E-Complex: Tocopherols and Tocotrienols

So since I had gotten a lot of positive feedback on the vitamin K for newborns article, and since I haven't found any interesting new studies to share with you recently, I thought I'd fill up this lull in activity with another article I wrote. Now, please keep in mind, that the following article was written back in 2005, and I know there's been a lot more studies on vitamin E since then (although, I don't think anything that would contradict what I have below).

This article was written for the purpose of publication in a peer-reviewed journal, and after I was done, I sent this to a friend who was suppose to edit it and expand the introduction section (in return for being the second author). For this reason, you'll notice the article being a lot more technical and science-geeky than I usually write in this blog (i.e. it was never meant for a general audience)..

I don't recall exactly what happened--probably "life" just getting in the way again--but we both eventually forgot about this and it never got submitted. So, here it is for your reading enjoyment. YOU are the peer-review...

Vitamin E-complex: tocopherols and tocotrienols.

Lee Know

Vitamin E refers to 8 different forms including alpha-, beta-, gamma-, and delta-tocopherols and four tocotrienols. Most vitamin E in foods is gamma-tocopherol. Unlike most nutrients, vitamin E does not appear to have a specific role in a required metabolic process. The major function of vitamin E is probably that of a chain-breaking antioxidant that prevents the formation of free radicals. Vitamin E's therapeutic benefits have primarily been attributed to its antioxidant effects. (Jellin et al. 2003)

Pharmacology

The tocotrienols differ from the tocopherols in the chemical nature of the side chain or tail. Tocopherols have a saturated phytyl side chain, whereas tocotrienols have an unsaturated isoprenoid or farnesyl side chain possessing three double bonds.

The four natural tocotrienols are characterized by the number of methyl groups and their position in the chromanol ring. Alpha-tocotrienol has three methyl groups located on positions 5, 7 and 8 of the chromanol ring; beta-tocotrienol has two methyl groups located on positions 5 and 8 of the ring; gamma-tocotrienol has two methyl groups located on positions 7 and 8 of the ring and delta-tocotrienol has one methyl group located on position 8 of the ring.

All the tocotrienols are lipid soluble, chain-breaking, peroxyl radical scavengers. As such, they can protect polyunsaturated fatty acids (PUFAs) within membrane phospholipids as well as PUFAs within plasma lipoproteins, such as low density lipoproteins, from lipid peroxidation.

The possible anti-atherogenic activity of tocotrienols can be accounted for by a few mechanisms. These include inhibition of LDL oxidation, suppression of HMG-CoA reductase activity and inhibition of platelet aggregation. Additional possible mechanisms include tocotrienol-mediated reduction of plasma apolipoprotein B-100 (apoB) levels, reduction of lipoprotein (a) [Lp (a)] plasma levels and inhibition of adhesion molecule (e.g., ICAM-1 and VCAM-1) expression and monocyte cell adherence. High plasma levels of apoB as well as Lp (a) are considered risk factors for coronary artery disease.

Tocotrienols' possible antithrombotic effect may be due to tocotrienols' (especially gamma-tocotrienol's) inhibition of thromboxane B₂ synthesis, as well as their suppression of plasma levels of platelet factor.

The efficiency of absorption of tocotrienol is low and variable. Absorption from the lumen of the small intestine is lower on an empty stomach than with meals. Prior to their absorption, tocotrienols are emulsified with the aid of bile salts and form micelles with dietary fats and products of lipid hydrolysis. Tocotrienols, after absorption into the enterocytes, are secreted by these cells into the lymphatics in the form of chylomicrons. The chylomicrons are transported by the lymphatics to the circulation where they are metabolized to chylomicron remnants. Some tocotrienols are transferred to various tissues, including adipose tissue, muscle and possibly the brain. Chylomicrons transfer tocotrienols to HDL, which, in turn, transfers them to LDL and VLDL. These remnants can also acquire apolipoprotein E, which directs them and the tocotrienols they contain to the liver for further metabolism.

