- Email: [email protected]
Beyond Cholesterol: The Atherogenic Consequences of Combined Dyslipidemia
Beyond Cholesterol: The Atherogenic Consequences of Combined Dyslipidemia
C
ardiovascular disease (CVD) has remained the leadOwing to the continuous remodeling of lipoproteins in ing cause of death and disability in the industrialized response to changing metabolic demands, there is wide world for 8 decades, and prevalence is increasing variation in the absolute amounts of both TC and TG in worldwide with the export of a Western lifestyle.1 Dating direct relation to particle size. In fact, within each lipoproto results of the original Framingham studies, an elevated tein density class, there are multiple size-differentiated level of cholesterol carried in low-density subclasses. This is more than semantics; liSee related article, p 991 lipoproteins (LDLs) has been considered poprotein particle size closely reflects meta critical risk factor for early CVD, and reduction of LDL abolic forces at play in lipid metabolism, with implications cholesterol (LDL-C) has been, and remains, a primary focus for CVD risk. of risk reduction.2,3 However, a substantial number of paThe findings of Burns et al illustrate that it is the TG load tients who develop CVD have normal or minimally elevated that sets a metabolic cascade in motion influencing the size, LDL-C levels. In fact, the most prevalent lipid pattern in incholesterol content, and stability of both LDL and HDL dividuals presenting with a CVD event is a combined dysliparticles in youth, as has been previously shown in adults. pidemia characterized on a standard lipid profile by elevated In obese individuals with insulin resistance like the adolestriglycerides (TG), decreased high-density lipoprotein cents in this study, TG clearance is impaired, and the liver (HDL) cholesterol (HDL-C), and normal or minimally elegenerates larger and more TG-rich VLDLs to compensate.5 These large VLDLs are quickly metabolized to small vated LDL-C. This is the profile seen in insulin resistance cholesterol-poor LDL subspecies that are cleared from the and the metabolic syndrome, often in the context of obesity. circulation 2-3 times less efficiently by the LDL receptor, It is the increasing prevalence of obesity and its accompanylingering longer in the vascular space and increasing the ing cardiometabolic risk associated with this dyslipidemia number of LDL particles present and susceptible to the vasthat makes the article by Burns et al4 in this issue of The Journal so timely. Their findings contribute to our understanding cular wall interactions that seed atherogenesis.6 Meanwhile, more TG-rich HDL particles are also generated and metabof why dyslipidemia with LDL-C levels below the traditional olized to small, less-stable HDL subspecies, driving down cutoff for risk is still an LDL problem. beneficial HDL-C levels. Burns et al demonstrate that these To appreciate this apparent paradox, it is helpful to conmetabolic forces are reflected in lipid subclass analysis as an sider some elements of lipid metabolism. The total cholesterol increased total LDL particle burden and an increased num(TC) reported on a lipid profile is often considered a discreet ber of small LDL particles, and on a standard lipid profile entity, but in reality no pure cholesterol circulates within the by a higher TG/HDL-C ratio and higher non–HDL-C levels. bloodstream—only a series of metabolically interconnected In adult longitudinal studies, increased carotid intima melipoprotein particles initially generated in the liver and the india thickness and incident CVD events are more strongly testinal tract to safely traffic this waxy cargo through an predicted by baseline LDL particle levels than by cholesterol aqueous circulatory environment. This is also true for TG. measures.7,8 Reported TC and TG values combine into single measures This does not refute the role of cholesterol; decades of evthe sum totals of cholesterol and TG found within the many idence support the absolute role of cholesterol infiltration circulating lipoprotein carriers. Lipoproteins are traditionally into the vascular space in atherogenesis.9 The uptake of quantified on the basis of cholesterol content and are categothis ectopic lipid by macrophages leads to foam cell and fatty rized by density as HDL-C, LDL-C, intermediate-density lipostreak formation in an intrinsically protective innate improtein (IDL) cholesterol, and very-low-density lipoprotein mune response to the toxicity of displaced cholesterol crys(VLDL) cholesterol. IDL cholesterol is not reported on a lipid tals.10 Cholesterol and other lipids can only enter the arterial profile, but rather is incorporated into the LDL-C readout. wall linked with lipoproteins that render them soluble, are <70 nm in diameter, and carry apolipoprotein B.11 This includes all of the LDL subspecies from very small to large LDL CVD Cardiovascular disease and, to a lesser extent, IDL and small VLDL subspecies. HDL High-density lipoprotein HDL-C High-density lipoprotein cholesterol Non–HDL-C (TC minus HDL-C), the relatively new lipid IDL LDL LDL-C TC TG VLDL
