Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selection

Vitamin E is a naturally occurring fat-soluble antioxidant which has been proposed as a treatment for both primary and secondary protection against cardiovascular (CV) events. Promising data from observational epidemiological studies associating higher vitamin E dietary intake with lower risk of CV events have not been validated in randomized controlled clinical trials assessing the effect of vitamin E on CV outcomes. While the pendulum of medical opinion has swung to suggest that high dose vitamin E supplements have no place in the treatment and prevention of CV disease, new data is emerging that allows identification of a specific target population for this treatment, namely patients with diabetes mellitus and the haptoglobin genotype 2-2. This review details the scientific basis and clinical evidence related to the effect of vitamin E on CV outcomes, and the importance of proper patient selection in gaining therapeutic benefit from this intervention.     

The effect of long-term homocysteine-lowering on carotid intima-media thickness and flow-mediated vasodilation in stroke patients: a randomized controlled trial and meta-analysis

Background

Experimental and epidemiological evidence suggests that homocysteine (tHcy) may be a causal risk factor for atherosclerosis. B-vitamin supplements reduce tHcy and improve endothelial function in short term trials, but the long-term effects of the treatment on vascular structure and function are unknown.

Methods

We conducted a sub-study of VITATOPS, a randomised, double-blind, placebo-controlled intervention trial designed to test the efficacy of long term B-vitamin supplementation (folic acid 2 mg, vitamin B₆ 25 mg and vitamin B₁₂ 0.5 mg) in the prevention of vascular events in patients with a history of stroke. We measured carotid intima-medial thickness (CIMT) and flow-mediated dilation (FMD) at least two years after randomisation in 162 VITATOPS participants. We also conducted a systematic review and meta-analysis of studies designed to test the effect of B-vitamin treatment on CIMT and FMD.

Results

After a mean treatment period of 3.9 ± 0.9 years, the vitamin-treated group had a significantly lower mean plasma homocysteine concentration than the placebo-treated group (7.9 μmol/L, 95% CI 7.5 to 8.4 versus 11.8 μmol/L, 95% CI 10.9 to 12.8, p < 0.001). Post-treatment CIMT (0.84 ± 0.17 mm vitamins versus 0.83 ± 0.18 mm placebo, p = 0.74) and FMD (median of 4.0%, IQR 0.9 to 7.2 vitamins versus 3.0%, IQR 0.6 to 6.6 placebo, p = 0.48) did not differ significantly between groups. A meta-analysis of published randomised data, including those from the current study, suggested that B-vitamin supplements should reduce CIMT (-0.10 mm, 95% CI -0.20 to -0.01 mm) and increase FMD (1.4%, 95% CI 0.7 to 2.1%). However, the improvement in endothelial function associated with homocysteine-lowering treatment was significant in short-term studies but not in longer trials.

Conclusion

Although short-term treatment with B-vitamins is associated with increased FMD, long-term homocysteine-lowering did not significantly improve FMD or CIMT in people with a history of stroke.

Trial Registration

Clinical Trial Registration URL: http://www.actr.org.au/ Trial Registration number: 12605000005651     

Vitamin D Supplementation and Breast Cancer Prevention: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I² test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L.     

Effect of B-vitamin Supplementation on Stroke: a Meta-Analysis of Randomized Controlled Trials

Background

B vitamins have been extensively used to reduce homocysteine levels; however, it remains uncertain whether B vitamins are associated with a reduced risk of stroke. Our aim was to evaluate the effects of B vitamins on stroke.

Methodology and Principal findings

We systematically searched PubMed, EmBase, and the Cochrane Central Register of Controlled Trials to identify studies for our analysis. Relative risk (RR) was used to measure the effect of B-vitamin supplementation on the risk of stroke. The analysis was further stratified based on factors that could affect the treatment effects. Of the 13,124 identified articles, we included 18 trials reporting data on 57,143 individuals and 2,555 stroke events. B-vitamin supplementation was not associated with a significant reduction in the risk of stroke (RR, 0.91, 95%CI: 0.82–1.01, P = 0.075; RD, -0.003, 95%CI: -0.007–0.001, P = 0.134). Subgroup analyses suggested that B-vitamin supplementation might reduce the risk of stroke if included trials had a man/woman ratio of more than 2 or subjects received dose of folic acid less than 1 mg. Furthermore, in a cumulative meta-analysis for stroke, the originally proposed nonsignificant B-vitamin effect was refuted by the evidence accumulated up to 2006. There is a small effect with borderline statistical significance based on data gathered since 2007.

