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2. State of the Science: Cardiovascular Risk Factors and the Development of Atherosclerosis in Childhood

This section presents the results of a critical review of the evidence that atherosclerosis begins in childhood and that this process, from its earliest phases, is related to the presence and intensity of known cardiovascular (CV) disease (CVD) risk factors (see Table 2–1). As described in Section I. Introduction, the literature search for these Guidelines addressed 14 critical questions (I. Introduction, Table 1–1). Of these, the first nine pertain to evidence that atherosclerosis begins in childhood and that early atherosclerosis is associated with the presence and intensity of identified risk factors; it is this evidence that is reviewed here. A conceptual model for CVD prevention by pediatric care providers beginning in childhood was developed based on the evidence review.

The risk factors considered in this analysis are listed in Table 2–1. Each risk factor exists within a behavioral, environmental, physiologic, and genetic context that provides the rationale for its consideration as a risk factor that could be used to identify persons who are at elevated risk or who may be the target of intervention. Included are conditions of life (family history, age, gender), measurable pathophysiologic risk factors (high blood pressure, lipids, overweight/obesity, diabetes mellitus), behavioral factors (tobacco exposure, nutrition/diet, physical inactivity), and emerging risk factors (metabolic syndrome, inflammatory markers, perinatal factors).

Table 2–1. Risk Factors for Cardiovascular Disease

Family history

Age

Gender

Nutrition/diet

Physical inactivity

Tobacco exposure

High blood pressure

Blood lipids

Overweight/obesity

Diabetes mellitus and other predisposing conditions

Metabolic syndrome

Perinatal factors

Inflammatory markers

Atherosclerotic vascular disease events—such as myocardial infarction, stroke, peripheral arterial disease, and ruptured aortic aneurysm—are the culmination of a lifelong disease process.[1],[2] Pathologically, the process begins with the accumulation of abnormal lipid in the carotid intima, a reversible stage, progressing to an advanced stage in which a core of extracellular lipid is covered by a fibromuscular cap, culminating in thrombosis, vascular rupture, or acute ischemic syndromes.[1] Although the advanced stages of atherosclerosis and related clinical events are observed almost exclusively in adults, the initial phases of this chronic process are observed in childhood, with early changes identified even in the fetus (Figure 2‑1).[2],[3],[4]

Figure 2–1. Atherosclerosis: A Progressive Process

Pathologic progression of atherosclerosis with aging, from no visible atheros at birth to development of complex plaques with potential rupture & thrombosis in mid-late adulthood. The process begins in the first decade of life when initial risk exposures occur. The progression of athero is exacerbated & intensified by the presence of risk factors. The solid white line indicates clinical events as shown. Except in rare circumstances atherosclerotic disease is subclinical for the first 2-3 decades of life.

Figure 2-1 depicts the pathologic progression of atherosclerosis with aging, from no visible atherosclerosis at birth to the development of complex plaques with potential rupture and thrombosis in mid- to late adulthood. The process begins in the first decade of life when initial risk exposures occur. The progression of atherosclerosis is exacerbated and intensified by the presence of risk factors. The solid white line indicates clinical events as shown. Except in rare circumstances, atherosclerotic disease is subclinical for the first two to three decades of life.

Relationship of Risk Exposure to Atherosclerosis Development and Cardiovascular Events

The most important evidence for the relationship of childhood risk factors to CVD is the establishment of a direct relationship between risk exposure and events. This evidence is best obtained from long-term observational studies beginning in childhood, with risk factors measured and related to CVD outcomes later in life. Because of the time course of atherosclerosis, studies of 50 to 60 years' duration linking early risk to CV events are impractical, although studies exist in which risk was measured in early adulthood and outcomes were measured much later in life. Clinical trials of voluntary risk exposure, in which children would be randomized at birth to become, for example, chronic smokers, to determine the likelihood of future heart attack decades later, would be both impractical and unethical.

Thus, studies examining the clinical importance of CV risk in childhood must consider end points recognized as intermediate stages in the pathogenesis of CVD. This pathway is illustrated in Figure 2–2. Studies of this pathway include correlation analyses of risk factors measured either ante mortem or post mortem, with the extent of atherosclerosis at autopsy following accidental death early in life; longitudinal studies of individuals with specific genetic mutations that confer either lifelong risk exposure or protection; studies of individuals with risk assessed in childhood and subclinical measures of atherosclerosis (e.g., carotid intima media thickness (cIMT), coronary calcium measurements by computerized tomography assessed in young adulthood; studies of high-risk children who demonstrate cardiac or vascular end organ injury; and population-based studies demonstrating that the presence of risk factors in childhood predict risk in adulthood (tracking studies). Also relevant are studies of factors associated with the development of risk factors, such as a high-fat diet and a physically inactive lifestyle. The evidence review for these Guidelines includes examples of all of these study types.

