Heart Disease
(See Table 1 for a summary of the following heart related studies.)
Blockage of an artery leading to heart tissue starves the affected area of vital oxygen and nutrients. Moreover, free radicals proliferate in such tissues, accelerating tissue damage and death. The region is called an myocardial infarction, and, if large enough, may disrupt or even stop the regular rhythm of the heart. That is, a heart attack may ensue. If the patient is given immediate care, he may recover and hopefully continue to live. However, massive free radical damage may have already occurred, some of which will never completely heal.
In this study from the University of Buenos Aires, Argentina, blood samples were taken from 120 patients who had suffered acute myocardial infarction. Creatine phosphokinase levels were measured. (Creatine phosphokinase is an enzyme which occurs only in heart tissue. When heart tissue dies, this enzyme is released into the blood. Thus, the level of this enzyme in the blood reflects how much heart tissue death had occurred: the higher the level, the more tissue death.) Vitamin E and beta-carotene levels were also measured, and an average value determined. The patients were categorized as having lower than or higher than average vitamin E levels, and lower than or higher than average beta-carotene levels. Those with lower than average vitamin E levels were found to have 47% greater creatine phosphokinase levels after 24 hours, signifying significantly greater damage in this group. After 48 hours, they suffered 75% higher levels. There was no difference in creatine phosphokinase levels in relation to beta-carotene levels. Electrocardiogram measurements also indicated less heart damage in those with higher than average vitamin E levels.
The researchers conclude that their results are consistent with the hypothesis that adequate levels of vitamin E offers protection against free radical destruction during acute myocardial infarction.
Carrasquedo, F., Glanc, M., Fraga, C. Tissue Damage in Acute Myocardial Infarction: Selective Protection by Vitamin E. Free Radical Biology & Medicine, Vol. 26, Nos. 11/12, pp.1587-1590, 1999.
While many vitamin E investigations involve younger subjects, few have examined the effect of supplementation specifically in the elderly. In this study from the National Institute on Aging in Bethesda, Maryland, 11,178 elderly subjects between 67 to 105 years of age participated in the Established Populations for Epidemiologic Studies of the Elderly. This study took over one decade to complete (1984-1993). The subjects reported their vitamin supplement usage and were classified as users of vitamin E alone, vitamin C alone, vitamin E and C together, other vitamins, multiple vitamin formulations, or no supplements. In all, 3490 subjects died during the follow-up period, and statistical analysis of the results yielded the following observations:
- Vitamin E users had 2/3 the risk of mortality due to all causes.
- Vitamin E users had 1/2 the risk of mortality due to heart disease.
- Vitamin E users had better than 1/2 the risk of mortality due to cancer.
- Use of both vitamin E and C provided the same level of risk reduction as vitamin E alone.
- Vitamin C use alone did not reduce mortality risk.
- Multiple vitamin formulation use did not reduce mortality risk.
These results persisted even after adjusting the data for other health habits, such as alcohol use, tobacco smoking, aspirin use, and medical conditions, although the researchers acknowledge other factors such as better health habits and access to superior health care of some subjects may have contributed positively. Unfortunately, information on the dosage amount or frequency of supplementation of the vitamins was not accessed. The authors conclude, "The results of our analyses are consistent with the hypothesis that use of the antioxidant supplements, vitamin E along with vitamin C, may reduce the risk of all-cause and coronary heart disease mortality. Further research using prospective data and trials in the elderly is warranted."
Losonczy, K., Harris, T., Havlik, R. Vitamin E and Vitamin C Supplement Use and Risk of All-Cause and Coronary Heart Disease Mortality in Older Persons: The Established Populations for Epidemiologic Studies of the Elderly. American Journal of Clinical Nutrition, Vol.64, pp.190-6, 1996.
This study from the University Medical School, Rotterdam, Netherlands examined 4,802 subjects, ages 55 to 95, who at the beginning of the study period, had no myocardial infarction. Every year for 4 years, each participant filled out a self- administered questionnaire involving 170 foods in 13 food groups and was interviewed by a dietitian. The diets were then analyzed in terms of nutritional content by using the computerized Dutch Food Composition Table. It is important to note that the nutritional supplement usage was not included in the study. Only the nutrients as found naturally in the diet were considered. The subjects' heart health were carefully documented before and after the study period, and the cause of death of those who deceased were determined by hospital records.
At the end of the study, the researchers observed the following:
- High dietary beta-carotene intakes protects against cardiovascular disease.
- High dietary values of vitamin E and vitamin C were not associated with decreased risk of developing myocardial infarction.
The researchers acknowledged the possibility that participants inaccurately reported their dietary intake as a weakness of their study. Moreover, while beta-carotene's apparent protective effect may be due to its antioxidant capacity, it may also be a present in foods such as fruits and vegetables which are rich in other compounds which actively contribute to the reduction in risk. Again, this study focuses on nutritive elements found naturally in the diet, not supplement intake. Thus, it is somewhat limited to the accuracy of the nutritive data available at the time, as well as on the accuracy of the reporting of foods in the diet by participants.
