CLINICAL PERSPECTIVE

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(Circulation. 2005;112:3786-3794.)
© 2005 American Heart Association, Inc.

Pediatric Cardiology

Endothelial Function in Healthy 11-Year-Old Children After Dietary Intervention With Onset in Infancy

The Special Turku Coronary Risk Factor Intervention Project for Children (STRIP)

Olli T. Raitakari, MD, PhD; Tapani Rönnemaa, MD, PhD; Mikko J. Järvisalo, MD, PhD; Tuuli Kaitosaari, MD; Iina Volanen, MD; Katariina Kallio, MD; Hanna Lagström, PhD; Eero Jokinen, MD, PhD; Harri Niinikoski, MD, PhD; Jorma S.A. Viikari, MD, PhD; Olli Simell, MD, PhD

From the Departments of Clinical Physiology (O.T.R.), Medicine (T.R., J.S.A.V.), Research Centre of Applied and Preventive Cardiovascular Medicine (M.J.J, T.K, I.V., K.K., H.L.), and Pediatrics (H.N., O.S.), University of Turku, Turku, Finland, and Hospital for Children and Adolescents (E.J.), University of Helsinki, Helsinki, Finland.

Correspondence to Olli T. Raitakari, MD, PhD, Department of Clinical Physiology, University of Turku, PO Box 52, FIN-20521 Turku, Finland. E-mail olli.raitakari{at}utu.fi

Received April 6, 2005; de novo received August 16, 2005; revision received September 27, 2005; accepted October 7, 2005.

	Abstract

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Background— Early childhood introduction of nutritional habits aimed at atherosclerosis prevention reduces children’s serum total cholesterol concentration, but its effect on vascular endothelial function is unknown.

Methods and Results— Between 1990 and 1992, we randomized healthy 7-month-old infants (n=1062) to intervention (low-saturated-fat diet) and control (unrestricted diet) groups. At the age of 11 years, endothelium-dependent (flow-mediated) and endothelium-independent (nitrate-mediated) vasodilatory responses of the brachial artery were measured with high-resolution ultrasound in 179 intervention and 190 control children. The effect of intervention on endothelial function was significant in boys (P=0.0034) but not in girls (P=0.69). The maximum endothelium-dependent dilation response (mean±SD) was 9.62±3.53% and 8.36±3.85% in intervention boys and control boys and 8.84±4.00% and 8.44±3.60% in intervention girls and control girls, respectively. Intervention had no effect on nitrate-mediated dilation. The difference in endothelial function in boys remained significant after adjustment for current serum total or LDL cholesterol but became nonsignificant after adjustment for mean cholesterol measured under 3 years of age (adjusted means: 9.46% [CI 8.68% to 10.24%] versus 8.54% [CI 7.75% to 9.32%], P=0.11).

Conclusions— A low-saturated-fat diet introduced in infancy and maintained during the first decade of life is associated with enhanced endothelial function in boys. The effect is explained in part by the diet-induced reduction in serum cholesterol concentration.

Key Words: endothelium • pediatrics • atherosclerosis • cholesterol • diet

	Introduction

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Hypercholesterolemia is associated with impaired endothelial function¹ and accelerated atherogenesis in children.^2,3 The relationship between cholesterol and endothelial function is not limited to extreme cholesterol levels, because serum cholesterol concentration also correlates with endothelial function in healthy children and adolescents.⁴ We and others have shown that exposure to high serum cholesterol concentration in childhood may induce changes in arteries that contribute to the development of atherosclerosis in adulthood.^5–7 Consequently, the long-term prevention of atherosclerosis might be most effective when initiated early in life.⁸

Clinical Perspective p 3794

In adults, the reduction of serum cholesterol concentration with diet or drug therapy improves endothelial function and is associated with decreased morbidity and mortality from cardiovascular disease.⁹ Enhanced endothelial function may be responsible for part of the benefits of cholesterol lowering on vascular health.¹⁰ The randomized, prospective Special Turku Coronary Risk Factor Intervention Project for children (STRIP) has demonstrated that a fat-modified diet (low in saturated fat) initiated in infancy and combined with repeated individualized dietary and lifestyle counseling lowers serum cholesterol concentration in children^11–13 without adversely influencing growth or neurological development.¹⁴ We have now examined the effects of the intervention on vascular endothelial function at the age of 11 years. We hypothesized that restricting dietary intake of saturated fat would lead to enhanced endothelium-dependent, flow-mediated dilation of the brachial artery in the intervention children.

