Download Antioxidants

Antioxidants
and
Coronary Artery Disease
Jason M. Lazar, MD
George Yiachos, MD
Winthrop-University Hospital
3/98
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Coronary ArteryDisease
• In 1997, the direct and indirect cost for
CAD was $90.9 billion in the U.S.
• only 50% of CAD can be attributed to
conventional risk factors:
smoking
diabetes
family history
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hypertension
hyperlipidemia
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Is the use of vitamins justified
• Although observational studies support a
cardio-protective effects of antioxidants,
clinical trials are disappointing
• In the mean time, Americans spend an
estimate $700 million on vitamin
supplements
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Epidemiologic Evidence
In Europe, those living in the south
consume greater amounts of fruits and
vegetables containing the antioxidants
beta-carotene, vitamin E and vitamin C,
have lower rates of CAD than those living
in the north
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NEJM 1997;337:408-416
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Lipid Oxidation Hypothesis
Lipid uptake across the cell wall is greatly
enhanced by oxidized LDL-C.
Antioxidants may therefore be beneficial
in reducing the risk of coronary artery
disease
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NEJM 1989;320:915-924
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Antioxidants
vitamins
herbs
estrogens
flavonoids
amino acids
beta-carotene
lipid-lowering agents
monounsaturated fats
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Vitamin E
• A family of fat-soluble compounds, the
tocopherols. Alpha-tocopherol is the
most common and most active.
• Best sources of vitamin E
– vegetable, seeds, nut oils
• recommended daily allowance is
15 IU
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Vitamin E
laboratory and animal studies
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Vitamin E  the oxidation of LDL-C
inhibit smooth-muscle cell growth
inhibit platelet adhesion
improves endothelial function
reduced the number and severity of
atherosclerotic lesions in rabbits fed highfat diets
Clin Cardiol 1993;16:I16-18
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Vitamin E
human studies
• Nurse’s Health Study
– 87,245 women, ages 34-59, with no prior heart
disease
– those taking  100 IU/d of vitamin E for
 2 years, had 40% lower risk of developing
CAD after 8 years
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NEJM 1993;328(20):1444-1449
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Vitamin E
human studies
• Health Professional’s Follow-up to the
Physician’s Health Study
– 39,910 men, ages 40-70
– subjects with the highest vitamin E intake (>
60 IU / day) had a 36% lower risk of coronary
disease after 4 years
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NEJM 1993;328(20):1450-1466
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Vitamin E
human studies
• Iowa Women’s Health
– a prospective cohort study of 34,000
postmenopausal women
– subjects with the highest vitamin E intake
from diet (but no vitamin supplements) had a
lower risk for CAD
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NEJM 1996;334(18):1156-1162
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Vitamin E
randomized trials
• CHAOS Study
(Cambridge Heart Antioxidant Study)
– a prospective randomized trial of 2,002
patients with prior coronary disease
– treated with vitamin E (400-800 IU / day) for 3
years
– 77% reduction in nonfatal MI
– no change in total mortality
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Lancet 1996;347(9004):781-786
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Vitamin E
randomized trials
• ABC Prevention Trial
(Alpha-tocopherol Beta-carotene Cancer
Prevention Trial)
– a lung cancer prevention trial
– 50 mg/d of vitamin E had no effect on the rate
of MI or death
– 50 mg/d vit E + 20 mg/d beta-carotene
resulted in greater coronary death
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NEJM 1994;330(15):1029-1035
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Vitamin C
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a water-soluble vitamin
found in many fruits and vegetables
a less potent antioxidant than vit E
associated with lower LDL-C, higher HDLC, and lower BP
• inhibits platelet aggregation
• recommended daily allowance 60 mg
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Vitamin C
human studies
• The benefit of vitamin C in CAD is
inconsistent and inconclusive
• only 3 of 8 observational studies found an
inverse relationship between vitamin C
intake and CAD
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Vitamin C
human studies
• First National Health and Nutritional
Examination Survey
– 11,349 subjects received vitamin C
supplements
– subjects taking vitamin C had a lower relative
risk of cardiovascular death of .58
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Epidemiology 1992;3(3):194-202
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Vitamin C
human studies
• The Nurse’s Health and the Health
Professional’s Follow-Up Study
– subjects in the highest quintile of vitamin C
intake had relative risk of cardiovascular
disease of .8
