Abstract
Background
Whether isoflavone has any effect on recurrent cardiovascular events is unknown.
Objective
To investigate the relations between isoflavone intake and the risk of stroke recurrence.
Subjects and Methods
We recruited 127 consecutive patients with prior history of atherothrombolic/ hemorrhagic stroke (mean age: 67 ± 11 years, 69% male) and prospectively followed up for a mean duration of 30 months. Stroke recurrence and major adverse cardiovascular events (MACE) were documented. Brachial flow-mediated dilatation (FMD) was measured using high-resolution ultrasound. Isoflavone intake was estimated using a validated food frequency questionnaire.
Results
Median isoflavone intake was 6.9 (range: 2.1–14.5) mg/day. Isoflavone intake was independently associated with increased FMD (Pearson R=0.23, p=0.012). At 30 months, there were 10 stroke recurrence and 12 MACE. Kaplan-Meier analysis showed that patients with isoflavone intake higher than median value had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4–27.6] mth versus 5.0 [range: 4.1–5.9] mth, p=0.021) and MACE-free survival time (19.0 [range: 10.4–27.6] mth versus 4.0 [range: 2.4–5.6] mth, p=0.013). Using multivariate cox regression, higher isoflavone intake was an independent predictor for lower risk of stroke recurrence (hazards ratio 0.18 [95%CI: 0.03–0.95], risk reduction 82%, p=0.043) and MACE (hazards ratio 0.16 [95%CI: 0.03–0.84], risk reduction 84%, p=0.030).
Conclusions
Higher isoflavone intake in stroke patients was associated with prolonged recurrence-free survival, and reduced risk of stroke recurrence and MACE, independent of baseline vascular.function. Whether isoflavone may confer clinically significant secondary protection in stroke patients should be further investigated in a randomized controlled trial.
Key words: Recurrent stroke, isoflavone, diet, secondary prevention, vascular function
Introduction
Stroke remains the second most common cause of death, and is the major cause of disability and functional impairment worldwide (1). In patients with a prior history of stroke, recurrent stroke is more likely to be fatal and to be associated with major disability (2). In fact, recurrent stroke accounted for nearly one quarter of the total incidence of stroke despite conventional interventions (3). The importance of effective secondary prevention thus cannot be over-emphasized. In addition to appropriate carotid revascularization and anticoagulant /anti-platelet therapy, risk factor control incorporating healthy lifestyle and dietary modifications certainly constitute a critical component of effective secondary prevention in stroke patients (4).
In recent years, increasing evidence showed that populations with higher legume, fruit and vegetable consumption experience a lower incidence of cardiovascular events (5., 6., 7.). This led to immense interests in the potential role of plant- derived polyphenolic chemicals for prevention of cardiovascular diseases (8., 9., 10., 11.). 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 soybeans, chick peas and clovers. Experimental studies suggested that they have anti-oxidant and hypocholesterolaemic properties, produce vasodilatation, and modulate platelet function and haemostasis (12). Our previous study have showed that a higher intake level of isoflavone, a major class of phytoestrogens, was associated with improved surrogate endpoints of vascular endothelial function and carotid atherosclerotic burden in patients with high risk for cardiovascular events (13). In a randomized controlled trial, we have demonstrated that isoflavone supplement given over a period of 12 weeks was able to dynamically reverse endothelial dysfunction in patients with prior ischemic stroke (14). However, whether this vasoprotective effect of isoflavone can translate into improved clinical outcome was unknown. While prospective studies in general healthy populations have shown that higher intake of soy food is associated with a lower risk of incident cardiovascular events (15), no studies to date have investigated the relations between differential isoflavone intake and clinical outcomes of patients with established cardiovascular diseases. Therefore, we performed a prospective cohort study to investigate the relations between isoflavone intake and long-term clinical outcomes in a sample of stroke patients.
