Effects of Soyfoods on Cardiovascular Disease

by Mary Anthony, MS

There is considerable evidence that soyfoods and soy protein in particular have beneficial effects on cardiovascular disease. Some of the key studies including cross-cultural data, epidemiologic observational studies, and experimental studies with both animals and human beings will be reviewed. However, there remains controversy about the cardioprotective component(s) of soy. This is an important issue given the considerable variability in the composition of different soyfoods. Studies to elucidate the effective component(s) of soyfoods will be described. Finally, the evidence regarding the potential for soyfoods to improve human health and unanswered questions will be summarized

Evidence that Soy Benefits Cardiovascular Disease

There are a variety of types of studies that support a protective effect of soyfoods on cardiovascular disease. The first are the cross-cultural studies comparing the rates of coronary heart disease (CHD) mortality in Japan and the United States. Among men 45 to 65 years of age, the rates of CHD death are about six times lower in Japan than the United States. For women, CHD rates are about eight-fold lower in Japan compared to women of the same age in the U.S. [Beaglehole, 1990]. While cross-cultural data cannot directly implicate soyfoods or even diet as being responsible for the difference in CHD rates, they are suggestive of such an association.

Migrant studies are often used to compare genetic versus environmental (lifestyle and diet) influences on disease risk. These studies add further support to the hypothesis that some component of diet and/or lifestyle are responsible for the differences in CHD rates between the U.S. and Japan. The Ni-Hon-San cohort study [Robertson et al, 1977] compared the rates of fatal and nonfatal myocardial infarction (MI) among men of Japanese origin who were 45-68 years of age and living in Hiroshima and Nagasaki, Japan; the island of Oahu, Hawaii; and the San Francisco Bay area, California. They found that the MI rates for the men of Japanese origin in Hawaii were about 2 times higher than for men in Japan and that the rates in California were even higher than in Hawaii. So as diet and lifestyle became more westernized among these men of Japanese origin, the CHD rates increased to approach those of non-Asian men in the UnitedStates suggesting that the differences in CHD risk between Japan and the United States are not strictly genetic, but are modulated by environmental differences.

In a recently published cross-sectional study [Nagata et al, 1998], a cohort of Japanese men and women 35 years of age or older had their usual diet evaluated by semi-quantitative food frequency questionnaire and total plasma cholesterol concentrations measured. They quantified the amount of soy protein the participants consumed and categorized the men and women separately into four groups based on soy protein intake. For men and women, the total cholesterol concentrations in the three highest quartiles of soy intake were compared to the total cholesterol concentrations in the group eating the least amount of soy. They found that as soy protein intake increased, the total cholesterol concentrations decreased for both men and women. Men appear to have a somewhat greater reduction in total cholesterol compared to the women, which might be explained by their greater soy protein intake; since even after adjusting for total energy consumed the men ate more soy protein than women in each of the quartiles. Interestingly, total fat, saturated fat, and cholesterol consumption increased in parallel with soy, thus the apparent benefits of increased soy intake cannot be explained by a substitution of soyfoods for fats and cholesterol. These data more directly implicate soy as affecting total cholesterol, an important risk factor for cardiovascular disease.

A study that has had an important influence on the recognition that soy protein could improve plasma lipid concentrations and might thereby reduce cardiovascular disease risk, was the meta-analysis published by Anderson and colleagues [1995]. They included 38 clinical trials that compared the effects on plasma lipid and lipoprotein concentrations of soy protein or textured soy protein containing diets to a control diet. They found that the soy-containing diets resulted in 9.3% lower total cholesterol, 12.9% lower low density lipoprotein (LDL) cholesterol, and 10.5% lower plasma triglyceride concentrations compared to the control diets. There was a 2.4% higher high density lipoprotein (HDL) cholesterol in the soy group that was not significantly different from control. They also noted that those with the highest baseline cholesterol concentrations had the greatest reductions in LDL cholesterol with soy. These improvements in plasma lipid and lipoprotein concentrations could potentially have a large impact on reduction of cardiovascular disease.

