(Circulation. 2000;102:2739.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Impaired Endothelial Function and Increased Carotid Stiffness in 9-Year-Old Children With Low Birthweight
From the Department of Women and Child Health, Division of Neonatology, Karolinska Hospital (H.M., M.N.) and Department of Clinical Science, Unit of Obstetrics and Gynecology, Huddinge Hospital (J.H., G.G.), Karolinska Institutet, Stockholm, Sweden
Correspondence to Dr Helena Martin, Department of Neonatology, Danderyd Hospital, S-182 88 Danderyd, Sweden. E-mail helena.martin{at}kbh.ki.se
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Abstract |
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Background—Low birthweight (LBW) has been associated with an increased incidence of adult cardiovascular disease. Endothelial dysfunction and loss of arterial elasticity are early markers of hypertension and atherosclerosis. We studied the prevalence of these markers in 44 healthy, prepubertal (age 9±1.3 years) children, 22 with LBW for age.
Methods and Results—Endothelial function in skin was tested with the local application of acetylcholine (inducing endothelium-dependent vasodilation) and nitroglycerin (endothelium-independent vasodilation), and local perfusion changes were measured with the laser Doppler method. The elastic properties of the abdominal aorta and common carotid artery were measured with an ultrasonic vessel-wall tracking system. Endothelium-dependent vasodilation was lower in children with LBW (88±33 perfusion units [PU]) than in normal-birthweight controls (133±34 PU, P<0.001). There was no difference in aortic or carotid elasticity between the 2 groups, but a negative correlation was found between birthweight and stiffness of the carotid artery wall (r=-0.45, P<0.01). Endothelium-independent vasodilation and blood pressure were similar in the 2 groups.
Conclusions—Schoolchildren with a history of LBW show impaired endothelial function and a trend toward increased carotid stiffness. These findings may be early expressions of vascular compromise, contributing to susceptibility to disease in adult life.
Key Words: endothelium • pediatrics • arteries • hypertension • elasticity
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Introduction |
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Since the first epidemiological reports a decade ago,1 2 the association between low birthweight (LBW) for age and increased incidence of adult cardiovascular disease has been repeatedly confirmed.3 4 Poor size at birth also relates to the unfavorable constellation of high blood pressure, glucose intolerance, and hyperlipidemia later in life.5 6 7 Considering LBW as one expression of a risk syndrome, studies of the functional characteristics of the vascular tree in these children offer an opportunity to further clarify the underlying susceptibility long before structural vascular disease has been established. Endothelial dysfunction and increased arterial stiffness have been reported to be early markers of accelerated vascular aging in prediabetic and prehypertensive states in young adults8 9 10 and have also been found in children with hypercholesterolemia or a family history of hypertension.11 12 13 The first studies on the prevalence of these markers in LBW children have recently been presented. The aortic elasticity in prepubertal schoolchildren with intrauterine growth retardation was normal,14 whereas endothelium-dependent brachial artery dilation in LBW children and young adults15 16 and endothelium-dependent microvascular vasodilation in LBW neonates17 were impaired.
We tested the hypothesis that the impairment of vasodilation in LBW newborn infants persists and can be detected in healthy, prepubertal children. Because there seem to be no reports in which the vasodilatory capacity was evaluated in small and large arteries of the same LBW children, we studied microvascular vasodilation in the skin and pulse-synchronous vasodilation in segments of 2 large arteries that are commonly affected by later atherosclerosis, ie, the aorta and common carotid artery. The data presented here suggest that LBW schoolchildren have an impaired vasodilatory capacity in small and large arteries and that endothelium-dependent mechanisms and mechanical properties of the large-artery vessel walls are involved.
