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May 2001; Volume 4; 49-52
By Matthew Sorrentino, MD, FACC
Coronary artery disease is the leading cause of morbidity and mortality in this country. Prevention of heart disease has focused on the recognition and treatment of classic and emerging risk factors that have been linked to the development of atherosclerotic disease and its complications. There is growing evidence suggesting that oxidative stress may play a role in the initial steps of atherosclerosis, and also may contribute to development of an unstable plaque. Antioxidant therapies may be useful in preventing both the initiation of atherosclerotic disease and its complications.Pathophysiology
A crucial step in the development of atherosclerotic disease is the oxidation of LDL cholesterol. Oxidized LDL is taken up by macrophages via the scavenger receptor pathway to form foam cells, an integral part of the atherosclerotic plaque. In addition, oxidized LDL has many other potentially deleterious effects. (See Table 1.) Oxidized LDL is cytotoxic to endothelial cells causing endothelial dysfunction and inappropriate vasoconstriction. Endothelial dysfunction is a major cause of cardiac ischemia and underlies the complications of coronary disease including sudden cardiac death.
Deleterious effects of oxidized LDL cholesterol
|1.||Formation of foam cells via the scavenger receptor pathway|
|2.||Cytotoxic to endothelial cells causing endothelial dysfunction|
|3.||Chemoattractant for monocytes|
|4.||Enhance binding of monocytes to endothelial cells|
|5.||Inhibits macrophage migration|
|7.||Increases platelet aggregation|
|8.||Increases tissue factor secretion|
Antioxidants have multiple potentially beneficial effects on coronary heart disease. The early prevention of LDL oxidation may prevent foam cell formation and the initial development of the fatty streak and early atherosclerotic plaques. In individuals with established atherosclerotic disease, antioxidants may improve endothelial function and prevent vasoconstriction and ischemic events. This in turn may help stabilize the atherosclerotic plaque reducing the chance of plaque rupture and an acute coronary thrombosis.Animal Studies
Primary Prevention of Atherosclerosis. Experimental studies have linked antioxidants with decreased atherosclerosis in animals. In these studies, antioxidants usually were administered before the development of atherosclerosis suggesting that the decrease in LDL oxidation may have reduced foam cell production and plaque formation.1Clinical Studies
Primary Prevention. Epidemiological data suggest that a dose of at least 100 mg/d vitamin E has a protective effect against coronary events.
The Nurses’ Health Study evaluated vitamin E supplementation as reported on questionnaires completed by more than 80,000 nurses. The group of nurses taking the largest amount of vitamin E had a lower risk of coronary events than those taking the lowest amount.2 The Health Professionals’ Follow-up Study found similar results in men with the highest vitamin E intake.3
There are minimal prospective primary prevention data from available studies to determine if vitamin E is an effective preventive agent for the development of coronary events. The only completed primary prevention trial is the alpha-tocopherol, beta-carotene cancer prevention study designed to evaluate the development of lung cancer in a cohort of Finnish male smokers.4 Coronary outcomes were evaluated in a subgroup of men who were randomized to either placebo or 50 mg of vitamin E. After a median of 6.1 years there was no statistically significant difference in the incidence of nonfatal myocardial infarction in the vitamin E group compared to placebo. There was a trend for a decrease in fatal coronary events (8% decrease, confidence interval -19% to 5%) in the vitamin E group but it was not statistically significant. The dose of vitamin E used in this study, however, may have been too small to achieve a benefit.
Secondary Prevention Trials. In patients with established coronary artery disease, antioxidants may improve endothelial function, reduce ischemia, and stabilize atherosclerotic plaques to prevent plaque rupture. The Cambridge Heart Antioxidant Study (CHAOS) was a prospective trial of vitamin E (400-800 IU) in patients with established coronary heart disease.5 The risk of the primary endpoint (a combination of death and nonfatal myocardial infarction) was reduced by 47% in the vitamin E group. There was no reduction in cardiovascular death in the vitamin E group. This study used significantly higher doses of vitamin E than had been studied previously.
The results of the CHAOS trial, however, have not been reproduced by two recently reported large trials, the Heart Outcomes Prevention Evaluation (HOPE) study and the GISSI-prevention trial. The HOPE study enrolled 2,545 women and 6,996 men at high risk of cardiovascular events because of the presence of previously diagnosed cardiac disease or diabetes mellitus with at least one other major risk factor.6 Patients were randomized to receive 400 IU of vitamin E from natural sources or an equivalent placebo for four to six years. There was no difference between the groups in the number of deaths from cardiovascular causes, myocardial infarctions, stroke, or hospitalizations for unstable angina or heart failure.
Why did this well-done prospective, randomized, controlled trial show no benefit when the epidemiological trials suggested benefit? Two main possibilities: First, vitamin E may need to be given with additional antioxidants to work as cofactors for a beneficial effect. This study used vitamin E alone as a supplement. And second, vitamin E may give benefit only early in the disease process (primary prevention) but not after significant disease is already established, as in the HOPE patients.
The GISSI-prevention trial investigated the effects of vitamin E and omega-3 fatty acids on cardiovascular events in individuals who already have suffered a first myocardial infarction.7 Vitamin E was given as a 300 mg capsule of synthetic alpha-tocopherol. All patients were also on a Mediterranean-type diet. In comparison with the placebo group, there was no effect on cardiovascular endpoints noted in the vitamin E group.
Why was GISSI also a negative study? There are three key possibilities. The Mediterranean-type diet may have given an antioxidant beneficial effect that was overlapped by additional vitamin E supplementation. Second, the dose of vitamin E used in this study is lower than used in the CHAOS trial, and may have been inadequate to achieve a cardiovascular effect. And third, synthetic vitamin E supplementation—which may not have the same biologic equivalency as natural, mixed vitamin E—was used.
