Skip Navigation



European Heart Journal Advance Access published online on September 23, 2008
European Heart Journal, doi:10.1093/eurheartj/ehn409
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/22/2800    most recent
ehn409v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Chan, Y.-H.
Right arrow Articles by Tse, H.-F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chan, Y.-H.
Right arrow Articles by Tse, H.-F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Reduction of C-reactive protein with isoflavone supplement reverses endothelial dysfunction in patients with ischaemic stroke

Yap-Hang Chan1, Kui-Kai Lau1, Kai-Hang Yiu1, Sheung-Wai Li2, Hiu-Ting Chan1, Daniel Yee-Tak Fong3, Sidney Tam4, Chu-Pak Lau1 and Hung-Fat Tse1,5,*

1 Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, People’s Republic of China
2 Department of Medicine, Tung Wah Hospital, Hong Kong, People’s Republic of China
3 Department of Nursing Studies, The University of Hong Kong, Hong Kong, People’s Republic of China
4 Department of Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong, People’s Republic of China
5 Li Ka Shing Faculty of Medicine, Research Centre of Heart, Brain, Hormone and Healthy Ageing, The University of Hong Kong, Hong Kong, People’s Republic of China

Received 16 April 2008; revised 26 July 2008; accepted 21 August 2008.

*Corresponding author. Tel: +852 2855 3598, Fax: +852 2818 6304, Email: hftse{at}hkucc.hku.hk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
Aims: To investigate the effect of oral isoflavone supplement on vascular endothelial function in patients with established cardiovascular disease.

Methods and results: A randomized, double-blinded, placebo-controlled trial was performed to determine the effects of isoflavone supplement (80 mg/day, n = 50) vs. placebo (n = 52) for 12 weeks on brachial flow-mediated dilatation (FMD) in patients with prior ischaemic stroke. Compared with controls, FMD at 12 weeks was significantly greater in isoflavone-treated patients [treatment effect 1.0%, 95% confidence interval (95% CI) 0.1–2.0, P = 0.035]. Adjusted for baseline differences in FMD, isoflavone treatment was independently associated with significantly less impairment of FMD at 12 weeks (odds ratio 0.32, 95% CI 0.13–0.80, P = 0.014). The absolute treatment effect of isoflavone on brachial FMD was inversely related to baseline FMD (r = –0.51, P < 0.001), suggesting that vasoprotective effect of isoflavone was more pronounced in patients with more severe endothelial dysfunction. Moreover, isoflavone treatment for 12 weeks resulted in a significant decrease in serum high-sensitivity (hs)-C-reactive protein level (treatment effect –1.7 mg/L, 95% CI –3.3 to –0.1, P = 0.033). Nevertheless, isoflavone did not have any significant treatment effects on nitroglycerin-mediated dilatation, blood pressure, heart rate, serum levels of fasting glucose and insulin, haemoglobin A1c, and oxidative stress as determined by serum superoxide dismutase, 8-isoprostane, and malondialdehyde (all P > 0.05).

Conclusion: This study demonstrated that 12 week isoflavone treatment reduced serum hs-C-reactive protein and improved brachial FMD in patients with clinically manifest atherosclerosis, thus reversing their endothelial dysfunction status. These findings may have important implication for the use of isoflavone for secondary prevention in patients with cardiovascular disease, on top of conventional interventions.

Key Words: Isoflavone • Endothelial dysfunction • C-reactive protein


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 
In recent years, epidemiological studies have demonstrated that populations with higher legume, fruit, and vegetable consumption had a lower incidence of cardiovascular events.1–3 This led to immense interest in the potential role of plant-derived polyphenolic chemicals for the prevention of cardiovascular diseases.4–7 Biochemically characterized by the presence of more than one phenol unit per molecule, the diverse family of polyphenols has been recognized for its subclasses of phytoestrogens and flavanols. Phytoestrogens are mainly found in soya beans, chick peas, and clovers. Experimental studies suggested that they exhibit versatile biochemical actions,8 including anti-oxidant and hypocholesterolaemic effects, direct action on vasorelaxation, and platelet function modulation. These and their peculiar function as partial estrogen agonist provided potential mechanisms for cardiovascular protection. Indeed, our recent study also showed that a higher intake level of isoflavone, a major class of phytoestrogens, was associated with better vascular endothelial function and lower carotid atherosclerotic burden in patients with high risk for cardiovascular events.9 Despite previous studies which documented the potentiating effect of isoflavone on vascular endothelial function in healthy subjects, no studies to date have yet provided an answer to whether isoflavone exerted cardiovascular benefits in patients with established atherosclerosis and endothelial dysfunction. Moreover, whether subjects who were already on regular conventional medical treatments received additional benefits from this novel intervention also remained unclear.

