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Symposium: Nutrient Disease Relationships: Closing the Scientific Knowledge Gap

Scientific Evidence to Support a Vitamin E and Heart Disease Health Claim: Research Needs^1,2

Laboratory for Atherosclerosis and Metabolic Research, UC Davis Medical Center, Sacramento, CA and VA Northern California Health Care System, Mather, CA

³To whom correspondence should be addressed. E-mail: ishwarlal.jialal{at}ucdmc.ucdavis.edu.

	ABSTRACT

TOP ABSTRACT LITERATURE CITED

 
In addition to epidemiologic studies suggesting a benefit for high intakes of -tocopherol, studies following supplementation in humans have clearly shown that -tocopherol decreases lipid peroxidation, platelet aggregation, and functions as a potent anti-inflammatory agent. However, prospective human clinical trials with -tocopherol alone and in combination with other antioxidants have been largely negative. In this review, we critically appraise the various clinical trials and provide recommendations for future research.

KEY WORDS: • antioxidant • -tocopherol • vitamin E • cardiovascular disease • clinical trials

Cardiovascular disease (CVD)⁴ is the leading cause of morbidity and mortality in the Western world. Several lines of evidence support a role for oxidative stress in the pathogenesis of atherosclerosis. Furthermore, epidemiologic studies appear to suggest that low levels of -tocopherol (AT) are associated with increased risk for CVD, and increased intakes appear to be protective (1). Studies in vitro showed that AT, in addition to functioning as an antioxidant, inhibits smooth muscle cell proliferation, platelet adhesion and aggregation, and monocyte endothelial adhesion (1,2). In addition, some studies in animal models showed a decrease in lesion progression with supplementation. Supplementation with AT in humans was shown by numerous groups to result in the following effects: decreased lipid peroxidation (decreased LDL oxidative susceptibility and decreased F₂-isoprostanes), decreased platelet adhesion and aggregation, and an anti-inflammatory effect (1,2).

In this review, we focus on the larger prospective clinical trials that have tested the effect of AT supplementation alone or in combination with other antioxidants on cardiovascular events in different populations.

-Tocopherol trials

    The Cambridge Heart Antioxidant Study (CHAOS). The Cambridge Heart Antioxidant Study (CHAOS) was a prospective, randomized, placebo-controlled, double-blind, single-center, secondary prevention trial from England that examined the effects of AT therapy on coronary artery disease (CAD) (3). A total of 2002 subjects with overt clinical and angiographic evidence of CAD were randomized to receive RRR-AT (n = 1035) or placebo (n = 967). The first 546 subjects in the AT group were given 800 IU/d for a median of 731 d (range: 3–981) and the remainder were given 400 IU/d for 366 d (range: 8–961), but the 2 groups were combined for statistical analysis (the trial was not designed to determine dose-response effects of AT on the primary endpoints). Both 400 and 800 IU/d of AT significantly increased serum AT levels at least 2-fold over baseline with no change in the placebo group. The primary outcome variables were a combined endpoint of cardiovascular death and nonfatal MI, and nonfatal MI alone (3). After a median follow-up of 510 d (range: 3–981), those administered AT experienced a significant 47% reduction (95% CI, –66 to –17%; P = 0.005) in CAD death and nonfatal myocardial infarction (MI), which was the primary trial endpoint (3). This effect was due to a significant 77% reduction (95% CI, –89 to –53%; P = 0.005) in the risk for nonfatal MI.

The salient characteristics of the CHAOS trial are as follows: the effect was examined in a homogenous population with established CAD consuming an English diet; in the CHAOS trial, a dose of natural AT (400 IU/d) that was shown to decrease LDL oxidizability and platelet aggregation was used; compliance was assessed by both drug accountability and serum levels of AT, which rose 2- to 2.5-fold in the AT group but were essentially unchanged in the placebo group; despite the larger dose used compared with the Alpha-Tocopherol Beta-Carotene (ATBC) study, AT supplementation in CHAOS was not associated with an increased risk for hemorrhagic stroke in spite of these patients also receiving antiplatelet therapy.

