Antioxidant Consumption and Risk of Coronary Heart Disease:            Emphasis on Vitamin C, Vitamin E, and beta-Carotene

A Statement for Healthcare Professionals From the American Heart Association

Diane L. Tribble, PhD, For the Nutrition Committee

Footnotes

Dietary recommendations aimed at reducing the risk of coronary heart disease have focused largely on the intake of nutrients that affect established risk factors, including plasma lipid and lipoprotein levels, blood pressure, and body weight. Recent developments in our understanding of the atherosclerotic process and factors that trigger ischemic events have led to the consideration of dietary constituents that may alter risk through other mechanisms. Prominent among these are antioxidants, which are proposed to inhibit multiple proatherogenic and prothrombotic oxidative events in the artery wall. This report provides a brief overview of evidence concerning a role for dietary antioxidants in disease prevention, with emphasis on studies in human populations, and describes a number of issues that should be resolved before it would be prudent to make recommendations regarding the prophylactic use of antioxidant supplements.

Proposed Influence of Oxidants and Antioxidants on the Development of Atherosclerosis and Its Complications

Atherosclerosis is a complex process involving the deposition of plasma lipoproteins and the proliferation of cellular elements in the artery wall. This chronic condition advances through a series of stages beginning with fatty streak lesions composed largely of lipid-engorged macrophage foam cells and ultimately progressing to complex plaques consisting of a core of lipid and necrotic cell debris covered by a fibrous cap.¹ These plaques provide a barrier to arterial blood flow and may precipitate clinical events, particularly under conditions that favor plaque rupture and thrombus formation.

Over the past 2 decades, considerable evidence has been gathered in support of the hypothesis that free-radical-mediated oxidative processes and specific products arising therefrom play a key role in atherogenesis.^2,3 At the center of this hypothesis are low-density lipoproteins (LDLs), which undergo multiple changes on oxidation that are thought to be proatherogenic (see Figure). Oxidation of LDL lipids leads to the production of a diverse array of biologically active compounds, including some that influence the functional integrity of vascular cells. Among the most well-characterized effects are increases in the expression of endothelial cell surface adhesion molecules that facilitate the mobilization and uptake of circulating inflammatory cells^4,5 and alterations in the chemotactic properties of monocytes and monocyte-derived macrophages^6,7 in a manner expected to increase their residence within the artery wall. Oxidation of the apolipoprotein B component alters LDL receptor recognition properties, leading to avid internalization of LDLs by macrophages via scavenger receptors,^8,9 a key step in the formation of macrophage-derived foam cells.

In addition to these effects, oxidative processes are proposed to play a role in lesion maturation and the precipitation of clinical events. This may involve effects on intimal proliferation, fibrosis, calcification, endothelial function and vasoreactivity, plaque rupture, and thrombosis.^10,11 To date, the role of oxidation in these processes has received less attention than that in the early stages of the disease, but this appears to be changing, in part because of findings from secondary prevention trials (discussed below).

Oxidants are products of normal aerobic metabolism and the inflammatory response. They constitute a chemically and compartmentally diverse group, and it is presently unknown which, if any, are critical to the disease process. In addition to the different sources and types of oxidants, ambiguity in relating specific oxidants to the disease process arises from the multitude of pathophysiological events linked to oxidation, the paucity of methods for measuring these short-lived species within the sequestered environment of the artery wall, and the variable modulating effects of counteractive antioxidants. With regard to the latter, although oxidant formation is an inevitable feature of aerobic life, oxidant-mediated disease promotion is proposed to occur only under circumstances in which these agents overwhelm antioxidant defenses.

Like oxidants, antioxidants constitute a diverse group of compounds with different properties. They operate by inhibiting oxidant formation, intercepting oxidants once they have formed, and repairing oxidant-induced injury. In terms of the coronary heart disease process, several points of antioxidant intervention have been proposed, as recently reviewed in detail.^10,11 Inhibition of LDL oxidation is the most well characterized of these and includes effects on the concentration or reactivity of oxidants capable of modifying LDL and on the susceptibility or resistance of LDL to these oxidants. Better definition of these and other disease processes in which antioxidants may intervene will allow optimization of conditions for testing the importance of antioxidants in disease prevention and ultimately for intervening in the disease process should antioxidants prove to be effective in this regard.

