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(Hypertension. 2006;48:424.)
© 2006 American Heart Association, Inc.

Original Articles

Elevated Blood Pressure in Adolescent Boys Predicts Endothelial Dysfunction

The Cardiovascular Risk in Young Finns Study

Markus Juonala; Jorma S.A. Viikari; Tapani Rönnemaa; Hans Helenius; Leena Taittonen; Olli T. Raitakari

From the Centre of Applied and Preventive Cardiovascular Medicine (M.J.) and Departments of Medicine (J.S.A.V., T.R.), Biostatistics (H.H.), and Clinical Physiology (O.T.R.), University of Turku, Turku, Finland; Department of Pediatrics (L.T.), University of Oulu, Oulu, Finland, and Vaasa Central Hospital, Vaasa, Finland.

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

	Abstract

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Hypertension is a major risk factor for atherosclerosis. It may cause or be a consequence of endothelial dysfunction. We studied whether systolic blood pressure measured in childhood and adolescence predicts endothelial-dependent brachial flow-mediated dilation (FMD) in adulthood. Brachial FMD was measured in 2109 white adults, aged 24 to 39 years, in the 21-year follow-up of the Cardiovascular Risk in Young Finns Study. These subjects have risk factor data available dating back to their childhood (baseline in 1980, ages 3 to 18 years). In male subjects, the level of systolic blood pressure measured in adolescence (at ages 12 to 18 years at baseline) was inversely related to adulthood FMD (P=0.004). This association was independent of brachial diameter and other childhood (P=0.003) and adulthood risk factors, including blood pressure (P=0.03). Childhood (age 3 to 9 years at baseline) systolic blood pressure did not correlate with adult FMD in men or in women (P always >0.2). In male subjects, elevated systolic blood pressure in adolescence predicts impaired brachial endothelial function 21 years later in adulthood. This association is independent of other childhood and adulthood cardiovascular risk factors suggesting that blood pressure elevation in adolescence may have an influence on biological processes that regulate endothelium-dependent flow-mediated vasodilatation capacity.

Key Words: atherosclerosis • blood pressure • children • endothelium

	Introduction

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Hypertension is a major risk factor for atherosclerosis. It has been estimated that the risk of coronary heart disease, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg.¹ In children and young adults, elevated blood pressure has been associated with atherosclerotic autopsy lesions, as well as with increased carotid intima–media thickness (IMT) and decreased arterial elasticity.^2–7 However, there is a paucity of information concerning the association between childhood blood pressure and endothelial function later in life.

Endothelial dysfunction is one of the earliest atherosclerotic changes in arteries. A noninvasive ultrasound technique to evaluate brachial artery flow-mediated dilation (FMD) has recently been much used in the study of endothelial function.^8,9 Brachial FMD response correlates significantly with invasive methods testing coronary and brachial endothelial function.^10,11 Conventional cardiovascular risk factors in children and adults are associated with FMD.^8,12,13 Moreover, impaired brachial endothelial function is associated with the prevalence and extent of coronary atherosclerosis^14,15 and independently predicts cardiovascular events in patient groups.^16,17 In cross-sectional studies, blood pressure levels have been shown to inversely correlate with FMD, and hypertensive subjects have been observed to have decreased FMD responses.^12,18,19

Elevated blood pressure in the vasculature may interfere with the integrity of endothelial cells causing endothelial activation or dysfunction.²⁰ The causality may also operate in the opposite direction, because it has been suggested that disturbances in endothelial function may predispose the development of hypertension.²¹ The current study investigated whether blood pressure levels in childhood and adolescence are related to endothelial function, that is, brachial FMD in adults. The study subjects were participants in the large, population-based Cardiovascular Risk in Young Finns Study. In the 21-year follow-up, brachial FMD was measured in 2109 subjects aged 24 to 39 years with risk factor data since their childhood.

