To investigate the effects of stanol ester margarine use in healthy subjects on arterial compliance, endothelial function and intima-media thickness.
Case–control study comparing regular stanol ester margarine users to non-users.
Occupational health service clinic.
We recruited 50 cases and 50 controls (mean age 51±8, range 26–65 years). All subjects were non-smokers and the study groups were matched for age and sex. As cases, we invited subjects who had been using regularly (daily) plant stanol ester margarine for a period of 2 years or longer. Non-invasive ultrasound was used to measure carotid artery compliance, carotid intima-media thickness and brachial artery flow-mediated endothelial dependent vasodilatation.
The carotid artery compliance was non-significantly higher in cases compared with controls, 1.84±1.02 vs 1.58±0.76 %/10 mm Hg (P=0.13). The difference in compliance became statistically significant (P=0.04) when the unbalance between the groups in family history of coronary artery disease and years of education were taken into account. There was also a significant dose–response relationship between stanol margarine use and carotid compliance, longer use being associated with higher compliance. Serum lipoproteins, blood pressure, flow-mediated dilation and intima-media thickness values did not differ between cases and controls.
These data raise the possibility that regular stanol ester margarine use may be associated with beneficial changes in arterial compliance. Intervention studies are needed to test this hypothesis and to reveal possible mechanisms.
Plant stanols inhibit the absorption of both exogenous dietary and endogenous biliary cholesterol from the proximal small intestine. This action leads to reductions in both serum low-density lipoprotein (LDL) cholesterol and total cholesterol concentrations, without affecting the concentrations of high-density lipoprotein (HDL) cholesterol or triglycerides (Miettinen et al., 1995; Tammi et al., 2000; Katan et al., 2003). The plant stanol ester margarine Benecol Raisio Group, Raisio, Finland has been shown to lower serum total and LDL cholesterol concentrations in several intervention studies (Law, 2000). It has been estimated that that life-long consumption of plant stanol ester spread may lower coronary events by about 20–25% (Law, 2000; Miettinen and Gylling, 2004). Therefore, the use of plant stanols have been recommended in guidelines for the prevention of coronary heart disease (Expert Panel, 1996, 2004; Third Report of the National Cholesterol Education Program (NCEP), 2002). Luoto et al. (2004) assessed plant stanol ester margarine use in Finland between 1996 and 1999. They reported that regular users of plant stanol ester margarine were more likely to be men and to have a higher household income than inconsistent users. Stanol margarine use was also associated with a healthy lifestyle and diet, as well as a history of cardiovascular disease. The investigators concluded that it would be important to examine the health effects of stanol ester margarines.
Ultrasonographically assessed changes in arterial function and structure are useful means to study early pathophysiological changes in the arteries relevant to the development of atherosclerosis. Carotid arterial compliance is a functional marker of arterial elasticity. Compliance decreases with age and as a consequence of many disease states such as atherosclerosis and diabetes (Zieman et al., 2005). Risk factors, such as high LDL-cholesterol, elevated blood pressure, obesity and smoking, have been associated with decreased arterial compliance in cross-sectional studies (Zieman et al., 2005). Impaired carotid artery compliance has been implicated as an independent predictor for cardiovascular events in high-risk individuals (Blacher et al., 1998). Arterial compliance may be influenced by life-style interventions, such as weight reduction, physical activity or changes in diet (Zieman et al., 2005).
The thickness of the common carotid intima-media complex measured by ultrasound represents a structural marker of preclinical atherosclerosis. Increased carotid intima-media thickness correlates with vascular risk factors (Poli et al., 1988; Haapanen et al., 1989) and predicts cardiovascular events in population groups (Salonen and Salonen, 1991; Chambless et al., 1997; Hodis et al., 1998; Bots et al., 1999; O'Leary et al., 1999). A third commonly used marker of arterial health is brachial artery flow-mediated dilatation (Celermajer et al., 1992). The dilatation response for increased blood flow is mainly mediated by nitric oxide released from arterial endothelial cells Mullen et al. (2001). Brachial flow-mediated dilatation response correlates with coronary endothelial function tested with invasive methods (Anderson et al., 1995) and has been shown to predict cardiovascular events (Chan et al., 2003; Gokce et al., 2003). We performed a case–control study to investigate the effects of regular stanol ester margarine use on these ultrasound markers of subclinical atherosclerosis.
