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CLINICAL REVIEW 168 |
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
Address all correspondence and requests for reprints to: Arnold H. Slyper, M.D., Loyola University Medical Center, 2160 South First Avenue, Maywood, Illinois 60153. E-mail: aslyper{at}lumc.edu.
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Abstract |
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 Top Abstract IntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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Introduction |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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Atherosclerosis affects primarily large elastic arteries, such as the aorta, carotid, and iliac arteries, and large and medium-sized muscular arteries, such as the coronary and popliteal arteries (1). The earliest abnormalities seen in the coronary vessels and aorta of pediatric subjects at postmortem are fatty streaks, composed of lipid-filled foam cells and extracellular lipid, and these are present throughout childhood, including the neonatal period. From 5–10% of coronary arteries of children aged 2–15 yr show fibrous plaques, and it is generally believed that these evolve from an initial fatty streak (2, 3, 4). Thickening of the intima and media can also be recognized at autopsy in the young and elderly (5, 6). The thickening adjacent to the endothelium consists predominantly of a matrix of proteoglycan molecules, whereas that adjacent to the media contains elastic fibers and smooth muscle cells that have migrated from the media. Thickening of the vessel wall affects equally the intima and media (5). Arteries with thickened walls have a predilection to develop necrotic atheroma, and it has been suggested that this occurs when the collagenous matrix of the intima exceeds a threshold value (5). Increased intima-medial thickening and atheroma develop particularly at areas of low shear and turbulence, for example at vessel branch points (6).
The endothelial surface of the blood vessel functions as a regulatory organ that maintains vasomotor tone, maintains the nonthrombogenic nature of its surface by regulation of platelet activity, and regulates the fluidity of blood by the secretion of anticoagulant and fibrinolytic factors (7). Vasodilatory factors produced by endothelial cells include nitric oxide, prostacyclin, bradykinin, and hyperpolarizing factor, and these are antagonized by contracting factors, such as endothelin, thromboxane, and activation of angiotensin II. Nitric oxide is the main dilating factor produced by endothelial cells and is derived from L-arginine by the action of nitric oxide synthase. Nitric oxide is also one of the main antiatherogenic factors, and among its many functions it maintains vascular tone, regulates vascular permeability, inhibits platelet adhesion and aggregation, inhibits leukocyte-vessel wall interaction, and prevents smooth muscle proliferation (8).
Coronary vascular disease is one facet of a generalized disturbance of vascular function present throughout the vascular tree. The first stage in this disturbance is dysfunction of the endothelium, and this leads over time to thickening of the intima and media and the eventual development of plaque in large elastic arteries, and large and medium-sized muscular arteries. Persistence of severe endothelial dysfunction can lead to instability of the endothelial surface, erosion of the fibrous cap overlying plaque, subclinical plaque rupture, and vessel thrombosis (9).
Two major advances in cardiovascular research have been the ability to assess endothelial function and to detect early anatomical evidence of atherogenesis by means of high resolution ultrasound. Before the use of these techniques, anatomical evidence of atherogenesis could only be recognized at the time of invasive cardiac catheterization or on postmortem examination. Endothelial function can be evaluated by measuring changes in blood vessel diameter in response to specific stimuli. These changes in diameter are inhibited by selective inhibitors of nitric oxide synthase, indicating that they provide an indirect assessment of nitric oxide production. Acetylcholine, when injected directly into healthy blood vessels, produces prompt vasodilation. In the presence of coronary vessel disease, direct injection of acetylcholine into the coronary circulation leads to a paradoxical vaso-constriction.
A commonly used test of endothelial function measures the vasodilator response to increased blood flow (flowmediated vasodilation), and this test is conveniently performed on the brachial artery. Adult studies have demonstrated a close relationship between endothelial function of the peripheral circulation and that of the coronary circulation (10). Brachial artery flow-mediated vasodilation is also closely related to the angiographic extent of coronary artery disease (11).
Blood flow occlusion by means of a cuff around the upper or lower arm to at least 50 mm Hg above systolic pressure produces ischemia, and this leads to vasodilation of the immediate downstream vessel. When the cuff is deflated, a brief 5- to 6-fold high blood flow state fills the dilated vessel, and the resulting increase in shear stress leads to dilation of the blood vessel over the next 30 sec to 5 min (12, 13). Chemical inhibition of nitric oxide production reduces flow-mediated vasodilation by about 70% (13). Flow-mediated vasodilation is expressed as the change in diameter divided by the baseline diameter, and this can be measured with considerable accuracy by high resolution ultrasound using digital calibers or automated edge detection (13). In many studies an assessment of nonendothelium-dependent vasodilation is also performed using nitroglycerin or nitroprusside, and this measures nonspecific smooth muscle effects. The changes in vessel diameter being measured are quite small. Nevertheless, there is excellent within-scan and within-subject coefficients of variation, even when the test is repeated after a duration of several months (14).
