See Related Articles pp. 346 and 352The pediatric origin of atherosclerosis is now well established. In an effort to ward off cardiovascular disease (CVD), the assessment and management of what could be termed traditional risk factors, such as lipids and lipoproteins [1National Cholesterol Education Program (NCEP): Highlights of the report of the expert panel on blood cholesterol levels in children and adolescents.Pediatrics. 1992; 89: 495-501PubMed Google Scholar, 2Daniels S.R. Greer F.R. Lipid screening and cardiovascular health in childhood.Pediatrics. 2008; 122: 198-208Crossref PubMed Scopus (957) Google Scholar], blood pressure [[3]The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114: 555-576Crossref PubMed Scopus (5755) Google Scholar], adiposity [4Daniels S.R. Arnett D.K. Eckel R.H. et al.Overweight in children and adolescents: Pathophysiology, consequences, prevention, and treatment.Circulation. 2005; 111: 1999-2012Crossref PubMed Scopus (1114) Google Scholar, 5Williams C.L. Hayman L.L. Daniels S.R. et al.Cardiovascular health in childhood: A statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association.Circulation. 2002; 106: 143-160Crossref PubMed Scopus (592) Google Scholar], and smoking [[6]Gidding S. Morgan W. Perry C. et al.Active and passive tobacco exposure: A serious pediatric health problem. A statement from the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, American Heart Association.Circulation. 1994; 90: 2581-2590Crossref PubMed Scopus (62) Google Scholar], in the pediatric setting have been endorsed in guidelines and consensus statements issued, in some instances, for over 15 years. The rationale for attention on these risk factors is the substantive evidence that accumulated first in adult populations of their association with clinical outcomes, followed by the accruement of evidence in the pediatric setting demonstrating (1) occurrence of risk factors in children that were predictive of CVD in adults [7Lauer R.M. Connor W.E. Leaverton P.E. et al.Coronary heart disease risk factors in school children: The Muscatine study.J Pediatr. 1975; 86: 697-706Abstract Full Text PDF PubMed Scopus (332) Google Scholar, 8Webber L.S. Voors A.W. Srinivasan S.R. et al.Occurrence in children of multiple risk factors for coronary artery disease: The Bogalusa heart study.Prev Med. 1979; 8: 407-418Crossref PubMed Scopus (95) Google Scholar], (2) cross-sectional association with other known CVD risk factors [9Aristimuno G.G. Foster T.A. Voors A.W. et al.Influence of persistent obesity in children on cardiovascular risk factors: The Bogalusa heart study.Circulation. 1984; 69: 895-904Crossref PubMed Scopus (108) Google Scholar, 10Schieken R.M. Clarke W.R. Lauer R.M. Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine study.Hypertension. 1981; 3: 669-675Crossref PubMed Scopus (120) Google Scholar, 11Burke G.L. Arcilla R.A. Culpepper W.S. et al.Blood pressure and echocardiographic measures in children: The Bogalusa heart study.Circulation. 1987; 75: 106-114Crossref PubMed Scopus (135) Google Scholar], (3) adults with elevated levels or high-risk status tended to have elevated levels or high-risk status during childhood as well (referred to as tracking) [12Porkka K.V. Viikari J.S. Taimela S. et al.Tracking and predictiveness of serum lipid and lipoprotein measurements in childhood: A 12-year follow-up. The cardiovascular risk in young Finns study.Am J Epidemiol. 1994; 140: 1096-1110PubMed Google Scholar, 13Chen X. Wang Y. Tracking of blood pressure from childhood to adulthood: A systematic review and meta-regression analysis.Circulation. 2008; 117: 3171-3180Crossref PubMed Scopus (1034) Google Scholar, 14Singh A.S. Mulder C. Twisk J.W. et al.Tracking of childhood overweight into adulthood: A systematic review of the literature.Obes Rev. 2008; 9: 474-488Crossref PubMed Scopus (1690) Google Scholar, 15Kelder S.H. Perry C.L. Klepp K.I. et al.Longitudinal tracking of adolescent smoking, physical activity, and food choice behaviors.Am J Public Health. 1994; 84: 1121-1126Crossref PubMed Scopus (1025) Google Scholar], (4) the presence of these risk factors was associated with the presence and extent of atherosclerosis [16Berenson G.S. Srinivasan S.R. Bao W. et al.Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa heart study.N Engl J Med. 1998; 338: 1650-1656Crossref PubMed Scopus (3076) Google Scholar, 17McGill Jr., H.C. McMahan C.A. Zieske A.W. et al.Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth.Circulation. 2000; 102: 374-379Crossref PubMed Scopus (273) Google Scholar], and (5) risk factor levels measured in childhood predicted preclinical atherosclerosis in adulthood [18Davis P.H. Dawson J.D. Riley W.A. et al.Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine study.Circulation. 