	Methods

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Study Design and Subjects
The study design of the ongoing STRIP study has been published previously.¹² Recruitment took place between March 1990 and June 1992. At the child’s routine 5-month visit to the child health center, all families were informed of the possibility of participating in the trial. There were 1054 voluntary families with 1062 infants (56.5% of the 1880 eligible infants in the age cohort). The children and their families were randomized to form an intervention group (n=540) and a control group (n=522) at the age of 7 months. The intervention group received dietary and lifestyle counseling twice a year given by a team of physicians and dietitians. The families recorded the child’s food consumption for 4 days twice a year. A dietitian examined the food records and gave appropriate individualized dietary instructions. The diet was designed to meet the Nordic Dietary Recommendations.¹⁵ To ensure compliance, parents were given detailed instructions on how to record food and fluid consumption. This was done by including drawings of ordinary foods with weights and common household measures in the instructions to help estimation of food consumption. To ensure compliance at day care, we informed the personnel about the study, emphasized the importance of maintaining the diet, gave instructions on how to take into consideration the special arrangements with regard to the child’s diet, and gave instructions on how to record food type and consumption. Similarly, at schools, kitchen personnel were informed about the study. Both the parents and the day care personnel were instructed to record the type, brand, and preparation method of all foods used. These records were reviewed by nutritionists for completeness and accuracy at each visit. Individualized counseling was targeted accordingly, and if needed, portion sizes were added to the instructions with, for example, food models and household measures, food descriptions, and food preparation methods provided. The control children received the basic health education given at Finnish well-baby clinics and schools with a minimal amount of nutritional counseling after infancy. During their regular STRIP visits, the control children received no detailed dietary instructions. Based on biannual 4-day food records, the fat intake of the intervention children was constantly &30% of the energy intake, whereas that of the control children was significantly (P<0.001) higher, by 2 to 3 calorie percentage units.¹⁶ The intervention children received 2 to 3 calorie percentage units fewer saturated fats and 0.5 to 1.0 calorie percentage units more polyunsaturated fats than the control children.¹⁶ The nutrient intakes of the parents were assessed with 24-hour recall.¹⁷ When children were 5 years of age, both parents of the intervention children consumed less saturated fat (P<0.001) than control parents. The intervention had no effect on early¹⁸ or later¹⁹ growth of the children.

The study was approved by the Joint Commission on Ethics of the Turku University and the Turku University Central Hospital. Informed consent was obtained from all guardians.

Physical Examination and Interview
Weight was measured with an electronic scale to the nearest 0.1 kg (Soehnle S10; Soehnle). Height was measured with the Harpenden stadiometer (Holtain). Blood pressure was measured from the nondominant arm with a standard sphygmomanometer. The mean of 3 measurements was used in the statistical analyses. Tanner staging was used to classify sexual maturation.²⁰ Participation in leisure-time physical activity was assessed by asking the frequency of participation in physical activity outside school hours. Exposure to environmental tobacco smoke (during the past 3 days) was assessed in an interview. Family history was considered positive if the study subject’s father, mother, grandfather, or grandmother had had a myocardial infarction.

Measurement of Serum Lipids
Serum total cholesterol, HDL cholesterol, and triglycerides concentrations were measured with standard methods as described previously.^12,21 Nonfasting blood samples were drawn when the child was less than 5 years old, and fasting samples were taken thereafter. Cholesterol measurements were performed at ages 7 and 13 months and at 2, 3, 4, 5, 7, 9, 10, and 11 years. Of the study children, 93% had data available on 8 or more cholesterol measurements (mean 9.2±1.0 measurements per child). The Friedewald formula was used to calculate serum LDL cholesterol values.²² To assess the relation of serum cholesterol measured at various ages to flow-mediated vasodilation, we calculated 3 mean cholesterol concentration variables: between 7 months and 2 years, between 3 and 5 years, and between 7 and 11 years.

