RESEARCH - Soy and Heart Health

SOY & HEART HEALTH
Prepared by Mark Messina, Ph.D.

Impact of Coronary Heart Disease
In the United States, 13 million people suffer from coronary heart disease (CHD). Among those at least 20 years of age, over 100 million have cholesterol levels above the recommended target goal of 200 mg/dl. In fact, nearly 38 million Americans have cholesterol levels above 240 mg/dl, which officially puts them at high risk of developing heart disease. Approximately one-half of men and one-third of women over the age of 40 will develop CHD in their lifetime. According to the American Heart Association, in 2005 the estimated direct and indirect cost of CHD is $142 billion.

While the statistics are grim, evidence indicates that dietary and lifestyle changes can have a significant impact on lowering the risk and incidence of heart disease. Soyfoods in particular have received widespread attention for their cholesterol-lowering effects and possible role in reducing risk of CHD. The purpose of this fact sheet is to provide perspective on the potential public health impact of the cholesterol-lowering effects of soy protein and to discuss the overall role of soyfoods in reducing CHD risk.

The Soy Protein Health Claim
The first rodent studies1, 2 showing soy protein lowered cholesterol were published more than 60 years ago and the first clinical trial demonstrating a reduction were published in 1967.3 However, health professionals did not start to become aware of this relationship until 1995, when a meta-analysis summarizing the human studies on the hypocholesterolemic effects of soy protein was published.4 Formal recognition came four years later when the U.S. Food and Drug Administration (FDA) approved a health claim for soy protein and CHD stating that 25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease.5 In 2002, a similar claim was approved in the United Kingdom and claims in several other countries are now being considered.

Cholesterol
Several meta-analyses have estimated the extent to which soy protein lowers serum cholesterol. For example, in 2005, Zhan and Ho reported that soy protein lowered low-density lipoprotein cholesterol (LDLC) by 5.25 percent.6 This analysis involved 33 comparisons (only post-1995 trials were considered) and 1,749 subjects. A meta-analysis conducted by Tufts University that involved 52 trials found the reduction to be slightly less – approximately 3 percent. These reported decreases are similar to the 1995-meta-analysis referred to in the previous section.4 In that analysis, the overall reduction in response to 47 g/d soy protein was 12.9 percent but the estimated decrease in response to 25 g/d (the amount established by the FDA as the threshold intake for cholesterol reduction) was approximately 5 percent. Of course, the reduction experienced by any given individual may vary as research has shown there is a considerable inter-individual response to cholesterol-lowering diets in general.

Factors thought to specifically impact the hypocholesterolemic effects of soy protein include initial cholesterol level, gender, the total amount of soy protein consumed and the isoflavone content of soy protein. The mechanism by which soy protein reduces cholesterol has not been established, although the reduction does not result from the low-saturated fat content of soyfoods. In most trials the fatty acid content of the control and soy-diets were similar. One hypothesis is that peptides formed from the digestion of soy protein upregulate LDLC receptors in the liver.8-10

Effects on HDLC and Triglycerides
There is widespread agreement that soy protein, in addition to lowering LDLC, lowers triglyceride levels and raises high-density lipoprotein cholesterol (HDLC). All three meta-analyses cited above concur on this point. In the meta-analysis by Zhan and Ho for example, triglyceride levels were decreased by 7 percent and HDLC levels were increased by 3 percent. Although modest, the latter effect is particularly noteworthy as it is relatively difficult to substantially raise HDLC levels through dietary modification.

Effects on non-lipid risk factors

Differences in the traditional risk factors – elevated cholesterol, blood pressure and smoking – explain a large part of the variation in CHD risk among individuals, but it is
Soy & Lipid Levels:

Summary
The effect of soy on lipid levels is similar to that of soluble fiber, and when combined with other dietary approaches may allow highly motivated individuals to avoid the use of cholesterol-lowering medications. Importantly, even the effects of soy protein alone have public health relevance since:
􀂃 Each 1 percent reduction in LDLC results in a 2-4 percent reduced risk for heart disease
􀂃 The favorable effects on triglycerides and HDLC further reduce risk
􀂃 Each 1 percent increase in HDLC reduces CHD risk by 2-3 percent

Elevated triglycerides are also thought to be an independent risk factor for CHD although there is debate on this point.

