Antioxidant Consumption and Risk of Coronary Heart Disease:

[Guest guest]

Antioxidant Consumption and Risk of Coronary Heart

Disease: Emphasis on Vitamin E,C and Beta Carotene

 

 

 

Collections under which this article appears:

Chronic ischemic heart disease-

Primary prevention

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

© 1999 American Heart Association, Inc.

 

---

AHA

Science Advisory

http://circ.ahajournals.org/cgi/content/full/99/4/591

 

Antioxidant Consumption and Risk of Coronary Heart Disease:

 

 

A Statement for Healthcare Professionals From the American Heart

Association

Diane L. Tribble, PhD

For the Nutrition Committee

 

 

 

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

fordietary antioxidants in disease prevention, with emphasis on

studiesin 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.

 

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.

 

At the center of this hypothesis are low-density lipoproteins

(LDLs),

which undergo multiple changes on oxidation that are thought to be

proatherogenic.

 

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

cells4 5 and alterations in the chemotactic properties of monocytes

and monocyte-derived macrophages in a manner expected to increase

theirresidence 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,

 

a key step in the formation of macrophage-derived foam cells.

 

 

 

View larger version (23K):

 

Figure 1. Proposed role of LDL oxidation in the initiation of

fatty

streak lesions. LDL crosses the endothelium in a concentration-

dependent

manner and can become trapped in the extracellular matrix (1).

 

The subendothelium is an oxidizing environment, and if the LDL

remains

trapped for a sufficiently long period of time, it undergoes

oxidative changes .

 

Mildly oxidized forms of LDL contain biologically active

phospholipid

oxidation products that affect the pattern of gene expression in

endothelial cells (ECs), leading to, among other things, changes in

the

expression of monocyte binding molecules (designated X-CAM),

monocytechemoattractant protein (MCP-1), and macrophage colony

stimulatingfactors (CSFs) .

 

These factors in turn promote the recruitment of monocytes (4) and

drive their phenotypic differentiation to macrophages (5). Further

oxidation

leads to alterations in apolipoprotein B such that LDL particles are

recognized and internalized by macrophages (6), progenitors of the

lipid-laden foam cells.

 

Marked increases in lipid and cholesterol oxidation products render

the

LDL particles cytotoxic, leading to further endothelial injury (7)

and favoring further entry of LDL and circulating monocytes and thus

a continuation of the disease process.

 

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, andthrombosis.

 

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.

 

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 ß-

carotene(provitamin A) have received the greatest attention with

regard tocoronary heart disease prevention.

 

-Tocopherol and ß-carotene have been of particular interest because

both are carried within LDL particles.

 

Enrichment with -tocopherol increases LDL oxidative resistance in

vitro.

This has rarely been observed for ß-carotene,

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.

 

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 but not all recent results have suggested the possible

importance of supplemental levels of antioxidants.

 

View this table:

 

Table 1. Food Sources 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 ß-carotene,

but in subgroup analyses, this relationship was only significant in

current and former smokers.

 

 

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 inpart 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 ß-carotene, both, or placebo for 5 to 8 years in

a population of >29 000 male smokers.

 

 

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

Reference2929 ),

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 ß-carotene also contain minerals,

flavonoids, and indoles, as well as carotenoids other than ß-

carotene.

 

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

ß-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

atthe lower end of the intake spectrum (eg, References 24 and 3124

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.

 

 

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.

 

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 oftreatment benefit of 200 days.

 

 

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.

 

Consideration ofthis 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 39 40 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 ß-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

thatgreater 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

vitaminE intake achievable only by supplementation.

 

There is currently no such evidence from primary prevention trials,

but

results from secondary prevention trials have shown beneficial

effectsof vitamin E supplements on some disease end points.

 

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

vegetablesand 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.

 

 

Acknowledgments

 

We thank Dr Charles Hennekens for his helpful comments.

 

Footnotes

 

This statement was approved by the American Heart Association

ScienceAdvisory and Coordinating Committee in October 1998. A single

reprint isavailable 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.

 

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