(Circulation. 2000;101:1533.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Cholesterol and Arterial Distensibility in the First Decade of Life
A Population-Based Study
From the Vascular Physiology Unit, Great Ormond Street Hospital (C.P.M.L., M.J.M., A.E.D., J.E.D.), London, UK; Cardiovascular Research Unit, Department of Primary Care and Population Sciences, Royal Free Hospital School of Medicine (P.H.W.), London, UK; Department of Public Health Sciences (D.G.C.) and Department of Clinical Biochemistry (C.A.S.), St Georges Hospital Medical School, London, UK; and the MRC Childhood Nutrition Research Centre, Institute of Child Health (C.P.M.L.), London, UK.
Correspondence to Professor J.E. Deanfield, Vascular Physiology Unit, Great Ormond Street Hospital, London WC1N 3JH, UK.
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Abstract |
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Background—Blood cholesterol levels are a key determinant of coronary heart disease risk in adults, but the importance of lipid levels in the general population during childhood is less clear. We related arterial distensibility, a marker of vascular function known to be altered early in atherosclerosis, to the lipid profile of a population-based sample of children aged 9 to 11 years.
Methods and Results—A noninvasive ultrasound technique was used to measure arterial distension during the cardiac cycle in the brachial arteries of 361 children from 4 towns in the United Kingdom. This measure was related to their pulse pressure to assess arterial distensibility. All the children had previously had a comprehensive assessment of cardiovascular risk including a full lipid profile, cotinine-assessed smoke exposure, serum glucose, and questionnaire data on socioeconomic and dietary factors. Mean total cholesterol in the population was 4.72 [SD 0.75] mmol/L. There was a significant, inverse relation between cholesterol and distension of the artery across this range (linear regression coefficient -11.8 µm · mmol-1 · L-1, P=0.003). Similar relationships were demonstrated with LDL and apolipoprotein B (-12.9 µm · mmol-1 · L-1, P=0.005 and -36.9 µm/mmol/L, P=0.01). HDL and triglyceride levels showed no consistent association with distensibility.
Conclusions—LDL cholesterol levels had an impact on arterial distensibility in the first decade of life. Furthermore, the functional differences in the arterial wall were demonstrated within the lipid range found in normal children, a finding that raises the possibility that cholesterol levels in the general population during childhood may already be relevant to the development of vascular disease.
Key Words: cholesterol • physiology • atherosclerosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypercholesterolemia is a key factor initiating early structural changes in atherosclerosis.1 There is a direct relationship between serum cholesterol level in adult life and the risk of cardiovascular morbidity and mortality.2 In animal experiments, the reduction of blood cholesterol levels leads to regression of atherosclerosis,3 and in humans, it has been shown to be beneficial for both primary and secondary prevention of heart disease.4 5 Cholesterol can therefore be considered an important modifiable risk factor that affects the natural history of atherosclerosis.
The relevance of cholesterol during childhood is more difficult to evaluate. Cholesterol levels in young men have been linked to eventual morbidity and mortality.6 However, the long period between these measurements in early life and the late clinical end points makes it difficult to establish causal relations, especially when studies are extended to include younger children.7 Autopsy investigations indicate pathological changes can be identified in large arteries as early as fetal life, and by the first decade, the majority of children are affected.8 9 10 Importantly, LDL cholesterol level appears to relate to the anatomic extent of atherosclerosis in these preclinical studies.11
Noninvasive assessment of disturbed arterial physiology, relevant to the atherosclerotic process, represents a novel means of studying the evolution of arterial disease during these key early years.12 13 14 We have previously demonstrated that young subjects with familial hypercholesterolemia have vascular endothelial dysfunction.15 However, there was no relationship between cholesterol level and endothelial response in a population-based study of normal 9- to 11-year-old children.16 It therefore remains unclear what effect cholesterol, at levels found in the general population, has on the vessel wall early in life.