Figure 2–2. Evidence Pathways Used in Developing Pediatric Cardiovascular Risk Reduction Guidelines

Figure 22. Flow chart showing evidence pathways used in developing pediatric cardiovascular risk reduction guidelines. A text description follows the chart.

Legend to Figure 22: This flow diagram depicts the timeline for development of cardiovascular (CV) risk, atherosclerosis, and CV events along a continuum extending from before birth to adult life. The studies composing the evidence pathway are displayed relative to this process. Studies describing environmental or behavioral factors that affect the process are shown on the left side, and potential pathophysiologic or medical actions are shown on the right. The complexity of the evidence development process is apparent in the multiple interrelationships between risk factors that change and evolve throughout the history of each individual from childhood to adulthood. Atherosclerosis develops more rapidly as the number and the intensity of risk factors increase.

Figure 2-2 Text Description

The figure is a flow chart with 11 labeled boxes linked by arrows. The chart flows in one direction with arrows pointing downward and lateral arrows to one or more boxes. Below, the flow chart is described as lists in which the possible next steps are listed beneath each box label.

  1. Newborns at Risk
    1. Forward to Risk Factor (RF) Exposures
    2. Forward to RF Identification
    3. Forward to Children at Risk
  2. Fetal Exposures
    1. Lateral to Newborns at Risk
  3. Genetic Input
    1. Lateral to Newborns at Risk
  4. Risk Factor (RF) Exposures:
    -Environment
    -Home
    1. Forward to Children at Risk
  5. RF Identification
    1. Forward to Children at Risk
  6. Children at Risk
    1. Forward to Lifestyle Interventions
    2. Forward to Intermediate Outcomes
    3. Forward to Pharmacologic Interventions
  7. Intermediate Outcomes
    Atherosclerosis
    Subclinical Atherosclerosis
    End organ injury
    1. Lateral to Lifestyle Interventions
    2. Lateral to Pharmacologic Interventions
    3. Forward to Adults at Risk
  8. Lifestyle Interventions
    1. Forward to Adults at Risk
    2. Lateral to Intermediate Outcomes
  9. Pharmacologic Interventions
    1. Forward to Adults at Risk
    2. Lateral to Intermediate Outcomes
  10. Adults at Risk
    1. Foward to Clinical Cardiovascular Disease Outcomes
  11. Clinical Cardiovascular Disease Outcomes
    Morbidity Mortality Quality of Life

Considered collectively, these studies constitute an evidence chain, with the strength of the body of evidence represented in the evidence grades. Studies evaluated for the Guidelines may have examined single links in the chain of evidence, may have connected several links simultaneously, or may have evaluated the consequences of specific interventions for risk-benefit analysis. Although each study is graded individually in the evidence tables, the Expert Panel assigned summary grades for the body of evidence reviewed in developing each recommendation. The many evidence pathways pursued in preventive cardiology research and included in the evidence reviewed for the Guidelines are displayed in Figure 2–2. Some studies encompass the entire lifespan (e.g., natural history of familial hypercholesterolemia, relationship of low birth weight to CV mortality), whereas others examine the impact of interventions on intermediate outcomes (e.g., impact of cholesterol-lowering therapy on subclinical atherosclerosis, effect of exercise on CV risk factor development). The studies that make up the pathways in Figure 2–2 provide evidence addressing the key questions critical to this evidence review—including associations between exposures and outcomes, efficacy of screening for conditions of interest, the presence of adverse consequences of screening, the efficacy of interventions on outcomes, and the adverse consequences of interventions. This evidence inquiry is limited by the absence of reports of cost-effectiveness analyses of the screening and intervention strategies to lower CV risk in childhood. In contrast to adult guidelines, the challenge of preparing evidence-based guidelines for CV risk reduction in childhood is augmented by the scarcity of evidence pertaining to the impact of preventive interventions on mortality, morbidity, and quality of life.