Materials and methods
Patients
A total of 127 patients with primary or recurrent ischaemic/ hemorrhagic stroke (>6 months) were recruited from our medical outpatient clinics. Diagnosis was made on the basis of clinical examinations and computed tomography brain imaging, according to current guidelines (16). 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 >220mmol/L), liver failure, clinical or biochemical evidence of chronic inflammatory disease, 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.
Study Design
Stroke recurrence and cardiovascular morbidities during follow-up were prospectively monitored using the central computerised clinical management system for at least 24 months from the date of recruitment. Major adverse cardiovascular events (MACE) were defined as recurrent stroke, new-onset / recurrent acute coronary syndrome, coronary revascularization, newly diagnosed peripheral artery disease, and new onset/ acute-on-chronic heart failure. 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.
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 >7.0mmol/L or on medications. Hypercholesterolemia was defined as a fasting total plasma cholesterol level of > 4.9mmol/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 to 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. Dietary intakes of study patients were estimated using a validated Food Frequency Questionnaire (FFQ) designed for Chinese populations (17., 18., 19.). The FFQ was specially structured to capture isoflavone contents in the diet, and food models were used to help patients in 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 2 experienced operators. All the scanned images were stored digitally and analyzed offline without knowledge of the subjects.
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 hours before the assessment. As previously described (20, 21), longitudinal scans of the brachial artery were obtained at rest, and then flow-mediated dilatation (FMD) was induced by inflation of a pneumatic tourniquet placed on the forearm to a pressure of 250 mmHg for 5 minutes. The cuff was then released, and serial imaging of the brachial artery was recorded for 5 minutes. The brachial artery was allowed to return to baseline. Finally, brachial artery was then measured again at 5 minutes after administration of 400 μg sublingual nitroglycerin spray. FMD was defined as the percentage change in brachial artery diameter by 1 minute after cuff deflation from that on the baseline scan. Interobserver variability testing for FMD measurement revealed an interclass correlation coefficient (ICC) (2-way mixed, random-effect model, absolute agreement) of 0.83 (95% CI [0.22 - 0.97], p=0.012), with a mean absolute difference of 0.6 ± 0.8%.
Statistical Analysis
Continuous variables were presented as mean ± 1 standard derivation (SD). Isoflavone intake had a skewed distribution and was presented as median [25%-75% range]. Statistical comparisons for continuous variables were performed using Student’s t test or Mann-Whitney U test, as appropriate. Chisquare test was used for binary measurements. Correlations were expressed in terms of Pearson Correlation Coefficient. To estimate the impact of isoflavone intake on risk of stroke recurrence and cardiovascular morbidities, hazard ratio (HR) and 95% confidence interval (CI) were calculated by univariate and multivariate Cox proportional hazards regression models. Multivariate analyses were performed with an enter regression model in which each variable with a p value of 0.05 as determined from the univariate analysis was entered into the model. All statistical analyses were performed using the SPSS program (version 15.0). A p-value of <0.05 was considered statistically significant.
Results
Baseline Characteristics
The baseline characteristics of the study population are presented in Table 1. Their overall mean age was 66.9 ± 10.5 years, and 69% were men. All of them had a prior history of stroke, among which 118 (93%) were of ischemic origin. Among this group of patients, 13% had concomitant coronary artery disease, and 45% had diabetes mellitus. Their mean FMD was 2.6%±2.3%, reflecting impaired vascular endothelial function overall. The median isoflavone intake was 6.9 (range: 2.1 - 14.5) mg/day. Patients with isoflavone intake higher than median value also had higher mean caloric intake (p=0.027), and a trend towards better vascular endothelial function as measured by FMD (p=0.10), compared to patients with isoflavone intake lower than median value. Isoflavone intake was significantly associated with FMD (Pearson Correlation Coefficient=0.23, p=0.012) at baseline. Multivariate analysis revealed that each 1 mg increase of isoflavone intake per day was independently predictive of an absolute increase in FMD by 0.02% (95%CI: 0.004% to 0.039%, p=0.015), after adjusting for potential confounders (age, gender, history of coronary artery disease, hypertension, diabetes, hyperlipidemia and smoking, use of antihypertensives, statins and aspirin, caloric intake, educational level and financial income) as determined from univariate analysis.