Intermediate-density lipoprotein Low-density lipoprotein Low-density lipoprotein cholesterol Total cholesterol Triglycerides Very-low-density lipoprotein
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.07.034
977
THE JOURNAL OF PEDIATRICS
www.jpeds.com
measure proposed for screening by the recently released National Heart, Lung and Blood Institute Expert Panel guidelines,12 captures the cholesterol content of LDL-C and all TG-rich IDL and VLDL subspecies, as well as the impact of reciprocal lowering of HDL-C. In multiple epidemiologic studies, non–HDL-C has been shown to be as good or better than LDL-C in predicting vascular measures of atherosclerosis and clinical CVD events.13 Non–HDL-C improves on LDL-C in hypertriglyceridemic conditions, addressing the metabolic fallout of obesity with insulin resistance and type 2 diabetes.14 It follows that Burns et al report that features of the metabolic or insulin resistance syndrome explain 79% of the variance in small LDL particle and total LDL particle burden: central adiposity, reflected in the waist circumference of their obese young subjects, together with the ratio of TG/HDL-C. Their findings also illustrate that the thresholds for lipid and lipoprotein levels predictive of LDL particles vary by race. A non–HDL-C $120 mg/dL and a TG/ HDL-C ratio $3 in white subjects versus a non–HDL-C $145 mg/dL and a TG/HDL-C ratio $2.5 in black subjects proved to be the best predictors of LDL particle concentration. These differences may be accounted for in part by previously identified metabolic distinctions that lower TG levels in blacks.15 The key impact of these findings transcends race and ethnicity. Thresholds vary modestly, but a combined atherogenic dyslipidemia in adolescents with abdominal obesity whose standard LDL-C results might not draw attention identifies them as high risk for accelerated atherosclerosis on the basis of an increased LDL particle burden. Both pathological and vascular studies have shown that the earlier primary prevention addresses childhood dyslipidemia, the better the result.16 By the time a 10-year risk score manifests itself, decades of atherosclerotic disease have had the opportunity to develop.17 Atherogenicity is manifested early in structural and functional vascular changes assessed noninvasively as arterial stiffness and thickening, hypothesized to result from subendothelial retention of apolipoprotein B lipoproteins, predominantly LDL particles. Thus, the most effective way to prevent atherosclerosis is to lower the burden of LDL particles and avoid the resultant inflammatory response. The Young Finns study has specifically documented the longitudinal power of non–HDL-C and apolipoprotein B (a surrogate for LDL particles) to predict increased arterial stiffness 6 years later.18 Ultrasound imaging has been used effectively to uncover the structural vascular response to early and aggressive treatment of familial hypercholesterolemia, another kind of LDL particle burden in children identified by LDL-C testing.19 Burns et al have demonstrated that in adolescents, the combined dyslipidemia associated with obesity and insulin resistance, characterized by elevated TG/HDL-C ratio and non–HDL-C value, represents an increased small and total LDL particle burden and thus is an important focus for early treatment. n 978
Vol. 161, No. 6 Rae-Ellen W. Kavey, MD, MPH Division of Pediatric Cardiology University of Rochester Medical Center Rochester, New York Michele Mietus-Snyder, MD Department of Pediatrics George Washington University and Medical Center Obesity Institute Children’s National Medical Center Washington, District of Columbia Reprint requests: Rae-Ellen W. Kavey, MD, MPH, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14690. E-mail: [email protected]