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Methods |
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Subjects
Forty-four healthy, prepubertal children (21 boys) were studied at a mean age of 9.0±1.3 years. All children were recruited from the same catchment area and had been born at Danderyd Hospital in northern Stockholm. All parents were clinically healthy and nonsmokers. Factors in addition to LBW that could have affected fetal-neonatal vascular development, such as a history of multiple pregnancies, maternal diabetes, hypertension, preeclampsia, maternal smoking or medication during the index pregnancy, preterm delivery, neonatal asphyxia, malformations, chromosomal disorders, or congenital infection excluded admission to this study. Moreover, children with present or previous cardiovascular disease and chronic illness or medication were not included. With these exclusion criteria and after examination of the local neonatal database from 1988 to 1991, we found 32 subjects who had been born at term with LBW for age (<mean -2 SD). In this group, 4 families declined to participate in the study, and 6 had moved from the catchment area. These 10 LBW subjects who were lost to follow-up had birthweights (2260±131 g) that did not differ from the remaining 22 LBW children (2188±224 g) included in the study. Twenty-two normal-birthweight children (3455±458 g, P<0.001, Table 1
) with similar age and sex distribution were
studied as controls. There was no overlapping in birthweight between
the 2 groups. In addition to birthweights, we calculated the difference
between actual and expected birthweights for the particular gestational
age, expressed as percentage of the expected birthweight. The
deviations in birthweight were -34±5.0% in LBW subjects and
1.7±5.1% in controls (P<0.001,
Table 1). To identify leanness at birth (disproportional
fetal growth), we studied the relation weight-for-length, both
variables given as SD scores and normalized for gestational age and
sex.18 Using a
linear regression model for these SD scores (intercept=0, regression
coefficient=0.7152) based on data from the Swedish Medical Birth
Register, we defined leanness at birth as a weight-for-length relation
<-2 SD.18 Among
LBW subjects, leanness at birth was found in 14 of 22, whereas the
remaining 8 of 22 LBW children were classified as proportionately small
at birth. In the control group, no subject was lean at
birth.
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There were no differences in age, weight, length, weight
gain, or parity between the 2 groups of mothers at the index pregnancy.
In the third trimester of the index pregnancy, the mean systolic and
diastolic blood pressures were higher in mothers of LBW infants
(P<0.05,
Table 1
). The gestational age had been estimated by early
routine ultrasound in all pregnancies. Because of a low symphysis
fundic height, a second antenatal ultrasound was performed during the
third trimester in 10 of 22 LBW pregnancies, and the fetal growth was
impaired in 6 of 10 subjects. Because of maternal concerns, a second
antenatal ultrasound was performed during the third trimester in 4 of
22 pregnancies in the control group and was normal in all 4 cases. Four
LBW infants were treated for transient neonatal hypoglycemia, but the
remaining infants had an uncomplicated neonatal period.
Informed consent was obtained from the children and their
parents before the investigation, and the study protocol was approved
by the local Ethics Committee at Karolinska Hospital. Both parents were
interviewed about a possible family history of diabetes, myocardial
infarction, stroke, hypertension, and hyperlipidemia among their
first-degree relatives
(Table 1).
Vascular Studies
A laser Doppler (LD) instrument (Periflux 4001,
wavelength 780 nm) and a micropharmacology system were used to measure
perfusion changes during vascular provocations in the dorsal hand skin
(Perimed AB). The LD signal is proportional to the number and
velocity of moving blood cells in illuminated superficial skin
microvessels. The LD output is semiquantitative and expressed in
perfusion units of output voltage (1 perfusion unit [PU]=10 mV). The
temperature of the LD probe facing the skin could be changed and was
standardized to 32°C. After adjustment to room temperature
(23±1°C) for 20 minutes, the vascular studies were performed with
the child lying supine with both arms beside the body.
To study endothelium-dependent vasodilation, basal perfusion
was recorded for 
2 minutes, after which 2% acetylcholine (ACh,
acetylcholine chloride, Sigma-Aldrich AB) was transferred across the
skin by iontophoresis (anodal current of 0.1 mA for 20 seconds). A
stimulus-response curve was produced by repeating iontophoretic
stimulation 6 times at 60-second intervals
(Figure 1). The anodal current alone does not elicit vascular
responses, and the CV was 18% for repeated measurements of maximum
perfusion change after ACh
stimulation.9
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To study endothelium-independent vasodilation, an exogenous
NO donor was applied to the contralateral dorsal hand skin.
Nitroglycerin cream (glyceryli nitratis 1% in Essex cream, 0.07 mL)
was placed in the drug-delivery chamber in the head of the LD probe and
attached to the skin for 30 minutes. Unlike ACh provocations,
nitroglycerin was allowed to diffuse through the skin without the use
of an electrical charge
(Figure 1). In a pilot study of 10 healthy volunteers, we
found a significant increase in local blood perfusion but no systemic
cardiovascular reactions in response to the same small amounts of
nitroglycerin as used in the present study. Thus, blood pressure, heart
rate, and skin perfusion in the contralateral hand did not change
during the 30 minutes of drug application (ANOVA:
P=0.72 to 0.75). The CV was 9.2% (n=8) for repeated
measurements of maximum local perfusion change after nitroglycerin
stimulation.
