© 1995 American Heart Association, Inc.
Articles |
The Effect of 
-Tocopherol Supplementation on LDL Oxidation
A Dose-Response Study
From the Center for Human Nutrition (I.J., C.J.F.), Laboratory of Molecular Pathology (I.J.), and the General Clinical Research Center (B.A.H.), Departments of Internal Medicine (I.J.) and Pathology (I.J.), University of Texas Southwestern Medical Center, Dallas.
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Abstract |
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Abstract Because much data have accrued to support the concept that oxidatively modified LDL (Ox-LDL) can promote atherogenesis, the role of antioxidants in decreasing LDL oxidation has assumed great importance. High-dose
-tocopherol
supplementation in humans decreases the susceptibility of LDL to
oxidation. Hence, the aim of the present study was to ascertain the
minimum dose of -tocopherol that would decrease the susceptibility
of LDL to oxidation. The effect of -tocopherol in doses of 60, 200,
400, 800, and 1200 IU/d on copper-catalyzed LDL oxidation was tested in
a randomized placebo-controlled study over 8 weeks. There were eight
subjects in each group. Oxidation of LDL was monitored by measuring the
formation of conjugated dienes and lipid peroxides by the
thiobarbituric acid–reacting substances (TBARS) assay over an 8-hour
time course at baseline and after 8 weeks of supplementation. Neither
placebo nor any of the doses of -tocopherol resulted in any side
effects or exerted an adverse effect on the plasma lipoprotein profile.
However, there was a dose-dependent increase in plasma and
lipid-standardized -tocopherol levels with increasing doses of
-tocopherol supplementation. LDL -tocopherol appeared to follow a
similar trend. When the time-course curves of LDL oxidation and the
kinetics of LDL oxidation were examined, there was no significant
effect at 8 weeks compared with baseline in the groups that received
placebo or -tocopherol 60 or 200 IU/d. However, in the groups that
received at least 400 IU/d -tocopherol, there was a
decreased susceptibility of LDL to oxidation, as shown by the mean
levels in the time-course curves, prolongation in the lag phase, and a
decrease in the oxidation rate. Furthermore, both plasma and LDL
-tocopherol correlated significantly with the lag phase of
oxidation and inversely with the oxidation rate. The results of the
present study show that the minimum dose of -tocopherol needed
to significantly decrease the susceptibility of LDL to oxidation is 400
IU/d.
Key Words: lipid peroxidation • -tocopherol • LDL oxidation • atherosclerosis • antioxidants
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Much data have accrued to support the concept that oxidatively modified LDL (Ox-LDL) can promote atherogenesis.1 2 Ox-LDL could promote atherogenesis in several ways: by uptake by the scavenger receptor mechanism, which would result in cholesterol ester accumulation3 ; by its cytotoxic effect, which could promote endothelial cell dysfunction and evolution of the fatty streak to the more advanced lesion4 ; and by its chemotactic effect on monocytes and its inhibitory effect on macrophage migration, which could result in accumulation of macrophages in the artery wall.5 6 It could also promote atherogenesis by altering gene expression in the arterial wall, such as induction of leukocyte adhesion molecules on monocytes and induction of monocyte chemotactic protein–1 and interleukin-1.7 8 9 Ox-LDL can adversely affect the coagulation pathway by inducing tissue factor synthesis10 ; it has also been shown that products of oxidized LDL can impair endothelium-derived relaxation factor–mediated vasorelaxation.11 12 Furthermore, several lines of evidence support the in vivo existence of oxidized LDL. Data have been presented for the occurrence of a modified form of LDL with many physical, chemical, and biological properties of Ox-LDL in arterial lesions.13 Antibodies against epitopes on oxidized LDL recognize material in atherosclerotic lesions but not normal arteries.14 15 16 Circulating antibodies against epitopes of oxidized LDL have been demonstrated in the plasma of humans,16 and in fact, the titer of this antibody correlates independently with the progression of carotid artery stenosis.17 In addition, the susceptibility of LDL to oxidation (the lag phase of oxidation) is correlated with the severity of coronary atherosclerosis as shown by angiography.18 However, the most persuasive data are the findings that antioxidant supplementation will inhibit the progression of atherosclerosis in animal models.19 20 21 22 Thus, a clinical trial in humans with antioxidants is crucial in validating the oxidized LDL hypothesis. Most of the antioxidants tested in animal models to date, probucol, butylated hydroxytoluene, and N,N'-diphenylphenylenediamine, carry potential side effects that preclude their utility in human clinical trials.22 23 24 However, the dietary micronutrients with antioxidant properties such as ascorbate,
