Cardiovascular Disease

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Vitamin E is most well known for its effects on the cardiovascular system, as it inhibits platelet aggregation and adhesion, smooth muscle cell proliferation, has an antiinflammatory effect on monocytes, improves endothelial function and decreases lipid peroxidation (Kaul et al 2001). It also modulates the expression of genes that are involved in atherosclerosis (e.g. scavenger receptors, integrins, selectins, cytokines, cyclins) (Munteanu et al 2004). Its ability to reduce oxidative stress both directly and indirectly as part of the antioxidant network is of particular importance because oxidation of LDL is a key process in atherogenesis, enhancing foam cell and early lesion formation (Terentis et al 2002).

As such, much investigation is being undertaken to determine whether it has a role in the primary and/or secondary prevention of cardiovascular disease. Epidemiological and clinical studies In 1946 Canadian physicians first reported that vitamin E could protect against coronary heart disease; however, it was not until

the results of two very large human studies were published nearly 50 years later that the greater scientific community and the public started to take note of vitamin E. In 1993, the prospective Nurses' Health Study and the Health Professionals Follow-up study both reported that vitamin E supplementation at a dose of at least 100 IU for at least 2 years significantly reduced the risk of coronary disease compared with nonusers by an estimated 40% (Rimm et al 1993, Stampfer et al 1993).

The prospective Nurses Health Study followed 87,245 women aged 34-59 years without known coronary disease over 8 years and identified that those women with the highest intake of vitamin E had the lowest relative risk of non-fatal myocardial infarction (Ml) or death from coronary disease compared with those with the lowest intake (Stampfer et al 1993). Interestingly, short-term use or dietary intake alone did not produce the same significant reduction. The Health Professionals Follow-up study observed 39,910 men aged between 40 and 75 years over 4 years and produced similar results, finding that long-term vitamin E (at least 100 lU/day) significantly reduced the relative risk of coronary disease compared with non-users (Rimm et al 1993).

Subsequently, a double-blind study conducted at Cambridge University and published in 1996 supported these results, but further suggested that higher doses could produce benefits more quickly and more dramatically (Stephens et al 1996). The placebo-controlled randomised study involved 2002 patients with angiographically proven coronary atherosclerosis and compared the effects of two different strengths of alpha-tocopherol supplementation (400 IU and 800 IU) and placebo over a median of 510 days. Treatment with either dose of vitamin E was seen to reduce the risk of cardiovascular death and non-fatal Ml by over 75% with effects established after 12 months.

Since these early studies were published, newer intervention studies using vitamin E as a sole agent or in combination with other antioxidants have generally produced negative results; however, a number of important factors could account for some of the inconsistent results (see Clinical note below).

In 1999, results from the large GISSI trial were published, which produced conflicting results. The trial, involving 11,324 patients who had recently survived a Ml (<3 months) investigated the effects of three different treatment protocols with placebo: 1 g omega-3 fatty acid/day, 300 IU synthetic vitamin E/day, fish oils plus vitamin E/day, or placebo. The four groups were observed for nearly 4 years for cardiovascular disease morbidity and mortality. Results showed that the fish oil treatment groups had significantly decreased combined end-points of death, non- Vitamin E 1332

fatal Ml and stroke over this time, whereas the vitamin E treatment produced little

effect. The trial has since been criticised because the form of vitamin E used was synthetic, the dose used was relatively low compared with other studies involving patients with pre-existing disease. Subgroup analysis of cardiovascular deaths ultimately did detect a protective effect for vitamin E that was similar to the fish oil treatment.

The Heart Outcomes Prevention Evaluation (HOPE) study observed the effects of natural vitamin E 400 lU/day, the drug ramipril or placebo over 4.5 years in 9541 subjects (>55 years old) who were considered a high-risk group for cardiovascular events (Yusuf et al 2000).This study failed to detect a protective effect for vitamin E supplementation on the primary outcome, which was a composite end-point of Ml, stroke, and death from cardiovascular disease. The study was extended for a mean of 7 additional years and renamed the HOPE-TOO study, which involved 3994 of the original subjects (Lonn et al 2005). Natural vitamin E (400 IU/day) failed to reduce the incidence of major cardiovascular events and there was suggestion it may increase the rate of heart failure.

