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Effects of Dietary Intake of Soy Protein and Isoflavones on Cardiovascular Disease Risk Factors in High Risk, Middle-Aged Men in Scotland

Department of Preventive Nutritional Medicine, Research Institute for Production Development (M.S.)
Graduate School of Human & Environmental Studies, Kyoto University, (T.K., M.N.)
WHO Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Kyoto (Y.Y.), Fujicco Co., Ltd., Kobe (T.T.), JAPAN
Wigan and Bolton Health Authority, Directorate of Public Health, Wigan (N.B., C.B.), SCOTLAND, HSMC
Department of Public Health, University of Birmingham, Birmingham (L.A.), ENGLAND

Address reprint requests to: Yukio Yamori, MD, PhD, FACN, WHO Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Kokusaikenju Bldg, 86, Shimobanba-cho, Sakyo-ku, Kyoto 6068431, JAPAN. E-mail: Yukio.Yamori{at}ma3.seikyou.ne.jp

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: To investigate the effects of soy protein and isoflavones on blood pressure (BP) and cholesterol levels among high risk middle-aged Scottish men.

Design: A randomized, double-blind, placebo-controlled, parallel-group dietary intervention study

Setting: Inhabitants on Isles of Lewis and Harris in Scotland

Subjects: Sixty-one men with relatively higher BP and/or total cholesterol (TC) levels aged 45 to 59 went through the dietary intervention.

Intervention: Diets containing at least 20 g of soy protein and 80 mg of isoflavones were compared to the placebo diets. Intervention period was 5 weeks duration.

Results: Significant difference was found in 24-hour urinary isoflavone excretion between the two groups after intervention. Significant reductions from the baselines were observed in systolic BP (SBP) and diastolic BP (DBP), TC and non-high density lipoprotein cholesterol (non-HDL-C) in the soy-containing diet group, but not in the olive oil containing active placebo group. Significant increases in high density lipoprotein cholesterol (HDL-C) were observed in both groups.

Conclusion: Dietary intakes of soy protein (at least 20 g) and isoflavones (at least 80 mg) for 5 weeks would be effective in reducing CHD risk among high-risk, middle-aged men.

Key words: soy protein, isoflavone, blood pressure, cholesterol, middle-aged, men

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Soybeans are one of the traditional foods consumed mainly in Asian countries such as China and Japan. It has been reported in epidemiological studies that Asian populations who consume soy foods in their daily diet have a lower incidence of cardiovascular disease (CVD) than those who consume a typical Western diet [1]. It was reported that soy protein and/or isoflavones improve lipid profiles [2] and exert antiatherogenic effects [3]. We have shown by worldwide epidemiological surveys that the age-adjusted mortality rates of coronary heart disease (CHD) were positively related with total cholesterol (TC) levels and inversely related with 24-hour urinary isoflavone excretions.[4]. Furthermore, some studies showed that soy isoflavones had beneficial effects on reducing blood pressure (BP) [5–7].

CHD is one of the major causes of death in Scotland, where the CHD death rate is among the highest in Europe [8]. Scottish people consume many high-fat foods and less vegetables or fruits [9]. Our previous epidemiological study also showed that 24-hour urinary isoflavone excretion among Scottish people was very low. These dietary habits may be related to the high prevalence of CHD [4,10,11].

We hypothesize that the daily intake of soybean products as a dietary supplement may reduce CHD risk factors among people whose daily consumption of soy products is low. In the previous intervention study, we showed the beneficial effects of a soybean diet on CVD risk factors in Japanese immigrants living in Hawaii [12]. Therefore, in the present study, we designed an intervention study to investigate the effects of soy protein and isoflavones on CVD risk factors such as BP and TC among high risk middle-aged people in Scotland. In this report, however, we focused on the results of men only because we did not obtain a sufficiently good compliance from women, judging from the urinary isoflavone excretion.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Subjects
A total of 156 male inhabitants on the Isles of Lewis and Harris (northwest part of Scotland), aged 45–59, were identified at random from age-gender registers of 12 local general practitioners and recruited by letter to participate in a health survey in April 2001. Out of 156, 61 males were screened at the health survey for the intervention study. Inclusion criteria were systolic blood pressure (SBP); 130 mmHg or higher and/or TC; 220 mg/dL or higher. Exclusion criteria included the presence of diabetes mellitus and any other chronic illness that could affect BP or blood lipid concentration or limit the individual’s ability to participate in the study, and the use of anti-hypertensive drugs, cholesterol-lowering drugs and any medication known to affect BP or lipid concentrations. Subjects who withdrew during the intervention period or who failed to collect blood samples were excluded from the analysis. The study design was approved by the Research Ethics Committee of the Western Isles Health Board and written informed consent was obtained from each participant.