Thickening of the intima and media of the vessel wall can also be visualized by high resolution ultrasound (Fig. 1
). The arteries most commonly examined by ultrasound are the internal and common carotid arteries in the vicinity of the carotid bulb, and the carotid bulb itself. Intima-medial thickening tends to be greater at the carotid bulb or carotid bifurcation than in the common carotid artery, with thickening of the internal carotid artery being more variable (15). Thickening of the intima-medial layer of the aorta and femoral vessels has also been assessed in some studies.
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The purposes of this review are 1) to examine what ultrasound testing has revealed about early atherogenesis in children and adolescents, and 2) to discuss the proposition that high resolution vascular ultrasound has considerable potential for assessing pediatric atherogenic risk within a clinical setting.
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Endothelial dysfunction in pediatric conditions |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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Other conditions in which endothelial dysfunction has been demonstrated in children are familial combined hyperlipidemia (27) and type 1 diabetes mellitus (28). Independent variables of flow-mediated vasodilation in this study of childhood type 1 diabetes were blood and red cell folate, glucose, and baseline vessel diameter (28). Endothelial dysfunction is present in severe pediatric obesity (29). Endothelial function is also impaired in children as young as 4 yr of age with homozygous homocystinuria, but not in their heterozygous parents (30). Gatea et al. (31) demonstrated a considerable decrease in flow-mediated vasodilation in children and young adults who were the offspring of a parent with premature coronary infarction. Total and LDL cholesterol did not clearly differentiate between subjects and healthy controls, although there were significant differences in apoprotein B and lipoprotein(a).
Endothelial dysfunction has also been associated with other pediatric risk factors. Pointing to the importance of inflammation in the development of early atherogenesis, Jarvisalo et al. (32) showed that children with higher levels of serum ultrasensitive C-reactive protein (
0.1 to 
0.7 and >0.7 mg/liter) demonstrated lower flow-mediated vasodilation than children with C-reactive protein levels that were under the detection limit of less than 0.1 mg (P = 0.015 for trend). C-Reactive protein remained a significant independent predictor for brachial artery flow-mediated vasodilation in multivariate analysis. Leeson et al. (33) demonstrated a significant positive graded relationship between flowmediated vasodilation and birth weight in 382 healthy 9- to 11-yr-old children (P = 0.02), and this relationship remained significant after adjusting for body build, parity, cardiovascular risk factors, social class, and ethnicity (25). The effect was small and would have little relevance on an individual basis, but it does lend support to the idea that fetal programing has an impact on early atherogenesis. In this study high density lipoprotein cholesterol was the only lipid factor that correlated with flow-mediated vasodilation. Habitual physical activity level, as determined by a validated stable isotope technique, is also strongly correlated with flowmediated vasodilation in young children (34).
In adults, baseline diameter is an important determinant of flow-mediated vasodilation, accounting for 15% of the variance in vasodilation (8). Aging results in a progressive dilation of the brachial artery and a diminution of the vasodilator response (13). Flow-mediated vasodilation is also greater in young women than in men, even after adjusting for baseline diameter (35). In healthy children, aged 5–10.5 yr, age was a weak correlate of flow-mediated vasodilation (r = 0.30; P = 0.048), but not baseline arterial diameter (34).
In total, these pediatric studies indicate that endothelial dysfunction is found in conditions predisposing to early atherogenesis, such as familial hypercholesterolemia, familial combined hyperlipidemia, morbid obesity, and type 1 diabetes, and may be present at a young age. Pediatric endothelial dysfunction is also associated with anticipated risk factors, such as age, family history of early coronary disease, birth weight, and physical activity. Inflammation, as evidenced by levels of C-reactive protein, appears to be as important in children as in adults (36).
On the other hand, total and LDL cholesterol do not emerge in most pediatric studies as strong correlates of endothelial dysfunction. The weak or absent correlation between LDL cholesterol and endothelial function in pediatric familial hypercholesterolemia is of particular interest, because a close relationship could have been anticipated given the importance usually ascribed to LDL cholesterol levels (22, 23, 27). However, the pediatric data do accord with many adult familial hypercholesterolemia studies (37, 38). For example, there are strong family similarities in age of death in this condition, but no significant correlation between age of death and serum cholesterol (39). In one study of genetically homogenous familial hypercholesterolemic adults, there was no association between coronary artery disease and LDL cholesterol levels in the men, and coronary disease correlated more strongly with very low density lipoprotein cholesterol than LDL cholesterol in the women (40). At least one adult familial hypercholesterolemia study has shown lipoprotein(a) to be a strong independent risk factor for coronary disease (41).