2001; 104: 2815-2819Crossref PubMed Scopus (745) Google Scholar, 19Li S. Chen W. Srinivasan S.R. et al.Childhood cardiovascular risk factors and carotid vascular changes in adulthood: The Bogalusa heart study.JAMA. 2003; 290: 2271-2276Crossref PubMed Scopus (812) Google Scholar, 20Raitakari O.T. Juonala M. Kähönen M. et al.Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: The cardiovascular risk in young Finns study.JAMA. 2003; 290: 2277-2283Crossref PubMed Scopus (1400) Google Scholar, 21Magnussen C.G. Venn A. Thomson R. et al.The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study.J Am Coll Cardiol. 2009; 53: 860-869Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar].In more recent times, a critical mass of evidence has emerged on the importance of inflammatory processes at all stages in the development of atherosclerosis and, consequently CVD [[22]Libby P. Ridker P.M. Maseri A. Inflammation and atherosclerosis.Circulation. 2002; 105: 1135-1143Crossref PubMed Scopus (5844) Google Scholar]. This has led to efforts to identify novel biomarkers of inflammation that may enhance CVD risk assessment. Of the candidate biomarkers identified to date, high-sensitivity C-reactive protein (hsCRP), has accumulated sufficient evidence to support its utility in clinical practice as an adjunct to traditional risk factors for prediction of CVD in adults [23Corson M.A. Jones P.H. Davidson M.H. Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker.Am J Cardiol. 2008; 101: 41F-50FAbstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 24Ridker P.M. High-sensitivity C-reactive protein and cardiovascular risk: Rationale for screening and primary prevention.Am J Cardiol. 2003; 92: 17K-22KAbstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Although hsCRP has received the most attention, other markers of inflammation, including soluble intercellular adhesion molecule (sICAM) and soluble vascular cell adhesion molecule (sVCAM), have also garnered interest in the adult literature [[25]Ridker P.M. Brown N.J. Vaughan D.E. et al.Established and emerging plasma biomarkers in the prediction of first atherothrombotic events.Circulation. 2004; 109: IV6-IV19Crossref PubMed Google Scholar]. As was the case decades past, when data on the importance of what is now considered traditional CVD risk factors were first emerging, there is limited available evidence for the utility of identifying these and other biomarkers in the pediatric setting.In this issue of the Journal of Adolescent Health, Wijnstok et al [[26]Wijnstok N.J. Twisk J.W.R. Young I.S. et al.Inflammation markers are associated with cardiovascular disease risk in adolescents: The Young Hearts Project 2000.J Adolesc Health. 2010; 47: 346-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] report on cross-sectional data among 2,000 adolescents aged between 12 and 15 years from the population-based Young Hearts Project that showcases relations between traditional CVD risk factors and a clustered CVD risk score, with hsCRP, sICAM, and sVCAM. hsCRP and sICAM were inversely related to LDL/HDL cholesterol ratio, and directly associated with triglycerides, low cardiorespiratory fitness (CRF), sum of skinfolds, and clustered CVD risk, whereas sVCAM was inversely associated with both sum of skinfolds and clustered CVD risk. On the basis of the available data published on adults, results for hsCRP and sICAM were in the expected direction, but those for sVCAM were not.The results by Wijnstok et al, although cross-sectional, outline one important caveat in the potential application of biomarkers found to be predictive of adult CVD to the pediatric setting. Many of these biomarkers, including sVCAM, are upregulated at different phases of the atherosclerotic process, particularly in the advanced or vulnerable lesion that typically does not present before middle-age [[27]Mulvihill N.T. Foley J.B. Crean P. et al.Prediction of cardiovascular risk using soluble cell adhesion molecules.Eur Heart J. 2002; 23: 1569-1574Crossref PubMed Scopus (74) Google Scholar]. Moreover, elevated levels of many of these biomarkers can be because of other systemic processes not related to atherosclerosis. That is, elevated biomarker levels in youth, when vascular damage is low, may not reflect future risk for CVD. Although the cross-sectional evidence for the benefit of identifying youth with high hsCRP is beginning to resemble the evidence for traditional risk factors [26Wijnstok N.J. Twisk J.W.R. Young I.S. et al.Inflammation markers are associated with cardiovascular disease risk in adolescents: The Young Hearts Project 2000.J Adolesc Health. 