Study Design
The study was performed in two separate stages, a health survey for the screening of high risk subjects as the first stage and a following 5-week randomized, double-blind, placebo-controlled, parallel-group trial with a follow-up examination at the end of the study. During the health survey, anthropometric measurements were carried out for height, weight and BP. Height and weight were measured in bare feet and in right clothing. BP was measured at the right arm after 10 minutes rest in a seated position using an automated sphygmomanometer (HEM-970; OMRON, Kyoto, Japan) and these measurement were repeated three times. Fourteen ml of overnight fasting blood samples were collected, and TC and HDL-C were measured using an Express Plus Operator machine (Ciba Corning Diagnostics Corp. Westlake Village, USA) [13]. Twenty-four-hour urine specimens were collected using a standard aliquot cup that allowed the participants to repeatedly collect an exact portion of voided urine [13,14] after the collection procedure had been carefully explained to each participant by a trained investigator. These urine specimens were used for the analyses of isoflavones using high-performance liquid chromatography (HPLC) and of creatinine [13]. The analytical methods used for isoflavones were described by Uesugi et al.[15]

All blood and urine samples were analyzed centrally in the WHO Collaborating Center for Research on Primary Prevention of Cardiovascular Diseases, Graduate School of Human and Environmental Studies, Kyoto University, Kyoto, Japan. Serum TC was also analyzed on-site to detect high risk subjects. This data was used only for the above purpose. A structured questionnaire to obtain information about demographic characteristics, medical history of CVD and medication use was used for face-to-face interviews [13]. More details of the study methods were published previously [13].

Sixty-one subjects identified as a high risk group were assigned randomly to either soy-containing diets (Soy) or active placebo diets (Placebo). In the Soy group, soy powder containing at least 20 g of soy protein and 80 mg of isoflavones per day, mixed in cereals, biscuits and bread rolls, were consumed in addition to the usual diet. The Placebo group consumed cereals, biscuits and bread rolls that were indistinguishable from the soy-containing diets in addition to the usual diet. The dietary data are shown in Table 1. Prior to commencement of the dietary intervention, the subjects were given detailed written and verbal information about the second stage. They were required to choose a combination of either 2 bread rolls and 2 cereal bars or 2 bread rolls and a packet of biscuits everyday and to consume them at any time of day. They were also asked to record their intervention consumption. After the 5-week intervention period, the participants went through a follow-up survey, which consisted of weight and BP measurements and the collection of blood and 24-hour urine.

Statistical Analysis
Statistical analyses were conducted with SPSS 10.0J for Windows (SPSS Japan Inc., Tokyo, Japan). Differences in frequency were tested by the ² test. Between-groups differences in urinary isoflavone excretions, SBP, DBP, TC, HDL-C, non-HDL-C and non-HDL-C/HDL-C ratio were tested by the unpaired Student’s t test. Within-groups differences were also analyzed using the paired Student’s t test by group for the above variables. Data are expressed as the mean ± SEM if not specified. Values of p < 0.05 were considered significant.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Out of 61 subjects, eight (13%) subjects withdrew during the 5-week intervention and 53 subjects returned for the follow-up examination. Two subjects were excluded prior to data analysis because of missing the blood sampling. Based on the record forms of food consumption, one subject was excluded prior to data analysis for noncompliance with the diet. Therefore, the data from 50 subjects were used for analysis and the numbers of the subjects in each group were 25. Between the two intervention groups, there were no significant differences in age, weight and BMI (Table 2).