Table 1.
Baseline characteristics of n=127 stroke patients
| Isoflavone Intake < Median (n=63) | Isoflavone Intake > Median (n=64) | p Value | |
|---|---|---|---|
| Male, n (%) | 41 (65%) | 47 (73%) | 0.31 |
| Mean age, years | 67.8 ± 9.3 | 66.0 ± 11.7 | 0.34 |
| Stroke type - Ischemic, n(%) | 58 (92%) | 60 (94%) | 0.36 |
| Coronary artery disease, n (%) | 9 (14%) | 7 (11%) | 0.57 |
| Hypertension, n (%) | 52 (83%) | 49 (77%) | 0.40 |
| Diabetes mellitus, n (%) | 27 (43%) | 30 (47%) | 0.65 |
| Hypercholesterolemia, n (%) | 35 (56%) | 41 (65%) | 0.28 |
| Current / Past smoker, n (%) | 33 (52%) | 33 (51%) | 0.56 |
| Medications: | |||
| ACEI/ARB, n (%) | 27 (44%) | 29 (45%) | 0.84 |
| Beta-blockers, n (%) | 16 (26%) | 20 (31%) | 0.47 |
| Calcium channel blockers, n(%) | 27 (44%) | 25 (39%) | 0.50 |
| Diuretics, n (%) | 4 (7%) | 8 (13%) | 0.25 |
| Aspirin/clopidogrel, n (%) | 56 (90%) | 61 (95%) | 0.28 |
| Statin, n (%) | 19 (31%) | 19 (30%) | 0.91 |
| NSAID, n (%) | 1 (2%) | 0 (0%) | 0.31 |
| Caloric Intake, kcal/day | 2704.9 ± 912.5 | 3088.8 ± 1017.3 | 0.027 |
| Body mass index, kgm-2 | 24.5 ± 3.7 | 25.6 ± 3.3 | 0.10 |
| Endothelial function FMD, % | 2.2 ± 2.0 | 2.9 ± 2.4 | 0.10 |
Abbreviations: ACEI= angiotensin-converting enzyme inhibitor; ARB=angiotenin receptor blocker; NSAID=Non-steroidal anti-inflammatory drugs; LDL=low-density lipoprotein; HDL=high-density lipoprotein; FMD=flow-mediated dilatation. Data expressed as mean ± SEM unless otherwise stated
Clinical Outcomes
At a mean of 30 months of follow-up, a total of 12 MACE were reported, including 10 cases of stroke recurrence and 2 cases of new-onset heart failure (Table 2). No acute coronary syndrome, coronary revascularization or new-onset peripheral artery disease was diagnosed during this period. There were 8 deaths, including 3 cardiovascular deaths and 5 non- cardiovascular deaths. A total of 45 hospitalizations were documented, of which 13 were cardiovascular-related. In patients with isoflavone intake higher than median level, there was a marginally significant lower number of all-cause hospitalizations as compared to those patients with isoflavone intake lower than median level (p=0.08). However, there were no significant differences between the 2 groups of patients in terms of cardiovascular death/ hospitalization or stroke recurrence (p>0.05).
Table 2.