2010; 47: 346-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 28Jarvisalo M.J. Harmoinen A. Hakanen M. et al.Elevated serum C-reactive protein levels and early arterial changes in healthy children.Arterioscler Thromb Vasc Biol. 2002; 22: 1323-1328Crossref PubMed Scopus (283) Google Scholar, 29Zieske A.W. Tracy R.P. McMahan C.A. et al.Elevated serum C-reactive protein levels and advanced atherosclerosis in youth.Arterioscler Thromb Vasc Biol. 2005; 25: 1237-1243Crossref PubMed Scopus (64) Google Scholar], the available longitudinal evidence is not convincing [30Juonala M. Viikari J.S. Rönnemaa T. et al.Childhood C-reactive protein in predicting CRP and carotid intima-media thickness in adulthood: The Cardiovascular Risk in Young Finns Study.Arterioscler Thromb Vasc Biol. 2006; 26: 1883-1888Crossref PubMed Scopus (136) Google Scholar, 31Kivimäki M. Lawlor D.A. Eklund C. et al.Mendelian randomization suggests no causal association between C-reactive protein and carotid intima-media thickness in the young Finns study.Arterioscler Thromb Vasc Biol. 2007; 27: 978-979Crossref PubMed Scopus (36) Google Scholar]. In this context, it is apparent that not all biomarkers identified in adults that refine CVD risk prediction will be useful in the pediatric setting. Critical to the debate concerning pediatric screening for potential cardiovascular biomarkers will be at what stage in the life-course that knowledge of elevated levels reflects underlying pathology, and whether or not the addition of biomarkers improves adult CVD risk prediction over traditional risk factors.Although the evidence for screening of inflammatory biomarkers in the pediatric setting is in its infancy, the evidence for another risk factor, low CRF, is much more compelling. There is good epidemiological and clinical evidence in adults that suggests that low CRF is a major risk factor for atherosclerosis, with the increased risk similar to that observed for conventional CVD risk factors of hypercholesterolemia, hypertension, and blood pressure [[32]Pate R.R. Pratt M. Blair S.N. et al.Physical activity and public health: A recommendation from the Centers for Disease control and prevention and the American College of Sports Medicine.JAMA. 1995; 273: 402-407Crossref PubMed Scopus (5881) Google Scholar]. Although the available published data in the pediatric setting are not as substantive, the evidence does suggest that low CRF in youth is associated with (1) other CVD risk factors [[33]Dwyer T. Gibbons L.E. The Australian Schools Health and Fitness Survey. Physical fitness related to blood pressure but not lipoproteins.Circulation. 1994; 89: 1539-1544Crossref PubMed Scopus (81) Google Scholar], (2) concurrent and adult markers of atherosclerosis [34Boreham C.A. Ferreira I. Twisk J.W. et al.Cardiorespiratory fitness, physical activity, and arterial stiffness: The Northern Ireland Young Hearts Project.Hypertension. 2004; 44: 721-726Crossref PubMed Scopus (139) Google Scholar, 35Ferreira I. Twisk J.W. Van Mechelen W. et al.Current and adolescent levels of cardiopulmonary fitness are related to large artery properties at age 36: The Amsterdam Growth and Health Longitudinal Study.Eur J Clin Invest. 2002; 32: 723-731Crossref PubMed Scopus (60) Google Scholar, 36Ferreira I. Twisk J.W. Stehouwer C.D. et al.Longitudinal changes in VO2max: Associations with carotid IMT and arterial stiffness.Med Sci Sports Exerc. 2003; 35: 1670-1678Crossref PubMed Scopus (65) Google Scholar], and (3) improved markers of atherosclerosis in obese youth after aerobic exercise interventions that increased CRF [37Woo K.S. Chook P. Yu C.W. et al.Effects of diet and exercise on obesity-related vascular dysfunction in children.Circulation. 2004; 109: 1981-1986Crossref PubMed Scopus (367) Google Scholar, 38Watts K. Beye P. Siafarikas A. et al.Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents.J Am Coll Cardiol. 2004; 43: 1823-1827Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 39Watts K. Beye P. Siafarikas A. et al.Effects of exercise training on vascular function in obese children.J Pediatr. 2004; 144: 620-625Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 40Meyer A.A. Kundt G. Lenschow U. et al.Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program.J Am Coll Cardiol. 2006; 48: 1865-1870Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 41Kelly A.S. Wetzsteon R.J. Kaiser D.R. et al.Inflammation, insulin, and endothelial function in overweight children and adolescents: The role of exercise.J Pediatr. 2004; 145: 731-736Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar].In this issue of the Journal, Lobelo et al [[42]Lobelo F. Pate R.R. Dowda M. et al.Cardiorespiratory fitness and clustered cardiovascular risk in U.S. adolescents.J Adolesc Health. 