Acute CV events in adults are the culmination of two processes: (1) the development and long-term progression of atherosclerosis and (2) a more acute thrombotic process associated with atherosclerotic plaque instability and rupture.[1] The pediatric component of this process is the development of atherosclerosis; thrombosis does not occur in the absence of the atherosclerotic substrate. With aging, the role of risk assessment changes. Prevention of atherosclerosis development receives greater emphasis in children and young adults. In older adults, importance is placed on factors associated with the progression of atherosclerosis and factors associated with acute events, such as predisposition to thrombosis or plaque instability.

SUMMARY OF THE EVIDENCE REVIEW OF PATHOLOGIC STUDIES OF ATHEROSCLEROSIS IN CHILDHOOD

Atherosclerosis at a young age was first identified in Korean War and Vietnam War casualties.[5],[6] Two major contemporary studies, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) and the Bogalusa Heart Study (Bogalusa), have subsequently demonstrated atherosclerosis, indicated by fatty streaks and more advanced lesions, in children, adolescents, and young adults who died as a result of unintentional injury. In the Bogalusa study, CV risk factors (lipids, blood pressure, body mass index (BMI), tobacco use) were measured as part of a comprehensive school-based epidemiologic study of a biracial community. Findings were related to atherosclerosis measured at autopsy after accidental death, and strong correlations were shown between the presence and intensity of risk factors and the extent and severity of atherosclerosis.[3],[7] In the PDAY study, risk factors and surrogate measures of risk factors were measured post mortem in 15- to 34-year-olds who died accidentally of external causes. Strong relationships were demonstrated between atherosclerotic severity and extent and the presence and intensity of known risk factors, including higher age, higher non-high-density lipoprotein cholesterol (non-HDL–C), lower HDL cholesterol (HDL–C), hypertension (determined by renal artery thickness), tobacco use (thiocyanate concentration), diabetes mellitus (glycohemoglobin), and obesity in males. There was a strikingly higher atherosclerotic severity and extent as the number of risk factors increased.[8],[9],[10],[11] An international study with more limited information on risk factors was consistent with these findings.[12]

Figure 2–3, from the PDAY study, shows the relationship between the number of identified CV risk factors and the pathologic lesions of atherosclerosis by age in the right coronary artery, using maps of arterial segments created by converting pathologically classified lesions to computerized images. These are displayed as prevalence maps of fatty streaks and raised lesions, with color intensity reflecting the density and grade of the lesions.[13] In 15- to 24-year-old subjects, the maps demonstrate the impact of increasing numbers of risk factors on both the presence and severity of the atherosclerotic process. Comparison with 25- to 34-year-olds shows the impact of both age and multiple risk factors. Risk, particularly the presence of multiple risk factors, accelerates the development of atherosclerosis. Finally, and most importantly, Figure 2–3 demonstrates that the absence of identified risk factors is associated with a virtual absence of advanced atherosclerotic lesions (American Heart Association Grades IV and V) in 15- to 34-year-olds.

Figure 2–3. Atherosclerosis Maps of the Right Coronary Artery

Figure 23. Computerized images from the Pathobiological Determinants of Atherosclerosis in Youth study are prevalence maps of fatty streaks and raised lesions, with color intensity reflecting the density and grade of the lesions for the two age groups and the number of risk factors.

These computerized images from the Pathobiological Determinants of Atherosclerosis in Youth study are prevalence maps of fatty streaks and raised lesions, with color intensity reflecting the density and grade of the lesions for the two age groups and the number of risk factors.

SOURCE: Edward E. Herderick and C. Alex McMahan for the Pathobiological Determinants of Atherosclerosis in Youth Study Group, unpublished observation.

Comparison of the PDAY cohort to population-based data on CV risk factors obtained concurrent with acquisition of PDAY specimens suggests that risk distribution of the PDAY cohort mirrors the general population, after adjustment for factors associated with premature death.[14] This comparison to a living cohort also suggests that the PDAY risk relationships are conservative; measuring risk post mortem adds additional variability to the plasma- and serum-based risk measures.

