EDITORIAL COMMENT
Metabolic Syndrome and Cardiovascular Abnormalities in Children*
Stephen R. Daniels, MD, PhD, FACC*
Department of Pediatrics, University of Colorado Denver, School of Medicine, Denver, Colorado
* Reprint requests and correspondence: Dr. Stephen R. Daniels, University of Colorado at Denver and Health Science Center, Department of Pediatrics, 13123 E. 16th Avenue, B065, Aurora, Colorado 80045 (Email: daniels.stephen{at}tchden.org).
Key Words: pediatric • left ventricular mass • metabolic syndrome
The clustering of risk factors for cardiovascular disease, particularly in the presence of obesity, has been recognized for some time. Reaven (1) first called this syndrome X. The common factors in this cluster are obesity, usually central obesity, increased blood pressure, lipid abnormalities, and increased fasting glucose. Since the initial description, a number of definitions have been proposed, but the one most widely used is that of the National Heart, Lung, and Blood Institute National Cholesterol Education Program in the Adult Treatment Panel III report (2). In this report, the concept of the metabolic syndrome was to characterize the risk of cardiovascular disease associated with obesity beyond that associated with elevation of low-density lipoprotein cholesterol and serve as a complement to the Framingham Risk Score for adults. The metabolic syndrome has been found to be associated with increased risk of development of cardiovascular disease and type 2 diabetes mellitus.
There have been both proponents and opponents to the metabolic syndrome concept in adults (3–6). The proponents have emphasized that the syndrome predicts increased risk of type 2 diabetes mellitus and cardiovascular disease. The opponents have indicated that although a cluster may exist from an epidemiologic standpoint, the pathophysiology underlying the metabolic syndrome remains unclear. This is one reason why it is called a syndrome. This also means there is no treatment for the metabolic syndrome other than weight loss. Opponents have also argued that there is no clear case for the metabolic syndrome cluster operating independent of its component parts. Physicians are left to treat the individual components of the syndrome. However, some components, such as hypertension, are more amenable to treatment than others, such as low high-density lipoprotein cholesterol or increased triglycerides. Still others have been concerned about the marked differences by gender or ethnic group in the prevalence of metabolic syndrome and the frequency of variables that make up the metabolic syndrome that are likely to be abnormal.
The issues regarding the metabolic syndrome in children and adolescents are even more complex. First, the link between cardiovascular disease risk factors and the development of clinical cardiovascular disease is much harder to establish because of the long timeline between things that occur in childhood and clinical outcomes that do not occur until later in adulthood. The questions remain concerning which are key variables in the metabolic syndrome for a young person. In addition, because children and adolescents are growing and developing, it is impossible to choose a single cutpoint for a risk factor variable. This problem has led to the use of percentiles, but it remains difficult to determine what percentile value to use as a cutpoint. In addition, it is not clear whether percentile values should be derived from children studied at the present time, when obesity is quite prevalent (approximately 17%) or from populations of children before the onset of the obesity epidemic. Despite these difficulties, numerous investigators have attempted to develop a definition for metabolic syndrome. As might be expected, with each different definition, there are differences in the prevalence of metabolic syndrome.
It is against this backdrop that Chinali et al. (7) performed the analyses presented in this issue of the Journal on children from the Strong Heart Study. They set out to answer 2 important questions: 1) Is the metabolic syndrome associated with cardiovascular abnormalities such as left ventricular hypertrophy and left atrial enlargement in adolescents? 2) Does the presence of the metabolic syndrome have ability to independently explain the variance of cardiovascular abnormalities after the individual components have been considered? Their analyses provide a potentially important "yes" to answer each question.
Chinali et al. (7) used 2 definitions of the metabolic syndrome. The first is the adult definition from the National Cholesterol Education Program in the Adult Treatment Panel III report (2). This approach can be seen as a very conservative one because adult values for waist circumference, blood pressure, and lipid abnormalities set a high bar even for adolescents. The second definition is one that uses percentile values by age and gender and is designed to be more applicable to use in children and adolescents (8). Indeed, Chinali et al. (7) found that the prevalence of the metabolic syndrome was greater when they used the pediatric percentile-based definition of Jolliffe and Janssen (8) compared with the adult definition. It is interesting, however, that further results regarding associations between the metabolic syndrome and cardiovascular outcome variables were generally similar and did not depend on which definition was used.
