- *Fellow, Division of Pediatric Nephrology, Department of Pediatrics
- †Associate Professor of Clinical Pediatrics, Department of General Pediatrics, Division of General Pediatrics
- ‡Professor of Clinical Pediatrics; Director, Division of General Pediatrics, Department of Pediatrics, Albert Einstein College of Medicine/Children’s Hospital at Montefiore, Bronx, New York
After completing this article, readers should be able to:
Describe the development of atherosclerotic plaque.
Discuss the two-pronged approach to addressing pediatric hypercholesterolemia advocated by the National Cholesterol Education Program and the American Academy of Pediatrics.
Describe the criteria for using lipid-lowering medication in children.
List risk factors for coronary artery disease that should be addressed in pediatric patients.
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.
Current Understanding of Atherosclerosis
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:
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 concentration is available through some commercial laboratories and is indicated for those people whose fasting triglyceride levels exceed 400 mg/dL (4.5 mmol/L).
Although most pediatric hyperlipidemia is primary, secondary hyperlipidemia does occur. The most recent American Heart Association (AHA) guidelines suggest screening all children who fail to meet lipid goals by measuring thyroid-stimulating hormone and employing liver function tests, renal function tests, and urinalysis. Currently, obesity is the most common cause of secondary hyperlipidemia in childhood. Other causes are listed in Table 1. Lipid specialists should be involved when secondary hyperlipidemia is suspected to be due to rare causes either because of the absence of a family history of hyperlipidemia or the presence of other unusual clinical or laboratory features that suggest another disorder. Contrary to the beliefs of many practitioners, obesity is associated more commonly with hypertriglyceridemia than hypercholesterolemia and is associated almost universally with reduced levels of HDL-C. Modest elevations of LDL-C are noted in 20% of obese patients.
|Storage and Metabolic Diseases|
Evaluating Children Who Have Risk Factors for Hypercholesterolemia
The NCEP and the American Academy of Pediatrics (AAP) initially considered but rejected universal childhood cholesterol screening. Instead, they have proposed a two-pronged approach to addressing pediatric hypercholesterolemia on a population-based and individual patient level. The population-based approach stipulates that all children older than 2 years of age should consume a low-fat diet (ie, 30% of daily calories from fat and no more than 10% from saturated fat). This is known as the AHA Step 1 diet. The Step 1 diet can be achieved by relatively simple measures familiar to most physicians, such as following the Food Pyramid and using low-fat dairy products, avoiding fried foods, and limiting the intake of trans unsaturated fatty acids. Trans fatty acids, which are found in food products containing partially hydrogenated vegetable oil, some margarines, and deep fried food from fast food chain restaurants, count as saturated fat and should be limited to 2% to 3% of total calories. These fatty acids raise LDL-C levels and lower HDL-C levels.
The individual patient approach sets forth criteria for targeted testing of children born to parents who have hypercholesterolemia or children from families in which premature CAD is documented. This approach recommends that all children who have a parental history of elevated total cholesterol (>240 mg/dL [6.2 mmol/L]) but no family history of premature CAD have a nonfasting total serum cholesterol level measured. Children whose total cholesterol level is less than 170 mg/dL (4.4 mmol/L) require no further intervention, but should be re-evaluated in 5 years. Children whose cholesterol level is greater than 200 mg/dL (5.2 mmol/L) should have a fasting lipid profile performed. A fasting lipid profile allows quantification of LDL and HDL levels, which is important because up to 15% of children who have total cholesterol levels greater than 200 mg/dL (5.2 mmol/L) may have an elevated HDL-C level and a normal value for LDL-C, a condition that confers a decreased risk of CAD. Children whose total cholesterol levels are between 170 and 200 mg/dL (4.4 and 5.3 mmol/L) should have a repeat test; if the average of the two tests is greater than 170 mg/dL (4.4 mmol/L), a fasting lipid profile is recommended.
The NCEP recommends fasting lipid profile testing of children who have a parent or grandparent who has a history of CAD at 55 years of age or younger. CAD is defined as myocardial infarction, angina pectoris, established coronary atherosclerosis on diagnostic studies, sudden cardiac death, or peripheral or cerebrovascular disease. This strategy identifies children who have hypercholesterolemia and those who have normal cholesterol levels but whose risk stems from dyslipidemia (increased triglyceride and low HDL-C levels) or an isolated decrease in HDL-C concentration. LDL-C cholesterol levels less than 110 mg/dL (2.8 mmol/L) are considered acceptable, and levels greater than 130 mg/dL (3.4 mmol/L) are considered elevated. LDL-C levels of 110 to 130 mg/dL (2.8 to 3.4 mmol/L) are considered borderline and necessitate repeat measurement in 1 year. The finding of elevated LDL-C values should trigger an individualized treatment plan, including dietary advice.
