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(Circulation. 1997;96:2233-2238.)
© 1997 American Heart Association, Inc.

Articles

Flow-Mediated Dilation in 9- to 11-Year-Old Children

The Influence of Intrauterine and Childhood Factors

C.P.M. Leeson, BSc; P.H. Whincup, PhD, FRCP; D.G. Cook, PhD; A.E. Donald; O. Papacosta, MSc; A. Lucas, FRCP; ; J.E. Deanfield, MB, BCh, FRCP

From the Vascular Physiology Unit (C.P.M.L., A.E.D., J.E.D.), Great Ormond Street Hospital; Department of Primary Care and Population Sciences (P.H.W., O.P.), Royal Free School of Medicine; Department of Public Health Sciences (D.G.C.), St George's Hospital Medical School; and MRC Childhood Nutrition Research Centre (C.P.M.L., A.L.), Institute of Child Health, London, England.

Correspondence to Dr P.H. Whincup, Cardiovascular Research Unit, Department of Primary Care and Population Sciences, Royal Free School of Medicine, Rowland Hill St, London, NW3 2PF UK.

	Abstract

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Background Early life factors, particularly size at birth, may influence later risk of cardiovascular disease, but a mechanism for this influence has not been established. We have examined the relation between birth weight and endothelial function (a key event in atherosclerosis) in a population-based study of children, taking into account classic cardiovascular risk factors in childhood.

Methods and Results We studied 333 British children aged 9 to 11 years in whom information on birth weight, maternal factors, and risk factors (including blood pressure, lipid fractions, preload and postload glucose levels, smoking exposure, and socioeconomic status) was available. A noninvasive ultrasound technique was used to assess the ability of the brachial artery to dilate in response to increased blood flow (induced by forearm cuff occlusion and release), an endothelium-dependent response. Birth weight showed a significant, graded, positive association with flow-mediated dilation (0.027 mm/kg; 95% CI, 0.003 to 0.051 mm/kg; P=.02). Childhood cardiovascular risk factors (blood pressure, total and LDL cholesterol, and salivary cotinine level) showed no relation with flow-mediated dilation, but HDL cholesterol level was inversely related (-0.067 mm/mmol; 95% CI, -0.021 to -0.113 mm/mmol; P=.005). The relation between birth weight and flow-mediated dilation was not affected by adjustment for childhood body build, parity, cardiovascular risk factors, social class, or ethnicity.

Conclusions Low birth weight is associated with impaired endothelial function in childhood, a key early event in atherogenesis. Growth in utero may be associated with long-term changes in vascular function that are manifest by the first decade of life and that may influence the long-term risk of cardiovascular disease.

Key Words: endothelium • cardiovascular diseases • population • risk factors • atherosclerosis

	Introduction

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There has been considerable interest in the possibility that adult cardiovascular risk has its origins early in life,¹ possibly in utero.² Historical cohort studies^{3 4} have demonstrated associations between markers of small size at birth and increased adult cardiovascular mortality. In addition, low birth weight and other measures of in utero growth have been related to unfavorable effects on blood pressure, glucose tolerance, blood lipids, and coagulation factors in both children and adults.^{5 6 7 8 9 10} This has led to the concept of fetal "programming" during critical phases of development in utero, resulting in long-term, permanent changes in organ development, including changes in cardiovascular structure and function.^{11 12 13} However, the nature and time course of the early vascular damage that may initiate or predispose to arterial disease in later life have not been studied.