Therefore, this study was carried out to investigate the effects of 12 week supplementation of isoflavone on the brachial flow-mediated dilatation (FMD) in a group of patients with clinically manifest atherosclerosis and impaired endothelial function.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 References
 
Patients
A total of 102 patients with primary or recurrent ischaemic stroke (>6 months) were recruited from our medical outpatient clinics during the period January–June 2006. Diagnosis was made on the basis of clinical examinations and computed tomography brain imaging, according to current guidelines.10 Excluded from the study were patients with cardioembolic stroke, paroxysmal or chronic atrial fibrillation, dilated cardiomyopathy, significant valvular heart disease, New York Heart Association class III or IV heart failure, significant renal impairment (creatinine >220 mmol/L), liver failure, thyroid disorders, endometrial or breast cancer, lactating or pregnant females and any recent stroke, myocardial infarction, unstable angina, coronary revascularization, or acute heart failure within the past 6 months. All patients had stable cardiovascular medications and diet pattern for at least 3 months prior to the day of recruitment. The study fully conformed to the Declaration of Helsinki, and the research protocol was approved by the institutional review board. A written informed consent was obtained for each subject. This study was registered with www.hkclinicaltrials.com, number HKCTR-163.

Study design and materials
The study design has been shown in Figure 1. Initially, 200 eligible patients as determined from medical records were interviewed by phone for recruitment into the study. Among them, 106 patients verbally consented to participate in the study. During the initial assessment, four patients were deemed ineligible for the exclusion criteria. The remaining 102 patients were randomized to receive either 80 mg isoflavone or placebo once daily for a period of 12 weeks, according to a randomization list generated by computer. Specifically, an independent party of the hospital pharmacy unit received the identity list of recruited patients from the investigators and was requested to assign each patient into one of the intervention groups by a randomly generated number (0 or 1) from computer. The list was kept concealed from the investigators by the hospital pharmacy unit until the end of trial, i.e. all final reassessments were completed. The investigators were required to write a formal application to request for the release of allocation sequence. Block randomizations of n = 20 were used throughout the drug-dispensing procedure. The medications were indistinguishable in packing and were dispensed by the pharmacists independent of the investigators, such that any drug label was double-blinded to both patients and investigators. The isoflavone and placebo were produced in the form of capsules and contained 80 mg/day purified isoflavone extracted from soya beans and powdered cellulose, respectively. The specific dosage of 80 mg/day was chosen because previous studies have shown that isoflavone at this dosage was well tolerated by both men and women without significant side effects.11,12


Figure 1
View larger version (12K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Figure 1 Study flowchart. A total of 200 eligible ischaemic stroke patients as determined from medical records were interviewed by phone for enrolment into the study. Of them, 106 patients verbally consented to participate in the study. During the initial assessment, four patients were deemed ineligible. The 102 patients fully conforming to the inclusion/exclusion criteria were formally recruited and assessed (week 0). They were randomized to receive either daily 80 mg isoflavone (n = 50) or placebo (n = 52). Re-assessment was performed for all patients after 12 week treatment. Six patients had defaulted for the follow-up. Intention-to-treat principles were observed throughout the entire analysis.

 
All patients had ultrasound vascular examinations performed during baseline assessment at week 0 and the final follow-up at week 12. During each visit, heart rate and systolic and diastolic blood pressures were measured. Fasting blood samples were taken to determine serum creatinine, lipid profile, blood glucose, insulin, glycosylated haemoglobin A1c (HbA1c), high-sensitivity (hs)-C-reactive protein, and oxidative stress as measured by serum superoxide dismutase, 8-isoprostane, and malondialdehyde.

Demographic, dietary, and laboratory evaluations
Baseline demographic data, cardiovascular risk factors, and cardiovascular medications were documented. Cardiovascular risk factors, including tobacco smoking, diabetes, hypercholesterolaemia, hypertension, and body mass index (BMI) were assessed. Hypertension was defined as either resting systolic or diastolic blood pressure ≥140/90 mmHg at two different clinic visits or on medications. Diabetes mellitus was defined as serum fasting glucose ≥7.0 mmol/L or on medications. Hypercholesterolaemia was defined as a fasting total plasma cholesterol level of ≥4.9 mmol/L or on cholesterol-lowering medications. BMI was calculated as weight in kilograms divided by square of height in metres, as yielded by measurements during the visit. Smoking status was recorded as either past smoker, current smoker, or non-smoker. Education level was divided into five categories, namely uneducated, primary, secondary, post-secondary, and tertiary, and was graded on a 0–4 scale. Family history of coronary artery disease was considered positive in first-degree relatives with diseases diagnosed at an age younger than 55 years. Oral medications defined as having anti-inflammatory effects included aspirin, clopidogrel, beta-blockers, angiotensin-converting enzyme-inhibitors, statins, non-steroidal anti-inflammatory drugs, and steroid.13–15 Dietary intakes of study patients were estimated using a validated Food Frequency Questionnaire (FFQ) designed for Chinese populations.16–18 The FFQ was specially structured to capture isoflavone contents in the diet, and food models were used to help patients in the quantification of their diet.