Klipstein-Grobusch, K., Geleijnse, J., den Breeijen, J., et al, Dietary Antioxidants and Risk of Myocardial Infarction in the Elderly: the Rotterdam Study. American Journal of Clinical Nutrition, Vol 69, pp.261-6, 1999.
In this study from the Universities of Laval and Montreal, Quebec, 4,576 Canadian men were examined for the incidence of ischemic heart disease and suspected risk factors. The study began in 1974, and in 1985, a follow-up was conducted and one of the questions on the survey was, "Did you take vitamin supplements during the past 12 months." Of the 2,313 respondents, 542 (23%) reported they did. Of these, 455 men gave more detailed information concerning what kinds of supplements they took, the amount, and duration. The type of vitamins included vitamins A, B complex, C, D, and E. The subjects were given a thorough medical examination to document the status of their heart health. Five years later in 1990-91, another follow-up was conducted and similar medical exams were performed to access heart problems which may have developed. Among the 2,313 original participants, 113 had deceased, and the cause of death was determined from death certificates and medical records. The results were statistically analyzed and the following observations were made:
- Compared to men who did not take vitamins from supplements, those who did had 1/3 the risk of dying from ischemic heart disease and 1/2 the risk of developing a myocardial infarction.
- A modest lowering of risk for angina and first ischemic heart disease event was enjoyed by those taking vitamins.
- Vitamin C intake from supplements significantly lowered the risk of death from ischemic heart disease.
- Vitamin E intake from supplements significantly lowered the risk of new ischemic heart disease events in those who developed the disease.
- The inverse association between ischemic heart disease risk and vitamin E intake was the most consistent.
The authors caution that the results, while encouraging, could be complicated by other factors which the study did not examine, such as other health habits by supplement takers which could contribute to the apparent protection against heart disease.
Meyer, F., Bairati, I., Dagenais, G. Lower Ischemic Heart Disease Incidence and Mortality Among Vitamin Supplement Users. Canadian Journal of Cardiology, Vol. 12, Issue 10, pp.930-4. 1996.
To test whether vitamin E supplementation could help patients with pre-existing cardiovascular disease or diabetes, the Heart Outcomes Prevention Evaluation (HOPE) study was conducted in Canada with 9,541 patients over age 55. Because of their medical history, the subjects were at high risk for cardiovascular events, which include heart attack, stroke, angina, heart failure, revascularizations, limb amputation, and death. The subjects were divided into two groups and, in a double-blind, randomized fashion, assigned either 400 IU per day of vitamin E (from "natural sources") or a placebo, and in addition, either 10 mg per day of the drug ramipril or another placebo. (Ramipril is a pharmaceutical classified as an angiotensin-converting-enzyme inhibitor. Its primary action is to help lower blood pressure.)
The subjects participated in the study for 4 to 6 years (a mean of 4.5 years). No significant adverse effects due to the vitamin E or ramipril were reported. Cardiovascular events were carefully documented and statistically analyzed to determine relative risk values. Unfortunately, those taking vitamin E enjoyed no reduction in risk compared to placebo, while those taking ramipril had a significant risk reduction of 22 percent. The study was terminated before the originally planned time by an independent safety board which determined that enough data had been collected to make a reasonable, early conclusion.
The researchers note that the results must be interpreted carefully. First, the subjects involved in the study already suffered from advanced stages of vascular disease. Possibly, the dosage of vitamin E was insufficient in such cases. Moreover, some have suggested that at least 5 years of supplementation is needed for the full benefits of vitamin E to be seen in these cases, so perhaps the present study's duration was not long enough. On the other hand, some studies show benefit within 2 years, so an equally compelling case can be made that the study duration was sufficient.
The authors also point out that vitamin E may need to be taken with other antioxidants for full benefit. Interactions between vitamin E, vitamin C, beta-carotene, and selenium exist in a complex antioxidant chain, and providing a singe nutrient without the other factors may not effectively enhance the protective system.
The Heart Outcomes Prevention Evaluation Study (HOPE) Investigators. Vitamin E Supplementation and Cardiovascular Events in High-Risk Patients. New England Journal of Medicine. Vol. 342, pp.154-60, 2000.
Omega-3 polyunsaturated fatty acids are found naturally in food sources such as fish and have been found to be highly beneficial to cardiovascular health. Researchers believe two fatty acids in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), play significant roles in reducing the risk of heart disease. Numerous studies suggest that one of the best ways to protect heart health is to eat more fish or take fish oil supplements. Whether fish oils and vitamin E could help patients with pre-existing heart disease was addressed in this large-scale study from Italy.