The dynamic properties of the large arteries were studied by measuring the abdominal aorta (3 to 4 cm above its bifurcation) and the left common carotid artery (1 to 2 cm proximal to its bifurcation). The methodological details have been described elsewhere.19 Briefly, a high-fidelity system comprising a real-time B-mode ultrasonic scanner (Hitachi EUB 240), 2 pairs of electronic echo-trackers ([TM]Diamove[/TM], Teltec), and a desktop computer was used to detect and measure the pulsatile movements of the vessel walls. From these waveforms, the following variables were measured: the end-diastolic diameter (mm), the pulse amplitude of the diameter (mm), and the maximum incremental velocity of the diameter during the systolic phase (MIV, mm/s). These data and those of simultaneously measured blood pressures in the brachial artery were computed to yield the stiffness index (ß)20 of the arterial wall at the selected sites. The mean value of 3 recordings, each comprising 6 to 10 consecutive heart cycles, was taken as the subject’s reading. The repeatability of the method has been shown to be satisfactory.9
The heart rate and brachial blood pressure were recorded intermittently with a sphygmomanometer of oscillometric type, and the values are presented as the mean of 3 repeated recordings.
Statistical Analyses
Values are given as mean±SD or as the number of
subjects and proportions. Student’s t test, ANOVA, or
2 test was used to compare groups of
data. Correlation coefficients were used to calculate possible
associations between variables, and multiple regression analysis was
used to detect any relationships between the variables studied.
Assessments of perfusion responses to drug provocations in the 2 groups
were made by use of 2-factor ANOVA for repeated measurements. A value
of P<0.05 was considered
significant.
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Results |
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Influence of Family History
Microvascular endothelial function, large-artery dynamics, and blood pressures were similar in children with a positive family history of cardiovascular disease among second-degree relatives (13 of 44) and in those without such a history.
Influence of Age, Sex, and Body Mass
Index
The distributions of age and sex were the same in both
study groups, but a trend toward a lower current body mass index (BMI)
in the LBW group was found
(Table 1). The variations in microvascular perfusion induced
by endothelium-dependent and -independent mechanisms were not
associated with age, sex, or current BMI. The arterial diameter
correlated with age (r=0.56,
P<0.001) and BMI (r=0.42,
P<0.01) in the aorta and with BMI
(r=0.44, P<0.01) in the carotid
artery. The stiffness index of the carotid artery correlated with age
(r=0.44, P<0.01) but not with sex or
current BMI. The stiffness index of the aorta did not correlate with
age, sex, or current BMI. No other associations were found between
large-artery dynamics and age, sex, or BMI.
Blood Pressure Data
The blood pressures were within normal limits in all
children, and no sex differences were found. The LBW group had almost
significantly lower systolic (106±10 mm Hg) and diastolic (57±6
mm Hg) blood pressures than the control children (systolic 111±6 and
diastolic 61±4 mm Hg). Lower systolic blood pressures were found only
in proportionately small children (102±8 mm Hg), whereas systolic
blood pressures were similar in LBW children lean at birth (110±12
mm Hg) and control children. Diastolic blood pressures were about the
same in proportionately small (57±6 mm Hg) and lean (58±7 mm Hg)
LBW children. In the multiple regression analysis, the apparent blood
pressure differences between the groups disappeared when BMI was added
as an independent variable. No difference in heart rate was found
between the 2 groups of children.
LBW and Microvascular Endothelial
Function
Basal skin perfusion values were similar in the 2
groups (8.3±4.6 PU in LBW and 7.1±2.8 PU in control children).
Endothelium-dependent vasodilation was significantly lower in LBW
children than in controls. The peak perfusion induced by ACh was 88±33
PU in LBW children and 133±34 PU in controls
(P<0.001,
Figure 1). Endothelium-dependent vasodilation correlated
with birthweight (r=0.54, P<0.001)
and with relative birthweight deviation (r=0.58,
P<0.001).
Endothelium-independent vasodilation values were similar in
the 2 groups of children. The basal perfusion was 10.6±4.3 PU in LBW
and 10.0±4.7 PU in control children, and the peak response to
nitroglycerin was 40±16 PU in LBW children and 41±16 PU in controls
(P=0.82,
Figure 1).