While studies evaluating the effects of soy on cardiovascular disease risk factors such as plasma lipids and lipoproteins are important, it is also critical to assess whether there is an effect on pathologic endpoints. Atherosclerotic lesions are the fatty build up in the inner lining of arteries that predispose to coronary heart disease, stroke, and peripheral vascular disease. Huff and colleagues [1982] did a study with rabbits comparing the effects of a diet containing soy protein isolate as the source of protein to one that had casein (a milk protein) as the protein on development of atherosclerotic lesions. These diets were low in fat and cholesterol-free. After 10 months of dietary treatment, they quantified the lesions in the aorta. They found that soy protein almost completely inhibited atherosclerosis while those in the casein-fed groups developed lesions in both the aortic arch and the thoracic aorta. This is just one of several studies that has shown the beneficial effects of soy protein in inhibiting atherogenesis.

Cardioprotective Component(s) in Soy

There has been much interest and research since the 1970's to identify the effective component(s) in soy protein for cardioprotection. The components most studied have been the amino acids, the saponins, and the isoflavones.

Huff, et al., [1977] published a report that reflects the findings of most of the studies assessing whether amino acids are the active component. They fed groups of rabbits diets that contained either intact casein or intact soy protein or amino acid mixtures that matched the amino acid composition in these proteins. The diets were fed for four weeks and total plasma cholesterol was measured at the end. The rabbits fed the amino acid mixture that duplicated that in casein had total cholesterol concentrations that were identical to the group fed the intact protein. The amino acid mixture that matched that in soy protein, however, did not result in plasma cholesterol concentrations that were as low as the intact protein. These data suggest that there is some additional component in intact soy protein that is required to achieve the maximum benefit.

In a study designed to determine whether the saponins were the lipid-lowering component in soy protein, four groups of male gerbils were fed diets that contained either casein or soy protein and either had saponins added to the diets or not [Potter, et al., 1993]. The group fed a diet in which saponins were added to casein had significantly lower LDL cholesterol concentrations than the group fed casein without the saponins. The group fed the diet containing soy protein without added saponins also had significantly lower LDL cholesterol concentrations than the casein-only group. However, when saponins were added to the soy protein diet, there was no additional improvement plasma LDL cholesterol. These authors went on to determine that the saponins and isolated soy protein appeared to form insoluble complexes. Thus, saponins in the presence of soy protein may be biologically unavailable to affect cholesterol metabolism.

Most recently the isoflavones (phytoestrogens) in soy have been studied for their potential role in prevention of cardiovascular disease. Genistein and daidzein are the two principle isoflavones in soy protein and are structurally similar to 17b-estradiol. These molecules bind to the two types of estrogen receptors, ERa and ERb with differing affinities. While genistein and daidzein have very weak affinity for ERa, they bind more avidly to ERb. These different types of estrogen receptors and the variability in their tissue distribution may account for the apparent tissue-specific effects of the phytoestrogens (i.e., no effect on endometrium but a robust effect on the cardiovascular system in nonhuman primates). The ability to activate estrogen-mediated pathways may not be their only mechanism of action of the phytoestrogens. Genistein is also a tyrosine kinase inhibitor and has been shown to have this activity in in vitro studies.

Several studies support the isoflavones as having a role in preventing cardiovascular disease. In a study with nonhuman primates [Anthony, et al., 1997], groups were fed diets containing casein and lactalbumin [Casein group] as a source of protein, soy protein isolate with the isoflavones intact [Soy(+)], or soy protein isolate that had been alcohol extracted to remove the isoflavones [Soy(-)]. Plasma lipids and lipoproteins were measured during the 14 months of treatment and atherosclerosis was measured at the end. When compared to the Casein group, the Soy(-) group has only slightly lower LDL cholesterol concentrations, but the Soy(+) group had LDL cholesterol concentrations that were significantly lower than both the Casein and Soy(-) groups. The Soy(+) group had the highest HDL cholesterol concentrations, the Soy(-) group was intermediate and the Casein group had the lowest HDL cholesterol. The effects on coronary artery atherosclerosis mirrored the effects on LDL cholesterol. The Casein group had the most atherosclerosis, the Soy(-) group was intermediate, and the Soy(+) group had the least.