The study group involved 11,324 patients with pre-existing myocardial infarction. Each subject was randomly assigned to one of four groups. One group received capsules of 850-882 mg EPA/DHA (average ratio of EPA/DHA was 1:2). Another received 300 mg of vitamin E ("synthetic alpha-tocopherol"). The third group received both the EPA/DHA and the vitamin E. The fourth group was the control group, which received neither supplement. The study lasted 3.5 years and the patients' cardiovascular events (death, non-fatal myocardial infarction and strokes) were monitored.
Compared to the control group, those taking the EPA/DHA enjoyed significant risk reduction (10% to 30%) for all cardiovascular events, with the greatest reduction in risk due to cardiovascular death (30%). However, no benefit was observed in those taking vitamin E. While a modest decrease in risk of 11% due to cardiovascular death was found in the vitamin E group, it was not statistically significant.
The researchers suggest perhaps the duration of the study and/or the amount of vitamin E given were inadequate for more positive results. However, the same considerations would apply to the EPA/DHA treatment, which did show a positive outcome. For now, they conclude their study suggests that patients with myocardial infarction may benefit from increased intake of omega-3 polyunsaturated fatty acids.
GISSI-Prevenzione Investigators. Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E After Myocardial Infarction: Results of the GISSI-Prevenzione Trial. Lancet, Vol. 354, pp.447-55, 1999.
Patients suffering from serious kidney disease require long-term hemodialysis, where a dialysis machine substitutes for the kidney to filter the blood of waste products. Such patients have a death rate many times greater than the general population, and 40% die of cardiovascular disease. The levels of free radicals in these patients were found to be much greater than normal, suggesting the higher mortality rates may be due to increased free radical damage.
A randomized, placebo-controlled, clinical trial from Tel Aviv University, Israel, examined whether the antioxidant benefits of vitamin E supplementation would prevent death due to heart disease in 196 hemodialysis patients with pre-existing cardiovascular disease. Ninety-seven patients were each given 800 IU/day of vitamin E ("natural alpha-tocopherol"), while another 99 patients, a placebo. The patients were followed for nearly two years. At the end of the study period, 15 patients in the vitamin E group died due to cardiovascular disease, whereas 33 died in the placebo group. Of these, 5 in the vitamin E group died of myocardial infarctions, compared to 17 in the placebo group. While the differences in the numbers of secondary conditions such as stroke, angina, and peripheral vascular disease were not statistically significant between the two groups, the numbers were consistently less in the vitamin E group.
The researchers conclude that while their study is not definitive and recommendations regarding vitamin E supplementation in hemodialysis patients has yet to be established, the results strongly suggest that vitamin E supplementation helps reduce risk of heart attack, stroke, and angina in hemodialysis patients with cardiovascular disease.
Boaz, M., Smetana, S., Weinstien, T., et al. Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE): Randomized Placebo-Controlled Trial. The Lancet, Vol 356, p.1213-, Oct 7, 2000.
Vitamin E's protective effects may exceed just its antioxidant properties. The vitamin has a direct molecular effect on a certain enzyme in heart muscle cells. The enzyme, called protein kinase C (PKC), is responsible for inducing cell proliferation and growth. In atherosclerosis (abnormal blood vessel thickening), such excessive cell activity is harmful and may lead to blockage of the vessel with obviously unhealthy consequences. Vitamin E was found to inhibit PKC, and thus potentially help lessen cell proliferation and growth.
In this in vitro (cell culture) study from the University of Genoa, Italy, vitamin E in two forms, RRR-alpha- and RRR-beta- tocopherol, was added to rat smooth-muscle cells. (The "RRR" specify specific steroisomers of the molecules. All naturally occurring vitamin E in foods is RRR-alpha-tocopherol.) Alpha-tocopherol was found to inhibit PKC activity. Moreover, the inhibition was time- and dose-dependent, indicating that the effect has a direct molecular basis. More specifically, alpha-tocopherol selectively affected the alpha form of PKC by activating another enzyme PP2A phosphatase, which deactivates PKC. On the other hand, beta-tocopherol was not found to effectively inhibit PKC.
Thus, in addition to its antioxidant potential, vitamin E may have specific roles in regulating enzymes such as PKC, ultimately inhibiting excessive cell proliferation and growth. This augments our understanding about how vitamin E helps prevent cardiovascular disease.
Ricciarelli, R., Tasinato, A., Clement, S. Ozer, N., Boscoboinik, D., Angelo, A. Alpha-tocopherol Specifically Inactivates Cellular Protein Kinase C Alpha by Changing Its Phosphorylation State. Biochemistry. Vol. 334, pp.243-9. 1998.