2010; 47: 352-359Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] provide more evidence regarding the cross-sectional relation between CRF and CVD risk among 1,200 youth aged 12–19 years who participated in the 1999–2002 National Health and Nutrition Examination Surveys (NHANES) and had CRF estimated from a sub-maximal treadmill exercise test. These population-based data showed that clustered CVD risk decreased as CRF increased, with the most substantial decrease in clustered risk observed from the first to the second quintile of CRF. Because the prevalence of overweight and obesity in their cohort was 33%, the authors were able to assess whether the effect of CRF differed, depending on weight for height status. Such analyses are important to tease-out the independent contribution of CRF and fatness to clustered CVD risk, and to provide insight as to the potential clinical and public health benefit of screening for both excess adiposity and low CRF. Among normal-weight boys and girls, and overweight or obese boys, clustered CVD risk decreased across quintiles of increasing CRF, whereas CRF was not associated with clustered CVD risk in overweight or obese girls. Thus, the results of Lobelo et al provide valuable data in the context of guidelines for screening to identify youth at risk of future CVD as their data highlight the importance of identifying not only youth with excess adiposity, but also those with low CRF.Although there are certainly evidence gaps in the association between youth CRF and adult CVD (such as the association between youth CRF and adult clinical outcomes as well as randomized, controlled prospective trials that evaluate the effects of differing combinations of dose, intensity, and frequency of CRF-enhancing exercise on specific CVD-related health outcomes), similar gaps existed when lipid screening guidelines for the pediatric setting were first implemented in the early 1990s. The consistency of results in youth and adults for CRF is important in this respect, and from a primary prevention standpoint, they suggest the existence of a tight biological relationship between low CRF and advanced CVD risk that could be identified and intervened against, early in life. CRF standards (as part of FITNESSGRAM) exist for youth [[43]Cureton K.J. Warren G.L. Criterion-referenced standards for youth health-related fitness tests: A tutorial.Res Q Exerc Sport. 1990; 61: 7-19Crossref PubMed Scopus (100) Google Scholar], that were theoretically linked to adult all-cause and CVD mortality and have been validated, in cross-sectional analyses, with clustered CVD risk in contemporary youth [[44]Lobelo F. Pate R.R. Dowda M. et al.Validity of cardiorespiratory fitness criterion-referenced standards for adolescents.Med Sci Sports Exerc. 2009; 41: 1222-1229Crossref PubMed Scopus (92) Google Scholar]. These standards are already widely implemented in schools across the United States but these data are not used for public health and clinical purposes for identifying the youth who are at risk.Important challenges for routine CRF screening in youth exist. The level of CRF attained is dependent on mode of the exercise test (running, walking, cycling, step-up), protocol (duration, indirect vs. direct gas analysis, sub-maximal vs. maximal), and setting (presence/absence of standardized, controlled conditions), which might result in misclassification if consistency in these areas is not enforced. This is important because in large-scale population-wide screening, validated field tests are the most practical and cost-efficient, whereas treadmill or bicycle ergometer tests may be more practical in the clinic setting. Moreover, extrapolation of submaximal exercise test data to attain the theoretical maximal level may also result in misclassification, whereas field-tests may be particularly affected by low participant motivation that would lead to an increased number of false positives for low CRF in youth. These and other challenges will have to be addressed in any guidelines issued for youth screening for low CRF. But in the interim, attention needs to be focused not only on strategies to increase physical activity and exercise in youth as a means for reducing overweight and obesity, but also to increase CRF in its own right.As with progress toward guidelines for screening and treatment of any risk variable in the pediatric setting considered to be important in the context of later CVD; it is always a long journey. But when the inevitable question comes, “Are we there yet?” the answer is a definite “No” for inflammatory biomarkers, but in the case of CRF, the answer is “No, but we’re nearly there.” See Related Articles pp. 346 and 352 See Related Articles pp. 346 and 352 See Related Articles pp. 346 and 352 The pediatric origin of atherosclerosis is now well established. In an effort to ward off cardiovascular disease (CVD), the assessment and management of what could be termed traditional risk factors, such as lipids and lipoproteins [1National Cholesterol Education Program (NCEP): Highlights of the report of the expert panel on blood cholesterol levels in children and adolescents.Pediatrics. 1992; 89: 495-501PubMed Google Scholar, 2Daniels S.R. Greer F.R. Lipid screening and cardiovascular health in childhood.Pediatrics. 2008; 122: 198-208Crossref PubMed Scopus (957) Google Scholar], blood pressure [[3]The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents.Pediatrics. 