-tocopherol, and
ß-carotene may provide an alternative approach to protect LDL against
oxidative modification and prevention of atherosclerosis. The most
consistent data with respect to micronutrient antioxidants and
atherosclerosis appear to relate to -tocopherol (vitamin E), which
is the major antioxidant in LDL.25 Several lines of
evidence support an inverse relationship between -tocopherol and
atherogenesis. Low levels of -tocopherol have been shown in
epidemiological studies to be related to an increased frequency of
cardiovascular disease mortality.26 27 Case-control
studies have shown lower levels in patients with angina pectoris
compared with control subjects,28 and both men and women
in the highest compared with the lowest quintile of vitamin E intake
have a significantly lower relative risk of coronary heart
disease.29 30 Numerous studies have now documented that
-tocopherol can inhibit LDL oxidation in vitro.31 32 In
addition, high-dose -tocopherol supplementation can decrease the
susceptibility of LDL to oxidation in human subjects.33 34 35 36
Furthermore, it appears that supplementation with ascorbate and
ß-carotene, in addition to high-dose -tocopherol, does not appear
to confer an additional benefit in decreasing the susceptibility of LDL
to oxidation.36 37 The doses of -tocopherol used in
these studies greatly exceed the RDA.38 Hence, it is
important to establish the minimum dose of -tocopherol that would
decrease the susceptibility of LDL to oxidation. Accordingly, the
present study was designed to examine the dose-response effect of
-tocopherol on the susceptibility of LDL to oxidation. |
Methods |
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This study was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. All subjects gave informed consent. The study design was that of a placebo-controlled, randomized trial. Healthy men had to fulfill all the following criteria to be entered into the study: nonsmokers; not on any vitamin supplements for at least 6 months before entry; alcohol intake <1 oz/d; normal plasma glucose, hepatic, and renal function tests; no evidence of malabsorption, pancreatic, or biliary disease; and no acute medical condition for at least 3 months prior to entry. A total of 48 subjects were selected. Fasting blood samples were obtained at baseline for complete blood count and plasma glucose, protein, hepatic, and renal function tests; these were all assayed in a standardized hospital laboratory.
Blood (120 mL) was also obtained for lipid and lipoprotein
profiles; plasma -tocopherol, ascorbate, and ß-carotene levels;
and for LDL isolation. The samples for LDL isolation were collected in
tubes containing EDTA (1 mg/mL). All blood samples were collected on
ice, and the plasma was separated by low-speed centrifugation at 4°C.
Thereafter, the participants were randomly assigned to receive either
placebo (soybean oil) or -tocopherol capsules at dosages of 60, 200,
400, 800, or 1200 IU/d for 8 weeks. The supplement was in the form of
DL--tocopherol, and all capsules were provided by
Hoffmann-La Roche Inc. All six groups were studied in parallel. They
were advised to maintain their usual diet and activities during the 8
weeks and to report any side effects immediately to the investigators.
The subjects returned to the clinic at 8 weeks. They continued to take
the -tocopherol capsules until the day on which blood samples were
obtained. At each visit a clinical examination was performed, and blood
samples were obtained as described above for the baseline period.
Samples for plasma ascorbate were deproteinized with ice-cold 10%
metaphosphoric acid and centrifuged, and the supernatant was purged
with nitrogen and stored below -20°C in foil-covered tubes.
The plasma lipid and lipoprotein levels were assayed by using Lipid
Research Clinics methodology, except that cholesterol and triglyceride
levels were determined enzymatically.39 The concentrations
of -tocopherol and ß-carotene were measured in plasma and LDL
following extraction by reverse-phase high-performance liquid
chromatography.40 The plasma levels of both -tocopherol
and ß-carotene were standardized to total plasma lipids as
described.41 The LDL concentrations were expressed per
milligram LDL protein. Plasma ascorbate levels were determined
spectrophotometrically after derivatization with
2,4-dinitrophenylhydrazine.42
Plasma fatty acids at baseline and 8 weeks were measured by gas-liquid chromatography after extraction and transmethylation.43 An internal standard of 17:0 was added to all samples; fatty acid standards were obtained from NuChek Prep. Data are expressed in millimoles per liter for 14:0, 16:0, 18:0, 18:1, 18:2, 18:3, and 20:4.