Chinali et al. (7) found that the prevalence of dilation of the left atrium and left ventricular hypertrophy were substantially greater in the adolescents with metabolic syndrome compared with those without it. These dependent cardiovascular variables are important in the study of adolescents. Left ventricular hypertrophy has been shown to be an independent risk factor for cardiovascular disease in adults (9). Left atrial enlargement has been shown to be associated with an increased risk of cerebrovascular disease in adults (10). Both left ventricular hypertrophy and left atrial enlargement have been found in children and adolescents with obesity and hypertension and are thought to represent evidence of early adverse impact of those factors on the cardiovascular system (11,12). They are useful surrogate end points at an age during which true clinical cardiovascular outcomes are uncommon. The findings of Chinali et al. (7) support the concept that the metabolic syndrome is already having an adverse effect even in adolescence. However, it is well known that obesity and blood pressure increases are associated with increased left atrial size (12) and increased left ventricular mass index (11). Chinali et al (7) also found that the presence of the metabolic syndrome as a cluster of variables was independently associated with left atrial enlargement and with left ventricular hypertrophy, even after controlling for the individual metabolic syndrome variables that had significant associations. This finding is a new and potentially important one and suggests that the metabolic syndrome as a cluster of variables may have biologic and perhaps clinical importance for cardiovascular outcomes.
There are some important caveats to consider. The Strong Heart Study cohort is valuable because it has been well-characterized. However, it is limited in that it includes only Native American subjects. The findings of Chinali et al. (7) will need to be validated in other populations. The mean age for the participants of this study was 17 years, and only 2 of the subjects were younger than 15 years of age, which means that most subjects were past the stage of sexual maturation. This fact clearly limits the ability of one to generalize the findings to younger adolescents and children. In addition, this study was a cross-sectional one, which is important because Goodman et al. (13) have reported that the diagnosis of metabolic syndrome in adolescents is relatively unstable. Further longitudinal studies will be needed in this and other cohorts to evaluate whether the relationships observed are stable over time. This will be an important aspect of determining the clinical utility of the findings reported.
Although the concept of the metabolic syndrome remains controversial, there can be no question that finding improved methods of determining which children and adolescents are at greatest risk of type 2 diabetes and cardiovascular disease would be useful. This determination would allow clinicians to implement more-aggressive lifestyle intervention in these patients and possibly initiate pharmacologic intervention when necessary. The current epidemic of obesity and the increase in prevalence of type 2 diabetes mellitus in adolescents makes the ability to identify these greater-risk children and adolescents even more important. The report by Chinali et al. (7) improves our understanding of these risk factors on the cardiovascular system and suggests that it may be useful to consider how these risk factors cluster as a metabolic syndrome in young individuals.
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Reaven GM. Role of insulin resistance in human disease (syndrome X): an expanded definition Annu Rev Med 1993;44:121-131.[CrossRef][Web of Science][Medline]2. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report Circulation 2002;106:3143-3421.[Free Full Text] 3. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute scientific statement. Circulation 2005;112:2735-2752.[Free Full Text] 4. Reaven GM. The metabolic syndrome: requiescat in pace Clin Chem 2005;51:931-938.[Abstract/Free Full Text] 5. Kahn R. The metabolic syndrome (emperor) wears no clothes Diabetes Care 2006;29:1693-1696.[Free Full Text] 6. Kahn R. Metabolic syndrome: is it a syndrome?. Does it matter?. Circulation 2007;115:1806-1811.[Free Full Text] 7. Chinali M, de Simone G, Roman MJ, et al. Cardiac markers of pre-clinical disease in adolescents with the metabolic syndrome: the Strong Heart Study J Am Coll Cardiol 2008;52:932-938.[Abstract/Free Full Text] 8. Jolliffe CJ, Janssen I. Development of age-specific adolescent metabolic syndrome criteria that are linked to the Adult Treatment Panel III and International Diabetes Federation criteria J Am Coll Cardiol 2007;49:891-898.[Abstract/Free Full Text] 9. de Simone G, Devereux RB, Daniels SR, Koren MJ, Meyer RA, Laragh JH. Effect of growth on variability of left ventricular mass: assessment of allometric signals in adults and children and of their capacity to predict cardiovascular risk J Am Coll Cardiol 1995;25:1056-1062.[Abstract] 10. Benjamin EJ, D'Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995;92:835-841.[Abstract/Free Full Text] 11. Daniels SR, Loggie JMH, Khoury P, Kimball TR. Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension Circulation 1998;97:1907-1911.[Abstract/Free Full Text] 12. Daniels SR, Witt SA, Glascock B, Khoury PR, Kimball TF. Left atrial size in children with hypertension: the influence of obesity, blood pressure and left ventricular mass J Pediatr 2002;141:186-190.[CrossRef][Web of Science][Medline] 13. Goodman E, Daniels SR, Meigs JB, Dolan LM. Instability in the diagnosis of metabolic syndrome in adolescents Circulation 2007;115:2316-2322.[Abstract/Free Full Text]
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Cardiac Markers of Pre-Clinical Disease in Adolescents With the Metabolic Syndrome: The Strong Heart Study
- Marcello Chinali, Giovanni de Simone, Mary J. Roman, Lyle G. Best, Elisa T. Lee, Marie Russell, Barbara V. Howard, and Richard B. Devereux
J. Am. Coll. Cardiol. 2008 52: 932-938.
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