References 1. Lloyd-Jones DM, Hong Y, Mozafferian D, Appel LJ, Van Hoen L, Greenlund G, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s Strategic Impact Goal through 2020 and beyond. Circulation 2010;121:586-613. 2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001; 285:2486-97. 3. Grundy SM. Use of emerging lipoprotein risk factors in assessment of cardiovascular risk. JAMA 2012;307:2540-1. 4. Burns SF, Lee SJ, Arslanian SA. Surrogate lipid markers for small dense LDL particles in overweight youth. J Pediatr 2012;161:991-6. 5. Robins SJ, Lyass A, Zachariah JP, Massaro JM, Vasan RS. Insulin resistance and the relationship of a dyslipidemia to coronary heart disease: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2011;31: 1208-14. 6. Packard CJ, Demant T, Stewart JP, Bedford D, Caslake MJ, Schwertfeger G, et al. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J Lipid Res 2000;41:305-18. 7. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study: implications for LDL management. J Clin Lipidol 2007;1:583-92. 8. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol 2011;5:105-13. 9. Tamminen M, Mottino G, Qiao JH, Breslow JL, Frank JS. Ultrastructure of early lipid accumulation in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999;19:847-53. 10. Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C. Innate immunity and monocyte-macrophage activation in atherosclerosis. J Inflamm (Lond) 2011;8:1-17. 11. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832-44. 12. Kavey R-E, Simons-Morton DG, DeJesus JM. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011; 128(Suppl 6):S1-44. 13. Frontini MG, Srinivasan SR, Xu J, Tang R, Bond MG, Berenson GS. Usefulness of childhood non–high-density lipoprotein cholesterol levels versus other lipoprotein measures in predicting adult subclinical atherosclerosis: the Bogalusa Heart Study. Pediatrics 2008;121: 924-9.
EDITORIAL
December 2012 14. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non– high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363-8. 15. Sumner AE. Ethnic differences in triglyceride levels and high-density lipoprotein lead to underdiagnosis of the metabolic syndrome in black children and adults. J Pediatr 2009;155:S7 e7-.11. 16. McGill HC, McMahan CA, Gidding SS. Are pediatricians responsible for prevention of adult cardiovascular disease? Nat Clin Pract Cardiovasc Med 2009;6:10-1.
17. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Greenland TA, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321-9. 18. Koivistoinen T, Hutri-Kahonen N, Juonala M, Koobi T, Lehtimaki T, Viikari JS, et al. Apolipoprotein B is related to arterial pulse wave velocity in young adults: the Cardiovascular Risk in Young Finns Study. Atherosclerosis 2011;214:220-4. 19. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation 2007;116: 664-8.
Preterm Birth and Airway Inflammation in Childhood
P
reterm birth is associated with a number of respiratory ber of children could be identified for follow-up, limiting abnormalities throughout childhood, including generalizability. Approximately 40% of patients could not increased respiratory symptoms, decreased lung funcproduce sputum with the induction procedure, though this tion, and impairment of exercise performance.1 Mechanisms is not unusual. Moreover, no sputum microbial cultures leading to these abnormalities are incompletely understood. were performed. Given the relationship between sputum inAirway inflammation is an important canflammation and infection, as seen in some See related article, p 1085 didate mechanism. It is known, for examconditions, including cystic fibrosis, identiple, that airway inflammation in the perinatal period is fication of airway microbes may have helped explain some associated with the development of bronchopulmonary of the findings.4 In the setting of preterm birth, for example, it appears that chorioamnionitis may be involved in the dedysplasia (BPD), the chronic lung disease seen in some velopment of BPD, though this is controversial.5 Infection patients following preterm birth.2 Airway inflammation, however, has received little attention in older children who may be important also in other potential mechanisms leading were born preterm. to BPD, including effects on circulating progenitor cells.6 3 Sputum induction has been used to assess airway In this issue of The Journal, Tieg et al report persuasive evidence of airway inflammation in a group of 16 children born inflammation and infection in clinical investigations and before 32 weeks gestation. The authors used spirometry and clinical decision making.7 It has not achieved widespread use because of the extra time, labor, and training involved sputum induction to measure lung function and biomarkers to achieve meaningful results. Nevertheless, it is a safe apof inflammation. They also examined 