2004; 114: 555-576Crossref PubMed Scopus (5755) Google Scholar], adiposity [4Daniels S.R. Arnett D.K. Eckel R.H. et al.Overweight in children and adolescents: Pathophysiology, consequences, prevention, and treatment.Circulation. 2005; 111: 1999-2012Crossref PubMed Scopus (1114) Google Scholar, 5Williams C.L. Hayman L.L. Daniels S.R. et al.Cardiovascular health in childhood: A statement for health professionals from the Committee on Atherosclerosis, Hypertension, and Obesity in the Young (AHOY) of the Council on Cardiovascular Disease in the Young, American Heart Association.Circulation. 2002; 106: 143-160Crossref PubMed Scopus (592) Google Scholar], and smoking [[6]Gidding S. Morgan W. Perry C. et al.Active and passive tobacco exposure: A serious pediatric health problem. A statement from the Committee on Atherosclerosis and Hypertension in Children, Council on Cardiovascular Disease in the Young, American Heart Association.Circulation. 1994; 90: 2581-2590Crossref PubMed Scopus (62) Google Scholar], in the pediatric setting have been endorsed in guidelines and consensus statements issued, in some instances, for over 15 years. The rationale for attention on these risk factors is the substantive evidence that accumulated first in adult populations of their association with clinical outcomes, followed by the accruement of evidence in the pediatric setting demonstrating (1) occurrence of risk factors in children that were predictive of CVD in adults [7Lauer R.M. Connor W.E. Leaverton P.E. et al.Coronary heart disease risk factors in school children: The Muscatine study.J Pediatr. 1975; 86: 697-706Abstract Full Text PDF PubMed Scopus (332) Google Scholar, 8Webber L.S. Voors A.W. Srinivasan S.R. et al.Occurrence in children of multiple risk factors for coronary artery disease: The Bogalusa heart study.Prev Med. 1979; 8: 407-418Crossref PubMed Scopus (95) Google Scholar], (2) cross-sectional association with other known CVD risk factors [9Aristimuno G.G. Foster T.A. Voors A.W. et al.Influence of persistent obesity in children on cardiovascular risk factors: The Bogalusa heart study.Circulation. 1984; 69: 895-904Crossref PubMed Scopus (108) Google Scholar, 10Schieken R.M. Clarke W.R. Lauer R.M. Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine study.Hypertension. 1981; 3: 669-675Crossref PubMed Scopus (120) Google Scholar, 11Burke G.L. Arcilla R.A. Culpepper W.S. et al.Blood pressure and echocardiographic measures in children: The Bogalusa heart study.Circulation. 1987; 75: 106-114Crossref PubMed Scopus (135) Google Scholar], (3) adults with elevated levels or high-risk status tended to have elevated levels or high-risk status during childhood as well (referred to as tracking) [12Porkka K.V. Viikari J.S. Taimela S. et al.Tracking and predictiveness of serum lipid and lipoprotein measurements in childhood: A 12-year follow-up. The cardiovascular risk in young Finns study.Am J Epidemiol. 1994; 140: 1096-1110PubMed Google Scholar, 13Chen X. Wang Y. Tracking of blood pressure from childhood to adulthood: A systematic review and meta-regression analysis.Circulation. 2008; 117: 3171-3180Crossref PubMed Scopus (1034) Google Scholar, 14Singh A.S. Mulder C. Twisk J.W. et al.Tracking of childhood overweight into adulthood: A systematic review of the literature.Obes Rev. 2008; 9: 474-488Crossref PubMed Scopus (1690) Google Scholar, 15Kelder S.H. Perry C.L. Klepp K.I. et al.Longitudinal tracking of adolescent smoking, physical activity, and food choice behaviors.Am J Public Health. 1994; 84: 1121-1126Crossref PubMed Scopus (1025) Google Scholar], (4) the presence of these risk factors was associated with the presence and extent of atherosclerosis [16Berenson G.S. Srinivasan S.R. Bao W. et al.Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa heart study.N Engl J Med. 1998; 338: 1650-1656Crossref PubMed Scopus (3076) Google Scholar, 17McGill Jr., H.C. McMahan C.A. Zieske A.W. et al.Association of coronary heart disease risk factors with microscopic qualities of coronary atherosclerosis in youth.Circulation. 2000; 102: 374-379Crossref PubMed Scopus (273) Google Scholar], and (5) risk factor levels measured in childhood predicted preclinical atherosclerosis in adulthood [18Davis P.H. Dawson J.D. Riley W.A. et al.Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine study.Circulation. 2001; 104: 2815-2819Crossref PubMed Scopus (745) Google Scholar, 19Li S. Chen W. Srinivasan S.R. et al.Childhood cardiovascular risk factors and carotid vascular changes in adulthood: The Bogalusa heart study.JAMA. 2003; 290: 2271-2276Crossref PubMed Scopus (812) Google Scholar, 20Raitakari O.T. Juonala M. Kähönen M. et al.Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: The cardiovascular risk in young Finns study.JAMA. 2003; 290: 2277-2283Crossref PubMed Scopus (1400) Google Scholar, 21Magnussen C.G. Venn A. Thomson R. et al.The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study.J Am Coll Cardiol. 