Vascular ultrasound examination
Vascular ultrasound was performed with a high-resolution ultrasound system (Agilent Sonos 5500, Philips, USA) using a 7.5 MHz linear array transducer by a single experienced operator without the knowledge of intervention status of the subjects. All the scanned images were stored digitally and analysed offline by the same operator who was blinded to the identity of subjects studied.

Patients were studied in the fasting state. To avoid any systematic differences in diurnal variation of vascular reactivity, all studies were performed in the morning (time range 0900–1200). All vasoactive medications, cigarette smoking, caffeine drink, and alcohol consumption were withheld for at least 12 h before the assessment. As described previously,9,19 longitudinal scans of the brachial artery were obtained at rest, and then FMD was induced by the inflation of a pneumatic tourniquet placed on the forearm to a pressure of 250 mmHg for 5 min. The cuff was then released, and serial imaging of the brachial artery was recorded for 5 min. The brachial artery was allowed to return to baseline. Finally, the brachial artery was then measured again at 5 min after the administration of 400 µg sublingual nitroglycerin spray. FMD was defined as the percentage change in the brachial artery diameter by 1 min after cuff deflation from that on the baseline scan. Nitroglycerin-mediated dilatation (NMD) was defined as the percentage change in the brachial artery diameter by 5 min after nitrate administration. Doppler-derived arterial flow was also measured at rest and during hyperaemia, as described previously.19 Interobserver variability testing for FMD measurement revealed an interclass correlation coefficient (two-way mixed, random-effect model, absolute agreement) of 0.83 [95% confidence interval (95% CI) 0.22–0.97, P = 0.012], with a mean absolute difference of 0.6 ± 0.8%. An FMD value of ≤3.7% was pre-determined to be the cut-off for impairment prior to the start of the study. This determination was based on previous observation that healthy elderly subjects had a mean FMD of 3–4%.20 The specific value of 3.7% was adopted since it was independently identified as the mean FMD by two well-structured studies21,22 in patients with risk factors but no history of cardiovascular disease, and with mean ages similar to ischaemic stroke patients recruited by our previous studies.23

Statistical analysis
Primary endpoint was the change from baseline in endothelium-dependent FMD. Secondary endpoints were changes in endothelium-independent NMD, heart rate, systolic and diastolic blood pressures, and serum markers of oxidative stress, inflammation, glycaemic control, and lipid profile.

On the basis of the data from our observational study,9 we took a standard deviation of 2.8% for the change of FMD at 12 week follow-up from baseline. In order to have at least 80% power to detect a difference of 1.6% (40 percentage points) between the control and the treatment group with a 5% maximum false-positive error rate, we would need a total of 96 patients with 1:1 randomization to isoflavone treatment (n = 48) and placebo (n = 48) by a two-tailed t-test. If 5% dropout rate is assumed, at least 102 patients would need to be enrolled.

Continuous variables were presented as mean ± standard deviation. Clinical characteristics at baseline between the isoflavone and control groups were compared by Student’s t-test for continuous measurements and {chi}2 test for binary measurements. Correlations were expressed in terms of Pearson’s correlation coefficient derived from the absolute values or absolute changes of parameters concerned. The analysis was performed in all randomized subjects according to the intention-to-treat principle. Specifically, patients defaulted before the follow-up measurements were made had the missing values replaced by the baseline values. The analysis of covariance (ANCOVA) was then used to make the comparisons after adjusting for the baseline values concerned. Adequacy of the model was checked by examining the standardized residuals. We estimated treatment effects by computing the differences (isoflavone vs. control) between the adjusted means and their corresponding 95% CIs. To examine the sensitivity of conclusions due to missing values, the analysis was repeated only among subjects with all measurements taken. Logistic regression was performed to examine the effect of isoflavone treatment on FMD impairment, after adjusting for baseline FMD. Hosmer and Lemeshow’s test of goodness of fit was used to evaluate overall fit of the model. Report of this trial fully conformed to the CONSORT guidelines.24 All statistical analyses were performed using the SPSS program (version 15.0). All statistical tests were two-sided and used 0.05 as the nominal level of significance.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 References
 
Effects of 12 week isoflavone supplementation
The baseline characteristics of the study population are shown in Table 1. Their overall mean age was 66 ± 10 years, and 66% were men. Among these patients, 9% had recurrent stroke, 10% had coronary artery disease, and 47% had diabetes mellitus. The vast majority of the patients had an impaired FMD <3.7% at baseline (81/102, 80%).