Antioxidant Activity

In order to understand why antioxidant activity is so important, I will discuss how oxidation works in cardiovascular disease. Atherosclerosis is a condition where the walls of the arteries are damaged and narrowed by deposits of plaque (cholesterol and other fatty substances, calcium, fibrin, and cellular wastes). Eventually, this block the flow of blood. Plaque deposits can result in bleeding (haemorrhage) or formation of a blood clot (thrombus). When hemorrhage or thrombus blocks the flow of blood through the entire artery, a heart attack or a stroke occurs. High blood levels of cholesterol—particularly the cholesterol carried by low-density lipoprotein (LDL)—are associated with an increased risk of atherosclerosis.

While normally the LDL in plasma is not oxidized, oxidation of LDL is believed to contribute to the development of atherosclerosis (Frei 1995). Macrophage cells preferentially take up oxidized LDL, become loaded with lipids, and convert themselves into "foam cells" (Aviram 1996). Foam cells accumulate in fatty streaks, early signs of atherosclerosis. Humans produce auto-antibodies against oxidized LDL, and the levels of such auto-antibodies are higher in patients with atherosclerosis (Frei 1995).

The identification of LDL oxidation as a key event in atherosclerosis suggests that it may be possible to reduce the risk of atherosclerosis by antioxidant supplementation (Ylä-Herttuala 1991). Vitamin E is the major naturally-occurring antioxidant in human lipoproteins (Bowry et al. 1992). The largest fraction of hydrocarbon carotenoids (e.g., beta-carotene and lycopene), as well as most vitamin E and other tocopherols, is transported by LDL (Clevidence and Bieri 1993; Goulinet and Chapman 1997; Oshima et al. 1997), suggesting that these compounds in particular may play an important role in preventing oxidative modification of this lipoprotein fraction. The subfractions of LDL that were more dense had lower overall vitamin E concentrations, and were also more easily oxidized (Lowe et al. 1999).

Studies have shown that supplementation with vitamin E (Reaven and Witztum 1993) and other small compounds (including vitamin C, beta-carotene and other carotenoids, and drugs such as probucol) can decrease the susceptibility of LDL to oxidation (Jialal and Fuller 1995)—what these compounds have in common is their antioxidant activity.

In general, vitamin E’s antioxidant activity is well known and is recognized in countless scientific references. In measuring plasma F2-isoprostanes (a widely used marker of lipid peroxidation), Kaikkonen et al. (2001) found that vitamin E significantly lowered the concentration of F2-isoprostanes when compared to the control group. Huang et al. (2002) and Bryant et al. (2003) found similar results.

However, it’s important to know that the antioxidant activities of the various forms of vitamin E are slightly different, and this is why an E-complex supplement is expected to have greater efficacy than alpha-tocopherol alone (the predominant form of vitamin E in most supplements). Packer et al. (2001) states that the antioxidant activity of tocotrienols is higher than that of tocopherols. Although the bioavailability of tocotrienols is less than tocopherols, the tocotrienols are rapidly absorbed through the skin and efficiently combats oxidative stress induced by UV or ozone (Packer et al. 2003).

PDR Health (2005) published a peer-reviewed monograph that also confirms tocotrienols’ antioxidant activity. It states that tocotrienols are lipid soluble, chain-breaking, peroxyl radical scavengers. As such, they can protect polyunsaturated fatty acids (PUFAs) within membrane phospholipids as well as PUFAs within plasma lipoproteins (such as LDL) from lipid peroxidation. It’s also known that tocotrienols may have a superior ability to suppress reactive oxygen species (ROS) compared to tocopherols (Sebastian et al. 2005).

Mixed-tocopherols seem to be efficient at activating superoxide dismutase, something that alpha-tocopherol alone was not shown to do (Liu et al. 2003). Perhaps this was due to gamma-tocopherol. Gamma-tocopherol appears to be a more effective trap for lipophilic free radicals than alpha-tocopherol (Jiang et al. 2001), and may explain why mixed-tocopherols show greater antioxidant activity than alpha-tocopherol alone.

It is clear that there is more to vitamin E than just alpha-tocopherol, or even mixed tocopherols. For optimum antioxidant activity, providing the complete spectrum in an E-complex is what is preferred.

Supporting healthy lipid/cholesterol levels

Epidemiological studies have shown a continuous relationship between total serum cholesterol and the risk of coronary heart disease (NHFA 2001; NHMRC 1999). Because most serum cholesterol is transported in the low-density-lipoprotein cholesterol (LDL) fraction, this relationship with coronary heart disease (CHD) holds equally well with LDL. The relationship is continuous, but not linear — CHD risk rises more steeply at higher LDL concentrations (Neaton et al. 1992).