11 age-matched fullproach to sample the airway to determine local inflammaterm control subjects. They found that preterm subjects tion. This technique has confirmed that asthma in children had significant decreases in the ratio of the forced expiratory is associated with increased eosinophil numbers, though neuvolume in 1 second to forced vital capacity and forced expitrophils may predominate in more severe cases. Whether ratory flow 25%-75%, as has been seen in other studies. With clinical decision-making regarding corticosteroid use is imregard to inflammation, sputum of preterm children had proved by determining sputum eosinophil number in chila 16-fold higher proportion of neutrophils and 3-fold higher dren is not yet clear.7 In cystic fibrosis, sputum induction interleukin-8/protein levels compared with sputum from has taught us that even children who cannot normally procontrols. In addition, only 1 of the 16 children born preterm duce sputum have striking neutrophil-dominated airway inhad respiratory symptoms in the previous year and none flammation.4 The current study indicates that children of the 16 was being treated with respiratory medications. following preterm birth also have neutrophil-dominated airOnly 2 of the 16 had been diagnosed previously with way inflammation. BPD. Taken together, these findings suggest that children The study of Tieg et al suggests that airway inflammation born prematurely are subject to subclinical airway inflammacan be seen in children and adolescents who were born pretion compared with control children. No correlations, maturely, irrespective of whether or not they developed however, were identified between spirometry results and BPD. The clinical significance of airway inflammation in inflammatory indices in sputum in either study group. preterm children was not established, however, because The study has a number of limitations. It was performed there was no correlation between degree of airway inflammore than a decade ago; hence, most patients who were old mation and lung function impairment or respiratory enough to perform lung functions at the time of the study were not treated with surfactant as infants. Only a small numThe authors declare no conflicts of interest.
BPD
Bronchopulmonary dysplasia
0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.08.002
979
C
ardiovascular disease (CVD) has remained the leadOwing to the continuous remodeling of lipoproteins in ing cause of death and disability in the industrialized response to changing metabolic demands, there is wide world for 8 decades, and prevalence is increasing variation in the absolute amounts of both TC and TG in worldwide with the export of a Western lifestyle.1 Dating direct relation to particle size. In fact, within each lipoproto results of the original Framingham studies, an elevated tein density class, there are multiple size-differentiated level of cholesterol carried in low-density subclasses. This is more than semantics; liSee related article, p 991 lipoproteins (LDLs) has been considered poprotein particle size closely reflects meta critical risk factor for early CVD, and reduction of LDL abolic forces at play in lipid metabolism, with implications cholesterol (LDL-C) has been, and remains, a primary focus for CVD risk. of risk reduction.2,3 However, a substantial number of paThe findings of Burns et al illustrate that it is the TG load tients who develop CVD have normal or minimally elevated that sets a metabolic cascade in motion influencing the size, LDL-C levels. In fact, the most prevalent lipid pattern in incholesterol content, and stability of both LDL and HDL dividuals presenting with a CVD event is a combined dysliparticles in youth, as has been previously shown in adults. pidemia characterized on a standard lipid profile by elevated In obese individuals with insulin resistance like the adolestriglycerides (TG), decreased high-density lipoprotein cents in this study, TG clearance is impaired, and the liver (HDL) cholesterol (HDL-C), and normal or minimally elegenerates larger and more TG-rich VLDLs to compensate.5 These large VLDLs are quickly metabolized to small vated LDL-C. This is the profile seen in insulin resistance cholesterol-poor LDL subspecies that are cleared from the and the metabolic syndrome, often in the context of obesity. circulation 2-3 times less efficiently by the LDL receptor, It is the increasing prevalence of obesity and its accompanylingering longer in the vascular space and increasing the ing cardiometabolic risk associated with this dyslipidemia number of LDL particles present