Conclusions/Significance

Our study indicates that B-vitamin supplementation is not associated with a lower risk of stroke based on relative and absolute measures of association. Subgroup analyses suggested that B-vitamin supplementation can effectively reduce the risk of stroke if included trials had a man/woman ratio of more than 2 or subjects received dose of folic acid less than 1 mg.     

Low essential fatty acid and B-vitamin status in a subgroup of patients with schizophrenia and its response to dietary supplementation

We assessed essential fatty acid (EFA) and B-vitamin status, together with their determinants, in 61 patients with schizophrenia and established whether those with poor status responded biochemically to the appropriate dietary supplements. As a group, the patients had high erythrocyte saturated fatty acids (FAs), monounsaturated FA and low polyunsaturated FA of the omega3 and omega6 series. Patients reporting not to take vitamin supplements had low vitamin B12 and high homocysteine. Homocysteine variance proved best explained by folate in both the total group and male patients, and by vitamins B12 and B6 in females. Alcohol consumption and duration of illness are risk factors for low polyunsaturated FA status (< P2.5 of reference range), while male gender and absence of fish consumption predict hyperhomocysteinemia (> P97.5 of reference range). Two patients exhibited biochemical EFA deficiency and seven showed biochemical signs of omega3/docosahexaenoic acid (DHA) marginality. Four patients exhibited moderate hyperhomocysteinemia with plasma values ranging from 57.5 to 74.8 micromol/L. None of the five patients with either moderate hyperhomocysteinemia, biochemical EFA deficiency, or both, was predicted by their clinicians to have poor diets. That diet was nevertheless at the basis of these abnormalities became confirmed after supplementing 4 of them with B vitamins and with soybean and fish oils. We conclude that a subgroup of patients with schizophrenia has biochemical EFA deficiency, omega3/DHA marginality, moderate hyperhomocysteinemia, or combinations. Correction seems indicated in view of the possible relation of poor EFA and B-vitamin status with some of their psychiatric symptoms, but notably to reduce their high risk of cardiovascular disease.     

Applying apoB to the diagnosis and therapy of the atherogenic dyslipoproteinemias: a clinical diagnostic algorithm

PURPOSE OF REVIEW: The first objective is to present the most recent evidence relating to the efficacy of apolipoprotein B as a diagnostic index of the risk of vascular disease and a therapeutic target for statin therapy. The second is to present a diagnostic algorithm for the apolipoprotein B100 dyslipidemias based on triglyceride and apoB. RECENT FINDINGS: The results from several recent prospective epidemiological studies demonstrate apoB to be superior to any of the cholesterol indices to estimate the risk of vascular disease. Similarly, the results of several of the major statin clinical trials demonstrate that apoB is a more adequate index of the adequacy of statin therapy than any of the cholesterol indices. Recent studies of lipoprotein subclass distribution in subjects with familial combined hyperlipidemia are reviewed. They demonstrate the limitations of the original lipid-based criteria and point to the necessity of using apoB as a fundamental diagnostic criterion for the disorder. A diagnostic algorithm for an apoB100 atherogenic dyslipoproteinemias is presented and the limitations of the lipid-based system described. SUMMARY: The evidence supporting the clinical use of apoB is solid, its measurement is standardized, and automated, inexpensive laboratory testing could easily be widely available. However, clinical benefit will only follow clinical application.     

Vitamin D and overall mortality

Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Several meta‐analyses of epidemiological studies support the evidence that low vitamin D serum level, which is highly prevalent worldwide, could be a ‘new’ risk factor for many chronic diseases including cancer, and for all‐cause mortality. A meta‐analysis in healthy subjects suggested that current doses of vitamin D supplements could be associated with decrease in total mortality rates. However, these associations are insufficient to establish causality between vitamin D and all‐cause mortality. Furthermore, long‐term health effects of high doses of vitamin D, that is, prolonged supplementation and association with different baseline vitamin D levels, remain to be investigated. Several trials are ongoing but population‐based, placebo‐controlled randomized trials with total mortality as the main endpoint should be planned to confirm a real beneficial effect of vitamin D for non‐skeletal diseases and to prove causality.     