High-density-lipoprotein cholesterol (HDL), through mediation of reverse cholesterol transport from peripheral tissues to the liver, is also an important regulator of CHD risk. Below average HDL concentrations are associated with increased CHD risk (NHMRC 1999). Elevated triglyceride concentrations, usually in association with a reduced HDL concentration, are related to increased CHD risk, although the evidence here is not as strong as for LDL (NHMRC 1999). A large international study recently concluded that the ratio of apolipoprotein B to apolipoprotein AI, a reflection of LDL and HDL, accounted for almost half the population-attributable risk of myocardial infarction (Yusuf et al. 2004).

Risk factors may be equated with some degree of causality. However, not every person with an elevated LDL concentration will have premature CHD. Nor will everyone with premature CHD show a lipid concentration abnormality, although other risk factors such as arterial calcification, hypertension, cigarette smoking, diabetes, family history or coagulopathy may be important in such cases (NHMRC 1999). The importance of lipid abnormalities in cardiovascular disease have become apparent to both doctors and the lay public over the past 10 years (Law et al. 2003).

Analysis of cohort studies by stroke subtype has shown that the risk of non-haemorrhagic (i.e. ischaemic) stroke increases as LDL concentration increases (a 15% increase for each 1- mmol/L increase in LDL concentration) (Law et al. 2003). Elevated LDL-C concentration is an important risk factor for ischaemic stroke.

Three studies backing-up this claim come from Qureshi et al. (1991, 1996, 2002) In 1991, they studied palmvitee (an excellent, and the only commercial source for gamma-tocotrienol) on serum cholesterol concentrations. They found that after supplementing for 8 weeks, total cholesterol decreased 15%, LDL decreased 8%, and apo B decreased 10%. They concluded that gamma-tocotrienol may be the most potent cholesterol inhibitor in palmvitee capsules. In a follow-up study, Qureshi et al. (1996) concluded that the impact of gamma-tocotrienol on cholesterol is traced back to the post-transcriptional down-regulation of HMG-CoA reductase, the enzyme responsible for cholesterol production in the liver. What was interesting about this study was that when they added alpha-tocopherol to the blend, they saw a suppression in the HMG-CoA reductase inhibition by gamma-tocotrienol (this negative effect of alpha-tocopherol will be discussed in further detail later). (Aside: they also found the gamma-tocotrienol suppressed tumour growth.) Finally, in 2002 they found that 100mg/day of tocotrienols may be the optimal dose for controlling the risk of coronary heart disease in hypercholesterolemic patients.

Essentially, cholesterol levels are related to lipid peroxidation in cardiovascular disease risk. Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation (as discussed) and by inhibiting HMG-CoA reductase (Packer et al. 2001; PDR Health 2005; Sebastian et al. 2005). These sources go on to mention its antiproliferative and neuroprotective effects, however these are not the focus of this review.

Inhibiting synthesis of inflammatory substances

A role for inflammation has become well established over the past decade or more in theories describing the atherosclerotic disease process (Tracy 1998; Ross 1999). From a pathological viewpoint, all stages (i.e. initiation, growth, and complication of the atherosclerotic plaque) (Libby & Ridker 1999; Plutzky 2001), might be considered to be an inflammatory response to injury. The major injurious factors that promote atherogenesis—cigarette smoking, hypertension, atherogenic lipoproteins, and hyperglycemia—are well established. These risk factors give rise to a variety of noxious stimuli that elicit secretion of both leukocyte soluble adhesion molecules, which facilitate the attachment of monocytes to endothelial cells, and chemotactic factors, which encourage the monocytes’ migration into the subintimal space. The transformation of monocytes into macrophages and the uptake of cholesterol lipoproteins are thought to initiate the fatty streak. Further injurious stimuli may continue the attraction and accumulation of macrophages, mast cells, and activated T cells within the growing atherosclerotic lesion. (Pearson et al. 2003)