Testing for lipid abnormalities is recommended for children who have another cardiovascular risk factor such as hypertension, diabetes, obesity, a high saturated fat intake, or smoking. Testing children whose family histories are unknown or unknowable is discretionary. The authors believe that a fasting lipid profile rather than a total cholesterol determination should be obtained for all obese children.
As carefully crafted as they are, the current guidelines for cholesterol testing in childhood are frustrating for many clinicians. First, targeted testing of children based on parental knowledge of their own cholesterol levels renders the sensitivity of the pediatric guideline dependent on the successful implementation of the adult NCEP guideline that all adults “know their cholesterol level.” Unfortunately, as few as 39% of adults in one survey had ever had their cholesterol levels measured, and up to one third of all children may have missing information with respect to a family history of premature CAD. This phenomenon affects predominately single parent families and medically underserved adults, who typically are economically disadvantaged and whose offspring have an increased risk of CAD related to socioeconomic disadvantage.
It is important to note that most children who have hyperlipidemia, as defined by NCEP cut points, do not have an easily clinically identifiable genetic abnormality. However, children who have severe hypercholesterolemia or hypertriglyceridemia may have clinically identifiable genetic conditions. One of these conditions is familial hypercholesterolemia (FH), which refers to a genetically transmitted disorder that has specific characteristics and is associated with high future risk of CAD. Although adults who have FH constitute a minority of CAD victims, affected individuals are at extremely high risk of future CAD. Every pediatric practice is likely to have several affected children. FH has an autosomal codominant inheritance, and heterozygous FH has an estimated incidence of 1 per 500 worldwide. More than 63 allelic mutations involving the LDL-C receptor currently are noted in the Online Mendelian Inheritance in Man™ database. The mutations affect either the quantity of receptors or one of several functions, including binding to LDL, internalization once bound to LDL, or recycling. Defects in any of these steps result in the phenotypic manifestations of FH. Affected individuals have approximately only 50% of the normal amount of LDL-receptor function on the endothelial surface, which effectively leads to a doubling of the plasma concentrations of LDL-C and total cholesterol. Most diminished LDL receptor activity is in the liver where LDL particles undergo uptake and metabolism.
In childhood heterozygous FH, total cholesterol and LDL-C levels are typically 300±60 mg/dL (7.8±1.6 mmol/L) and 240±60 mg/dL (6.2±1.6 mmol/L), respectively. Clinical manifestations are absent in most children. Fewer than 5% of males develop CAD prior to the third decade of life. Examinations of the parents for tendinous, cutaneous, or palpebral xanthomas (70% by age 30 years) and arcus corneae (10% by age 30 years) can aid in the diagnosis. Xanthomas, which present most commonly as a thickened Achilles tendon, develop in approximately 3% of affected children in the first decade of life and 13% in the second decade.
Prior to the availability of medication, 50% of men who had FH had symptomatic CAD by age 50 years, as did 50% of women by age 60 years. Thus, family history of premature CAD fails to identify many affected children, particularly if the condition is inherited from the maternal side. Universal adult cholesterol screening, as recommended by the NCEP, should identify affected adults and their children secondarily. The clinical diagnosis relies on total cholesterol and LDL-C levels in the FH range in the child as well as one parent and approximately 50% of the siblings. Quantitative or functional assessment of LDL receptors is not necessary for the clinical diagnosis, but such assessment may be available in lipid research facilities. Homozygous FH has an incidence of approximately 1 per 1 million. Affected children are either homozygous for one abnormal allele or are compound heterozygotes. Their plasma cholesterol levels frequently are in excess of 600 mg/dL (15.5 mmol/L) and may be as high as 1,200 mg/dL (31 mmol/L). They also have unique and prominent cutaneous xanthomas that frequently are present at birth, with virtually all children having physical findings by age 6 years. In contrast to children who have heterozygous FH, children who have homozygous FH are vulnerable to myocardial infarction during childhood.