Clinical Outcomes of n=127 Stroke Patients After 30 Months of Follow-up
| Isoflavone Intake < Median (n=63) | Isoflavone Intake > Median (n=64) | p Value | |
|---|---|---|---|
| Mortality: | |||
| Total | 6 | 2 | 0.14 |
| Cardiovascular | 2 | 1 | 0.84 |
| Non-cardiovascular | 4 | 1 | 0.21 |
| Hospitalization: | |||
| Total | 27 | 18 | 0.08 |
| Cardiovascular | 7 | 6 | 0.75 |
| Non-cardiovascular | 20 | 12 | 0.09 |
| Major Adverse Cardiovascular Events: | |||
| Total | 6 | 6 | 1.00 |
| Stroke recurrence | 5 | 5 | 0.98 |
| Acute coronary syndrome | 0 | 0 | − |
| New-onset heart failure | 2 | 0 | 0.15 |
| Coronary revascularisation | 0 | 0 | − |
| Peripheral vascular disease | 0 | 0 | − |
Predictor for Risk of Stroke Recurrence
Kaplan-Meier analysis revealed that patients with higher than median intake of isoflavone had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4 - 27.6] months versus 5.0 [range: 4.1 - 5.9] months, p=0.021, Figure 1), as well as median MACE-free survival time (19.0 [range: 10.4 - 27.6] mth versus 4.0 [range: 2.4 - 5.6] mth, p=0.013, Figure 2) when compared to patients with isoflavone intake lower than the median value.
Figure 1.
Kaplan-Meier Curves for the unadjusted rates of stroke recurrence in patients with isoflavone intake higher than or below the median level. Patients with higher than median intake of isoflavone had significantly longer median stroke recurrence-free survival time (19.0 [range: 10.4 - 27.6] mth versus 5.0 [range: 4.1 - 5.9] mth, p=0.021) than patients with isoflavone intake below the median value. Cox-proportional hazards regression model also showed a reduced risk for stroke recurrence (HR 0.18 [95%CI: 0.03 - 0.95], p=0.043) in these patients
Figure 2.
Kaplan-Meier Curves for the unadjusted rates of major adverse cardiovascular events (MACE) in stroke patients with isoflavone intake higher than or below the median level. Patients with higher than median intake of isoflavone had significantly longer median MACE-free survival time (19.0 [range: 10.4 - 27.6] mth versus 4.0 [range: 2.4 - 5.6] mth, p=0.013) than patients with isoflavone intake below the median value. Cox-proportional hazards regression model also showed a reduced risk for MACE (HR 0.15 [95%CI: 0.03 - 0.78], p=0.024) in these patients
Using Cox-proportional hazards regression model, isoflavone intake higher than median value was an independent predictor for reduced risk for stroke recurrence (HR 0.18 [95%CI: 0.03 - 0.95], p=0.043, Table 3) and MACE (HR 0.15 [95%CI: 0.03 - 0.78], p=0.024, Table 4). However, there was no statistically significant difference between isoflavone intake in patients who had positive MACE (n=12) and those who did not (n=113) experience MACE (p=0.47).
Table 3.
Univariate and Multivariate Predictors for Stroke Recurrence1
| Univariate | Multivariate | |||
|---|---|---|---|---|
| HR [95% CI] 23 | p Value | HR [95% CI] 2 | p Value | |
| Age | 1.02 [0.88 - 1.18] | 0.77 | ||
| Gender | 0.51 [0.11 - 2.49] | 0.41 | ||
| Coronary artery disease | 1.25 [0.15 - 10.86] | 0.84 | ||
| Hypertension | 0.00 [0.00 - 0.00] | 0.93 | ||
| Diabetes Mellitus | 0.85 [0.23 - 3.24] | 0.82 | ||
| Hyperlipidaemia | 0.56 [1.11 - 2.93] | 0.49 | ||
| Past / Current Smoker | 2.21 [0.45 - 10.75] | 0.33 | ||
| Brachial FMD | 0.87 [0.58 - 1.29] | 0.48 | ||
| Serum LDL | 1.37 [0.58 - 3.23] | 0.47 | ||
| Serum HDL | 0.80 [0.12 - 5.32] | 0.82 | ||
| Serum triacyglycerol | 0.61 [0.20 - 1.89] | 0.39 | ||
| Educational level | 0.18 [0.01 - 2.20] | 0.18 | ||
| Financial Income | 1.41 [0.09 - 23.56] | 0.81 | ||
| Medications: | ||||
| Antihypertensive | 0.57 [0.06 - 5.16] | 0.62 | ||
| Aspirin | 0.61 [0.15 - 2.47] | 0.49 | ||
| ACEI / ARB | 0.57 [0.15 - 2.17] | 0.41 | ||
| Statin | 0.33 [0.07 - 1.52] | 0.15 | ||
| Body-Mass Index | 0.96 [0.79 - 1.16] | 0.65 | ||
| Calorie intake | 1.00 [0.999 - 1.001] | 0.93 | 1.00 [0.999 - 0.001] | 0.84 |
| Antioxidant Vitamins 4 | 0.50 [0.11 - 2.28] | 0.37 | ||
| Isoflavone 3 | 0.18 [0.03 - 0.95] | 0.043 | 0.18 [0.03 - 0.95] | 0.043 5 |
| Soy protein 3 | 0.31 [0.07 - 1.42] | 0.13 |
Table 4.