2009; 53: 860-869Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar]. In more recent times, a critical mass of evidence has emerged on the importance of inflammatory processes at all stages in the development of atherosclerosis and, consequently CVD [[22]Libby P. Ridker P.M. Maseri A. Inflammation and atherosclerosis.Circulation. 2002; 105: 1135-1143Crossref PubMed Scopus (5844) Google Scholar]. This has led to efforts to identify novel biomarkers of inflammation that may enhance CVD risk assessment. Of the candidate biomarkers identified to date, high-sensitivity C-reactive protein (hsCRP), has accumulated sufficient evidence to support its utility in clinical practice as an adjunct to traditional risk factors for prediction of CVD in adults [23Corson M.A. Jones P.H. Davidson M.H. Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker.Am J Cardiol. 2008; 101: 41F-50FAbstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar, 24Ridker P.M. High-sensitivity C-reactive protein and cardiovascular risk: Rationale for screening and primary prevention.Am J Cardiol. 2003; 92: 17K-22KAbstract Full Text Full Text PDF PubMed Scopus (215) Google Scholar]. Although hsCRP has received the most attention, other markers of inflammation, including soluble intercellular adhesion molecule (sICAM) and soluble vascular cell adhesion molecule (sVCAM), have also garnered interest in the adult literature [[25]Ridker P.M. Brown N.J. Vaughan D.E. et al.Established and emerging plasma biomarkers in the prediction of first atherothrombotic events.Circulation. 2004; 109: IV6-IV19Crossref PubMed Google Scholar]. As was the case decades past, when data on the importance of what is now considered traditional CVD risk factors were first emerging, there is limited available evidence for the utility of identifying these and other biomarkers in the pediatric setting. In this issue of the Journal of Adolescent Health, Wijnstok et al [[26]Wijnstok N.J. Twisk J.W.R. Young I.S. et al.Inflammation markers are associated with cardiovascular disease risk in adolescents: The Young Hearts Project 2000.J Adolesc Health. 2010; 47: 346-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar] report on cross-sectional data among 2,000 adolescents aged between 12 and 15 years from the population-based Young Hearts Project that showcases relations between traditional CVD risk factors and a clustered CVD risk score, with hsCRP, sICAM, and sVCAM. hsCRP and sICAM were inversely related to LDL/HDL cholesterol ratio, and directly associated with triglycerides, low cardiorespiratory fitness (CRF), sum of skinfolds, and clustered CVD risk, whereas sVCAM was inversely associated with both sum of skinfolds and clustered CVD risk. On the basis of the available data published on adults, results for hsCRP and sICAM were in the expected direction, but those for sVCAM were not. The results by Wijnstok et al, although cross-sectional, outline one important caveat in the potential application of biomarkers found to be predictive of adult CVD to the pediatric setting. Many of these biomarkers, including sVCAM, are upregulated at different phases of the atherosclerotic process, particularly in the advanced or vulnerable lesion that typically does not present before middle-age [[27]Mulvihill N.T. Foley J.B. Crean P. et al.Prediction of cardiovascular risk using soluble cell adhesion molecules.Eur Heart J. 2002; 23: 1569-1574Crossref PubMed Scopus (74) Google Scholar]. Moreover, elevated levels of many of these biomarkers can be because of other systemic processes not related to atherosclerosis. That is, elevated biomarker levels in youth, when vascular damage is low, may not reflect future risk for CVD. Although the cross-sectional evidence for the benefit of identifying youth with high hsCRP is beginning to resemble the evidence for traditional risk factors [26Wijnstok N.J. Twisk J.W.R. Young I.S. et al.Inflammation markers are associated with cardiovascular disease risk in adolescents: The Young Hearts Project 2000.J Adolesc Health. 2010; 47: 346-351Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 28Jarvisalo M.J. Harmoinen A. Hakanen M. et al.Elevated serum C-reactive protein levels and early arterial changes in healthy children.Arterioscler Thromb Vasc Biol. 2002; 22: 1323-1328Crossref PubMed Scopus (283) Google Scholar, 29Zieske A.W. Tracy R.P. McMahan C.A. et al.Elevated serum C-reactive protein levels and advanced atherosclerosis in youth.Arterioscler Thromb Vasc Biol. 2005; 25: 1237-1243Crossref PubMed Scopus (64) Google Scholar], the available longitudinal evidence is not convincing [30Juonala M. Viikari J.S. Rönnemaa T. et al.Childhood C-reactive protein in predicting CRP and carotid intima-media thickness in adulthood: The Cardiovascular Risk in Young Finns Study.Arterioscler Thromb Vasc Biol. 2006; 26: 1883-1888Crossref PubMed Scopus (136) Google