A clinically similar disorder, known as familial defective apo B, affects the binding of the LDL to its receptor by a mutation in the apolipoprotein B moiety on the LDL particle that results in hypercholesterolemia. Familial defective apo B may be clinically indistinguishable from FH, and the treatment is similar. This condition may be identified by molecular analysis, which will disclose a single missense mutation causing an amino acid substitution in the apo B molecule.
For children who are identified as having elevated levels of circulating total cholesterol or LDL-C, the attention of the family and the pediatrician must shift to the issue of treatment: what is safe and what is effective. For all children who have hypercholesterolemia, the treatment of elevated LDL-C begins with dietary intervention by instituting the AHA Step 1 diet. The goal of this therapy is to lower the LDL-C to below 130 mg/dL (3.4 mmol/L). If this goal is not achieved with a Step 1 diet, a Step 2 diet is initiated. This diet limits the amount of saturated fat calories to less than 7% of total calories and the amount of cholesterol to less than 66 mg/dL (1.7 mmol/L) of cholesterol per 1,000 kcal daily (to a maximum of 200 mg [5.2 mmol]/24 h). Diets restricting fat intake to less than 20% of total calories should not be used in children. The Dietary Intervention Study for Children (DISC) has demonstrated the safety of low-fat diets in children when implemented under medical supervision. In contrast, unsupervised parental implementation of low-fat hypocaloric diets in young children has been reported to result in failure to thrive in young children and inadequate caloric intake in older children. Therefore, dietitians should be involved in the implementation of Step 2 diets. Physicians should monitor weight and growth parameters carefully for any children who have been prescribed a diet.
Depending on the severity of initial hypercholesterolemia and the dietary responsiveness of the individual LDL-C levels, goals may not be attainable with dietary therapy alone. The effectiveness of a low-cholesterol diet on reducing LDL-C levels varies. The DISC demonstrated only an average 2-mg/dL (0.5-mmol/L) reduction in LDL-C over the 7-year study period; other studies have reported as high as 10% to 15% reductions in LDL-C over the dietary intervention period. When the LDL-C levels of children remain higher than 130 mg/dL (3.4 mmol/L) but lower than 190 mg/dL (4.9 mmol/L) after implementation of a diet but LDL-C levels are too low for drug treatment, there can be the sense that a problem has been identified that cannot be remediated fully. This is frustrating for clinicians who, after creating anxiety over this issue, then must reassure parents that these levels are acceptable. Updated guidelines need to address these issues as well as the identification and treatment of the dyslipidemia of obesity.
No known studies directly demonstrate the efficacy of administering lipid-lowering medication in childhood to prevent adult CAD. Nor are there as yet any long-term safety studies of the newer lipid-lowering agents. Beyond this, the optimal timing of when to initiate treatment of severe hypercholesterolemia in children is not established. The following guidelines, therefore, represent expert consensus rather than evidence-based medicine.
The use of lipid-lowering medication can be considered for children ages 10 years and older if an adequate dietary trial fails and a) LDL-C levels remain greater than 190 mg/dL (4.9 mmol/L), b) LDL-C levels remain greater than 160 mg/dL (4.1 mmol/L) and there is a family history of premature CAD, or c) the LDL-C levels remain greater than 160 mg/dL (4.1 mmol/L) and the patient has two or more of the following six risk factors: diabetes mellitus, smoking, hypertension, obesity, HDL-C less than 35 mg/dL (0.9 mmol/L), or physical inactivity. Bile acid sequestrants such as cholestyramine reduce LDL-C levels by 10% to 30% in some patients and have a long history of safe use in children. Initial unpleasant but minor adverse effects are common and frequently impair long-term adherence. Lovastatin and atorvastatin recently have been approved by the United States Food and Drug Administration for use in male children older than 10 years of age and postmenarchal females who are older than 10 years of age. These drugs inhibit endogenous cholesterol synthesis, upregulate LDL-receptor expression, and dramatically lower cholesterol levels.
Although adverse effects rarely limit the use of statins, physicians prescribing them should be familiar with their adverse effects profiles. Among the potentially serious adverse effects are hepatitis, myositis, and rhabdomyolysis resulting in renal failure. The statins have been proven to be safe for short-term use in children when monitoring protocols are followed. Medication use should be targeted to children deemed to be at the highest level of risk for early onset of CAD. In clinical practice, children who are receiving lipid-lowering medication generally are teenage males and females who have achieved menarche, most of whom have heterozygous FH and a positive family history of premature CAD. Patients requiring lipid-lowering medication should be managed with the help of a pediatric lipid specialist. Lipid specialists at referral centers may come from various academic backgrounds, including cardiology, gastroenterology, endocrinology, genetics/metabolic diseases, or general pediatrics.