SUMMARY OF THE EVIDENCE REVIEW ON MEASURES OF END ORGAN INJURY AND ATHEROSCLEROSIS IMAGING STUDIES

Measures of subclinical atherosclerosis and end organ injury include the presence of coronary calcium on electron beam computerized tomography (EBCT) imaging, increased medial thickness of the carotid artery assessed with ultrasound (cIMT), reduced endothelium-dependent dilation of the brachial artery with ultrasound imaging (flow-mediated dilation (FMD)), and increased left ventricular mass (LVM) by cardiac ultrasound. In adolescents with familial heterozygous hypercholesterolemia (FH), studies have shown abnormal levels of coronary calcium, increased cIMT, and impaired FMD.[15],[16],[17] Children with hypertension have increased cIMT, increased LVM, and eccentric left ventricular geometry.[18],[19],[20] Children with type 1 diabetes mellitus (T1DM) have significantly abnormal FMD and, in some studies, increased cIMT. In addition, adverse interactions with hypertension, obesity, and a high-fat diet have been observed in children with T1DM.[21],[22],[23],[24],[25] Children and young adults with a family history of myocardial infarction have increased cIMT, higher prevalence of coronary calcium, and impaired FMD.[26],[27],[28],[29] Endothelial dysfunction has been demonstrated by ultrasound and plethysmography in association with cigarette smoking (passive and active) and obesity.[30], [31],[32],[33] In several randomized controlled trials, a change in FMD has been used to assess the response to an exercise intervention. [34],[35],[36] Left ventricular hypertrophy at levels associated with excess mortality in adults has been demonstrated in children with severe obesity and impaired glucose tolerance.[37]

Subclinical atherosclerosis imaging studies (coronary calcium by EBCT, cIMT) have been important in demonstrating the importance of childhood risk factors to future atherosclerosis. Four longitudinal studies have shown the relationships of risk factors measured in childhood and young adulthood—low-density lipoprotein cholesterol (LDL–C), non-HDL–C and serum apolipoproteins, obesity, hypertension, tobacco use, and diabetes—with measures of subclinical atherosclerosis in later adulthood.[38],[39],[40],[41],[42],[43],[44],[45],[46] In many of these studies, risk factors measured in childhood and adolescence were better predictors of adult atherosclerosis than were risk factors measured at the time of the subclinical atherosclerosis study.[38],[41],[42],[43],[45] In two of these cohorts, worsening risk status between the earliest and latest measurements was associated with increased evidence of the presence of atherosclerosis.[47],[48]

SUMMARY OF THE EVIDENCE REVIEW LINKING RISK FACTORS IN CHILDHOOD TO CLINICAL CARDIOVASCULAR DISEASE

The most important evidence relating risk in childhood to clinical CVD is the observed association of risk factors for atherosclerosis to clinically manifest CV conditions. Genetic disorders related to high cholesterol are the biologic model for risk factor impact on the atherosclerotic process. In homozygous hypercholesterolemia, where LDL–C levels exceed 800 mg/dL beginning in infancy, coronary events begin in the first decade of life, and lifespan is severely shortened. In heterozygous hypercholesterolemia, in which LDL–C levels are minimally 160 mg/dL and typically higher than 200 mg/dL beginning in infancy, 50 percent of men and 25 percent of women experience clinical coronary events by age 50 years.[49],[50] In contrast, genetic traits associated with low cholesterol are associated with longer life expectancy.[51] In the PDAY study, every increase in non-HDL–C of 30 mg/dL was associated with incremental increases in the extent and severity of atherosclerosis, including the presence of advanced lesions associated with clinical myocardial ischemia.[52] In natural history studies of diabetes mellitus, early CVD mortality is so consistently observed that the presence of diabetes mellitus is considered evidence of vascular disease in adults.[53] Consonant with this, in 15- to 19-year-olds in the PDAY study, the presence of hyperglycemia was associated with advanced atherosclerosis of the coronary arteries.[54],[55] In a 25-year followup, the presence of the metabolic syndrome risk factor cluster in children predicted clinical CVD in adults ages 30–48 years.[56] In the PDAY study, there is a strong relationship between abdominal aortic atherosclerosis and tobacco use.[12],[52] This aligns with the epidemiologic evidence of an observed attributable risk of 80 percent for tobacco use with the incidence of abdominal aortic aneurysms.

