BACKGROUND. Until recently, our understanding of the childhood antecedents of adult cardiovascular disease was limited mainly to autopsy studies and pathologic findings in teens and young adults who died from accidental causes. Recent advances in the understanding of atherosclerosis and new technologies allowing detection of early events have made it possible to observe anatomic and physiologic evidence of cardiovascular disease in young adults and children.
OBJECTIVES. The goal of this article was to introduce pediatricians to new methods for noninvasive measurement of cardiovascular disease and its precursors, to describe the potential application of these techniques in detecting childhood precursors of adult cardiovascular disease, and to summarize knowledge gained from this approach.
METHODS. We conducted a computerized search of peer-reviewed articles listed in PubMed and Medline from 1980 to April 2006. We reviewed 63 and 84 articles from the adult and pediatric literature, respectively.
RESULTS. Reviewing the research on childhood antecedents of adult cardiovascular disease is sobering. Vascular alterations in anatomy, physiology, mechanical properties, and proinflammatory and prothrombotic changes are present from a very early age of childhood and are associated with the risk factors common in adult cardiovascular disease. At the same time, this body of research supports the concept that the vascular impairment from childhood may improve over time with appropriate intervention.
CONCLUSIONS. The measurement tools and concepts described in this article offer diagnostic and therapeutic opportunities for collaboration between clinical pediatricians and pediatric researchers. These partnerships will enable pediatricians to contribute in an effort to reduce the burdens of cardiovascular disease to individuals, families, and society.
- cardiovascular disease
- flow-mediated dilation
- intima-medial thickness
- arterial distensibility
- childhood obesity
Adult cardiovascular disease (CVD) begins and progresses during childhood and adolescence. Pediatricians are currently witnessing a pandemic of childhood obesity, with concomitant secondary hypertension, hyperlipidemia, and the metabolic syndrome, which are linked to CVD in adulthood. The atherosclerotic process develops silently for decades during childhood and adolescence before cardiovascular complications such as myocardial infarction and stroke occur in adulthood. Until recently, our understanding of the childhood antecedents of adult CVD was limited, having been based on autopsy studies of pathologic findings in teens and young adults who died of accidental causes. However, recent advances in the conceptualization of the process of atherosclerosis and the development of new noninvasive technologies has made it possible to detect early changes (anatomic, physiologic, mechanical, proinflammatory, and prothrombotic) of CVD in adults and children.
The blood vessel wall consists of 3 concentric layers: intima, media, and adventitia. The intima, adjacent to the blood vessel lumen, is composed of a monolayer of endothelial cells with minimal underlying connective tissue. Far from being inert, endothelial cells perform crucial roles in regulating vascular tone and structure.1 These roles include providing a nonthrombotic surface, maintaining vascular tone by releasing small molecules such as nitric oxide, prostacyclin, and endothelin (which modulate vasodilation or vasoconstriction), and providing a nonadherent surface of leukocytes.2 Endothelial dysfunction was initially identified as impaired vasodilation to specific stimuli, but recent investigations have broadened the term to also include a proinflammatory and prothrombotic state. Traditional risk factors for CVD (hypercholesterolemia, hypertension, diabetes, family history of CVD, and active smoking) and more-recently identified risk factors (inflammation, infection, secondhand smoke exposure, homocystinemia, physical inactivity, and obesity) are associated with endothelial dysfunction in both adults and children (Fig 1). 1,3–10 Dysfunction of the endothelium over time leads to measurable thickening of the intima and media of the vessel wall of large- and medium-sized muscular arteries and large elastic arteries such as the aorta, carotid, and iliac arteries.11 This thickening is typically considered the earliest anatomic change of atherosclerosis.
The role of inflammation in the development of CVD has been appreciated in the past several years, and subsequent processes leading to increased cellular oxidation have been implicated.3,12 Atherosclerosis, the main cause of coronary artery disease, is now thought to be a chronic inflammatory disease in which immune mechanisms interact with metabolic risk factors to initiate, maintain, and activate arterial lesions.13 In this process, immune cells dominate early atherosclerotic lesions, and activation of inflammation can elicit acute coronary symptoms.