View this table:
[in this window]
[in a new window]

  		Table 1 Baseline characteristics of patients completing the 12 week follow-up

 
Of the 102 patients randomized in the trial, 96 patients completed the final follow-up after 12 week intervention, and six patients defaulted for the follow-up (Figure 1). Using FMD < 3.7% as cut-off, the prevalence of impaired FMD was similar between the two groups at baseline (isoflavone: 82% vs. control: 79%, P = 0.69). The capsules were well tolerated by patients and no significant side effects were noted.

Compared with controls, FMD at the 12 week follow-up was significantly greater in isoflavone-treated patients (treatment effect 1.0%, 95% CI 0.1–2.0, P = 0.035, Table 2). Furthermore, the prevalence of impaired FMD at 12 weeks became significantly lower in isoflavone-treated patients than controls (isoflavone: 58% vs. control: 79%, P = 0.023). After adjusting for baseline differences in FMD by logistic regression analysis, isoflavone treatment was independently associated with a significantly lower prevalence of impaired FMD at 12 weeks (odds ratio 0.32, 95% CI 0.13–0.80, P = 0.014, Hosmer and Lemeshow’s test of goodness of fit P = 0.367). The brachial artery diameter and increase in blood flow in response to hyperaemia did not significantly change after 12 week intervention (P > 0.05). In addition, the absolute treatment effect of isoflavone on brachial FMD was inversely related to baseline FMD (Pearson’s correlation coefficient –0.514, P < 0.001), suggesting that the beneficial effect of isoflavone was more pronounced in patients with more severe endothelial dysfunction.


View this table:
[in this window]
[in a new window]

  		Table 2 Twelve week treatment effects of isoflavone on brachial endothelial function, and haemodynamic and biochemical parameters

 
Subgroup analyses were performed to determine the treatment effects of isoflavone therapy in smokers vs. non-smokers and in diabetics vs. non-diabetics. The treatment effect of isoflavone on FMD was observed only in past or current smokers (treatment effect 1.0%, 95% CI 0.0–1.9, P = 0.045), but not in non-smokers (P > 0.05). In contrast, the therapeutic effect of isoflavone was prominent in non-diabetics (treatment effect 1.6%, 95% CI 0.2–3.1, P = 0.030) than in diabetic patients (treatment effect 0.4%, 95% CI –1.0 to 1.7, P = 0.596). In fact, each unit increase (%) in baseline HbA1c level was independently predictive of reduced FMD response to treatment by 0.3% (treatment effect –0.3%, 95% CI –0.7 to 0.0, P = 0.047).

Furthermore, exploratory analysis revealed a treatment effect of isoflavone on hs-C-reactive protein level (treatment effect –1.7 mg/L, 95% CI –3.3 to –0.1, P = 0.033, Table 2), adjusting for baseline differences in hs-C-reactive protein level and the use of anti-inflammatory medications. Moreover, hs-C-reactive protein level was significantly lower in patients with normalized FMD than those with impaired FMD at 12 weeks (normal FMD 2.8 ± 0.5 mg/L vs. impaired FMD 4.4 ± 0.5 mg/L, P = 0.037).

Nevertheless, isoflavone treatment for 12 weeks did not have significant effects on NMD, systolic and diastolic blood pressures, heart rate, and serum levels of fasting triglyceride, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, blood glucose, insulin, HbA1c, and oxidative stress as measured by malondialdehyde, 8b-isoprostane, and superoxide dismutase (ANCOVA: all P > 0.05, Table 2).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 References
 
To our knowledge, this was the first randomized controlled trial studying the effect of isoflavone supplement on vascular function in patients with established cardiovascular disease. Results of this study demonstrated that chronic isoflavone supplement at a dosage of 80 mg/day improved vascular endothelial function in patients with prior history of ischaemic stroke. Endothelial dysfunction, as reflected by the impairment of endothelium-dependent FMD, has been shown to be associated with adverse clinical outcomes in patients with cardiovascular disease.25–27 The findings suggest that isoflavone exerts a secondary vascular protective effect in patients with established atherosclerosis, despite a lack of effect on conventional cardiovascular risk factors including blood pressure, lipid profile, and blood glucose.

The precise mechanisms that mediate the vasoactive effects of isoflavone resulting in a change in FMD had remained unclear. Prior experimental studies showed that isoflavone had a stimulatory effect on endothelial function via the activation of endothelial nitric oxide synthase system within a short period of exposure.28,29 Acute positive vascular effects were also reported in interventional studies using oral doses of flavanols,5 which were strong antioxidants both in vitro and in vivo. In our study, there were no significant changes in serum oxidative stress as determined by the serum levels of both peroxidation products and antioxidant enzyme activity after 12 week isoflavone treatment. The findings thus suggested against that antioxidant effect was an important mechanism that mediated the vasoprotective effects of isoflavone in patients with established atherosclerosis.