Univariate and Multivariate Predictors for Major Adverse Cardiovascular Events1
| Univariate | Multivariate | |||
|---|---|---|---|---|
| HR [95% CI] 2 | p Value | HR [95% CI] 2 | p Value | |
| Age | 1.03 [0.90 - 1.18] | 0.62 | ||
| Gender | 0.74 [0.19 - 2.88] | 0.66 | ||
| Coronary artery disease | 2.14 [0.41 - 11.17] | 0.37 | ||
| Hypertension | 0.00 [0.00 - 0.00] | 0.95 | ||
| Diabetes Mellitus | 1.05 [0.30 - 3.37] | 0.94 | ||
| Hyperlipidaemia | 0.67 [0.13 - 3.37] | 0.63 | ||
| Past / Current Smoker | 1.51 [0.39 - 5.89] | 0.55 | ||
| Brachial FMD | 0.85 [0.58 - 1.25] | 0.41 | ||
| Serum LDL | 1.27 [0.57 - 2.81] | 0.56 | ||
| Serum HDL | 0.55 [0.08 - 3.61] | 0.53 | ||
| Serum triacyglycerol | 0.73 [0.26 - 2.03] | 0.54 | ||
| Educational level | 0.64 [0.32 - 1.26] | 0.20 | ||
| Financial Income | 1.00 [1.00 - 1.00] | 0.70 | ||
| Medications: | ||||
| Antihypertensive | 0.68 [0.08 - 5.86] | 0.72 | ||
| Aspirin | 0.73 [0.19 - 2.73] | 0.63 | ||
| ACEI / ARB | 0.67 [0.19 - 2.42] | 0.54 | ||
| Statin | 0.46 [0.11 - 1.90] | 0.28 | ||
| Body-Mass Index | 0.98 [0.81 - 1.18] | 0.82 | ||
| Calorie intake | 1.00 [0.999 - 1.001] | 0.87 | 1.00 [0.999 - 1.001] | 0.98 |
| Antioxidant Vitamins 3 | 0.43 [0.10 - 1.83] | 0.25 | ||
| Isoflavone 3 | 0.16 [0.03 - 0.84] | 0.030 | 0.16 [0.03 -0.84] | 0.030 4 |
| Soy protein 3 | 0.26 [0.06 - 1.15] | 0.08 |
1. Hazards ratio (HR) and 95% confidence interval (CI) for composite cardiovascular endpoints were calculated by cox regression analysis. 2. 95% confident interval in parentheses [all such values]. FMD, flow-mediated dilatation; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACEI, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blockers. Calorie intake was entered into the model based on its significant difference between patients with isoflavone intake >median and those ≤ median as shown in Table 1. 3. Long-term daily intake > median value. 4. Significant independent predictor for composite cardiovascular endpoints.