LDL (d=1.019 to 1.063 g/mL) was isolated by preparative ultracentrifugation in NaBr-NaCl solutions containing 1 mg/mL EDTA as described.44 The isolated LDL was extensively dialyzed against three exchanges (4, 4, and 2 L) of saline-EDTA (150 mmol/L NaCl, 1 mmol/L EDTA, pH 7.4) at 4°C over 24 hours. Thereafter the LDL was filtered and stored at 4°C under nitrogen until protein was measured by the method of Lowry et al45 on the same day using bovine serum albumin as the standard. Stock LDL solutions obtained at 8 weeks were diluted with the NaCl-EDTA dialysis buffer such that the protein concentration did not vary from baseline levels by more than 0.5 mg/mL. LDL oxidation was undertaken after an overnight dialysis against 1 L phosphate-buffered saline (PBS), pH 7.4, at 4°C. Thus, oxidation studies were performed within 48 hours of LDL isolation by ultracentrifugation. LDL (200 µg protein/mL) was oxidized in a cell-free system using 5 µmol/L copper in PBS at 37°C.33 The time course of oxidation was studied over an 8-hour period. Each time point was set up in triplicate. At 0, 0.5, 1, 1.5, 2, 3, 5, and 8 hours, oxidation was arrested by refrigeration and the addition of 200 µmol/L EDTA and 40 µmol/L BHT.
Two indices of oxidation were used in this study. The lipid peroxide
content of oxidized LDL was measured by a modification of the
thiobarbituric acid–reactive substances (TBARS) assay of Buege and
Aust.46 TBARS activity was expressed as malondialdehyde
equivalents using freshly diluted 1,1,3,3-tetramethoxypropane as the
standard. The amount of conjugated dienes formed during LDL oxidation
was determined by measuring the absorbance of LDL against a PBS blank
at 234 nm following a 1:4 dilution of the samples in
PBS.47 We have shown that dilution of an oxidized LDL
sample to 1:2, 1:4, and 1:8 displays linearity and excellent recovery;
the data are expressed as the increase in conjugated dienes over
baseline (
A234).48 The rate of LDL oxidation was
determined from the propagation phase of the time-course curve using a
spline function. The lag phase was obtained by drawing a tangent to the
slope of the propagation phase and extrapolating it to the horizontal
axis.48 The lag time constitutes the interval from zero
time to the intersection point.
Statistical Methods
Results are expressed as mean±SD or for skewed data as median
(range). ANOVA with the Student-Newman-Keuls multiple range test was
used to assess differences between groups at baseline. Paired
t tests were used to determine differences within each group
between baseline and 8 weeks for plasma lipid and lipoprotein levels
(except triglycerides) and LDL oxidation kinetic parameters. For skewed
data such as plasma triglycerides and antioxidant levels, the Wilcoxon
signed rank test was used to compare baseline and week 8
measurements.49 50 Comparison of baseline and 8-week
time-course curves within each group were made by using two-factor
repeated-measures analysis of variance. Where the weekxhour
interaction was significant, comparisons at each time point were made
using paired t tests. The relationships between percent
change in plasma and LDL -tocopherol concentrations and lag phase
and oxidation rates were determined using Spearman rank correlation.
For -tocopherol levels and oxidation kinetic parameters, percent
change from baseline was computed for each subject and is reported as
median because of skewness. The level of significance was =.05.
Analyses were performed using BMDP programs
3D, 2V, and 3S (BMDP
Statistical Software, Inc).
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Results |
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Table 1
shows the characteristics of the subjects
at baseline. Both age and body mass index were similar across the six
groups. There were no changes in diets, activity levels, or weights
while the subjects were on supplementation. In addition, none of the
subjects reported any adverse effects of supplementation, nor did
routine laboratory values change for any subject. Table 1 also displays
the plasma lipid and lipoprotein profiles of the study participants at
baseline and at 8 weeks. All groups had similar baseline lipid and
lipoprotein concentrations. No significant differences were seen within
each group between levels at baseline and after 8 weeks of
supplementation, except for a marginally significant increase in HDL
cholesterol in the group that received 200 IU/d.
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The fatty acid profiles for the subjects are shown in Table 2. The concentrations of the fatty acids measured were
not significantly different by ANOVA among the groups at either
baseline or 8 weeks. In addition, paired t tests revealed no
significant differences within any group during the study except for
linoleic acid levels in the group that took 200 IU/d.