As described above, there is evidence to indicate that hypertension, dyslipidemia, diabetes, obesity, and cigarette smoking—established risk factors for CVD in adults—contribute to the early development of atherosclerosis, with the exception of two risk factors. The first is physical fitness. Studies directly relating fitness levels in childhood to future atherosclerosis have not been performed. However, longitudinal studies have shown that optimal CV risk profiles are seen in individuals who are consistently physically active.[57],[58],[59] Tracking of both sedentary and active behaviors is moderately strong from childhood to young adulthood, with the most consistent tracking seen for higher levels of physical activity at 9–18 years of age, predicting higher levels of physical activity later in life.[60],[61] The second risk factor is HDL–C. In adults, lower HDL levels are consistently shown to be associated with increased risk for CVD. In children, relationships between this risk factor and future atherosclerosis have been demonstrated, but the magnitude of the relationship is smaller than that shown in studies in adults.[38],[42],[52]

SUMMARY OF THE EVIDENCE REVIEW ON THE IMPACT OF RACIAL/ETHNIC BACKGROUND AND SOCIOECONOMIC STATUS IN CHILDHOOD ON THE DEVELOPMENT OF ATHEROSCLEROSIS

CVD has been observed in diverse geographic areas and in all racial and ethnic backgrounds. Cross-sectional research in children has shown differences by race and ethnicity and by geography for the prevalence of CV risk factors; these differences are often partially explained by differences in socioeconomic status (SES).[62],[63],[64],[65],[66],[67],[68],[69],[70],[71],[72] No group within the United States is without a significant prevalence of risk. Several longitudinal cohort studies referenced extensively in these Guidelines (Bogalusa, PDAY, Coronary Artery Risk Development in Young Adults (CARDIA)) examine biracial populations, although longitudinal data for Hispanic, Native American, and Asian children are lacking. Clinically important differences in the prevalence of risk factors exist by race and gender, particularly with regard to tobacco use rates, obesity prevalence, hypertension, and dyslipidemia. In adults, the influence of obesity on CV risk may vary by ethnicity.[73] Low SES in and of itself confers substantial risk. Evidence is not adequate for the recommendations provided in these Guidelines to be specific to racial or ethnic groups or to SES.

SUMMARY OF THE EVIDENCE REVIEW ON THE IMPACT OF MULTIPLE RISK FACTORS IN CHILDHOOD ON THE DEVELOPMENT OF ATHEROSCLEROSIS

Although genetic dyslipidemias and diabetes mellitus are recognized as high-risk states, from a population standpoint, it is the clustering of multiple risk factors that is most commonly associated with premature atherosclerosis. As demonstrated in the PDAY, CARDIA, Young Finns, and Bogalusa studies and as shown in Figure 2–3, the presence of multiple risk factors is associated with striking evidence of an accelerated atherosclerotic process. The two most prevalent multiple risk combinations are tobacco use with one other risk factor[74] or the development of obesity, which often is associated with insulin resistance (as opposed to elevated blood sugar in adults), elevated triglycerides, reduced HDL–C, and elevated blood pressure. This latter combination, known as the metabolic syndrome in adults, has become increasingly prevalent in childhood. [67][75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85] Another risk factor that frequently occurs in combination is low cardiorespiratory fitness. This was identified in 33.6 percent of adolescents in the National Health and Nutrition Examination Survey from 1999 to 2002 and was inversely associated with overweight and obesity, elevated total cholesterol levels, higher systolic –C.[86]

The relationship of the current obesity epidemic in children to future CVD and diabetes in adulthood is considered one of the most important public health challenges in the United States, particularly given the fact that more than 30 percent of the U.S. pediatric population is above the 85th percentile of the age- and gender-specific BMI for the generation of the 1970s and 1980s, with Native Americans, Hispanics, and African Americans disproportionately affected.[87] There is ample evidence from both cross-sectional and longitudinal studies that obesity-related risk factor clustering exists in childhood and continues into adulthood. [57],[67],[78],[79],[82],[88],[89],[90],[91]