Arterial distensibility, a measure of vascular elastic behavior, is altered during early arterial cholesterol accumulation in animal models, before other vessel wall changes,17 and in adults, loss of distensibility is related to risk factors for clinical vascular disease.18 19 20 In the present study, we investigated the pathophysiology behind changes in distensibility and examined the influence of childhood lipid profiles on this measure. We show for the first time a relationship between lipid levels and conduit artery function, within the range of cholesterol found in the normal United Kingdom childhood population, as early as the first decade of life.
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Methods |
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The study was performed as part of a larger, mixed longitudinal investigation of cardiovascular risk factors in 10 British towns.21 Within each town, the study was based on a stratified random sample of 10 local authority primary schools; in each school, 50 children aged 9 to 11 years were invited for measurement (overall response rate 75%). The present study was performed in the last 4 towns, 2 with high adult cardiovascular mortality rates (Rochdale and Rhondda) and 2 with very low adult cardiovascular mortality rates (Bath and Tunbridge Wells). Thirty-three of 40 schools in the original study could provide suitable accommodation for the vascular studies and were included. In each school, the oldest 15 of the 37 pupils who had participated in the previous study were invited to take part.
Vascular Study Measurements
Brachial artery distension during the cardiac cycle was measured
for each child at rest. The subject lay supine on a couch, and room
temperature was recorded. After 10 minutes’ rest, the right
brachial artery was imaged in longitudinal section at 10 to 15 cm above
the antecubital fossa with a 7-MHz linear array transducer and Acuson
128XP/10.13 To measure arterial distension,
the M-mode cursor was positioned at right angles to the
arterial lumen over the clearest defined section of the
artery on the B-mode image. A 5-second segment of the radiofrequency
signal was recorded by a separate commercially available Wall
Tracking System (Ingenious Medical Systems) at a rate of 800 Hz (1
frame/ms). The initial frame (amplitude waveform) is displayed, and the
operator selects 2 sample volumes coinciding with the
arterial wall-lumen interfaces. The relative position of
the walls within these volumes is measured every 25 ms (
20% of the
expected time for an upstroke) by use of a displacement detection
algorithm based on the cross-correlation model for corresponding
segments of the radiofrequency lines (Figure 2
).14 Arterial
distension is measured as the mean diameter changes between
diastole and systole over the 5-second period. Coefficients
of variation for diameter and distension measurements with this
technique are reported as 2% to 3%.22 23 Pulse pressure
was measured in the left brachial artery with a Dinamap 1846SX
oscillometric blood pressure recorder (Critikon Inc) at the same
time that distensibility was measured in the right arm. This method has
been shown to provide a representative measure of the
pulse pressure in the right brachial artery during data
collection.14
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Scan quality analysis was performed by independent observers as described previously.16 24 To assess within-subject reproducibility of the technique, the third subject each day was invited back in the afternoon for repeat measurements, with the ultrasonographer blinded to the earlier results.
Height and weight were measured with a portable stadiometer (CMS Ltd) and digital weighing scale (Soehnle Ltd). Ethnic group was recorded as Caucasian, Asian, or other. A saliva sample was collected for cotinine analysis.25
Cardiovascular Risk Factor Measurements
The risk factor profile of each subject had been established 8
months earlier.21 This included total
cholesterol, LDL, HDL, ApoB, and plasma glucose
measurements. Half of the subjects had a venipuncture while
in the fasted state and the remainder 30 minutes after a standard
glucose load (1.75 g/kg). Samples were separated and frozen for storage
within 6 hours. Total serum cholesterol was measured with
the Technicon Dax system, HDL cholesterol with the
dextran-sulfate-magnesium precipitation method,26 and ApoB
by the Beckman rate nephelometric method. LDL cholesterol
was calculated from the Friedewald method.27 Fasting and
nonfasting lipid levels were similar and were therefore combined for
analysis. A self-completion questionnaire was forwarded to
parents that provided information on head-of-household occupation for
socioeconomic coding and data on diet, exercise, and medical and birth
history of the child.