Scholar, 31Kivimäki M. Lawlor D.A. Eklund C. et al.Mendelian randomization suggests no causal association between C-reactive protein and carotid intima-media thickness in the young Finns study.Arterioscler Thromb Vasc Biol. 2007; 27: 978-979Crossref PubMed Scopus (36) Google Scholar]. In this context, it is apparent that not all biomarkers identified in adults that refine CVD risk prediction will be useful in the pediatric setting. Critical to the debate concerning pediatric screening for potential cardiovascular biomarkers will be at what stage in the life-course that knowledge of elevated levels reflects underlying pathology, and whether or not the addition of biomarkers improves adult CVD risk prediction over traditional risk factors. Although the evidence for screening of inflammatory biomarkers in the pediatric setting is in its infancy, the evidence for another risk factor, low CRF, is much more compelling. There is good epidemiological and clinical evidence in adults that suggests that low CRF is a major risk factor for atherosclerosis, with the increased risk similar to that observed for conventional CVD risk factors of hypercholesterolemia, hypertension, and blood pressure [[32]Pate R.R. Pratt M. Blair S.N. et al.Physical activity and public health: A recommendation from the Centers for Disease control and prevention and the American College of Sports Medicine.JAMA. 1995; 273: 402-407Crossref PubMed Scopus (5881) Google Scholar]. Although the available published data in the pediatric setting are not as substantive, the evidence does suggest that low CRF in youth is associated with (1) other CVD risk factors [[33]Dwyer T. Gibbons L.E. The Australian Schools Health and Fitness Survey. Physical fitness related to blood pressure but not lipoproteins.Circulation. 1994; 89: 1539-1544Crossref PubMed Scopus (81) Google Scholar], (2) concurrent and adult markers of atherosclerosis [34Boreham C.A. Ferreira I. Twisk J.W. et al.Cardiorespiratory fitness, physical activity, and arterial stiffness: The Northern Ireland Young Hearts Project.Hypertension. 2004; 44: 721-726Crossref PubMed Scopus (139) Google Scholar, 35Ferreira I. Twisk J.W. Van Mechelen W. et al.Current and adolescent levels of cardiopulmonary fitness are related to large artery properties at age 36: The Amsterdam Growth and Health Longitudinal Study.Eur J Clin Invest. 2002; 32: 723-731Crossref PubMed Scopus (60) Google Scholar, 36Ferreira I. Twisk J.W. Stehouwer C.D. et al.Longitudinal changes in VO2max: Associations with carotid IMT and arterial stiffness.Med Sci Sports Exerc. 2003; 35: 1670-1678Crossref PubMed Scopus (65) Google Scholar], and (3) improved markers of atherosclerosis in obese youth after aerobic exercise interventions that increased CRF [37Woo K.S. Chook P. Yu C.W. et al.Effects of diet and exercise on obesity-related vascular dysfunction in children.Circulation. 2004; 109: 1981-1986Crossref PubMed Scopus (367) Google Scholar, 38Watts K. Beye P. Siafarikas A. et al.Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents.J Am Coll Cardiol. 2004; 43: 1823-1827Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar, 39Watts K. Beye P. Siafarikas A. et al.Effects of exercise training on vascular function in obese children.J Pediatr. 2004; 144: 620-625Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 40Meyer A.A. Kundt G. Lenschow U. et al.Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program.J Am Coll Cardiol. 2006; 48: 1865-1870Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 41Kelly A.S. Wetzsteon R.J. Kaiser D.R. et al.Inflammation, insulin, and endothelial function in overweight children and adolescents: The role of exercise.J Pediatr. 2004; 145: 731-736Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar]. In this issue of the Journal, Lobelo et al [[42]Lobelo F. Pate R.R. Dowda M. et al.Cardiorespiratory fitness and clustered cardiovascular risk in U.S. adolescents.J Adolesc Health. 2010; 47: 352-359Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] provide more evidence regarding the cross-sectional relation between CRF and CVD risk among 1,200 youth aged 12–19 years who participated in the 1999–2002 National Health and Nutrition Examination Surveys (NHANES) and had CRF estimated from a sub-maximal treadmill exercise test. These population-based data showed that clustered CVD risk decreased as CRF increased, with the most substantial decrease in clustered risk observed from the first to the second quintile of CRF. Because the prevalence of overweight and obesity in their cohort was 33%, the authors were able to assess whether the effect of CRF differed, depending on weight for height status. Such analyses are important to tease-out the independent contribution of CRF and fatness to clustered CVD risk, and to provide insight as to the potential clinical and public health benefit of screening for both excess adiposity and low CRF. Among