increasingly recognized that other factors are also important. Recent research suggests that soy protein, likely in part because of its isoflavone content, may favorably affect several of these. Indirect support for this suggestion comes from a prospective epidemiologic study involving nearly 65,000 women from Shanghai.11 Even after controlling for a wide variety of risk factors, this study found that soy protein intake was associated with a marked reduction (relative risk = 0.14 for the highest vs. the lowest quartile of intake; P for trend = 0.001) in the risk of non-fatal myocardial infarction, a protective effect far beyond that which could be expected from a modest reduction in cholesterol. One risk factor that soy may favorably affect is endothelial function.
Endothelial dysfunction is thought to be a global indicator of CHD risk.12 The endothelium is the thin layer of cells that line blood vessels. By secreting several biologically active molecules (such as nitric oxide), the endothelium influences the health of the coronary vessels and, as a result, CHD risk. Endothelial health can be assessed by ultrasonically measuring the ability of the brachial artery to dilate following reactive hyperemia (blood occlusion). Several studies have shown that isoflavone-rich soy protein and isolated isoflavones increase arterial dilation in postmenopausal women – indicating improved endothelial health.13, 14 15, 16

In addition to endothelial function, there are also more speculative data suggesting that soy:
􀂃 Lowers blood pressure (especially in hypertensives)17, 18
􀂃 Improves systemic arterial compliance (increasing arterial flexibility)19
􀂃 Inhibits LDLC oxidation20, 21
􀂃 Reduces LDLC particle size (making LDLC less atherogenic).

While the conflicting or limited data in each of these areas prohibits a firm conclusion from being made, the hypotensive effects of soy protein are particularly intriguing.
Soy Protein and Blood Pressure

Although there is only limited evidence in support of soy protein lowering blood pressure in comparison to other proteins, a recently conducted large 12-week trial involving ~300 prehypertensive and stage 1 hypertensive patients found that in comparison to a carbohydrate control, 40 g/d soy protein significantly lowered blood pressure.17 In the hypertensive subjects, the effect of soy protein (~8 mm Hg ↓) on systolic blood pressure was equivalent in potency to currently used blood pressure medications. Even modest reductions in blood pressure can result in significant benefits; for example, reducing systolic blood pressure by just 2-5 mm Hg reduces risk of CHD and stroke from 4 to 9 percent and 6 to 14 percent, respectively.22

Soy Oil – A Source of Both Essential Fatty Acids
Approximately 56 percent of the fat content of the soybean is comprised of linoleic acid, making soybeans and full-fat soyfoods excellent sources of this essential polyunsaturated fatty acid. Linoleic acid lowers serum cholesterol when added to the diet and when substituted for saturated fat.23 The soybean is also one of the few good plant sources of the essential omega-3 fatty acid, alpha-linolenic acid (ALA). Importantly, a recent meta-analysis found that those subjects who consumed the most ALA were approximately 20 percent less likely to die from CHD as compared to those whose consumption was low.24 The ALA intake difference between the high and low consumers was only 1.2 g/d; three cups of full-fat soymilk provide approximately this amount.

The means by which ALA reduces CHD risk have not been established, but omega-3 fatty acids in general are thought to reduce risk of cardiac arrhythmia.25 Interestingly, one recent study found that soy oil was almost as effective as fish oil in increasing heart rate variability, which decreases risk of arrhythmia.26

Conclusions
Substantially reducing CHD risk through lifestyle modification requires making comprehensive changes. No single food or nutrient is sufficiently potent to produce meaningful reductions in risk. It is clear however that the established coronary benefits of soy protein (reductions in triglycerides and LDLC, and increased HDLC) in combination with the possible benefits (such as reduction in blood pressure and improved endothelial health) justify recommendations to include soyfoods in a heart-healthy diet. For cholesterol reduction, an intake of 25 g/d soy protein is recommended (see Protein Content of Soyfoods table).