	Methods

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Subjects
The Cardiovascular Risk in Young Finns Study is an ongoing 5-center follow-up study of atherosclerosis precursors of Finnish children and adolescents. The study has been carried out in all 5 of the Finnish university cities with medical schools (Helsinki, Kuopio, Oulu, Tampere, and Turku) and their rural surroundings. In 1980, altogether 4320 children and adolescents aged 3, 6, 9, 12, 15, and 18 years were randomly chosen from the national population register of these areas. Of those invited, 3596 participated in the cross-sectional study in 1980.²² In 2001, 2265 of these individuals, now aged 24 to 39 years, participated in the 21-year follow-up examination.²³ The study was approved by local ethics committees, and all of the subjects gave their written informed consent.

Clinical Characteristics and Risk Factors
Height and weight were measured, and body mass index (BMI) was calculated. In 1980, blood pressure was measured from 3-year-olds with an ultrasound device (Arteriosonde 1020, Roche) and in others with a standard mercury sphygmomanometer.²⁴ The measurements were taken from fasting subjects at 8 to 10 AM. The registration was made only after the subject had become relaxed and calm. If the subject was restless, the values were excluded. Systolic blood pressure was recorded for Korotkoff’s first phase. Diastolic blood pressure was recorded at the change in sound in the 3-year-old children and for both Korotkoff’s fourth and fifth phases in the others. Korotkoff’s fifth phase results have been used in the analysis. Readings were made to the nearest 2 mm Hg. The average of 3 measurements was used in the analysis. In 1983, blood pressure was measured using a standard mercury sphygmomanometer, and in 1986 and 2001, a random 0 sphygmomanometer was used.²³ Smoking habits were investigated with a questionnaire in subjects aged 12 years. The data on birth weight were collected in the second cross-sectional study in 1983, and parents were requested to confirm the information from the well-baby clinics’ medical charts. For the determination of serum lipoprotein levels, venous blood samples were drawn after an overnight fast. All of the lipid determinations were done using standard methods.²³ The fasting plasma high-sensitive C-reactive protein (CRP) concentrations (in 2001) were analyzed by latex turbidometric immunoassay (Wako Chemicals GmbH). Homocysteine concentrations (in 2001) were analyzed with a microparticle enzyme immunoassay kit (Imx assay, Abbott Laboratories). In 1980, serum insulin was measured using a modification of the immunoassay method of Herbert et al.²⁵ In 2001, serum insulin was measured by a microparticle enzyme immunoassay kit (Abbott Laboratories, Diagnostic Division). Details of the methods have been presented elsewhere.^6,23

Ultrasound Imaging
Brachial FMD
Brachial artery ultrasound studies were performed successfully for 2109 subjects, as reported previously.²⁶ To assess brachial FMD, the left brachial artery diameter was measured both at rest and during reactive hyperemia. Increased flow was induced by inflation of a pneumatic tourniquet placed around the forearm to a pressure of 250 mm Hg for 4.5 minutes, followed by a release. The ultrasound probe was handheld during the study. Three measurements of arterial diameter were performed at end diastole at a fixed distance from an anatomic marker at rest and 40, 60, and 80 seconds after cuff release. The reader was blinded to the study subjects’ identity but not to the time of measurement. The vessel diameter in scans after reactive hyperemia was expressed as the percentage relative to the resting scan (100%). The average of 3 measurements at each time point was used to derive the maximum FMD (the greatest value between 40 and 80 seconds). The 3-month between-visit coefficient of variation (CV) was 3.2% for brachial artery diameter measurements and 26.0% for FMD measurements. All of the ultrasound scans were analyzed by a single reader.

Carotid IMT and Elasticity
Carotid artery ultrasound studies were performed in 2265 subjects, as reported previously.⁶ In brief, the image was focused on the posterior (far) wall of the left carotid artery. A magnified image was recorded from the angle showing the greatest distance between the lumen–intima interface and the media–adventitia interface. At least 4 measurements of the common carotid far wall were taken 10 mm proximal to the bifurcation to derive mean carotid IMT. The between-visit CV of IMT measurements was 6.4%.⁶