normal-weight boys and girls, and overweight or obese boys, clustered CVD risk decreased across quintiles of increasing CRF, whereas CRF was not associated with clustered CVD risk in overweight or obese girls. Thus, the results of Lobelo et al provide valuable data in the context of guidelines for screening to identify youth at risk of future CVD as their data highlight the importance of identifying not only youth with excess adiposity, but also those with low CRF. Although there are certainly evidence gaps in the association between youth CRF and adult CVD (such as the association between youth CRF and adult clinical outcomes as well as randomized, controlled prospective trials that evaluate the effects of differing combinations of dose, intensity, and frequency of CRF-enhancing exercise on specific CVD-related health outcomes), similar gaps existed when lipid screening guidelines for the pediatric setting were first implemented in the early 1990s. The consistency of results in youth and adults for CRF is important in this respect, and from a primary prevention standpoint, they suggest the existence of a tight biological relationship between low CRF and advanced CVD risk that could be identified and intervened against, early in life. CRF standards (as part of FITNESSGRAM) exist for youth [[43]Cureton K.J. Warren G.L. Criterion-referenced standards for youth health-related fitness tests: A tutorial.Res Q Exerc Sport. 1990; 61: 7-19Crossref PubMed Scopus (100) Google Scholar], that were theoretically linked to adult all-cause and CVD mortality and have been validated, in cross-sectional analyses, with clustered CVD risk in contemporary youth [[44]Lobelo F. Pate R.R. Dowda M. et al.Validity of cardiorespiratory fitness criterion-referenced standards for adolescents.Med Sci Sports Exerc. 2009; 41: 1222-1229Crossref PubMed Scopus (92) Google Scholar]. These standards are already widely implemented in schools across the United States but these data are not used for public health and clinical purposes for identifying the youth who are at risk. Important challenges for routine CRF screening in youth exist. The level of CRF attained is dependent on mode of the exercise test (running, walking, cycling, step-up), protocol (duration, indirect vs. direct gas analysis, sub-maximal vs. maximal), and setting (presence/absence of standardized, controlled conditions), which might result in misclassification if consistency in these areas is not enforced. This is important because in large-scale population-wide screening, validated field tests are the most practical and cost-efficient, whereas treadmill or bicycle ergometer tests may be more practical in the clinic setting. Moreover, extrapolation of submaximal exercise test data to attain the theoretical maximal level may also result in misclassification, whereas field-tests may be particularly affected by low participant motivation that would lead to an increased number of false positives for low CRF in youth. These and other challenges will have to be addressed in any guidelines issued for youth screening for low CRF. But in the interim, attention needs to be focused not only on strategies to increase physical activity and exercise in youth as a means for reducing overweight and obesity, but also to increase CRF in its own right. As with progress toward guidelines for screening and treatment of any risk variable in the pediatric setting considered to be important in the context of later CVD; it is always a long journey. But when the inevitable question comes, “Are we there yet?” the answer is a definite “No” for inflammatory biomarkers, but in the case of CRF, the answer is “No, but we’re nearly there.” Inflammation Markers are Associated with Cardiovascular Diseases Risk in Adolescents: The Young Hearts Project 2000Journal of Adolescent HealthVol. 47Issue 4PreviewThe traditional approach for identifying subjects at risk from cardiovascular diseases (CVD) is to determine the extent of clustering of biological risk factors adjusted for lifestyle. Recently, markers of endothelial dysfunction and low grade inflammation, including high sensitivity C-reactive protein (hsCRP), soluble intercellular adhesion molecules (sICAM), and soluble vascular adhesion molecules (sVCAM), have been included in the detection for high risk individuals. However, the relationship of these novel biomarkers with CVD risk in adolescents remains unclear. Full-Text PDF Open AccessCardiorespiratory Fitness and Clustered Cardiovascular Disease Risk in U.S. AdolescentsJournal of Adolescent HealthVol. 47Issue 4PreviewTo study the association between the cardiorespiratory fitness (CRF) distribution and cardiovascular disease (CVD) risk measured as continuous scores for individual and clustered CVD risk factors and to explore the potential effect modification of this association exerted by weight status among adolescents. Full-Text PDF