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ABSTRACT INTRODUCTION
Background: Dietary isoflavones are thought to be cardioprotective
Cardiovascular disease is partially characterized by chronic
because of their structural similarity to estrogen. The reduction of
inflammation and increased expression of cell adhesion mole-
1260 Am J Clin Nutr 2005;82:1260 – 8. Printed in USA. © 2005 American Society for Nutrition
SOY ISOFLAVONES AND INFLAMMATORY FACTORS 1261
a beneficial effect on the vascular endothelium (7–10). Replace- (Nuthetal, Germany), the Royal Veterinary and Agricultural
ment of natural hormones in the form of hormone replacement University (Copenhagen, Denmark), and the Istituto Nazionale
therapy (HRT) was shown to decrease concentrations of di Ricerca per gli Alimenti e la Nutrizione (Rome, Italy). The
endothelin-1 (11) and cell adhesion molecules (12). Until re- study was advertised in the local media and via internal e-mails
cently, HRT was widely advocated as an effective means of and posters at each study center. Women who were interested in
delaying the progression of atherosclerosis in postmenopausal participating in the study contacted the investigators at the 4
women. However, the lack of efficacy of HRT with respect to centers and were interviewed over the telephone with a detailed
cardiovascular disease progression, evidence of an increased risk screening questionnaire. The women who met the inclusion cri-
of thrombosis (13) and increased concentrations of CRP (14, 15), teria were invited to take part in a physical examination and a
as well as an increased risk of hormone-dependent cancers has biochemical screening. All subjects had a body mass index
led to a search for alternative therapies to counteract the loss of (BMI; in kg/m2) between 20 and 32, had not menstruated in the
natural estrogens at menopause. previous 12 mo, had not received HRT in the previous 6 mo or
Isoflavones are phytoestrogens (chemicals that have a struc- antibiotics at screening in the previous 3 mo, and had not been
tural similarity to estrogen) and can bind to estrogen receptors. vaccinated in the previous 3 mo. In addition, women who had a
The most important dietary source of isoflavones is soy. Epide- history of cardiovascular disease, inflammatory disease, diabe-
miologic evidence in humans suggests that increased soy con- tes, or other significant medical history, or those who were re-
sumption is cardioprotective. This may be due to the ability of the ceiving certain medications known to affect the outcome mea-
isoflavones found in soy (genistein, daidzein, and glycitein) to sures (eg, antiinflammatories, hypertension medication, or
act as estrogen mimics or selective estrogen receptor modulators. statins) were excluded from the study. The subjects who were
included in the present study either did not smoke or smoked 쏝5
were apricot and almond, apple and cardamon, hazelnut, and Kingdom). ER␣, endothelial nitric oxide synthase, apolipopro-
raspberry. The subjects perceived the isoflavone-enriched and tein E, and cholesteryl ester transfer protein polymorphisms were
placebo foods as identical in appearance and taste. analyzed at the University of Reading, Reading, United King-
dom, with PCR amplification followed by enzymatic digestion
Diet diaries with specific restriction endonucleases (24, 25, 26). ER poly-
Dietary intake was evaluated at 3 time points during the study morphisms were analyzed by the collaborating group at the Karo-
by the collection of 3-d food records. Diet diaries were completed linska Institute, Stockholm, Sweden, with the use of restriction
at baseline (t0) and midway during each intervention period at 4 fragment length polymorphism analysis (27). The details of the
wk (t4 of the placebo and isoflavone intervention arms). Esti- primer sequences and PCR conditions are shown in Table 1.
mated amounts and weights of foods consumed were recorded in Isoflavone analysis
the diaries, and the diaries included 2 weekdays and 1 weekend
day. The dietary intake of the Danish, German, English, and Italian The isoflavone content of the enriched and unenriched cereal
subjects was analyzed at each center with the use of food- bars were measured at Wageningen UR, Netherlands, by HPLC
composition databases that were developed in each country. (28). Samples were extracted by stirring with 20 mL of a 50%
acetonitrile and 50% MilliQ water (Millipore BV, Amsterdam,
Sample collection, assays, and blood pressure Netherlands) mixture for 2 h at room temperature. The obtained
measurements solution was filtrated (Spartan 30, 0.45 m RC filter units; What-
man International Ltd, Maidstone, United Kingdom) and diluted
To standardize the food consumption of the subjects, a set with extraction medium if necessary. The sample was injected
low-fat (쏝15 g fat) recipe evening meal was consumed by the
TABLE 2
Urinary isoflavone yields at baseline (t0) and week 8 (t8) of the isoflavone and placebo intervention arms1
Isoflavones Placebo
t0 t8 t0 t8 P2
Genistein (mg/d) 0.37 앐 0.40 [114] 7.27 앐 3.58 [117] 0.37 앐 0.40 [117] 0.42 앐 0.32 [117] 쏝 0.0001
Daidzein (mg/d) 0.16 앐 0.22 [114] 5.76 앐 2.70 [117] 0.22 앐 0.30 [117] 0.22 앐 0.32 [117] 쏝 0.0001
Equol (mg/d) 0.08 앐 0.06 [114] 0.85 앐 1.43 [117] 0.08 앐 0.05 [117] 0.11 앐 0.08 [117] 쏝 0.0001
Equol producers3 0.10 앐 0.05 [31] 2.61 앐 1.73 [33] 0.09 앐 0.05 [33] 0.13 앐 0.09 [33] 쏝 0.0001
Equol nonproducers4 0.07 앐 0.06 [82] 0.15 앐 0.08 [83] 0.08 앐 0.05 [84] 0.094 앐 0.08 [83] 쏝 0.0001
1
All values are x 앐 SD, n in brackets.