Status of B-vitamins and homocysteine in diabetic retinopathy: association with vitamin-B12 deficiency and hyperhomocysteinemia

Diabetic retinopathy (DR) is a common cause of blindness. Although many studies have indicated an association between homocysteine and DR, the results so far have been equivocal. Amongst the many determinants of homocysteine, B-vitamin status was shown to be a major confounding factor, yet very little is known about its relationship to DR. In the present study, we, therefore, investigated the status of B-vitamins and homocysteine in DR. A cross-sectional case-control study was conducted with 100 normal control (CN) subjects and 300 subjects with type-2 diabetes (T2D). Of the 300 subjects with T2D, 200 had retinopathy (DR) and 100 did not (DNR). After a complete ophthalmic examination including fundus fluorescein angiography, the clinical profile and the blood levels of all B-vitamins and homocysteine were analyzed. While mean plasma homocysteine levels were found to be higher in T2D patients compared with CN subjects, homocysteine levels were particularly high in the DR group. There were no group differences in the blood levels of vitamins B1 and B2. Although the plasma vitamin-B6 and folic acid levels were significantly lower in the DNR and DR groups compared with the CN group, there were no significant differences between the diabetes groups. Interestingly, plasma vitamin-B12 levels were found to be significantly lower in the diabetes groups compared with the CN group; further, the levels were significantly lower in the DR group compared with the DNR group. Higher homocysteine levels were significantly associated with lower vitamin-B12 and folic acid but not with other B-vitamins. Additionally, hyperhomocysteinemia and vitamin-B12 deficiency did not seem to be related to subjects' age, body mass index, or duration of diabetes. These results thus suggest a possible association between vitamin-B12 deficiency and hyperhomocysteinemia in DR. Further, the data indicate that vitamin-B12 deficiency could be an independent risk factor for DR.     

Female athletes: A population at risk of vitamin and mineral deficiencies affecting health and performance

Adequate vitamin and mineral status is essential for optimal human health and performance. Female athletes could be at risk for vitamin and mineral insufficiency due to inadequate dietary intake, menstruation, and inflammatory responses to heavy physical activity. Recent studies have documented poor iron status and associated declines in both cognitive and physical performance in female athletes. Similarly, insufficient vitamin D and calcium status have been observed in female athletes, and may be associated with injuries, such as stress fracture, which may limit a female athlete's ability to participate in regular physical activity. This review will focus on recent studies detailing the prevalence of poor vitamin and mineral status in female athletes, using iron, vitamin D, and calcium as examples. Factors affecting the dietary requirement for these vitamins and minerals during physical training will be reviewed. Lastly, countermeasures for the prevention of inadequate vitamin and mineral status will be described.     

Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment

Background  

Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment.     

Vitamin D and Its Potential Benefit for the COVID-19 Pandemic

Vitamin D is known not only for its importance for bone health but also for its biologic activities on many other organ systems. This is due to the presence of the vitamin D receptor in various types of cells and tissues, including the skin, skeletal muscle, adipose tissue, endocrine pancreas, immune cells, and blood vessels. Experimental studies have shown that vitamin D exerts several actions that are thought to be protective against coronavirus disease (COVID-19) infectivity and severity. These include the immunomodulatory effects on the innate and adaptive immune systems, the regulatory effects on the renin-angiotensin-aldosterone-system in the kidneys and the lungs, and the protective effects against endothelial dysfunction and thrombosis. Prior to the COVID-19 pandemic, studies have shown that vitamin D supplementation is beneficial in protecting against risk of acquiring acute respiratory viral infection and may improve outcomes in sepsis and critically ill patients. There are a growing number of data connecting COVID-19 infectivity and severity with vitamin D status, suggesting a potential benefit of vitamin D supplementation for primary prevention or as an adjunctive treatment of COVID-19. Although the results from most ongoing randomized clinical trials aiming to prove the benefit of vitamin D supplementation for these purposes are still pending, there is no downside to increasing vitamin D intake and having sensible sunlight exposure to maintain serum 25-hydroxyvitamin D at a level of least 30 ng/mL (75 nmol/L) and preferably 40 to 60 ng/mL (100-150 nmol/L) to minimize the risk of COVID-19 infection and its severity.     