These two recent secondary prevention vitamin E studies raise important concerns about the use of vitamin E to prevent subsequent cardiac events, especially in individuals with established coronary artery disease. The amount of vitamin E used in these studies exceeds an easily obtainable daily dose through diet alone and should have had an impact on cardiac events if this therapy is indeed effective. These studies do not address primary prevention, however, and it remains possible that the early use of vitamin E may prevent initial plaque formation. Ongoing primary prevention studies may clarify this issue.Secondary Prevention in Renal Patients
Chronic hemodialysis patients are known to have a high cardiovascular mortality rate thought to be caused, in part, by enhanced oxidative stress. Recently a small trial in patients with end-stage renal disease treated with hemodialysis was completed. The results suggest a benefit of vitamin E in this high-risk group of patients.8
In this study, 196 hemodialysis patients with preexisting coronary artery disease were assigned to receive 800 IU/d vitamin E or placebo and were followed for two years. The primary endpoint (a combination of fatal and nonfatal myocardial infarction, ischemic stroke, peripheral vascular disease, and unstable angina) occurred in 16% of the vitamin E group compared with 33% of the placebo group. The only individual endpoint that reached significance was myocardial infarction: five patients receiving vitamin E and 17 assigned to placebo had a myocardial infarction. Two deaths associated with hemorrhage occurred in the vitamin E group. Although this was not statistically significant, vitamin E is known to inhibit protein kinase C and is associated with an increased risk of bleeding.
The benefit of vitamin E in this study may have occurred because the cohort of patients was at higher risk than patients in the other vitamin E studies, and because hemodialysis patients are known to have evidence of greater oxidative stress. More work will need to be done to define other populations of patients likely to benefit from antioxidant therapy.Formulation and Dosage
Vitamin E, a fat-soluble vitamin contained in vegetable, nut, and seed oils, exists as at least eight naturally occurring compounds, all of which have antioxidant activity.9 Alpha-tocopherol is the most active component. Dietary vitamin E usually is expressed as mg of alpha-tocopherol equivalents or in an older designation, IUs (international units). One IU is equivalent to approximately 1 mg of dl-alpha-tocopheryl acetate.10 A well-balanced, Mediterranean-type diet should supply about 8-12 IU/d of vitamin E. (See Table 2 for food sources.)
Food sources of vitamin E
Vitamin E (mg)
|Wheat germ oil||1 tablespoon||37.2|
|Sunflower seeds||1/4 cup||26.8|
|Wheat germ, raw||1/4 cup||12.8|
|Pecan halves||1/4 cup||12.5|
|Safflower oil||1 tablespoon||7.9|
|Corn oil||1 tablespoon||4.8|
|Peanut butter||2 tablespoons||3.8|
|Soybean oil||1 tablespoon||3.5|
|Cod-liver oil||1 tablespoon||3|
|Salmon, fillet||3 oz||0.6|
|Source: Reproduced with permission from La Puma J, Becker J. CHEF Clinic: Cooking with Antioxidant Vegetables. Elk Grove Village, IL: 2000; 10.|
Epidemiological data, derived from studies of synthetic dl-alpha-tocopherol, suggest that at least 100 mg/d are needed to derive protection against coronary events.
Adverse Effects and Interactions
Tocopherols inhibit platelet aggregation in vitro and may interfere with vitamin K-dependent coagulation and, therefore, may cause bleeding when used alone or in conjunction with other antiplatelet agents like aspirin or NSAIDs and with coumadin. Both the HOPE and GISSI trials, using up to 400 mg/d of alpha-tocopherol, did not show excessive bleeding risk.
Vitamin E is an antioxidant vitamin that may help prevent the oxidation of LDL cholesterol and the development of atherosclerosis. The use of vitamin E in patients with established coronary heart disease, however, has not been shown to reduce cardiovascular events. There still may be a role for vitamin E in primary prevention to prevent early plaque development, but more studies are needed to clarify this use.Recommendation
Vitamin E currently cannot be recommended as therapy for secondary prevention. There may be subgroups of patients, however, such as cardiac patients on chronic hemodialysis, who may benefit from antioxidant therapy. The potential for an increased risk of bleeding complications needs to be considered before recommending this therapy. The benefit for primary prevention has yet to be determined although there are good theoretical reasons why vitamin E may prevent LDL oxidation and the development of atherosclerosis. Supplemental vitamin E of at least 400 IU can be considered in individuals at increased risk for but who do not yet have heart disease.
1. Diaz MN, et al. Antioxidants and atherosclerotic heart disease. New Engl J Med 1997;337:408-416.
2. Stampfer MJ, et al. Vitamin E consumption and the risk of coronary disease in women. New Engl J Med 1993;328:1444-1449.
3. Rimm EB, et al. Vitamin E consumption and the risk of coronary heart disease in men. New Engl J Med 1993:328:1450-1456.
4. Virtamo J, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med 1998;158:668-675.
5. Stephens NG, et al. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;374:781-786.
6. Yusuf S, et al. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Study Investigators. New Engl J Med 2000;342:154-160.
7. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: Results of the GISSI-Prevenzione trial. Lancet 1999:354;447-455.
8. Boaz M, et al. Secondary prevention with antioxidants of cardiovascular disease in end stage renal disease (SPACE): Randomised placebo-controlled trial. Lancet 2000;356:1213-1218.
9. Spencer AP, et al. Vitamin E and coronary artery disease. Arch Intern Med 1999;159:1313-1320.
10. Meyers DG, et al. Safety of antioxidant vitamins. Arch Intern Med 1996;156:925-935.