References
1. Meeker DR, Kesten D. Effect of high protein diets on experimental atherosclerosis of rabbits. Arch Pathol 1941;31:147-162.
2. Meeker DR, Kesten HD. Experimental atherosclerosis and high protein diets. Proc Soc Exp Biol Med 1940;45:543-545.
3. Hodges RE, Krehl WA, Stone DB, Lopez A. Dietary carbohydrates and low cholesterol diets: effects on serum lipids on man. Am J Clin Nutr 1967;20:198-208.
4. Anderson JW, Johnstone BM, Cook-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333:276-282.
5. Food and Drug Administration. Food labeling, health claims, soy protein, and coronary heart disease. Fed Reg 1999;57:699-733.
6. Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 2005;81:397-408.
7. Gardner CD, Coulston A, Chatterjee L, Rigby A, Spiller G, Farquhar JW. The effect of a plant-based diet on plasma lipids in hypercholesterolemic adults: a randomized trial. Ann Intern Med 2005;142:725-733.
8. Anderson JW. Diet first, then medication for hypercholesterolemia. JAMA 2003;290:531-533. Food Serving size Kcal Protein (g) Tofu, silken, lite firm 1 slice 32 5.3 Tofu, raw, firm ½ cup 183 19.9 Soy burger 1 patty 125 12.5 Soynuts ¼ cup 203 15.2 Edamame ½ cup 127 11.1 Soymilk 1 cup 127 5.5 Protein Content of Soyfoods
9. Manzoni C, Duranti M, Eberini I, Scharnag H, Marz W, Castiglioni S, Lovati MR. Subcellular Localization of Soybean 7S Globulin in HepG2 Cells and LDL Receptor Up-Regulation by Its alpha' Constituent Subunit. J Nutr 2003;133:2149-2155.
10. Duranti M, Lovati MR, Dani V, Barbiroli A, Scarafoni A, Castiglioni S, Ponzone C, Morazzoni P. The alpha' subunit from soybean 7S globulin lowers plasma lipids and upregulates liver beta-VLDL receptors in rats fed a hypercholesterolemic diet. J Nutr 2004;134:1334-1339.
11. Zhang X, Shu XO, Gao YT, Yang G, Li Q, Li H, Jin F, Zheng W. Soy food consumption is associated with lower risk of coronary heart disease in Chinese women. J Nutr 2003;133:2874-2878.
12. Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23:168-175.
13. Walker HA, Dean TS, Sanders TA, Jackson G, Ritter JM, Chowienczyk PJ. The phytoestrogen genistein produces acute nitric oxide-dependent dilation of human forearm vasculature with similar potency to 17b- Estradiol. Circulation 2001;103:258-262.
14. Squadrito F, Altavilla D, Morabito N, Crisafulli A, D'Anna R, Corrado F, Ruggeri P, Campo GM, Calapai G, Caputi AP, Squadrito G. The effect of the phytoestrogen genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium dependent vasodilation in postmenopausal women. Atherosclerosis 2002;163:339-347.
15. Colacurci N, Chiantera A, Fornaro F, de Novellis V, Manzella D, Arciello A, Chiantera V, Improta L, Paolisso G. Effects of soy isoflavones on endothelial function in healthy postmenopausal women. Menopause 2005;12:299-307.
16. Cuevas AM, Irribarra VL, Castillo OA, Yanez MD, Germain AM. Isolated soy protein improves endothelial function in postmenopausal hypercholesterolemic women. Eur J Clin Nutr 2003;57:889-894.
17. He J, Gu D, Wu X, Chen J, Duan X, Whelton PK. Effect of soybean protein on blood pressure: a randomized, controlled trial. Ann Intern Med 2005;143:1-9.
18. Yang G, Shu XO, Jin F, Zhang X, Li HL, Li Q, Gao YT, Zheng W. Longitudinal study of soy food intake and blood pressure among middle-aged and elderly Chinese women. Am J Clin Nutr 2005;81:1012-1017.
19. Nestel PJ, Yamashita T, Sasahara T, Pomeroy S, Dart A, Komesaroff P, Owen A, Abbey M. Soy isoflavones improve systemic arterial compliance but not plasma lipids in menopausal and perimenopausal women. Arterioscler Thromb Vasc Biol 1997;17:3392-3398.
20. Wiseman H, O'Reilly JD, Adlercreutz H, Mallet AI, Bowey EA, Rowland IR, Sanders TA. Isoflavone phytoestrogens consumed in soy decrease F(2)-isoprostane concentrations and increase resistance of low-density lipoprotein to oxidation in humans. Am J Clin Nutr 2000;72:395-400.
21. Tikkanen MJ, Wahala K, Ojala S, Vihma V, Adlercreutz H. Effect of soybean phytoestrogen intake on low density lipoprotein oxidation resistance. Proc Natl Acad Sci U S A 1998;95:3106-3110.
22. Stamler R. Implications of the INTERSALT study. Hypertension 1991;17:I16-20.
23. Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol 2003;23:151-152.
24. Brouwer IA, Katan MB, Zock PL. Dietary alpha-linolenic acid is associated with reduced risk of fatal coronary heart disease, but increased prostate cancer risk: a meta-analysis. J Nutr 2004;134:919-922.
25. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease--fishing for a natural treatment. BMJ 2004;328:30-35.
26. Holguin F, Tellez-Rojo MM, Lazo M, Mannino D, Schwartz J, Hernandez M, Romieu I. Cardiac autonomic changes associated with fish oil vs soy oil supplementation in the elderly. Chest 2005;127:1102-1107.