View larger version (14K): [in this window] [in a new window]   Fig. 1. Effects of the soy-containing diets (Soy) and the placebo diets (Placebo) on systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), non-HDL-C and non-HDL-C to HDL-C ratio. Values are shown as percentage changes from the baselines (|a@) and S.D. There was no significant difference between the two groups in either parameter.

	DISCUSSION

In the present study, we observed a reduction in SBP and DBP in the Soy group. Washburn et al. reported that 40 g of soy protein containing 68 mg of phytoestrogens reduced BP in perimenopausal women [17]. Teede et al. also reported that a 3-month intervention with 40 g of soy protein containing 118 mg of isoflavones reduced SBP, mean BP, and DBP in healthy men and women [18]. Furthermore, Rivas et al. observed that soy milk lowered BP in men and women with mild-to-moderate hypertension and that this hypotensive effect was correlated with urinary excretion of the isoflavonoid genistein [19]. Although the present study was tested over a shorter period and with a smaller amount of soy protein and isoflavone supplementation, our findings were consistent with these previous studies.

Isoflavones are one of the phytoestrogens, which are structurally similar to estrogen and exhibit both estrogen agonistic and antagonistic activities [20]. Estrogen replacement therapy has been shown to attenuate BP elevation in postmenopausal women [21]. It has also been documented that the incidence of hypertension is significantly lower in premenopausal women than in age-matched men or postmenopausal women [22,23]. Experimental evidence suggests that estrogen prevents BP elevation through an increase in the biological actions of nitric oxide (NO) and a decrease in the actions of angiotensin [24]. In a previous study, we showed that isoflavones attenuated postovariectomized blood pressure elevation by accelerating NO production in stroke-prone spontaneously hypertensive rats (SHRSP) [25]. We also found that isoflavones promote the mRNA expression of endothelial nitric oxide synthase in the aorta and have anti-hypertensive effects in SHRSP [26]. Considering these studies, we could consider the possibility that isoflavones exhibit anti-hypertensive activities like estrogen even in men through an increase in the actions of NO.

The most consistently demonstrated beneficial effect of soy has been on lipids [2]. In a meta-analysis of 38 controlled clinical trials, an average consumption of 47 g of soy protein daily (primarily in subjects with hyperlipidemia) significantly decreased the serum concentrations of TC and low density lipoprotein cholesterol (LDL-C) and triglycerides without significantly affecting the serum HDL-C concentration [2]. In the present study, we observed significant improvements in TC, HDL-C, non-HDL-C and non-HDL-C/HDL-C ratio in the Soy group. Our findings on lipid profiles agree with the results of the above meta-analysis [2], although we observed a significant increase in HDL-C as well.

Isoflavones have also been implicated as the components of soy that improve lipid profiles. Gardner reported that TC and LDL-C decreased more in a group receiving soy protein containing 80 mg of aglycone isoflavones than in a group receiving trace amounts of isoflavones [27]. Moreover, Crouse et al. reported a dose-response effect of increasing amounts of isoflavones on TC and LDL-C levels using isolated soy protein containing 3, 27, 37, or 62 mg of isoflavones in mildly hypercholesterolemic men and women [28]. Considering these studies, not only soy protein but also isoflavones seem to have beneficial effects on lipid profiles which seem to be dose-dependent. On the other hand, Baum et al. tested the effects of soy protein containing 2 doses of isoflavones (56 and 90 mg/day) and found an improvement in HDL-C, non-HDL-C and TC to HDL-C in both groups [29]. Even 56 mg of isoflavones seem to be enough to improve lipid profiles, considering other studies [28,30].