    The Heart Outcomes Prevention Evaluation (HOPE) Study. In the HOPE Study, 2545 women and 6996 men 55 y old who were at high risk for cardiovascular events because they had CVD or diabetes in addition to one other risk factor were enrolled (4). These patients were randomly assigned according to a 2 x 2 factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting enzyme inhibitor (ramipril) or matching placebo. Follow-up was for 4–6 y (mean 4.5 y). The primary outcome was a composite endpoint of MI, stroke, and death from CVD. There was no significant difference between the patients who received vitamin E (n = 4761) and those receiving placebo (n = 4780) with respect to the primary endpoint. Furthermore, there was no significant difference in incidence of secondary cardiovascular outcomes or in death from any cause. Also, there was no increase in hemorrhagic stroke. Finally, there were no significant adverse effects from vitamin E supplementation in that study.

This is an important study, which arrived at the negative conclusion that vitamin E is without effect in patients at high risk for CVD. However, this study suffers from certain deficiencies (4–7). Although it was undertaken in many geographic areas (United States, Canada, Western Europe and South America) with clearly different dietary intakes, data on the dietary intakes, especially antioxidants, were not reported. In addition, for no subgroup were plasma levels of vitamin E provided.

    Secondary Prevention with Antioxidants of Cardiovascular disease in End-stage renal disease (SPACE). The SPACE study was a double-blind, placebo-controlled, randomized, secondary prevention trial performed at 6 hemodialysis units in Israel, which examined the effect of high-dose AT supplementation on CVD outcomes in hemodialysis patients with preexisting CVD (8). These patients have increased oxidative stress and inflammation (9). Hemodialysis patients with preexisting CVD (n = 196) aged 40–75 y at baseline from 6 dialysis centers were enrolled and randomly assigned to receive 800 IU/d RRR-AT (n = 97) or matching placebo (n = 99). Patients were followed for a median of 519 d. The primary endpoint was a composite variable consisting of MI (fatal and nonfatal), ischemic stroke, peripheral vascular disease (excluding the arteriovenous fistula), and unstable angina. Lipid-adjusted AT levels rose from 22.0 ± 7.7 µmol/L in the AT group to 27.8 ± 9.3 µmol/L on treatment and unchanged in the placebo group (23.3 ± 10.7 µmol/L at baseline and 20.2 ± 6.9 µmol/L with treatment). Treatment with AT significantly decreased primary cardiovascular endpoints (54% reduction in primary endpoint risk in the AT group, P = 0.014). There was a 39% nonsignificant reduction in CAD mortality relative risk [(RR) 0.61, 95% CI, 0.28–1.3, P = 0.25]. In addition, AT supplementation was associated with a 70% reduction in total MI rate (P = 0.016). It would have been instructive if the authors had assayed biomarkers of oxidative stress.

    The Vitamin E Atherosclerosis Prevention Study (VEAPS). Men and women > 40 y old with LDL cholesterol > 130 mg/dL were randomly assigned to receive all-rac-AT (400 IU/d) or placebo for an average 3-y of follow-up (10). The primary outcome was a change in common carotid artery far-wall intimal medial thickness (IMT). Compared with placebo, AT supplementation significantly increased plasma AT levels (P < 0.0001). AT supplementation decreases levels of oxidized LDL and LDL oxidizability significantly.

There was no significant change in the progression of IMT over 3 y compared with placebo (0.0023 + 0.0007 vs. 0.004 + 0.007, P = 0.08). The main drawback of this study was that plasma AT levels also rose significantly in the placebo group (P < 0.0001) and this could have confounded their findings.

Antioxidant trials

    The ATBC Cancer Prevention Study. This study was the first double-blind, randomized intervention trial designed to determine whether vitamin E (synthetic, all-rac-AT acetate, 50 mg/d, 50 IU/d) and ß-carotene (20 mg/d), either alone or in combination, would decrease lung cancer incidence (11). A total of 29,133 male smokers 50–69 y old from Finland were randomly assigned to 1 of the 4 regimens and were followed for 5–8 y. At entry, on average, the men were 57.2 y old, smoked 20.4 cigarettes daily and had smoked for 35.9 y. Although AT supplementation had no effect on the primary end point (lung cancer), an 18% increase in lung cancer incidence was observed in the ß-carotene-supplemented group (P = 0.01).

Serum AT and ß-carotene concentrations were measured before and after supplementation. The median values of serum AT at baseline were 26.7 µmol/L, which increased to 40.2 µmol/L after 3 y of AT supplementation. In contrast to the rather modest increase in serum AT observed in the ATBC study, serum ß-carotene increased 16-fold, from 0.17 to 3.0 mg/L.