Investigations of the Disease-Preventive Effects of Dietary Antioxidants in Humans

Although the antioxidant defense system includes both endogenously and exogenously (diet) derived compounds, dietary antioxidants including vitamin C (ascorbic acid), vitamin E (eg, -tocopherol), and -carotene (provitamin A) have received the greatest attention with regard to coronary heart disease prevention. -Tocopherol and -carotene have been of particular interest because both are carried within LDL particles. Enrichment with -tocopherol increases LDL oxidative resistance in vitro.^12,13 This has rarely been observed for -carotene,^13,14 however. A number of other dietary factors are proposed to act as antioxidants and have been suggested to protect against coronary heart disease. Among these are trace elements, including selenium, copper, zinc, and manganese,¹⁵ some of which serve as cofactors for enzymes with antioxidant activity (eg, glutathione peroxidase and superoxide dismutase). Because little information is available on the preventive effects of these other nutrients in human populations, they will not be discussed further herein.

Observational Studies

Support for the importance of dietary antioxidants in coronary heart disease prevention has come from observational studies, including descriptive, case-control, and cohort studies, in which disease outcomes have been examined in relation to measures of antioxidant intake or tissue levels.^16-18 In many cases, increased antioxidant intake has been shown to be associated with reduced disease risk. This generally has involved increased consumption of antioxidant-rich foods (see Table), although some^19-21 but not all²² recent results have suggested the possible importance of supplemental levels of antioxidants.

Two particularly illustrative prospective cohort studies were published as companion papers in 1993.^19,20 The first, by Stampfer et al,¹⁹ involved analyses of data from >85 000 Nurses' Health Study participants who were followed up for periods of 8 years. Risk of major coronary disease was lowest in women within the highest compared with those within the lowest quintile of reported vitamin E intake after adjustment for age and smoking status (relative risk, 0.66; 95% CI, 0.50 to 0.87). Lower risk was associated with levels of vitamin E intake that were achievable only by supplementation. Subsequent analyses revealed a 43% lower risk for vitamin E supplement users versus nonusers and an inverse relationship between risk and duration of supplement use. The second study, by Rimm et al,²⁰ described a similar benefit for vitamin E based on data from >39 000 male participants of the Health Professionals Follow-up Study (HPFS) who were followed up for 4 years.

Rimm et al²⁰ also observed a lower risk of major coronary events in men reporting high versus those reporting low intakes of -carotene, but in subgroup analyses, this relationship was only significant in current and former smokers. These findings are consistent with several other studies that indicated an inverse association between dietary intake of -carotene or provitamin A carotenoids and risk of cardiovascular disease, particularly among smokers (eg, References 23 to 25^23-25).

None of the aforementioned analyses revealed a relationship between vitamin C intake and disease risk, in contrast to the results of Enstrom et al²¹ based on data from >11 000 US adults examined in the first National Health and Nutrition Examination Survey (NHANES I). Individuals reporting high intakes of vitamin C exhibited significantly lower risk of death from all causes, particularly from coronary heart disease, over a 10-year follow-up period. Among men, multivariate-adjusted relative risk was 0.75 (95% CI, 0.53 to 0.97) in individuals within the highest versus those within the lowest vitamin C intake group (50 mg/d dietary vitamin C plus regular supplements containing vitamin C versus <50 mg/d dietary vitamin C). Results were not adjusted for the intake of other antioxidants, however.

Primary Prevention Trials

Although observational studies have provided support for the potential health benefits of antioxidants, there remains a deficiency of direct experimental evidence from randomized trials. This deficiency may in part reflect the fact that few large-scale trials have been completed to date, although recently published results from several intervention trials have not supported hypotheses generated on the basis of results from observational studies.