SUMMARY OF THE EVIDENCE REVIEW ON RISK FACTOR TRACKING

Tracking studies from childhood to adulthood exist for all the major risk factors, including obesity, dyslipidemia, diabetes, cigarette smoking, and hypertension. Obesity tracks more strongly than any other risk factor. Among the many studies demonstrating this tracking,[72],[92],[93],[94] one of the most recent is a report from the Bogalusa study, which followed more than 2,000 children from 5 to 14 years of age at initial evaluation to adult followup at a mean age of 27 years. Based on BMI percentiles derived from the study population, 84 percent of those with a BMI in the 95th to 99th percentiles as children were obese as adults.[95] For obesity, increased correlation is seen with increasing age at which the elevated BMI is obtained. For cholesterol and blood pressure, tracking correlation coefficients in the range of 0.4 have been reported and are consistent across many studies, correlating these measures in children 5 to 10 years of age with results 20 to 30 years later.[96],[97],[98],[99],[100],[101],[102],[103],[104] These data suggest that having cholesterol or blood pressure levels in the upper portion of the pediatric distribution makes having these as risk factors as adults likely but not certain. Individuals who develop obesity have been shown to be more likely to develop hypertension or dyslipidemia as adults.[72],[94] Tracking data on physical activity are more limited. Physical activity levels do track but not as strongly as the other risk factors.[60],[61], [105] Because of tobacco's addictive nature, its use often persists into adulthood, although approximately 50 percent of those who have ever smoked eventually quit.[106] T1DM is a lifelong condition. The insulin resistance of T2DM can be reduced by exercise, weight loss, and bariatric surgery, but the long-term outcome of T2DM diagnosed in childhood is not known.[107] As stated above, risk factor clusters, such as those seen with obesity and the metabolic syndrome, have been shown to track from childhood to adulthood.[67],[78],[79],[82],[88],[89],[90],[91]

CARDIOVASCULAR DISEASE PREVENTION BEGINNING IN CHILDHOOD

The rationale for these Guidelines derives from several factors:

  • Atherosclerosis, the precursor of CV morbidity in later life, originates in childhood.
  • Risk factors for the development of atherosclerosis can be identified in childhood.
  • To a greater or lesser extent, risk factors track from childhood to adulthood.
  • Safe and effective interventions exist to manage identified risk factors.

It is important to distinguish between the goals of prevention at young ages and such goals at older ages when atherosclerosis is well-established, morbidity already may exist, and the process is only minimally reversible (Figure 2–2). At middle age and older, the goals are to prevent clinical events from occurring and to minimize the risk of future events in those with existing morbidity. At a young age, historically there have been two goals of prevention: (1) prevent the development of risk factors (primordial prevention) and (2) recognize and manage those children and adolescents at high risk due to the presence of one severe risk factor or multiple risk factors (primary prevention). With the development of measures of subclinical atherosclerosis, left ventricular hypertrophy, and endothelial function, the potential to assess a third goal has emerged: documentation of the prevention of the early stages of atherosclerosis and other forms of CV pathology. It is well-established that a population that enters adulthood with lower risk will have less atherosclerosis and will collectively have lower CVD rates.[1] This concept is supported by research showing that (1) populations with low levels of CV risk factors have low CVD rates and that changes in risk in those populations are associated with changes in CVD rates; (2) control of risk factors in those populations leads to declines in CVD morbidity and mortality; and (3) individuals in those populations without childhood risk have minimal atherosclerosis at ages 30–34 years, absence of subclinical atherosclerosis as young adults, extended life expectancy, and a better of quality of life free from CVD.[1][107],[108],[109],[110],[111],[112]

Pediatric CVD prevention occurs in two settings: clinical practice and public health. These Guidelines focus on the clinical practice setting. That does not diminish the critical importance of public health measures to CVD prevention. For risk factors such as tobacco use and physical inactivity, public health measures are critical for risk reduction. For risk factors such as hypertension, diabetes mellitus, obesity, and dyslipidemia, public health measures will affect prevalence, but without medical recognition and treatment, effective risk reduction cannot occur.

The Pathway to Recommending Clinical Practice-Based Prevention

The most direct means of establishing evidence for active CVD prevention beginning at a young age would be to randomize young individuals with defined risks to treatment of CV risk factors or to no treatment and then to follow both groups over sufficient time to determine whether CV events are prevented without undue increase in morbidity arising from treatment. This direct approach is attractive because atherosclerosis prevention would begin at the earliest stage of the disease process, thereby maximizing benefit. Of course, this approach is as unachievable as it is attractive. Such a study would be extremely expensive and would require a high level of adherence and participant retention over several decades, during which time changes in environment and medical practice would diminish the relevance of the results. Many scenarios could arise in which the ethics of such a trial could be questioned, including undue exposure to risk in one of the trial arms, the discovery of novel treatments of improved efficacy during the conduct of the trial, environmental changes or shifts in priorities of the funding entity that complicate its completion, and the potential withholding of effective therapy to a generation of youths with identified risk who do not receive treatment.