In a study by Crouse and coworkers [1998], they treated moderately hypercholesterolemic individuals with a 25 gram protein supplement given as a daily beverage. In one group the protein was casein, and in four groups soy protein isolates with varying concentrations of isoflavones were used. For one month prior to treatment, participants were counseled to eat a low-fat, low-cholesterol diet (National Cholesterol Education Program Step 1 diet). Baseline plasma lipids were then measured and they were randomly assigned to one of the supplement groups for nine weeks. LDL cholesterol concentrations were lower in the soy supplement groups compared to the casein group, but the difference was only significant in 62 mg/day group. Importantly, there was also a significant trend toward lower LDL cholesterol concentrations with increasing isoflavone dose. As in the meta-analysis by Anderson, et al., [1995], the greatest benefit was in the group with the highest baseline LDL cholesterol concentrations. In the half of the group with higher baseline LDL cholesterol concentrations, both the 37 and 62 mg/day supplements resulted in significantly lower LDL cholesterol compared to the casein group. Another important aspect of this study is that these beneficial effects on plasma lipids were seen when added to a low-fat, low-cholesterol diet. These studies and others suggest that the isoflavones modulate plasma lipid concentrations and cardiovascular disease.

Potential Mechanisms for Cardiovascular Disease Protection

The soy and the isoflavones have been studied extensively for the mechanisms by which they might affect cholesterol metabolism and cardiovascular disease. Soy protein has been shown to decrease cholesterol absorption, increase cholesterol excretion, and upregulate LDL receptors; all processes that would improve plasma lipid concentrations. Normal vascular function was maintained in premenopausal monkeys fed soy protein with its isoflavones compared to a group fed isoflavone-devoid soy protein and genistein restored normal vascular function in this latter group [Honoré, et al., 1997]. The isoflavones have been shown to have antioxidant effects, inhibit smooth muscle cell migration and proliferation (cells important in atherogenesis), and to promote apoptosis (normal cell cycling).

Lack of Effect of Purified Isoflavones on Plasma Lipid Concentrations

Two recent studies, however, suggest that the purified isoflavones do not have the same effects on plasma lipids. In a study by Nestel, et al., [1997], peri- and postmenopausal women were treated with 80 mg isoflavones in a tablet or with a placebo pill and then these groups were switched to receive the other treatment. They found the isoflavone pills had no effects on plasma lipid concentrations, although they did find a beneficial effect on systemic arterial compliance (a measure of elasticity of arteries). In a second study [Hodgson, et al., 1998], a purified isoflavone tablet (55 mg/day) had no effect on LDL or HDL cholesterol concentrations in a group of men and women. These two studies suggest that the isoflavones might need to be given in the presence of soy protein in order to have their effects on plasma lipids. However, the finding of a beneficial effect of the purified isoflavone pills on systemic arterial compliance might suggest that the purified isoflavone pills do have some biologic effects.

This finding that neither the soy protein devoid of isoflavones nor the purified isoflavones given without soy protein have the same beneficial effects on plasma lipids is important in counseling people about dietary modifications. Soyfoods can vary more than 100-fold in their isoflavone content [Coward, et al., 1993; Wang & Murphy, 1994]. Many second generation foods, such as soy burgers and hot dogs, are made from soy products that have been processed to improve their flavor; this extraction method also removes the isoflavones. While there are purified isoflavone pills available in the health food stores, there is no evidence to show they will have any beneficial effects.