A major case in point is the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized trial that tested the effects of daily doses of 50 mg (50 IU) of vitamin E (all-racemic -tocopheryl acetate), 20 mg of -carotene, both, or placebo for 5 to 8 years in a population of >29 000 male smokers.²⁶ The major end point was lung cancer, but the investigators also evaluated coronary heart disease. No reduction in risk of lung cancer or major coronary events was observed with any of the treatments. Moreover, with vitamin E supplementation, there was an unexpected increase in risk of death from hemorrhagic stroke, and with -carotene supplementation, there were unexpected increases in mortality from lung cancer and ischemic heart disease. Increases in risk of both lung cancer and cardiovascular disease mortality also were observed in the Beta-Carotene and Retinol Efficacy Trial (CARET),²⁷ which tested the effects of combined treatment with -carotene (30 mg/d) and retinyl palmitate (25 000 IU/d) in 18 000 men and women with a history of cigarette smoking or occupational exposure to asbestos.

There was no evidence of a significant beneficial or harmful effect of -carotene on cancer or cardiovascular disease in the Physicians' Health Study, which involved 22 071 US male physicians randomized to -carotene (50 mg every other day), aspirin (325 mg), both, or neither for 12 years.²⁸ A small absolute increase in risk could not be ruled out in smokers, however. These results are considered to be particularly informative because of the large sample size and long duration and may be more generalizable than those of the ATBC and CARET studies because the population was not limited to smokers or high-risk individuals.

A number of factors could account for the lack of correspondence between observational studies and randomized trials. In addition to the usual caveats regarding the interpretation of observational studies, including self-selection and uncontrolled confounding (eg, see Reference 29²⁹), it is worth noting that the observed associations between antioxidant intake and disease risk could reflect the importance of other dietary factors. In general, diets rich in antioxidants are also lower in saturated fat and cholesterol and higher in fiber. Moreover, other potentially important micronutrients distribute similarly within foods. For example, foods rich in vitamins C and E and -carotene also contain minerals, flavonoids, and indoles, as well as carotenoids other than -carotene.³⁰ It is often not possible to decipher the influence of these other dietary variables because many of them are not currently included in nutrient databases.

Antioxidant dose could also be an important factor, particularly for -carotene. Results from observational studies suggest that the relationship between carotenoid intake and disease risk may not be linear and, with notable exceptions (eg, Reference 20²⁰), that carotenoid-related variations in disease outcomes may occur largely at the lower end of the intake spectrum (eg, References ^24,31). In contrast, most of the intervention trials completed to date have involved supplementation with moderate to high levels of antioxidants in relatively well-nourished populations. It is perhaps relevant that the 1 trial that did show a trend toward decreased cardiovascular mortality involved low-dose supplementation (with a combined regimen of vitamin E, -carotene, and selenium) in a poorly nourished population in Linxian, China.³²

Secondary Prevention Trials

Results from secondary prevention trials have been more supportive of the potential health benefits of antioxidants. The Cambridge Heart Antioxidant Study (CHAOS) tested the effects of high doses (400 or 800 IU/d) of -tocopherol on subsequent cardiovascular events in patients with angiographic evidence of coronary atherosclerosis.³³ On the basis of the combined results for the 2 dose levels, risks of myocardial infarction (MI) and all cardiovascular events were reduced by 77% and 47%, respectively, in the treatment group, with a delay in the onset of treatment benefit of ~~200 days. Similar reductions were not observed for fatal cardiovascular end points. Although there are some concerns regarding the design of the CHAOS trial, including the use of 2 vitamin E doses, similar results have been obtained in other recent trials. Less impressive but consistent with the CHAOS study were results from a secondary analysis of the ATBC Study.³⁴ In individuals with a history of MI at the start of the study, risk of subsequent nonfatal MI was reduced by 38% in the -tocopherol group; in contrast, risk of fatal coronary end points was not reduced. As in the larger study, risk of fatal coronary end points was increased with -carotene supplementation (both with and without -tocopherol).

The apparent benefits of vitamin E (-tocopherol) in individuals with existing coronary disease are not consistent with the proposed role of oxidants in initiating lesions. Recent results from subgroup analyses of the Cholesterol Lowering Atherosclerosis Study (CLAS) suggest that high vitamin E intake could inhibit lesion progression.^35,36 Consideration of this effect as well as other possible effects of vitamin E on the clinical expression of cardiovascular disease is warranted.