The goal of this article is to introduce pediatricians to the noninvasive methods for measurement of CVD and to summarize knowledge gained from the application of these techniques to pediatric populations. Understanding these advances will help pediatricians develop a greater appreciation of their role in preventing, detecting, and ameliorating conditions in childhood that lead to CVD later in life.
We conducted a computerized search of articles in PubMed and Medline from 1980 to April 2005 using the search terms “atherosclerosis,” “atherosclerosis and children,” “cardiovascular disease,” “cardiovascular disease and children,” “intima-medial thickness,” “intima-medial thickness and children,” “flow-mediated dilation,” “flow-mediated dilation and children,” “arterial distensibility,” “arterial distensibility and children,” “inflammation and atherosclerosis,” “inflammation and atherosclerosis and children,” “homocysteine,” and “homocysteine and children.” Because our focus was on pediatric populations, we selected only key review and summary articles from the adult literature and reviewed most of the articles from the pediatric literature. We reviewed 63 and 84 articles from the adult and pediatric literature, respectively.
Noninvasive Measurement of CVD in Adults
Anatomic Changes: Intima-Medial Thickness
The first morphologic changes of the arterial wall, thickening of the intima and media, can be imaged by B-mode, high-resolution ultrasound. Intima-medial thickening (IMT), which precedes clinical cardiovascular events by decades, is considered a marker of generalized atherosclerosis in adults. The arteries most commonly examined in adults are the internal and common carotid arteries in the vicinity of the carotid bulb and the carotid bulb itself.14 Carotid IMT in adults is associated with arteriographically documented lesions and subsequent myocardial infarction and stroke and also with the presence of known cardiovascular risk factors such as diabetes and obesity.14,15 The routine use of IMT as an outcome measure has been recommended for many epidemiologic and interventional trials in adults dealing with vascular disease.16 IMT measurement is currently being integrated into the clinical practice of adult medicine.
Physiologic Changes: Flow-Mediated Dilation and Endothelial Performance
Noninvasive ultrasound measurement of flow-mediated dilation (FMD) was developed in the 1990s and has been extensively used in adult cardiovascular research to assess endothelial functional integrity. This test is performed at the brachial artery and measures the vasodilator response to increased blood flow. The underlying physiologic principle is a phenomenon known as shear-stress–induced vasorelaxation. This response is known to be endothelium mediated and is governed by the ability of the endothelial monolayer to produce nitric oxide in response to shear stress, which in turn causes smooth-muscle dilation.17,18 Studies on adults have shown a close correlation between the endothelial function peripherally (at the brachial artery) and that of the coronary circulation.19 In adults, endothelial dysfunction measured by FMD has been shown to be an independent predictor of CVD events in both the short- and long-term.20
Mechanical Changes: Arterial Distensibility
Arterial distensibility or, conversely, arterial stiffness is a measure of vascular elastic behavior.21 In addition to reflecting the structural arrangement of the artery, endothelial function is also implicated in arterial distensibility by directly affecting the vascular tone through the nitric-oxide pathway.21 Distensibility or stiffness can be assessed noninvasively using B- or M-mode imaging by measuring change in lumen diameter from systole to diastole, coupled with the measure of the local pulse pressure.22 An alternative measure, pulse-wave velocity, has also been used to assess arterial distensibility. The propagation of the pulse wave along the arteries is related to the elastic properties of the arterial wall.21 The reproducibility of these measurements is adequate for application in epidemiologic studies.22
The most prominent factor in increasing arterial stiffness is aging, which equally affects males and females.21 Pathologic reductions of arterial distensibility lead to increased left ventricular afterload, decreased coronary artery perfusion, increased systolic blood pressure, and trauma to the vessel wall, which, in turn, leads to atherosclerotic vascular changes.23 Active smoking, hyperlipidemia, hypertension, congestive heart failure, and diabetes (types 1 and 2) are all associated with decreased arterial distensibility.23
The body of research on arterial stiffness as a risk factor for CVD is not as extensive as that on IMT or FMD. Despite substantial cross-sectional evidence, longitudinal data on the relationship of arterial stiffness with future CVD is limited to patients with hypertension, patients with end-stage renal disease, the elderly, and renal transplant recipients.