To assess carotid artery distensibility coefficient (CADC), the best quality cardiac cycle was selected from the 5-second clip images. The common carotid diameter was measured at least twice in end diastole and end systole. Ultrasound and concomitant brachial blood pressure measurements were used to calculate CADC=([Ds^2–Dd²]/Dd²)/(Ps–Pd), where Ds is the systolic diameter; Dd, the diastolic diameter; Ps, systolic blood pressure; and Pd, diastolic blood pressure. The between-visit CV was 14.3% for CADC and 2.7% for diastolic carotid diameter.⁷

Statistical Methods
The association between childhood/adolescence systolic blood pressure and FMD was studied, stratified by sex and the age when the risk factor measurement was taken, that is, separately in 3- to 9- or 12- to 18-year-olds.⁶ This age stratification paralleled pubertal staging, because 85% of 12- to 18 year-olds at baseline were classified as having puberty ongoing or completed (Tanner staging). Univariate correlations between childhood/adolescence systolic blood pressure and adult FMD were tested with regression analysis after dividing subjects into sex and age cohort–specific quartiles. Stepwise multivariate linear regression models were used to examine whether the association between adolescent blood pressure and adult FMD is independent of brachial artery baseline diameter, childhood and adulthood risk factors, and carotid artery IMT and elasticity. Group comparisons in clinical characteristics were made using the ANOVA. Tracking of blood pressure from childhood to adulthood was studied with Pearson’s correlation analysis.

Values for triglycerides, insulin, and CRP were log₁₀-transformed before analyses because of skewed distributions. All of the analyses were repeated after exclusion of subjects with antihypertensive medication (N=47) with similar results. The statistical tests were performed with SAS version 8.1, and statistical significance was inferred at a 2-tailed P<0.05.

	Results

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Figure shows the FMD values in adulthood according to childhood/adolescent systolic blood pressure quartiles stratified by age and sex. In boys aged 12 to 18 years at baseline, a decreasing trend in FMD values was observed across systolic blood pressure quartiles (P=0.004). The clinical characteristics in this subgroup are shown according to systolic blood pressure quartiles in Table 1. Diastolic blood pressure and BMI in childhood and adulthood and low-density lipoprotein (LDL) cholesterol and triglycerides in childhood correlated significantly across these quartiles. In girls or boys aged 3 to 9 years, childhood/adolescence blood pressure did not correlate with adult FMD (Figure). Diastolic blood pressure did not correlate with FMD in any subgroup, nor in the total cohort (P always >0.05). A significant tracking in blood pressure values from childhood to adulthood was observed in each subgroup (P always <0.0001; Table 2).

View larger version (20K): [in this window] [in a new window]   Boxplot of adult (at ages 24 to 39 years) brachial flow-mediated dilation values according to age-specific quartiles of childhood/adolescence systolic blood pressure measured 21 years earlier. Results are shown stratified according to age and sex at blood pressure measurement: (a) male subjects aged 12 to 18 years (N=468); (b) female subjects aged 12 to 18 years (N=615); (c) male subjects aged 3 to 9 years (N=464); and (d) female subjects aged 3 to 9 years at baseline (N=562).

View this table: [in this window] [in a new window]   TABLE 1. Clinical Characteristics in Adolescence (in 1980) and in Adulthood (in 2001) According to Age-Specific Systolic Blood Pressure Quartiles in Male Subjects Aged 12 to 18 Years at Baseline

View this table: [in this window] [in a new window]   TABLE 2. Pearson’s Correlation Coefficients for 21-Year Tracking of Systolic Blood Pressure From Childhood/Adolescence to Adulthood

We also studied whether the combining of several blood pressure measurements in childhood/adolescence has an effect on the association between blood pressure and FMD. Therefore, we constructed a "load" variable of systolic blood pressure, that is, systolic blood pressure values in 1980, 1983, and 1986 were first all ranked using sex-specific percentile points (range: 0 to 100). Then, a sum variable of these 3 measures was calculated and used as a systolic blood pressure variable. We also compared the subjects with constantly high systolic blood pressure from childhood to adolescence (75th percentile in 1980 and 1986) with those with constantly low systolic blood pressure (25th percentile in 1980 and 1986). In both of these additional analyses, the results remained similar: systolic blood pressure was associated with FMD only in boys aged 12 to 18 years at baseline (in 1980; data not shown).