The recognition that evidence from this direct pathway is unlikely to be obtained requires an alternate stepwise approach, linking segments of an evidence chain in a manner that serves as a sufficiently rigorous proxy for the causal inference of a clinical trial. Figure 2–2 demonstrates the components of this evidence chain, with links comprising a series of critical studies leading from risk beginning before birth, to risk acquisition during childhood, to risk modification by reduction strategies, and finally to clinical disease in adulthood. Studies evaluated for these Guidelines may examine single links in this evidence train, connect several links simultaneously, or evaluate the consequences of specific interventions to allow risk-benefit analysis. Some studies encompass the entire lifespan, whereas others examine the impact of interventions on intermediate states. Many of these evidence links come from the epidemiologic studies described in this entire section and provide answers to the first nine critical questions of the evidence review: atherosclerosis begins in childhood, atherosclerosis is related to risk factors that can be identified in childhood, and the presence of these risk factors in a given child predicts an adult with risk factors.

The remaining evidence links pertain to the determination of whether interventions that aim to reduce risk factors will have a health benefit and whether the risk and cost of interventions to reduce risk are outweighed by the reduction in CVD morbidity and mortality. These issues are captured in the critical questions related to intervention (see I. Introduction, Table 1–1, questions 9–14), which are addressed subsequently in the evidence review of each risk factor. The best evidence for answering these questions derives from randomized trials showing event reduction in adults, randomized trials in children showing risk reduction with change in subclinical measures of atherosclerosis or target organ damage and patient safety, genetic studies that provide a model for the adverse effects of sustained exposure to risk, and long-term observational studies demonstrating the benefit of maintenance of low risk on health and all-cause mortality. Recommendations to intervene must consider not only the relationship of the risk factor to future disease but also whether reduction of that risk factor will result in an appreciable decline in subclinical disease or in adverse clinical events with an acceptable safety profile. The presence of a risk factor may confer a high relative risk of a future CV event, but intervention may not be warranted if actual event rates in the next several decades are low; conversely, a lower relative risk may be acceptable for intervention if the likelihood of an adverse event related to that risk factor is high. The timing and safety profile of pharmacologic interventions are important considerations for CVD prevention. The lifetime risk of disease associated with high risk in childhood may identify candidates for more aggressive intervention.

Intervention planning must consider that each risk factor exists within an individual's unique combination of environmental, behavioral, physiologic, and genetic characteristics. This context determines the timing and type of intervention under consideration. A family history showing multiple members affected by clinical CVD at a young age suggests the need to investigate both genetic risk and toxic environmental exposure and to consider early risk reduction. For example, tobacco use is a behavior with significant environmental predictors. That this behavior is highly addictive means that the use of tobacco alone is an indication for smoking cessation counseling. In contrast, recommendations to treat elevated blood pressure are based on multiple elevated measures over time because of the intrinsic variability of blood pressure and the possibility of significant modification through diet and exercise. However, the presence of elevated blood pressure and evidence of target organ damage (i.e., left ventricular hypertrophy) prompt more aggressive intervention. The presence of multiple risk factors represents a powerful stimulus for accelerated atherosclerosis, and knowledge of this situation affects treatment decisions. As described throughout these Guidelines, recommended strategies for intervention should consider environmental, behavioral, physiologic, and genetic attributes, as well as the efficacy and safety of potential treatment modalities, in selecting the type and timing of any intervention and in measuring outcomes.

For certain behavioral risk factors, limitations in measurement and data collection make the establishment of a causal pathway between the risk factor and disease impossible. There is unlikely to be a study comparing the effect of a lifetime of whole-milk consumption with fat-free milk consumption, or a study comparing daily physical training for decades with a lifetime of inactive television watching on the amount of atherosclerosis or rates of myocardial infarction. What is important about diet and exercise in childhood is the relationship of healthful behaviors to the development of future risk factors, including obesity, diabetes mellitus, hypertension, and dyslipidemia. Consequently, recommendations must include studies that examine the impact of interventions on risk factor development and reduction rather than studies that only examine the effects on subclinical disease measures or clinical events.