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Table 3 shows the concentrations of plasma and LDL
antioxidants. No differences were seen between baseline and 8 weeks for
plasma ascorbate or ß-carotene within any group, regardless of
whether the plasma ß-carotene concentration was lipid standardized.
The group supplemented with 60 IU/d -tocopherol had a rise in LDL
ß-carotene at 8 weeks that was marginally significant
(P=.047) relative to baseline; there were no other
differences in LDL ß-carotene. All supplemented groups showed
significant increases in plasma and lipid-standardized plasma
-tocopherol levels (plasma, P<.01 for 60 to 1200 IU/d;
lipid-standardized plasma, P<.05 for 60 IU/d,
P<.01 for 200 to 1200 IU/d). Plasma -tocopherol
increased from 60.5% in the 60 IU/d group to 235.8% in the 1200 IU/d
group. Plasma lipid-standardized -tocopherol levels increased
in a similar fashion. For the five doses of -tocopherol (60, 200,
400, 800, and 1200 IU/d), the increases were 48.3%, 80.4%, 110.9%,
145.3%, and 260.3%, respectively. Due to small sample size (n=6)
(there was insufficient LDL available in two subjects to assay for
-tocopherol), LDL -tocopherol in the 400 IU/d group did
not reach statistical significance (P=.063); otherwise,
there were significant increases at 8 weeks over baseline (60, 200, and
1200 IU/d, P<.05; 800 IU/d, P<.01; Table 3).
The increments in LDL -tocopherol were not as marked with
increasing doses compared with the responses in plasma.
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The time courses of LDL oxidation showed significant changes at 8 weeks
versus baseline only for the groups that took at least 400 IU/d. For
both TBARS and conjugated dienes, there were no significant differences
for the placebo, 60 IU, or 200 IU groups (Fig 1),
whereas the differences between time-course curves were highly
significant for the 400 to 1200 IU/d groups (ANOVA, weekxhour
interaction, P<.001). In addition, time point comparisons
revealed significantly lower means in the 
400 IU/d groups (Fig 2). The kinetics of LDL oxidation (lag phase and
oxidation rate) were also computed from the time-course curves. In the
groups that received placebo or 60 or 200 IU/d -tocopherol, there
were no significant differences in lag phase or oxidation rate.
However, there were significant changes for the 400, 800, and 1200 IU/d
groups for both the TBARS and conjugated dienes assays (Table 4). The lag phase of LDL oxidation as measured by the
TBARS assay increased 16% at 400 IU/d, 36% at 800 IU/d, and 64% at
1200 IU/d (all P<.01 within groups). The TBARS oxidation
rate decreased 34% at 400 IU/d, 50% at 800 IU/d, and 55.7% at 1200
IU/d dosages (P<.05 for 400 and 1200 IU/d;
P<.01 for 800 IU/d). The lag phase for the conjugated
dienes assay showed a similar pattern, with increases of 27.9%,
36.9%, and 62.9%, respectively, in the groups that received 400, 800,
and 1200 IU/d. While the oxidation rate at 400 IU/d was not
significantly decreased (P=.06), both 800 and 1200 IU/d
resulted in significant reductions in the oxidation rate. As can be
seen in Fig 3, there was a wide interindividual
variation in the response to similar doses of -tocopherol, as
assessed by the lag phase of oxidation for the conjugated diene assay.
This was most evident for the groups that received 200 or 800 IU/d of
-tocopherol. Similar interindividual variability was seen with the
lag phase computed from the TBARS data (results not shown).
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) and 8 weeks (
), LDL was isolated and
subjected to copper-catalyzed oxidation as described in
"Methods." Oxidation was stopped at the time points shown, and
samples were assayed for thiobarbituric acid–reactive substances
(TBARS) activity (A) and the formation of conjugated dienes (B). Data
are presented as mean±SD. No differences were seen in the curves
between baseline and 8 weeks for either analysis in these three
groups. MDA indicates malondialdehyde.
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P<.01;
P<.001.
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There were no significant differences in maximum TBARS activity and conjugated dienes formed between baseline and 8 weeks in any of the studied groups.