In the LBW group, children lean at birth (n=14) had lower endothelium-dependent vasodilation than children born proportionately small (n=8, peak perfusion 68±5 versus 107±36 PU, P<0.01). No such difference was found regarding endothelium-independent vasodilation.
LBW and Dynamic Properties of the Large
Arteries
Carotid Measurements
Comparison between children of low and normal
birthweight showed no significant differences in arterial diameter,
pulse amplitude of the diameter, stiffness index (ß), and MIV of the
carotid artery
(Table 2). The carotid stiffness index correlated with
birthweight (r=-0.45, P<0.01,
Figure 2) and with relative birthweight deviation
(r=-0.46, P<0.01). LBW children
lean at birth had a higher stiffness index (5.0±1.0) than those born
proportionately small (4.2±0.6, P<0.05) and control
children (4.2±0.8, P<0.05). In LBW children lean at
birth, the carotid stiffness index correlated with birthweight
(r=-0.76, P<0.01,
Figure 2) and with relative birthweight deviation
(r=-0.73,
P<0.01).
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Aortic Measurements
The aortic diameter, pulse amplitude of the diameter,
stiffness index, and MIV were similar in the 2 groups
(Table 2). Unlike the findings in the carotid artery, aortic
measurements showed no correlation with birthweight or relative
birthweight deviation, and the stiffness indices were similar in lean
and proportionately small LBW children (3.5±0.9 versus 3.2±0.6) and
in controls (3.1±0.6).
Relation Between Microvascular Endothelial
Function and Large-Artery Dynamics
A weak negative correlation was found between
ACh-induced peak perfusion in the skin of the hand and carotid
stiffness (r=-0.33, P<0.05). No
other relations were found between microvascular endothelial function
and large-artery dynamics.
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Discussion |
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This study showed that LBW correlated with disturbed vasoregulation at school age in terms of limited vasodilatory reserve in the peripheral circulation and premature stiffening of the carotid artery. Impaired capacity for endothelium-dependent vasodilation and loss of large-artery elasticity are thought to be related to adult hypertension, diabetes, and atherosclerosis, including coronary disease.8 12 21 The prevalence of these markers in a group of healthy children may therefore be expressions of early atherogenetic susceptibility linked to LBW and a potential risk of clinical vascular complications later in life. In this pediatric study, other known causes of vascular compromise presumably did not affect the findings. For example, adult lifestyle factors, such as smoking, could not have confounded the results. Our findings are in line with those of other studies in which conventional cardiovascular risk factors, including blood lipids, showed little if any relationship with endothelium-dependent vasodilation in 9- to 11-year-old children15 and fit young adults,16 whereas LBW did. We have previously reported impaired microvascular endothelium–dependent vasodilation in LBW infants, even at birth.17 Although longitudinal studies are needed to pursue endothelial function over time, present and previous studies point to the possibility that endothelial dysfunction may be an inborn characteristic of subjects with LBW that persists throughout childhood into adult life.
A growing literature indicates that leanness at birth, as opposed to LBW, is associated with metabolic disturbances such as glucose intolerance and insulin resistance.7 22 In our study, leanness at birth correlated with the lowest endothelium-dependent microvascular responses and the highest carotid stiffness indices measured in healthy schoolchildren. The small number of subjects who had been proportionately small at birth (n=8) limits the conclusions that can be drawn from our measurements in this subgroup of LBW children. However, they had vascular functions that did not differ greatly from those in the control group. Our observations support the hypothesis that disproportionate intrauterine growth, whether a direct effect of poor nutrition or secondary to genetic factors influencing fetal insulin secretion,23 may have large and lasting effects on angiogenesis and vascular function in the developing fetus.
The structure and mechanical properties of large arteries can be permanently affected by altered hemodynamic stress in fetal life. For example, subjects born with a single umbilical artery exhibit a significant difference in vessel wall compliance between the 2 iliac arteries, and in the iliac artery accommodating increased blood flow in utero, established atherosclerotic changes have been described already in childhood.24 25 Moreover, selective atherosclerosis of the carotid arteries in elderly people has been reported to be more prevalent and severe in subjects with LBW.26 As an interesting explanation for this association, it has been suggested that the preferential perfusion of the fetal head and the altered blood flow velocity waveforms that can be seen in intrauterine growth retardation may selectively accelerate degenerative processes in the carotid arteries.26 Our study adds further knowledge to the association between LBW and carotid atherosclerosis, ie, the carotid artery was found to be less elastic and prone to premature stiffening already at school age in LBW subjects lean at birth.
