Circulation. 2002;105:2107-2111
doi: 10.1161/01.CIR.0000014762.06201.06
(Circulation. 2002;105:2107.)
© 2002 American Heart Association, Inc.
Is the Oxidative Modification Hypothesis Relevant to Human Atherosclerosis?
Do the Antioxidant Trials Conducted to Date Refute the Hypothesis?
Daniel Steinberg, MD, PhD;
Joseph L. Witztum, MD
From the Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, Calif.
Correspondence to Dr Daniel Steinberg, School of Medicine (0682), University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0682. E-mail dsteinberg{at}ucsd.edu
Key Words: atherosclerosis coronary disease antioxidants trials lipoproteins
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Introduction
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Several large-scale, double-blind, placebo-controlled trials
have shown convincingly that neither ß-carotene
13 nor vitamin E, alone
35 or in combination with other antioxidant
vitamins,
6 reduces the risk of fatal or nonfatal infarction
(or other hard clinical end points) in an unselected population
of people with established coronary heart disease (CHD) or at
high risk of CHD. Two end point trials, much smaller trials
that used vitamin E, have reported positive results,
7,8 and
one trial, which used ultrasound, showed that a combination
of vitamins E and C slowed the progression of carotid artery
lesions.
9However, these are far outweighed by the negative results
in the other, much larger trials. Certainly there is no basis
for recommending vitamin E supplementation to patients with
CHD, especially because it may blunt the effectiveness of hypolipidemic
therapy with statins and niacin.
6 A surprisingly large fraction
of cardiologists (

40%) have been recommending such regimens
10 despite warnings that this use was premature.
11
At first glance, it might seem that these negative results close the book and that additional clinical trials of any antioxidants would be pointless. Closer examination, we believe, will show that such a conclusion would be premature and inappropriate.12 The hypothesis that oxidative modification of LDL plays a significant role in atherogenesis in humans is not necessarily disproved by the failure of these particular clinical trials any more than a negative trial of an ineffectual antibiotic in Pneumococcal pneumonia would prove that pneumonia is not a bacterial disease. The oxidative modification hypothesis is not that vitamin E will ameliorate the human disease but that oxidative modification of LDL and/or other oxidative events play a significant role in human atherogenesis as it does in animal models of atherogenesis. A corollary of the hypothesis is that some appropriate antioxidant intervention, at some appropriate dosage, in appropriately selected patients over an appropriate time interval has the potential to improve prognosis. Otherwise, of course, the role of oxidation would remain of academic interest only. In the present report, we put the currently available information into context by briefly reviewing the origins of the LDL modification hypothesis and explaining why the trials to date have not adequately tested the basic hypothesis, as pointed out by a number of authors.1221 It would be a mistake to jettison as irrelevant to humans a hypothesis that is so strongly supported by many epidemiological studies and by so many positive results in several animal models, including nonhuman primates, and with the use of several different antioxidant compounds.12 Instead, perhaps we should be reexamining the science underlying the hypothesis and asking what additional basic information we need to design trials that will appropriately test the hypothesis.
 |
Origins of the Oxidative Modification Hypothesis
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The concept that circulating LDL must undergo some kind of structural
modification before it becomes fully proatherogenic was put
forward originally by the Brown and Goldstein laboratory.
22 They discovered that the macrophage, the precursor of the cholesterol-loaded
foam cell, took up native LDL at a rate insufficient to load
the cell with cholesterol. They also pointed out that patients
totally lacking the native LDL receptor nevertheless accumulate
large amounts of cholesterol in their macrophages. Therefore,
they postulated that modifications of LDL must occur, leading
to uptake of the modified forms through receptors other than
the classic LDL receptor, which they termed "scavenger receptors."
Goldstein et al
23 identified the first of these scavenger receptors,
the acetyl LDL receptor, which was later cloned in Kriegers
laboratory and renamed scavenger receptor A.