Materials and methods
The cases (users) were 50 healthy subjects (25 men) recruited from an occupational health service clinic in Turku, Finland. Information about the study was sent to several work places to be distributed among their employees. We invited healthy 20-to–65-year-old subjects who had been using regularly (daily) plant stanol margarine for period of 2 years or longer. The study subjects needed to be non-smokers (at least for 5 years), and without antihypertensive and cholesterol lowering medications. The exclusion criteria were diabetes and pregnancy. Potential participants were also informed that alcohol and drug abuse were included in the exclusion criteria, and at the entry they filled in a form declaring that they have no past or present history of alcohol or drug abuse. The controls (non-users) were also recruited from the occupational health service clinic. For each user case, we selected a nonuser control subject matched for sex and age (difference in age <3 years). All study subjects completed a questionnaire on physical activity, education and family risk of coronary heart disease. Family history was considered positive if study subjects' first-degree relative had been diagnosed with premature coronary artery disease (before the age 65 years in women and 55 years in men). Physical activity index was calculated from the frequency, intensity and duration of reported physical activity (Raitakari et al., 1994). The frequency was assessed by inquiring how often the participants engaged in physical activities (choices included: 1=never, 2=monthly, 3=weekly, 4=two to three times a week, 5=four to six times a week and 6=daily). The intensity was assessed by inquiring ‘becoming breathless and sweating during exercise' (choices included: 1=never, 2=a little, 3=much). The duration was assessed by inquiring the usual time spend in one physical activity session (choices included: 1=<20 min, 2=20–40 min, 3=40–60 min and 4⩾60 min). A physical activity index was calculated from the product of these three variables. The users were also asked to provide categorical information about the duration of their stanol product use (2 years, 2–4 years and more than 4 years). The study was conducted according to the guidelines of the Helsinki declaration and the study protocol was approved by the Joint Ethics Committee of Turku University and Turku University Central Hospital. All subjects gave their informed consent.
Fasting blood samples were taken on the same day as the ultrasound study. Serum total cholesterol, HDL-cholesterol, triglycerides and plasma glucose concentrations were measured using standard enzymatic methods. LDL-cholesterol was calculated (Friedewald et al., 1972). Oxidized LDL was measured by determining the level of LDL diene conjugation, as described previously (Toikka et al., 2000). Serum high-sensitivity C-reactive protein was analyzed using an immunoturbidimetric assay (Orion Diagnostica, Finland).
We used Acuson Sequoia 512 mainframe (Mountain View, CA, USA) with 8.0 MHz linear array transducer. Studies were performed after an overnight fast. The digitally stored scans were analyzed by one reader blinded to subjects' details.
Carotid artery intima-media thickness
Left carotid artery was scanned following a standardized protocol. A moving image clip of the beginning of the common carotid artery with duration of 5 s was acquired and stored in digital format for subsequent offline analysis. Carotid artery intima-media thickness was measured in the far wall, as described previously. We have reported previously 5.2% between observer and 6.4% between-visit coefficients of variation in carotid artery intima-media thickness measurements (Raitakari et al., 2003).
Carotid artery compliance
To assess carotid artery compliance, the best quality cardiac cycle was selected from the 5-s clip image. The common carotid diameter 10 mm from carotid bifurcation was measured from the B-mode images using ultrasonic calipers in end-diastole and end-systole, respectively. Brachial blood pressure was measured during the ultrasound study with an automated sphygmomanometer (Omron M4, Omron Matsusaka Co., Ltd., Japan). The ultrasound and concomitant brachial blood pressure measurements were used to calculate carotid artery compliance, as ([Ds−Dd]/Dd)/(Ps−Pd), where Dd is the diastolic diameter; Ds, the systolic diameter; Ps, systolic blood pressure and Pd, diastolic blood pressure (Juonala et al., 2005). Thus, compliance is a marker of arterial elasticity, which measures the ability of the arteries to expand as a response to pulse pressure caused by cardiac contraction and relaxation. We have previously reported 2.7% between-visit coefficient of variation for carotid artery diastolic diameter measurements, and 19.5% for carotid artery compliance (Juonala et al., 2005).
Brachial artery test
Brachial artery diameter was measured as described previously (Juonala et al., 2004). In brief, a resting scan above the elbow was performed. Thereafter, hyperemia was induced by inflation of a cuff placed around the forearm followed by release. Subsequent scans were taken at 40, 60 and 80 s after the cuff release. Flow-mediated dilatation, as a marker of endothelial function, was calculated as the maximal percent increase in arterial diameter during hyperemia compared with the resting value. This dilation response reflects endothelium-dependent vasorelaxation capacity, because it can be blunted by simultaneous infusion of nitric oxide synthase inhibitor (Mullen et al., 2001). We did not perform flow measurements to quantify the hyperemia stimulus after the cuff release. This was justified by our earlier findings showing that the flow stimulus does not correlate with the flow-mediated response (Järvisalo et al., 2002). Nitrate-mediated, endothelium-independent, vasodilatation was tested by scanning the artery 4 min after a sublingual dose of 1.25 mg isosorbide dinitrate.
