Antioxidants and Coronary Artery Disease

Jason M. Lazar, MD George Yiachos, MD Winthrop-University Hospital

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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
Vitamin E q 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
Nurses Health Study
87,245 women, ages 34-59, with no prior heart disease those taking u 100 IU/d of vitamin E for u 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 Professionals Follow-up to the Physicians 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 Womens 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
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 Nurses Health and the Health Professionals 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
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% o in mortality from lung cancer 17% o in all-cause mortality 29% o 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 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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Vitamin C

60 mg

-carotene

NA

Selenium

70 ug 55 ug

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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
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
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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