Oxidized LDL (as discussed) may be one of several factors that contribute to loss of smooth muscle cells through apoptosis in the atherosclerotic plaque cap, and secretion of metalloproteinases and other connective tissue enzymes by activated macrophages may break down collagen, weakening the cap and making it prone to rupture. This disruption of the atherosclerotic plaque then exposes the atheronecrotic core to arterial blood, which induces thrombosis. Thus, virtually every step in atherogenesis is believed to involve cytokines, other bioactive molecules, and cells that are characteristic of inflammation. (Pearson et al. 2003)

In addition to its anti-thrombotic and cholesterol lowering effects, Qureshi et al. (1991) also found that gamma-tocotrienol decreased thromboxane by 25%. Thomboxane, along with an assortment of other inflammatory substances, including COX-2, PGE-2, etc. are all implicated in the progression of cardiovascular diseases.

Possibly one of the more in-depth studies on gamma-tocopherol’s anti-inflammatory mechanisms was conducted by Jiang et al. (2000). They reported that gamma-tocopherol reduced PGE-2 synthesis in both lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and IL-1beta-treated A549 human epithelial cells. The major metabolite of dietary gamma-tocopherol, 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC), also exhibited an inhibitory effect in these cells. In contrast, alpha-tocopherol slightly reduced (by 25%) PGE-2 formation in macrophages, but had no effect in epithelial cells. The inhibitory effects of gamma-tocopherol and gamma-CEHC stemmed from their inhibition of COX-2 activity, rather than affecting protein expression or substrate availability, and appeared to be independent of antioxidant activity. Gamma-CEHC also inhibited PGE(2) synthesis when exposed for 1 hr to COX-2-preinduced cells followed by the addition of arachidonic acid (AA, a pro-inflammatory mediator), whereas under similar conditions, gamma-tocopherol required an 8- to 24-h incubation period to cause the inhibition. The inhibitory potency of gamma-tocopherol and gamma-CEHC was diminished by an increase in AA concentration, suggesting that they might compete with AA at the active site of COX-2. Jiang et al. (2000) also observed a moderate reduction of nitrite accumulation and suppression of inducible nitric oxide synthase expression by gamma-tocopherol in lipopolysaccharide-treated macrophages. These findings indicated that gamma-tocopherol and its major metabolite possess anti-inflammatory activity and that gamma-tocopherol at physiological concentrations may be important in human disease prevention.

Conclusion

In addition to the three mechanisms just discussed—antioxidant activity, lowering cholesterol, and anti-inflammatory activity—there are numerous studies that show vitamin E has beneficial effects on the cardiovascular system via other mechanisms as well. Gamma-tocotrienol has been shown to have antithrombotic action via inhibition of thromboxane B2 synthesis and suppression of platelet factor (PDR Health 2005). Gamma-tocotrienol with alpha-tocopherol (as Palmvitee) were shown cause atherosclerotic regression in the carotid artery of patients with cerebrovascular disease (Tomeo et al. 1995).

In one animal study where researchers induced ischemia, then reperfused the heart, a tocotrienol-rich fraction of palm oil was able to reverse the ischemia/reperfusion-mediated cardiac dysfuncions (Das et al. 2005). These included ventricular dysfunction, electrical rhythm disturbances, and increase myocardial infarct size.

Mixed-tocopherols were able to increase nitric oxide, which is a key player in vasodilation and blood pressure reduction (Liu et al. 2003).

When compared to controls, the gamma-tocopherol levels were significantly lower in the plasma of CHD patients (Kontush et al. 1999). The analysis showed that decreased gamma-tocopherol (and alpha-carotene) was significantly associated with the presence of CHD. No decrease of plasma alpha-tocopherol was detected in those with CHD (Kontush et al. 1999). This is interesting to note because it seems, from the research available, that gamma-tocopherol is much more biologically active and beneficial to cardiovascular health than alpha-tocopherol, which is the main vitamin E available in supplements. In fact, supplementation with alpha-tocopherol seems to lower the levels of gamma-tocopherol (but not the reverse), which may explain why those that chronically supplement with isolated alpha-tocopherol, were shown not to have any increased protection from cardiovascular disease. The following study (along with what’s already been discussed on the other forms of vitamin E) clearly shows that supplementing with just alpha-tocopherol may actually be detrimental to cardiovascular health.

