Coronary heart disease (CHD) is a multifactorial disease, for which the main established risk factors are raised serum cholesterol, raised blood pressure and smoking. The proportion of both men and women who are hypertensive steadily increases with age. Compared with men, serum cholesterol levels are lower in women up to the age of 50 years. After the menopause, levels of serum cholesterol in women exceed those of men. In women, therefore, the relative importance of CHD as a cause of death steadily increases with age, whereas in men, its importance declines after 55-64 years of age . CHD accounts for 23 % of deaths in women in the UK, and 30 % of deaths in men, although rates have been falling since the late 1970s. Rates are low in Far East countries, such as Japan, and also declining [181,182]. Postmenopausal estrogen replacement has been shown to decrease lipoprotein (a) [Lp(a)] [183, 184]. The synthetic anti-estrogen, tamoxifen, has also been shown to beneficially alter serum lipid and Lp(a) concentrations [184,185]. In addition, there may be similar beneficial effects of estrogen on low density lipoprotein (LDL) and high density lipopro-tein (HDL) cholesterol concentrations in men [186-188].
The importance of lowering serum cholesterol in reducing the risk of CHD and total mortality is now well established. It has been estimated that a 1 % lowering of plasma cholesterol translates on a population basis to a 2-3% reduction in risk of CHD . Decreases in serum cholesterol concentrations of ~5.5 mM, even within subjects with average total cholesterol concentrations, can reduce cardiovascular disease risk . Cholesterol reduction can be achieved by a reduction in the saturated fatty acid content of the diet and by drugs. Both estrogens in HRT and the anti-estrogen tamoxifen can lower LDL cholesterol although the decrease in LDL is complemented by an increase in HDL levels with HRT [190, 191]. Much of the effect of soybean in lowering serum cholesterol has been attributed to the phytoestrogens [192,193]. There is evidence to support the hypothesis that phytoestrogen consumption contributes to the lower incidence of cardiovascular disease in Asian countries and in vegetarians and that phytoestrogens may be cardioprotective . However, the mechanism is uncertain, since genistein is reported to both up- and down-regulate LDL receptors, and some of the products used in studies reporting cholesterol-lowering effects contained unexpectedly low levels of isoflavones . In addition, because of its effects on tyrosine kinases, genistein may have a role in the suppression of the cellular processes which lead to thrombus formation and eventually, atherosclerosis. In cell lines, genistein has been found to inhibit the proliferation brought about by platelet-derived growth factor in the artery wall, and to interfere with release of inflammatory cytokines from macrophages. It also inhibits platelet aggregation and acts as a thromboxane receptor agonist [195, 196]. Some of these effects are brought about at low levels. Genistein is also able to suppress the release of the endothelial relaxing factor NO via its effect on inducible NO synthase [174,197].
Animal studies have demonstrated that the concentration of cholesterol in blood is lowered by the consumption of soy protein rather than animal protein . A study of male and female Rhesus monkeys (Macaca mulatta) has demonstrated that an isoflavone-containing soy protein supplementation results in a hypocholesterolemic effect when compared with a soy diet depleted of phytoestrogen . Both male and female animals receiving the soy diet were observed to have LDL cholesterol and very low density lipoprotein (VLDL) cholesterol values 30-40% lower than controls. HDL cholesterol ratio increased by 50% in female and 20% in male animals. To distinguish the relative contributions of the protein moiety versus the alcohol-extractable phytoestrogens for cardiovascular protection, Anthony et al.  studied young male cynomolgus macaques fed a moderately atherogenic diet and randomly assigned to three groups for 14 months. The groups differed only in the source of dietary protein, which was either casein/lactalbumin, soy protein with the phytoestrogen intact (soy+), or soy protein with the phytoestrogens mostly extracted (soy-). Animals fed soy+ had significantly lower total and LDL plus VLDL cholesterol concentrations compared with the other two groups. The soy+ animals had the highest HDL cholesterol concentrations, the casein group had the lowest and the soy- group was intermediate. Coronary artery atherosclerotic lesions were smallest in the soy+ group, largest in the casein group and intermediate in the soy- group. It could not be determined whether the beneficial effects seen in the soy- group relate to the protein itself or to the remaining traces of phyto-estrogens. The beneficial effects of soy protein on atherosclerosis appear to be mediated primarily by the phytoestrogen component. In a study conducted by Wagner et al. , ovarectomized female monkeys fed soy protein compared with casein consumption resulted in a significant improvement in plasma lipid and lipoprotein concentration, and a decrease in arterial lipid peroxidation. This study also demonstrated that E2 reduced the number of CHD risk factors, and the combination of both soy and E2 resulted in a significant interactive effect with regard to aortic cholesteryl ester content. Another study examined the effects of soy phytoestrogens on coronary vascular reactivity in 22 rhesus mon keys with pre-existing diet-induced atherosclerosis. The monkeys were randomized to a soy-enriched or non-enriched diet for 6 months. The soy-enriched diet enhanced the dilator responses of atherosclerotic coronary arteries to acetylcholine in female rhesus monkeys . These animal studies further encourage studies in humans in this area.