and susceptible to the vasthat makes the article by Burns et al4 in this issue of The Journal so timely. Their findings contribute to our understanding cular wall interactions that seed atherogenesis.6 Meanwhile, more TG-rich HDL particles are also generated and metabof why dyslipidemia with LDL-C levels below the traditional olized to small, less-stable HDL subspecies, driving down cutoff for risk is still an LDL problem. beneficial HDL-C levels. Burns et al demonstrate that these To appreciate this apparent paradox, it is helpful to conmetabolic forces are reflected in lipid subclass analysis as an sider some elements of lipid metabolism. The total cholesterol increased total LDL particle burden and an increased num(TC) reported on a lipid profile is often considered a discreet ber of small LDL particles, and on a standard lipid profile entity, but in reality no pure cholesterol circulates within the by a higher TG/HDL-C ratio and higher non–HDL-C levels. bloodstream—only a series of metabolically interconnected In adult longitudinal studies, increased carotid intima melipoprotein particles initially generated in the liver and the india thickness and incident CVD events are more strongly testinal tract to safely traffic this waxy cargo through an predicted by baseline LDL particle levels than by cholesterol aqueous circulatory environment. This is also true for TG. measures.7,8 Reported TC and TG values combine into single measures This does not refute the role of cholesterol; decades of evthe sum totals of cholesterol and TG found within the many idence support the absolute role of cholesterol infiltration circulating lipoprotein carriers. Lipoproteins are traditionally into the vascular space in atherogenesis.9 The uptake of quantified on the basis of cholesterol content and are categothis ectopic lipid by macrophages leads to foam cell and fatty rized by density as HDL-C, LDL-C, intermediate-density lipostreak formation in an intrinsically protective innate improtein (IDL) cholesterol, and very-low-density lipoprotein mune response to the toxicity of displaced cholesterol crys(VLDL) cholesterol. IDL cholesterol is not reported on a lipid tals.10 Cholesterol and other lipids can only enter the arterial profile, but rather is incorporated into the LDL-C readout. wall linked with lipoproteins that render them soluble, are <70 nm in diameter, and carry apolipoprotein B.11 This includes all of the LDL subspecies from very small to large LDL CVD Cardiovascular disease and, to a lesser extent, IDL and small VLDL subspecies. HDL High-density lipoprotein HDL-C High-density lipoprotein cholesterol Non–HDL-C (TC minus HDL-C), the relatively new lipid IDL LDL LDL-C TC TG VLDL
Intermediate-density lipoprotein Low-density lipoprotein Low-density lipoprotein cholesterol Total cholesterol Triglycerides Very-low-density lipoprotein
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.07.034
977
THE JOURNAL OF PEDIATRICS
www.jpeds.com
measure proposed for screening by the recently released National Heart, Lung and Blood Institute Expert Panel guidelines,12 captures the cholesterol content of LDL-C and all TG-rich IDL and VLDL subspecies, as well as the impact of reciprocal lowering of HDL-C. In multiple epidemiologic studies, non–HDL-C has been shown to be as good or better than LDL-C in predicting vascular measures of atherosclerosis and clinical CVD events.13 Non–HDL-C improves on LDL-C in hypertriglyceridemic conditions, addressing the metabolic fallout of obesity with insulin resistance and type 2 diabetes.14 It follows that Burns et al report that features of the metabolic or insulin resistance syndrome explain 79% of the variance in small LDL particle and total LDL particle burden: central adiposity, reflected in the waist circumference of their obese young subjects, together with the ratio of TG/HDL-C. Their findings also illustrate that the thresholds for lipid and lipoprotein levels predictive of LDL particles vary by race. A non–HDL-C $120 mg/dL and a TG/ HDL-C ratio $3 in white subjects versus a non–HDL-C $145 mg/dL and a TG/HDL-C ratio $2.5 in black subjects proved to be the best predictors of LDL particle concentration. These differences may be accounted for in part by previously identified metabolic distinctions that lower TG levels in blacks.15 The key impact of these findings transcends race and ethnicity. Thresholds vary modestly, but a combined atherogenic dyslipidemia in adolescents with abdominal obesity whose standard LDL-C results might not draw attention identifies them as high risk for accelerated atherosclerosis on