Inflammatory Changes: C-Reactive Protein
Low-grade chronic inflammation, as indicated by C-reactive protein (CRP), prospectively defines the risk of atherosclerotic complications, adding prognostic information to the traditional risk factors. In the mid-1990s, immunoassays for CRP, with greater sensitivity than those used previously, revealed that increased CRP values, even those within the range previously considered normal, strongly predicted future coronary events.24 Recent studies have also suggested that CRP is not only a predictor but also a mediator of endothelial injury. CRP, at concentrations known to predict vascular disease, has a direct effect in stimulating diverse early atherosclerotic processes.25,26 Intensive statin therapy has been shown to have a beneficial effect on the rate of progression of coronary artery disease because of an independent effect of lowering the CRP level in addition to the classic lowering of low-density lipoprotein (LDL) cholesterol.5 Measurement of CRP is currently emerging as a clinical tool in adult medicine for risk-factor assessment and as a marker of clinical improvement for patients on statin therapy.
Inflammatory and Prothrombotic Changes: Homocysteine
The observed high frequency of premature occlusive vascular disease among young people with homocystinuria, caused by a rare hereditary defect in homocysteine metabolism, prompted the hypothesis that moderately elevated homocysteine levels may be a risk factor for CVD and stroke in the general population.27 Elevated plasma total homocysteine may be a result of genetic defects, vitamin deficiencies, or renal impairment.28 The pathophysiology of the atherogenic propensity of homocysteine is hypothesized to be based on direct toxic endothelial cell damage generating potent reactive oxygen species, which can induce oxidative damage to endothelial cells, in addition to directly decreasing endothelial production of nitric oxide. This leads to impaired endothelial-dependent vascular reactivity, resulting in platelet activation and thrombus formation.10,29,30
Vitamins B6 and B12 and folate are involved in homocysteine metabolism. Because an elevated homocysteine level is treatable (hypothetically) with these substances, there has been considerable interest in determining if, indeed, elevated homocysteine is an independent risk factor for CVD and if dietary changes could produce significant clinical effects in decreasing both homocysteine levels and the rate of CVD.31 Currently, the importance of the contribution of a moderately elevated homocysteine level to CVD in the general population is uncertain. Multiple prospective studies suggest an association of homocysteine with CVD, but the relationship is weaker than previously believed.29 The American Heart Association,32 at present, does not recommend generalized population screening for homocysteine levels but does advocate targeted homocysteine screening for adults at high risk. Recent reports indicate that supplementation with B vitamins does not lower the risk of recurrent CVD33 or reduce the risk of major cardiovascular events in patients with preexisting vascular disease.34
Use of New Techniques: Childhood Antecedents of Adult CVD
Information on the prevalence and extent of atherosclerotic changes in teens and young adults in the United States comes from several large studies, both prospective and cross-sectional. The Muscatine and Bogalusa studies are relevant to this discussion because large cohorts of subjects recruited and followed in these 2 studies became available as young adults for noninvasive imaging studies. Researchers are now able to relate risk factors measured during childhood to preclinical vascular changes in young adults. The relationship between childhood risk factors and adult vascular changes is complicated by the fact that some risk factors (eg, obesity) tend to track from childhood to adulthood. Relationships between childhood risk factors and vascular changes in adulthood may be a result of the persistence of the particular risk factor into adulthood. Complex statistical analyses are required to determine the contribution of risk factors present during childhood to adult vascular changes. The large sample sizes involved in these cohort studies makes such analyses possible.