24 Subsequently,
several other scavenger receptors have been identified.
25,26 The fundamental correctness of this concept of LDL modification
is now supported by many lines of evidence. Any scheme for the
pathogenesis of atherosclerosis must include one or more modified
forms of LDL and macrophage receptor(s) for them.
Oxidative stress may contribute to atherogenesis by mechanisms that are not necessarily linked to LDL oxidation. For example, free radical oxygen species such as superoxide anion can rapidly react with and inactivate nitric oxide, enhancing proatherogenic mechanisms (eg, leukocyte adherence to endothelium, impaired vasorelaxation, platelet aggregation).13 As pointed out by Landmesser and Harrison,13 vitamin E would be an inappropriate antioxidant in such a system because it reacts very slowly with superoxide. Oxidized LDL (OxLDL) itself can inactivate nitric oxide and induce the same proatherogenic processes, but OxLDL may not be an obligatory intermediate.
 |
Modifications of LDL That Might Be Involved
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Several different modifications of LDL have been described that
convert it to a form recognized by one or more macrophage scavenger
receptors. Modifications that can favor foam cell formation
in vitro include oxidation, aggregation, enzymatic modification,
complexing with immunoglobulins, and possibly others.
27 The
best studied of these and the only one for which there is good
in vivo data are oxidative modification. As reviewed elsewhere,
12 six different antioxidant compounds (probucol, probucol analogues,
vitamin E, coenzyme Q, diphenylphenylenediamine, and butylated
hydroxytoluene) have been studied in four different animal models
of atherosclerosis (rabbits, mice, hamsters, and monkeys) and
most of the results have been strikingly positive. A number
of important ancillary lines of evidence are consonant with
the hypothesis, including the fact that oxidation of LDL has
been shown to occur in vivo and that OxLDL is demonstrable in
lesions; that autoantibodies are generated against OxLDL and
that the titers are correlated with the extent of atherosclerosis;
that knocking out scavenger receptors (either scavenger receptor
A or CD36) ameliorates atherosclerosis (establishing that some
modified form of LDL is involved); and that knocking out 12/15-lipoxygenase,
shown previously to be able to oxidize LDL, ameliorates atherosclerosis.
12,15,1821,28,29 Because the basic pathology and pathogenesis of human atherosclerosis
appears to be remarkably similar to that in these animal models,
it would be surprising if oxidation were relevant to one and
not the other. Why then have the clinical trials to date been
mostly negative? One possibility is that oxidation is relevant
to atherosclerosis in animal models but not in humans. However,
the other possibility is that the design of current clinical
trials has not been appropriate for testing the hypothesis.
 |
Have the Clinical Trials Been Done With the Right Antioxidants at the Right Dosages?
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Because of a large body of epidemiological data showing a protective
role for dietary antioxidants
30 and because of the impressive
data from experimental studies, a workshop was convened by the
National Heart, Blood and Lung Institute in 1991
31 to review
all of the available evidence about the oxidative modification
hypothesis. The panel of experts concluded that the evidence
was sufficiently strong to justify initiating clinical intervention
trials. At the time, the data from trials that used antioxidants
in experimental animal models were already quite persuasive,
but the field was relatively new and there were many unanswered
questions. Just to cite one important example, although OxLDL
had been demonstrated in the atherosclerotic lesions of animals
and humans, the mechanisms leading to such oxidation were not
known and in fact remain unknown to this day.