The importance of hypertension as a well-established risk factor for both CAD and stroke derives from pathophysiologic and epidemiologic studies of adults and children. These studies have demonstrated convincing links between the presence of hypertension and the development of atheromatous lesions.
Evidence from laboratory investigations confirming this linkage include animal studies of hyperlipidemia that demonstrate the acceleration of atherogenesis in animals that have elevated blood pressure.
Epidemiologic evidence linking hypertension to the development of atherosclerosis is not limited to adults. Observational studies of children indicate that the effects of high blood pressure begin well before adulthood. Among 204 children enrolled in the Bogalusa Heart Study who died accidentally of trauma, antemortem measurements of blood pressure in concert with other risk factors such as obesity and abnormal serum lipid levels were found to be significantly associated with the extent of postmortem atherosclerotic lesions. Individuals who had no risk factors were found to have 1.3% of the intimal surfaces of their coronary arteries covered in atheromatous changes; individuals who had four risk factors had 11% of the intimal surfaces involved. The PDAY study also demonstrated a strong relationship between thickening of the renal arterial walls (a surrogate pathologic marker of hypertension) and atherosclerotic lesions found on autopsy. The strength of these associations and their trends over time are equally alarming. Recently published surveys have demonstrated an increasing prevalence of high blood pressure and obesity among children and adolescents over the past several decades. Moreover, there is evidence that hypertension clusters with factors such as dyslipidemia and insulin resistance, which also favor the progression of atherosclerosis.
The concern about an epidemic of these cardiovascular risk factors in children is augmented by the National Heart, Lung and Blood Institute survey findings that demonstrate deficiencies on the part of clinicians in recognizing and managing hypertension and other cardiovascular risk factors. (See the list of Internet resources at the end of the article for the full report.) Because essential hypertension in older children appears to persist into adulthood, identifying affected children and implementing preventive health care strategies as a complement to public health measures should be a priority. Too often, hypertension remains a childhood risk factor for adult cardiovascular disease that is poorly recognized and undertreated.
Pediatricians throughout the developed world are well aware of the recent epidemic of childhood obesity with its attendant secondary epidemics of cardiovascular and noncardiovascular complications. This epidemic threatens the tremendous gains that have been achieved in the reduction of CAD over the last 3 decades.
Numerous epidemiologic studies have established obesity as a risk factor for premature CAD. This is not surprising, given the frequent association of obesity with hypertension, dyslipidemia, insulin resistance, and frank diabetes. Acknowledging the significant rise in obesity prevalence among children and adults, the AHA classifies obesity as a major risk factor for CAD and the Centers for Disease Control and Prevention (CDC) have added body mass index (BMI) charts to the National Center for Health Statistics (NCHS) pediatric growth charts. The new charts allow serial assessment of adiposity in childhood. Using the NCHS charts, children who have BMIs at the 95th percentile or greater are classified as obese and children whose BMIs are between the 85th and 95th percentiles are considered to be at risk for persistent obesity.
These actions by the AHA and the CDC are public health measures intended to raise awareness of the clustering of CAD risk factors in obese individuals. This clustering has been noted repeatedly in obese children. The particular association of obesity with hypertension, dyslipidemia, and evidence of insulin resistance is known as the metabolic syndrome. Current estimates are that 47 million American adults have the metabolic syndrome.
Among obese children followed in the Bogalusa Heart Study, 58% had at least one CAD risk factor, and 75% of children who had three risk factors were obese. Furthermore, 77% of obese children followed in this study became obese adults. Thus, physicians caring for obese children should take particular note of the presence of CAD risk factors.
Physicians discussing CAD risk with individual patients should be aware of several points. First, it is still unclear whether obesity is an independent risk factor for CAD; that is, risk for CAD in overweight individuals may be mediated by dyslipidemia, hypertension, sedentariness, diabetes, or other aspects of the metabolic syndrome, but whether overweight individuals free of these risk factors are at increased CAD risk is unknown. Many epidemiologic studies of obese patients do not control for physical condition and, therefore, their conclusions regarding the association of obesity with coronary disease may not apply to obese individuals who exercise regularly. In addition, the distribution of body fat appears to modulate risk, with abdominal obesity conferring a greater risk than fat distributed around the hips.