The appropriate use of carotid endarterectomy

FOR THE FIRST 30 YEARS AFTER CAROTID ENDARTERECTOMY WAS FIRST DEVELOPED, anecdotal evidence was used to identify patients with internal carotid artery disease for whom this procedure would be appropriate. More recently, the appropriateness of carotid endarterectomy for symptomatic patients and asymptomatic subjects has emerged from 7 randomized trials. Risk of stroke and benefit from the procedure are greatest for symptomatic patients with at least 70% stenosis of the internal carotid artery. Within this group, carotid endarterectomy is most beneficial for the following patients: otherwise healthy elderly patients, those with hemispheric transient ischemic attack, those with tandem extracranial and intracranial lesions and those without evidence of collateral vessels. Risk of perioperative stroke and death is higher in the following groups, although they still benefit: patients with widespread leukoaraiosis, those with occlusion of the contralateral internal carotid artery and those with intraluminal thrombus. Patients with 50% to 69% stenosis experience lesser benefit, and some other groups may even be harmed by carotid endarterectomy, including women and patients with transient monocular blindness only. The procedure is indicated for patients presenting with lacunar stroke and for those with a nearly occluded internal carotid artery, but the benefit is muted. Patients with less than 50% stenosis do not benefit. In the largest randomized trial of asymptomatic subjects, the perioperative risk of stroke and death was very low (1.5%), but the results indicated that a prohibitively high number of subjects (83) must be treated to prevent one stroke in 2 years. The subsequent literature reported higher perioperative risks (2.8% to 5.6%). In asymptomatic individuals nearly half of the strokes that occur may be due to heart and small-vessel disease. These limitations counter any potential benefit. Another trial is in progress and may identify subgroups of asymptomatic subjects who would benefit. Meanwhile, most individuals without symptoms fare better with medical care.The prevention of ischemic stroke by surgical means goes back half a century. After initial endorsement of carotid endarterectomy, confusion arose as to the appropriate selection of patients and the allowable risk from the procedure. In the past 2 decades large randomized trials have been used to evaluate the benefit of the procedure for patients with symptomatic and asymptomatic disease of the internal carotid artery. Sufficient time has now passed since the publication of these trials to analyze their impact on practice and to make recommendations about the application of carotid endarterectomy. There is strong evidence of benefit in some symptomatic patients, whereas other patients will not benefit and may even face harm. There is weak statistical and weaker clinical evidence that asymptomatic subjects will survive longer without experiencing stroke if they undergo endarterectomy than if they do not. The evidence supporting carotid angioplasty and stenting remains anecdotal and conflicting.The purpose of the present report is to provide a clinical roadmap to which symptomatic patients and asymptomatic subjects with carotid stenosis are candidates for endarterectomy. The risks and complications of endarterectomy are also reported. The outlook and benefit for symptomatic patients and asymptomatic subjects are so different that the evidence supporting appropriate use of endarterectomy in these 2 groups will be presented separately.     

Homocysteine and vitamin therapy in stroke prevention and treatment: a review

Homocysteine (Hcy), a sulfur amino acid, is the only direct precursor for L-methionine synthesis through a reaction that requires vitamin B??, representing a connection with "one-carbon" units metabolism. Hcy catabolism requires vitamin B? and as a consequence, alteration in folic acid and B vitamins status impairs Hcy biotransformation. Numerous studies have indicated that Hcy is an independent risk factor for cardio- and cerebrovascular diseases. In the last decade, several clinical trials have investigated the possible correlation between the use of folic acid and vitamins B? and B?? for lowering Hcy plasma concentration and the reduced risk of stroke or its recurrence. This review is aimed to present some aspects of Hcy biochemistry, as well as the mechanisms through which it exerts the toxic effects on the vascular endothelium. We also discuss the results of some of the clinical trials developed to investigate the beneficial effects of vitamin therapy in the prevention and management of stroke.     

Cognitive impairment and mortality in a cohort of elderly people.