In this study in smokers without preexisting CVD, AT therapy had no significant effect on the first major coronary event (fatal and nonfatal) (5–7). In a further analysis of the ATBC study in male smokers with previous MI, although there were no significant effects on the number of major coronary events or fatal CAD, there was a significant reduction in the multivariate-adjusted RR for nonfatal CAD (RR 0.62, CI, 0.41–0.96) in the AT group (4–6). In a subsequent report on the ATBC study, Rapola et al. (12) also showed that AT supplementation was associated with a minor decrease in the incidence of angina pectoris (RR 0.91, CI, 0.83–0.99, P = 0.04).

The incidence and mortality from stroke in the ATBC trial were examined in detail (5–7). AT supplementation appeared to increase the risk of subarachnoid hemorrhage by 50% (95% CI, –3 to 132%, P = 0.07), but decreased cerebral infarction 14% (95% CI, –25 to –1%, P = 0.03). The increase in mortality caused by subarachnoid hemorrhage with AT supplements was 181% (95% CI, 37 to 479%, P = 0.01). The overall net effects of supplementation on the incidence and mortality from total stroke were nonsignificant. The interpretation that AT supplements increase the incidence of hemorrhagic stroke is not uniformly accepted because this adverse effect was not observed in the other intervention trials with vitamin E as pointed out in a recent editorial (7).

Steiner et al. (13), in fact, showed in a double-blind, randomized study of 100 patients with transient ischemic attacks (TIAs), minor strokes, or residual neurologic deficits that the patients who received AT and the antiplatelet agent, aspirin (400 and 325 IU/d, respectively), had a significant reduction in ischemic strokes and recurrent TIAs compared with patients taking aspirin alone (13). Moreover, no increase in hemorrhagic strokes was observed in a study that was designed to evaluate neurological function in patients with Alzheimer’s disease consuming 2000 IU/d of supplemental all-rac-AT for 2 y (14). However, the number of subjects and the trial length may have been insufficient to detect an effect. Nevertheless, because AT has antiplatelet effects (15), which may promote bleeding, the observation that AT supplementation increases hemorrhagic stroke incidence in smokers with other untreated risk factors such as hypertension warrants caution in using AT supplementation in these individuals.

    GISSI Prevenzione Trial (Grupppo Italiano per lo Studio della Supravivenza nell’Infarto miocardico). The GISSI trial, conducted in Italy among 11,324 patients within 3 mo of a MI, investigated whether (n-3) PUFA (1 g/d, n = 2836), all-rac-AT (300 mg/d or 330 IU/d, n = 2830), a combination of (n-3) PUFA and AT (n = 2830), or usual care (n = 2828) over 3.5 y had an effect on the primary combined efficacy endpoint of death, MI, and stroke (16). This was a multicenter study with an open-label design. The patients received, in addition to the supplements, the usual preventative measures including aspirin, ß-blockers, and angiotensin-converting enzyme inhibitors. A major strength of this study, in contrast to the other clinical trials, was that dietary information was detailed for intakes of fish, fruit, vegetables, and olive oil. The primary combined efficacy endpoints were the cumulative rate of all-cause death, nonfatal MI, and nonfatal stroke, and the cumulative rate of cardiovascular death, nonfatal MI, and nonfatal stroke.

Although 2-way analyses showed no benefit with AT, when the more appropriate 4-way analyses were performed, AT supplementation compared with placebo resulted in a significant 20% reduction in cardiovascular deaths (5–7,16). These patients were consuming a Mediterranean diet, which could have also confounded the benefits of AT because it is a diet enriched in antioxidants. Also, there was no objective assessment of compliance such as measurement of (n-3) PUFA and AT levels in even a subgroup of subjects. Another weakness of this study was that it was an open-label trial with an 25% dropout rate at the end of the study.

    Collaborative Group for the Primary Prevention Project (PPP). In the Primary Prevention Project (PPP), the investigators followed 4495 people with hypertension, hypercholesterolemia, diabetes, obesity, family history of premature MI, or those who were elderly (17). The mean age of the patients was 64.4 y and 58% were women. The patients were prescribed either 100 mg/d of aspirin or 300 mg/d of all-rac-AT. This was a 2 x 2 factorial design study with a mean follow-up period of 3.6 y. The primary endpoint of this study was cardiovascular death, nonfatal MI, or nonfatal stroke. In this study, AT supplementation had no benefit on the primary endpoint. The investigators reported a benefit of AT therapy on peripheral artery disease RR of 0.54 (0.3–0.99). Thus, this study reported a 46% reduction in the incidence of peripheral artery disease among patients taking vitamin E (P = 0.043). Like the other clinical trials, this study suffers from certain weaknesses. There was no objective measure of compliance, i.e., measurement of plasma AT or biomarkers of oxidative stress and inflammation. Second, as the authors themselves pointed out, the findings for vitamin E could be regarded as a false-negative result because of the inadequate power of a prematurely interrupted trial. Furthermore, the authors used a synthetic form of AT; although it decreased LDL oxidation after supplementation, it did not appear to yield a benefit associated with markers of inflammation in supplementation studies.

