Vitamin E and Cardiovascular Disease
Vitamin E and Cardiovascular Disease
By Lynn Keegan, RN, PhD, HNC-BC, FAAN, Director, Holistic Nursing Consultants, Port Angeles, WA. Dr. Keegan reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Supplemental vitamin e for the prevention of cardiovascular disease has been widely used in the United States. New studies emerged in 2005 suggesting that this supplement may not be as effective as previously thought and, indeed, in high doses might be detrimental.
Complementary Therapies in Heart Disease
Heart disease is the leading cause of death in the United States. The relationship between heart disease and inflammation has been the focus of many recent studies. Dietary supplementssuch as vitamins C and E, beta-carotene, and seleniumhave been suggested as complementary therapies to combat oxidative stress and ameliorate this complicated disease. This article focuses solely on the supplement vitamin E, a potent antioxidant with anti-inflammatory properties. Several lines of evidence suggest that among different forms of vitamin E, alpha-tocopherol has potential beneficial effects with regard to cardiovascular disease.1
Mechanism of Action
The mechanism of action of vitamin E in processes associated with heart disease is the subject of ongoing discussions.2 The most commonly offered explanation focuses on inhibition of low-density lipoprotein (LDL) cholesterol peroxidation.3 Changes in LDL have been shown to be important both in new atherogenesis and in destabilization of existing plaques. As lipophilic molecules, the various isomers of vitamin E incorporate readily into unsaturated fats, effectively pre-empting the action of free-radical oxidants. However, this property also can have negative consequences. In the right circumstances, vitamin E can act as a pro-oxidant, prompting the observation that vitamins E and C are more effective together, with vitamin C acting as a restorative agent to return vitamin E to its stable form.4
Another suggested mechanism of action for vitamin E is its role in suppressing the expression of adhesion molecules that have a role in atherogenesis, and the inhibition of endothelial cell proliferation.5,6 Neither of these possibilities is as well-characterized as the oxidative stress hypothesis, which has been the underlying rationale in most of the trials conducted so far. Alpha-tocopherol therapy, especially at high doses, has been shown to decrease the release of proinflammatory cytokines, decrease chemokine IL-8 and plasminogen activator inhibitor-1 levels, and decrease adhesion of monocytes to endothelium. In addition, alpha-tocopherol has been shown to decrease C-reactive protein levels in patients with cardiovascular disease and in those with risk factors for cardiovascular disease. The mechanisms that account for non-antioxidant effects of alpha-tocopherol include the inhibition of protein kinase C, 5-lipoxygenase, tyrosine-kinase, and cyclooxygenase-2. Based on its antioxidant and anti-inflammatory activities, alpha-tocopherol (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.1
Animal Studies
Oxidative stress may involve overproduction of hydrogen peroxide, which can generate highly cytotoxic hydroxyl radicals in the presence of ferrous ions. A study with mice demonstrated that tricomponent antioxidant therapy (TCAT), an association of pyruvate, vitamin E, and fatty acids, provides neuronal and cardiac protection in oxidative stress ex vivo. Analysis of the contribution of TCAT components to neuroprotection showed that while vitamin E and fatty acids enhanced pyruvate action, they displayed no neuroprotection by themselves. In contrast, vitamin E and fatty acids were as potent as pyruvate in an in vitro cell-free assay, indicating that TCAT protection is modulated by the existence of the cellular membrane barriers. The results indicate that TCAT could have a broad therapeutic utility in neurological and cardiac injuries associated with oxidative stress. The protective action of TCAT can surpass that of its components, revealing a benefit of the association.7
Clinical Trials
Two significant clinical trials were published in 2005 suggesting that the use of vitamin E in cardiovascular disease needs to be reconsidered.
