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Antioxidants and Coronary Artery Disease. Jason M. Lazar, MD George Yiachos, MD Winthrop-University Hospital. 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:

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antioxidants and coronary artery disease
Antioxidants and Coronary Artery Disease

Jason M. Lazar, MD

George Yiachos, MD

Winthrop-University Hospital

coronary arterydisease
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 hypertension

diabetes hyperlipidemia

family history

is the use of vitamins justified
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

epidemiologic evidence
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

NEJM 1997;337:408-416

lipid oxidation hypothesis
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

NEJM 1989;320:915-924


vitamins herbs

estrogens flavonoids

amino acids beta-carotene

lipid-lowering agents

monounsaturated fats

vitamin e
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

vitamin e laboratory and animal studies
Vitamin Elaboratory and animal studies
  • 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 high-fat diets

Clin Cardiol 1993;16:I16-18

vitamin e human studies
Vitamin Ehuman 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

NEJM 1993;328(20):1444-1449

vitamin e human studies10
Vitamin Ehuman 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

NEJM 1993;328(20):1450-1466

vitamin e human studies11
Vitamin Ehuman 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

NEJM 1996;334(18):1156-1162

vitamin e randomized trials
Vitamin Erandomized 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

Lancet 1996;347(9004):781-786

vitamin e randomized trials13
Vitamin Erandomized 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

NEJM 1994;330(15):1029-1035

vitamin c
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 HDL-C, and lower BP
  • inhibits platelet aggregation
  • recommended daily allowance 60 mg

vitamin c human studies
Vitamin Chuman 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

vitamin c human studies16
Vitamin Chuman 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

Epidemiology 1992;3(3):194-202

vitamin c human studies17
Vitamin Chuman 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

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

beta carotene human studies
Beta-carotenehuman 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

beta carotene human studies20
Beta-carotenehuman 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

NEJM 1993;328(20):1450-1466

beta carotene human studies21
Beta-carotenehuman 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 p-value and post hoc nature

Circ 1990;82s:202

beta carotene human studies22
Beta-carotenehuman 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

beta carotene human studies23
Beta-carotenehuman studies
  • The CARET Studysubjects treated with 30 mg /d of beta-carotene had
    • 28%  in mortality from lung cancer
    • 17%  in all-cause mortality
    • 29%  in cardiovascular mortality

N Engl J Med 1996;334(18):11150-1155

flavonoids human studies
Flavonoidshuman studies
  • The Zutphen Elderly Study
    • the consumption of flavonoid was inversely related to the occurrence of coronary heart disease

Lancet 1993;342:1007-1011

antioxidants at a glance
Antioxidants at a glance

Nutrient RDI Dietary Sources Evidence

Vitamin E 30 IU 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%

Vitamin C 60 mg Citrus fruits, strawberries, tomatoes, no evidence that RDI in cantaloupe, broccoli, asparagus, supplement form can peppers, spinach, potatoes prevent CHD or cancer

ß-carotene NA Dark green, yellow, and orange may protect against vegetables: spinach, collard green CHD and macular broccoli, carrots, peppers, sweet degeneration potatoes; yellow fruits: peaches

Selenium 70 ug Egg yolks, tuna, seafood, chicken, 150-200 ug may lower

55 ug liver, whole grains, plant grown in prostate cancer risk selenium-rich soil ( west of Mississippi)

  • 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


“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”

  • 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

  • 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