dimanche 22 septembre 2013

The Functional Properties of Vitamin E in Preventing Heart Disease

form used in research. Synthetic vitamin E is usually refers to all-racemic alpha­tocopheryl acetate. The `all-racemic’ part of this name refers to the fact that three particular carbons atoms can be in either the R- or the S- confirmation (these three carbons are shown in Fig. 4.2 by the dotted lines and the solid bars). In natural vitamin E, all three of these carbons are in the R-confirmation. The `alpha-’ part of the name refers to the number (and position) of methyl groups on the vitamin E ring structure. The `acetate’ part of the name refers to the fact that the active part of the vitamin E molecule (which is the phenolic ±OH shown in Fig. 4.1) is esterified to an acetic acid molecule. This is done to prevent the vitamin E from oxidizing during storage. Vitamin E will, however, remain inactive until this acetate group is removed in the intestine.

The role of vitamin E in preventing CVD is not yet fully defined (Meydani, 2000). Although many clinical trials do not support a protective role for vitamin E (as detailed below), these trials often have major design flaws (as discussed below). Recent clinical trials have found that vitamin E supplementation reduces levels of C-reactive protein (CRP), which is a very powerful marker and predictor of CVD. Furthermore, new data suggest that CRP may directly promote atherosclerosis by causing the expression of adhesion molecules on the surface of arteries. The expression of these adhesion molecules is known to be involved in the inflammatory process that leads to CVD.

Excellent animal models are now available for studying the role of functional foods, specific nutrients, or pharmaceutical agents on the process of atherosclerosis. Most animal experiments support a role for vitamin E in preventing the oxidation of LDL and in slowing the development or progression of atherosclerosis (Steinberg, 2000; Chisolm and Steinberg, 2000). Very recent animal data show, however, a tendency to not be as supportive as earlier experiments. For example, in rabbit (Tijburg et al., 1997; Djahansouzi et al., 2001), hamster (El-Swefy et al., 2000) and mouse (Paul et al., 2001; Munday et al., 1998; Shaish et al., 1999) models, vitamin E did not prevent atherosclerosis or fatty streak formation (Tijburg et al., 1997; Djahansouzi et al., 2001).

A very interesting paper by Terasawa et al. (Terasawa et al., 2000) recently showed that disruption of the alpha-tocopherol transfer protein increased the severity of atherosclerosis in apoE (—/—) mice and also increased levels of isoprostanes, which are markers of lipid peroxidation. The alpha-tocopherol transfer protein is responsible for selectively transferring alpha-tocopherol from the liver to lipoproteins and animals deficient in this gene develop vitamin E deficiency. This paper provides convincing evidence that lipid peroxidation and atherosclerosis are increased in response to alpha-tocopherol deficiency.

Observational studies of vitamin E and CVD

Study                             Design/follow-up                                  Outcome

Nurses’ health              87 000 women, 8 years                          Reduced MI or stroke

Health professionals 39 000 men, 4 years                                Reduced MI

Iowa women                 34 000 women, 7 years                          Reduced fatal MI

Finnish cohort              5000 men and women, 14 years           Reduced fatal MI

EPESE                            11 000 elderly men and women,           Reduced fatal MI

6 years

Scottish Heart Health 11000 men and women, 8 years             No effect

Rotterdam                    4800 men and women, 4 years             No effect

Observational studies just look at the association between vitamin E status (either in the diet or in blood samples) and clinical measures of heart disease such as myocardial infarction (MI) or stroke. These studies are summarized in Table 4.1 and generally support the idea that vitamin E helps prevent heart disease. Observational studies do not, however, show cause and effect and have many major limitations. For example, people who are health conscious in general may exercise, maintain an ideal body weight, have a low-fat diet, and also take vitamin E supplements. In this case, vitamin E consumption is just a marker for a healthy lifestyle.

The ultimate experimental design for testing the potential efficacy of vitamin E on atherosclerosis and heart disease is the randomized, double-blind, placebo-controlled clinical trial. These trials are very expensive and therefore often limited to participants who already have documented cardiovascular disease (i.e. a secondary prevention trial).