Soya protein with isoflavone has been shown to be associated with significant decreases in serum total cholesterol and LDL cholesterol and significant increases in serum HDL cholesterol. The therapeutic effects on serum lipid appeared to be directly related to the initial serum cholesterol.30,31 However, whether such hypocholesterolaemic effect could be attributed to isoflavone or soya protein has remained controversial.32 Prior clinical studies showed that isoflavone has inconsistent effects on blood pressure reduction,29,33,34 and might improve glycaemic control.35 Our results suggest that isoflavone improves endothelial function independent of changes in blood pressure, the lipid profile, or glycaemic control.

Inflammatory stress, as reflected by elevated C-reactive protein levels, is an independent predictor of incident cardiovascular events.36 It also consistently predicted recurrent coronary events in patients with unstable angina and acute myocardial infarction and was associated with reduced survival in these patients.37 Furthermore, prior clinical study had shown that elevated C-reactive protein was associated with blunted endothelial vasoreactivity; specifically, normalizations of the two parameters were correlated over time.38 In our study, hs-C-reactive protein level was reduced in isoflavone-treated patients, and lower in those patients with normalized FMD after 12 weeks. These findings suggested that isoflavone treatment alleviated vascular inflammatory stress and was an important component that mediated the reversal of endothelial dysfunction in this group of patients.

There are other potential mechanisms which may contribute to the beneficial effects of chronic treatment with isoflavone. For instance, isoflavone has a similar affinity as oestrogen to the ER-β in blood vessels and has been shown to achieve similar extents of vasodilatation as beta-estradiol in human subjects.39 Furthermore, isoflavone may affect platelet function by decreasing thromboxane A2 receptor density, potentially reducing the risk of platelet aggregation and vascular thrombosis.40

In this study, the absolute treatment effect on FMD (~1%) accounted by isoflavone was much smaller than those observed in previous clinical studies, which were mainly confined to healthy post-menopausal women.41–44 The oestrogen-deficient state in post-menopausal women may have potential influence on their response to exogenous phytoestrogens.45 Furthermore, the beneficial vascular effects of isoflavone in healthy populations should not be regarded as a prerequisite to explain a positive effect in patients with established cardiovascular disease. The impaired endothelial nitric oxide synthesis in our patients with established cardiovascular diseases may contribute to a generalized attenuated vasodilator response to pharmacological challenge.46 Furthermore, the older age of our study population also accounted for a poorer response to vasodilators.47,48 Nevertheless, the treatment effect of isoflavone in our study was comparable with lifestyle changes with endurance training49 or pharmacological interventions with statin therapy50 in patients with coronary artery disease. Remarkably, this 1% difference in FMD also corresponded to 12% lower incidence of cardiovascular events observed in a multi-ethnic cohort after 36 month follow-up.51 Moreover, the beneficial effect was more pronounced in patients with a lower FMD and smokers. Indeed, the incidence of impaired FMD in isoflavone-treated patients was significantly lower after 12 week intervention. These findings suggest that isoflavone reverses endothelial dysfunction in this group of patients with cardiovascular disease. This has important clinical implications, as the benefit of treatment is conferred to the group of patients with the highest risks for cardiovascular events, and this effect persists even at this rather late stage of the cardiovascular continuum.

In this study, we observed a loss of protective effect of isoflavone in patients with diabetes mellitus. Previous studies have shown that diabetes undermines the protective effect of endogenous oestrogen and alters ER expression patterns.52 Although the mechanism remains unclear, diabetes may have a similar attenuating effect on the actions of isoflavone due to its biochemical resemblance to oestrogen.

Prior studies43,53 identified potential benefits of soya proteins and isoflavone on vascular function in healthy subjects; nevertheless, whether such effects were conferred by both or either of the components remained unclear. Furthermore, the effects of isoflavone on vascular function in patients with cardiovascular disease were also unknown. This study confirmed that pure isoflavone alone could produce significant benefits on vascular endothelial function and inflammatory stress in patients with cardiovascular disease after 12 week supplementation. In addition, the background isoflavone intake in our population was high when compared with populations adopting Western diets.54,55 Thus it is possible that the treatment effect in this study could have been underestimated owing to the masking effect of background isoflavone levels.