Brachial Artery Ultrasound Studies
Recruitment for ultrasound studies begun in the middle of the year when the 11-year follow-up visits were ongoing. Children who had not already participated in their 11-year visit were recruited for the study. Thus, the ultrasound group represents a time-restricted cohort. The reasons given for nonparticipation for the ultrasound study were child’s unwillingness to participate (50%, n=42), lack of time (25%, n=21), fear of the study (20%, n=17), and transportation problems (5%, n=4). Of the 1062 children randomized, 614 children attended the 11-year follow-up study. Complete ultrasound data were available on 369 children, with similar rates in the intervention and control groups (Figure 1).

View larger version (31K): [in this window] [in a new window]   Figure 1. Flow diagram of the STRIP trial.

All ultrasound studies were performed with an Acuson Sequoia 512 mainframe (Acuson) with a 13.0-MHz linear-array transducer. To minimize external stimuli, all studies were performed in silence in a temperature-controlled clinical research laboratory. Left brachial artery diameter was measured from B-mode ultrasound images at rest, during reactive hyperemia, and after administration of sublingual nitroglycerin as described previously.⁴ Briefly, a resting scan was performed and arterial flow velocity measured with a Doppler signal. Increased flow was then induced by inflation of a blood pressure cuff placed around the forearm to a pressure of 250 mm Hg for 4.5 minutes, followed by release. A second continuous scan was recorded between 30 and 180 seconds after cuff deflation, including a repeated flow-velocity measurement during the first 15 seconds after cuff release. All ultrasound scans were analyzed by the same reader, who was blinded to the subject’s details. Vessel diameter was measured offline at a fixed position with ultrasonic calipers at end diastole, incident with the R wave on a continuously recorded ECG. We measured dilation from baseline at 10-second intervals between 30 and 180 seconds. In addition, we assessed the total dilatation response. This was defined as the area under the dilation response versus time curve between 30 and 180 seconds after hyperemia. The nitrate-mediated endothelium-independent dilation response was tested by administration of a 250-µg sublingual dose of nitroglycerin. Maximum arterial diameter 5 minutes after nitrate administration was used to calculate nitrate-mediated dilation. In our laboratory, the interobserver variation (coefficient of variation) of flow-mediated dilation measurements was 8.6%, and the between-study coefficient of variation was 9.3%.²³

Statistical Analyses
The groups were compared with Student’s t test or nonparametric Mann-Whitney U test as appropriate. Regression coefficients were calculated to study the determinants of flow-mediated vasodilation. ANCOVA was used to calculate adjusted means. We used repeated-measures ANOVA to test whether there were differences between children with and without complete ultrasound data in longitudinal values of serum cholesterol and saturated fat intake, whether there was a sex difference in the effect of the intervention on endothelial function, and whether the magnitude of flow-mediated vasodilatory responses differed between the study groups. A 2-tailed P<0.05 was considered significant. SAS version 8.01 was used for statistical analyses.

	Results

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The baseline characteristics at randomization of all children and those with complete ultrasound data at follow-up are shown in Table 1. Comparison of baseline characteristics between children with and without complete ultrasound data revealed no significant differences (P always >0.15). In addition, those intervention children who had complete ultrasound data did not differ significantly from other intervention children participating in the 11-year study with respect to serum lipoproteins, anthropometry, or blood pressure values (Table 2). Comparison of control children with and without ultrasound data at the age of 11 years yielded similar results (data not shown). Figure 2 shows that the mean values of serum cholesterol concentration and saturated fat intake at each follow-up point was different between intervention and control children but that there were no systematic differences in these 2 variables between children with and without ultrasound data. The results of a dropout analysis (shown in Figure 3) suggested that had been no systematic differences in participants and dropouts with respect to saturated fat intake and serum cholesterol concentration.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of Study Children at Randomization

View this table: [in this window] [in a new window]   TABLE 2. Comparison of Intervention Children With and Without Complete Ultrasound Data at the Age of 11 Years

View larger version (23K): [in this window] [in a new window]   Figure 2. Serum saturated fat intake values (top) and total cholesterol values (bottom) are shown at each study point in children with and without complete data on ultrasound at the 11-year visit. Intervention children had consistently lower saturated fat intake (P<0.001) and mean cholesterol concentration (P<0.001) in repeated-measures of analysis from age 13 months than control children. However, intervention and control children with ultrasound data had similar cholesterol (P=0.11) and saturated fat intake (P=0.13) values as other intervention and control children.