Clearly, vigilance for CAD risk factors is warranted in overweight children. However, physicians must be sensitive to the complexities of human obesity, including the finding that not all obese individuals are destined to be unhealthy adults. Finally, physicians managing obese children must be alert to the social stigma associated with overweight and strive to counsel families in a manner that preserves the family’s and the child’s self-esteem.
Diabetes is an extremely potent risk factor for atherosclerosis. This increased risk is mediated through multiple mechanisms, including chemical modification of the LDL particles (glycation) that makes them more atherogenic, adverse effects on the lipid profile (diabetic dyslipidemia), prothrombotic effects on both platelets and the coagulation factors, and the association of diabetes with other risk factors. The net effect of these changes is that adults who have diabetes have the same 10-year risk of future coronary events as do adults who already have had one coronary event. Longitudinal studies suggest that maximal glycemic control prevents microvesicular complications but not the coronary and peripheral vascular complications of diabetes. Consequently, the new adult NCEP treatment guidelines call for aggressive lipid lowering in affected adults.
As with hypertension, there is incontrovertible evidence that the current epidemic of obesity has created a secondary epidemic of insulin resistance and type 2 diabetes among children throughout the developed world. Fully 24% of obese children recently studied were shown to have glucose intolerance. Because prevention or postponement of type 2 diabetes in obese individuals who have glucose intolerance can be achieved through relatively modest weight reduction coupled with regular exercise, identification of at-risk children is clearly justified. A consensus statement by the American Diabetes Association and endorsed by the AAP outlines the guidelines for testing, preventing, and treating type 2 diabetes in children. (See the list of Internet resources at the end of the article.)
Family History of Premature CAD
The weighting of family history in assessing a child’s future CAD risk is a complex issue. A family history of CAD encompasses genetically transmitted risk as well as shared environment and behaviors that affect modifiable risk factors.
Several studies have suggested that a family history of premature CAD confers an additional (independent) risk of future CAD. Given the complexity of the atherosclerotic process, it is reasonable to assume that a family history of premature CAD is a proxy for numerous inherited conditions favoring the progression of atherosclerosis and thrombosis that are not yet understood fully. Several such cardiovascular risk factors have been elucidated and currently are referred to as nontraditional risk factors. Many more are likely to emerge as both the pathophysiology and genetics of atherosclerosis are studied. Currently, family history is the best, albeit crude, clinical tool for assessing the inherited tendency toward CAD risk that is not captured by evaluation of the established risk factors.
As with other risk factors, evidence linking tobacco exposure to the development of atherosclerosis and CAD has accumulated from pathologic studies in humans and animals and epidemiologic observation.
The underlying pathophysiologic effect of tobacco exposure and its constituents is complex. Among blood components, both neutrophils and platelets are activated upon tobacco exposure, resulting in elevations in free radicals and platelet-derived growth factor. Free radicals damage endothelium, and platelet-derived growth factor increases intimal smooth muscle proliferation, both initial steps in the development of atherosclerosis. Tobacco also affects circulating lipoproteins. The cholinergic stimulation that results from nicotine exposure activates hormone-sensitive lipase, increasing levels of free fatty acids, VLDL-C, and LDL-C. There is also an independent dose-dependent decline in circulating HDL-C levels that leads to an elevation in the total cholesterol:HDL-C ratio. In a recent study of suburban New York high school adolescents exposed to environmental tobacco smoke, researchers found that adolescents who had two smoking parents had significantly higher plasma cotinine concentrations and that plasma cotinine levels in excess of 2.5 ng/mL were associated with an 8.9% greater total cholesterol:HDL ratio.
Tobacco smoke also contributes to the development of atherosclerosis through the oxidative modification of LDC itself, resulting in enhanced uptake of LDL-C by scavenger macrophages that become foam cells deposited in vessel walls, which are early precursors of other atherosclerotic changes.
The United States government estimates that 20% of young people ages 12 to 17 years or about 4.5 million adolescents are regular smokers. When combined with the numbers of infants, children, and adolescents exposed to environmental tobacco smoke, cigarette smoking must be recognized as the single most prevalent preventable risk factor for the development of CAD and premature death in the United States. Pediatricians addressing at-risk children, particularly those who have nonmodifiable CAD risk factors, should devote time counseling families on smoking prevention and or smoking cessation for parents and teens. Guidelines for these activities have been issued by the Surgeon General (see “Tobacco Prevention and Cessation in Pediatric Patients” in this issue).