Study Determining the Contribution of
Endothelium-Derived NO to Arterial
Distensibility
To investigate the pathophysiology behind changes in
arterial distensibility, we related measures of
arterial distension in the cohort to data on
endothelium-dependent flow-mediated dilatation
collected for each subject.16 We then performed a new
laboratory-based study in a smaller group of older subjects using an
intra-arterial infusion of the specific NO synthesis
inhibitor L-NMMA to determine the relationship between
distensibility and endothelium-dependent NO release. In
6 healthy normocholesterolemic adults (mean age 34
years; range 30 to 40), radial artery distensibility during infusion of
L-NMMA (4 µmol/min) was compared with normal saline and a
nonspecific endothelium-independent constrictor, NE
(240 pmol/min). The saline and drugs were infused at a constant
rate (0.5 mL/min) via a 27-gauge needle introduced under local
anesthetic into the proximal brachial artery. Measures of
arterial distensibility were based on the mean of 3
separate measurements of arterial distension during an
infusion in relation to the pulse pressure.
Statistical Analysis
Arterial distensibility is usually
represented as the DC, calculated as the change in
cross-sectional area between diastole and systole relative
to the area at diastole, divided by the pulse
pressure.22 DC was used to analyze data from the
smaller groups involved in studying ultrasound measurement
repeatability and investigating endothelium dependence
of distensibility. Ultrasound repeatability is presented as the
correlation of repeat measurements and as the mean of the differences
with the SD. The effect of L-NMMA and NE on DC was compared by
repeated-measures ANOVA.
For analysis of the complete cohort, relations between explanatory variables and arterial distensibility were assessed with a linear regression model, with absolute arterial distension as the dependent variable and pulse pressure as an independent variable. This method is justified, because distension is normally distributed, and over the blood pressure range in our cohort, distension was linearly related to pulse pressure (regression coefficient 0.91 µm/mm Hg, 95% CI 0.33 to 0.49, P=0.002). The main model examined the effect of each variable on absolute distension of the vessel wall, with pulse pressure, age, sex, and town included as independent variables. Additional models adjusted for body size and other risk factors. Linearity of associations was examined visually and by fitting quadratic and cubic terms in the model.
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Results |
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Five hundred and fourteen children with blood sample data were invited to participate in the study; 390 took part, and 361 had both satisfactory ultrasound measurements and a complete lipid profile available (181 girls and 180 boys; 70% of children invited). Characteristics of the participants are listed in Table 1
. Age, sex, or body build had no
influence on whether a full set of data was obtained. Twenty-nine
subjects had repeat vascular measurements (mean difference in the
distensibility coefficient [DC] between the first and second reading
0.01 [SD 0.06] mm Hg-1; correlation
between measurements 0.84).
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There was no significant difference in distensibility between children
from the 4 towns in which this study was conducted, and there was no
relation with room temperature or the time of day. Distensibility was
similar in girls and boys and was not affected by age. Salivary
cotinine concentration (to assess passive smoke exposure), social
class, ethnicity, and preload and postload glucose showed no
significant relationship with distensibility (data not
presented). Height was related to distensibility, but relations
with ponderal index and resting vessel size were not significant.
Diastolic but not systolic blood pressure was
related to distensibility. Regression coefficients are
presented in Table 2.
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Blood Lipids and Arterial Distensibility
Arterial distensibility declined with increasing
cholesterol levels. With this cohort size, the precise
nature of the relationship could not be determined. A linear model
provided the closest fit and is therefore used in describing the
relations; however, cubic, quadratic, and logarithmic models were also
significant, and a threshold cholesterol level within the
population range beyond which arterial distensibility was
significantly affected could not be excluded (Figure 1A). Similar associations were found with
LDL (Figure 1B) and apolipoprotein B (ApoB). Relations between
HDL or triglycerides and distensibility were
inconsistent and not statistically significant. The association
was similar in girls and boys.