The vascular diseases that have been linked to low birth weight are characterized by dysfunction of the endothelium, with loss of nitric oxide bioavailability playing a central role in their pathogenesis.^{14 15} High-resolution ultrasound can now be used to assess endothelial function noninvasively in the conduit arteries of the systemic circulation of young subjects from as early as the first decade of life.^{16 17} This measures the dilation response of an artery to increase in flow, an endothelium-dependent process¹⁸ that we have shown is attenuated in the presence of classic risk factors for atherosclerotic vascular disease, such as smoking, hypercholesterolemia, and diabetes.^{19 20 21}

We have now used this technique to test the hypothesis that endothelial function is also modified by prenatal influences independently of exposure to classic postnatal risk factors. Young subjects aged 9 to 11 years were studied to minimize the confounding effects of the adult environment on this key vascular function. We provide the first direct evidence of an independent effect of birth weight by the first decade of life, suggesting a primary influence of prenatal factors on vascular development that may be relevant to the risk of atherosclerotic disease and hypertension in adult life.

	Methods

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Subjects were recruited in four British towns in which we had recently surveyed cardiovascular risk factors in children aged 8 to 11 years.²² Adult cardiovascular mortality rates were low in two of the towns (Bath and Tunbridge Wells) and high in the other two (Rochdale and Rhondda). Thirty-three of the 40 primary schools in the earlier survey had suitable facilities for the current study and were therefore included. In each school, the oldest 15 children (9 to 11 years), most of whom had provided blood samples in the earlier study were invited to take part. Ethical approval was obtained from all relevant local research ethics committees. Informed written parental consent was sought in all cases; parents were also asked to obtain their child's assent before agreeing.

Survey Procedures
Each school was visited on a single day by the same ultrasound operator and nurse assistant; height and weight measurements were made by a separate trained observer.

Ultrasound Study Measurements
The right brachial artery was imaged with a 7-MHz linear-array transducer and standard Acuson 128XP/10 system, with automated arterial diameter measurement using a wall tracking system. Images of the brachial artery were obtained as described previously.¹⁶ The diameter was measured by selecting the most clearly defined section of the artery on B-mode imaging and positioning the M-mode cursor at right angles to the arterial lumen. A 5-second segment of the A-mode signal was then routed to the wall tracking system. This calculated the arterial diameter by identifying the lumen/arterial wall interfaces on the amplitude waveform.^{23 24}

Each child had a single set of vascular measurements made according to the previously described protocol for assessment of flow-mediated dilation.¹⁶ This involves a baseline arterial diameter, a 4.5-minute period of forearm blood flow occlusion using a pneumatic tourniquet, and a second post–blood flow occlusion arterial diameter measurement. All scans were recorded on videotape for subsequent flow measurements, and hard-copy printouts of arterial diameter measurements were kept for quality analysis. After completion of the study, all records were assessed blindly by two independent observers. Vascular measures were considered unsatisfactory if the M-mode cursor position varied between the baseline and post–forearm cuff occlusion images or if mean diameter measurements were not available for at least four cardiac cycles or if they varied by >0.06 mm.²³ Studies of nitroglycerin-induced dilation used in our earlier investigations to test endothelium-independent dilation^{16 17} were omitted because in a pilot study in 53 subjects, nitroglycerin-induced dilation occurred in all subjects irrespective of the extent of flow-mediated dilation.

Blood pressure was measured twice in the left arm with the child supine at the beginning and at the end of the ultrasound measurements by use of a Dinamap 1846SX oscillometric blood pressure recorder (Critikon Inc).²⁵ All measurements were made with the small adult cuff size (cuff-bladder dimensions 22x10 cm). A saliva sample was measured for salivary cotinine by use of a gas-liquid chromatographic method.²⁶ Height was measured to the last complete millimeter with a portable stadiometer (CMS Ltd). Weight was measured to the last complete 0.1 kg with a digital electronic weighing scale (Soehnle Ltd). Ethnic group was classified on the basis of the child's appearance into white, Asian, or other. Room temperature was measured at the beginning of each ultrasound measurement with an electronic thermometer.

To assess within-subject reproducibility of the technique, the third subject measured on each day was invited to return in the afternoon for a repeat set of vascular measurements. This second investigation was performed with the ultrasound operator blinded to the results of the earlier scan.