The Muscatine study
Between 1971 and 1981, >14000 schoolchildren (aged 8–18 years, predominantly white) in Muscatine, Iowa, underwent biennial examinations that assessed their height, weight, blood pressure, triceps skinfold thickness, and total cholesterol and triglyceride levels. Every 10 years, a subset of the original sample underwent repeat testing, which included more advanced noninvasive assessments that were not available at the original recruitment time.35 In the late 1990s, a subset of ∼750 of the original participants (with equal proportions of men and women) underwent repeat testing, including measurement of carotid intima-medial thickness. This assessment revealed that total cholesterol level, measured during childhood, was a significant independent risk factor for carotid thickening during adulthood for both men and women; elevated BMI during childhood was also a significant independent risk factor for women only.35
The Bogalusa Heart Study
This project is one of the longest and most detailed prospective studies of children with a focus on the early natural history of coronary artery disease and essential hypertension. The study began in 1973 in Bogalusa, Louisiana, and is still ongoing. The original population consisted of both white (65%) and black (35%) school-aged children and young adults up to 35 years of age. More than 16000 individuals have participated, and >9500 have had multiple measurements of cardiovascular risk factors, including BMI, triceps skinfold thickness, lipid profile, and smoking status. Observations from the Bogalusa Heart Study have shown that major etiologies of adult CVD, atherosclerosis, coronary artery disease, and essential hypertension begin in childhood, with documented anatomic changes as early as 5 to 8 years of age.36
A recent examination of 500 young adults from the Bogalusa Heart Study revealed that childhood risk factors were associated with adult carotid IMT. An elevated LDL-cholesterol level and elevated BMI during childhood were found to be independent risk factors for increased carotid thickening in young adulthood.37 Another analysis using the Bogalusa data set revealed that adult obesity modified the association between childhood obesity and IMT; arterial thickening was seen only among overweight children who became obese adults. IMT was not present among nonobese adults who had been overweight children or among obese adults who had been nonoverweight children. These results emphasize the adverse, cumulative effects of childhood-onset obesity that persist into adulthood.38
In addition to using the newer noninvasive measurements in adult cohorts who have been followed since childhood, researchers have investigated vascular anatomy, physiology, and inflammation in both clinical and population-based samples of children.
Application of New Measurement Modalities to Pediatric Populations
Anatomic Changes: IMT
Investigators have used IMT measurements to study children at high risk for development of atherogenesis later in life. Children with familial hypercholesterolemia were found to have higher IMT than age-matched healthy children.39 IMT was associated directly with elevated total and LDL cholesterol and triglyceride levels and inversely correlated with high-density lipoprotein cholesterol levels in the affected children.6,39 Children with hypertension have higher carotid IMT than normotensive children; these differences remained significant even after controlling for gender, race, age, and BMI.40 Investigations of IMT in children with type 1 diabetes have shown conflicting results, with some researchers reporting no effect on IMT and others reporting IMT related to the duration of diabetes.6,41–43
Findings with clinical applicability to pediatricians include:
Overweight and obesity are related to vascular thickening. Obesity has been shown to be highly associated with IMT in several studies.7,44,45 Additional research has demonstrated that overweight alone, without extreme obesity, was independently associated with arterial thickening in a population in whom excess weight was not confounded by coexisting risk factors such as hypertension and hyperlipidemia. A group of 36 overweight but nonobese children was found to have significant carotid thickening compared with age-matched nonoverweight controls. The children were between the ages of 7 and 12 years and were matched for age, gender, blood pressure, and cholesterol and glucose levels.44
Carotid IMT is reversible. Investigators measured IMT in overweight and obese children who were enrolled in a clinical trial of lifestyle modification and assigned to 1 of 3 groups: dietary modification alone for 1 year, dietary modification for 1 year plus exercise for 6 weeks, and dietary modification plus exercise sustained for 1 year. There was no change detected in IMT after 6 weeks in any of the 3 groups. However, at 1 year, children in the diet-only group and in the diet-plus-sustained-exercise group showed significant regression in carotid IMT despite the fact that there was no significant change in BMI in any of the groups.45 The implication of this research is that, over time, anatomic changes consistent with early atherosclerosis in children are modifiable by sustained diet or sustained diet and exercise.
Physiologic Changes: FMD
FMD has been used in pediatric research since the 1990s. To date, at least 19 studies using this technique in children have been published. Investigators have assessed FMD in special populations of children such as those with type 1 diabetes, familial dyslipidemias, hypertension, Kawasaki’s disease, and severe obesity.9,11,46–50 This body of research has confirmed that endothelial dysfunction is found in the childhood conditions that are known to predispose to early atherogenesis.
