, D. J. Rader, A. Sevanian, R. Zechner, G. Hoefler, et al. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: Evidence for an antiinflammatory role for lipoprotein lipase PNAS, March 4, 2003; 100(5): 2730 - 2735. [Abstract] [Full Text] [PDF]
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P. Tilly, C. Sass, M. Vincent-Viry, D. Aguillon, G. Siest, and S. Visvikis Biological and genetic determinants of serum apoC-III concentration: reference limits from the Stanislas Cohort J. Lipid Res., February 1, 2003; 44(2): 430 - 436. [Abstract] [Full Text] [PDF]
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References Circulation, December 17, 2002; 106(25): 3373 - 3421. [Full Text]
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K. Olin-Lewis, R. M. Krauss, M. La Belle, P. J. Blanche, P. H. R. Barrett, T. N. Wight, and A. Chait ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan J. Lipid Res., November 1, 2002; 43(11): 1969 - 1977. [Abstract] [Full Text] [PDF]
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H. N. Ginsberg New Perspectives on Atherogenesis: Role of Abnormal Triglyceride-Rich Lipoprotein Metabolism Circulation, October 15, 2002; 106(16): 2137 - 2142. [Full Text] [PDF]
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K. K. Berneis and R. M. Krauss Metabolic origins and clinical significance of LDL heterogeneity J. Lipid Res., September 1, 2002; 43(9): 1363 - 1379. [Abstract] [Full Text] [PDF]
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O. Olivieri, C. Stranieri, A. Bassi, B. Zaia, D. Girelli, F. Pizzolo, E. Trabetti, S. Cheng, M. A. Grow, P. F. Pignatti, et al. ApoC-III gene polymorphisms and risk of coronary artery disease J. Lipid Res., September 1, 2002; 43(9): 1450 - 1457. [Abstract] [Full Text] [PDF]
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K. Olin-Lewis, J. L. Benton, J. C. Rutledge, D. G. Baskin, T. N. Wight, and A. Chait Apolipoprotein E Mediates the Retention of High-Density Lipoproteins by Mouse Carotid Arteries and Cultured Arterial Smooth Muscle Cell Extracellular Matrices Circ. Res., June 28, 2002; 90(12): 1333 - 1339. [Abstract] [Full Text] [PDF]
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R. A. Kreisberg and A. Oberman Lipids and Atherosclerosis: Lessons Learned from Randomized Controlled Trials of Lipid Lowering and Other Relevant Studies J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 423 - 437. [Full Text] [PDF]
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D. C. Chan, G. F. Watts, P. H. Barrett, J. C.L. Mamo, and T. G. Redgrave Markers of Triglyceride-rich Lipoprotein Remnant Metabolism in Visceral Obesity Clin. Chem., February 1, 2002; 48(2): 278 - 283. [Abstract] [Full Text] [PDF]
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J. Frohlich, A. Sniderman, and R. H. Eckel Familial Combined Hyperlipidemia and Insulin Resistance Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 2100 - 2101. [Full Text] [PDF]
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 H. Campos, L. A. Moye, S. P. Glasser, M. J. Stampfer, and F. M. Sacks Low-Density Lipoprotein Size, Pravastatin Treatment, and Coronary Events JAMA, September 26, 2001; 286(12): 1468 - 1474. [Abstract] [Full Text] [PDF]
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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]
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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]
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