During the initial stages of atherosclerosis, the damaged cells in a blood vessel wall signals immune cells called monocytes to adhere to the damaged regions and become foam cells. This is the body's natural response to cell wall injury, but it can become counterproductive if too many monocytes respond. The excessive accumulation of monocytes on a blood vessel wall may result in a plaque and restrict blood flow through the vessel. Another role vitamin E may play in helping the heart is by making monocytes less sticky and potentially helping to avoid plaque build-up.
In the in vitro study from the USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Maryland, by Martin, et al, vitamin E in the form of alpha-tocopherol reduced monocyte adhesion to human aortic cells in a dose-dependent manner. Incubation of cells in vitamin E at 15, 19, and 37 micromol per liter resulted in 6%, 37%, and 69% reduction in monocyte adhesion respectively. On a molecular level, vitamin E was found to specifically inhibit the production of intracellular cell adhesion molecule (ICAM-1) which a damaged cell would release to increase its stickiness. Minimizing expression of ICAM-1 discourages monocytes from sticking to the cells.
In the related in vitro study from the University of Texas Southwestern Medical Center, Dallas, Texas, by Islam, et al, similar experiments showed vitamin E to significantly decrease adhesion of monocytes to cells. The authors conclude, "These studies provide evidence for the beneficial effects of alpha-tocopherol on a crucial early event in atherosclerosis ... This beneficial effect of alpha-tocopherol further strengthens its evolving role as an adjunctive therapy in the management of atherosclerosis ... These and other studies support the concept that the possible beneficial effects of alpha-tocopherol supplementation in reducing coronary artery disease can be attributed to its combined effects on inhibition of the oxidative modification of lipoproteins and its intracellular effects on cells critical in atherogenesis, such as monocytes."
Martin, A., Foxall, T., Blumberg J., Meydani, M. Vitamin E Inhibits Low-Density Lipoprotein-Induced Adhesion of monocytes to Human Aortic Endothelial Cells in Vitro. Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 17, Issue 3, pp. 429-36, 1997.
Islam, K., Devaraj, S., Jialal, I. Alpha-Tocopherol Enrichment of Monocytes Decreases Agonist-Induced Adhesion to Human Endothelial Cells. Circulation. Vol. 98, pp. 2255-61. 1998.
Early in the development of atherosclerosis, white blood cells called macrophages engulf low-density lipoproteins (LDL) which have been oxidized (damaged by free radicals). Then, they may stick to the surface of an artery, potentially causing an obstruction to blood flow. So, if oxidation of LDL is prevented, macrophages may not react and thus not clog arteries. Then, atherosclerosis can be prevented. Antioxidants such as vitamin E can effectively neutralize free radical damage and possibly be an important element in the prevention and treatment of diseases such as athersclerosis.
In this study from the University La Sapienza, Rome, Italy, LDL was radioactively tagged and injected into 7 patients with existing heart disease. Three of these patients had been taking 900 mg/d vitamin E for 4 weeks. In patients who did not take vitamin E, tagged LDL was found to accumulate rapidly in atherosclerotic cells. On the other hand, in those who took vitamin E, tagged LDL was not detected. The results indicate that macrophage uptake of LDL is usually quite rapid, but vitamin E helps prevent the normal process, offering some protection against further atherosclerotic buildup.
While the study population of this study was small, the results were clear-cut between the two groups. Further investigation into the details of how vitamin E protects against LDL uptake by macrophages is warranted.
Iuliano, L., Mauriello, A., Sbarigia, E., Spagnoli, L., Violi, F. Radiolabeled Native Low-Density Lipoprotein Injected Into Patients With Carotid Stenosis Accumulates in Macrophages of Atherosclerotic Plaque: Effect of Vitamin E Supplementation. Circulation. Vol. 101, pp.1249-54, 2000.
As described previously, the immune response to oxidized LDL is believed to play a significant role in the genesis and progression of coronary artery disease such as atherosclerosis. Vitamin E may protect LDL and help prevent such coronary artery disease. The levels of vitamin E in LDL may thus provide an important measurement of heart health.
In this study from Karolinska Hospital, Stockholm, Sweeden, the vitamin E levels in LDL of 64 men with myocardial infarction and 35 age-matched healthy men were measured. The LDL vitamin E levels were significantly lower in the heart patients compared to the healthy controls. Moreover, the worse the arterial disease a patient suffered, the lower his LDL vitamin E levels. Thus, an inverse relationship was found between severity of coronary artery disease and vitamin E levels in LDL.
On the other hand, how readily LDL could be oxidized in vitro did not correlate with the severity of coronary artery disease. That is, patients with more severe coronary artery disease did not necessarily have more easily oxidized LDL. Apparently in this instance, vitamin E's protective effect is due to some mechanism other than preventing oxidation of LDL. The researchers surmise that low levels of vitamin E may accelerate cell death, causing a buildup of dead cells which lead to coronary artery disease, or that high levels of vitamin E suppress expression of other cellular factors which may attract an immune response. The mechanism requires further study to elucidate, but the evidence indicates vitamin E's beneficial role may go beyond its antioxidant potential.