OBJECTIVES--To investigate the relation between cognitive function and cause specific mortality in people aged 65 and over. DESIGN-A 20 year follow up study of a cohort of randomly selected elderly people living in the community who in 1973-4 had taken part in a nutritional survey funded by the Department of Health and Social Security. SETTING--Eight areas in Britain (five in England, two in Scotland, and one in Wales). SUBJECTS--921 men and women whose cognitive function was assessed by a geriatrician in 1973-4 and for whom data on health, socioeconomic circumstances, and diet had been recorded. RESULTS--Cognitive impairment was associated with increased mortality, in particular death from ischaemic stroke. Those who scored 7 or less on the Hodkinson mental test had a relative risk of dying from stroke of 2.8 (95% confidence interval 1.4 to 5.5), compared with those who gained the maximum score (10), after adjustment for age, sex, blood pressure, serum cholesterol concentration, and vitamin C intake. These associations were independent of illness or social class. At the time of the nutritional survey, cognitive function was poorest in those with the lowest vitamin C status, whether measured by dietary intake or plasma ascorbic acid concentration. The relation between vitamin C status and cognitive function was independent of age, illness, social class, or other dietary variables. CONCLUSION--The relation between cognitive function and risk of death from stroke suggests that cerebrovascular disease is an important cause of declining cognitive function. Vitamin C status may be a determinant of cognitive function in elderly people through its effect on atherogenesis. A high vitamin C intake may protect against both cognitive impairment and cerebrovascular disease.     

Vitamin D for Treatment and Prevention of Infectious Diseases; A Systematic Review of Randomized Controlled Trials

ObjectiveTo review the existing human controlled intervention studies of vitamin D as adjunctive therapy in settings of infection and provide recommendations for design and implementation of future studies in this field on the basis of the evidence reviewed.MethodsWe conducted a systematic review of randomized controlled clinical trials that studied vitamin D for treatment or prevention of infectious diseases in humans. Studies from 1948 through 2009 were identified through search terms in PubMed and Ovid MEDLINE.ResultsThirteen published controlled trials were identified by our search criteria. Ten trials were placebo controlled, and 9 of the 10 were conducted in a rigorous double-blind design. The selected clinical trials demonstrated substantial heterogeneity in baseline patient demographics, sample size, and vitamin D intervention strategies. Serious adverse events attributable to vitamin D supplementation were rare across all studies. On the basis of studies reviewed to date, the strongest evidence supports further research into adjunctive vitamin D therapy for tuberculosis, influenza, and viral upper respiratory tract illnesses. In the selected studies, certain aspects of study design are highlighted to help guide future clinical research in the field.ConclusionMore rigorously designed clinical trials are needed for further evaluation of the relationship between vitamin D status and the immune response to infection as well as for delineation of necessary changes in clinical practice and medical care of patients with vitamin D deficiency in infectious disease settings. (Endocr Pract. 2009;15:438-449)     

The case for improving vitamin D status

Evidence from both physiological experiments and randomized trials demonstrates that elevating vitamin D status above levels prevailing in the North American and European adult populations improves calcium absorption and reduces fall risk and osteoporotic fractures. Additionally observational data suggest that raising vitamin D status protects against various cancers and autoimmune disorders as well. Hence a strong case can be made for immediate improvement in vitamin D status of the general population.     

Homocysteine and atherosclerosis.

Elevated plasma total homocysteine is an independent risk factor for atherosclerotic vascular disease. Risk rises continuously across the spectrum of homocysteine concentrations and may become appreciable at levels greater than 10 mumol/l. A compelling case can be made for screening all individuals with atherosclerotic disease or at high risk. A reasonable, but unproven, goal for treatment is a plasma total homocysteine concentration less than 10 mumol/l. Folic acid is the mainstay of treatment, but vitamins B12 and B6 may have added benefit in selected patients. The results of ongoing randomized placebo-controlled trials will not be available for several years, but will help determine whether homocysteine lowering reduces the risk of cardiovascular disease.     

Opportunism: a panacea for implementation of whole-genome sequencing studies in nutrigenomics research?

Observational studies have consistently shown associations between mild deficiencies in folate and vitamin B₁₂ with increased risk of a myriad of common diseases. These findings have invariably translated into null outcomes in intervention trials due in part to our ignorance of the specific genomic and environmental factors that underpin population variability in requirements to these B-vitamins. Although genome-wide association studies have shed initial light on the genetic architecture of variability in status of these vitamins, particularly vitamin B₁₂, the causal mechanisms remain uncharacterised. A recent study by Grarup et al. (PLoS Genet 9(6):e1003530, 2013) used next-generation whole-genome sequencing to gain further insight into the genetic architecture of vitamin B₁₂ and folate status in the general population. Their study represents the analysis of approximately ten times greater number of genetic variants and nearly four times the number of individuals compared to the largest previous GWAS study of these B-vitamins. In light of this, we purport that although the study may be viewed as the state of the art in the roadmap to personalised or precision nutrition, the lack of insight provided by the study serves as a cautionary reminder of the importance of study design, particularly when leveraging large-scale data, such as those from whole-genome sequences. We believe that the precedent set by such large-scale “proof of principle” type projects will wrongly enforce a negative outlook for nutrigenomics research and present alternative study designs, which although less opportunistic are far more likely to be informative and yield novel results.     