A meta-analysis examining the dose-response relationship between vitamin E supplementation and total mortality used data from 19 randomized, controlled trials (n = 135,967). Nine of these trials tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The vitamin E dosages ranged from 16.5 IU/d to 2,000 IU/d (median 400 IU/d). The Cochrane Clinical Trials Database reviewed citations of published reviews and meta-analyses from 1966 to 2000. Nine of 11 trials testing high-dosage vitamin E (≥ 400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E vs. control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% confidence interval [CI] 3-74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (95% CI -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk at dosages greater than 150 IU/d. The conclusion of this study is that high-dosage (≥ 400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.8
The Heart Outcomes Prevention Evaluation (HOPE) trial, conducted between December 21, 1993, and April 15, 1999, was a 19-country, prospective randomized trial that found the ACE-inhibitor Ramipril, but not vitamin E, significantly reduced the risk of future cardiovascular events in a high-risk population of men and women.9
A significant Canadian study evaluated whether long-term vitamin E supplementation decreases the risk of cancer, cancer death, and major cardiovascular events. HOPE-The Ongoing Outcomes (HOPE-TOO), which extended the HOPE trial from April 16, 1999, to May 26, 2003, was a randomized, double-blind, placebo-controlled international trial of patients age 55 years or older with vascular disease or diabetes mellitus. Of the initial 267 HOPE centers that had enrolled 9,541 patients, 174 centers participated in the HOPE-TOO trial.10 Of 7,030 patients enrolled at the participating centers, 3,994 continued to take the study intervention (916 were deceased at the beginning of the extension, 1,382 refused participation, and 738 agreed to passive follow-up). Median duration of follow-up was 7.0 years. Patients were given a daily dose of natural source vitamin E (400 IU) or matching placebo. Primary outcomes included cancer incidence, cancer deaths, and major cardiovascular events (myocardial infarction, stroke, and cardiovascular death). Secondary outcomes included heart failure, unstable angina, and revascularizations. Among all HOPE patients, there were no significant differences in the primary analysis: for cancer incidence, there were 552 patients (11.6%) in the vitamin E group vs. 586 (12.3%) in the placebo group (relative risk [RR] 0.94, 95% CI 0.84-1.06; P = 0.30); for cancer deaths, 156 (3.3%) vs. 178 (3.7%), respectively (RR 0.88, 95% CI 0.71-1.09; P = 0.24); and for major cardiovascular events, 1,022 (21.5%) vs. 985 (20.6%), respectively (RR 1.04, 95% CI 0.96-1.14; P = 0.34). Patients in the vitamin E group had a higher risk of heart failure (RR 1.13, 95% CI 1.01-1.26; P = 0.03) and hospitalization for heart failure (RR 1.21, 95% CI 1.00-1.47; P = 0.045). Similarly, among patients enrolled at the centers participating in the HOPE-TOO trial, there were no differences in cancer incidence, cancer deaths, and major cardiovascular events, but higher rates of heart failure and hospitalizations for heart failure. The study concluded that long-term vitamin E supplementation does not prevent cancer or major cardiovascular events and may increase the risk of heart failure in patients with vascular disease or diabetes mellitus.
Finally, new information and a commentary on landmark trials relevant to the pathophysiology, prevention, and treatment of heart failure was presented at the 2005 American College of Cardiology meeting. Of significance to this topic is the fact that the Women's Health Study showed no benefit of vitamin E supplementation or aspirin in the primary prevention of cardiovascular disease.11
A Polish pilot trial with 800 patients was designed to test the effects of antioxidant vitamins C and E on the clinical outcome of patients with acute myocardial infarction.12 This randomized pilot trial concluded that supplementation with antioxidant vitamins is safe and seems to positively influence the clinical outcome of patients with acute myocardial infarction.
Researchers at the University of Maryland measured flow-mediated dilation by high-resolution brachial ultrasound in 61 women who participated in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a randomized controlled trial.13 There were no significant differences in the baseline demographics of women receiving hormone therapy (0.625 mg/d of conjugated equine estrogen plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy) or placebo, or vitamins (400 IU vitamin E and 500 mg vitamin C twice daily) or placebo. Baseline flow-mediated dilation was impaired in all subjects. Neither hormone therapy nor antioxidant vitamins improved flow-mediated dilation. In univariate and multivariate analysis, neither hormone therapy nor antioxidant vitamins were associated with flow-mediated dilation. Women with established coronary artery disease have impaired flow-mediated vasodilation of the brachial artery that does not improve after three months or up to 34 months of treatment with postmenopausal hormone therapy or antioxidant vitamins.
Safety and Cautions
Studies involving the safety of vitamin E supplementation are ongoing, so there is still controversy about the long-term safety of vitamin E supplementation. The National Institutes of Health, Office of Dietary Supplements is updating its recommendations for the vitamin E fact sheet to include the results of recently published meta-analyses and clinical trials. A new version will be available shortly.14
Practitioners should be aware that the clinical trials that tested high dosages of vitamin E involved adults with chronic diseases, so these findings may not be generalizable to healthy adults. In addition, some trials evaluated multivitamin combinations. The findings do not clearly establish the lowest dosage of supplementation that is associated with increased mortality risk. In general, supplements should be no greater than 400 IU/d.