Cardiovascular Risk Factor Measurements
Ultrasound study results were related to the subject's risk factor profile, which had been established during the screening study 8 months previously.²² After an overnight fast, half the subjects, randomly selected, had a blood sample for total cholesterol and HDL, apolipoprotein B, and plasma glucose levels. The remaining half had the same measurements 30 minutes after a standard glucose load (1.75 g/kg). Samples were separated and frozen for storage within 6 hours. Cholesterol was analyzed by use of the Technicon Dax system (method SM4-1139M90). HDL cholesterol was measured by use of the dextran sulfate–magnesium precipitation method.²⁷ LDL cholesterol was calculated by use of the Friedewald method.²⁸ Apolipoprotein B was analyzed by use of the Beckman rate nephelometric method using specific antiserum. A self-completed questionnaire with postage-paid reply envelope was forwarded to parents on the day of the study. Parents were asked to provide information on their present or most recent occupation(s), coded into the Registrar General's six occupational groups with a seventh group for unemployed and single parent households. Information was also sought on the child's birth weight, maternal parity, and maternal smoking during pregnancy. The validity of birth weight data was cross-checked with birth record information for children born in the town of measurement. Agreement between birth weight data from recall and birth record sources was good (n=156; mean difference [birth record-recall]=0.00 kg [SD=0.13 kg]; r=.96).

Outcomes and Statistical Methods
Flow-mediated dilation was represented by two measurements: the absolute difference between the diameter of the brachial artery during reactive hyperemia and at rest (FMDA) and the change in brachial artery diameter as a proportion of initial diameter (FMD%), as used in earlier studies.^{16 17} The first measure takes into account the statistical relationship between proportional change in vessel diameter and resting vessel size. Whereas FMDA was normally distributed, FMD% was positively skewed, and logarithmic transformation proved inappropriate because it overcorrected for skewness. All analyses were performed with the use of the SAS statistical package. Ponderal index (weight/height³), independent of age as well as height in the present study, has been used as a measure of weight-for-height in childhood. Where appropriate, standard linear regression techniques (PROC GLM) were used to model the relations between explanatory variables and flow-mediated dilation. Linearity of associations was examined both visually and by fitting quadratic and cubic terms in the models. To compare the strengths of associations with flow-mediated dilation, standardized regression coefficients, which represent the estimated effect on FMDA or FMD% of a 1-SD increase in the explanatory variable, were used. These were calculated as Regression CoefficientxSD of Explanatory Variable. In adjusted models, age, height, and ponderal index have been fitted in fifths with room temperature as a continuous variable. Hour of day, town, social class, and ethnic origin have been fitted as dummy variables (with 6, 4, 7, and 3 levels, respectively). Lipid analyses have been adjusted for fasting/nonfasting status. Repeatability of ultrasound measurements is presented as the correlation of the two readings on the repeat subjects as well as the mean difference and its SD.

	Results

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Of 488 children invited, 382 (78%) agreed to take part in the study. Satisfactory brachial artery diameter measurements both at rest and during reactive hyperemia were obtained in 333 children (165 girls and 168 boys; satisfactory scans in 87%). Two hundred eighty-three of these children had provided blood samples in the earlier survey. Data on social class were missing on 14 subjects, on parity for 22, and on salivary cotinine for 9. The characteristics of the participants are summarized in Table 1. Most subjects were white (n=317; 95%), the remainder being Indian (n=10; 3%), Afro-Caribbean (n=3; 1%), or of mixed race (n=3; 1%). Age, sex, and body build had no influence on whether a full set of ultrasound or other measurements was obtained.