View larger version (15K): [in this window] [in a new window]   Figure 3. Saturated fat intake values (top) and total cholesterol values (bottom) are shown at each study point in participants and in children who were lost to follow-up after the particular study point. The values of cholesterol and saturated fat intake were similar in each study year (P always >0.05 in multiple pairwise comparison at each follow-up study point for both cholesterol and saturated fat intake).

The characteristics of the study children at 11 years are shown in Table 3. Intervention children had lower intake of saturated fat and a higher ratio of polyunsaturated to saturated fatty acid than control children (all P<0.001). The boys in the intervention group had 0.23 mmol/L lower serum total cholesterol concentration (P=0.035) and 0.26 mmol/L lower LDL concentration (P=0.009) than the boys in the control group, whereas these values did not differ between intervention girls and control girls. No significant differences were noted in HDL cholesterol, triglycerides, body size measures, blood pressure, family risk of myocardial infarction, leisure-time physical activity, or exposure to environmental cigarette smoke. At the age of 11 years, puberty was ongoing in 65.7% and had not started in 34.3% of the children, but none of the children had completed puberty. The distribution of pubertal stages did not differ between intervention and control groups (P=0.64).

View this table: [in this window] [in a new window]   TABLE 3. Characteristics of 369 Study Children at the Age of 11 Years

The results of the ultrasound studies are shown in Table 4. Maximum flow-mediated dilation (P=0.012) and the area under the dilation response versus time curve (P=0.004) were higher in the intervention boys than in the control boys. Brachial artery vessel size and increase in blood flow after cuff release were similar. The values of intervention and control girls did not differ.

View this table: [in this window] [in a new window]   TABLE 4. Ultrasound Results of 369 Study Children at the Age of 11 Years

The temporal development of flow-mediated dilation responses measured between 30 and 180 seconds after cuff release followed a similar pattern over time in the study groups, but the magnitude of the response was significantly greater in the intervention boys than in the control boys (group-by-sex interaction P=0.01; effect of intervention in boys P=0.0034; effect of intervention in girls P=0.69; Figure 4).

View larger version (24K): [in this window] [in a new window]   Figure 4. Flow-mediated vasodilation responses in the intervention () and control children () at each measurement point between 30 and 180 seconds after cuff release (top, boys; bottom, girls). There was a significant sex difference in the effect of the intervention on flow-mediated vasodilation (interaction term P=0.01). The magnitude of the response was greater in intervention boys than in control boys (effect of intervention P=0.0034) but similar in intervention girls compared with control girls (effect of intervention P=0.69). Error bars show SEM.

The relations between maximum flow-mediated dilation and mean serum cholesterol concentrations measured at various ages in all subjects are shown in Table 5. Mean cholesterol values measured between ages 7 months and 2 years and between 3 and 5 years were significantly related to flow-mediated dilation. Mean cholesterol values measured between 7 and 11 years and current cholesterol and current LDL cholesterol (single measurements at 11 years) were not significantly correlated with flow-mediated vasodilation (Table 3). These relations were similar in boys and girls, because the interactions between sex and cholesterol were nonsignificant (interaction terms P always >0.4).

View this table: [in this window] [in a new window]   TABLE 5. Relationships Between Flow-Mediated Vasodilation and Average Serum Total Cholesterol Measured at Different Ages in All 369 Study Children

The difference in endothelial function between the intervention and control boys remained significant after adjustments for current LDL cholesterol and mean total cholesterol measured between ages 7 and 11 years (Table 2). Similarly, the difference remained significant after adjustment for body mass index. The body mass index adjusted means were 9.60% versus 8.43% (P=0.036) for maximal flow-mediated dilation and 921%xs versus 727%xs (P=0.014) for area under dilation versus time curve, in intervention and control boys, respectively. After the adjustment for mean total cholesterol measured between 7 months and 2 years, the difference in maximum flow-mediated dilation became statistically nonsignificant (P=0.11; Table 2).

