Antioxidant Supplementation in Atherosclerosis

T. H. Rissanen, T. P. Tuomainen et al. Antioxidant Supplementation in Atherosclerosis Prevention. 2003. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. 1 - 947-953. 

SALONEN, J. T NYYSSONEN, K SALONEN, R LAKKA, H. M KAIKKONEN, J PORKKALA-SARATAHO, E VOUTILAINEN, S LAKKA, T. A., RISSANEN, T LESKINEN, L TUOMAINEN, T. P., VALKONEN, V. R, RISTONMAA, U. POULSEN, H. E. 2000. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study A randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Intern Med, 248, 377-86. 

Antioxidants of Cardiovascular Disease in Endstage Renal Disease (SPACE) study and the Antioxidant Supplementation in Atherosclerosis Prevention Study (ASAP). 

CHOPRA M, MCLOONE u L, o neill m, WILLIAMS N and THURNHAM DI (1996) Fruit and vegetable supplementation - effect on ex vivo LDL oxidation in hiunans , in Kumpulainen, J T and Saonen, J T (eds), Natural Antioxidants and Food Quality in Atherosclerosis and Cancer Prevention, Cambridge, Royal Society of Chemistry, 150-55. 

Kim, H.S. and Lee, B.M., Protective effects of antioxidant supplementation on plasma lipid peroxidation in smokers, J. Toxicol. Environ. Health A, 63, 583, 2001. Gaziano, J.M. et al.. Supplementation with beta-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation. Atherosclerosis, 112, 187, 1995. Sutherland, W.H.F. et al.. Supplementation with tomato juice increases plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal transplant recipients, Clin. Nephrol, 52, 30, 1999. 

Oxidized low-density lipoprotein (LDL) may play a key role in the initiation and progression of atherosclerosis. Risk factors for elevated levels of oxidized LDL are not well established and may be important in identifying individuals who may benefit from antioxidant supplementation or interventions to reduce oxidant stress. 

The role of the antioxidant properties of vitamins C, E, and p-carotene in the prevention of cardiovascular disease has been the focus of several recent studies. Antioxidants reduce the oxidation of low-density lipoproteins, which may play a role in the prevention of atherosclerosis. However, an inverse relationship between the intake or plasma levels of these vitamins and the incidence of coronary heart disease has been found in only a few epidemiological studies. One study showed that antioxidants lowered the level of high-density lipoprotein 2 and interfered with the effects of lipid-altering therapies given at the same time. While many groups recommend a varied diet rich in fruits and vegetables for the prevention of coronary artery disease, empirical data do not exist to recommend antioxidant supplementation for the prevention of coronary disease. 

Interventions that block oxidative modification of LDL are currently under intensive study [1,3-5,10]. If oxidative modification of LDL results in enhanced uptake by macrophages, use of an appropriate antioxidant should protect LDL from oxidation, decrease the rate of LDL uptake by macrophage foam cells and slow the development of fatty streaks in the arterial wall. The role of antioxidants in preventing oxidative modification of LDL has been evaluated in a number of studies [1,5,8,10]. In our investigation we studied the influence of the vitamin E reach diet on the copper-mediated oxidizability of plasma LDL from patients with atherosclerosis. So far as LDL is the main transport form of natural antioxidant a-tocopherol we were surprised to find that during 3-months vitamin E supplementation in the daily dose 400 mg the oxidation resistance of LDL did not increase (Figure 14). 

Although ex vivo studies in a-tocopherol-supplemented humans have generally shown beneficial effects [30], clinical trials with a-tocopherol therapy have produced diverse results [31-36]. If a-tocopherol has no effects in humans with established coronary artery disease then either the role of LDL oxidation in human atherosclerosis or the ability of vitamin E to exert an antioxidant function in vivo may become highly questionable [37]. 

Tocotrienals are the new antioxidants found in the oil fractions of cereal grains. Examples would be wheat, rice, rye, and barley grains. The benefits of tocotrienals are similar to those of tocopherols and vitamin E. They can reduce cholesterol and slow the advance of atherosclerosis and the progress of certain cancers. These nutraceuticals are available as supplements. 

Although most studies have reported beneficial effects of vitamin C supplementation on the extent of atherosclerosis observed in cholesterol-fed rabbits (Table III), some (Finamore et aL, 1976 Morel et aL, 1994 Sun et aL, 1994) have reported no significant effect. The observation of nonsignificant decreases in the extent of aortic atherosclerosis by Finamore et aL (1976) and Morel et aL (1994) suggests that these investigators may have used too low an antioxidant dose in their supplement or may have terminated their study at a point where the effect of... 