    Antioxidant Supplementation in Atherosclerosis Prevention Study (ASAP Study). The ASAP study was a randomized trial of the effect of vitamins E and C on the 3-y progression of carotid atherosclerosis. This was a placebo-controlled, randomized, 2 x 2 factorial trial in hypercholesterolemic patients and consisted of an 8-wk placebo lead-in phase, followed by a 3-y double blind treatment period (18). Subjects (n = 520) were randomly assigned to receive either RRR-AT (136 IU twice a day), slow release ascorbate (250 mg twice a day), or both RRR-AT and ascorbate or placebo. Carotid atherosclerosis was assessed by quantitating common carotid IMT over semiannual assessments. Plasma levels of vitamins E and C were significantly increased in the groups randomized to the respective vitamins. The average increase in common carotid artery-IMT was 0.02 mm/y in men randomized to placebo and 0.018 mm/y in men who received only vitamin E, 0.017 mm/y in men who received only vitamin C, and 0.011 mm/y in men who received both vitamins E and C (P = 0.043 for heterogeneity). IMT progression was significantly reduced in men administered both vitamins compared with all other men (P = 0.009) or men who were given placebo (P = 0.008). No significant differences were observed in women. The covariate-adjusted IMT increase in men was 45% less with both vitamins compared with placebo (P = 0.049), with the treatment effect being largest in smoking men (64% less) than in nonsmoking men (30% less).

In a study cohort, lipid peroxidation measurements were carried out in 100 consecutive men at entry and repeated at 12 mo. Plasma F₂-isoprostanes were lowered by 17.3% (95% CI, 3.9–30.8%) in the vitamin E group (P = 0.006 for the change, compared with the placebo group). The strengths of this study were that plasma levels of the vitamins were measured and significantly increased after supplementation, and biomarkers of oxidative stress were measured in a cohort. However, biomarkers of inflammation were not studied, and it is possible that this dose of AT may not have been sufficient to observe significant effects on atherosclerosis.

Recently the follow-up of the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study (19) was reported. This was a randomized trial of the effect of AT and ascorbic acid (AA) on the 6-y progression of carotid atherosclerosis in 440 hypercholesterolemic patients (including smokers and postmenopausal women between the ages of 45 and 69 y). The combination of RRR-AT (272 IU/d) and AA (500 mg/d) resulted in a significant increase in plasma levels of AT and AA. Furthermore, the group that received the combined antioxidants had a significant decrease in the rate of progression of carotid IMT (30% treatment effect) compared with placebo. However, this effect was confined to men. Interestingly, the effect was larger in subjects with either low baseline plasma AA levels or common carotid artery plaque. Although both antioxidant levels increased to a similar extent, isoprostane levels were decreased only in men. A clear explanation for this finding was not provided. Also, no deleterious effect on HDL cholesterol was observed with combined supplementation of RRR-AT and AA. Thus, these data replicate their 3-y findings, confirming that supplementation with both AT and slow-release AA decreases atherosclerosis progression in hypercholesterolemic subjects. The strengths of the 6-y ASAP study include a cohort of patients with increased oxidative stress due to hypercholesterolemia or smoking, excellent follow-up (>83% of patients completed the study), regular examination of patients throughout the 6-y study period, and the use of antioxidants with meals to ensure optimum absorption. However, there are certain weaknesses even in this study, which incorporated measures of antioxidant levels, biomarkers of oxidative stress, and a population at high risk for oxidative stress (7). It would have been ideal if at the outset, both groups received either placebo or the combination of AA and AT, because only 34% of the patients in the AA+AT supplementation received both vitamins from the outset. Thus, the majority of patients received either AA or AT alone for the first 3 y of the study. Although it appeared that these antioxidant levels significantly increases plasma AA and AT levels during the first 3 y of the study and decreased various measures of oxidative stress including LDL oxidation and F₂-isoprostanes, it is unclear at 6 y what benefit the antioxidants had on measures of oxidative stress because this was not reported. Also, the investigators did not report on any markers of inflammation.