Although some positive results were obtained, most placebo-controlled clinical studies (see Table 4.2) have not been supportive of a protective role for vitamin E in preventing cardiovascular disease. In the Finnish ATBC study, 50 mg of synthetic vitamin E (all-racemic-alpha-tocopheryl acetate) did not show any positive effect on heart disease. This level of vitamin E may not be sufficient to have an effect.

The British study (CHAOS) study did show a 47 per cent reduction (compared with placebo) in the combined rate of CHD death plus nonfatal infarction in subjects provided with 400±800 IU per day of vitamin E (RRR­alpha-tocopherol) and with a documented coronary heart disease. The positive effect observed in the CHAOS trial has, however, been criticized since the subject population was small, there were numerous imbalances in the base-line characteristics, and it was very short in duration (1.5 years).

The Heart Outcomes Prevention Evaluation (HOPE) Study was a large-scale, randomized, double-blind, and secondary prevention trial with men and women 55 years of age or older (Yusuf et al., 2000). In this study, half the subjects received `natural source vitamin E’ and half placebo for 4.5 years. Vitamin E had no effect on myocardial infarction, stroke, or death from heart disease. Unfortunately, this study had many confounding factors. Many of the HOPE subjects took various medications such as aspirin or other anti-platelet agents (75 per cent), lipid-lowering drugs (28 per cent) or beta-blockers (39 per cent). Some subjects took `non-trial’ vitamin E. No plasma vitamin E levels (or index of oxidative stress) were measured in the subjects to ensure compliance. Unfortunately, this trial does not help us understand the role of vitamin E in preventing heart disease.

The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) trial was a double-blind, 2 x 2 factorial study looking at the effects of RRR-alpha­tocopherol (2 x136 IU/day), vitamin C (2 x 250 mg/day) or placebo for 3 years in 520 men and women (45±69 years) with hyperlipidemia (in Finland). RRR-alpha­tocopherol is `natural vitamin E.’ In this study a combined supplementation (E plus C) retarded the progression of carotid atherosclerosis (measured by ultrasonography) in men. Without vitamin C, the antiatherogenic influence of vitamin E was muted. In this study subjects were excluded if they had regular intake of aspirin or antioxidant supplements, but 30 per cent were taking some type of CVD drug. Only 2 per cent were taking statins. In contrast to the HOPE study, plasma levels of tocopherol and ascorbate were measured to confirm compliance. In this study, however, the benefit of taking the vitamin E and vitamin C supplement appeared to be limited to men and possibly only to men who smoke or have increased oxidative stress due to low levels of endogenous antioxidants.

It should be noted that human trials are generally conducted with elderly subjects and utilize endpoints such as myocardial infarction or stroke (that do not occur in animal models) and not the underlying process of atherosclerosis. Atherosclerosis starts during childhood and there is no reason to suspect that vitamin E could reverse atherosclerosis that is fully developed in the elderly. If vitamin E acts by preventing atherosclerosis then the optimal experiment would be a very large-scale clinical study in which children (starting at about 10 years of age) are provided with a vitamin E (or placebo) and followed until they develop cardiovascular disease at 60±70 years of age. This study would be a major undertaking and would be very costly.

Placebo-controlled vitamin E trials

Cambridge Antioxide Study (CHAOS) (secondary)2000 men/women with CVD, 1.5 yearsCVD death, fatal or nonfatal MIPositive for nonfatal MI, no effect on fatal MI9500 men/women with CVD 4.5 years11300 men/women with CVD, 3.5 years529 men/women with hyperlipidemia

Despite the mixed results when the outcome measures are myocardial infarction or stroke, there is considerable evidence that vitamin E has a positive effect on other measures of cardiovascular function. For example, a study by Skyrme­Jones et al. (2000) found that 1000 IU of vitamin E (all-racemic alpha­tocopherol) for 3 months improved endothelial function and blood flow in patients with type I diabetes and reduced the oxidative susceptibility of LDL. This study had an excellent study design, i.e. double-blind, placebo-controlled, and randomized. The relationship of oxidative stress to diabetes and the potential use of antioxidants is an area of intensive research (Laight et al., 2000). Owing to an epidemic of childhood obesity, the incidence of type II diabetes is expected to dramatically increase in the near future.