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Early atherogenesis in pediatric conditions, as demonstrated by increased carotid artery intima-medial thickening |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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Increased intima-medial thickening has been consistently demonstrated in children and adolescents with familial hypercholesterolemia diagnosed on the basis of lipid levels. Virkola et al. (45) found a considerable difference in maximal common carotid artery intima-medial thickening (i.e. the maximal value recorded for each patient) in 23 familial hypercholesterolemic subjects, aged 2.7–19 yr, compared with healthy controls (0.7 vs. 0.45 mm; P < 0.0001). In 28 patients, aged 11–27 yr, Lavrencic et al. (46) also found a large increase in carotid artery thickening (mean of common carotid, bulb, and internal carotid) compared with normocholesterolemic controls (0.71 vs. 0.49 mm; P < 0.001). No sex difference was noted between the hypercholesterolemic male and female subjects. Tonstad et al. (47) found a small, but significant, difference in mean intima-medial thickening of the carotid bulb in 90 hypercholesterolemic children, aged 10–19 yr, compared with healthy controls (0.54 vs. 0.50 mm; P < 0.03), although mean and maximum intima-medial thickening of the common carotid artery were similar. However, areas of plaque, defined as distinct areas of protrusion into the vessel wall, were present in 10% of the familial hypercholesterolemic children, but in none of the controls. Paucciulla et al. (48) compared mean and maximum intima-medial thickening of the common carotid artery in 46 hypercholesterolemic children, aged 2–15 yr, who had total cholesterol levels greater than 244 mg/dl (>6.40 mmol/liter) with controls who had total cholesterol levels less than 244 mg/dl (<6.40 mmol/liter) and noted that maximum thickening of the common carotid artery, but not mean thickening, was increased in hypercholesterolemic children older than 6 yr of age (0.50 vs. 0.47 mm; P = 0.007). Jarvisalo et al. (49) noted increased intima-medial thickening of the common carotid artery in 16 familial hypercholesterolemic children compared with normocholesterolemic controls (0.53 vs. 0.46 mm; P < 0.01). Also noted in this study was that intima-medial thickening of the aorta showed a greater increase and, hence, better differentiation between subjects and controls than intima-medial thickening of the carotid artery.
As in studies with brachial artery flow-mediated vasodilation, the relationship between LDL cholesterol and intima-medial thickening within familial hypercholesterolemic patients is ambiguous. Two studies in children and adolescents with familial hypercholesterolemia demonstrated a relationship between carotid intima-medial thickness and LDL cholesterol levels (45, 47), whereas other studies were unable to find a relationship (46, 48). In one study the only correlation with carotid intima-medial thickening among the various clinical and laboratory variables was age (46).
Studies have demonstrated increased carotid intimamedial thickening in children with type 1 diabetes (49, 50). In 39 older adolescents and young adults with type 1 diabetes (mean age, 17.5 yr ± 5.2 yr), Peppa-Patrikiou et al. (51) found common carotid intima-medial thickening to be increased in male diabetics (0.52 vs. 0.44 mm for controls; P = 0.015), but not in female diabetics. However, other studies have been unable to demonstrate increased carotid thickening in children with a short and longer duration of diabetes (52, 53).
Compared with age- and sex-matched controls, Gaeta et al. (31) demonstrated both reduced brachial artery flow-mediated vasodilation and increased intima-medial thickening of the common carotid artery in children and young adults who were offspring of parents with premature myocardial infarction (0.49 vs. 0.44 mm; P = 0.004). Carotid thickening and brachial artery flow-mediated vasodilation were independently associated with parental coronary disease. Jarvisalo et al. (32) showed that healthy children with elevated levels of ultrasensitive C-reactive protein had significantly greater carotid intima-medial thickening than children with normal levels of C-reactive protein; these results were consistent with the results for brachial artery flow-mediated vasodilation discussed previously.
In healthy children and young adults, Sass et al. (44) found no relationship between blood cholesterol and carotid intima-medial thickening, although a relationship was evident with age and systolic blood pressure in the males. However, focusing specifically on hypertension, Sorof et al. (54) were unable to demonstrate a relationship between maximum common carotid artery intima-medial thickness and blood pressure in hypertensive male and female children, aged 6–18 yr, referred to a pediatric hypertension clinic because of a blood pressure greater than the 90th percentile for gender, age, and height.