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Cholesterol was independently correlated to height
(r=-0.13, P=0.01) and body size, assessed by
ponderal index (r=0.16, P=0.002). However, the
association between cholesterol and distensibility remained
significant after these factors were included in the model (Table 3). Adjustment for diastolic
and systolic blood pressures in the model did not significantly
alter the relation between cholesterol and distension
(regression coefficient after adjustment -9.41 µm ·
mmol-1 · L-1,
P=0.02).
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Study Determining the Contribution of
Endothelium-Derived Nitric Oxide to
Distensibility
Neither absolute distension nor DC was correlated to
endothelium-dependent flow-mediated dilatation in the
children (correlation of DC on flow-mediated dilatation,
r=-0.04, P=0.52).
In the 6 adults studied, intra-arterial infusion of NG-monomethyl-L-arginine (L-NMMA) had no significant effect on DC, which indicates that this measure is not importantly influenced by endothelium-derived nitric oxide (NO) (change in DC after infusion of L-NMMA, -0.01 mm Hg-1; 95% CI -0.05 to 0.03, P=0.53; after norepinephrine [NE] -0.01 mm Hg-1, 95% CI -0.04 to 0.03, P=0.49). There was no significant change in systemic blood pressure after local forearm infusion of L-NMMA and NE. Mean vessel size was 2.83 [SD 0.75] mm; both vessel size and levels of flow were similar after infusion of L-NMMA and NE.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study shows an association between arterial distensibility and cholesterol in a population of apparently healthy 9- to 11-year-olds. In children with higher serum cholesterol levels, the brachial artery was less distensible. The association with arterial distensibility in our young population was found within the range of LDL and ApoB levels of the general population, which suggests that these lipid subfractions may be relevant to arterial disease from a point very early in life.
The data are consistent with accumulating experimental and clinical evidence that cholesterol is integral to the early pathophysiology of atherosclerosis.28 Elevated LDL levels result in accumulation of lipoproteins in the vessel wall, which when oxidized are rapidly taken up by macrophages to form foam cells.1 29 This process starts remarkably early in life. LDL accumulation has been shown in fetal aortas even before monocyte migration into the vessel wall, with the degree of vascular change depending on fetal and maternal lipid levels.10 The role of HDL early in disease is less clear. In adult population studies and in coronary disease cohorts, HDL levels have an inverse association with adverse events. In the present study, there was no relation between HDL and distensibility, and studies of HDL in children with high familial risk do not always show anticipated associations.30 The importance of HDL may therefore differ between stages of atherogenesis.31
The precise characteristic of the vessel wall underlying changes in distensibility and its relation to disease pathogenesis require further study. Previous work in animals and humans indicates distensibility is related to the structural arrangement of the artery and that subjects with risk factors for clinical coronary disease have reduced distensibility resulting from changes in wall architecture.32 33 34 Animal studies show arterial elasticity is reduced even during early fatty streak formation, before other pathophysiological changes.17 Our results in the present study suggest that differences in distensibility found in young children are not likely to represent impaired endothelial NO synthesis, because distensibility was not significantly blocked by L-NMMA in healthy adults. We and others have demonstrated that endothelium-dependent flow-mediated dilatation is abnormal in young subjects with risk factors for vascular disease. However, it was not related to cholesterol level or arterial distensibility in this normal cohort.16 Distensibility therefore provides different information about the vasculature than measures of endothelium-dependent response.13 The impact of LDL cholesterol levels found in the normal population on distensibility will need to be evaluated further in terms of its interactions with other risk factors that may be operating at this early stage of disease, including homocysteine, blood pressure, and genetic influences.
Interestingly, we have also shown a graded relation between diastolic blood pressure and arterial distensibility in this group of normotensive children. A similar relation has been reported in adults at various ages and over larger blood pressure ranges, including hypertensive patients.35 36 However, the demonstration of an association between distensibility and blood pressure in children in the general population is new. This finding supports the idea of an intrinsic relationship between blood pressure and distensibility and indicates that the impact of blood pressure on the vessel wall may start very early in life.