Paolisso et al. (2000) found that vitamin E therapy (8 weeks, chemical form not identified) was effective in improving brachial artery reactivity. Brachial artery reactivity measures the change in brachial artery diameter after release of an occluding cuff and is a measure of endothelial function. It is thought to be a useful marker for atherosclerosis and coronary artery disease.

A number of studies have looked at the potential of vitamin E therapy in people with type II diabetes. Devaraj and Jialal (2000b) studied the influence of RRR­alpha-tocopherol therapy (1200 IU/day for 3 months) on controls and people with type II diabetes (with and without microvascular disease). The vitamin E supplement significantly decreased the monocyte release of O2—, IL-1-beta, tumor necrosis factor-alpha, and decreased monocyte-endothelium adhesion in all three groups. Increased levels of IL-I-beta, O2—, TNF-alpha, and the increased adherence of monocytes to arterial endothelium are all thought to be markers of inflammation and proatherogenic.

C-reactive protein (CRP) is extremely important because it is emerging as a major risk factor for atherosclerosis and cardiovascular disease (Folsom, 1999). Patrick and Uzick (2001) have written an excellent review on the relationship of cardiovascular disease to CRP. The association between atherosclerosis and CRP is strong even in the absence of classical risk factors such as high cholesterol, triglycerides, and blood pressure (Ridker et al., 2001).

CRP is an acute phase protein released by the liver in response to acute injury, infection, or other inflammatory stimuli. It is, therefore, a marker for acute inflammation and infection. It is now known that even mild elevations of CRP may indicate an ongoing inflammatory process and that even values in the `normal’ range may have clinical importance. The recent development of a high sensitivity assay for CRP (hs-CRP) has rapidly accelerated research on this marker of systemic inflammation. Obesity is highly correlated with increased levels of CRP and, as mentioned above, it is dramatically increasing in Western countries (Yudkin et al., 1999; Ford, 1999; Visser et al., 1999; Lemieux et al., 2001; Ford et al., 2001; Cook et al., 2000).

A number of studies have now shown that vitamin E supplementation reduces levels of CRP. Upritchard et al. (2000) studied 57 people with type II diabetes who received placebo for 4 weeks and were then randomized to receive tomato juice (500 ml/day), vitamin E (800IU/day chemical form not specified), vitamin C (500 mg/day), or continued placebo treatment for 4 weeks. Vitamin E supplementation was found to decrease CRP levels.

Devaraj and Jialal (2000a) tested the effect of RRR-alpha-tocopherol supplementation (1200 IU/day) on CRP and interleukin-6 (IL-6) release from activated monocyte in people with type II diabetes with and without macrovascular complications compared with matched controls. Vitamin E supplementation was found to significantly lower levels of C-reactive protein and monocyte interleukin-6 in all three groups.

Since vitamin E has been shown to reduce levels of CRP it is reasonable to suggest that vitamin E supplementation could, thereby, reduce the risk of future CVD. This suggestion rests on the assumption that CRP is a causative factor and not just a marker for CVD. The evidence supporting this assumption is not yet conclusive but is certainly intriguing. New research has shown that CRP directly causes the induction of adhesion molecules on the endothelial cells of both human veins and arteries (Pasceri et al., 2000). The expression of these adhesion molecules is known to be essential for the development of CVD. Pasceri et al. (2000) concluded that CRP `may play a direct role in promoting the inflammatory component of atherosclerosis and presents a potential target for the treatment of atherosclerosis.’

Additional evidence suggesting that the lowering of CRP could be important in preventing CVD comes from recent research on the use of statin therapy in the primary prevention (i.e. in people who have no obvious heart disease when enrolled in the study) of acute coronary events (Ridker et al., 2001). Statins are very popular and effective drugs that reduce plasma-cholesterol and LDL-C levels. It is very interesting, however, that statins also reduce CRP levels. Work by Ridker et al. (2001) found that statin therapy could reduce the risk of acute coronary events associated with CRP even in the absence of elevated blood lipids.

Aucun commentaire:

Enregistrer un commentaire