3/98medslides.com1 antioxidants and coronary artery disease jason m. lazar, md george yiachos, md...

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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:

smoking hypertension

diabetes hyperlipidemia

family history


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

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 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


Antioxidants

vitamins herbs

estrogens flavonoids

amino acids beta-carotene

lipid-lowering agents

monounsaturated fats


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 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 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



• 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



• 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 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 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

• 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 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



• 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



• 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-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



• 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



• 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



• 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



• 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


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

Nutrient RDI Dietary Sources Evidence

Vitamin E 30 IU Vegetable oils (soy, corn, olive, 100-800 IU may lowercotton-seed, safflower, sunflower), heart disease risk bynuts, sunflower seed, wheat germ 30%-40%

Vitamin C 60 mg Citrus fruits, strawberries, tomatoes, no evidence that RDI incantaloupe, broccoli, asparagus, supplement form canpeppers, spinach, potatoes prevent CHD or cancer

ß-carotene NA Dark green, yellow, and orange may protect againstvegetables: spinach, collard green CHD and macularbroccoli, carrots, peppers, sweet degenerationpotatoes; 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 riskselenium-rich soil ( west of Mississippi)


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


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”


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


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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