All subjects underwent maximal bicycle exercise testing using a protocol with fixed load increments every minute (20 W in men; 15 W in women). Subjects exercised the protocol until limited by fatigue. The electrocardiogram was continuously recorded. Blood pressure was measured at every load increment stage. Two indicators of exercise capacity are reported: the estimated maximal oxygen uptake and maximal workload achieved (Arstila et al., 1990).
The comparisons between study groups were performed using t-test, χ2 test and analysis of covariance, as appropriate. Associations between variables were studied by calculating Pearson's correlation coefficients and using multivariate linear regression analysis. Values for carotid artery compliance, triglycerides and C-reactive protein were log-transformed before analyses owing to skewed distributions. All analysis was performed using Statistical Analysis System, SAS (version 8.1), and statistical significance was inferred at a two-tailed P-value ⩽0.05.
The characteristics of study subjects are shown in Table 1. There were equal number of men and women among users and controls, and the study groups were well matched for age. The mean age was 51 years in both groups. Body mass index, serum lipids, glucose, C-reactive protein and blood pressure values were similar between the groups. In addition, the users and non-user groups did not differ in respect of physical activity index, smoking history and exercise capacity, but the users tended to report more often than the non-users a positive family risk for coronary heart disease (34 vs 20%, P=0.11).
The characteristics of users categorized according to the duration of stanol ester margarine use are shown in Table 2. The duration of stanol ester margarine use was associated with higher prevalence of positive family history of coronary artery disease, lower body mass index and, borderline significantly, with higher education. Subjects who had longer history of stanol product use also tended to be older and more often males (Table 2). Lipid profile and blood pressure values were similar in each category (data not shown).
The bivariate correlations coefficients between vascular parameters and other continuous study variables in all subjects are shown in Table 3. Carotid compliance correlated inversely with age, body mass index, total cholesterol, LDL cholesterol, oxidized LDL, triglycerides, glucose, systolic blood pressure and diastolic blood pressure. Intima-media thickness correlated directly with age, body mass index, total cholesterol, LDL cholesterol and glucose. The associations between flow-mediated dilatation and other continuous study variables were generally in the anticipated direction but did not reach statistical significance. The bivariate relations between vascular parameters and two-level study variables (family risk and sex) we assessed by linear regression. Male sex was inversely associated with carotid compliance (β=−0.235±0.102, P=0.023), flow-mediated dilation (β=−3.1±0.8, P=0.0004), and directly with intima-media thickness (β=0.059±0.028, P=0.040). Family risk of premature coronary artery disease was inversely related with carotid compliance (β=−0.231±0.115, P=0.049).
The comparison of ultrasound variables between users and non-users are shown in Table 4. The distributions of intima-media thickness, flow-mediated dilation and nitrate-mediated dilatation were similar between the groups. Carotid artery compliance was non-significantly higher in users compared to non-users, and the difference between the groups was statistically significant after adjustment for family risk and years of education. We adjusted primarily for family risk and years of education because there seemed to be an unbalance in these variables between the groups. However, the result remained essentially similar after further adjustments for age, sex, body mass index, LDL cholesterol, ox-LDL, triglycerides and blood pressure (P⩽0.05 for carotid compliance between study groups).
In a subgroup analysis, comparing only users and non-users with negative family history, the carotid compliance was 2.03±1.15 vs 1.62±0.79 10%/mm Hg (P=0.06) in users (N=33) and non-users (N=40), respectively. In subjects with positive family history, the carotid compliance was 1.47±0.56 in users (N=17) and 1.43±0.62 10%mm Hg (P=0.62) in non-users (N=10), respectively.
As there was a suggestion towards higher carotid compliance among the stanol ester margarine users, we examined whether a dose–response relation exists between the duration of stanol ester margarine use and compliance. Carotid compliance values in the categories of stanol ester margarine use duration are shown in the Figure 1. There was a significant relation between the duration of stanol ester margarine use and compliance when the effects of age, sex and family risk were taken into account using multiple linear regression (β=0.112±0.041, P=0.008). And this association further remained significant after simultaneously controlling for body mass index and years of education (β=0.107±0.043, P=0.016). The regression coefficient (β) indicates the increase in log-transformed carotid compliance across each category of stanol ester margarine use duration.