Compared with placebo, supplementation with alpha-tocopherol reduced serum gamma-tocopherol concentrations by a median change of 58%, and reduced the number of individuals with detectable delta-tocopherol concentrations. Consistent with trial results were the results from baseline cross-sectional analyses, in which prior vitamin E supplement users had significantly lower serum gamma-tocopherol than nonusers. In view of the potential benefits of gamma- and delta-tocopherol, the efficacy of alpha-tocopherol supplementation may be reduced due to decreases in serum gamma- and delta-tocopherol levels. (Huang & Appel 2003)

Similarly, Qureshi et al. (1996) found that the HMG-CoA reductase inhibition was reduced when alpha-tocopherol was added to the “blend.” Maximum efficacy was found in those blends without alpha-tocopherol. This is why it is so important to ensure that a vitamin E supplement is not just alpha-tocopherol, but a mix of all 8 forms of vitamin E, especially gamma-tocopherol.

With respect to dosing, it can be concluded that any dosage would beneficially contribute to its therapeutic benefits. Also, an E-complex would be intended for long-term or chronic use. Cardiovascular disease is considered a chronic disorder (except for acute episodes such as MI or stroke, which is actually the result of a chronic state), and therefore necessitates ongoing preventative therapy. Studies as long as 5-10 years have been conducted on vitamin E supplementation without any adverse effects (except in the case of unbalanced alpha-tocopherol supplementation).

There cannot possibly be any concern of safety from an E-complex product. There have not been any reported adverse effects from this supplement other than rare and minor reactions such as nausea, cramps, fatigue and weakness, and headaches (Jellin et al. 2003).

There is no need to exclude any subpopulation from taking an E-complex. Pregnant and lactating women have an increased need for vitamin E (Jellin et al. 2003), and the children’s need/dose is typically half of an adult’s (Jellin et al. 2003). In a safety review by Hathcock et al. (2005), it was reported that 1000mg of vitamin E was the tolerable upper intake level. They report that many clinical trials on vitamin E on subjects with various diseases showed no consistent pattern of adverse effects at any intake. Hathcock et al. (2005) concluded from clinical trial evidence, that vitamin E supplements appear to be safe for most adults in amounts equal to or less than 1600 IU daily (=1073mg RRR-alpha-tocopherol or molar equivalents of its esters).

When considering all that’s been discussed, the strength of scientific evidence supporting tocopherols’ and tocotrienols’ therapeutic efficacy is undeniable.

REFERENCES

Bryant RJ, Ryder J, et al. 2003. Effects of vitamin E and C supplementation either alone or in combination on exercise-induced lipid peroxidation in trained cyclists. J Strength Cond Res. Nov;17(4):792-800.

Das S, Powell SR, et al. 2005. Cardioprotection with palm tocotrienol antioxidant activity of tocopherol is linked with its ability to stabilize proteasomes. Am J Physiol Heart Circ Physiol. Feb 11; [Epub ahead of print]

Hathcock JN, Azzi A, et al. 2005. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr. 2005 Apr;81(4):736-45.

Huang HY, Appel LJ, et al. Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. Am J Clin Nutr. 2002;76549-55.

Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003 Oct;133(10):3137-40.

Jellin JM, Gregory PJ, Batz F, Hitchens K, et al. Pharmacist's Letter/Prescriber's Letter Natural Medicines Comprehensive Database. 5^th ed. Stockton, CA: Therapeutic Research Faculty; 2003.

Jiang Q, Christen S, Shigenaga MK, Ames BN. Gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001 Dec; 74(6): 714-22.

Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11494-9.

Kaikkonen J, Porkkala-Sarataho E, et al. Supplementation with vitamin E but not with vitamin C lowers lipid peroxidation in vivo in mildly hypercholesterolemic men. Free Radic Res. 2001 Dec;35(6):967-78

Kontush A, Spranger T, Reich A, Baum K, Beisiegel U. Lipophilic antioxidants in blood plasma as markers of atherosclerosis: the role of alpha-carotene and gamma-tocopherol. Atherosclerosis. 1999 May; 144(1): 117-22.

Liu M, Wallmon A, Olsson-Mortlock C, Wallin R, Saldeen T. Mixed tocopherols inhibit platelet aggregation in humans: potentialmechanisms. Am J Clin Nutr 2003 Mar; 77(3): 700-6.