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Beta-carotene
• A plant-derived nutrient
• contained in yellow and orange
vegetables and fruits, and leafy green
vegetables
• provides up to half of dietary vit A
• recommended daily allowance is 5,000 IU
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Beta-carotene
human studies
• The antioxidant effects of beta-carotene
and vitamin A have been well established
• The clinical studies are disappointing
• Only 3 of 6 observational studies found a
decreased coronary risk associated with
beta-carotene
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Beta-carotene
human studies
• The Physician Health Study
– over 22,000 male physicians
– randomized to 50 mg of beta-carotene every
other day
– after 12 years, there was no difference in
cardiovascular, cancer, and all-cause
mortality
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NEJM 1993;328(20):1450-1466
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Beta-carotene
human studies
• The Physician Health Study
– in a subset of 333 subjects with preexisting
coronary disease
– beta-carotene was associated with a 44%
reduction of coronary events (p=0.046)
– the analysis was limited by its borderline pvalue and post hoc nature
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Circ 1990;82s:202
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Beta-carotene
human studies
• The CARET Study
(Carotene and Retinol Efficacy Trial)
– a randomized placebo-controlled trial of
18,000 male smokers with history of
asbestos exposure
– randomized to beta-carotene and vit A
– the trial was terminated 21 months early
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N Engl J Med 1996;334(18):11150-1155
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Beta-carotene
human studies
• The CARET Study
subjects treated with 30 mg /d of betacarotene had
– 28%  in mortality from lung cancer
– 17%  in all-cause mortality
– 29%  in cardiovascular mortality
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N Engl J Med 1996;334(18):11150-1155
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Flavonoids
human studies
• The Zutphen Elderly Study
– the consumption of flavonoid was inversely
related to the occurrence of coronary heart
disease
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Lancet 1993;342:1007-1011
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Antioxidants at a glance
Nutrient
Vitamin E
RDI
30 IU
Vitamin C
60 mg
ß-carotene
NA
Selenium
70 ug
55 ug
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Dietary Sources
Evidence
Vegetable oils (soy, corn, olive,
100-800 IU may lower
cotton-seed, safflower, sunflower),
heart disease risk by
nuts, sunflower seed, wheat germ
30%-40%
Citrus fruits, strawberries, tomatoes, no evidence that RDI in
cantaloupe, broccoli, asparagus,
supplement form can
peppers, spinach, potatoes
prevent CHD or cancer
Dark green, yellow, and orange
may protect against
vegetables: spinach, collard green
CHD and macular
broccoli, carrots, peppers, sweet
degeneration
potatoes; yellow fruits: peaches
Egg yolks, tuna, seafood, chicken,
150-200 ug may lower
liver, whole grains, plant grown in
prostate cancer risk
selenium-rich soil ( west of Mississippi)
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Summary
• Current data do not support a large role
for the use of antioxidant supplements in
the prevention of CAD
• Nonetheless, many Americans rather
consume vitamin supplements and
neglect modification of known coronary
risk factors
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Summary
“Until further studies are completed, it is
reasonable to recommend a diet rich in
vegetable products, combined with
exercise, risk modification behaviors, and
appropriate medications”
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References
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Antioxidants and atherosclerotic heart disease.
Diaz MN, Frei B, Vita JA, et al. NEJM 1997;337:408-416
Beyond cholesterol:modifications of low-density lipoprotein that increase its
atherogenicity.
Steinberg D, ParthasarathyS, et al. NEJM 1989;320:915-924
Vitamin E: more than an antioxidant.
Steiner M. Clin Cardiol 1993;16 (4 Suppl 1):I16-18
Vitamin E consumption and the risk of coronary disease in women.
Stampfer MJ, Hennekens CH, et al. NEJM 1993;328(20):1444-1449
Vitamin E consumption and the risk of coronary disease in men.
Rimm EB, Stampfer MJ, et al. NEJM 1993;328(20):1450-1466
Dietary antioxidant vitamins and death from coronary heart disease in
postmenopausal women. Kushi LH, et al. NEJM 1996;334:1156-1162
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References
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Randomized controlled trial of vitamin E in patients with coronary disease:
Cambridge Heart Antioxidant Study (CHAOS).
Stephens NG, Parson A, et al. Lancet 1996;347(9004):781-786
The Alpha-tocopherol Beta-carotene Cancer Prevention Sutdy Group: the effect
of vitamin E and beta-carotene on the incidence of lung cancer and other
cancers in male smokers.
NEJM 1994;330(15):1029-1035
Effects of a combination of beta-carotene and vitamin A on lung cancer and
cardiovascuar disease.
Omenn GS, et al. N Engl J Med 1996;334(18):11150-1155
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