Summary and Conclusions

While there is convincing evidence that soyfoods with the isoflavones have beneficial effects on cardiovascular disease risk factors and atherosclerosis, there remain unanswered questions. First, we are uncertain what amount of soy protein and isoflavones is necessary to have maximal benefits and minimal risks. Second, what is the optimal combination of isoflavones; i.e., is genistein the active isoflavone or is the mixture of genistein, daidzein, and glycentin more effective? Third, are there any benefits of the purified isoflavone pills (e.g. effects on cancer or bone)? Fourth, what are the effects of soy and the isoflavones on other disease endpoints, such as cancer, Alzheimer's disease, and cognitive function? Finally, what form of soy will people eat regularly? Can it be incorporated into processed foods such as baked goods, snacks, and other prepared foods? Therefore, while there are still some unanswered questions, it appears that soyfoods may have the potential for reducing the burden of chronic diseases including hormone dependent cancers, osteoporosis, and cardiovascular disease.

References

Anderson JW, Johnstone BM, Book-Newell ME (1995). Meta-analysis of the effects of soy protein intake on serum lipids. New England Journal of Medicine 333, 276-282.

Anthony MS, Clarkson TB, Bullock BC, Wagner JD (1997). Soy protein versus soy phytoestrogens in the prevention of diet-induced coronary artery atherosclerosis of male cynomolgus monkeys. Arteriosclerosis Thrombosis and Vascular Biology 17, 2524-2531.

Beaglehole R (1990). International trends in coronary heart disease mortality, morbidity, and risk factors. Epidemiology Reviews 12, 1-15.

Coward L, Barnes NC, Setchell KDR, Barnes S (1993). Genistein, daidzein and their b-glycoside conjugates; antitumor isoflavones in soybean foods from American and Asian diets. Journal of Agricultural and Food Chemistry 41, 1961-1967.

Crouse JR, Terry JG, Morgan TM, McGill BL, Davis DH, King T, Ellis JE, Burke GL (1998). Soy protein containing isoflavones reduces plasma concentrations of lipids and lipoproteins. Circulation 97, 816 (abstract).

Hodgson JM, Puddey IB, Beillin LJ, Mori TA, Croft KD (1998). Supplementation with isoflavonoid phytoestrogens does not alter serum lipid concentration; a randomized controlled trial in humans. Journal of Nutrition 128, 728-732.

Honoré EK, Williams JK, Anthony MS, Clarkson TB (1997). Soy isoflavones enhance vascular reactivity in atherosclerotic female macaques. Fertility and Sterility 67, 148-154.

Huff MW, Hamilton RMG, Carroll KK (1977). Plasma cholesterol levels in rabbits fed low fat, cholesterol-free, semipurified diets; Effects of dietary protein, protein hyprolysates and amino acid mixtures. Atherosclerosis 28, 187-195.

Huff MW, Roberts DCK, Carroll KK (1982). Long-term effects of semipurified diets containing casein or soy protein isolate on atherosclerosis and plasma lipoproteins in rabbits. Atherosclerosis 41, 327-336.

Nagata C, Takatsuka N, Kurisu Y, Shimizu H (1998). Decreased serum total cholesterol concentration is associated with high intake of soy products in Japanese men and women. Journal of Nutrition 128, 209-213.

Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, Owen A, Abbey M (1997). Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arteriosclerosis Thrombosis and Vascular Biology 17, 3392-3398.

Potter SM, Jimenez-Flores R, Pollack J-A, Lone TA, Berber-Jimenez MD (1993). Protein-saponin interaction and its influence on blood lipids. Journal of Agricultural and Food Chemistry 41, 1287-1291.

Robertson TL, Kato H, Rhoads GG, Kagan A, Marmot M, Syme SL, Gordon T, Worth RM, Belsky JL, Dock DS, Miyanishi M, Kawamoto S (1977). Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California. American Journal of Cardiology 39, 239-243.

Wang H-J, Murphy PA (1994). Isoflavone content in commercial soybean foods. Journal of Agricultural and Food Chemistry 42, 1666-1673.

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