Clinical studies investigated the antioxidative effects of antioxidant supplementation of humans on ex vivo LDL oxidation [48-52], We have shown that dietary supplementation of p-carotene of healthy subjects resulted in a moderate inhibitory effect on the susceptibility of LDL to oxidative modification [53-55] in some, but not in all studied subjects. The combination of carotenoids with vitamin E, in contrast, demonstrated a synergistic inhibitory effect on LDL oxidation in all studied cases [56], We showed that supplementation of vitamin E of atherosclerotic apolipoprotein E-deficient mice (25 pg/mouse/day for 3 months) inhibited LDL oxidation by 40% and the atherosclerotic lesion area by 35% [57], In humans, unlike in animal models, both vitamin E and carotenoids did not significantly reduce atherosclerosis in primary prevention trials [58], This result may be related to insufficient absorption, insufficient potency, and inappropriate tissue distribution,... 

Kooyenga et al (2001) conducted a 4-year study to evaluate the effects of antioxidants in patients with carotid atherosclerosis. Patients supplemented with tocopherol and tocotrienol from rice bran oil had approximately double the serum a-tocopherol levels of those not given the supplements. In addition, cholesterol and LDL values decreased by 14% and 20%, respectively, supporting the use of antioxidants as a way to control carotid atherosclerosis. In a double-blind 12-week study, hypercholesterolemic human subjects fed 200 mg of a tocotrienol-rich fraction (obtained by molecular distillation from specially processed rice bran oil) had 12% and 16% reductions in total cholesterol and LDL cholesterol levels, respectively (Qureshi etal, 1997). Subjects consuming the American Heart Association Step 1 diet plus 200 mg of a tocotrienol-rich rice bran oil fraction had 17% and 24% reductions in total cholesterol and LDL cholesterol levels, respectively. Significant decreases in apolipoprotein B,... 

There have been more than 20 studies relating to the prevention of atherosclerosis by antioxidants. In vitro, several studies have shown that antioxidant treatment (e.g. vitamin E) inhibits both oxidation and the formation of cytotoxic LDL (Steinbrecher etal., 1984 Par-thasarathy etal., 1986 Esterbauer etal., 1987). In vivo, vitamin E supplementation prevents LDL oxidation in... 

The effects of wine and its polyphenol constituents on early indicators of coronary heart disease such as elevated levels of plasma lipids, platelets and serum antioxidant activity were discussed in a review by Cooper et al. (2004). This review also addressed whether the polyphenols or alcohol are responsible for the beneficial effects of wine on cardio-vascular health. The authors conclude that red wine polyphenols have little effect on plasma lipid concentrations, but that wine consumption reduces the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation and increase serum antioxidant capacity. These effects, however, do depend on the amount of wine that is consumed and the period of supplementation. It was suggested that specific polyphenols appear to have endothelium-dependent vaso-relaxing abilities. Red wine phenolics also have an inhibitory effect on platelet aggregation. Evidence suggests that alcohol has a positive synergistic effect with wine polyphenols on some atherosclerosis risk factors. Thus, evidence that wine drinking is beneficial for cardiac health appears positive. 

Katsiki, N. Manes, C. 2009. Is there a role for supplemented antioxidants in the prevention of atherosclerosis Clin. Nutr. 28 3-9. 

Change in the cellular redox environment can lead to several biological effects ranging from altered signal transduction pathways, gene expression, mutagenesis and cell death (apoptosis). Oxidative stress has now been implicated in many diseases such as atherosclerosis, Parkinson s disease, Alzheimer s disease, cancer, etc. For the protection of cells from oxidative stress, supplementation with exogenous antioxidants becomes necessary. 

Free radical damage is considered to be a causative factor in the development of cancer and inflammatory and chronic diseases. Therefore, free radical scavenging molecules (antioxidants) may play a beneficial role in these conditions. With repect to CVD, the oxidation of low-density lipoprotein (LDL) is believed to be a critical process in the development of atherosclerosis (Berliner et al., 1995 Navab et al., 1995). The presence of oxidized LDL in the intima of an artery leads to the production of macrophage-derived foam cells, the main cell type present in fatty streaks that are believed to be the earliest lesion of atherosclerosis (Fuster, 1994). Therefore, the use of antioxidants as dietary supplements to protect against LDL oxidation may reduce both the development and progression of atherosclerosis (Gey, 1995). 

A recent stndy on the first dose-response comparison of a green tea and a black tea on normal hamsters after long-term supplementation and on a hamster model of atherosclerosis was reported. Both teas were equally effective in inhibiting atherosclerosis with the lower dose (0.0625% tea solution), decreasing it 26-40%, and the high dose (1.25% tea solntion), decreasing it 46-63%. Atherosclerosis was inhibited by three mechanisms hypolipidemic, antioxidant, and antifibrinolytic. There was a significant correlation between atherosclerosis and the three mechanisms. ... 

---