Effects of Dietary Antioxidants on Clinical Outcomes

Recent studies have suggested that antioxidants may affect clinical outcomes. The Indian Experiment of Infarct Survival Study³⁷ tested the therapeutic efficacy of antioxidants in reducing post-MI complications, many of which are proposed to result from oxidative reperfusion injury. Infarct size (as assessed from plasma levels of cardiac enzymes and ECG changes) and angina and total cardiac events (within the study period) were significantly reduced in individuals receiving antioxidants in the post-MI period. It is unclear whether such benefits are limited to the administration of antioxidants after MI or whether better antioxidant nutriture, as determined by longer-term intake, would have similar effects.

Another potential therapeutic role for antioxidants is in the reduction of restenosis after angioplasty. This role has been addressed in several recent trials.^38-41 The Multivitamins and Probucol (MVP) Study tested the effects of a combination of vitamin C (1000 mg/d), vitamin E (1400 IU/d), and -carotene (100 mg/d); probucol (a lipid-lowering drug with antioxidant effects; 1000 mg/d); the dietary antioxidants plus probucol (in the same amounts); or placebo alone on the rate and severity of restenosis.³⁸ The Probucol Angioplasty Restenosis Trial (PART) compared probucol (1000 mg/d) with placebo.³⁹ In both studies, treatments were initiated 1 month before and maintained for 6 months after elective angioplasty. Relative to placebo, probucol significantly reduced restenosis. The authors proposed that the beneficial effects of probucol were due to its antioxidant properties. Yet in the MVP study, similar results were not observed for the dietary antioxidants, which had no effect alone and appeared to negate the beneficial effects of probucol when given in combination.³⁸ Beneficial effects have been observed for vitamins C and E in other studies,^40,41 however. Because the long-term use of probucol in diseased individuals is of concern, owing to adverse effects on plasma high-density lipoprotein levels (a 41% reduction was noted in the MVP study), dietary antioxidants, if efficacious, could represent a good alternative. Clearly, more research is needed in this area.

Summary and Conclusions

Our concept of the relationship between diet and coronary heart disease has changed considerably over the past 2 decades, in large part because of the accrual and analysis of large population data sets, the availability of more detailed food composition information, and, particularly, critical breakthroughs in our understanding of disease mechanisms. With regard to the latter, considerable evidence now suggests that oxidants are involved in the development and clinical expression of coronary heart disease and that antioxidants may contribute to disease resistance. Consistent with this view is epidemiological evidence indicating that greater antioxidant intake is associated with lower disease risk. Although this increased antioxidant intake generally has involved increased consumption of antioxidant-rich foods, some recent observational studies have suggested the importance of levels of vitamin E intake achievable only by supplementation.^19,20 There is currently no such evidence from primary prevention trials, but results from secondary prevention trials have shown beneficial effects of vitamin E supplements on some disease end points. In contrast, trials directly addressing the effects of -carotene supplements have not shown beneficial effects, and some have suggested deleterious effects, particularly in high-risk population subgroups.

In view of these findings, the most prudent and scientifically supportable recommendation for the general population is to consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains. This advice, which is consistent with the current dietary guidelines of the American Heart Association,⁴² considers the role of the total diet in influencing disease risk. Although diet alone may not provide the levels of vitamin E intake that have been associated with the lowest risk in a few observational studies,^19,20 the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation. In the case of secondary prevention, the results from clinical trials of vitamin E have been encouraging, and if further studies confirm these findings, consideration of the merits of vitamin E supplementation in individuals with cardiovascular disease would be warranted.

Acknowledgment

We thank Dr Charles Hennekens for his helpful comments.

References

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Table. Food Sources of Antioxidants

Antioxidant	Food Sources
Vitamin C	Fruits (especially citrus) and vegetables, including green and red peppers, tomatoes, potatoes, and green, leafy varieties (eg, spinach and collard greens)
Vitamin E	Vegetable oils (eg, soybean, corn, and safflower) and vegetable oil products (eg, margarine), whole grains, wheat germ, nuts and seeds, and green, leafy vegetables
-Carotene	Yellow-orange fruits (eg, cantaloupe) and vegetables (eg, carrots) and green, leafy vegetables

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in October 1998. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Avenue, Dallas, TX 75231-4596. Ask for reprint No. 71-0158.

(Circulation. 1999;99:591-595.)

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