2
P values are shown for the treatment effect within a stepwise-generated general linear mixed model. Differences from baseline were used as the response
variable. Only subjects with no missing data points were included in the analysis.
3
Urinary equol concentration 쏜0.45 mg/d.
4
Urinary equol concentration 쏝0.45 mg/d.
urinary daidzein concentrations of 31.4 and 786 nmol/L were VAR ҃ 1 if CRP 쏜1 and VAR ҃ 0 if CRP 울1. A stepwise
4.9% and 2.2%, respectively, and the interassay CVs were 2.4% variable selection procedure was then followed, with the fixed
intake or macronutrient intake were observed either across the remained in the data after log transformation, particularly at t4.
treatments or compared with baseline. Therefore, a logistic regression procedure was performed. The
No significant differences in plasma VCAM-1, ICAM-1, model fitted well to the data (P 쏜 0.20, Hosmer and Lemeshow
E-selectin, MCP-1, endothelin-1, and vWF concentrations were goodness-of-fit test) and the results were robust to the removal of
seen after the 2 intervention periods (Table 4). CRP concentra- influential points. An overall treatment effect including t4 and t8
tions, which were measured at t4 in addition to t8, showed an was shown (P 쏝 0.001). The odds ratio (and 95% Wald CI)
overall treatment effect (P 쏝 0.05), but not when the analysis was estimate for the treatment effect was 0.43 (0.27, 0.69). This
repeated without t4 (P 쏜 0.05). A high degree of skewness indicated that CRP concentrations at t4 and t8 were significantly
TABLE 4
Plasma inflammatory factor concentrations at baseline (t0) and week 8 (t8) of the isoflavone and placebo intervention arms1
Isoflavones Placebo
t0 t8 t0 t8 P2
vWF (IU/dL) 104.96 앐 53.77 [116] 105.46 앐 53.07 [116] 103.27 앐 49.46 [115] 99.99 앐 39.92 [116] 0.883
sICAM-1 (ng/mL) 215.04 앐 51.60 [116] 220.40 앐 52.77 [117] 217.45 앐 52.21 [116] 217.78 앐 48.28 [115] 0.147
sVCAM-1 (ng/mL) 504.79 앐 134.39 [114] 503.48 앐 146.66 [113] 498.14 앐 129.00 [114] 499.76 앐 135.88 [111] 0.475
E-selectin (ng/mL) 42.14 앐 15.41 [117] 42.17 앐 15.82 [117] 40.67 앐 15.05 [117] 41.26 앐 15.17 [117] 0.307
MCP-1 (ng/mL) 259.36 앐 95.93 [117] 260.43 앐 101.23 [117] 262.40 앐 85.74 [117] 260.49 앐 106.17 [117] 0.928
Endothelin-1 (pg/mL) 1.15 앐 0.39 [107] 1.20 앐 0.43 [107] 1.15 앐 0.39 [106] 1.21 앐 0.40 [107] 0.800
hs-CRP (mg/L)3 1.71 앐 1.89 [114] 1.70 앐 1.89 [113] 1.64 앐 1.73 [116] 1.76 앐 1.83 [113] 0.086
1
All values are x 앐 SD, n in brackets. vWF, von Willebrand Factor; sICAM-1, soluble intracellular adhesion molecule 1; sVCAM-1, soluble vascular cell
adhesion molecule 1; MCP-1, monocyte chemoattractant protein 1; hs-CRP, highly sensitive C-reactive protein.
2
P values are shown for the treatment effect within a stepwise-generated general linear mixed model. Differences from baseline were used as the response
variable. Only subjects with no missing data points were included in the analysis. No significant differences were observed between the isoflavone and placebo
intervention arms.
3
Hs-CRP was analyzed at t4 in addition to t0 and t8. The mean results at t4 were 1.54 앐 1.67 mg/L (isoflavones) and 1.89 앐 3.24 mg/L (placebo). A
significant effect of treatment on CRP concentrations was seen when change from baseline at t4 and t8 was considered (P ҃ 0.015); however, t4 data were highly
skewed despite log transformation, and the statistical data at t4 were not robust.
1266 HALL ET AL
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