In 1953, Enos and colleagues published the then extraordinary finding that coronary artery atheroma could be found in the majority of young US soldiers killed in action during the Korean war.1 This finding has since been replicated by other pathologists who not only documented a high prevalence of aortic and coronary atherosclerosis in teenagers and young adults, but also linked the amount of atherosclerosis to serum lipoprotein concentrations, cigarette smoking and obesity, among other risk factors.2
In the last few years it has become apparent that risk factors can begin in childhood and start to affect arterial structure and function even in the first decade of life. The relatively recent development of imaging techniques to interrogate arterial structure and function in children and young adults has allowed investigators to document the association between risk factors and vascular disease in childhood and, importantly, to investigate strategies for the potential reversibility of early arterial abnormalities, at which time arterial changes may be amenable to therapeutic intervention.
Studying Arterial Structure and Function in Childhood
Of all the imaging modalities currently available, the one that has proved most popular for studying arteries in children is ultrasound as it is safe, relatively inexpensive and relatively readily available. Measurement of the thickness of the intima-media complex of the carotid arteries has been practised in pre-symptomatic adults for many years, and it is now well-documented that carotid intima-media thickness (IMT) can be documented accurately and reproducibly in the majority of subjects.3 Carotid IMT is related to most of the traditional risk factors and is well-correlated with the burden of atheroma in both the carotid and coronary circulations; recent data suggest that it is also predictive of cardiovascular risk in follow-up studies.4
Although technically more difficult, measurement of the intima-media of the abdominal aorta may be a more sensitive means of detecting early atherosclerosis in children. Pathology studies indicate that the abdominal aorta is the site of the first fatty deposits in most children and young adults at risk of atherosclerosis, and this may be detectable in vivo in the first decade of life. Recent work has shown that aortic IMT is more sensitive for the detection of early arterial structural abnormalities of carotid IMT in children with hyperlipidaemia or diabetes.5
The study of vascular function also appears to be particularly important in detecting early arterial abnormalities. As the arterial endothelium plays a key role in atherogenesis, clinical evaluation of the function of the arterial endothelium is an important tool for the assessment of vascular health.
In 1992, we first described the ultrasound-based measurement of flow-mediated dilatation (FMD) in the systemic arteries, where the diameter of a blood vessel is measured before and after a condition of induced shear stress.6 In a normal vessel, shear stress prompts the arterial endothelium to release nitric oxide, a powerful antiatherogenic molecule and, thus, FMD can be observed by ultrasound as a healthy response. When endothelial function is impaired, nitric oxide release is attenuated and a lower value for FMD is observed. In expert hands, FMD can be measured accurately and reproducibly7 and has proved to be an extremely useful tool in clinical research.
Childhood Risk Factors and Early Arterial Abnormalities
Over the last decade, most of the traditional vascular risk factors have been studied in relation to abnormalities of arterial structure and function. One of the more remarkable studies in this area examines the relationship between foetal growth restriction and aortic wall thickening in the first few days of life. This study was prompted by the so-called ‘Barker hypothesis’, which proposes that poor foetal growth predisposes an individual to hypertensive and atherosclerotic disease many decades later by a variety of mechanisms. In growth-restricted neonates, the aortic IMT certainly appears thicker than in control babies, lending indirect support to the concept of low birth weight at term as a novel risk factor.8 Hyperlipidaemia and type 1 diabetes mellitus have also been linked with thickened arterial walls, particularly in the carotid as well as the aortic circulation.5 Of great recent interest is the relationship between childhood obesity and measures of early arterial structural abnormalities. In 2001, Tounian and colleagues found impaired carotid distensibility in severely obese children.9 In 2004 our group extended these findings to document arterial wall thickening in even mildly to moderately obese children in a study carried out in an Asian population.10 These observations highlight the relationship between being even modestly overweight in childhood and early arterial structural damage.
Risk Factors and Endothelial Dysfunction
In 1994, Sorensen et al. made the seminal observations that children with familial hypercholesterolaemia had impaired FMD and that the degree of impairment was proportional to their LDL level.11 Furthermore, in those with elevated LDL cholesterol there was a significant association between elevated lipoprotein (a) levels and impaired FMD. This work highlighted the fact that hyperlipidaemia could affect the arteries significantly, even in the first decade of life.
At this time, our group also published the observation that children with homozygous homocystinuria had impaired arterial endothelial function, although this was not observed in the heterozygous parents.12 This observation lends important support to the concept of very high homocysteine levels as a vascular risk factor.
Cigarette smoking is clearly of great importance as a vascular risk factor, and smoking can certainly begin in childhood. In 1993 we published our first observations concerning the effects of active cigarette smoking on endothelial function, showing a dose-related and potentially reversible effect of smoking on the endothelium in young adults.13 Several years later we extended these findings to show that passive smoking (exposure to environmental tobacco smoking in high doses) was also associated with endothelial dysfunction in teenagers,14 highlighting the importance of environmental tobacco smoke control. Subsequently, most of the traditional risk factors have been linked to arterial endothelial dysfunction by the measurement of FMD, including diabetes mellitus and a positive family history in a young relative.
The link between childhood obesity and endothelial dysfunction has also recently been documented. Although obesity has several important ‘fellow travelling’ risk factors such as dyslipidaemia and hypertension, the existence of endothelial dysfunction in association with children in the first decade of life10 certainly supports the concept that obesity itself may have important arterial effects in childhood. Finally, and interestingly, it appears that certain types of congenital heart disease may be associated with arterial functional abnormalities. Cyanosis has been associated with endothelial dysfunction,15 which may predispose such individuals to later atherosclerosis in addition to their already pre-existing serious heart problems. Furthermore, children who have had repaired coarctation of the aorta have vascular dysfunction in the pre-coarctation circulations, although not in the post-coarctation vascular beds, even after technically successful repair with no residual obstruction. This identified such children as being at risk of late cardiovascular complications, particularly systemic hypertension.