12,15,17,18,29 Nevertheless, the 1991 conferees thought that the use of naturally
occurring antioxidants would be safe and that one could therefore
proceed even without requiring the kind of in-depth evidence
regarding mechanisms that would have been expected if the trials
were to be done with drugs. Hence, the recommendations of the
committee were to start trials with vitamin E, vitamin C, or
ß-carotene. Yet, there was at that time no experimental
evidence in animal models that any of these natural antioxidants
would have an effect on atherosclerosis. The animal trials available
at that time had been carried out mostly with probucol or probucol
analogues, and only one study each with diphenylphenylenediamine
and butylated hydroxytoluene. What the expert committee was
saying, even if not explicitly, was that antioxidants could
be looked on as a class of compounds sharing certain common
properties and that they would be functionally more or less
interchangeable. There may be some justification for such "lumping"
when dealing with simple in vitro redox systems, although there
are some striking differences. For example, ß-carotene
is an excellent trapper of singlet oxygen but much less effective
at terminating free radical chain reactions; the reverse is
true of vitamin E. In the context of a complex biological system,
such "lumping" becomes indefensible. For example, vitamin C
is water-soluble, readily absorbed, and transported in the aqueous
phase of the plasma; vitamin E is lipid-soluble, poorly absorbed,
and transported in lipoproteins. The pharmacodynamics of the
various antioxidants differ greatly, and until we know where
and how LDL is oxidatively modified in vivo, we have no way
to predict which antioxidant, at what dosage and administered
by what route, would be most effective.
Vitamin E is the antioxidant used in most of the clinical trials to date. In mouse models of atherosclerosis it has been effective alone32 or in combination with other antioxidants,33,34 but most of the studies in rabbits have been negative.35 Moreover, when administered to humans, vitamin E has been shown to have only a modest inhibitory effect on LDL oxidation ex vivo (delaying copper-induced oxidation by 15 to 20 minutes) but nowhere near the almost complete protection afforded by such a potent antioxidant as probucol (which can delay oxidation for as much as 20 hours). A recent report by Meagher et al36 is highly relevant to this discussion. They fed normal subjects doses of vitamin E ranging from 200 to 2000 mg/d for 8 weeks. The highest dose increased plasma vitamin E levels 5-fold, but urinary excretion of isoprostanes and 4-hydroxynonenal (breakdown products of fatty acid auto-oxidation) was unaffected. The results suggest that in normally nourished subjects, additional vitamin E will not necessarily confer any additional antioxidant protection. Earlier studies in cigarette smokers, in contrast, did show a vitamin E effect on plasma isoprostane levels, suggesting that only in subjects under some oxidative stress will a vitamin E effect be obtained.37 The protective effect of vitamin E against coronary events in the Boaz study7 may reflect the fact that the subjects were under the oxidant stress known to accompany hemodialysis. Moreover, it should be noted that in the absence of an appropriate coantioxidant such as vitamin C, vitamin E can, paradoxically, act as a prooxidant.35 In any case, the available data suggest that vitamin E is not an appropriate antioxidant with which to test the hypothesis in otherwise healthy humans.
Observational data over the years have shown rather consistently that ß-carotene intake is negatively correlated with risk of CHD.30 However, as mentioned above, ß-carotene is not very effective as a chain-breaking antioxidant, compared with vitamin E. Moreover, ß-carotene, even at very high doses, fails to protect circulating LDL against ex vivo oxidation and even fails to protect it in vitro.3841 Consequently, the trials using ß-carotene are in no sense meaningful tests of the oxidative modification hypothesis.
Clearly, we need more potent antioxidants, possibly with different pharmacodynamic properties. We have much to learn about the very different available antioxidant compounds, how they work, and how they are metabolized.
 |
The Need for Markers to Assess Whether or Not Oxidation of LDL is Being Successfully Inhibited During a Clinical Trial
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It is relatively easy to test whether a given antioxidant at
a given dosage reaches concentrations sufficient to protect
the circulating LDL against oxidation ex vivo. In general, the
compounds that have been effective in inhibiting atherosclerosis
in animal studies have done so, but the correlation has been
far from perfect
35,42 and so even this most widely used test
cannot be accepted as a satisfactory marker. Other approaches,
such as the measurement of urinary or plasma levels of isoprostanes
or of hydroperoxides or of OxLDL itself have been suggested.
As discussed above, Pratico et al
32 showed that vitamin E treatment
of apolipoprotein Edeficient mice inhibited atherogenesis.