View this table: [in this window] [in a new window]   Table 1. Means (SDs) of Main Variables for the 333 Study Subjects

The repeatability of flow-mediated dilation was assessed in 29 subjects. Both measurements of flow-mediated dilation were highly repeatable; FMDA had a mean difference of 0.017 mm (SD=0.060 mm) and a correlation between measurements of 0.86 mm, and FMD% had a mean difference of 0.551 (SD=2.110 and a correlation between measurements of 0.88. There was no significant difference between FMDA or FMD% in the four towns (mean [SE] FMDA values were 0.117 mm [0.013] in Bath, 0.115 mm [0.013] in Rochdale, 0.140 mm [0.011] in Tunbridge Wells, and 0.131 mm [0.013] in Rhondda; test for heterogeneity between towns, P=.40). Both flow-mediated dilation measures increased with room temperature (FMDA increased by 0.007 mm/°C [95% CI, 0.001 to 0.013 mm/°C], P=.01; FMD% by 0.24%/°C [95% CI, 0.02 to 0.46%/°C], P=.03) and tended to fall slightly during the day (FMDA by -0.006 mm/h [95% CI, 0.001 to -0.012 mm/h], P=.13; FMD% by -0.25%/h [95% CI, -0.54 to 0.04%/h], P=.08). Flow-mediated dilation was similar in boys and girls and showed no consistent variation with age (data not presented). However, all subsequent analyses presented are adjusted for age and sex as well as for town, room temperature, and hour of day.

Size at Birth and Flow-Mediated Dilation
The relationships between birth weight and flow-mediated dilation are presented in the Figure and the corresponding regression coefficients in Table 2. Birth weight showed a graded positive relationship with both FMDA and FMD% (Figure); formal testing showed no evidence of a quadratic or cubic relationship. The correlation between birth weight and FMDA was 0.13 and between birth weight and FMD% was 0.12. Across the range of birth weight, FMDA increased by 0.060 mm and FMD% by 2.0%. For a 1-SD increase in birth weight (0.53 kg), FMDA increased by 0.014 mm (SE=0.006 mm) and FMD% by 0.501% (SE=0.024%).

View larger version (15K): [in this window] [in a new window]   Figure 1. Birth weight (in tenths of kilograms) is positively associated with endothelium-dependent, flow-mediated dilation in 333 children aged 9 to 11 years. Means and 95% CIs for both the absolute change in brachial artery diameter after increased blood flow (FMDA) and change in diameter as a proportion of resting vessel size (FMD%) are shown. All analyses are adjusted for age, sex, town, temperature, and hour of day. The crosses show the effect of additional adjustment for childhood size, parity, childhood cardiovascular risk factors, ethnic group, and social class.

View this table: [in this window] [in a new window]   Table 2. Birth Weight and Flow-Mediated Dilation: Adjustment for Potential Confounding Factors

Cardiovascular Risk Factors in Childhood and Flow-Mediated Dilation
The relations between body size, blood pressure, blood lipids, passive smoking exposure, and flow-mediated dilation are presented in Table 3. Standardized regression effects showing the change in FMDA (FMD%) for a 1-SD increase in each independent variable and allowing a comparison of the strength of relationships are presented. Childhood height and ponderal index, blood pressure, total and LDL cholesterol, apolipoprotein B, and cotinine concentration showed no consistent association with either FMDA or FMD%. HDL cholesterol, however, showed a graded inverse relationship with both FMDA and FMD%, which was not affected by adjustment for childhood height or ponderal index. Postload glucose showed no significant relation with flow-mediated dilation, nor did parity, social class, or ethnic group (data not presented).

View this table: [in this window] [in a new window]   Table 3. Cardiovascular Risk Factors and Flow-Mediated Dilation

Birth Weight, Cardiovascular Risk Factors in Childhood, and Flow-Mediated Dilation
The effect of adjustment for childhood body size, parity, childhood cardiovascular risk factors, social class, and ethnicity on the relationship between birth weight and flow-mediated dilation is also shown in the Figure, and the effect of stepwise adjustments adding each factor in turn is presented in Table 2. The coefficients relating birth weight and flow-mediated dilation were little affected by adjustment, if anything being strengthened by the inclusion of the additional factors. Relations for both FMDA and FMD% remained statistically significant throughout despite the smaller numbers of subjects available for adjusted analyses.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In this study of 9- to 11-year-old children, low birth weight was related to reduced vascular reactivity. Conventional cardiovascular risk factors showed little relationship with this measure, and adjustment for them had little effect on the birth size–endothelial function relationship, which was strong and graded. These novel findings raise the possibility that endothelial function, a key factor in atherogenesis, is "programmed" in early life and thereby influences the long-term risk of cardiovascular disease.

