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 blocking off the flow of blood. Plaque deposits can result in bleeding (hemorrhage) 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", a protein found in blood) - are associated with an increased risk of atherosclerosis.

Normal 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 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). Most circulating carotenoids are associated with lipoproteins in plasma (Clevidence and Bieri 1993). The largest fraction of total carotenoids is found in LDL, as evidenced by the typically yellow color of this lipoprotein fraction (Clevidence and Bieri 1993). 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 more polar xanthophylls (oxygenated carotenoids such as lutein, zeaxanthin, canthaxanthin, beta-cryptoxanthin, and capsanthin) are distributed more evenly between HDL and LDL (Clevidence and Bieri 1993; Goulinet and Chapman 1997; Oshima et al. 1997). For example, a Japanese study found that ~70% of hydrocarbon carotenoids (lycopene, alpha-carotene, and beta-carotene) were found in LDL, whereas the polar xanthophylls (capsanthin, lutein, and zeaxanthin) were distributed about equally between HDL and LDL (Oshima et al. 1997). The authors speculated that these polar xanthophylls might be localized at the polar surface of lipoproteins high in phospholipids (as is HDL) (Oshima et al. 1997). Upon subfractionation of LDL particles, it was found that lycopene, beta-carotene and beta-cryptoxanthin are found mostly in larger, less-dense LDL particles whereas lutein and zeaxanthin are mostly in the smaller, more dense LDL particles (Lowe et al. 1999). Interestingly, the more dense LDL subfractions, which had lower overall carotenoid and vitamin E concentrations, were also more easily oxidized (Lowe et al. 1999).

Epidemiological and clinical data indicate that dietary antioxidants may protect against cardiovascular disease (Frei 1995). Several epidemiological studies have shown an inverse association between serum levels of beta-carotene and other carotenoids and coronary heart disease (reviewed by Kritchevsky 1999). One study found that serum levels of alpha- and beta-carotene and lycopene were 1.9-, 1.7-, and 2.7-fold higher, respectively, in Israeli men than in Czech men; mortality rates, blood pressure, and coronary heart disease rates in the subjects were highest in Czech and lowest in Israeli men (Bobak et al. 1999). However, clinical studies with carotenoid supplementation have been equivocal, and in fact some major clinical trials with beta-carotene supplementation have shown either no or negative effects on chronic diseases such as cardiovascular disease and cancer (reviewed by Mayne 1996 and Kritchevsky 1999). Carotenoids are regarded as good biomarkers for fruit and vegetable dietary intake, but other plant-derived compounds may well play a significant role in health. Still, 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); these compounds have in common their antioxidant activity.

Carotid intima-media thickness ("carotid IMT", essentially the thickness of one of the main arteries in the neck) is a measure of asymptomatic early atherosclerosis; in one atherosclerosis risk study, carotid IMT was found to be inversely correlated to the levels of lutein and zeaxanthin, which are xanthophylls (oxygenated carotenoids) regarded as biomarkers of fruit and vegetable intake (Iribarren et al. 1997). Another study found that lutein and cryptoxanthin were twice as high in a population (Toulouse) that had a much lower incidence of coronary heart disease than another group (Belfast), suggesting that such xanthophylls (hydroxycarotenoids) may be useful as antioxidant supplements (Howard et al. 1996).

Few studies have used carotenoids (other than beta-carotene) as anti-atherogenic dietary supplements. One in vitro study showed that cell-mediated oxidation of LDL was inhibited by beta-carotene, but enhanced by lutein or lycopene (Dugas et al. 1998). The same researchers later reported that dietary (i. e., in vivo) supplementation of 15 mg per day of beta-carotene over four weeks resulted in a 3- to 6-fold increase in the beta-carotene content of LDL; the in vitro-tested increase in oxidation resistance of LDL isolated from the subjects was greater than the increase in oxidation resistance seen in LDL enriched in vitro 11- to 12-fold with beta-carotene (Dugas 1999). Again, no effect on LDL resistance to oxidation was seen for lycopene supplied as a dietary supplement (Dugas 1999). These results are in contradiction to studies that reported a significant decrease in serum lipid peroxidation and LDL oxidation after three weeks of lycopene dietary supplementation (Agarwal and Rao 1998), and that in vitro supplementation of beta-carotene, canthaxanthin, or zeaxanthin inhibited cell-mediated LDL oxidation (Carpenter et al.1997) A recent large study of the relationship between dietary antioxidant intake and risk for ischemic stroke (as a consequence of atherosclerosis) followed 43,738 men aged 40 -75 years over 8 years (Ascherio et al. 1999). This study found a significant inverse relation between lutein intake and risk for ischemic stroke but this was not independent of other dietary factors. The authors concluded that vitamin E and vitamin C supplements and specific carotenoids did not substantially reduce risk for stroke in the population studied.

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