Studies of Disease Reversibility
A key question of importance regarding the relationship between risk factors and early arterial abnormalities is the question of reversibility. That is, if children have been identified with structural or functional abnormalities in relation to a risk factor, does risk factor control and/or other strategies for disease prevention elicit reversibility of the abnormalities? In general, studies of reversibility of arterial structural abnormalities have been disappointing as the changes are modest and take months to years to occur. In the adult literature, modest decreases in carotid IMT are observed after several years of aggressive lipid-lowering treatment. However, the degree of structural improvement is far lower than the degree of clinical benefit observed. These studies have suggested that improvements in vascular function rather than structure may mediate much of the observed clinical benefit of risk factor control.
In this regard, there have been several encouraging observations in children with risk factors and vascular dysfunction. Prolonged withdrawal from environmental tobacco smoke is associated with better endothelial function than continued exposure.17 L-arginine, the substrate for nitric oxide production, has been shown in one small study to improve endothelial dysfunction in children with familial hypercholesterolaemia, suggesting that strategies to improve nitric oxide bioavailability at the vessel wall may indeed have cardiovascular benefits.18 One of the most encouraging areas for reversibility of childhood arterial damage is in the control of obesity-related vascular dysfunction. We have recently shown that a programme of sustained dietary and exercise intervention can return arterial endothelial function to nearly normal in obese children, even without great weight loss.19 The optimum form of diet and exercise and the mechanism of such benefit is yet to be elucidated; however, we and others have hypothesised that regular exercise improves endothelial nitric oxide production via increasing shear stress at the arterial wall during the periods of exertion.
The extent and severity of atherosclerosis in childhood and young adult life is certainly associated with the major cardiovascular risk factors such as hyperlipidaemia, cigarette smoking and obesity. Early changes in arterial structure and function that are indicative of vascular damage can be detected in high-risk children by non-invasive methods. Such methods not only identify the relationship between risk factors and arterial changes in the first decades of life, but may also identify a subgroup of children at particularly high risk in whom intervention strategies may be cardioprotective. The assessment of such potential interventions is facilitated by the availability of non-invasive tests of arterial structure and function that permit serial study of vascular health in the young.
- Enos WF, Holmes RH, Beyer J, Coronary disease among US soldiers killed in action in Korea: preliminary report, JAMA, 1953;153:1090–93.
- McGill HC Jr, relationship of atherosclerosis in young men to serum lipoprotein cholesterol concentrations and smoking: a preliminary report from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group, JAMA, 1990;264:3018–24.
- Salonen JT, Salonen R, Ultrasound B-mode imaging in observational studies of atherosclerotic progression, Circulation, 1993;87(Suppl. 3):II56–65.
- O’Leary DH, Polak JF, Kronmal RA, et al., Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults, Cardiovascular Health Study Collaborative Research Group, N Engl J Med, 1999;340:14–22.
- Jarvisalo MJ, Jartti L, Nanto-Salonen K, et al., Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children, Circulation, 2001;104:2943–7.
- Celermajer DS, Sorensen KE, Gooch VM, et al., Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis, Lancet, 1992;340:1111–15.
- Sorensen KE, Celermajer DS, Spiegelhalter DJ, et al., Noninvasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility, Br Heart J, 1995;74:247–53.
- Skilton MR, Evans N, et al., Aortic wall thickness is increased in newborns with intrauterine growth restriction – insights into the foetal origins of atherosclerosis, Lancet, 2005;365:1484–6.
- Tounian P, Aggoun Y, Dubern B, et al., Presence of increased stiffness of the common carotid artery and endothelial dysfunction in severely obese children: a prospective study, Lancet, 2001;358:1400–1404.
- Woo KS, Chook P, Yu CW, et al., Overweight in children is associated with arterial endothelial dysfunction and intimamedia thickening, Int J Obes Metab Disord, 2004;28:852–7.
- Sorensen KE, Celermajer DS, Georgakopoulos D, et al., Impairment of endothelium-dependent dilation is an early event in children with familial hypercholesterolemia and is related to the lipoprotein(a) level, J Clin Invest, 1994;93:50–55.
- Celermajer DS, Sorensen K, Ryalls M, et al., Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents, J Am Coll Cardiol, 1993;22:854–8.
- Celermajer DS, Sorensen KE, Georgakopoulos D, et al., Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults, Circulation, 1993;88:2149–55.
- Celermajer DS, Adams MR, Clarkson P, et al., Passive smoking and impaired endothelium-dependent arterial dilatation in healthy young adults, N Engl J Med, 1996;334:150–54.
- Oechslin E, Kiowski W, Schindler R, et al., Systemic endothelial dysfunction in adults with cyanotic congenital heart disease, Circulation, 2005;112:1106–12.
- Gardiner HM, Celermajer DS, Sorensen KE, et al., Arterial reactivity is significantly impaired in normotensive young adults after successful repair of aortic coarctation in childhood, Circulation, 1994;89:1745–50.
- Raitakari OT, Adams MR, McCredie RJ, et al., Arterial endothelial dysfunction related to passive smoking is potentially reversible in healthy young adults, Ann Intern Med, 1999;130:578–81.
- Clarkson P, Adams MR, Powe AJ, et al., Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults, J Clin Invest, 1996;97:1989–94.
- Woo KS, Chook P, Yu CW, et al., Effects of diet and exercise on obesity-related vascular dysfunction in children, Circulation, 2004;109:1981–6.