DISEASES
JAAK PH. JANSSENS
Cardiovascular diseases (CVD), particularly coronary heart diseases (CHD), are responsible for the largest number of hospitalisations in Western countries and consume by far the highest part of the health care budget (Bendich & Deckelbaum, 1997). It can be estimated that half of the costs of the health care budget for CVD, risk of disease and mortality can be effectively reduced by prevention. In this overview, the power of prevention by nutrition is gauged as well as the contribution of soy deri- vatives to this prevention. Finally, the Food and Drug Administration's (FDA) food labelling health claim on soy protein and CHD is discussed. Risk factors for CVD and prevention through nutrition
Male gender, age, smoking, hypertension, obesity, diabetes and choles- terol are the best known risk factors for atherosclerosis and CVD (see Table 5.1). Many of these factors are causal and can be managed by life- style and diet. Not smoking, the lowering of LDL-cholesterol in the blood, Mediterranean food, physical exercise and control of hypertension are well established and most of them work through the lowering of serum cholesterol. In fact, there is an almost linear to exponential correlation between serum cholesterol and risk of and mortality from CVD. Based on this simple relation, nutritional and lifestyle measures to lower serum cholesterol are encouraged in all Western countries for the whole popu-
lation. In addition, consensus emerges that these dietary measures should have a priority in the treatment of moderate hypercholesterolemia (>190 mg%).
Cholesterol is transported in the blood through the solvent properties of high (HDL) and low density lipoproteins (LDL). About 70% of the cho- lesterol is bound to LDL. A high amount of cholesterol bound to the LDL group is correlated with increased risk of CVD of which CHDs are the most common. Increased binding to HDL lowers the risk. Higher trigly-
Table 5.1 Cardiovascular disease risk factors. Demography Age Male gender Menopausal status Lifestyle Smoking Physical activity Obesity Medical Hypertension Diabetes Hyperhomocystinemia Lipid disorders Hypercholesterolemia
Increase in LDL-cholesterol Decrease in HDL-cholesterol Hypertriglycidemia
Increases in apolipoprotein B Decreases in apolipoprotein A1 Increase in oxidized LDL-cholesterol Increase of small dens LDL-cholesterol Increase in lipoproteins
Apolipoprotein E4 allele Haemostasis Increase in fibrinogen
Increase in factor VII
Increase in von Willebrand factor
Increase in Plasminogen activator inhibitor Infections Cytomegalovirus
Chlamydia pneumoniae Helicobacter pylori Inflammation White blood cell count
C-reactive protein Serum amyloid protein
Intercellular adhesion molecule-1
ceride levels increase the risk of CVD as well. Nutrition can alter the lipoprotein profile of the blood. Lowering dietary cholesterol (C) lowers plasma cholesterol and LDL-C in humans depending on the expression of the apoprotein isoforms and decreases the risk of CVD. Also the lipo- protein status of the host, affected both by previous and concurrent dietary or longstanding genetic factors, dictates the potential impact on cholesterol rise after intake of high cholesterol foods and saturated fat. An increased intake in short and middle chain saturated fatty acids (SFAs >C12) increases the LDL and to a lesser extent HDL fractions. Increased consumption of stearine FA (C18) has a similar effect to carbohydrates and increases LDL and HDL-type cholesterol. Palmitine FA has an ambivalent effect on cholesterol. SFAs in general should be lowered in the diet from an average of 14% to about 10% of total energy intake. Mono-unsaturated FAs (MUFAs) are recently getting more attention because they do not increase triacylglycerol and lower HDL. In addition, they seem to play a direct role in the inflammatory reaction at the initial steps of athero- sclerosis (Massaro et al., 1999). The polyunsaturated FAs (PUFAs) decrease LDL and increase HDL. The LDL response is non-linear with an apparent threshold at 5% of energy intake level.
The old dogma says that PUFAs should be increased in the diet. Prob- ably the most favourable LDL/HDL ratio (i.e. lowest LDL and highest HDL) is induced by a diet with 30% energy as fat containing a combina- tion of 16:0-rich SFAs (to elevate HDL) and PUFAs (to assure removal of LDL by the liver), each representing 8±10%. The intake of cholesterol can be modified also by inhibition of intestinal absorption through phytosterols and phytostanols. Oat bran diets containing glucan, a cho- lesterol binding water soluble gum, significantly increase faecal sterol elimination.
Non-oxidized LDL are recognised by receptors, which can be saturated, in contrast to oxidized LDL which cause an unlimited accumulation in the intima cells of arteries without the characteristics of saturation. The for- mation of the resulting `foam cells' is a first sign of atherosclerosis. Endothelial damage is seen subsequently along with monocyte/macro- phage recruitment, alteration in vascular tone and induction of growth factors. If this hypothesis is true, antioxidants may cause a significant reduction of atherosclerosis but up to now, the results of implementation trials are very disappointing. The polyphenols, which include the flavo- noids, are worth studying because they are potent antioxidants and pre- sent in various foods.