Many of the published studies examining the relations between fetal factors and adult cardiovascular risk have taken selected cohorts of adults from their fifth decade of life and related cardiovascular morbidity and mortality back to birth records.^{3 4 5 6 7 8} The interpretation of the influence of fetal factors on cardiovascular risk in these studies is complicated by potential confounding factors such as smoking, diet, and lifestyle differences during the long intervening period.^{29 30} The present study differs by examining the impact of early life factors on an objective measure of vascular physiology at a much younger age, thus minimizing the potential influence of these other risk factors. Our cohort was specially chosen because detailed maternal and birth records as well as subsequent risk factor measurements, including cholesterol level, passive smoke exposure, and glucose tolerance, were available. The noninvasive nature of the arterial measurements enabled us to study a large population-based sample with a broad representation of cardiovascular risk, including socioeconomic factors and regional influences. The ultrasound technique for assessment of flow-mediated dilation has been developed and validated for use in children and young adults to study endothelial function.¹⁷ Brachial artery reactivity is related to coronary endothelial function in invasive testing³² and can be attenuated by N^G-monomethyl-L-arginine, a specific antagonist for nitric oxide production.³² Endothelial function was studied because it is central to the atherogenic process.¹⁴ Abnormalities of flow-mediated dilation using this technique have previously been shown in association with all the major risk factors for atherosclerosis^{16 20} and are also now linked to birth weight.

The observed association between birth weight and flow-mediated dilation is graded and independent of social class, region, ethnic group, and maternal smoking, suggesting a causal relationship. Other cardiovascular risk factors, such as hypertension, are known to affect this measure of vascular function,^{16 20} and their presence has been linked to birth weight in other studies.^{5 6 7} These did not, however, appear to be responsible for the observed association between birth weight and flow-mediated dilation in the present cohort because incorporation of these risk factors in the multivariate model did not alter the strength of the association. Low birth weight has been related to a higher mean systolic blood pressure in this study population³³ ; however, the overall correlation (-0.07) is less than that between birth weight and flow-mediated dilation (0.13). Moreover, a 1-kg increase in birth weight is associated with a 0.027-mm (SD, 0.25 mm) change in FMDA, relatively greater than the 1.5-mm Hg (SD, 0.13 mm Hg) change in systolic blood pressure. Not surprisingly, the relationship between birth weight and flow-mediated dilation is weaker than that previously described for active cigarette smokers. There is a 2% difference in flow-mediated dilation across the range of birth weight compared with a difference of 5% between nonsmokers and heavy smokers.²⁰ This relatively small effect may mean the influence of birth weight is more relevant to public health and the understanding of the disease process than it is of clinical significance for the individual.

What happens to the association between birth weight and vascular function with increasing age is of crucial interest. The relative importance of early life factors may diminish and be overwhelmed by the increasing influence of classic risk factors with time. Alternatively, the association between birth weight and endothelial function may be amplified with age, as has been reported for the relationship between birth weight and blood pressure.³⁴ A third possibility is that the influence of low birth weight may interact with factors operating later in life, comparable to the interaction between small size at birth and adult obesity on insulin resistance reported by other investigators.³⁵ Longitudinal study of the relationship between size at birth, other cardiovascular risk factors, and endothelial function during adolescence and early adult life will help to clarify these issues. Follow-up investigations would also help elucidate whether flow-mediated dilation tracks between childhood and adult life, because although the measured range of flow-mediated dilation is similar in subjects aged from 5 to 50 years,¹⁶ matched data in single subjects is not yet available. An unexpected finding was the relation between high HDL cholesterol and lower flow-mediated dilation and therefore potentially greater risk. Although this may be consistent with an earlier observation of high HDL levels in children with a family history of unstable angina,³⁶ this finding is of interest and requires confirmation and study in older children.