Regnstrom, J., Nilsson, J., Moldeus, P., et al. Inverse Relation Between the Concentration of Low-Density-Lipoprotein Vitamin E and Severity of Coronary Artery Disease. American Journal of Clinical Nutrition, Vol. 63, pp.377-85, 1996.
In this study from the Southwestern Medical Center in Dallas, Texas, 24 healthy men were divided into two groups of 12. In one group, each received a placebo, while in the other, 800 IU/day of vitamin E ("alpha-tocopherol"). No reports of side effects were reported during the study. After 12 weeks, blood samples were taken and vitamin E levels in the plasma and LDL measured. The supplemented group enjoyed levels 3 to 4 times greater than the control group. Moreover, in vitro tests showed both susceptibility of LDL to oxidation and LDL oxidation rate to be significantly lower in those who took the vitamin E.
Jialal, I., Grundy, S. Effect of Dietary Supplementation with Alpha-Tocopherol on the Oxidative Modification of Low Density Lipoprotein. Journal of Lipid Research, Vol 33, pp. 899-906, 1992.
Another study from the Southwestern Medical Center in Dallas, Texas, involved 48 non-smoking, healthy men who were assigned to 6 groups. Each group was randomly assigned to receive placebo or different amounts of vitamin E ("alpha-tocopherol"): 60, 200, 400, 800, and 1200 IU per person, per day. No side effects due to either placebo or vitamin E were reported.
At the end of the 8 week study, blood samples were taken from all participants. The results showed that the plasma, lipid, and LDL levels of vitamin E increased in a dose-dependent manner, that is, the higher the vitamin E intake, the higher the resulting vitamin E levels in the body.
The susceptibility of LDL to oxidation was also measured in vitro by measuring the formation of free radical by-products using a standard test, thethiobarbituric acid‚reacting substances (TBARS) assay. Compared to values at thebeginning of the study, the LDL susceptibility to oxidation of those taking placebo, 60 or 200 IU/day vitamin E did not change. However, a significant decrease was observed for those taking 400 IU/day or more, in a dose-dependent manner. The researchers conclude that at least 400 IU/day of vitamin E is necessary to significantly reduce susceptibility of LDL to oxidation.
Jialal, I. Fuller, C., Huet, B. The Effect of -Tocopherol Supplementation on LDL Oxidation. Arteriosclerosis, Thrombosis, and Vascular Biology. Vol.15, pp. 190-198,1995.
Besides its antioxidant potential, vitamin E may have other significant, health-promoting functions in cells. For instance, when immune cells respond to oxidized LDL during the initial stages of atherosclerosis, they release inflammatory agents called cytokines which aggravate the situation by signaling more immune cells to the area. Moreover, part of the immune response involves production of free radicals called superoxides, meant to destroy diseased tissue, but may harm normal cells as well, ultimately making the situation worse. The present study from the University Hospital Nijmegen, Netherlands, suggests vitamin E effectively quenches production of superoxides and cytokines by these immune cells.
For 6 weeks, 12 men with hypertriglyceridemia (high levels of blood fats) and 8 healthy men where given 600 IU vitamin E (natural-source "RRR-alpha-tocopherol") per day. Vitamin E, superoxide radical, and cytokine production by immune cells from blood samples were measured in vitro before and after the supplementation period. After the trial period, vitamin E levels increased 2 to 3 times in plasma and 2 times in LDL. While superoxide and cytokine production were equivalent in both hypertriglyceridemic and healthy subjects, they were significantly reduced after vitamin E supplementation. The results point to the importance of vitamin E as both an antioxidant as well as an anti-inflammatory agent.
van Tits, L., Demacker, P., Graaf, J., Hak-Lemmers, H., Stalenhoef, A. Alpha-Tocopherol Supplementation Decreases Production of Superoxide and Cytokines by Leukocytes ex vivo in Both Normolipidemic and Hypertriglyceridemic Individuals. American Journal of Clinical Nutrition. Vol. 71, pp.458-64, 2000.
To test whether vitamin E reduces risk of myocardial infarction in patients with coronary atherosclerosis, researchers from Cambridge University, United Kingdom, conducted a double-blind, randomized study involving 2,002 patients who had been recently diagnosed with atherosclerosis. The subjects were divided into three groups. The first group of 546 patients received 800 IU vitamin E ("free 2R,4'R,8'R-alpha-tocopherol from natural sources in soya oil") daily; the second group of 489 patients, 400 IU per day; and the control group of 967, placebo. The patients were then followed up to 3 years, and the incidence of cardiovascular death with non-fatal myocardial infarction as well as non-fatal myocardial infarction alone was documented.