Dietary soy phytoestrogens may provide cardioprotective benefits for humans via a direct effect on lipids. Many human clinical trials have examined the effects of dietary estrogens on serum lipids. Meta-analysis of controlled clinical trials examining soy protein consumption and serum lipid concentrations found that consumption of 47 g soy protein daily, significantly decreased serum concentrations of total cholesterol (~ 9 %), LDL cholesterol (~13%) and triglycerides in 34 of 38 studies . Cassidy et al.  observed a 9% reduction in total cholesterol in a small study of normolipemic premenopausal women given a 60 g soy protein supplement. In another study, men consuming 1 L of soy drink daily, reduced their elevated cholesterol and LDL cholesterol by 9.3 % and 11.3%, respectively . A soybean protein diet in subjects with type II hyperlipoproteinemia may lower cholesterol on average by 20% . Consumption of 25 g soy protein-enriched bread resulted in a decreased total serum cholesterol and increased HDL cholesterol in hypercholesterolemic men . A study of normolipidemic postmenopausal women supplemented with a 40 mg phytoestrogen pill demonstrated a 22% increase in HDL cholesterol and no significant change in other parameters . Another study also observed a significant increase in HDL cholesterol on subjects consuming soy milk . In a cross-sectional study conducted by Nagata et al. , the relationship between soy products and serum cholesterol concentration in a community in Japan was examined and a significant trend was observed for decreasing total cholesterol concentration with an increasing intake of soy products in men after controlling for age, smoking status and intake of total energy, total protein and total fat. This negative trend was also noted in women after controlling for age, menopausal status, body mass index and intake of total energy and vitamin C. In another study, 66 hypercholesterolemic, free-living, post-menopausal women were investigated during a 6-months parallel-group, double-blind trial with 3 interventions . After a control period of 14 days, all subjects were randomly assigned to 1 of 3 dietary groups (all with 40 g protein): a National Cholesterol Education Program (NCEP) Step 1 diet with protein from casein and nonfat dry milk (control), an NCEP Step 1 diet with protein from isolated soy protein (ISP) containing moderate amounts of isoflavones (ISP56), or an NCEP Step 1 diet with protein from ISP containing high amounts of isoflavones (ISP90). Non-HDL cholesterol (LDL and VLDL) in both the ISP56 and ISP90 groups was significantly reduced compared to the control group, whereas total cholesterol was not changed. HDL cholesterol significantly increased in both the ISP56 and ISP90 groups, whereas the ratio of total to HDL cholesterol decreased significantly in both groups compared with the control. Mononuclear cell LDL receptor messenger RNA concentrations significantly increased in subjects consuming ISP56 or ISP90 compared with the control. These results indicate that soy protein with different amounts of isoflavones may decrease the risk of cardiovascular disease via improved blood lipid profiles, and that the mechanism by which apolipoprotein B-containing lipoproteins were depressed may be via alterations in LDL receptor quantity or activity. Low-fat, low-cholesterol diets similar to the NCEP Step 1 diet have been shown to reduce serum cholesterol concentrations in humans by as much as 14% . The enhanced effects on plasma lipoproteins observed with the addition of soy protein to an NCEP Step 1 diet provide additional evidence that dietary protein influences the risk of CHD in humans. It is reasonable to postulate that soy protein, by some not yet understood mechanism, may also increase hepatic LDL receptor mRNA concentrations to enhance LDL receptor activity. Reductions in LDL-cholesterol concentrations with soy protein by way of increased LDL receptor activity in human blood monocytes was demonstrated by Lovati et al. , whereas Angelin et al.  documented the effects of estrogen on the up-regulation of human hepatic LDL receptors. It has also been hypothesized that isoflavonoid antioxidants derived from soy could be incorporated into lipopro-teins and could possibly protect them against oxidation, which is regarded as atherogenic. Six healthy volunteers received 3 soy bars containing 12 mg genistein and 7 mg daidzein daily for 2 weeks . Compared with baseline values, lag phase of LDL oxidation curves were significantly prolonged by a mean of 20 min during soy intake, indicating a reduced susceptibility to oxidation. These results suggest that intake of soy-derived antioxidants such as genistein and daidzein may provide protection against oxidative modification of LDL. Hodgson et al.  conducted a study to determine if isoflavonoids could improve serum lipids in 46 men and 13 postmenopausal women. One tablet containing 55 mg of isoflavonoids (predominantly in the form of genistein) or one placebo tablet was taken daily with the evening meal for 8 weeks. After adjustment for baseline values, no significant differences in post-intervention serum lipid and Lp(a) concentrations between groups were identified. Further adjustment for age, gender, and weight did not alter the results. In addition, changes in urinary isoflavonoids were not significantly correlated with changes in serum lipids and Lp(a). This study does not support the hypothesis that isoflavonoid phytoestrogens can improve the serum lipids, at least in subjects with average serum cholesterol concentrations. The effect of dietary soy protein on serum cholesterol concentration has been examined in humans in many clinical trials, but the results have not been consistent. Some factors which may affect the outcome of these clinical trials include the study design, type of phy-toestrogen used, dosage and pretreatment cholesterol level. Although some studies reported a significant decrease in plasma or serum cholesterol concentration in some hypercholesterolemic subjects as a result of soy-protein diets [203,204,214], most studies of normocholesterolemic subjects have shown little difference in effects on plasma or serum cholesterol concentration between soy protein and control diets [215-220].
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