Side effectsincluding skeletal muscle weakness; headache; blurred vision; fatigue; nausea; diarrhea; intestinal cramps; gonadal dysfunction; increased serum creatine kinase, cholesterol, and triglycerides, decreased serum thyroxine; increased urinary estrogens and androgens; creatinuria; sterile abcesses; thrombophlebitis; and contact dermatitishave been reported when taking excessive doses for prolonged periods of time.15
Conclusion and Recommendation
The consumption of adequate levels and proper balance of essential nutrients is critical for maintaining health. The challenge is to discover the right amounts. The identification, isolation, and purification of nutrients in the early 20th century raised the possibility that optimal health outcomes could be realized through nutrient supplementation. Recent attempts using vitamin E supplementation for cardiovascular disease have been disappointing. In addition, previously unrecognized risks caused by nutrient toxicity and nutrient interactions have surfaced during intervention studies. The most promising data in the area of nutrition and positive health outcomes relate to dietary patterns, not nutrient supplements. These data suggest that other factors in food or the relative presence of some foods and the absence of other foods are more important than the level of individual nutrients consumed.16 (See Tables 1 and 2 for food sources of vitamin E.)
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Until recently, vitamin E was thought to be a most promising antioxidant supplement in the fight against cardiovascular disease. New research brings evidence for little or no benefit from vitamin E intake in those patients with established heart disease. Consequently, supplements should be no greater than 400 IU per day in this subset of patients. The benefits of a well-balanced, whole food diet should be promulgated.
References
1. Singh U, et al. Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr 2005;2:151-174.
2. Sasser H. Faltering promise: Vitamin E and heart disease. Altern Med Alert 2004;7:101-104.
3. Traber MG. Does vitamin E decrease heart attack risk? Summary and implications with respect to dietary recommendations. J Nutr 2001;131:395S-397S.
4. Heinecke JW. Is the emperor wearing clothes? Clinical trials of vitamin E and the LDL oxidation hypothesis. Arterioscler Thromb Vasc Biol 2001;21:1261-1264.
5. Inokuchi H, et al. Anti-angiogenic activity of tocotrienol. Biosci Biotechnol Biochem 2003;67:1623-1627.
6. Theriault A, et al. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis 2002;160:21-30. Erratum in: Atherosclerosis 2002;164:389.
7. Paquin J, et al. Neuroprotective and cardioprotective actions of an association of pyruvate, vitamin E and fatty acids. Arzneimittelforschung 2005;55:359-369.
8. Miller ER 3rd, et al. Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46. Epub 2004 Nov 10.
9. McQueen MJ, et al. The HOPE (Heart Outcomes Prevention Evaluation) Study and its consequences. Scand J Clin Lab Invest Suppl 2005;240:143-156.
10. Lonn E, et al; HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. JAMA 2005;293:1338-1347.
11. Cleland JG, et al. Clinical trials update from the American College of Cardiology meeting: CARE-HF and the remission of heart failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER. Eur J Heart Fail 2005;7:931-936.
12. Jaxa-Chamiec T, et al; MIVIT Trial Group. Antioxidant effects of combined vitamins C and E in acute myocardial infarction. The randomized, double-blind, placebo controlled, multicenter pilot Myocardial Infarction and VITamins (MIVIT) trial. Kardiol Pol 2005;62:344-350.
13. Kelemen M, et al. Hormone therapy and antioxidant vitamins do not improve endothelial vasodilator function in postmenopausal women with established coronary artery disease: A substudy of the Women's Angiographic Vitamin and Estrogen (WAVE) trial. Atherosclerosis 2005;179:193-200. Epub 2004 Dec 28.
14. National Institutes of Health. Office of Dietary Supplements. Vitamin E fact sheet. Available at: http://ods.od.nih.gov/factsheets/vitamine.asp#h7. Accessed Dec. 18, 2005.
15. Shannon MT, et al. Health Professionals Drug Guide. Upper Saddle River, NJ: Prentice Hall; 2002.
16. Lichtenstein AH, Russell RM. Essential nutrients: Food or supplements? Where should the emphasis be? JAMA 2005;294:351-358.
Keegan L. Vitamin E and cardiovascular disease. Altern Ther Womens Health 2006;8(2):9-13.Subscribe Now for Access
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