the basis of an increased LDL particle burden. Both pathological and vascular studies have shown that the earlier primary prevention addresses childhood dyslipidemia, the better the result.16 By the time a 10-year risk score manifests itself, decades of atherosclerotic disease have had the opportunity to develop.17 Atherogenicity is manifested early in structural and functional vascular changes assessed noninvasively as arterial stiffness and thickening, hypothesized to result from subendothelial retention of apolipoprotein B lipoproteins, predominantly LDL particles. Thus, the most effective way to prevent atherosclerosis is to lower the burden of LDL particles and avoid the resultant inflammatory response. The Young Finns study has specifically documented the longitudinal power of non–HDL-C and apolipoprotein B (a surrogate for LDL particles) to predict increased arterial stiffness 6 years later.18 Ultrasound imaging has been used effectively to uncover the structural vascular response to early and aggressive treatment of familial hypercholesterolemia, another kind of LDL particle burden in children identified by LDL-C testing.19 Burns et al have demonstrated that in adolescents, the combined dyslipidemia associated with obesity and insulin resistance, characterized by elevated TG/HDL-C ratio and non–HDL-C value, represents an increased small and total LDL particle burden and thus is an important focus for early treatment. n 978
Vol. 161, No. 6 Rae-Ellen W. Kavey, MD, MPH Division of Pediatric Cardiology University of Rochester Medical Center Rochester, New York Michele Mietus-Snyder, MD Department of Pediatrics George Washington University and Medical Center Obesity Institute Children’s National Medical Center Washington, District of Columbia Reprint requests: Rae-Ellen W. Kavey, MD, MPH, Division of Pediatric Cardiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14690. E-mail: [email protected]
References 1. Lloyd-Jones DM, Hong Y, Mozafferian D, Appel LJ, Van Hoen L, Greenlund G, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s Strategic Impact Goal through 2020 and beyond. Circulation 2010;121:586-613. 2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the 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). JAMA 2001; 285:2486-97. 3. Grundy SM. Use of emerging lipoprotein risk factors in assessment of cardiovascular risk. JAMA 2012;307:2540-1. 4. Burns SF, Lee SJ, Arslanian SA. Surrogate lipid markers for small dense LDL particles in overweight youth. J Pediatr 2012;161:991-6. 5. Robins SJ, Lyass A, Zachariah JP, Massaro JM, Vasan RS. Insulin resistance and the relationship of a dyslipidemia to coronary heart disease: the Framingham Heart Study. Arterioscler Thromb Vasc Biol 2011;31: 1208-14. 6. Packard CJ, Demant T, Stewart JP, Bedford D, Caslake MJ, Schwertfeger G, et al. Apolipoprotein B metabolism and the distribution of VLDL and LDL subfractions. J Lipid Res 2000;41:305-18. 7. Cromwell WC, Otvos JD, Keyes MJ, et al. LDL particle number and risk of future cardiovascular disease in the Framingham Offspring Study: implications for LDL management. J Clin Lipidol 2007;1:583-92. 8. Otvos JD, Mora S, Shalaurova I, Greenland P, Mackey RH, Goff DC Jr. Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. J Clin Lipidol 2011;5:105-13. 9. Tamminen M, Mottino G, Qiao JH, Breslow JL, Frank JS. Ultrastructure of early lipid accumulation in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999;19:847-53. 10. Shalhoub J, Falck-Hansen MA, Davies AH, Monaco C. Innate immunity and monocyte-macrophage activation in atherosclerosis. J Inflamm (Lond) 2011;8:1-17. 11. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832-44. 12. Kavey R-E, Simons-Morton DG, DeJesus JM. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011; 128(Suppl 6):S1-44. 13. Frontini MG, Srinivasan SR, Xu J, Tang R, Bond MG, Berenson GS. Usefulness of childhood non–high-density lipoprotein cholesterol levels versus other lipoprotein measures in predicting adult subclinical atherosclerosis: the Bogalusa Heart Study. Pediatrics 2008;121: 924-9.
EDITORIAL
December 2012 14. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non– high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol 2006;98:1363-8. 15. Sumner AE. Ethnic differences in triglyceride levels and high-density lipoprotein lead to underdiagnosis of the metabolic syndrome in black children and adults. J Pediatr 2009;155:S7 e7-.11. 16. McGill HC, McMahan CA, Gidding SS. Are pediatricians responsible for prevention of adult cardiovascular disease? Nat Clin Pract Cardiovasc Med 2009;6:10-1.