The MRC7BHF study of 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes found that a daily antioxidant supplement containing 600 mg vitamin E, 250 mg vitamin C, and 20 mg beta-carotene produced no significant differences in all-cause mortality, or in deaths due to vascular or non-vascular causes (Parkinson Study Group 2002). Additionally, no significant differences in the numbers of participants having non-fatal Ml or coronary death, non-fatal or fatal stroke or coronary or non-coronary revascularisation were observed.

A low-dose study investigating the effects of synthetic alpha-tocopherol at a dose of 50 mg/day failed to detect a significant protective effect against coronary disease (Virtamo et al 1998). The Alpha-Tocopherol Beta-carotene Cancer (ATBC) Prevention Study found that treatment with low-dose vitamin E produced a non-significant reduction of 8% on the incidence of fatal coronary disease in smokers (n = 27,271) but had no influence over non-fatal Ml (Virtamo et al 1998). The population studied were Finnish male smokers aged 50-69 years with no history of Ml.

In the Primary Prevention Project (PPP), 100 mg/day of aspirin or 300 mg/day of all-rac-alpha-tocopherol was investigated in 4495 people with hypertension, hypercholesterolemia, diabetes, obesity, family history of premature Ml, or the elderly (de Gaetano 2001). The study had a mean follow-up period of 3.6 years. Vitamin E had no significant effect on cardiovascular death, non-fatal Ml, or non-fatal stroke; however, a significant 46% reduction in the incidence of peripheral artery Vitamin E 1333

disease was reported. The authors pointed out that the findings for vitamin E could

be regarded as a false-negative result because of the inadequate power of the prematurely interrupted trial.

Most recently, data from a major randomised study involving 39,876 healthy women of at least 45 years of age from the Women's Health Study found that long-term use of natural vitamin E (600 IU) taken on alternate days provided no overall benefit for major cardiovascular events (Lee et al 2005).

Alternatively, the Secondary Prevention with Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) trial demonstrated a striking 50% reduction in cardiac events in renal failure patients with established disease receiving 800 lU/day vitamin E (Boaz et al 2000). It is thought that the SPACE trial produced positive results because the dose was comparable to that used in the CHAOS study and it involved a population known to be under increased oxidative stress.

Clinical note — Confusing results for vitamin E

To date, many in vitro, animal and epidemiological studies support the use of vitamin E in the prevention of cardiovascular disease (Clarke & Armitage 2002). However, intervention studies are equivocal. Many factors could account for the lack of benefit on the primary end-point in the majority of trials.

1. Dose selection

A closer look at the evidence shows that dose selection varies enormously from levels just above the RDI (50 mg/day) to large doses of 800 lU/day. Clinical research shows that a daily dose of at least 400 IU is required for LDL to become less susceptible to oxidation (Brockes et al 2003) and an effective threshold dose may be as high as 800 lU/day (Jialal & Devaraj 2005a).

2. Measurement of biomarkers of oxidative stress

Just as the statin trials investigate subjects with high cholesterol levels rather than the general population, it can be reasonably assumed that antioxidant treatment is best suited to those people with increased oxidative stress rather then the general population, yet researchers consistently fail to consider this as a biochemical basis for patient inclusion (Meagher 2003). The levels of oxidised amino acids in urine and plasma can reflect those in tissues and identify people with high levels of oxidative stress and may be one method of subject selection (Heinecke 2002).

3. Type of vitamin E supplement

In the specific case of vitamin E, the form of tocopherol used is crucial, as synthetic forms have less biological activity than RRR D-alpha-tocopherol. According to a 2002 FAO/WHO report, cross-country correlations between coronary heart disease mortality in men and the supply of vitamin E homologues across 24 © 2007 Elsevier Australia

European countries shows a highly significant (P < 0.001) correlation for D-alpha-tocopherol, whereas all other forms of vitamin E do not achieve statistical significance.