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 References
 
In this randomized, double-blinded, placebo-controlled trial, we demonstrated that 12 week isoflavone treatment improved brachial FMD in patients with clinically manifest atherosclerosis, and thus reversing their endothelial dysfunction status. There was significant improvement in serum hs-C-reactive protein, the level of which was lower in patients with normalized post-intervention FMD, suggesting that the effect of isoflavone on endothelial function was mediated at least partly by the alleviation of vascular inflammatory stress. These findings may have important implications for the use of isoflavone for secondary prevention in patients with cardiovascular disease, on top of conventional cardiovascular interventions.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
References
 
CRCG Small Project Funding of the University of Hong Kong (Project No. 200507176137), Sun Chieh Yeh Heart Foundation, Outstanding Young Investigator Award of the University of Hong Kong, and an unconditional research donation from Great Liaison Limited, Hong Kong.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 References
 

  1. Vanharanta M, Voutilainen S, Lakka TA, van der Lee M, Adlercreutz H, Salonen JT. Risk of acute coronary events according to serum concentrations of enterolactone: a prospective population-based case–control study. Lancet (1999) 354:2112–2115.[CrossRef][Web of Science][Medline]
  2. Bazzano LA, He J, Ogden LG, Loria C, Vupputuri S, Myers L, Whelton PK. Legume consumption and risk of coronary heart disease in US men and women: NHANES I Epidemiologic Follow-up Study. Arch Intern Med (2001) 161:2573–2578.[Abstract/Free Full Text]
  3. He FJ, Nowson CA, MacGregor GA. Fruit and vegetable consumption and stroke: meta-analysis of cohort studies. Lancet (2006) 367:320–326.[CrossRef][Web of Science][Medline]
  4. Taubert D, Roesen R, Lehmann C, Jung N, Schomig E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA (2007) 298:49–60.[Abstract/Free Full Text]
  5. Heiss C, Kleinbongard P, Dejam A, Perre S, Schroeter H, Sies H, Kelm M. Acute consumption of flavanol-rich cocoa and the reversal of endothelial dysfunction in smokers. J Am Coll Cardiol (2005) 46:1276–1283.[Abstract/Free Full Text]
  6. Anthony MS. Phytoestrogens and cardiovascular disease: where’s the meat? Arterioscler Thromb Vasc Biol (2002) 22:1245–1247.[Free Full Text]
  7. Sacks FM, Lichtenstein A, Van Horn L, Harris W, Kris-Etherton P, Winston M. Soy protein, isoflavones, and cardiovascular health: an American Heart Association Science Advisory for professionals from the Nutrition Committee. Circulation (2006) 113:1034–1044.
  8. Lissin LW, Cooke JP. Phytoestrogens and cardiovascular health. J Am Coll Cardiol (2000) 35:1403–1410.[Abstract/Free Full Text]
  9. Chan YH, Lau KK, Yiu KH, Li SW, Chan HT, Tam S, Shu XO, Lau CP, Tse HF. Isoflavone intake in persons at high risk of cardiovascular events: implications for vascular endothelial function and the carotid atherosclerotic burden. Am J Clin Nutr (2007) 86:938–945.[Abstract/Free Full Text]
  10. Adams H, Adams R, Del Zoppo G, Goldstein LB. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke (2005) 36:916–923.[Free Full Text]
  11. 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.[Abstract/Free Full Text]
  12. Adams KF, Newton KM, Chen C, Emerson SS, Potter JD, White E, Lampe JW. Soy isoflavones do not modulate circulating insulin-like growth factor concentrations in an older population in an intervention trial. J Nutr (2003) 133:1316–1319.[Abstract/Free Full Text]
  13. Palmas W, Ma S, Psaty B, Goff DC Jr, Darwin C, Barr RG. Antihypertensive medications and C-reactive protein in the multi-ethnic study of atherosclerosis. Am J Hypertens (2007) 20:233–241.[CrossRef][Web of Science][Medline]
  14. Kinlay S, Schwartz GG, Olsson AG, Rifai N, Szarek M, Waters DD, Libby P, Ganz P. Inflammation, statin therapy, and risk of stroke after an acute coronary syndrome in the MIRACL Study. Arterioscler Thromb Vasc Biol (2008) 28:142–147.[Abstract/Free Full Text]
  15. Prasad K. C-reactive protein (CRP)-lowering agents. Cardiovasc Drug Rev (2006) 24:33–50.[CrossRef][Web of Science][Medline]
  16. Zhang X, Shu XO, Li H, Yang G, Li Q, Gao YT, Zheng W. Prospective cohort study of soy food consumption and risk of bone fracture among postmenopausal women. Arch Intern Med (2005) 165:1890–1895.[Abstract/Free Full Text]