The plasma levels of vitamin E correlated inversely with the
extent of lesions and inversely with the urinary excretion,
plasma levels, and arterial levels of isoprostanes. Similarly,
the titers of autoantibodies to OxLDL correlated directly with
the extent of lesions in both LDL receptor-negative and apolipoprotein
Enegative mice.
43,44 Recently it was shown that the ability
of vitamin C to improve the vasodilatory response to acetylcholine
could identify patients more likely to have a CHD event.
45 If
further studies show that these correlations obtain at graded
intakes of vitamin E (or other antioxidants) and in other species,
they could become examples of the badly needed markers for oxidative
stress. So far, none of the candidate markers has been tested
in a sufficiently systematic way in animal models to allow them
to be used with any confidence as surrogate markers in a clinical
trial. Therefore, even if the teams that designed the first
generation of human trials had wanted to use a marker, that
is, something that would tell them whether or not the antioxidant
was "working," they would not have found a tested, reliable
method. In fact, with the exception of the Swedish probucol
study, in which efficacy was shown with respect to inhibition
of LDL oxidation ex vivo,
46 none of the reported human trials
to date has attempted to assess the efficacy of their antioxidant
regimen. Thus, there is no way for us to know whether there
was any reason to expect a positive resultthere was no
independent measure of efficacy. By analogy, it is as if a cholesterol-lowering
drug were being tested for efficacy in preventing CHD events
but without measurements of plasma cholesterol as part of the
protocol. If for no other reason, the results of all of these
trials are moot. But there are a number of additional reasons
why these trials, however rigorously conducted, have not ruled
out the role of oxidative processes in the pathogenesis of human
atherosclerosis.
 |
Identification of Patients Likely to Benefit From Antioxidant Intervention Because of Increased Oxidative Stress
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In designing clinical trials of hypolipidemic therapy, it was
assumed that patients with more marked degrees of hypercholesterolemia
would be more likely to show the maximum benefit; therefore,
patients with severe hypercholesterolemia were selected. Plasma
cholesterol levels were monitored during therapy to document
the effectiveness of the given hypolipidemic agent, and the
impact on CHD events was correlated to the drop in cholesterol
level. However, as noted above, we have no analogous marker
to identify patients at high risk because of oxidative stress,
that is, patients who would theoretically be expected to benefit
most from antioxidant intervention. Equally frustrating is the
fact that we have no reliable way to know whether a given antioxidant
intervention, whether in patients under oxidative stress or
not, effectively reduces the level of oxidant stress. It would
seem reasonable that a population under high oxidative stress
would stand to benefit the most from antioxidant intervention,
and the results of the recently reported Secondary Prevention
with Antioxidants of Cardiovascular disease in Endstage renal
disease (SPACE) Trial provide some evidence in support of that
idea.
7 Patients with end-stage kidney disease who were undergoing
hemodialysis were randomly assigned to 800 mg/d vitamin E or
placebo. End points were myocardial infarction, ischemic stroke,
peripheral vascular disease, or unstable angina. This population
was chosen because it is well established that patients undergoing
chronic hemodialysis are exposed to increased oxidative stress
induced by the membranes used in dialysis.
47,48 Events were
reduced by 54% (
P=0.014) and myocardial infarction by 70% (
P=0.016).
The study was small (n=196), but the results are suggestive.
Will other patients under increased oxidative stress, such as
diabetics, also constitute a population more likely to benefit
from antioxidants? Obviously, biomarkers are urgently needed
to identify such high-risk populations and to assess whether
therapy effectively lowers the oxidative burden.
 |
Have the Trials Been Started Early Enough and Have They Lasted Long Enough?