In those who received vitamin E, plasma concentrations of vitamin E increased, verifying that the vitamin had been effectively absorbed. The placebo group showed no rise in vitamin E plasma levels. Vitamin E significantly reduced the risk of patients having the combined incidence of cardiovascular death and non-fatal myocardial infarction by 47%. This result was mostly due to a 77% reduction in risk of non-fatal myocardial infarction. Vitamin E apparently did not reduce risk of cardiovascular death alone, since the same numbers of patients in all groups died due to cardiovascular events. No dose-dependent risk reduction was found. Compared with placebo, the total mortality was slightly greater in the vitamin E group (3.5% vs 2.7%), but this was not statistically significant.
The authors conclude that "in patients with angiographically proven symptomatic coronary atherosclerosis, alpha-tocopherol treatment substantially reduces the rate of non-fatal myocardial infarction, with beneficial effects apparent after 1 year of treatment. The effect of alpha-tocopherol treatment on cardiovascular deaths requires further study."
Stephens, N., Parsons, A., Scholfield, P., et al. Randomised Controlled Trial of Vitamin E in Patients with Coronary Disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet, Vol. 347, pp.781-86, 1996.
Just as macrophages activated by uptake of oxidized LDL may clog coronary arteries and cause heart disease, they may undergo the same atherosclerotic processes in blood vessels in the brain to cause stroke. Thus, antioxidant nutrients can potentially lower the risk of stroke by protecting LDL.
In the Iowa Women's Health Study, 41,836 post-menopausal women ages 55 to 69 responded to questions concerning their medical history, health habits, reproductive history, and dietary intake, including vitamin supplements. For this particular analysis, 34,392 women formed the study population, the others being excluded for having heart disease or consuming less than 30 of 127 foods on the dietary intake survey. Nutritional content of the foods reported in the survey was determined by data from the US Department of Agriculture. After 11 years, a follow-up was conducted. During this time, 215 deaths from stroke occurred. Statistical analysis found the following:
- The greater the intake of the most concentrated vitamin E foods (mayonnaise, nuts, margarine), the more reduction in risk of stroke (up to 45% risk reduction).
- Other dietary antioxidants such as vitamin C and beta-carotene did not show similar risk reduction.
- Supplemental vitamin E or C were not found to reduce risk.
The researchers point out that they did not collect information regarding the duration of supplement use, which may be an important reason why no risk reduction was found in those reporting taking supplements.
Yochum, L., Folsom, A., Kushi, L. Intake of Antioxidant Vitamins and Risk of Death from Stroke in Postmenopausal Women. American Journal of Clinical Nutrition. Vol. 72, pp.476-83, 2000.
Angina pectoris, or heart pain, is the mildest and frequently the first sign that something is wrong with the heart. In this large-scale, double-blind, randomized, controlled trial from the National Public Health Institute, Helsinki, Finland, 29,133 male smokers (more than 5 cigarettes daily) ages 50 to 69 were monitored for the incidence of angina pectoris. After excluding the subjects who had some form of heart disease and/or angina in the past, 22,269 remained to form the study population. Of these, 5,570 men received 50 mg/day vitamin E (synthetic "dl-alpha tocopherol acetate"); 5602 men, 20 mg/day beta-carotene; 5548 men, both vitamin E and beta-carotene; and 5549 men, placebo. Thus, about half received vitamin E and half, beta-carotene.
The subjects were followed for an average of 4.7 years, during which 1,983 new cases of angina were reported on an annually administered World Health Organization (Rose) Chest Pain Questionnaire. Upon statistical analysis, the researchers found that those taking vitamin E had a modest 9% reduction in risk of developing angina, while those taking beta-carotene had a slight increase in angina risk, though not statistically significant. No extra benefit was observed in those taking both vitamin E and beta-carotene. In fact, the researchers speculate that in this case, beta-carotene seemed to act as a pro-oxidant, while vitamin E neutralized its effects, thus canceling out any protective potential. While the results of this and other studies are consistent with that hypothesis, it has not been conclusively demonstrated to be true. Other factors may be involved, and further research is needed to elucidate the mechanism in detail.
Noteworthy, the amount of vitamin E used in this study was comparatively small, equivalently around 37 IU alpha-tocopherol per day. Moreover, the study population consisted of older, heavy smokers in whom free radical damage may have accumulated over a lifetime. The authors acknowledge that the 4.7 years of the study "is a relatively short time in the natural history of evolving atherosclerosis." On the other hand, other studies suggest 2 years of supplementation is sufficient to begin seeing positive effects. Nevertheless, positive results in the difficult conditions of the present study is remarkable and encourages more research to better understand the optimal dosage and duration of supplementation.
Rapola, J., Virtamo, J., Haukka, J., et al. Effect of Vitamin E and Beta Carotene on the Incidence of Angina Pectoris. Journal of the American Medical Association. Vol. 275, pp.693-8, 1996.