Packer L, Weber SU, Rimbach G. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr. 2001 Feb; 131(2): 369S-73S.

PDR Health. http://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/toc_0254.shtml. Accessed July 14, 2005.

Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM, Elson CE. Dietary alpha-tocopherol attenuates the impact of Gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr. 1996 Feb; 126(2): 389-94.

Qureshi AA, Qureshi N, Wright JJ, et al. 1991. Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee). Am J Clin Nutr. 1991 Apr;53(4 Suppl):1021S-1026S.

Qureshi AA, Sami SA, et al. 2002. Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis. Mar;161(1):199-207.

Sebastian Schaffer, Walter E. Müller, et al. 2005. Tocotrienols: Constitutional Effects in Aging and Disease^. J. Nutr. 135:151-154.

Therapeutic Products Directorate. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/vitsupls_e.html

Tomeo AC, Geller M, et al. 1995.Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids. 1995 Dec;30(12):1179-83

References for background information – oxidation in cardiovascular disease:

Aviram, M. Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. Eur. J. Clin. Chem. Clin. Biochem. 1996;34(8):599-608.

Bowry, V. W., Ingold, K. U., and Stocker, R. Vitamin E in human low-density lipoprotein: when and how this antioxidant becomes a pro-oxidant. Biochem. J. 1992;288(Part 2):341-344.

Clevidence, B. A. and Bieri, J. G. Association of carotenoids with human plasma lipoproteins. Methods Enzymol. 1993;214:33-46.

Frei, B. Cardiovascular disease and nutrient antioxidants: role of low-density lipoprotein oxidation. Crit. Rev. Food Sci. Nutr. 1995;35(1-2):83-98.

Goulinet, S. and Chapman, M. J. Plasma LDL and HDL subspecies are heterogeneous in particle content of tocopherols and oxygenated and hydrocarbon carotenoids: relevance to oxidative resistance and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 1997;17:786-796.

Jialal, I. and Fuller, C. J. Effect of vitamin E, vitamin C, and beta-carotene on LDL oxidation and atherosclerosis. Can. J. Cardiol. 1995;11(Suppl. G):97G-103G.

Lowe, G. M., Bilton, R. F., Davies, I. G., Ford, T. C., Billington, D., and Young, A. J. Carotenoid composition and antioxidant potential in subfractions of human low-density lipoprotein. Ann. Clin. Biochem. 1999;36:323-332.

Oshima, S., Sakamoto, H., Ishiguro, Y., and Terao, J. Accumulation and clearance of capsanthin in blood plasma after the ingestion of paprika juice in men. J. Nutr. 1997;127:1475-1479.

Reaven, P. D. and Witztum, J. L. Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans: effects on lipid levels and lipoprotein susceptibitily to oxidation. Arterioscler. Thromb. 1993;13(4):601-608.

Ylä-Herttuala, S. Macrophages and oxidized low density lipoproteins in the pathogenesis of atherosclerosis. Ann. Med. 1991;23(5):561-567.

References for background information – cholesterol in cardiovascular disease:

Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 1423-1429.

National Heart Foundation of Australia and The Cardiac Society of Australia and New Zealand. Lipid management guidelines – 2001. Med J Aust 2001; 175 (9 Suppl 5 Nov): S57-S88.

National Health and Medical Research Council. Guide to the development implementation and evaluation of clinical practice guidelines. Canberra: NHMRC, 1999. Available at: www.health.gov.au/nhmrc/publications/pdf/cp30.pdf (accessed July 2005).

Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality findings for men screened in the multiple risk factor intervention trial. Arch Intern Med 1992; 152: 1490-1500.

Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-952.

References for background information – inflammation in cardiovascular disease:

Libby P, Ridker PM. Novel inflammatory markers of coronary risk. Circulation. 1999; 100: 1148–1150.

Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO 3rd, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F; Centers for Disease Control and Prevention; American Heart Association. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003 Jan 28;107(3):499-511.

Plutzky J. Inflammatory pathways in atherosclerosis and acute coronary syndromes. Am J Cardiol. 2001; 88: 10K–15K.

Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.

Tracy RP. Inflammation in cardiovascular disease. Circulation. 1998; 97: 2000–2002.

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