The effects of stanol ester margarine use on health, other than on cholesterol metabolism, have not been previously studied. We used a case–control design to test if markers of arterial function and structure would differ between stanol ester margarine users and non-users. The mean values for brachial artery flow mediated dilation and carotid artery intima-media thickness were similar between users and non-users. A significant difference in compliance was observed when the imbalance between the groups in family history of coronary artery disease was taken into account. In addition, there was a significant dose–response relationship between stanol margarine use and carotid compliance, longer use being associated with increased compliance.
In all subjects, carotid artery compliance correlated inversely with total cholesterol and LDL cholesterol concentrations. Cholesterol lowering has been shown to improve arterial compliance in patients with familial hypercholesterolemia (Tomochika et al., 1996; Smilde et al., 2000) and hypertension (Ferrier et al., 2002). Stanol ester margarine lowers serum total and LDL cholesterol concentrations (Law 2000). However, in the present study, by using a case–control design, we were unable to demonstrate significant differences in serum cholesterol concentrations between users and non-users. We did not have information about the cholesterol values in the cases before they had started using stanol ester margarine. Therefore, it remains unclear whether changes in cholesterol concentration due to stanol ester margarine use have influenced arterial compliance. History of high cholesterol and cardiovascular disease have been associated with stanol ester margarine use. Therefore, subjects at increased risk presumably use plant stanol ester margarine in order to control serum cholesterol levels through dietary practices (Luoto et al., 2004). In line, we found that longer use was associated with more prevalent family history of coronary artery disease.
In addition to cholesterol lowering stanol ester, the Benecol margarine contains n-3 α linolenic fatty acid from rapeseed oil. Previous observations have suggested that n-3 fatty acids may increase arterial compliance. Systemic arterial compliance was improved in dyslipidaemic subjects after 7-week supplementation with n-3 eicosapentaenoic acid and docosahexaenoic acid (Nestel et al., 2002). In addition, dietary fish oil supplementation for 6 weeks improved arterial compliance in patients with non-insulin dependent diabetes (McVeigh et al., 1994). Furthermore, n-3 rich flaxseed oil supplementation for 4 weeks increased systemic arterial compliance in obese subjects (Nestel et al., 1997). Thus, the association between stanol ester margarine use and higher arterial compliance may partly be mediated by α linolenic fatty acid.
Our study had limitations. The use of stanol ester margarine was self-reported, and the exact information of the amounts consumed and the regularity of use were lacking. Another limitation of our study is the blood pressure measurement method used in the calculation of carotid artery compliance. The pulse pressure used in the equations to calculate carotid compliance was measured from the brachial artery. It would be more ideal to study the pulse pressure from the artery in question, because the use of brachial pressures may overestimate pulse pressure in central arteries (Karamanoglu et al., 1993). This increase is a consequence of pulse wave reflection from the periphery, which augments the peak of the pressure wave in peripheral arteries close to the reflection sites. However, Borow and Newburger (1982) have shown an excellent correlation of r=0.98 between systolic blood pressures and r=0.97 between diastolic pressures measured invasively from ascending aorta and non-invasively from brachial artery supporting the assumption that brachial pulse pressure can be used in deriving carotid compliance. The reported variation in arterial compliance measured with the ultrasound method is rather high (between 15 and 20%) (Arnett et al., 1999; Toikka et al., 2002; Juonala et al., 2005). This is, in part, owing to the fact that several variables including arterial diameter and blood pressure measurements are used to derive this index. The large variation in carotid compliance is a limitation and the results need to be interpreted with caution. The noise in the data is likely to weaken any observed relationship, and the present study may have been underpowered to detect a significant difference in compliance between the study groups. Although the users and non users were well matched for age and sex, there was a tendency for higher prevalence for family history of coronary artery disease. Finally, we did not measure other variables potentially relevant in a study of vascular structure and function, such alcohol consumption, estrogen use among post-menopausal women subjects, vitamin intake and homocysteine.
Our study has restrictions. The study was a case–control study without randomization and double-blind, and overall the results were essentially negative. Significant results were seen only a posteriori after adjustments. Therefore, the results should be considered as hypothesis generating. However, the data raise the possibility that regular stanol ester margarine use may be associated with beneficial changes in arterial compliance. Intervention studies are needed to test this hypothesis and to reveal possible mechanisms.
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This study was partially supported by Raisio Finland Inc.
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Raitakari, O., Salo, P. & Ahotupa, M. Carotid artery compliance in users of plant stanol ester margarine. Eur J Clin Nutr 62, 218–224 (2008). https://doi.org/10.1038/sj.ejcn.1602705
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