The mean cholesterol levels are high compared with those in American children; however, they are similar to results in the whole study population21 and findings in other British children.37 This may reflect higher fat intake of British children,38 which is paralleled by higher cholesterol levels in adults.39 Our sampling procedure has been shown to produce a socially representative population of children in whom the prevalence of private education is low. Because neither blood lipids nor distensibility was related to social class, socioeconomic and educational differences are unlikely to have influenced the findings. The cohort has a narrow age range, and the effects of age on arterial distensibility are therefore minimal; however, our observations in 9- to 11-year-olds cannot provide information about the development of the relation between risk and the arterial wall over time. In these prepubertal children, the association of cholesterol to distensibility did not differ between sexes. Risk factor levels also do not normally vary between sexes at this age,40 which suggests that the determinants of the variation in vascular disease risk between sexes later in life are not yet operating. Height was related to distensibility, but the reason is not immediately apparent. Short adult stature is known to be an independent risk factor for cardiovascular morbidity and mortality.41 The relation in our group was only partly explained by the association of increased height with lower cholesterol and greater vessel size. Biochemical variables including glucose and insulin did not appear to influence the association of distensibility with cholesterol levels.
This study has established for the first time that changes in the arterial wall relevant to the atherosclerotic process can be identified in a population-based sample of children who have a normal range of cholesterol levels. Our findings suggest that the emergence of arterial disease at this early stage may not be confined to high-risk groups, but that early arterial changes are already present within the general population. We were unable to establish the precise shape of the association between LDL cholesterol and arterial distensibility and therefore cannot determine whether there is a linear relation or threshold effect for cholesterol. This may have potentially important management implications in terms of cholesterol-level recommendations and reduction targets in a population. Whether these vascular differences can be modified to prevent the development of arterial disease is presently unknown but will be of considerable interest. In adults, a reduction in cholesterol of 1% reduces the risk of coronary heart disease by 2% to 3%.4 5 The potential benefit, however, may be greater if intervention is started earlier in the atherogenic process. Additional longitudinal and interventional studies using noninvasive vascular measures will be able to assess disease development during these key years.
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Acknowledgments |
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The vascular study was supported by a project grant from the British Heart Foundation (grant No. PG/95026) and the earlier survey of risk factors by the Wellcome Trust (grant No. 038976/Z/93/Z). We are grateful to the schools, parents, and children who took part and to Fiona Adshead, Robyn Totenhofer, Lucy Lennon, and Valerie Wilson for their help with fieldwork.
Received April 9, 1999; revision received October 19, 1999; accepted November 2, 1999.
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J. A. Groner, M. Joshi, and J. A. Bauer Pediatric Precursors of Adult Cardiovascular Disease: Noninvasive Assessment of Early Vascular Changes in Children and Adolescents Pediatrics, October 1, 2006; 118(4): 1683 - 1691. [Abstract] [Full Text] [PDF]
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P.H. Whincup, J.A. Gilg, A.E. Donald, M. Katterhorn, C. Oliver, D.G. Cook, and J.E. Deanfield Arterial Distensibility in Adolescents: The Influence of Adiposity, the Metabolic Syndrome, and Classic Risk Factors Circulation, September 20, 2005; 112(12): 1789 - 1797. [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]
