Pediatric Precursors of Adult Atherosclerosis

After completing this article, readers should be able to: Despite significant declines in death rates from heart disease in recent years, this continues to be the leading cause of death in the United States. In 1999, heart disease was responsible for more than 30% of all deaths, with ischemic heart disease representing 65% of this total. With improved mortality rates of coronary artery disease (CAD) has come greater understanding of how atherosclerosis arises and may be prevented.This review summarizes recent findings regarding the development of cardiovascular disease and alerts pediatricians to how they can screen patients for precursors of CAD. It provides primary and secondary prevention strategies to manage risk factors when they are detected and directs readers to sources that include detailed guidelines for the risk factors that are discussed.Central to an appreciation of childhood risk factors for adult heart disease is an understanding of how the principal feature of coronary artery disease—the atherosclerotic plaque—develops. Rather than a simple accumulation of cholesterol on the intimal surface of vessel walls, the atherosclerotic plaque represents the culmination of a complex series of events involving inflammatory mediators, macrophages, and activated T lymphocytes in addition to circulating lipoproteins.The sequence begins when low-density lipoprotein (LDL) particles, those composites of lipid and protein designed to transport cholesterol from the liver and intestine to other organs, accumulate beneath the endothelial layer of the arterial wall. There, the central lipid portion of the LDL particle undergoes oxidation, and the proteins on the surface of the particle undergo glycation. These reactions stimulate endothelial and smooth muscle cells to elaborate chemical signals that attract and activate circulating monocytes and T lymphocytes. Activated monocytes and lymphocytes amplify the initial immune response, and in particular, as monocytes mature into macrophages, these cells express specific receptors that allow them to engulf the excess LDL. The resulting lipid-laden macrophages or foam cells combine with activated T cells to form a fatty streak, the initial atherosclerotic element, on the intimal surface of the coronary artery.As endothelial cells, macrophages, and T cells continue to secrete inflammatory mediators, smooth muscle cells from the intima are induced to migrate to the site to cover the luminal surface of the fatty streak. These cells secrete a collagen matrix that forms a fibrous cap or plaque that walls off the underlying collection of cells and lipid from the circulating blood. The plaque matures and initially grows outward into the vessel wall away from the lumen in a way that preserves the vessel’s luminal diameter. As the plaque matures further, however, it begins to occlude the lumen, causing narrowing or even occlusion of the artery. The catastrophic event that unleashes a stroke or myocardial infarction often is rupture of the fibrous plaque and exposure of its core constituents (Figure). When circulating blood contacts the lipid and protein core of the plaque, platelets are activated, and clotting precursors of the coagulation cascade unleash the formation of a thrombus. Whether an acute coronary event results in myocardial damage depends on a further set of extremely complex determinants involving circulatory factors, such as plasminogen activators and inhibitors, the thrombus, and the extent of collateral circulation. Increased understanding of these processes has reduced the morbidity of acute coronary syndromes. Nonetheless, primary prevention clearly is justified by the statistic that 30% of initial myocardial infarctions are fatal. Nonfatal myocardial infarctions cause substantial subsequent morbidity, and secondary prevention efforts incur tremendous costs.In view of the signal importance of LDL particles in initiating the sequence of events just described, a basic familiarity with lipoproteins is indispensable for pediatricians seeking to manage at-risk children. The physiology of lipids and cholesterol is complex, and excellent detailed reviews are available. In plasma, cholesterol is transported by lipoproteins, which contain a core of nonpolar lipid (triglycerides and esterified cholesterol) and a surface monolayer composed of phospholipids, a small amount of unesterified cholesterol, and apoproteins. The lipoproteins are divided into classes based on density, composition, and function. Apoproteins play a major role in the trafficking and metabolism of lipoproteins by either catalyzing enzymatic reactions, binding to cellular receptors, or facilitating transfer of core components from one lipoprotein to another.A large body of evidence drawn from epidemiologic studies and autopsy, animal, and human experiments conclusively links diet with hypercholesterolemia and heart disease. Several pathology studies have shown that the atherosclerotic process begins in childhood and early adolescence. The Korean War study by Enos and associates demonstrated a 77% incidence rate of coronary arterial lesions on autopsy in young American soldiers. The ongoing Bogalusa Heart Study and the Pathological Determinants of Atherosclerosis in Youth Study (PDAY) has demonstrated unequivocally the presence of early atherosclerotic lesions in pediatric patients who died from accidents. These studies clearly documented a graded risk relationship between established cardiovascular risk factors and the extent of early atherosclerotic plaque in children.Despite the strength of these data, no longitudinal studies have demonstrated that cholesterol reduction in childhood results in a decrease of CAD in adulthood. Nevertheless, the relevance of the cholesterol hypothesis