Spearman's rank correlation coefficients between plasma and LDL
-tocopherol concentration and lag phase and rate of LDL oxidation
are presented in Table 5. Both plasma and LDL
-tocopherol correlated significantly with the lag phase determined
from both the TBARS and conjugated dienes time-course curves. Also,
there were significant inverse correlations between plasma and LDL
-tocopherol and the oxidation rate determined from both the TBARS
and conjugated dienes data.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Numerous lines of evidence support a relation between low levels of
-tocopherol and increased risk of atherosclerosis and the
hypothesis that supplementation may be potentially beneficial. Some
studies have suggested that -tocopherol supplementation can
moderately reduce the progression of atherosclerosis in animal
models.20 51 52 53 54 A plausible mechanism for this beneficial
effect of -tocopherol is by decreasing the oxidative susceptibility
of LDL. Since high doses of -tocopherol can decrease the
susceptibility of LDL to oxidation in human
volunteers,33 34 35 36 the aim of the present study was to
ascertain the minimum dose of -tocopherol that would decrease the
susceptibility of LDL to oxidation by conducting a placebo-controlled
dose-response study. In this study, healthy male volunteers were given
dosages of -tocopherol ranging from 0 to 1200 IU/d for 8 weeks. None
of the subjects experienced any side effects as determined by clinical
examination or routine laboratory analysis. Furthermore, in none of
the groups receiving -tocopherol was there a deleterious effect on
the plasma lipid and lipoprotein profile. These findings are in accord
with the literature33 34 35 36 and contrast with findings with
other antioxidants such as probucol,55 which can alter the
lipoprotein profile by lowering HDL cholesterol levels. In addition,
-tocopherol supplementation did not affect the circulating
concentrations of ascorbate and ß-carotene. However, -tocopherol
supplementation resulted in significant increases in plasma and LDL
concentrations of -tocopherol. While 60 IU/d resulted in a 60.5%
increment in plasma -tocopherol levels, 1200 IU/d produced a 235.8%
increase in plasma -tocopherol concentrations. Similar findings were
observed for lipid-standardized levels and to some extent for LDL
-tocopherol concentrations.
The effect of -tocopherol supplementation on LDL oxidative
susceptibility was measured over an 8-hour time course. Two different
indices of oxidative modification were used, the formation of
conjugated dienes and lipid peroxides (measured as TBARS activity), to
obtain a better appreciation of the effect of -tocopherol on LDL
oxidation. It is clear that the mean levels of conjugated dienes and
TBARS at 8 weeks were significantly lower than at baseline in the
groups supplemented with at least 400 IU -tocopherol per day. The
groups supplemented with less than 400 IU/d -tocopherol showed no
significant changes at 8 weeks in the time-course curves compared with
baseline.
To gain more insight on the effect of -tocopherol
supplementation on the susceptibility of LDL to oxidation, the duration
of the lag phase and oxidation rate were computed from the time-course
data.48 It is evident that only doses of at least 400 IU
-tocopherol per day had significant effects on the kinetics of LDL
oxidation. The lag phase of oxidation was significantly prolonged by
doses 400 IU/d, as measured by both indices of oxidation. In
agreement with the findings of Rifici and Khachadurian,56
the present study, conducted in a larger number of subjects, shows
high interindividual variability in responses to similar doses of
-tocopherol. The lag phase correlates inversely with the severity of
clinical atherosclerosis18 ; thus, prolongation of the lag
phase with -tocopherol could prove beneficial. Furthermore, the
oxidation rate was decreased after supplementation with 400 IU/d as
manifested by the formation of conjugated dienes and TBARS. The
findings of significant positive correlations between plasma and LDL
-tocopherol and the lag phase of oxidation as well as significant
inverse correlations between plasma and LDL -tocopherol and the
oxidation rate clearly demonstrate that -tocopherol decreased the
susceptibility of LDL to oxidation at doses 400 IU/d. Thus the major
novel observation as it relates to antioxidants and LDL oxidation is
that this is the first dose-response study to show by statistical
analysis that there is a significant protection of LDL with doses
400 IU/d of -tocopherol.
Dieber-Rotheneder et al35 examined LDL oxidation
after supplementation with varying doses of -tocopherol
for 21 days, but this study was severely handicapped by the small
number of subjects (n=2) in each supplemented group. This did not allow
them to undertake statistical analyses to determine the minimum dose of
-tocopherol needed to decrease the susceptibility of LDL to
oxidation. The findings in the present study that -tocopherol,
in doses 400 IU/d, decreases the susceptibility of LDL to oxidation
may explain in part why, in the recent publication of the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group, no
benefit on cardiovascular disease was seen in male
smokers.57 The low dose of -tocopherol used in this
study (50 IU/d) has not been shown to decrease the susceptibility of
LDL to oxidation.