    HDL-Atherosclerosis Treatment Study (HATS). In this 3-y double-blind study, 160 patients with CAD and a low HDL cholesterol were randomly assigned to a placebo group, a group that received simvastatin and niacin, an antioxidant group, or a simvastatin, niacin, and antioxidant group (20). The antioxidant supplement that was given twice daily resulted in doses of 800 IU/d of RRR-AT, 1000 mg/d of vitamin C, 25 mg/d of ß-carotene, and 100 µg/d of selenium. The patients were followed up for 3 y, and the endpoint was arteriographic evidence of a change in coronary stenosis and occurrence of a first cardiovascular event. The antioxidant supplementation significantly increased plasma levels of AT, ascorbate, and ß-carotene, with the most profound increase in the ß-carotene levels of 380%. In addition, the antioxidant cocktail significantly prolonged (35%) the lag phase of LDL oxidation (P < 0.001). Compared with placebo, simvastatin and niacin and the combination of simvastatin, niacin, and antioxidants significantly decreased the percentage of stenosis. Also, compared to placebo, the antioxidant cocktail resulted in 50% reduction in the percentage of stenosis; however, this was not significant, P = 0.16. When the endpoint of mean change in minimal lumen diameter was examined, there was a significant reduction with all therapies, simvastatin and niacin, simvastatin and niacin and antioxidants, and antioxidants alone. This included the change in minimal luminal diameter of the 9 proximal lesions or all lesions.

Although this is an important study, clearly emphasizing the benefit for a low-HDL cholesterol group with CAD of the combined therapy of simvastatin and niacin, it suffers from the small sample size (n = 39) of the antioxidant limb. Also, it should be emphasized that in this study, an antioxidant cocktail was given; thus, the benefit of a high-dose AT supplementation alone was not tested.

    Transplant Associated Arteriosclerosis Study. Fang et al. (21) tested the effect of Vitamin C and Vitamin E in Transplant Associated Arteriolosclerosis in patients (n = 20) within 2 y of cardiac transplantation. The patients were assigned to placebo (n = 21) or combined antioxidants (n = 19) comprising 800 IU/d RRR-AT and 1 g/d vitamin C. The patients were followed up for a duration of 1 y with the primary endpoint being a change in average intimal index measured by intravascular ultrasound. In this study, there was a significant reduction compared with placebo in maximum intimal thickness and plaque area and a significant increase in AT and ascorbate levels in the antioxidant group. No measures of oxidative stress or inflammation were reported in the study.

    Heart Protection Study (HPS). This was a randomized secondary prevention trial in which, subjects aged 40–80 y, who had high risk of death from coronary heart disease (CHD) over the next 5 y due to prior disease (MI or other CHD or occlusive disease of no coronary arteries or diabetes or hypertension) received either statin therapy and or a cocktail of antioxidant vitamins (600 mg/d all-rac-AT, 250 mg/d ascorbate and 20 mg/d ß-carotene) or placebo (22). Antioxidant vitamin therapy significantly increased plasma antioxidant levels. There was also a significant increase in plasma cholesterol and triglycerides. They did not appear to show any significant effect on HDL cholesterol levels as reported by the investigators. However, antioxidant vitamin therapy did not alter cardiovascular, nonvascular, and total mortality.

    Women’s Angiographic Vitamin and Estrogen Trial (WAVE). This was a trial in postmenopausal women to determine if hormone replacement therapy or antioxidant vitamins alone or in combination influenced the progression of CAD (23). A total of 423 women with at least one 15–75% coronary stenosis at baseline were recruited. This was a 2 x 2 factorial design study where they received 800 IU/d of all-rac-AT and 1 g/d vitamin C or placebo. The primary outcome was an annualized mean change in minimum luminal diameter (MLD). Exit angiograms were completed in 79% administered placebo and in 64% given antioxidant vitamins. Antioxidants did not have any effect on blood lipids, but significantly increased plasma AT levels and ascorbate. Vitamin treatment was associated with a nonsignificant change in MLD (antioxidants –0.044, control –0.28 mm/y, P = 0.32). In this trial, all-cause mortality was significantly higher in women assigned to antioxidants vs. placebo [hazard ratio 2.8 (1.1–7.2), P = 0.047]. No clear explanation was provided for this unexpected finding, which was not a primary endpoint.