to children is recognized both nationally and internationally; in the United States, it forms the basis for National Cholesterol Education Program (NCEP) guidelines issued for children.Large cross-sectional studies of adults and children (such as the Seven Country study of Keys and colleagues) have demonstrated that the total and saturated fat intake of a population is correlated positively with mean levels of total and LDL-cholesterol (LDL-C), which in turn predicts the incidence of CAD within that population. In addition, the Framingham Study demonstrated that the relationship of increased LDL-C (and decreased high-density lipoprotein cholesterol [HDL-C]) levels with CAD risk was continuous and did not exhibit threshold values. Therefore, cut-off lipid levels do not represent ideal values, but rather statistical levels above which the risk of CAD is unacceptably high.Both cross-sectional and longitudinal studies of lipid levels in United States children are available. Systematic but small differences are noted in lipid and lipoprotein levels in children based on age, gender, pubertal status, and race. Of particular note, males experience a decrease in HDL-C levels and a slow increase of LDL-C at puberty, which explains in part the propensity of men to have CAD at an earlier age than women. Although rank order is preserved in tracking of lipid and lipoprotein levels over time, changes in diet, activity, hormonal influences, and possibly the age-related expression of genes influencing lipid metabolism all conspire to make tracking of lipoprotein levels imperfect. In the Muscatine Study, Lauer and Clarke found that approximately one third of boys and three fifths of girls identified as having hypercholesterolemia in childhood would not qualify for intervention when they were followed up as adults.Extremely precise measurements of lipids and lipoproteins obtained on national samples of United States children by the Lipid Research Clinics in the 1970s established the most widely quoted “normal” lipid levels for children. These data were used to establish the currently used cut points for classification and intervention. In that data set, the average total cholesterol is approximately 150 to 160 mg/dL (3.9 to 4.1 mmol/L) between childhood and adolescence, with the 75th and 95th percentiles at 170 and 200 mg/dL (4.4 and 5.2 mmol/L), respectively. The median, 75th, and 95th percentiles for LDL-C are approximately 100, 110, and 130 mg/dL (2.6, 2.8, and 3.4 mmol/L), respectively. The 5th percentile for HDL is approximately 35 mg/dL (0.9 mmol/L), and the 95th percentile for triglycerides is approximately 130 mg/dL (0.03 mmol/L). More recent values are different.* For adults, the NCEP classifies a total cholesterol level of 200 to 239 mg/dL (5.2 to 6.2 mmol/L) as borderline and more than 240 mg/dL (6.2 mmol/L) as high.Considerable confusion surrounds the measurement of lipids and lipoproteins, particularly with respect to the effect of fasting. Fasting does not diminish values for total cholesterol or LDL-C markedly, but it is necessary for the measurement of triglycerides and for the estimation of the cholesterol content of the individual lipoproteins. In the fasting state, total plasma cholesterol is the sum of HDL-C, LDL-C, and very-low density lipoprotein (VLDL)-C. Total cholesterol and HDL-C can be measured easily in routine clinical laboratory studies, but LDL-C and VLDL-C cannot. However, the level of LDL-C can be calculated by substituting a measurable quantity for the immeasurable VLDL-C. For example, triglycerides can be measured and are entirely contained within the VLDL particle. Further, in the fasting state, the ratio of triglycerides to cholesterol is relatively fixed at 5:1. Therefore, the cholesterol content of VLDL-C can be represented by the measurement of total triglyceride divided by 5. With this substitution, LDL-C can be calculated by using the Friedwald equation as follows: [fleqn,10pt,legalpaper]{article} {amssymb} {amsfonts} {amsmath} {empty} {document} \[LDL-C{=}total\ cholesterol{-}(HDL-C){-}(TG/5)\] {document}Fasting is required to eliminate chylomicrons, which add variable amounts of triglyceride to the plasma and invalidate the assumption of a 5:1 triglyceride-to-cholesterol ratio. Direct measurement of LDL-C is and is for those fasting triglyceride levels mg/dL most pediatric is secondary does The most recent American Heart guidelines all children who to lipid by and liver and is the most cause of secondary in are in Lipid should be when secondary is to be to either of the of a of or the presence of other clinical or laboratory that to the of is more with than hypercholesterolemia and is with reduced levels of of LDL-C are noted in of NCEP and the American of initially but childhood cholesterol they have a to pediatric hypercholesterolemia on a and individual The that all children than of age should a diet 30% of from fat and no more than from saturated is as the The diet can be by relatively simple to most such as the and using and the intake of fatty fatty which are found in and from as saturated fat and should be to to of total These fatty LDL-C levels and HDL-C individual for of children to who have hypercholesterolemia or children from in which CAD is that all children who have a of total cholesterol mg/dL but no of CAD have a total cholesterol level total cholesterol level is than 170 mg/dL (4.4 mmol/L) no further but should be in cholesterol level is greater than 200 mg/dL (5.2 mmol/L) should have a fasting lipid fasting lipid of LDL and HDL which is up to of children who have total cholesterol levels greater than 200 mg/dL (5.2 mmol/L) may have an HDL-C level and a for LDL-C, a that a decreased risk of CAD. total cholesterol levels are between 170 and 200 mg/dL (4.4 and mmol/L) should have a the average of