In the present study, we observed a significant increase in HDL-C not only in the Soy group but also in the Placebo group. We considered a few possible reasons for this result. For one, the subjects might have changed their daily diet patterns. Although they were required to consume a certain amount of study foods in addition to their daily diet, they might not have been able to meet the requirements unless they reduced their own daily food intake. Moreover, we informed the subjects as to the advantages of traditional Japanese foods such as soy products and fish throughout the study period. Both of these may have possibly resulted in a reduced intake of animal fat, which is rich in their daily diet, and increased their vegetable and fish intake. It is known that substituting vegetables and fish, rich in unsaturated fatty acids, for animal meat, rich in saturated fatty acids, improves lipid profiles [31]. Secondly, we considered the effects of olive oil, which was used in the Placebo. Increased dietary intake of the olive oil has been found to lower several cardiovascular risk factors [32,33]. Therefore, we added a small amount of olive oil to the Placebo (2.6 g/day) because we also needed to add something beneficial to this from an ethical point of view. It has been reported that olive oil improves lipid profiles and that polyunsaturated fatty acids in olive oil increase HDL-C [34–38].

In the present study, we observed a significant decrease in TC and non-HDL-C as well as the increase in HDL-C in the Soy group. However, the differences between the two groups were not significant in any parameter, although the changes in TC and non-HDL-C were greater in the Soy group than in the Placebo group. We discussed some of the possible reasons we did not observe a significant difference in the lipid profiles between the two groups. Firstly, the intervention duration might have been comparatively short considering the amount of soy protein and isoflavones consumed in the study foods. The amount of soy protein used in this study was selected so as to be similar to the amount (25g) recommended by the Food and Drug Administration (FDA) in 1999 as a health claim for reducing the risk of heart disease [39]. Previous studies which reported a significant improvement in lipid profiles using similar amounts of soy protein continued the intervention for a longer period than the 5 weeks adopted in our study [40,28]. On the other hand, the above-mentioned meta-analysis on the effects of soy protein, which reported significant effects on lipid profiles, calculated the average intake of soy protein as 47 g per day [2]. Secondly, the effects of the study foods might have been reduced to some extent; we did not impose any restrictions or make any requests regarding the participants’ daily diet, and only asked that they consume a certain amount of the study foods. Thirdly, we also considered that, regardless of the dosages of soy protein or isoflavones ingested, or even if the amount of those nutrients was sufficient, the properties of serum lipids per se may react more slowly than expected to the changes in individual dietary patterns.

In addition to the effects of soy protein and isoflavones on blood pressure and lipid metabolism, soy has been reported to improve platelet function, which also plays an important role in cardiovascular system. It has been reported that the inhibitory effects of soy isoflavone genistein on thrombotic vessel occlusion in the mouse femoral artery using a photochemical reaction, and in vitro platelet aggregation in whole blood measured by single platelet counting [41]. An inhibitory effect of isoflavone-rich soy protein on platelet aggregability has been reported in female rhesus monkey [42]. Therefore, platelet function in our study might have been changed as well by the supplement of soy protein and isoflavones. However, most of the reports are in vitro studies or animal studies, and there are few report on in vitro studies. This is because platelet rich plasma has a readily-destroyed nature and consequently quit difficult to observe platelet function in an epidemiological set-up. Further studies are required to determine whether the effects of isoflavones and soy protein on cardiovascular system reported in the current in vitro or animal studies are applicable to in vivo condition.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Our findings confirmed that dietary intake of at least 20 g of soy protein and at least 80 mg of isoflavones for 5 weeks improved BP, TC, HDL-C and non-HDL-C in high-risk, middle-aged men in Scotland, whose consumption of soy products is much lower than that of Japanese. Further studies are needed to obtain more conclusive results.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
We thank all the participants for their invaluable cooperation and Dr. Dalton Hill and his laboratory staff for their much appreciated assistance in the study and laboratory work at the Western Isles Hospital for the quick plasma lipid analysis for detecting relatively high risk participants. Study foods were kindly provided by MIKI Corporation, Nishinomiya, Japan, Kellogg (Australia) Pty. Ltd., Botany, Australia, MacKinnon’s Bakery, Stornoway, UK and KITII Corporation Ltd., Tokyo, Japan.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
This study was supported by an International Research Grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

Received May 14, 2003. Accepted December 15, 2003.

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TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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