Associations Between Adulthood Blood Pressure and FMD
In cross-sectional analysis, in 24- to 39-year-old subjects, systolic blood pressure correlated inversely with FMD (r=–0.09; P<0.0001). In addition, those subjects with systolic blood pressure 140 mm Hg had decreased FMD (7.1±4.1% [N=87] versus 8.0±4.4% [N=2022]; t test P=0.04). These associations remained significant after adjustment for sex, age, LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, BMI, smoking, insulin, CRP, and homocysteine. In multivariate models, a 10-mm Hg increase in systolic blood pressure was associated with a decrease of 0.21±0.08% in FMD (P=0.007), and subjects with systolic blood pressure 140 mm Hg had 1.22±0.50% lower FMD compared with control subjects (P=0.01).

Independent Effect of Adolescent Systolic Blood Pressure on Adult FMD
The association between adolescent blood pressure and adult FMD was independent of brachial artery diameter and other childhood (P=0.003) or adulthood risk factors (P=0.03) in boys aged 12 to 18 years at baseline (Tables 3 and 4). Variables in these models included BMI, LDL cholesterol, high-density lipoprotein cholesterol, smoking, triglycerides, insulin (childhood and adulthood), birth weight (only in childhood model) and systolic blood pressure, CRP, homocysteine, carotid IMT, and carotid elasticity (only in adulthood). When both adolescent and adulthood systolic blood pressure were included in the same model, only adolescent blood pressure correlated significantly with FMD (P=0.03 for adolescent and P=0.52 for adulthood blood pressure).

View this table: [in this window] [in a new window]   TABLE 3. Association Between Adolescence Systolic Blood Pressure and Adult Brachial FMD (%) in Stepwise Multivariate Analysis Adjusted for Adolescence Cardiovascular Risk Factors and Adult Brachial Artery Diameter in Male Subjects Aged 12 to 18 Years at Baseline (N=466)

View this table: [in this window] [in a new window]   TABLE 4. Associations Between Adulthood Cardiovascular Risk Factors and Brachial FMD (%, Measured at Ages 33 to 39 Years) in Stepwise Multivariate Analysis in Male Subjects Aged 12 to 18 Years at Baseline (N=445)

	Discussion

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We found that in male subjects systolic blood pressure measured in adolescence was inversely associated with brachial FMD, a marker of endothelial function, measured 21 years later in adulthood. This relation was independent of other childhood and adult cardiovascular risk factors, including blood pressure, suggesting that blood pressure regulation during maturation from childhood to adulthood may have biological consequences on later vascular endothelial health.

Blood pressure levels in childhood and adolescence have been linked previously to postmortem markers of atherosclerosis in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY)² and the Bogalusa Heart Study.³ In our study cohort^6,7 and in the Bogalusa Heart Study,⁵ childhood blood pressure has been shown to predict increased carotid IMT and decreased arterial elasticity in adulthood. However, to the best of our knowledge, there are no previous prospective data concerning the relationship between childhood blood pressure and adult FMD. We have shown previously that childhood risk factors, including elevated blood pressure, are related to increased carotid artery IMT and decreased elasticity measured in adulthood.^6,7 In the present analysis, the relation between adolescent systolic blood pressure and adult FMD remained statistically significant and of the same magnitude after adjustment for adult IMT and elasticity. This suggests that the relationship between blood pressure and endothelial function is independent of alterations in carotid artery structure and function. Atherosclerosis is a dynamic process affecting the whole arterial tree. Arterial remodeling including increased wall thickness, decreased elasticity, and endothelial dysfunction may represent different aspects of vascular damage, which occur earlier in subjects with early onset of high blood pressure.