the is greater than 170 mg/dL (4.4 mmol/L), a fasting lipid is NCEP fasting lipid of children who have a or who has a of CAD at of age or CAD is as myocardial established coronary atherosclerosis on studies, or or disease. children who have hypercholesterolemia and those who have cholesterol levels but risk from triglyceride and HDL-C or an decrease in HDL-C LDL-C cholesterol levels than mg/dL mmol/L) are and levels greater than 130 mg/dL mmol/L) are LDL-C levels of to 130 mg/dL to 3.4 mmol/L) are borderline and measurement in The of LDL-C values should an for lipid is for children who have cardiovascular risk such as a saturated fat or children are or is The that a fasting lipid rather than a total cholesterol should be obtained for all as they the guidelines for cholesterol in childhood are for of children based on of cholesterol levels the of the pediatric on the of the adult NCEP that all adults cholesterol as as of adults in one cholesterol levels and up to one third of all children may have with respect to a of CAD. and adults, who are and have an increased risk of CAD to is to that most children who have as by NCEP cut do not have an easily However, children who have hypercholesterolemia or may have of these is hypercholesterolemia which to a that has specific and is with risk of CAD. Although adults who have a of CAD are at extremely risk of CAD. pediatric is to have children. has an and has an incidence of More than involving the LDL-C currently are noted in the in The either the quantity of receptors or one of binding to to or in of these in the of have approximately of the amount of on the endothelial which to a of the plasma of LDL-C and total LDL is in the liver LDL particles undergo and childhood total cholesterol and LDL-C levels are mg/dL mmol/L) and mg/dL mmol/L), respectively. are in most children. than of males CAD to the third of of the for or by age and by age can in the which most as a in approximately of children in the of and in the to the of of men who CAD by age years, as did of by age of CAD to particularly the is from the adult cholesterol as by the should adults and children The clinical on total cholesterol and LDL-C levels in the in the as as one and approximately of the or of LDL receptors is not necessary for the clinical but such may be in lipid has an incidence of approximately children are either for one or are plasma cholesterol levels are in excess of mg/dL mmol/L) and may be as as mg/dL mmol/L). have and that are at with all children having findings by age In to children who have children who have are to myocardial infarction as the binding of the LDL to its by a in the on the LDL particle that results in may be from and the is may be identified by which a causing an in the children who are identified as having levels of circulating total cholesterol or LDL-C, the of the and the to the of is and is For all children who have the of LDL-C begins with intervention by the The of this is to the LDL-C to 130 mg/dL mmol/L). this is not with a diet, a diet is diet the amount of saturated fat to than of total and the amount of cholesterol to than mg/dL mmol/L) of cholesterol a of 200 fat intake to than of total should not be used in children. The Study for has demonstrated the of in children when In of in young children has to in to in young children and intake in children. Therefore, should be in the of should and for children who have a on the of initial hypercholesterolemia and the of the individual LDL-C may not be with The of a diet on LDL-C levels The demonstrated an average reduction in LDL-C over the study other studies have as as to in LDL-C over the intervention When the LDL-C levels of children than 130 mg/dL mmol/L) but than mg/dL mmol/L) of a diet but LDL-C levels are for can be the that a has identified that be is for over this that these levels are guidelines to these as as the and of the of studies the of in childhood to adult CAD. are as studies of the the of when to of hypercholesterolemia in children is not The represent rather than of can be for children and an and LDL-C levels greater than mg/dL mmol/L), LDL-C levels greater than 160 mg/dL mmol/L) and is a of or the LDL-C levels greater than 160 mg/dL mmol/L) and the has or more of the risk HDL-C than 35 mg/dL (0.9 mmol/L), or such as LDL-C levels by to 30% in patients and have a of in children. but are and and have by the United States and for in children than of age and who are than of These cholesterol and cholesterol the of them should be with the are and resulting in The have to be for in children when are should be to children to be at the level of risk for early of CAD. In clinical children who are are males and who have most of have and a of CAD. should be with the of a pediatric lipid Lipid at may come from or importance of as a risk for both CAD and stroke from and epidemiologic studies of adults and children. These studies have demonstrated links between the presence of and the development of from laboratory this include studies of that the of in that have blood evidence to the development of atherosclerosis is not to studies of children that the of blood adulthood. children in the Bogalusa Heart Study who died of measurements of blood in with other risk factors such as and lipid levels were found to be with the extent of atherosclerotic who no risk factors were found to have of the intimal of coronary in who risk factors of the intimal The study demonstrated a relationship between of the arterial walls of and atherosclerotic lesions found on The strength of these and over are have demonstrated an of blood and children and over the is evidence that with factors such as and which the of an of these cardiovascular risk factors in children is by the National and findings that on the part of in and and other cardiovascular risk