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J. Bellien, R. Joannides, M. Iacob, P. Arnaud, and C. Thuillez Calcium-Activated Potassium Channels and NO Regulate Human Peripheral Conduit Artery Mechanics Hypertension, July 1, 2005; 46(1): 210 - 216. [Abstract] [Full Text] [PDF]
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M. Schmitt, A. Avolio, A. Qasem, C. M. McEniery, M. Butlin, I. B. Wilkinson, and J. R. Cockcroft Basal NO Locally Modulates Human Iliac Artery Function In Vivo Hypertension, July 1, 2005; 46(1): 227 - 231. [Abstract] [Full Text] [PDF]
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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]
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 M. Frick, S. P. Schwarzacher, H. F. Alber, A. Rinner, H. Ulmer, O. Pachinger, and F. Weidinger Morphologic rather than functional or mechanical sonographic parameters of the brachial artery are related to angiographically evident coronary atherosclerosis J. Am. Coll. Cardiol., November 20, 2002; 40(10): 1825 - 1830. [Abstract] [Full Text] [PDF]
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A. Singhal, I. S. Farooqi, T. J. Cole, S. O'Rahilly, M. Fewtrell, M. Kattenhorn, A. Lucas, and J. Deanfield Influence of Leptin on Arterial Distensibility: A Novel Link Between Obesity and Cardiovascular Disease? Circulation, October 8, 2002; 106(15): 1919 - 1924. [Abstract] [Full Text] [PDF]
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 S. A. Hope, D. B. Tay, I. T. Meredith, and J. D. Cameron Comparison of generalized and gender-specific transfer functions for the derivation of aortic waveforms Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1150 - H1156. [Abstract] [Full Text] [PDF]
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I. B. Wilkinson, D. J. Webb, J. R. Cockcroft, S. Kinlay, P. Ganz, and M. A. Creager Nitric Oxide and Regulation of Arterial Elasticity: Right Idea, Wrong Vascular Bed? * Response Hypertension, September 1, 2002; e4(3): . [Full Text] [PDF]
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I. B. Wilkinson, A. Qasem, C. M. McEniery, D. J. Webb, A. P. Avolio, and J. R. Cockcroft Nitric Oxide Regulates Local Arterial Distensibility In Vivo Circulation, January 15, 2002; 105(2): 213 - 217. [Abstract] [Full Text] [PDF]
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S. Kinlay, M. A. Creager, M. Fukumoto, H. Hikita, J. C. Fang, A. P. Selwyn, and P. Ganz Endothelium-Derived Nitric Oxide Regulates Arterial Elasticity in Human Arteries In Vivo Hypertension, November 1, 2001; 38(5): 1049 - 1053. [Abstract] [Full Text] [PDF]
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J. C. LaRosa Prevention and Treatment of Coronary Heart Disease: Who Benefits? Circulation, October 2, 2001; 104(14): 1688 - 1692. [Abstract] [Full Text] [PDF]
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 K. A Dettwyler, W. Holmes, T. Greiner, J. Sikorski, C. Dezateux, A. Holt, I. B Wilkinson, J. R Cockcroft, P. M. Dark, M.-J. Rolli, et al. Duration of breast feeding and adult arterial distensibility BMJ, September 22, 2001; 323(7314): 689 - 689. [Full Text]
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M. de Divitiis, C. Pilla, M. Kattenhorn, M. Zadinello, A. Donald, P. Leeson, S. Wallace, A. Redington, and J. E. Deanfield Vascular dysfunction after repair of coarctation of the aorta: Impact of Early Surgery Circulation, September 18, 2001; 104 (2009): I-165 - I-170. [Abstract] [Full Text] [PDF]
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I. Booth Does the duration of breast feeding matter? BMJ, March 17, 2001; 322(7287): 625 - 626. [Full Text]
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C P M Leeson, M Kattenhorn, J E Deanfield, and A Lucas Duration of breast feeding and arterial distensibility in early adult life: population based study BMJ, March 17, 2001; 322(7287): 643 - 647. [Abstract] [Full Text]
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H. M Colhoun, M. B Rubens, S R. Underwood, and J. H Fuller Cross sectional study of differences in coronary artery calcification by socioeconomic status BMJ, November 18, 2000; 321(7271): 1262 - 1263. [Full Text]
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 Cholesterol Correlates With Vascular Health in First Decade of Life Journal Watch (General), April 14, 2000; 2000(414): 8 - 8. [Full Text]
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