The elastic properties of the large arteries are not uniformly distributed in the vascular tree, and they exhibit differential changes over time. As confirmed by our study, the carotid artery is normally stiffer than the aorta in children and young adults.9 27 During aging, however, stiffness increases to a greater extent in the aorta, and from middle age onward, the aorta is stiffer than the carotid artery vessel wall.27
Rapid vasodilation induced by ACh is a well-established method to evaluate endothelial function. The vascular response to ACh is impaired or lost once the endothelium is damaged or removed.28 We have previously ruled out the possibility that iontophoresis causes nonspecific neurogenic skin vasodilation due to current alone.17 In addition, considering the similar basal perfusion values and the stimulus-response curves, there is no reason to believe that the 2 groups received different doses of the drug in the skin. The vascular response to ACh involves endothelial release of NO, endothelium-derived hyperpolarizing factor, and/or prostanoids.29 30 Compared with children of normal birthweight, a dysfunction in one or several of these endothelial systems probably contributed to the low microvascular responses induced by ACh in LBW children. A selective endothelial dysfunction in these children was confirmed by transdermal introduction of an exogenous NO donor, resulting in similar skin microvascular responses in children of low and normal birthweight.
Impaired endothelium may be involved in both microvascular and large arterial dysfunction found in LBW children. In addition to its key role in vascular reactivity, experimental studies have shown that the endothelium may also be important for long-term arterial remodeling and in the control of elastic properties of the arterial wall.31 32 Damage to the endothelium in large arteries has been shown not only to impair active diameter changes33 but also to increase the viscosity of the arterial wall.32
A total of 10 of 32 eligible LBW subjects were lost to follow-up. Because the birthweights of these children did not differ from those in the study cohort, we do not believe that the selection biased the results in this study.
In summary, schoolchildren who had been small and lean at birth exhibited impaired endothelial function and increased carotid stiffness. These results contribute to a better understanding of the link between LBW and adult cardiovascular disease, and they have implications for lifestyle and health risks in children and adults.
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Acknowledgments |
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This study was supported by grants from the research foundations of the Karolinska Institute, Stockholm, the Swedish Society of Medicine, the Samariten Foundation, the General Maternity Hospital Foundation, and the First Mayflower Annual Campaign, Sweden.
Received April 10, 2000; revision received July 6, 2000; accepted July 13, 2000.
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 F. Tabassum, M. Kumari, A. Rumley, G. Lowe, C. Power, and D. P. Strachan Effects of Socioeconomic Position on Inflammatory and Hemostatic Markers: A Life-Course Analysis in the 1958 British Birth Cohort Am. J. Epidemiol., June 1, 2008; 167(11): 1332 - 1341. [Abstract] [Full Text] [PDF]
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M. Kaijser, A.-K. E. Bonamy, O. Akre, S. Cnattingius, F. Granath, M. Norman, and A. Ekbom Perinatal Risk Factors for Ischemic Heart Disease: Disentangling the Roles of Birth Weight and Preterm Birth Circulation, January 22, 2008; 117(3): 405 - 410. [Abstract] [Full Text] [PDF]
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M. C.P. Franco, E. M.S. Higa, V. D'Almeida, F. G. de Sousa, A. L. Sawaya, Z. B. Fortes, and R. Sesso Homocysteine and Nitric Oxide Are Related to Blood Pressure and Vascular Function in Small-for-Gestational-Age Children Hypertension, August 1, 2007; 50(2): 396 - 402. [Abstract] [Full Text] [PDF]
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H. Martin, B. Lindblad, and M. Norman Endothelial Function in Newborn Infants Is Related to Folate Levels and Birth Weight Pediatrics, June 1, 2007; 119(6): 1152 - 1158. [Abstract] [Full Text] [PDF]
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S. Rasmussen and L. M. Irgens Pregnancy-Induced Hypertension in Women Who Were Born Small Hypertension, April 1, 2007; 49(4): 806 - 812. [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. Mori, N. Uchida, A. Inomo, and S.-i. Izumi Stiffness of Systemic Arteries in Appropriate- and Small-for-Gestational-Age Newborn Infants Pediatrics, September 1, 2006; 118(3): 1035 - 1041. [Abstract] [Full Text] [PDF]
