Over The past several years, there has been an increasing interest in the role of free radical scavengers, particularly antioxidant vitamins in cardiovascular disease prevention. Free radicals are common by products of many oxidative biochemical reactions in the body. They can damage or destroy biological molecules and have the potential for causing serious tissue and organ damage. They have been implicated in aging and chronic disease processes, including atherosclerotic coronary heart disease. Substantial laboratory, animal, and human data suggest that oxidation of low density lipoprotein (LDL) cholesterol is an important step in the pathogenesis of atherosclerotic lesions1.
Antioxidants vitamins presumably exert their effects through the protection of oxidation. However, some studies have shown that these vitamins may also preserve endothelial function 2, affect hemostasis3, and lower LDL cholesterol level4.
The predominant antioxidants protecting the LDL molecule are a tocopherol, retinyl stearate, gamma tocopherol , and beta carotene. Being lipid soluble, these agents are incorporated into the LDL molecule. a Tocopherol, the most active isomer of the vitamin E family, is the principal lipid soluble antioxidant in tissues and plasma57. Ascorbic acid, on the other hand, is the first line of defense against oxygen free radicals in the water soluble compartment 6,7.
Vitamin E supplementation was found to reduce the risk of coronary heart disease in a study in which 39,910 male health professionals with no history of cardiovascular disease were followed for 4 years9, About 17% of the men took vitamin E supplements. The adjusted relative risk reduction (RRR) of coronary heart disease in men taking at least 100 IU of vitamin E supplements for at least 2 years compared with the men not taking vitamin E supplements was 44% (CI, 19% to 56%).
In a study of 34,486 postmenopausal women10 with no cardiovascular disease followed up for 7 years, the intake of vitamin E from food was inversely associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vitamins A and C was not associated with lower risks of dying from coronary disease11.
Vitamin C clearly reduced risk in only one large cohort study (in which vitamin E intake was not ascertained) and in none of the small cohort studies. In a prospective study of 11,348 American adults, researchers found a 34% lower standardized mortality ratc (CI, 18% to 47%) among participants who received 50 mg of vitamin C/day or more (by dietor supplements) compared with persons who received less vitamin C12. In another cohort study, Galc and colleagues13 examined the 20year survival of 730 elderly persons who had no initial history of vascular disease. The incidence of stroke in subjects in the highest tertile of vitamin C intake (mean,> 45 mg/day) was significantly reduced (RRR of 50%). However, no such reduction was seen in mortality from coronary heart disease.
Experimental data suggest that vitamin C lowers blood pressure by a small amount, that 2 g daily lowers serum cholesterol concentration and prevents oxidation of LDL and that a similar dose may increase fibrinolytic activity in those with coronary heart disease14,15. However, evidence is required to show more benefit than harm from treatment16.
Reliable estimates of efficacy of antioxidant vitamins can only be obtained from large scale randomized trials. None of the completed randomized trials showed any clear reduction in cardiovascular disease with vitamin E, vitamin C, or beta carotenc supplementation. The trials were not specifically designed to address cardiovascular disease, did not provide data on nonfatal cardiovascular end points, may have had insufficient treatment duration, and used suboptimal vitamin E doses12.
More recently, however, the Cambridge Heart Antioxidant Study (CHAOS) looked at the effects of vitamin E in the secondary prevention of coronary heart disease17, 2002 patients with angiographically confirmed coronary artery disease were randomly assigned to take vitamin E or placebo. Half the patients who had vitamin E were randomized to receive 800 IU daily for 2 years while the other half had 400 IU for 1 year. The primary end points were a combination of cardiovascular death plus nonfatal myocardial infarction. Vitamin E reduced these two end points significantly by 36%;and 66% respectively. There is still much uncertainty about the dose of vitamin E in primary and secondary coronary heart disease prevention. The follow-up of patients receiving 800 IU daily dose was twice as long, yet the number of nonfatal myocardial infarction in the 400 IU daily group seems to have been reduced more18.
The Alpha Tocopherol, Beta Carotene and Cancer Prevention Study (ATBC) of 29,133 middle aged heavy smokers in Finland were followed for 6.1 years20. The participants were treated with vitamin E (50 mg/day), beta carotene (20 mg/day), both, or neither. There was no reduction in the incidence of lung cancer nor was there any significant reduction in the incidence of coronary heart disease. The dose of vitamin E was probably too low but the dose of beta carotene was adequate. The participants were heavy smokers and therefore at high risk of both lung cancer and coronary heart disease. It is conceivable that this was a group of men with advanced atherosclerosis. A legitimate question is whether their disease was so far advanced which limits the validity of the trial19.
Recently, the data of two large placebo controlled studies have been published. In the Physicians Health Study, 22,071 American male doctors treated with 50 mg of beta carotene or placebo every other day were followed for an average of 12years20. There were virtually no early or late differences in the overall incidence of malignant neoplasm or cardiovascular disease, deaths from cardiovascular disease, or in the overall mortality.
The Beta Carotene and Retinol Efficacy Trial (CARET) studied 18,314 persons at high risk for lung cancer because of exposure to asbestos or cigarette smoking. They were treated daily with a combination of 30mg of beta carotenc and 25,000 IU of retinol (vitamin A) or with placebo for an average of 4 years20. The trial was stopped 21 months earlier than planned when researchers recognized an elevated risk of death from lung cancer in the group receiving the supplements.
The study showed that the combination of beta carotene and vitamin A had no benefits and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos20.
The results of these last two trials send a clear message to the public , the tens of millions of dollars spent annually on beta carotene supplements should now be diverted to more useful purposes21.
Randomized trials of sufficient power to establish the effectiveness of higher dose antioxidant supplementation in preventing coronary heart disease are currently unerway.
In all trials of vitamin E, doses greater than 3IU/day are being used; such doses should be sufficient to increase serum levels at least two to threefold. A future metaanalysis or a systematic overview of the cumulative numbers from these trials should, by the end of the decade, provide clear answers about the efficacy and safety of the various antioxidant vitamins12.
The combined evidence currently does not support the routuse of antioxidavitamins apreventive measure against cardiovascular disease.
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