Most studies that have examined the effect of -tocopherol
on LDL oxidation, including those from this
laboratory,33 37 have used doses ranging from 800 to 1600
IU/d.34 35 36 The findings in this study agree with these
studies that -tocopherol decreases the susceptibility of LDL to
oxidation although present results suggest that 400 IU/d
-tocopherol can decrease the susceptibility of LDL to oxidation.
Abbey et al58 report that 200 IU/d -tocopherol could
decrease the oxidative susceptibility of LDL. However, the authors used
a combined supplement that also included ascorbate and ß-carotene.
The authors point out in their discussion that although multiple
regression analysis supported the hypothesis that -tocopherol
was the major antioxidant, ß-carotene was also correlated with the
change in -tocopherol, and in turn the oxidizability of LDL. They
suggest that ascribing the antioxidant effect to -tocopherol alone
should be treated with caution. Since these investigators did not use a
parallel group that received -tocopherol alone, their study design
does not allow them to ascribe the decreased oxidation of LDL solely to
-tocopherol.
By decreasing LDL oxidation in normal volunteers, -tocopherol
prevented a proatherogenic biological effect, ie, cytotoxicity to
porcine aortic endothelial cells.59 Also, two groups have
demonstrated a preservation of endothelium-dependent
vasodilation by -tocopherol supplementation in rabbits rendered
hypercholesterolemic through cholesterol feeding60 61 ;
-tocopherol also inhibited in vitro lipoprotein oxidation in both
studies. -Tocopherol has other antiatherogenic effects in addition
to inhibition of LDL oxidation, eg, reducing platelet aggregation and
adhesion.62 63 Furthermore, -tocopherol can decrease
smooth muscle cell proliferation by inhibiting protein kinase C
activity.64 Thus, it is possible that -tocopherol could
exert an antiatherogenic effect at lower dosages if these dosages can
significantly affect platelet function and smooth muscle cell
proliferation. It would be difficult to assess the effect of
-tocopherol supplementation on smooth muscle cell proliferation in
human subjects; however, examining the effect of -tocopherol on
smooth muscle cell proliferation in experimental models of
atherosclerosis could prove very instructive. Insight could also be
gained by examining the dose-response effects on monocytes and
macrophages by assaying the release of cytokines and growth factors
from human mononuclear cells, such as interleukin-1 and
platelet-derived growth factor, which appear to stimulate smooth muscle
cell proliferation.65 Reports on the inhibitory effect of
-tocopherol on platelet aggregation appear to
conflict.62 66 67 68
In conclusion, the results of the present study show that in a
randomized placebo-controlled dose-response design, the minimum dose of
-tocopherol needed to significantly decrease the susceptibility of
LDL to copper-catalyzed oxidation is 400 IU/d. Future studies should
concentrate on dosages of at least 400 IU/d to ascertain the effects of
-tocopherol supplementation on cardiovascular end points in primary
and secondary prevention trials.
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Acknowledgments |
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This work was supported by research grants from the American Heart Association (Texas Affiliate), Hoffman-La Roche, and General Clinical Research Center grant No. M01-RR00633. We thank Dr S.M. Grundy for support, Dr A. Bendich for her assistance with study design and critical discussions, and Nancy Cade for manuscript preparation.
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Footnotes |
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Reprint requests to I. Jialal, MD, Center for Human Nutrition, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235-9052.
Received August 2, 1994; accepted November 8, 1994.