Action of estrogens in the aging brain: Dementia and cognitive aging

Background

Menopause is associated with sharp declines in concentrations of circulating estrogens. This change in hormone milieu has the potential to affect brain functions relevant to dementia and cognitive aging.

Scope of review

Focused review of published results of randomized clinical trials of estrogen-containing hormone therapy for Alzheimer's disease treatment and dementia prevention, observational research on cognition across the menopause transition, and observational research on the association of hormone therapy and Alzheimer's disease risk.

Major conclusions

Clinical trial evidence supports conclusions that estrogen therapy does not improve dementia symptoms in women with Alzheimer's disease and that estrogen-containing hormone therapy initiated after about age 65 years increases dementia risk. Hormone therapy begun in this older postmenopausal group does not ameliorate cognitive aging. Cognitive outcomes of midlife hormone exposures are less well studied. There is no strong indication of short-term cognitive benefit of hormone use after natural menopause, but clinical trial data are sparse. Little research addresses midlife estrogen use after surgical menopause; limited clinical trial data imply short-term benefit of prompt initiation at the time of oophorectomy. Whether exogenous estrogen exposures in the early postmenopause affect Alzheimer risk or cognitive aging much later in life is unanswered by available data. Observational results raise the possibility of long-term cognitive benefit, but bias is a concern in interpreting these findings.

General significance

Estrogen-containing hormone therapy should not be initiated after age 65 to prevent dementia or remediate cognitive aging. Further research is needed to understand short-term and long-term cognitive effects of estrogen exposures closer to the age of menopause.     

Vitamin E and heart disease: basic science to clinical intervention trials

A review is presented of studies on the effects of vitamin E on heart disease, studies encompassing basic science, animal studies, epidemiological and observational studies, and four intervention trials. The in vitro, cellular, and animal studies, which are impressive both in quantity and quality, leave no doubt that vitamin E, the most important fat-soluble antioxidant, protects animals against a variety of types of oxidative stress. The hypothesis that links vitamin E to the prevention of cardiovascular disease (CVD) postulates that the oxidation of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a complex sequence of events that leads to the development of atherosclerotic plaque. This hypothesis is supported by numerous studies in vitro, in animals, and in humans. There is some evidence that the ex vivo oxidizability of a subject's LDL is predictive of future heart events. This background in basic science and observational studies, coupled with the safety of vitamin E, led to the initiation of clinical intervention trials. The three trials that have been reported in detail are, on balance, supportive of the proposal that supplemental vitamin E can reduce the risk for heart disease, and the fourth trial, which has just been reported, showed small, but not statistically significant, benefits. Subgroup analyses of cohorts from the older three trials, as well as evidence from smaller trials, indicate that vitamin E provides protection against a number of medical conditions, including some that are indicative of atherosclerosis (such as intermittent claudication). Vitamin E supplementation also produces an improvement in the immune system and protection against diseases other than cardiovascular disease (such as prostate cancer). Vitamin E at the supplemental levels being used in the current trials, 100 to 800 IU/d, is safe, and there is little likelihood that increased risk will be found for those taking supplements. About one half of American cardiologists take supplemental vitamin E, about the same number as take aspirin. In fact, one study suggests that aspirin plus vitamin E is more effective than aspirin alone. There are a substantial number of trials involving vitamin E that are in progress. However, it is possible, or even likely, that each condition for which vitamin E provides benefit will have a unique dose-effect curve. Furthermore, different antioxidants appear to act synergistically, so supplementation with vitamin E might be more effective if combined with other micronutrients. It will be extremely difficult to do trials that adequately probe the dose-effect curve for vitamin E for each condition that it might affect, or to do studies of all the possible combinations of other micronutrients that might act with vitamin E to improve its effectiveness. Therefore, the scientific community must recognize that there never will be a time when the science is "complete." At some point, the weight of the scientific evidence must be judged adequate; although some may regard it as early to that judgement now, clearly we are very close. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.