There are various potential mechanisms explaining the relationship between adolescent blood pressure and endothelial dysfunction later in life. Endothelial alterations occur early in hypertension with enhanced adherence of leukocytes to the endothelial surface and increased endothelial permeability.²⁰ Elevated blood pressure is associated with macrophage accumulation, stimulation of smooth muscle cell proliferation, and enhanced expression of cytokines and growth factors in the intima.²⁰ High blood pressure may exacerbate the inflammatory response on the arterial wall by increasing oxidative stress, production of oxygen-free radicals, and recruitment of mononuclear cells.²⁷ Increased blood pressure has also been shown to disrupt endothelial integrity in experimental studies.²⁸ Moreover, antihypertensive treatment may improve endothelial function,²⁹ and an improvement of initially impaired FMD, obtained with optimized antihypertensive therapy, has been shown to provide a more favorable cardiovascular prognosis in hypertensive postmenopausal women.³⁰

We observed an association between systolic blood pressure and adult brachial FMD only in male subjects aged 12 to 18 year at baseline. We have reported previously that the associations between childhood risk factors and adult carotid IMT are also strongest in this subgroup.⁶ Similar previous reports from the Bogalusa Heart Study and the Muscatine Study have shown that blood pressure levels in young adulthood, but not in childhood, associate with carotid IMT and coronary artery calcification in adulthood.^4,31,32 The observations from the PDAY study³³ have suggested that, between 15 to 34 years of age, women are &5 to 10 years behind men in the development of raised lesions. This finding is in line with the fact that men usually develop clinical cardiovascular disease about a decade earlier than women. It is also possible that women at a younger age are protected from endothelial dysfunction that develops as a result of hypertension.

Study Limitations
This study has several limitations. Blood pressure was measured with standard mercury sphygmomanometer in 1980. The indirect blood pressure measurements are vulnerable to different kinds of errors and bias, for example, terminal digit preference and variability between observers. In the present study, the interobserver reproducibility of systolic blood pressure measurements was satisfactory.³⁴ The correlation coefficient was r=0.72 in 635 paired observations. For diastolic blood pressure, the correlation coefficient was only r=0.51. This may explain why only systolic blood pressure in adolescence predicted adult FMD. We found relatively large long-term variation in FMD measurements,²⁶ which is, however, in agreement with several previous reports.^35–38 Several factors, including physiological and technical issues, may affect FMD variation.⁹ However, the long-term reproducibility of the brachial artery diameter measurements was excellent. This suggests that much of the long-term variation of FMD is because of physiological fluctuation and not measurement error. It may be argued that the observed association between adolescent blood pressure and adulthood FMD would have been even stronger if the variation in FMD had been smaller. We did not measure endothelium-independent nitrate-mediated vasodilatation that is often included as a control test for the FMD test to ensure that the decreased FMD capacity observed is a consequence of endothelial dysfunction, not a reflection of underlying smooth muscle dysfunction. However, nitrate-mediated arterial relaxation also seems to attenuate in the process of atherosclerosis.^39,40 Although adolescent blood pressure was significantly associated with FMD in adulthood, it had only a small contribution (1%) to the variance of FMD. Therefore, the results need to be interpreted with caution. The participation rate of the follow-up study was &65%. We have reported recently that baseline risk factors (in 1980) were similar among participants and dropouts in the 21-year follow-up.²³ Therefore, the present study cohort seems to be representative of the original study population.

The present study also has several strengths. The large sample of young adults gives statistical power to detect relations between risk factors and subclinical atherosclerosis. The study subjects have been prospectively followed since childhood, resulting in a vast amount of data on cardiovascular risk factors.

Perspectives
These data demonstrate that elevated blood pressure in adolescence is inversely related to endothelial function 21 years later. Systolic blood pressure measured in adolescence was a stronger correlate for endothelial function than systolic blood pressure measured in adulthood. In addition, the association was independent of other adolescent or adulthood cardiovascular risk factors. These findings suggest that blood pressure elevation in adolescence may have an influence on biological processes that regulate endothelium-dependent flow-mediated vasodilatation capacity.

	Acknowledgments

 
Sources of Funding

This study was financially supported by the Academy of Finland (grants 53392 and 34316), the Social Insurance Institution of Finland, the Turku University Foundation, the Juho Vainio Foundation, the Research Fund from the Turku University Hospital, the Finnish Foundation of Cardiovascular Research, the Finnish Medical Foundation, and the Finnish Cultural Foundation.

Disclosures

None.

Received March 27, 2006; first decision April 22, 2006; accepted July 12, 2006.

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