In the past few years, it has further been proposed that the lack of efficacy of commercial tocopherol preparations in some clinical trials may be due to the absence of other natural tocopherols, primarily gamma- and delta-tocopherol. Preliminary studies provide some support for this view (Jialal & Devaraj 2005a, Saldeen & Saldeen 2005). Studies using different mixtures of alpha-, beta-, gamma-and delta-tocopherol have found that a mixture of gamma-, delta- and alpha-tocopherol with the ratio of 5:2:1 had a much better antioxidant effect than alpha-tocopherol alone. This mixture is similar to that found in nature. In human and animal studies, the mixed tocopherol preparation also had much more favourable effects on constitutive NO synthase (ecNOS) and superoxide dismutase activity than alpha-tocopherol and in a rat model was more effective in decreasing platelet aggregation and inhibiting thrombus formation. Mixed tocopherol preparation is also superior to alpha-tocopherol in terms of myocyte protection (Chen et al 2002).

4. Plasma vitamin E levels

The measurement of plasma vitamin E levels in the supplemented groups has been inconsistent in the studies, so it is uncertain whether levels significantly rose in response to treatment and subjects were compliant. For example, in the CHAOS, ASAP, ASAP follow-up and SPACE studies a significant increase in the plasma antioxidant levels was reported and all studies found a benefit on the primary endpoint whereas measurement of plasma levels has been inconsistent in the negative studies (Jialal & Devaraj 2005a).

Clearly, the optimal form/s, dosage regimen, duration of use and subpopulation best suited to preventive treatment still needs to be clarified with future trials.

Slowing carotid atherosclerosis The ASAP study was a placebo-controlled, randomised study comparing the effects of vitamin E (136 IU twice daily) and/or slow release vitamin C (250 mg twice daily) on the 3-year progression of carotid artery disease in hypercholesterolaemic subjects (n = 502) (Salonen et al 2000). Combination treatment had the strongest effects and resulted in an average increase in common carotid artery intima-media thickness (IMT) of only 0.011 mm/year in men compared to 0.018 mm/year for vitamin E only, 0.017 mm/year for vitamin C only and 0.02 mm/year for placebo. The covariate-adjusted IMT increase in men was 45% less with both vitamins compared with placebo (P = 0.049), with the treatment effect being largest in smoking men (64% less) than in non-smoking men (30% less). This

suggests a synergistic effect when vitamins C and E are combined. Interestingly, no significant differences were observed in women.

A follow-up to the ASAP study was reported (Salonen et al 2003). It involved 440 of the original subjects and this time only used the combination of vitamin E (272 lU/day) and ascorbic acid (500 mg/day). Once again, a significant decrease in the rate of progression of carotid IMT was seen, with combination treatment compared with placebo. Those subjects with low baseline plasma vitamin C or common carotid artery plaque experienced the greatest effects. Just as reported in the original study, the effect was restricted to males only. It is worthwhile noting that both ASAP studies were of populations at high risk for oxidative stress, biomarkers of oxidative stress were measured and plasma levels of vitamins E and C were significantly increased with their respective treatments.

Restenosis Restenosis is a major limitation to the long-term success of angioplasty Therefore, measures that prevent or delay this occurrence are being investigated to extend the beneficial effects of the procedure.

Studies in experimental models have identified vitamin E as helping to stabilise atherosclerotic plaque after angioplasty and favouring vascular remodelling, thereby suggesting it may be of benefit in preventing or slowing restenosis (Orbe et al 2003). An early double-blind study using oral synthetic vitamin E (1200 IU) for 4 months found that treatment did not significantly reduce the rate of restenosis after percutanous transluminal coronary angioplasty; however, a minor reduction was detected (DeMaio et al 1992).