Since risk levels in the preadolescent pediatric population with normal weight for height are generally below levels associated with CV events,[113] a critical component of pediatric CVD prevention is understanding those factors associated with the evolution from the low-risk state of childhood to the presence of risk in adulthood. The well-established factors on this environmental-behavioral axis are initiating tobacco use and becoming obese. Although the evidence for a heart healthy diet and physical activity in the treatment of established risk factors is strong, less strong but emerging evidence suggests that an energy-balanced, nutrient-dense diet and consistent routine levels of physical activity that promote physical fitness prevent risk factor acquisition over the course of decades. Given that at least 40 percent of the U.S. population currently experiences CVD and that maintaining a low-risk state prevents CVD most effectively, emphasis on healthful behaviors in children, in the absence of established risk factors, assumes added importance.1,2

A new consideration is the role of new noninvasive measures of cardiac and vascular injury in the evaluation of evidence. These include measurements of vascular functioning and arterial stiffness like FMD; noninvasive measures of atherosclerosis, such as cIMT and coronary artery calcium; and measures of cardiac characteristics, such as LVM by echocardiography. For adults, the primary use of these technologies has been in event prediction; that is, whether the presence of one of these markers increases the likelihood of a future CV event beyond that expected from conventional risk factor assessment. There remains considerable controversy over the clinical roles of these tests in adults. For children and adolescents, the role of these measurements may be different. Rather than predicting clinical events, future research may show that a positive test signals the transition to more advanced atherosclerosis or the presence of CV target organ damage. Studies of subclinical atherosclerosis and LVM have been important in establishing the relationship of risk in childhood to evidence of CV injury. Monitoring of LVM has been incorporated into treatment algorithms for hypertension in childhood.[113] However, only a few studies in the pediatric age group have used these measures as clinical end points. It is expected that research using these intermediate end points will be used to clarify knowledge gaps identified in the evidence review for these Guidelines; the clinical importance of these new studies in adults and children remains to be fully established.

Thus, for each risk factor discussed in the sections below, recommendations reflect a complex decision process that integrates the strength of the evidence with knowledge of the natural history of atherosclerotic vascular disease, estimates of intervention efficacy and risk, and the physician's responsibility to provide both health education and effective disease prevention and treatment. These recommendations for providers of health care to children will be most effective when complemented by a broader public health strategy, as discussed in Section XVI. Implications of the Guidelines for Public Policy.

The Childhood Medical Office Visit: the Ideal Setting for Cardiovascular Health Management

In the beginning of this section, the differences in goals for CV risk management in children and in adults were presented, along with the dual pediatric focus on primordial prevention (i.e., the prevention of risk factor development) and primary prevention (i.e., the management of specific identified risk factors). One cornerstone of pediatric care is placing clinical recommendations in a developmental context. As opposed to virtually universal recommendations that apply to nearly all adults, pediatric recommendations must consider not only the relationship of age to disease expression but also the ability of the child and the family to understand and implement medical advice and the safety of the intervention modality. For each risk factor, recommendations must be specific to age and developmental stage. Therefore, the Bright Futures concept of the American Academy of Pediatrics, in which age-specific prevention measures are embedded in routine pediatric care, is used to provide a framework for these Guidelines, with CV risk reduction recommendations specific for each age group.[114]

The concept of primordial prevention is a major theme in all pediatric care. Based on the results of the evidence review, the Guidelines provide recommendations for preventing the development of risk factors and optimizing CV health beginning in infancy. Pediatric care providers—pediatricians, family practitioners, nurses and nurse practitioners, physician assistants, and registered dietitians—are ideally positioned to reinforce these CV health behaviors as part of routine care. The Guidelines also offer specific guidance on primary prevention, with age-specific, evidence-based recommendations for individual risk factor detection. Management algorithms provide staged care recommendations for risk reduction within the pediatric care setting and identify risk factor levels requiring referral to a specialist. The Guidelines also identify specific medical conditions, such as diabetes and chronic kidney disease, which are associated with increased risk for accelerated atherosclerosis. Recommendations for ongoing CV health management for children and adolescents with these diagnoses are provided.

A second cornerstone of pediatric care is the provision of health education. In the U.S. health care delivery system, doctors and nurses are perceived as credible messengers for health information. Patients and families expect physicians, nurses, dietitians, and other health care providers and counselors to provide accurate health information. The childhood health maintenance visit provides a useful context for effective delivery of the CV health message. Providing health information alone is insufficient since reduction of CV risk typically requires behavioral changes by the child and/or the family. The office of the pediatric care provider provides an effective setting for the health care team to engage children and families in the initiation of behavior change to reduce the risk of CVD and promote lifelong CV health.


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