Recently, investigations of endothelial function in children have revealed findings with clinical applicability for pediatric populations:
Obesity and overweight are related to FMD impairment and are reversible with exercise. Obese and overweight children have been shown to have FMD impairment that is reversible with exercise even in the absence of weight loss. In the past 2 years, 3 research groups have reported on the effect of exercise training on FMD in overweight and obese children.44,45,51,52 In all of the studies, FMD impairment was noted in the overweight or obese children that subsequently improved after exercise training even in the absence of weight loss. FMD was an additional outcome measurement in the clinical trial of lifestyle modification described above. Investigators randomly assigned overweight children to 1 of 3 interventions: dietary modification alone for 1 year, dietary modification for 1 year plus exercise for 6 weeks, and dietary modification plus exercise sustained for 1 year. Children in the diet-only and diet-plus-exercise groups both showed FMD improvement in the short-term (6 weeks), although there was no significant change in BMI in either group. The improvement was significantly greater in the diet-plus-exercise group. Children who continued to exercise showed sustained improvement in FMD after 1 year, whereas those in the diet-only group showed no sustained improvement.45 These findings imply that, for children, sustained exercise even in the absence of change in BMI in children has a protective effect on their vascular physiology.
Regular physical activity in healthy children is associated with greater endothelial function. Investigators measured habitual physical activity levels using a well-validated technique in a group of healthy children (aged 5–10 years) in Australia. The level of physical activity emerged as a strong and consistent predictor of FMD.8 This research suggests that physical activity at a very young age may influence arterial health.
Mechanical Changes: Arterial Distensibility
Arterial distensibility during childhood can be measured by assessing changes to vessel diameter during the cardiac cycle or by pulse-wave velocity53 and can be determined at either the carotid or brachial artery.54,55 Arterial distensibility decreases from early childhood to adolescence.56–58 Research in pediatric populations has shown that early mechanical changes in the arterial wall may precede the appearance of arterial structural changes. Boys aged 10 to 19 years who have heterozygous familial hypercholesterolemia had decreased brachial artery distensibility independent of their LDL or total cholesterol levels.54 None of the children had echographic evidence of atherosclerotic lesions, and no IMT was found. The decreased distensibility may be a result of the effects of endothelial dysfunction, via the nitric-oxide pathway, rather than the effect of actual physical changes in the arterial wall.
Arterial distensibility has been studied in a large population-based sample of almost 500 children aged 9 to 11 years.55 Total and LDL-cholesterol levels were inversely related to arterial distensibility in this sample. This finding is intriguing, because the children were from a nonclinical population, with total and LDL-cholesterol levels in the range of the general population.
In addition to these investigations, researchers have focused on arterial distensibility and obesity and found that arterial distensibility inversely correlates with BMI. A relationship between obesity in childhood and increased arterial stiffness (as defined by decreased arterial distensibility) has been described.47,59,60 This association has been noted among severely obese children59,61,62 and among those with the metabolic syndrome.62 The relationship remains even among “normal” children from nonclinical samples. Whincup et al59 described a consistent independent inverse relationship between all measures of adiposity and arterial distensibility among nearly 500 children aged 13 to 15 years. It is interesting to note that the research group had studied the same population of children 2 years earlier and did not find the association between obesity and arterial stiffness. This finding of a particular timing for the adverse effects of obesity on arterial distensibility is intriguing and warrants further investigation.
Inflammatory Changes: CRP
The CRP level in children has been shown to correlate most consistently with BMI.63–65 Children and adolescents with the metabolic syndrome are ∼4 times more likely than those without the syndrome to show evidence of low-grade inflammation as measured by the CRP level.66 CRP levels seem to increase with the degree of obesity65 along with other markers of inflammation. There is conflicting evidence regarding the presence of a direct relationship between elevated CRP and insulin resistance in children.51,65 Key findings from research on CRP in children include:
Low-level inflammation is present in very young children and is related to BMI. Analysis of the National Health and Nutrition Examination Survey from 1999–2000 showed that BMI had a strong independent association with CRP level for children in all age groups from 3 to 17 years. This relationship was noted even in the subgroup of very young children between the ages of 3 and 7 years.66
Evidence of inflammation is associated with endothelial dysfunction. Recent research has demonstrated that the relationship between inflammation and endothelial dysfunction emerges even during childhood. An elevated CRP level even among healthy children has been shown to be associated with a reduction in FMD.67 Recently, investigators have shown impaired FMD in children with acute infection; children recovering from infections also showed impairment but to a lesser degree.68 This research on healthy children supports a potential role for previously unsuspected extrinsic inflammation in the pathogenesis of CVD.