Angina pectoris Low-dose vitamin E supplements (50 mg/day) produce a minor decrease in the incidence of angina pectoris in smokers without previous coronary heart disease according to a RCT (Rapola et al 1996). A smaller study of 29 subjects with variant angina identified six patients who did not respond to calcium-channel blockers and had lower plasma levels than normal, who responded positively to supplementation with 300 mg/day. Treatment resulted in significantly reduced incidence of angina episodes (Miwa et al 1996). Several years later, the same research group identified a transcardiac reduction in plasma vitamin E concentrations concomitant with lipid peroxide formation, suggesting that oxidative stress and vitamin E depletion may be involved in the pathogenesis of coronary artery spasm (Miwa et al 1999).

Nitrate tolerance Vitamin E supplements (200 mg three times daily) prevented nitrate tolerance when given concurrently with transdermal nitroglycerin (NTG

10 mg/24 hours) according to one randomised, placebo-controlled study in which 24 Vitamin E 1336

patients with ischaemic heart disease were compared with 24 healthy volunteers over

a 6-day period (Watanabe et al 1997). New research indicates that continuous NTG infusion causes vitamin E depletion, as well as nitrate tolerance, and as the vitamin E levels continue to fall, NTG tolerance becomes greater (Minamiyama et al 2006). Hypertension Vitamin E supplementation may reduce blood pressure, LDL oxidation and improve endothelial dysfunction in hypertension, according to current research.

An early double-blind, placebo-controlled study found that DL-alpha-tocopherol nicotinate (3000 mg) significantly reduced SBP pressure from 1 51.0 to 139.2 mmHg within 4-6 weeks in hypertensive subjects; however, DBP remain unchanged (lino et al 1977). More recently, long-term vitamin E (200 lU/day) was shown to decrease SBP by 24% compared with a 1.6% reduction with placebo in mildly hypertensive patients, according to a triple-blind placebo-controlled study conducted over 27 weeks (Boshtam et al 2002). The study involved 70 hypertensive patients (SBP 140-160 mmHg; DBP 90-100 mmHg) aged 20-60 years without other cardiovascular risk factors. Besides reducing SBP, DBP was reduced by 12.5% compared with 6.2% with placebo.

Some studies have revealed that hypertensive patients have a higher susceptibility to LDL oxidation than normotensive subjects and, therefore, increased atherogenic potential. One study measured the effect of vitamin E (400 lU/day) on the resistance of LDL to oxidation in 47 volunteers (Brockes et al 2003). Comparisons made before and after 2 months' supplementation showed that vitamin E caused a significant increase in the lag time in normotensive and hypertensive patients, ultimately bringing hypertensive patients up to the same point as the healthy controls.

Research with experimental models shows that vitamin E modulates vascular function by regulating enzymatic activities of eNOS and NAD(P)H oxidase and, therefore, may also have a role in normalising genetic endothelial dysfunction in genetic hypertension (IIker et al 2003).

Clinical note — LDL oxidation and vitamin E

Oxidative stress affects lipid metabolism by producing an oxidised LDL that has greater atherogenic potential than its original form. In the past attention focussed was on investigating various antioxidants, such as vitamin E, for their ability to prevent LDL oxidation. In recent years, researchers have started to focus on identifying the biological oxidants responsible for initiating oxidation of LDL within the human arterial wall and better understand what makes oxidised LDL pro-atherogenic. In 2003, in vitro testing with LDL discovered that myeloperoxidase is a pathway that promotes LDL oxidation in the human artery wall, although others are also likely to exist. It is noteworthy that vitamin E failed to inhibit LDL oxidation by © 2007 Elsevier Australia

myeloperoxidase in vitro (Heinecke 2003), although it does reduce LDL oxidation within animals and humans when given in doses well above RDI (Brockes et al 2003). If further testing confirms these results, it may mean that vitamin E reduces LDL oxidation in vivo, mainly through its role in the antioxidant network. In other words, its ability to regenerate antioxidants such as vitamin C, coenzyme Q10 and selenium may be more important than its direct antioxidant action.

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