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 J M Rapola, J Virtamo, S Ripatti, J K Haukka, J K Huttunen, D Albanes, P R Taylor, and O P Heinonen Effects of alpha tocopherol and beta carotene supplements on symptoms, progression, and prognosis of angina pectoris Heart, May 1, 1998; 79(5): 454 - 458. [Abstract] [Full Text]
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H. T. Bowen and S. T. Omaye Oxidative Changes Associated with {beta}-Carotene and {alpha}-Tocopherol Enrichment of Human Low-Density Lipoproteins J. Am. Coll. Nutr., April 1, 1998; 17(2): 171 - 179. [Abstract] [Full Text] [PDF]
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J. Virtamo, J. M. Rapola, S. Ripatti, O. P. Heinonen, P. R. Taylor, D. Albanes, and J. K. Huttunen Effect of Vitamin E and Beta Carotene on the Incidence of Primary Nonfatal Myocardial Infarction and Fatal Coronary Heart Disease Arch Intern Med, March 23, 1998; 158(6): 668 - 675. [Abstract] [Full Text] [PDF]
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M. Torzewski, M. Klouche, J. Hock, M. Meßner, B. Dorweiler, J. Torzewski, H. E. Gabbert, and S. Bhakdi Immunohistochemical Demonstration of Enzymatically Modified Human LDL and Its Colocalization With the Terminal Complement Complex in the Early Atherosclerotic Lesion Arterioscler. Thromb. Vasc. Biol., March 1, 1998; 18(3): 369 - 378. [Abstract] [Full Text] [PDF]
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M. E. Tornwall, J. Virtamo, J. K. Haukka, A. Aro, D. Albanes, B. K. Edwards, and J. K. Huttunen Effect of {alpha}-Tocopherol (Vitamin E) and ß-Carotene Supplementation on the Incidence of Intermittent Claudication in Male Smokers Arterioscler. Thromb. Vasc. Biol., December 1, 1997; 17(12): 3475 - 3480. [Abstract] [Full Text]
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 S E Edmonds, P G Winyard, R Guo, B Kidd, P Merry, A Langrish-Smith, C Hansen, S Ramm, and D R Blake Putative analgesic activity of repeated oral doses of vitamin E in the treatment of rheumatoid arthritis. Results of a prospective placebo controlled double blind trial Ann Rheum Dis, November 1, 1997; 56(11): 649 - 655. [Abstract] [Full Text]
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S. Devaraj, B. Adams-Huet, C.J. Fuller, and I. Jialal Dose-Response Comparison of RRR-{alpha}-Tocopherol and All-Racemic {alpha}-Tocopherol on LDL Oxidation Arterioscler. Thromb. Vasc. Biol., October 1, 1997; 17(10): 2273 - 2279. [Abstract] [Full Text]
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M. Seccia, E. Albano, and G. Bellomo Suitability of chemical in vitro models to investigate LDL oxidation: study with different initiating conditions in native and {alpha}-tocopherol-supplemented LDL Clin. Chem., August 1, 1997; 43(8): 1436 - 1441. [Abstract] [Full Text] [PDF]
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H. Yoshida, T. Ishikawa, and H. Nakamura Vitamin E/Lipid Peroxide Ratio and Susceptibility of LDL to Oxidative Modification in Non–Insulin-Dependent Diabetes Mellitus Arterioscler. Thromb. Vasc. Biol., July 1, 1997; 17(7): 1438 - 1446. [Abstract] [Full Text]
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C. Iribarren, A. R. Folsom, D. R. Jacobs Jr, M. D. Gross, J. D. Belcher, and J. H. Eckfeldt Association of Serum Vitamin Levels, LDL Susceptibility to Oxidation, and Autoantibodies Against MDA-LDL With Carotid Atherosclerosis: A Case-Control Study Arterioscler. Thromb. Vasc. Biol., June 1, 1997; 17(6): 1171 - 1177. [Abstract] [Full Text]
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M. Seccia, E. Albano, E. Maggi, and G. Bellomo Circulating Autoantibodies Recognizing Peroxidase-Oxidized Low Density Lipoprotein: Evidence for New Antigenic Epitopes Formed In Vivo Independently From Lipid Peroxidation Arterioscler. Thromb. Vasc. Biol., January 1, 1997; 17(1): 134 - 140. [Abstract] [Full Text]
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S. R. Thomas, J. Neuzil, and R. Stocker Cosupplementation With Coenzyme Q Prevents the Prooxidant Effect of {alpha}-Tocopherol and Increases the Resistance of LDL to Transition Metal–Dependent Oxidation Initiation Arterioscler. Thromb. Vasc. Biol., May 1, 1996; 16(5): 687 - 696. [Abstract] [Full Text]
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J. M. Rapola, J. Virtamo, J. K. Haukka, O. P. Heinonen, D. Albanes, P. R. Taylor, and J. K. Huttunen Effect of Vitamin E and Beta Carotene on the Incidence of Angina Pectoris: A Randomized, Double-blind, Controlled Trial JAMA, March 6, 1996; 275(9): 693 - 698. [Abstract] [PDF]
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