The results from epidemiological (large population group) studies are often difficult to interpret, because many factors and uncertainties must be taken into account before valid conclusions can be drawn. Confidence in findings of a particular study increases when results from other studies support them.
In this review paper, the author compares the findings of 6 major epidemiological studies regarding vitamin E intake and risk of coronary heart disease. The study populations include:
87,245 female nurses (Stampfer, et al, N Engl J Med 1993;328:1444-9)
19,687 Iowa women (Kushi, et al, N Engl J Med 1996; 334:1156-62)
17,916 male health professionals (Rim, et al, N Engl J Med 1993;328:1450-6)
11,178 US residents of four areas (Losonczy, et al, Am J Clin Nur 1996;64:190-6)
2,748 Finnish men and
2,385 Finnish women (Knekt, et al, Am J Epidemiol 1994;139:1180-9)
2,313 Quebec City men (Meyer, et al, Can J Cardiol 1996;12:930-4).
Also included in the analysis were a few large-scale, randomized, controlled trials in which subjects were given vitamin E:
29,133 Finnish male smokers (ATBC, N Engl J Med 1994; 330:1029-35)
2,002 patients with coronary athersclerosis (Stephens, et al, Lancet 1996;275:693-8).
1,862 male smokers (Rapola, et al, Lancet, 1997; 349:1715-20)
Analyzing the results of these studies using a set of criteria set forth by the renowned medical statistician Sir Austin Hill, as well as using criterion proposed by the US Preventive Services Task Force, the author makes the following conclusions with high confidence:
- Vitamin E intake from foods or from supplements is inversely associated with coronary disease risk.
- There is no consistent relationship between the amount of vitamin E taken and reduction in risk.
- Other nutritive factors found in foods rich in vitamin E may play important roles in reducing risk.
- Vitamin E does not lower the incidence of angina pectoris or mortality rates from coronary heart disease in male smokers.
- Vitamin E supplements may decrease risk of recurrence of nonfatal heart attacks, but not fatal cardiovascular events.
Kushi, L. Vitamin E and Heart Disease: A Case Study. American Journal of Clinical Nutrition. Vol. 69(suppl), pp. 1322S - 9S, 1999.
In this review article, the results from 17 major studies regarding vitamin E were analyzed and balanced conclusions drawn. While not every study showed obvious benefits, enough evidence existed for the researchers to suggest the following:
For cardiac benefits,
- A low-fat diet with high intake of fruits and vegetable sources containing vitamin E should be emphasized.
- Vitamin E supplementation is not useful at low levels, less than 50 IU/day.
- Doses of 100 to 400 IU/day are recommended for those who choose to take vitamin E as a supplement, the higher values for those with a history of coronary artery disease.
- Current results encourage further studies to answer questions such as the optimal dose, duration, and method of taking vitamin E (diet vs. supplement).
Spencer, A., Carson, D., Crouch, M. Vitamin E and Coronary Artery Disease. Archives of Internal Medicine. Vol. 159, pp.1313-20, 1999.
In this in vitro study from Georgetown University Medical Center, Washington, D.C., blood samples were drawn from healthy volunteers who were not taking vitamin supplements or aspirin. The blood was then highly filtered and only the platelet-rich plasma was collected. Platelet cells are responsible for blood clotting, and previous studies suggest vitamin E helps prevent blood clotting by inhibiting the platelet cells from aggregating.
The platelet cell samples were then introduced to three vitamin E preparations: 1) natural vitamin E (RRR-alpha-tocopherol), 2) natural vitamin E acetate (RRR-alpha-tocopherol acetate), and 3) synthetic vitamin E (all-rac-alpha-tocopherol). Both the natural vitamin E and natural vitamin E acetate were successfully absorbed by the platelet cells, but virtually no synthetic vitamin E was absorbed. The researchers then introduced arachidonic-acid to the platelet cells to induce aggregation. Compared to controls, the aggregation of samples was reduced by 57% (RRR-alpha-tocopherol) and 52% (RRR-alpha-tocopherol acetate), while the sample with synthetic vitamin E showed less than 20% reduction. A further test confirmed that the vitamin E acetate in the platelet cells did not have antioxidant potential (since it was still esterified due to the lack of de-esterifying enzymes in the purified samples), so the anti-aggregation properties of vitamin E was independent of its antioxidant potential. Another test using the non-antioxidant form of vitamin E, RRR-alpha-tocopherol quinone, verified that inhibition of aggregation occurs even without antioxidant function. The experiment was then repeated with different amounts of vitamin E and a dose-dependent effect observed.
The authors surmise that the minimal incorporation of the synthetic form of vitamin E into the platelet cells (perhaps due to the absence of other blood factors in the present test-tube experiment) most likely accounts for why synthetic vitamin E did not inhibit aggregation to the same extent as the natural forms. Nevertheless, they succeeded to demonstrate vitamin E's ability to inhibit platelet aggregation, which may be independent of its antioxidant function. This has important implications when interpreting the studies of vitamin E and heart health.