The fact that specific pediatric atherogenic conditions and risk factors are common correlates of both flow-mediated vasodilation and carotid thickening lends credence to the idea that endothelial dysfunction is a facet of thickening of the intima and media. Further support is the significant negative correlation between flow-mediated vasodilation and carotid intima-medial thickening (r = –0.36; P < 0.01) demonstrated in men with and without coronary disease (55). On a multiple regression analysis that included flow-mediated vasodilation, age, body mass index, mean blood pressure, hemoglobin A1c, and blood lipids, flow-mediated vasodilation was the only independent variable related to intima-medial thickening (9). A significant relationship between brachial artery flow-mediated vasodilation and carotid intima-medial thickening has also been shown in children and young adults, aged 6–30 yr (r = –0.46; P = 0.003) (31).
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Measurement of brachial artery flow-mediated vasodilation as a potential clinical tool for pediatric risk assessment |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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There has been considerable interest in the adult literature as to whether assessment of brachial artery flow-mediated vasodilation could have clinical utility (12, 56, 57, 58). A number of studies in patients with established coronary disease have shown that flow-mediated vasodilation predicts coronary events (59, 60, 61). In a 5-yr study of patients with chest pain, brachial artery flow-mediated vasodilation predicted those patients who were at risk for short- and long-term cardiac events (62). Schroeder et al. (63) compared the predictive value of angina pectoris, brachial artery flow-mediated vasodilation, exercise electrocardiography, and myocardial perfusion imaging for coronary disease in 122 patients scheduled for coronary angiography and found flow-mediated vasodilation to be a specific and sensitive screening test.
This raises the question of whether brachial artery flow-mediated vasodilation could be a useful marker of preclinical vascular disease in the pediatric population. Clermajer et al. (35) note that the risk factors that predispose to atherosclerosis are associated with endothelial dysfunction throughout life and suggest that the procedure could have value for risk modification during the preclinical phase of vascular disease. Influencing factors, such as vessel diameter, age, and therapeutic interventions, may be of less significance in children and adolescents than they are in adults. Furthermore, ultrasound testing is reproducible, noninvasive, low risk, and nonpainful, making it an ideal procedure for the young.
The test needs to be performed in the fasting state, because endothelial function is influenced by the fat content of a meal, probably as a consequence of the formation of potentially atherogenic triglyceride-rich lipoprotein remnants (64, 65). There are also significant changes in endothelial function during the menstrual cycle. In one study, flow-mediated vasodilation increased from the menstrual to the late follicular phase, fell sharply during the early luteal phase (d 20 ± 3), and increased again in the late luteal phase (66). Others, however, found flow-mediated vasodilation to be lowest during the menstrual phase (67, 68). Measuring flow-mediated vasodilation during the late follicular phase, during the second week of the menstrual cycle, may therefore provide the most consistency.
To obtain accurate results, a period of training is required. There also needs to be consistent testing conditions in terms of the position of the occluding cuff, the timing of the occlusion, and the blood pressure used, with scrupulous attention to detail. The International Brachial Artery Reactivity Talk Force lists criteria that should be fulfilled for participation in multicenter research studies, and these criteria could equally well be applied to clinical testing centers (12). Provided these conditions are met, ultrasound laboratories should be capable of providing data that could be of considerable valuable for pediatric risk assessment.
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Assessment of carotid artery intima-medial thickening as a potential clinical tool for pediatric risk assessment |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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The strongest statement comes from the Primary Prevention Writing Group III for the AHA Prevention Conference V, which concluded that a carefully performed carotid ultrasound could add incremental information to traditional risk factor assessment in asymptomatic persons greater than 45 yr and could be considered a useful clinical tool when performed in experienced laboratories (57).
There is, in fact, no a priori reason why ultrasound evaluation of wall thickening should be of less benefit in children than adults. The value of carotid intima-medial measurements has been recognized for high risk hypercholesterolemic children (49). Tonstad et al. (47) also suggested that carotid artery intima-medial measurement could be a useful tool for risk stratification in familial hypercholesterolemic children, thereby permitting identification of children who would benefit most from intensified therapy. From their study of offspring of patients with premature myocardial infarction, Gaeta et al. (31) appreciated the potential implications for clinical practice of assessing arterial function and intima-medial thickening in adolescents and young adults, particularly those at high risk for coronary disease. Measurement of intima-medial thickening has excellent reproducibility, although in adults, measurement variability increases proportionally with the level of thickening (77). In a typical pediatric study, reading procedure reproducibility was between 2.9% and 3.0%, and the coefficient of variation for whole procedure reproducibility was 3.3% when measurements were redone 24 h apart (49).
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Conclusion |
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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Footnotes |
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Received April 15, 2003.
Accepted March 28, 2004.
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TopAbstractIntroductionEndothelial dysfunction in...Early atherogenesis in pediatric...Measurement of brachial artery...Assessment of carotid artery...ConclusionReferences |
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