  17. Xu WH, Zheng W, Xiang YB, Ruan ZX, Cheng JR, Dai Q, Gao YT, Shu XO. Soya food intake and risk of endometrial cancer among Chinese women in Shanghai: population based case–control study. Br Med J (2004) 328:1285.[Abstract/Free Full Text]
  18. Shu XO, Yang G, Jin F, Liu D, Kushi L, Wen W, Gao YT, Zheng W. Validity and reproducibility of the food frequency questionnaire used in the Shanghai Women’s Health Study. Eur J Clin Nutr (2004) 58:17–23.[CrossRef][Web of Science][Medline]
  19. Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med (2004) 169:348–353.[Abstract/Free Full Text]
  20. Lind L. Arterial compliance influences the measurement of flow-mediated vasodilation, but not acetylcholine-mediated forearm blood flow. The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Atherosclerosis (2007) 190:212–215.[CrossRef][Medline]
  21. Wendelhag I, Fagerberg B, Hulthe J, Bokemark L, Wikstrand J. Endothelium-dependent flow-mediated vasodilatation, insulin resistance and the metabolic syndrome in 60-year-old men. J Intern Med (2002) 252:305–313.[CrossRef][Web of Science][Medline]
  22. Campuzano R, Moya JL, Garcia-Lledo A, Tomas JP, Ruiz S, Megias A, Balaguer J, Asin E. Endothelial dysfunction, intima-media thickness and coronary reserve in relation to risk factors and Framingham score in patients without clinical atherosclerosis. J Hypertens (2006) 24:1581–1588.[Web of Science][Medline]
  23. Lau KK, Chan YH, Yiu KH, Li SW, Tam S, Lau CP, Kwong YL, Tse HF. Burden of carotid atherosclerosis in patients with stroke: relationships with circulating endothelial progenitor cells and hypertension. J Hum Hypertens (2007) 21:445–451.[Web of Science][Medline]
  24. Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet (2001) 357:1191–1194.[CrossRef][Web of Science][Medline]
  25. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation (2001) 104:191–196.[Abstract/Free Full Text]
  26. Mancini GB. Vascular structure versus function: is endothelial dysfunction of independent prognostic importance or not? J Am Coll Cardiol (2004) 43:624–628.[Free Full Text]
  27. Chan SY, Mancini GB, Kuramoto L, Schulzer M, Frohlich J, Ignaszewski A. The prognostic importance of endothelial dysfunction and carotid atheroma burden in patients with coronary artery disease. J Am Coll Cardiol (2003) 42:1037–1043.[Abstract/Free Full Text]
  28. Rathel TR, Leikert JF, Vollmar AM, Dirsch VM. The soy isoflavone genistein induces a late but sustained activation of the endothelial nitric oxide-synthase system in vitro. Br J Pharmacol (2005) 144:394–399.[CrossRef][Web of Science][Medline]
  29. Mahn K, Borras C, Knock GA, Taylor P, Khan IY, Sugden D, Poston L, Ward JP, Sharpe RM, Vina J, Aaronson PI, Mann GE. Dietary soy isoflavone induced increases in antioxidant and eNOS gene expression lead to improved endothelial function and reduced blood pressure in vivo. FASEB J (2005) 19:1755–1757.[Abstract/Free Full Text]
  30. 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.[Abstract/Free Full Text]
  31. Reynolds K, Chin A, Lees KA, Nguyen A, Bujnowski D, He J. A meta-analysis of the effect of soy protein supplementation on serum lipids. Am J Cardiol (2006) 98:633–640.[CrossRef][Web of Science][Medline]
  32. Kris-Etherton PM, West SG. Soy protein with or without isoflavones: in search of a cardioprotective mechanism of action. Am J Clin Nutr (2005) 81:5–6.[Free Full Text]
  33. Teede HJ, Dalais FS, Kotsopoulos D, Liang YL, Davis S, McGrath BP. Dietary soy has both beneficial and potentially adverse cardiovascular effects: a placebo-controlled study in men and postmenopausal women. J Clin Endocrinol Metab (2001) 86:3053–3060.[Abstract/Free Full Text]
  34. Kreijkamp-Kaspers S, Kok L, Bots ML, Grobbee DE, Lampe JW, van der Schouw YT. Randomized controlled trial of the effects of soy protein containing isoflavones on vascular function in postmenopausal women. Am J Clin Nutr (2005) 81:189–195.[Abstract/Free Full Text]
  35. Jayagopal V, Albertazzi P, Kilpatrick ES, Howarth EM, Jennings PE, Hepburn DA, Atkin SL. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Diabetes Care (2002) 25:1709–1714.[Abstract/Free Full Text]
  36. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med (2002) 347:1557–1565.[Abstract/Free Full Text]
  37. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, Fadl YY, Fortmann SP, Hong Y, Myers GL, Rifai N, Smith SC Jr, Taubert K, Tracy RP, Vinicor F. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation (2003) 107:499–511.[Free Full Text]