Freedman, J.E., Keany, J.F. Jr., Vitamin E Inhibition of Platelet Aggregation Is Independent of Antioxidant Activity. Journal of Nutrition. Vol. 131, pp. 374S-377S, 2001.
"Vitamin E" is actually a general term for a family of compounds, including the tocopherols and the tocotrienols. In terms of vitamin E activity in humans, alpha- tocopherol is the most effective, and the other compounds are rated in terms of units of alpha-tocopherol. However, some earlier studies found that the tocotrienols were able to lower cholesterol in various animal species, while tocopherols were not. A few uncontrolled human trials reported positive cholesterol-lowering effects of tocotrienol supplementation, but due to the informal nature of the study protocols, the results were not entirely reliable.
The present study from Maastricht University, Netherlands, was carefully designed to test whether tocotrienols effectively lowered cholesterol in humans. In this randomized, double-blind, placebo-controlled parallel trial, 40 men with mildly elevated cholesterol levels were divided into two groups. One group received daily 35 mg tocotrienols and 20 mg alpha-tocopherol, while the other group, 20 mg D-L-alpha-tocopherol. At the end of the 6 week trial, changes in LDL or HDL cholesterol, triacylglycerol, lipoprotein(a), and lipid peroxide concentrations did not significantly change for either group. The authors concluded that tocotrienol supplements did not have marked favorable effects on serum lipoprotein profiles or platelet function in men with slightly elevated lipid concentrations.
In their discussion of the results, the authors speculate on possible reasons to explain the neutral outcome of their study. They note that some studies indicate alpha-tocopherol may interfere with the cholesterol-lowering action of tocotrienols, in particular, gamma-tocotrienol. Another possibility is that tocotrienols were not well absorbed by the subjects, since despite a substantial increased intake of tocotrienols, their levels in the blood rose only slightly.
Mensink, R., von Houwelingen, A., Kromhout, D., Hornstra, G. A Vitamin E Concentrate Rich in Tocotrienols Had No Effect on Serum Lipids, Lipoproteins, or Platelet Function in Men with Mildly Elevated Serum Lipid Concentrations. American Journal of Clinical Nutrition, Vol.69, pp.213-9, 1999.
Qureshi, A.A., Bradlow, B.A., Brace, L. et al. Response of Hypercholesterolemic Subjects to Administration of Tocotrienols. Lipids, Vol. 30, Issue 12, pp.1171-7, 1995.
Stenosis, the constriction of blood vessels due to atherosclerotic plaque buildup, can be measured non-invasively using ultrasound detectors. In this study from the Elmhurst Medical Center, Queens, New York, 50 subjects (49 to 83 years old) who suffered from atherosclerois, were examined for the degree of carotid stenosis. The grades of stenosis were: 0-15%, 16-49%, 50-79%, and 80-99%. They were then randomly assigned in a double-blind fashion to take either an antioxidant supplement or placebo. Each antioxidant supplement capsule contained 16 mg alpha-tocopherol, 40 mg gamma- and alpha-tocotrienols, and 240 mg palm superolein oil. Initially, 4 capsules were taken per day and later increased to 6 capsules daily. The placebo was only the palm superolein oil. Also, aspirin was taken by both groups.
Every 3 months for 18 months, ultrasound examination and blood tests were performed to determine progression of atherosclerosis and levels of blood lipid factors. Throughout the study period, no changes in blood lipid factors such as HDL, LDL, and triglyceride levels were found in either group. In the antioxidant supplement group, certain individuals enjoyed substantial improvement in stenosis. Six (24%) of these patients moved to a lower grade of stenosis, one (4%) moved two grades lower, two (8%) exhibited worsening of stenosis, and the remainder (64%) showed no changes. In contrast, of those in the placebo group, six (24%) had worsening of stenosis, four (16%) had marked worsening, and the remainder (50%) had no change. No one taking the placebo enjoyed improvement in stenosis. Also, in vitro tests of lipid peroxidation showed those taking the antioxidants had a 20% decrease in free radical activity, while those in the placebo group had a 20% increase.
The authors conclude, "These findings suggest that antioxidants, such as tocotrienols, may influence the course of carotid atherosclerosis."
Tomeo, A.C., Geller, M., Watkins, T.R., Gapor, A., Bierenbaum, M.L. Antioxidant Effects of Tocotrienols in Patients with Hyperlipidemia and Carotid Stenosis. Lipids, Vol. 30, pp.1179-83, 1995.
Theriault, A., Chao, J.T., Wang, Q, Gapor, A., Adeli, K. Tocotrienol: A Review of Its Therapeutic Potential. Clinical Biochemistry, Vol. 32, No. 5, pp.309-319. 1999.