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J. L. Segar, R. D. Roghair, E. M. Segar, M. C. Bailey, T. D. Scholz, and F. S. Lamb Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R481 - R488. [Abstract] [Full Text] [PDF]
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M. C.P. Franco, D. M.J. Christofalo, A. L. Sawaya, S. A. Ajzen, and R. Sesso Effects of Low Birth Weight in 8- to 13-Year-Old Children: Implications in Endothelial Function and Uric Acid Levels Hypertension, July 1, 2006; 48(1): 45 - 50. [Abstract] [Full Text] [PDF]
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 A. Covic, N. Mardare, P. Gusbeth-Tatomir, O. Brumaru, C. Gavrilovici, M. Munteanu, O. Prisada, and D. J. A. Goldsmith Increased arterial stiffness in children on haemodialysis Nephrol. Dial. Transplant., March 1, 2006; 21(3): 729 - 735. [Abstract] [Full Text] [PDF]
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B. T. Alexander Fetal programming of hypertension Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R1 - R10. [Abstract] [Full Text] [PDF]
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F. Khan, J. J.F. Belch, M. MacLeod, and G. Mires Changes in Endothelial Function Precede the Clinical Disease in Women in Whom Preeclampsia Develops Hypertension, November 1, 2005; 46(5): 1123 - 1128. [Abstract] [Full Text] [PDF]
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R. D. Roghair, J. L. Segar, R. V. Sharma, M. C. Zimmerman, D. K. Jagadeesha, E. M. Segar, T. D. Scholz, and F. S. Lamb Newborn lamb coronary artery reactivity is programmed by early gestation dexamethasone before the onset of systemic hypertension Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R1169 - R1176. [Abstract] [Full Text] [PDF]
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J. Brodszki, T. Lanne, K. Marsal, and D. Ley Impaired Vascular Growth in Late Adolescence After Intrauterine Growth Restriction Circulation, May 24, 2005; 111(20): 2623 - 2628. [Abstract] [Full Text] [PDF]
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S. J. Williams, D. G. Hemmings, J. M. Mitchell, I. C. McMillen, and S. T. Davidge Effects of maternal hypoxia or nutrient restriction during pregnancy on endothelial function in adult male rat offspring J. Physiol., May 15, 2005; 565(1): 125 - 135. [Abstract] [Full Text] [PDF]
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 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
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S. J. Williams, M. E. Campbell, I. C. McMillen, and S. T. Davidge Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2005; 288(2): R360 - R367. [Abstract] [Full Text] [PDF]
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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]
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 Y F Cheung, K Y Wong, B. C C Lam, and N S Tsoi Relation of arterial stiffness with gestational age and birth weight Arch. Dis. Child., March 1, 2004; 89(3): 217 - 221. [Abstract] [Full Text] [PDF]
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R. J. Irving, A. C. Shore, N. R. Belton, R. A. Elton, D. J. Webb, and B. R. Walker Low Birth Weight Predicts Higher Blood Pressure But Not Dermal Capillary Density in Two Populations Hypertension, March 1, 2004; 43(3): 610 - 613. [Abstract] [Full Text] [PDF]
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A. Hellstrom, J. Dahlgren, K. Marsal, and D. Ley Abnormal Retinal Vascular Morphology in Young Adults Following Intrauterine Growth Restriction Pediatrics, February 1, 2004; 113(2): e77 - 80. [Abstract] [Full Text] [PDF]
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M. Norman and H. Martin Preterm Birth Attenuates Association Between Low Birth Weight and Endothelial Dysfunction Circulation, August 26, 2003; 108(8): 996 - 1001. [Abstract] [Full Text] [PDF]
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 J. J. Oliver and D. J. Webb Noninvasive Assessment of Arterial Stiffness and Risk of Atherosclerotic Events Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 554 - 566. [Abstract] [Full Text] [PDF]
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 T. S. Hermann, C. Rask-Madsen, N. Ihlemann, H. Dominguez, C. B. Jensen, H. Storgaard, A. A. Vaag, L. Kober, and C. Torp-Pedersen Normal Insulin-Stimulated Endothelial Function and Impaired Insulin-Stimulated Muscle Glucose Uptake in Young Adults with Low Birth Weight J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1252 - 1257. [Abstract] [Full Text] [PDF]
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