  38. Fichtlscherer S, Rosenberger G, Walter DH, Breuer S, Dimmeler S, Zeiher AM. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation (2000) 102:1000–1006.[Abstract/Free Full Text]
  39. 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 17beta-estradiol. Circulation (2001) 103:258–262.[Abstract/Free Full Text]
  40. Garrido A, De la Maza MP, Hirsch S, Valladares L. Soy isoflavones affect platelet thromboxane A2 receptor density but not plasma lipids in menopausal women. Maturitas (2006) 54:270–276.[CrossRef][Web of Science][Medline]
  41. Squadrito F, Altavilla D, Crisafulli A, Saitta A, Cucinotta D, Morabito N, D’Anna R, Corrado F, Ruggeri P, Frisina N, Squadrito G. Effect of genistein on endothelial function in postmenopausal women: a randomized, double-blind, controlled study. Am J Med (2003) 114:470–476.[CrossRef][Web of Science][Medline]
  42. 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.[CrossRef][Web of Science][Medline]
  43. van der Schouw YT, Pijpe A, Lebrun CE, Bots ML, Peeters PH, van Staveren WA, Lamberts SW, Grobbee DE. Higher usual dietary intake of phytoestrogens is associated with lower aortic stiffness in postmenopausal women. Arterioscler Thromb Vasc Biol (2002) 22:1316–1322.[Abstract/Free Full Text]
  44. Simons LA, von Konigsmark M, Simons J, Celermajer DS. Phytoestrogens do not influence lipoprotein levels or endothelial function in healthy, postmenopausal women. Am J Cardiol (2000) 85:1297–1301.[CrossRef][Web of Science][Medline]
  45. Vincent A, Fitzpatrick LA. Soy isoflavones: are they useful in menopause? Mayo Clin Proc (2000) 75:1174–1184.[Abstract]
  46. Panza JA, Garcia CE, Kilcoyne CM, Quyyumi AA, Cannon RO III. Impaired endothelium-dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation (1995) 91:1732–1738.[Abstract/Free Full Text]
  47. Matz RL, Andriantsitohaina R. Age-related endothelial dysfunction: potential implications for pharmacotherapy. Drugs Aging (2003) 20:527–550.[CrossRef][Web of Science][Medline]
  48. Sherwood A, Bower JK, McFetridge-Durdle J, Blumenthal JA, Newby LK, Hinderliter AL. Age moderates the short-term effects of transdermal 17beta-estradiol on endothelium-dependent vascular function in postmenopausal women. Arterioscler Thromb Vasc Biol (2007) 27:1782–1787.[Abstract/Free Full Text]
  49. Steiner S, Niessner A, Ziegler S, Richter B, Seidinger D, Pleiner J, Penka M, Wolzt M, Huber K, Wojta J, Minar E, Kopp CW. Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis (2005) 181:305–310.[CrossRef][Web of Science][Medline]
  50. Jarvisalo MJ, Toikka JO, Vasankari T, Mikkola J, Viikari JS, Hartiala JJ, Raitakari OT. HMG CoA reductase inhibitors are related to improved systemic endothelial function in coronary artery disease. Atherosclerosis (1999) 147:237–242.[CrossRef][Web of Science][Medline]
  51. Shimbo D, Grahame-Clarke C, Miyake Y, Rodriguez C, Sciacca R, Di Tullio M, Boden-Albala B, Sacco R, Homma S. The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis (2007) 192:197–203.[CrossRef][Medline]
  52. Maggi A, Cignarella A, Brusadelli A, Bolego C, Pinna C, Puglisi L. Diabetes undermines estrogen control of inducible nitric oxide synthase function in rat aortic smooth muscle cells through overexpression of estrogen receptor-beta. Circulation (2003) 108:211–217.
  53. Crouse JR III, Morgan T, Terry JG, Ellis J, Vitolins M, Burke GL. A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins. Arch Intern Med (1999) 159:2070–2076.[Abstract/Free Full Text]
  54. Schabath MB, Hernandez LM, Wu X, Pillow PC, Spitz MR. Dietary phytoestrogens and lung cancer risk. JAMA (2005) 294:1493–1504.[Abstract/Free Full Text]
  55. Kreijkamp-Kaspers S, Kok L, Grobbee DE, de Haan EH, Aleman A, Lampe JW, van der Schouw YT. Effect of soy protein containing isoflavones on cognitive function, bone mineral density, and plasma lipids in postmenopausal women: a randomized controlled trial. JAMA (2004) 292:65–74.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Eur Heart JHome page
H. Teragawa, Y. Higashi, and Y. Kihara
Effect of isoflavone supplement on endothelial function: does efficacy vary with atherosclerotic burden?
Eur. Heart J., November 2, 2008; 29(22): 2710 - 2712.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/22/2800    most recent
ehn409v1
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Chan, Y.-H.
Right arrow Articles by Tse, H.-F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chan, Y.-H.
Right arrow Articles by Tse, H.-F.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?