	Discussion

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Alterations in endothelial function have been documented in children with hypercholesterolemia or diabetes.^1,24,25 This supports the concept that endothelial dysfunction plays a role in the early pathophysiology of atherosclerosis. Endothelial function may be enhanced by various therapies.²⁶ Interventions that have been applied successfully in high-risk children have included the use of antioxidants²⁷, lipid-lowering with statins,²⁸ and exercise training.²⁹ The results of previous dietary interventions have been inconsistent. Woo et al³⁰ studied the effect of a hypocaloric low-fat diet on flow-mediated vasodilation in obese children. The intervention decreased serum cholesterol level and improved endothelial function in the short term (at 6 weeks). The effect of a low-saturated-fat diet on endothelial function has been studied by Engler and coworkers.²⁷ They examined the effects of the National Cholesterol Education Program Step II diet on endothelium-dependent vasodilation in children with familial hypercholesterolemia or familial combined hyperlipidemia. The diet induced a significant reduction in LDL cholesterol concentration but failed to improve endothelial function during the 6-month trial. de Jongh et al³¹ evaluated the effect of plant sterols on cholesterol and vascular function in children with familial hypercholesterolemia. Daily intake of plant sterols for 4 weeks decreased total cholesterol and LDL cholesterol but did not improve flow-mediated vasodilation. Compared with these studies, the present study differed markedly in length and target population. The present study cohort was recruited from the general population and included a relatively large number of healthy children who had been exposed to life-long cholesterol-lowering dietary intervention immediately after weaning.

In the present study, the mean serum cholesterol concentration measured during the life course correlated with flow-mediated dilation. Interestingly, cholesterol concentration measured before the age of 5 years was a stronger correlate than the mean cholesterol concentration measured after this age. Furthermore, the difference in endothelial function between intervention boys and control boys remained significant after adjustments for current total cholesterol and LDL cholesterol levels. However, the difference became nonsignificant after we took into account the mean cholesterol concentration measured between ages 7 months and 2 years. This suggests that the higher flow-mediated dilation seen in boys in the intervention group is not merely a reflection of recent cholesterol control but reflects the importance of early and long-term cholesterol control in influencing vascular function. These observations, however, need to be interpreted cautiously, because cholesterol values show significant tracking, ie, a concentration measured at 1 time point reflects the concentration later in life. The mechanisms by which cholesterol interferes with endothelial function are not fully understood but may include reduced availability of nitric oxide through a combination of decreased production, increased inactivation, and abnormal signaling.³²

During the trial, the intervention children consistently received 2 to 3 calorie percentage units fewer saturated fats and 0.5 to 1.0 calorie percentage units more polyunsaturated fats than the control children.¹⁶ With these dietary fat changes, the expected reduction in serum cholesterol concentration would be 0.16 to 0.24 mmol/L according to the Keys’ equation.³³ In intervention boys, serum cholesterol concentration has been consistently &0.2 to 0.3 mmol/L or 5% to 8% lower than in control boys, ie, the intervention effect has been slightly greater than predicted. A meta-analysis by Law et al³⁴ indicated that the benefits of cholesterol reduction are greater in younger subjects: a 10% reduction in cholesterol concentration produces a reduction in ischemic heart disease of 50% at age 40 and 20% at age 70 years. Estimating the magnitude of risk reduction associated with cholesterol lowering achieved in the STRIP trial will require long-term follow-up of these children, but the associated enhancement of endothelial function in boys suggests potentially advantageous effects on cardiovascular health.

The intervention influenced endothelial function in boys but not in girls. This is consistent with the lack of intervention effect on serum cholesterol concentration in girls.^12,13 Despite similar intervention-control group differences in the composition of the diet throughout the years,¹⁶ the follow-up has consistently shown significant cholesterol-lowering effects only in boys. Some^35–38 but not all³⁹ earlier studies in adults have suggested that men show greater changes than women in LDL cholesterol concentration in response to changes in dietary intake of saturated fatty acids. The mechanism for the possible higher resistance to diet-induced LDL lowering in females is unknown but may relate to differences in sex hormone levels. Estrogens regulate serum LDL cholesterol concentration by affecting the number of hepatic LDL receptors.⁴⁰ Similarly, changes in dietary saturated fat intake influence serum LDL cholesterol concentration by inducing changes in the number of LDL receptors.⁴¹ Therefore, a potential for interaction in lipoprotein metabolism exists between fat intake and estrogens. Differences in estrogen levels between boys and girls are many-fold and become evident before puberty.⁴² Thus, it is plausible that the inefficient impact of intervention in girls may be due to gender differences in serum sex hormone concentrations.