Inflammatory and Prothrombotic Changes: Homocysteine
Homocysteine levels in children are substantially lower than those in adults, and increase with age.69 Levels are higher in boys than in girls after age 10.70 Homocysteine levels in children seem to be inversely related to serum folate levels.69,71,72 The role of homocysteine in the general pediatric population (without homocystinuria) as a childhood antecedent of adult CVD is unclear. No relationships have been reported between lipid profile, blood pressure, and BMI and homocysteine levels in children.69–71 However, one research group reported that homocysteine levels in children aged 10 to 19 were independently correlated to carotid IMT in children.72
Homocysteine has been investigated as a serum marker of risk in children from families with a history of premature CVD, with conflicting findings.69,71 Tonstad et al investigated ∼700 children aged 8 to 12 years and reported that homocysteine was higher among children whose father, grandfather, or uncle died at ≤55 of age as a result of myocardial infarction or sudden cardiac arrest than control children after adjusting for socioeconomic status. Analysis of a subsample of children involved in the Bogalusa study produced similar findings.71 Children with a positive parental history of coronary artery disease had significantly greater age-adjusted homocysteine levels than those without a positive history; this relationship was observed in each race and gender group. However, analysis of another large data set from the CATCH (Children and Adolescent Trial for Cardiovascular Health) cohort did not support these findings.67 Investigators found no relationship to the child’s homocysteine level and family history of stroke or myocardial infarction or premature CVD as defined by these events in a relative younger than 60 years. It is possible that this definition of family history of CVD was not sensitive enough to capture the at-risk children.
IMPLICATIONS FOR PEDIATRICIANS
The measurement tools described here offer diagnostic and therapeutic opportunities for collaboration between clinical pediatricians and pediatric researchers. The availability of adequate noninvasive measures of anatomic, functional, mechanical, proinflammatory, and prothrombotic vascular changes during childhood will greatly enhance our insight into causes, development, and pathophysiologic mechanisms of CVD. In addition, these tools will be essential in assessing treatment protocols for reversing or ameliorating these changes before adulthood. For example, assessment of arterial thickness, distensibility, endothelial function, and the proinflammatory and prothrombotic state, alone or in combination, may offer a method for identifying children who are the highest risk for CVD in adulthood and to form specific treatment strategies. Children with hypercholesterolemia who have impaired FMD may benefit from pharmacologic therapy (statins) more than those without endothelial dysfunction. Obese children with abnormally thickened arteries may be targeted for more intensive exercise and dietary modifications. Conversely, children with a particular risk factor who have normal endothelial function, normal CRP levels, and normal FMD may be followed sequentially with less-aggressive intervention.
Once identified, there is a role for repeat testing in measuring the result of a particular intervention. The research reviewed here has shown that obese children showed improvement of endothelial function in the short-term and reversed vascular change in the long-term via long-term sustained lifestyle modifications, although there was no actual reduction in their BMI. Sequential measurements of FMD and IMT for children who are undergoing intensive lifestyle modifications will provide positive feedback for those who are actually making the desired changes, even if BMI reduction is not attained.
Reviewing the research on childhood antecedents of adult CVD is sobering. Vascular alterations in anatomy, physiology, mechanical properties, and proinflammatory and prothrombotic changes are present from a very early age and are associated with the risk factors common in adult CVD: overweight and obesity, inflammation, hypertension, and abnormal lipid profiles. Many of these risk factors are known to track into adulthood. For at least 1 of the risk factors (obesity) there is evidence of a cumulative negative impact on adult cardiovascular health from its presence during both childhood and adulthood. At the same time, this body of research supports the concept that the vascular changes in childhood may improve over time with appropriate intervention. Advances in this field will be made when clinical pediatricians collaborate with pediatric researchers. These partnerships will enable pediatricians to contribute in an effort to reduce the burdens of CVD to individuals, families, and society.
This work was supported in part by National Institute of Child Health and Human Development grant 1R21 HD 50944-01, Health Resources and Services Administration grant 5D52 HP007-05-00, the Flight Attendant Medical Research Institute, and the American Diabetes Association.
- Accepted May 15, 2006.
- Address correspondence to Judith A. Groner, MD, Department of Pediatrics, Ohio State University, Center for Cardiovascular Medicine, Columbus Children’s Hospital Research Institute, Columbus Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
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- Copyright © 2006 by the American Academy of Pediatrics