Earlier studies in middle-aged subjects have suggested that early life factors might also affect cardiovascular measures such as left ventricular size¹¹ and arterial compliance¹² but were unable to determine whether these effects were secondary to factors such as raised blood pressure. Our observations strongly support the concept of a primary alteration in the vessel wall because objective changes in arterial physiology are already detectable from early life. Evidence of a direct association between the degree of flow-mediated dilation in an individual and the risk of a future clinical cardiac event is not yet available; however, the effects on endothelial function demonstrated in the present study are likely to be relevant to a wide range of later cardiovascular diseases because of the central role of the endothelium in vascular homeostasis. Loss of nitric oxide activity in particular appears to be a key early event in the atherogenic process, influencing vascular tone, coagulation, inflammation, and cell proliferation.^{14 15} The underlying mechanism linking fetal and early life factors to vascular function remains unclear. Tissues are most susceptible to programming during periods of rapid growth, as occur during fetal development.³⁷ Nutritional events might operate during critical periods for different organs, altering the activity of key genes and/or resulting in a permanent change in proportion of particular cell lines.¹³

Fetal programming may represent a novel influence on vascular disease and may alter the understanding of the pathophysiological basis of the atherosclerotic diseases. The extent to which adverse effects in early life may be modifiable by appropriate risk-reduction strategies in later life is not certain. However, the elucidation of the mechanism for the impact of fetal and birth-related factors on endothelial function and vascular physiology may lead to development of novel primary prevention strategies.

	Acknowledgments

 
The ultrasound measurement study was supported by a project grant from the British Heart Foundation (grant No. PG/95026) and the earlier cardiovascular risk factor survey by the Wellcome Trust (grant No. 038976/Z/93/Z). C.P.M. Leeson is supported by a Medical Research Council Studentship and A.E. Donald by a grant from CORDA. We are grateful to the schools, parents, and children who took part in the study and to Lucy Lennon, Robyn Totenhofer, and Valerie Wilson for their help with fieldwork. Biochemical analyses were performed by the Department of Clinical Biochemistry at St George's Hospital (Prof Carol Seymour, Dr J.A. Nisbet). Salivary cotinine measurements were performed at the Institute of Psychiatry (Dr Martin Jarvis and Dr Andrew Bryant).

	Footnotes

 
Reprint requests to J.E. Deanfield, Vascular Physiology Unit, Great Ormond Street Hospital, London, WC1N 3JH, UK.

Received February 17, 1997; revision received April 30, 1997; accepted May 13, 1997.

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				M. Juonala, J. S.A. Viikari, M. Kahonen, T. Solakivi, H. Helenius, A. Jula, J. Marniemi, L. Taittonen, T. Laitinen, T. Nikkari, et al. Childhood Levels of Serum Apolipoproteins B and A-I Predict Carotid Intima-Media Thickness and Brachial Endothelial Function in Adulthood: The Cardiovascular Risk in Young Finns Study J. Am. Coll. Cardiol., July 22, 2008; 52(4): 293 - 299. [Abstract] [Full Text] [PDF]

				A. Jones, A. Beda, C. Osmond, K. M. Godfrey, D. M. Simpson, and D. I. W. Phillips Sex-specific programming of cardiovascular physiology in children Eur. Heart J., July 22, 2008; (2008) ehn292v1. [Abstract] [Full Text] [PDF]