Derived from methionine, homocysteine is an intermediary amino acid positively related to CVD. The evidence is very strong and consistent with an estimated risk of 1.6 for males and 1.5 for females for an increase of 5 mmol/L. Atherogenic mechanisms promoted by homocysteine include endothelial cell desquamation, oxidation of LDL and monocyte adhesion to the vessel wall. The concentration of homocysteine depends on genetic, lifestyle and nutritional factors and individuals with concentra- tions beyond 15 mmol/L are considered to suffer from hyperhomo- cyteinemia. Total homocysteine levels of 10 mmol/L are considered `healthy' and a reduction of 5 mmol/L from 15 to 10 seems beneficial. Nutritional factors are folic acid, vitamin B12 and B6. Up to now, no study or randomised clinical trials firmly relate dietary folate intake or folic acid with the risk of CVD.
Soy protein metabolism
An increased consumption of soya products can provide a large amount of protein with a high amino acid quality and is associated with a very low incidence of cardiovascular disease. Serum and LDL-cholesterol con- centrations can be lowered by approximately 13%. The plasma tri- glycerides are lowered by about 10% and the HDL is somewhat increased by 2%. The action of soya protein presumably is not at the intestinal level. Soya contains a heterogeneous mixture of proteins, the bulk being 7S and 11S globulins, and variable amounts of minor components, including isoflavones ± consisting largely of genistein and daidzein ± phytic acid and saponins. All these components can have a contribution to the LDL low- ering effects of soya protein.
Studies in validated animal models and in humans have suggested that soya protein might directly activate LDL receptors in liver cells, which are chronically depressed in hypercholesterolemia. The responsible proteins include the 7S globulin, one of the major storage proteins of soya beans, and more precisely, the a and a' sub units. These proteins directly up- regulate LDL receptor expression by 50% or more. Soya protein, parti- cularly the 7S globulin, lowers hepatic production of LDL structural pro- tein, apo B, which is associated with a reduced rate of synthesis of cellular lipids, free cholesterol, cholesteryl esters and triacylglycerols. Some reports have also demonstrated that treatment with soya protein results in moderate reductions of serum triacylglycerols and small increases of HDL- cholesterol concentrations. Soya protein with higher levels of isoflavones might have more robust effects. Nevertheless, there is no evidence that purified soya isoflavones can improve plasma lipid concentrations.
Genistein might have more potent effects in tissues expressing ERb, including arterial walls. Genistein appears equally effective compared to 17b estradiol in inhibiting atherogenesis. Soya protein isolate with iso- flavones has been shown to lower diastolic blood pressure in women. The SPI improves vascular function by inhibition of coronary artery vascular constriction in response to acetylcholine (endothelium-dependent vas- cular response). This effect has not been seen with purified soya iso- flavones. Isoflavones might inhibit platelet activation and aggregation and reduce the amount of serotonin in the platelets, all of which could con- tribute to a reduction in coronary vasospasm and thrombosis.
Soya treatment significantly inhibits LDL oxidation. Studies suggest that the isoflavones also have effects on smooth muscle cells which are involved in atherosclerosis promotion and progression. Genistein inhibits the migration and proliferation of smooth muscle cells in vivo.
Food and Drug Administration guideline on food labelling
The validity of lowering total cholesterol and LDL-C by soya derivatives is recently supported by the US FDA, approving a health claim about the role of soya protein in reducing the risk of CHD. On 26 October 1999 the FDA finalised a rule that authorises the use, on food labels and in food labelling of products under FDA jurisdiction, of the health claims concerning the association between soya protein and reduced risk of CHD (Federal Register Part 11, 1999): `25 grams of soy proteina day, as part of a diet low insaturated fat and cholesterol, may reduce the risk of heart disease'. This authorisation is based on numerous publications on the subject and high consistency between the publications, almost all proving beneficial effects. The goal to reach a sufficient daily consumption is achievable through the amazing transformation possibilities of soya bean into various food constituents.
Conclusion
When added to maintenance of a body mass index under 25, a good physical condition, a lowered fat intake < 30% of total energy with SFAs < 10% of total energy, and avoidance of foods rich in cholesterol, soya protein may reduce the risk of heart disease through various mechanisms. The epidemiological and laboratory evidence is sufficient for the FDA to endorse the statement on food labels that soya may effectively reduce the risk of CHD.
References
Bendich, A. & Deckelbaum, R.J. (eds) (1997) Preventive Nutrition. The Com- prehensive Guide for Health Professionals. Humana Press, Totowa, New Jersey.
Federal Register Part II (1999) 21 CFR Part 101: Food labelling: Health Claims: Soy Protein and Coronary Hearth Disease: Final Rule, October 26 1999. Department of Health and Human Services, Food and Drug Administration. Massaro, M., Carluccio, M.A. & De Caterina, R. (1999) Direct vascular anti-
atherogenic effects of oleic acid: a clue to the cardioprotective effects of the Mediterranean diet. Cardiologia, 44, 507±13.