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The outstanding successes of clinical trials with lipid-lowering
regimens led to the almost universal adoption of the canonical
5-year trial. It was natural to settle initially on 5 years
as the appropriate duration for trials of antioxidants and,
for the same reason, to choose fatal or nonfatal myocardial
infarction as primary end points. Yet, the mechanisms by which
cholesterol lowering reduces risk could be quite different from
the mechanisms by which antioxidants work. For example, the
unexpectedly early drop in clinical event rates with intensive
cholesterol lowering
6 may be caused by mechanisms not shared
at all by antioxidants. Furthermore, the animal model studies
on which the clinical trials are based do not deal with lesions
that cause plaque rupture. Conceivably, the antioxidants might
be effective in inhibiting the initial stages of human atherosclerosis,
as they are in animals, and yet ineffective or much less effective
in reducing plaque instability and rupture. If this were the
case, it might be necessary to find some way to assess early
stages of lesion development (eg, high resolution ultrasound
or MRI) rather than relying on the usual late clinical end points.
Of course if the development of early lesions were successfully
inhibited, there should eventually be a decrease in the frequency
of clinical events, but in that case, the trials might need
to extend beyond the conventional 5 years.
 |
Are There Species Differences Such That the Results in Animal Models Do Not Extrapolate to Humans?
|
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Most of the animal model studies demonstrating antioxidant inhibition
of atherosclerosis have been done in small animalsrabbits,
hamsters, or mice. Only one systematic study has been done in
nonhuman primates.
49 Is the pathogenesis of the disease in other
animal models similar to that in humans? Certainly the morphology
is pretty much the same.
5052 There may well be subtle
differences, but none has been clearly delineated to date. However,
mice and men differ notably with respect to the rate at which
they produce free radicals. The rate of free radical generation
per unit of body weight is multifold higher in small animals,
reflecting their higher metabolic rate; most free radicals are
generated within the mitochondria. As discussed above, it is
still not known with certainty how oxidation of LDL occurs in
vivo, but it is reasonable to assume that it is somehow proportional
to the rate of generation of free radical oxygen species (ROS).
If so, small animals may always be generating OxLDL at a higher
rate than humans and may therefore stand to benefit more than
humans from antioxidant treatment. If some threshold value of
ROS generation is needed to trigger OxLDL production at a rate
that enhances atherogenesis and if ROS generation is below that
threshold in humans, then atherosclerosis may develop in normal
humans in a manner less sensitive or even totally insensitive
to treatment with antioxidants. In addition, hypercholesterolemia
per se promotes oxidation
13,53 by mechanisms still unclear,
and the degree of hypercholesterolemia in animal models far
exceeds that seen in human subjects. Still, we know that oxidation
of LDL does occur at some rate in humans. Inhibition of that
oxidation might prove effective if maintained over a sufficient
period of time.
 |
Summary
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The lipid hypothesis, despite an overwhelming body of experimental
evidence in animal models and epidemiological evidence in humans,
was only definitively proved after the development of effective
hypolipidemic agents. Similarly, there is now a large body of
experimental evidence in animal models and epidemiological data
in humans to support the oxidation hypothesis, but effective
antioxidant regimens have yet to be developed. With the benefit
of hindsight, the decision of the 1991 National Heart, Lung,
and Blood Institute workshop to give a green light to trials,
even trials that use safe, naturally occurring antioxidants,
may have been premature. Not knowing how LDL is oxidized in
vivo, we cannot be certain which antioxidants are likely to
be most effective. We lack markers that would let us evaluate
the efficacy of any given antioxidant intervention, and we lack
criteria for rational selection of patients under high oxidative
stress. Until we have such basic information, we should put
a hold on further clinical trials. Instead, we should concentrate
on developing the scientific base that will enable us to design
an appropriate trial to test the oxidation hypothesis.
 |
Acknowledgments
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The authors are indebted to the National Heart, Lung, and Blood
Institute for continuing support of the La Jolla Specialized
Center of Research on Molecular Medicine and Atherosclerosis
(NHLBI 56989) and to the reviewers of the manuscript for valuable
suggestions.
 |
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