				G. Liew, J. J. Wang, B. B. Duncan, R. Klein, A. R. Sharrett, F. Brancati, H.-C. Yeh, P. Mitchell, T. Y. Wong, and for the Atherosclerosis Risk in Communities Study Low Birthweight Is Associated With Narrower Arterioles in Adults Hypertension, April 1, 2008; 51(4): 933 - 938. [Abstract] [Full Text] [PDF]

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				K. J. Bubb, M. L. Cock, M. J. Black, M. Dodic, W.-M. Boon, H. C. Parkington, R. Harding, and M. Tare Intrauterine growth restriction delays cardiomyocyte maturation and alters coronary artery function in the fetal sheep J. Physiol., February 1, 2007; 578(3): 871 - 881. [Abstract] [Full Text] [PDF]

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				A. Singhal, N. Jamieson, M. Fewtrell, J. Deanfield, A. Lucas, and N. Sattar Adiponectin Predicts Insulin Resistance But Not Endothelial Function in Young, Healthy Adolescents J. Clin. Endocrinol. Metab., August 1, 2005; 90(8): 4615 - 4621. [Abstract] [Full Text] [PDF]

				M. Charakida, A. E. Donald, H. Green, C. Storry, M. Clapson, M. Caslake, D. T. Dunn, J. P. Halcox, D. M. Gibb, N. J. Klein, et al. Early Structural and Functional Changes of the Vasculature in HIV-Infected Children: Impact of Disease and Antiretroviral Therapy Circulation, July 5, 2005; 112(1): 103 - 109. [Abstract] [Full Text] [PDF]

				O A Khan and C Shearman Is there a fetal origin of peripheral vascular disease? Heart, July 1, 2005; 91(7): 869 - 870. [Full Text] [PDF]

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				A. L. Moens, I. Goovaerts, M. J. Claeys, and C. J. Vrints Flow-Mediated Vasodilation: A Diagnostic Instrument, or an Experimental Tool? Chest, June 1, 2005; 127(6): 2254 - 2263. [Abstract] [Full Text] [PDF]

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				D. G. Hemmings, S. Veerareddy, P. N. Baker, and S. T. Davidge Increased Myogenic Responses in Uterine but not Mesenteric Arteries from Pregnant Offspring of Diet-Restricted Rat Dams Biol Reprod, April 1, 2005; 72(4): 997 - 1003. [Abstract] [Full Text] [PDF]

				M. L. Bots, J. Westerink, T. J. Rabelink, and E. J.P. de Koning Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response Eur. Heart J., February 2, 2005; 26(4): 363 - 368. [Abstract] [Full Text] [PDF]

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				A. H. Slyper What Vascular Ultrasound Testing Has Revealed about Pediatric Atherogenesis, and a Potential Clinical Role for Ultrasound in Pediatric Risk Assessment J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3089 - 3095. [Abstract] [Full Text] [PDF]

				M. d. C. P. Franco, Z. B. Fortes, E. H. Akamine, E. M. Kawamoto, C. Scavone, L. R. G. de Britto, M. N. Muscara, S. A. Teixeira, R. C. A. Tostes, M. H. C. Carvalho, et al. Tetrahydrobiopterin improves endothelial dysfunction and vascular oxidative stress in microvessels of intrauterine undernourished rats J. Physiol., July 1, 2004; 558(1): 239 - 248. [Abstract] [Full Text] [PDF]

				S. M. Mone, M. W. Gillman, T. L. Miller, E. H. Herman, and S. E. Lipshultz Effects of Environmental Exposures on the Cardiovascular System: Prenatal Period Through Adolescence Pediatrics, April 1, 2004; 113(4/S1): 1058 - 1069. [Abstract] [Full Text] [PDF]

				A. Singhal, T. J. Cole, M. Fewtrell, J. Deanfield, and A. Lucas Is Slower Early Growth Beneficial for Long-Term Cardiovascular Health? Circulation, March 9, 2004; 109(9): 1108 - 1113. [Abstract] [Full Text] [PDF]