European Heart Journal Advance Access originally published online on October 21, 2008
European Heart Journal 2008 29(22):2710-2712; doi:10.1093/eurheartj/ehn468
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Effect of isoflavone supplement on endothelial function: does efficacy vary with atherosclerotic burden?
1 Department of Cardiovascular Medicine
2 Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan
* Corresponding author. Tel: +81 82 257 5540, Fax: +81 82 257 5554, Email: hteraga{at}hiroshima-u.ac.jp
This editorial refers to ‘Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke’
by Y.-H. Chan et al., on page 2800
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Endothelial dysfunction is widely considered as a prognostic marker of future cardiovascular events in clinical settings, even in patients who do not have untoward symptoms of cardiovascular disease.1 Thus, treatments aimed at restoring endothelial dysfunction have important implications Many studies have demonstrated that supplementary treatments can improve endothelial function.2 These favourable effects may be due to improved abnormal nitric oxide metabolism, mediated by mechanisms such as antioxidant or anti-inflammatory effects.
Isoflavones are contained in soy and are mainly phyto-oestrogens, which are chemically similar in structure to physiological oestrogens. It has been demonstrated that isoflavones can lower blood pressure and serum lipid levels, as well as function as antioxidant and anti-inflammatory agents in both laboratory and clinical settings.3 It is therefore apparent that treatment with isoflavones could ameliorate endothelial dysfunction. However, the effect of isoflavone supplements on endothelial function remains controversial.4–15
The results of several studies regarding the effect of isoflavone supplementation on endothelial function, as determined by assessing brachial flow-mediated dilatation (FMD), are summarized in Table 1. Because of the oestrogen-like nature of isoflavones, the subjects in many of these studies were menopausal women. It has been demonstrated that endothelial dysfunction often develops in women after the menopause2 and that FMD values can range from ‘severely reduced’ to ‘normal’ in these subjects.4–13 Therefore, it is not surprising that isoflavones had no effect on the endothelial function in subjects with normal FMD readings (>8.0%).5,6,12,13 On the other hand, isoflavone supplementation improved endothelial function in subjects with a reduced FMD (<6.0%),4,7,11,12 even if the patient was menopausal. Cuevas et al.7 demonstrated that isoflavones restored normal FMD readings, while both Simons et al.4 and Hallund et al.11 reported that isoflavones elevated FMD levels but also stated that these changes were not significant. Cupisti et al.14 reported that soy protein improves endothelial function in renal transplant patients with naturally reduced FMD values. This was the first study demonstrating the effect of isoflavone supplements on the endothelial function of patients with severe diseases. Unfortunately, this was not a randomized, double-blind, placebo-controlled study.
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Chan et al. demonstrated that oral isoflavone supplements, taken over 12 weeks, mildly but significantly restored FMD levels in patients with prior ischaemic stroke.15 This study therefore raised two important points that must be emphasized. First, this is the first study to confirm the effect of isoflavones on endothelial function in patients with established atherosclerosis in a randomized, double-blind, placebo-controlled trial. Secondly, this study demonstrated that the improved FMD measurements inversely correlated with baseline FMD levels with isoflavone treatment, indicating that isoflavones could restore endothelial function in patients with severe endothelial dysfunction. These findings imply that future clinical trials of isoflavone supplementation should be conducted mainly in patients with endothelial dysfunction.
In this report, the isoflavone-induced change in FMD values was only 1.2%. However, measurements of brachial artery diameter and increased brachial blood flow after hyperaemia did not change with treatment. Furthermore, although this was a parallel-group design study, the number of subjects was sufficient to detect a small FMD change.2 Therefore, the small but significant change in the observed FMD values has important implications. Despite these promising findings, future studies that examine the effect of the duration and dose of isoflavone supplements, as well as the type of delivery vehicle and source of isoflavones, are required to evaluate how well these supplements can improve endothelial function.
On the other hand, Chan et al.15 performed various subgroup analyses to examine the effect of isoflavone supplements on FMD values in the presence of atherosclerotic risk factors such as smoking and diabetic mellitus (DM). They found that isoflavone supplements had a favourable effect on FMD measurements in past and current smokers, as well as in patients without DM. However, this subgroups analysis may be incapable of detecting small but significant FMD changes due to the small sample size. Therefore, the minimal isoflavone effect on the endothelial function in patients with DM might have been due to the calculation of the type II error in the subgroup analysis. Implementation of counter-measures against secondary prevention especially in patients with DM and established atherosclerosis is now considerably critical in the clinical setting. Therefore, the effect of isoflavones on the endothelial function in patients with DM should be confirmed in further studies.
Chan et al.15 also demonstrated that isoflavone supplements lowered the detectable levels of C-reactive protein, an established inflammatory marker. On the other hand, antioxidant indicators, such as serum superoxide dismutase, 8-isoprostane, and malondialdehyde, were not affected by isoflavone supplementation. While their measurements of oxidative stress would be more complete if the urinary excretion of 8-isoprostane and 8-hydroxy-2'-deoxyguanosine had been measured, it is admirable that they endeavoured to examine the anti-inflammatory effect of isoflavones in patients with ischaemic stroke. Many studies have demonstrated the close relationship between inflammation and endothelial dysfunction, and the anti-inflammatory effects of isoflavones may be one mechanism responsible for restoring endothelial function in these cases.
In conclusion, Chan et al.15 demonstrated the effect of oral isoflavone supplements on the endothelial function in patients with ischaemic stroke in a randomized, double-blind, placebo-controlled trial. This effect may be more pronounced in patients with severe endothelial dysfunction, and further clinical studies using isoflavone supplements should be conducted in such patients. In addition, based on the findings of Chan et al.,15 it is anticipated that a large study will show that isoflavone supplementation has a positive influence on endothelial function in patients with DM.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehn409 
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[Abstract/Free Full Text] - Chan YH, Lau KK, Yiu KH, Li SW, Chan HT, Fong DY, Tam S, Lau CP, Tse HF. Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke. Eur Heart J (2008) 29:2800–2807. First published on September 23, 2008. doi:10.1093/eurheartj/ehn409.
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