17. Berry JD, Dyer A, Cai X, Garside DB, Ning H, Greenland TA, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321-9. 18. Koivistoinen T, Hutri-Kahonen N, Juonala M, Koobi T, Lehtimaki T, Viikari JS, et al. Apolipoprotein B is related to arterial pulse wave velocity in young adults: the Cardiovascular Risk in Young Finns Study. Atherosclerosis 2011;214:220-4. 19. Rodenburg J, Vissers MN, Wiegman A, van Trotsenburg AS, van der Graaf A, de Groot E, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation 2007;116: 664-8.
Preterm Birth and Airway Inflammation in Childhood
P
reterm birth is associated with a number of respiratory ber of children could be identified for follow-up, limiting abnormalities throughout childhood, including generalizability. Approximately 40% of patients could not increased respiratory symptoms, decreased lung funcproduce sputum with the induction procedure, though this tion, and impairment of exercise performance.1 Mechanisms is not unusual. Moreover, no sputum microbial cultures leading to these abnormalities are incompletely understood. were performed. Given the relationship between sputum inAirway inflammation is an important canflammation and infection, as seen in some See related article, p 1085 didate mechanism. It is known, for examconditions, including cystic fibrosis, identiple, that airway inflammation in the perinatal period is fication of airway microbes may have helped explain some associated with the development of bronchopulmonary of the findings.4 In the setting of preterm birth, for example, it appears that chorioamnionitis may be involved in the dedysplasia (BPD), the chronic lung disease seen in some velopment of BPD, though this is controversial.5 Infection patients following preterm birth.2 Airway inflammation, however, has received little attention in older children who may be important also in other potential mechanisms leading were born preterm. to BPD, including effects on circulating progenitor cells.6 3 Sputum induction has been used to assess airway In this issue of The Journal, Tieg et al report persuasive evidence of airway inflammation in a group of 16 children born inflammation and infection in clinical investigations and before 32 weeks gestation. The authors used spirometry and clinical decision making.7 It has not achieved widespread use because of the extra time, labor, and training involved sputum induction to measure lung function and biomarkers to achieve meaningful results. Nevertheless, it is a safe apof inflammation. They also examined 11 age-matched fullproach to sample the airway to determine local inflammaterm control subjects. They found that preterm subjects tion. This technique has confirmed that asthma in children had significant decreases in the ratio of the forced expiratory is associated with increased eosinophil numbers, though neuvolume in 1 second to forced vital capacity and forced expitrophils may predominate in more severe cases. Whether ratory flow 25%-75%, as has been seen in other studies. With clinical decision-making regarding corticosteroid use is imregard to inflammation, sputum of preterm children had proved by determining sputum eosinophil number in chila 16-fold higher proportion of neutrophils and 3-fold higher dren is not yet clear.7 In cystic fibrosis, sputum induction interleukin-8/protein levels compared with sputum from has taught us that even children who cannot normally procontrols. In addition, only 1 of the 16 children born preterm duce sputum have striking neutrophil-dominated airway inhad respiratory symptoms in the previous year and none flammation.4 The current study indicates that children of the 16 was being treated with respiratory medications. following preterm birth also have neutrophil-dominated airOnly 2 of the 16 had been diagnosed previously with way inflammation. BPD. Taken together, these findings suggest that children The study of Tieg et al suggests that airway inflammation born prematurely are subject to subclinical airway inflammacan be seen in children and adolescents who were born pretion compared with control children. No correlations, maturely, irrespective of whether or not they developed however, were identified between spirometry results and BPD. The clinical significance of airway inflammation in inflammatory indices in sputum in either study group. preterm children was not established, however, because The study has a number of limitations. It was performed there was no correlation between degree of airway inflammore than a decade ago; hence, most patients who were old mation and lung function impairment or respiratory enough to perform lung functions at the time of the study were not treated with surfactant as infants. Only a small numThe authors declare no conflicts of interest.
BPD
Bronchopulmonary dysplasia
0022-3476/$ - see front matter. Copyright ª 2012 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2012.08.002
979