Physical Activity and CAD Risk
Physical inactivity and decreased exercise capacity have been linked repeatedly with multiple adverse health outcomes in both men and women, including a risk of coronary events. The risk of death was recently shown to be fourfold greater for men in the lowest quintile of exercise capacity relative to those in the highest quintile. Fully 50% of youth ages 12 to 21 years do not engage in regular vigorous activity. Studies of sedentariness among American children have demonstrated convincingly that the duration of daily television viewing is strongly linked to the risk of future obesity. Decreasing sedentariness requires a multipronged public health effort. Several agencies have issued recommendations for activity levels in children and adolescents. Messages for adolescents and young adults issued by the CDC are presented in Table 2.
Nontraditional Risk Factors for CAD
Lipoprotein(a) (Lp(a)) has generated interest as a risk factor for CAD for a number of reasons. First, Lp(a) concentration has been linked to atherosclerosis risk independently of other risk factors in numerous epidemiologic studies of adults. Second, an elevated concentration of Lp(a) has been observed in the children of parents who have had myocardial infarction. Lp(a) is a subclass of the LDL particle that is present in varying amounts in the plasma in which the apoprotein B is linked covalently to another apoprotein, apoprotein(a), which surrounds the LDL particle. Apoprotein(a) has shared gene sequence and structural homology with plasminogen, yet it lacks the fibrinolytic activity of plasminogen. Thus, Lp(a) is hypothesized to inhibit plasminogen activity competitively at the site of a thrombus or clot in the coronary circulation, thereby favoring the stabilization rather than the dissolution of both macro- and microthrombi. Lp(a) concentrations within an individual are determined genetically and are unaffected by diet, exercise, and almost all lipid lowering-drugs. Lp(a) levels are not measured routinely in the assessment of CAD risk in adults, although in the future it may play a role in the assessment of individuals from families that have a high risk of premature CAD unexplained by traditional risk factors.
Interest in increased plasma levels of homocysteine as a risk factor for CAD grew out of an appreciation of the early thrombotic events noted in young adults who had homocystinuria. This understanding led to population surveys in which an association was found between increased plasma homocysteine concentrations and risk of coronary atherosclerosis. Increased levels of plasma homocysteine may result from relatively common mutations involving the enzymes that regulate homocysteine metabolism as well as subclinical deficiencies of vitamins B6, B12, and folate or an interaction of the two. Two studies of the offspring of adults experiencing premature CAD showed that children who had a parental history of CAD had higher mean levels of homocysteine, although these differences were neither dramatic nor distinguishing. Given the complexity of the determinants of homocysteine levels, it seems unlikely that they would track well throughout childhood. Many questions remain regarding the role that homocysteine concentration plays in the progression of silent atherosclerosis for children. Nonetheless, similar to the situation with Lp(a), testing for an elevation of homocysteine level may be justified in individuals and families in whom traditional risk factors do not explain premature CAD adequately.
A fascinating association of increased CAD risk with serologic evidence of preceding infection with Chlamydia has been described. In addition, autopsy studies of animals have shown that Chlamydia infection may potentiate the atherosclerotic process. The association is biologically plausible because both leukocytes and molecular mediators of inflammation play roles in the maturation of atherosclerotic plaque. The link is sufficiently strong to have generated several large-scale ongoing prospective trials of antibiotic use for the prevention of CAD.
Remarkable advances have been made in the understanding of the molecular pathogenesis of atherosclerosis over the last decade and will continue to drive great progress in the treatment of established atherosclerosis in adults. Primary prevention of CAD that begins in childhood, however, remains the greatest challenge for pediatricians, especially because the current epidemic of obesity threatens to reverse reductions of CAD prevalence that have been achieved in the past few decades.
Pediatricians need to be more vigilant in detecting CAD risk factors, particularly among obese patients, and it is likely that forthcoming guidelines will address CAD risk in obese children more systematically. This is an opportune moment for renewed engagement of pediatricians in CAD risk prevention and for a greater pediatric public health presence in community-based efforts to increase childhood activity levels, decrease smoking, and promote healthful eating habits.
Ironically, the pediatrician who takes a child’s cardiovascular risk factors seriously often provides the most effective impetus for parents to begin to address their own risk factors, and the entire family benefits.
|Many of the following sites offer excellent information for both professionals and patients or parents beyond what is identified below.|
|Physical Activity and Fitness|
The authors are indebted to Dr. Michael I. Cohen for his support and to Ms. Zenaida Soto for her help with the manuscript.
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