Problems with the trials and future directions

Many factors could account for the lack of benefit on the primary endpoint in the majority of trials (7). These include assessment of compliance, omission of measurement of biomarkers of oxidative stress and inflammation, and studying populations including women of similar age who appear to have a 10-y age lag in the incidence of CVD (19). For instance, in all studies in which there was a benefit on the primary endpoint (Table 1), a significant increase in the respective plasma antioxidant levels was reported. However, in only 5 of the 8 negative studies were antioxidant levels reported (Table 1). In the VEAPS study, plasma levels of AT increased significantly in both the placebo (33%) and AT groups; thus, it is difficult to determine the effect of this on the primary endpoint (10).

The form of AT might be very crucial as it relates to a lack of antioxidant effects. Although both RRR- and all-rac-AT were shown by various groups to decrease LDL oxidation, with respect to cell signaling and inflammation (inhibition of protein kinase-C and decreasing the release of proinflammatory cytokines), it might be crucial for AT to transfer from the plasma membrane to the cytosol. The importance of intracellular transfer of AT by tocopherol-associated protein might be crucial in this regard (7). Interestingly, all 4 studies that yielded a positive result on the primary endpoint used RRR-AT alone or in combination with AA.

The doses of antioxidants used varied considerably, and this could affect the results. It appears that there may be a threshold dose of AT that is effective, i.e., 800 IU/d. In addition, the form of AT might be very important, especially for cell signaling, because most of the reported anti-inflammatory effects of AT appear to be due to RRR-AT (7). In this regard, we showed that 800 IU of all-rac-AT did not have any significant anti-inflammatory effects (24). Also, of the 8 studies with a negative result on the primary endpoint, 6 used all-rac-AT, comprising 8 stereoisomers.

It is clear that the antioxidant cocktails have no benefit in the prevention of CVD (7,20,22,23). Furthermore, the antioxidant ß-carotene was shown to increase lung cancer and CVD mortality; in the ATBC study, it appeared to attenuate the benefit of AT (11).

In conclusion, although much effort has been directed at proving the benefits of antioxidants, the findings to date are far from clear. However, it should be pointed out that there does not appear to be any major harm inflicted with AT and AA supplementation to date, and studies using combinations of RRR-AT in doses > 600 IU/d, plus AA at 500 mg/d might prove beneficial. In addition, serious consideration should be given to the use of flavonoids and -tocopherol supplementation on biomarkers of oxidative stress and inflammation. It is imperative that future studies, in addition to the right antioxidant cocktail compared with placebo, include biomarkers of oxidative stress and inflammation and also cardiovascular end points such as IMT and carotid calcium scores.

	FOOTNOTES

 
¹ Presented as part of the symposium, "Nutrient Disease Relationships: Closing the Scientific Knowledge Gap," given at the 2004 Experimental Biology meeting on April 19, 2004, Washington, DC. The symposium was sponsored by the American Society for Nutritional Sciences and supported in part by McNeil Nutritionals. The proceedings are published as a supplement to The Journal of Nutrition. This supplement is the responsibility of the Guest Editors to whom the Editor of The Journal of Nutrition has delegated supervision of both technical conformity to the published regulations of The Journal of Nutrition and general oversight of the scientific merit of each article. The opinions expressed in this publication are those of the authors and are not attributable to the sponsors or the publisher, editor, or editorial board of The Journal of Nutrition. The Guest Editors for the symposium publication are Leila G. Saldanha, Scientific Consultant, Alexandria, VA, and Mary Ann Johnson, Department of Foods and Nutrition, University of Georgia, Athens, GA.

² Supported by National Institutes of Health Grant K24AT00596.

⁴ Abbreviations used: AA, ascorbic acid; ASAP, Antioxidant Supplementation in Atherosclerosis Prevention; AT, -tocopherol; ATBC, The Alpha-Tocopherol Beta-Carotene Cancer Prevention Study; CAD, coronary artery disease; CHAOS, Cambridge Heart Antioxidant Study; CHD, coronary heart disease; CVD, cardiovascular disease; GISSI, Gruppo Italiano per lo Studio della Supravivenza nell’Infarto miocardico; HATS, HDL-Atherosclerosis Treatment Study; HOPE, Heart Outcomes Prevention Evaluation; HPS, Heart Protection Study; IMT, intimal medial thickness; MI, myocardial infarction; MLD, minimum luminal diameter; PPP, Primary Prevention Project; RR, relative risk; SPACE, Secondary Prevention with Antioxidants of Cardiovascular disease in End-stage renal disease; TIA, transient ischemic attack; VEAPS, Vitamin E Atherosclerosis Prevention Study; WAVE, Women’s Angiographic Vitamin and Estrogen Trial.

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