The present study had limitations. A substantial number of children were lost to follow-up. The results of a dropout analysis, however, indicated that there were no systematic differences between participants and dropouts with respect to saturated fat intake and serum cholesterol concentration. This suggests that the children remaining in the study are representative of the original sample. The major weakness is that the ultrasound study was performed only in a subgroup of the initial study cohort; however, those children who had complete ultrasound data did not differ significantly from the other children at baseline or at the 11-year study in any of the measured characteristics. Furthermore, children who had complete ultrasound data had similar cholesterol values and similar saturated fat intake as other children participating at the 11-year study in each of the previous study years. These observations suggest that the children with ultrasound data are representative of the other study children.

The magnitude of difference in flow-mediated dilation between intervention and control boys was relatively small. Previous studies have shown much larger differences in endothelial function between children "at risk" and healthy controls; however, all children in the present study were healthy and were recruited from a general population. Our aim was not to improve endothelial dysfunction in a group of high-risk children but to investigate whether a long-term cholesterol-lowering diet would have a beneficial influence on endothelial health in a pediatric population with high adult rates of coronary artery disease.⁴³ The mean flow-mediated dilation values were within the normal range in all children⁴ and were comparable for girls and control boys; however, the values for intervention boys were higher, which suggests a better endothelial status than would normally be expected in children consuming a regular Finnish diet. The intervention boys had been exposed to a lower cholesterol concentration throughout their lives, whereas the other groups had been exposed to cholesterol concentrations typical for Finnish children. In all subjects, cholesterol concentration correlated with flow-mediated dilation, which suggests a mechanistic relationship between cholesterol metabolism and endothelial function. Furthermore, the difference between intervention boys and control boys was attenuated when we took into account the cholesterol values measured during their lives. Therefore, the higher flow-mediated vasodilation responses observed in the intervention boys is consistent with the long-term cholesterol control induced by the dietary intervention begun in infancy.

	Acknowledgments

 
This study was financially supported by the Academy of Finland (grants 34316, 11053, 73582, and 64/2003); City of Turku; the Finnish Foundation for Pediatric Research; the Finnish Foundation of Cardiovascular Research; the Finnish Cultural Foundation; government grants for Turku University Hospital; Juho Vainio Foundation; the Mannerheim League for Child Welfare; Raisio Group Research Foundation; the Social Insurance Institution of Finland; the Turku University Foundation; the Van den Bergh Foods Company; the Yrjö Jahnsson Foundation; and the Sigrid Juselius Foundation.

Disclosures

None.

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CLINICAL PERSPECTIVE

Exposure to high serum cholesterol concentration in childhood may accelerate the development of atherosclerosis. Consequently, the long-term prevention of atherosclerosis might be most effective when initiated early in life. The prospective STRIP trial was launched in 1990 to examine the effects of a low-saturated-fat diet in atherosclerosis risk prevention in children. At the age of 7 months, healthy Finnish children were randomized to low-saturated-fat diet and unrestricted diet groups. During the first decade of the trial, the children in the intervention group received 2 to 3 calorie percentage units less saturated fats than the children in the control group. The serum cholesterol concentration was consistently &0.2 to 0.3 mmol/L lower in intervention boys than in control boys. Despite similar changes in the diet, no significant cholesterol-lowering effect was observed in girls. Because endothelial function may play a role in the early pathophysiology of atherosclerosis, a noninvasive ultrasound study was performed in these children at the age of 11 years to measure endothelium-dependent flow-mediated vasodilatory responses. Consistent with the long-term cholesterol control induced by the dietary intervention, the intervention was associated with enhanced endothelial function in boys. The STRIP study indicates that it is feasible to reduce saturated-fat intake in children. Estimating the magnitude of risk reduction associated with cholesterol lowering achieved in the STRIP trial will require long-term follow-up of these children, but the associated enhancement of endothelial function in boys suggests potentially advantageous effects on cardiovascular health.

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