the of at the of the for the in children to into children and strategies as a to should be a a childhood risk for adult cardiovascular disease that is recognized and the are of the recent of childhood with its secondary of cardiovascular and the tremendous that have in the reduction of CAD over the epidemiologic studies have established as a risk for CAD. is not the of with and the significant in children and adults, the classifies as a major risk for CAD and the for and have body to the National for pediatric The allow of in the children who have at the 95th percentile or greater are as and children are between the and 95th percentiles are to be at risk for by the and the are to of the of CAD risk factors in has noted in children. The particular of with and evidence of is as the are that American adults have the children followed in the Bogalusa Heart Study, at one CAD risk and of children who three risk factors were 77% of children followed in this study for children should particular of the presence of CAD risk CAD risk with individual patients should be of it is is an risk for that risk for CAD in may be by or other of the but of these risk factors are at increased CAD risk is epidemiologic studies of patients do not for regarding the of with coronary disease may not to who In addition, the of body fat to with a greater risk than fat the for CAD risk factors is in children. However, be to the of human the that not all are to be children be to the with and to in a that preserves the and the is an extremely risk for increased risk is chemical of the LDL particles that them more on the lipid on both platelets and the coagulation factors, and the of with other risk The effect of these changes is that adults who have have the risk of coronary events as do adults who have one coronary studies that but not the coronary and of the adult NCEP guidelines for lipid in with is evidence that the of has a secondary of and children the of children were shown to have prevention or of in who have can be relatively reduction with of at-risk children is clearly by the American and by the the guidelines for and in children. the of at the of the of in a CAD risk is a complex of CAD risk as as and that risk studies have that a of CAD an risk of CAD. the of the atherosclerotic it is to that a of CAD is a for the of atherosclerosis and that are not Several such cardiovascular risk factors have and currently are to as risk more are to as both the and of atherosclerosis are is the clinical for the CAD risk that is not by of the established risk with other risk factors, evidence exposure to the development of atherosclerosis and CAD has from studies in and and epidemiologic underlying effect of exposure and its constituents is blood both and platelets are activated resulting in in and damage and intimal smooth muscle both initial in the development of circulating lipoproteins. The that results from exposure levels of fatty and is an in circulating HDL-C levels that to an in the total ratio. In a recent study of to found that who plasma and that plasma levels in excess of were with an greater total to the development of atherosclerosis the of resulting in of LDL-C by macrophages that foam cells in vessel walls, which are early precursors of other atherosclerotic United States that of young to or are When with the of and to be recognized as the most risk for the development of CAD and death in the United States. at-risk particularly those who have CAD risk factors, should on prevention and or for and for these have issued by the and in in this and decreased have with in both men and a risk of coronary The risk of death was shown to be greater for men in the of to those in the of to do not in of American children have demonstrated that the of is to the risk of a Several have issued for levels in children and for and young adults issued by the are in has as a risk for CAD for a of has to atherosclerosis risk of other risk factors in epidemiologic studies of an of has in the children of who have myocardial is a of the LDL particle that is in amounts in the plasma in which the is to which surrounds the LDL particle. has sequence and with it the of is to plasminogen at the site of a or in the coronary the rather than the of both and within an individual are and are by diet, and all lipid levels are not measured in the of CAD risk in adults, in the it may play a role in the of from that have a risk of CAD by risk in increased plasma levels of as a risk for CAD of an appreciation of the early events noted in young adults who understanding to population in which an was found between increased plasma and risk of coronary Increased levels of plasma may from relatively involving the that metabolism as as of and or an of the studies of the of adults CAD that children who a of CAD mean levels of these differences were the of the determinants of it that they would regarding the role that in the of atherosclerosis for children. Nonetheless, to the with for an of level may be justified in and in risk factors do not CAD of increased CAD risk with evidence of with has In addition, autopsy studies of have shown that may the atherosclerotic The is both and of play in the of atherosclerotic The is to have ongoing of for the prevention of have in the understanding of the of atherosclerosis over the and continue to in the of established atherosclerosis in prevention of CAD that begins in however, the for the of to of CAD that have in the to be more in CAD risk factors, particularly and it is that guidelines CAD risk in children more is an for of pediatricians in CAD risk prevention and for a greater pediatric presence in efforts to increase childhood decrease and the who a cardiovascular risk factors often provides the most for to to risk factors, and the are to for and to for with the