Discussion
To our knowledge, this study was the first to suggest that a higher habitual intake of isoflavone is associated with better long-term clinical outcomes in patients with established cardiovascular disease. Although there was no difference in stroke recurrence between patients with below or above the median isoflavone intake, survival analysis revealed that a higher isoflavone intake level was independently predictive of longer recurrence-free survival periods and reduced risk of recurrence in patients with a prior history of stroke. Furthermore, a higher intake level of isoflavone was also independently predictive of longer MACE-free survival and reduced risk of MACE.
Endothelial dysfunction, as reflected by impaired FMD, has been shown to predict cardiovascular outcomes in patients with coronary artery disease and/or hypertension (22, 23). Whether FMD has independent prognostic significance for stroke recurrence has yet remained unclear. Our previous study has showed that isoflavone intake was associated with better vascular endothelial function and reduced carotid atherosclerosis in patients at higher risk for cardiovascular events (13). In coherence with our previous findings, this study confirms that a higher isoflavone intake is associated with a better FMD, and provides further evidence on the possible vascular protective effects of isoflavone in terms of improved clinical outcomes in patients at advanced stages of the cardiovascular continuum (24). Nevertheless, the results from this study did not show a significant predictive value of FMD for stroke recurrence.
A number of potential mechanisms have been proposed to explain the vascular protective effects of isoflavone. Firstly, isoflavone has a similar affinity as estrogen to the ER-β in blood vessels, and has been shown to achieve similar extents of vasodilatation as beta-estradiol in human subjects (25). Isoflavone may also have favourable effects on glycemic control (26). Studies have also suggested anti-oxidant (27) and immuno-modulatory (28) effects of isoflavone. Furthermore, isoflavone may affect platelet function by decreasing thromboxane A2 receptor density, potentially reducing the risk of platelet aggregation and vascular thrombosis (29). In our study, the improved clinical outcomes were associated with higher intakes of isoflavone but not soy protein. This lends further support to the hypothesis that isoflavone rather than soy protein was the active component that may confer vascular protection.
Finally, it is worth-noting that the median isoflavone intake (6.9 mg/day) of our study population, albeit higher than that of Western populations, (30) was far lower than that of the Japanese 15 and mainland China populations (18). Therefore, if this relation is causal increasing habitual isoflavone intake to this moderate level with a balanced diet is adequate to achieve a clinically significant beneficial effect on the risk of stroke recurrence, without active supplementation.
Several limitations of this study should be noted. Firstly, this study comprised a small number of stroke patients with mean follow-up of only 30 months. The lack of difference in terms of number of stroke recurrence at 30 months between the 2 groups could therefore be due to a lack of statistical power. Secondly, the study design adopted a highly specialized setting, investigating ischemic/hemorrhagic stroke patients under optimal specialist care. Thus the results may not extrapolate to other groups of patients at risk of cardiovascular disease. Thirdly, in this study any subsequent changes in dietary patterns after the initial assessment could not be assessed. Fourthly, the relative risk reduction was high and unknown/ unmeasured confounding could potentially exist. Finally, this is an observational study and the results did not demonstrate causality and should be verified in a randomized controlled trial.
Conclusions
The present study demonstrates that a higher habitual intake of isoflavone in stroke patients is associated with lower risk of stroke recurrence and MACE independent of baseline vascular function, suggesting that isoflavone may confer clinically significant secondary protection in stroke patients, on top of conventional interventions. This observation should be further studied in future randomized controlled trials.
Acknowledgements
This study was supported by CRCG Small Project Funding of University of Hong Kong (Project No. 200807176179) and the Sun Chieh Yeh Heart Foundation.
Conflict of Interest Statement
The authors declare no financial or other conflict of interest.
Sources of Support
This study was supported by CRCG Small Project Funding of University of Hong Kong (Project No. 200807176179) and the Sun Chieh Yeh Heart Foundation.
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