2. State of the Science: Cardiovascular Risk Factors and the Development of Atherosclerosis
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 21). As described in Section I. Introduction, the literature search
for these Guidelines addressed 14 critical questions (I. Introduction, Table 11).
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 21. 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,
Table 21. Risk Factors for Cardiovascular Disease
High blood pressure
Diabetes mellitus and other predisposing conditions
Atherosclerotic vascular disease eventssuch as myocardial infarction, stroke,
peripheral arterial disease, and ruptured aortic aneurysmare the culmination
of a lifelong disease process., 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.
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).,,
Figure 21. Atherosclerosis: A Progressive Process
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
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 22. 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 22. Evidence Pathways Used in Developing Pediatric Cardiovascular Risk
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.
- Newborns at Risk
- Forward to Risk Factor (RF) Exposures
- Forward to RF Identification
- Forward to Children at Risk
- Fetal Exposures
- Lateral to Newborns at Risk
- Genetic Input
- Lateral to Newborns at Risk
- Risk Factor (RF) Exposures:
- Forward to Children at Risk
- RF Identification
- Forward to Children at Risk
- Children at Risk
- Forward to Lifestyle Interventions
- Forward to Intermediate Outcomes
- Forward to Pharmacologic Interventions
- Intermediate Outcomes
End organ injury
- Lateral to Lifestyle Interventions
- Lateral to Pharmacologic Interventions
- Forward to Adults at Risk
- Lifestyle Interventions
- Forward to Adults at Risk
- Lateral to Intermediate Outcomes
- Pharmacologic Interventions
- Forward to Adults at Risk
- Lateral to Intermediate Outcomes
- Adults at Risk
- Foward to Clinical Cardiovascular Disease Outcomes
- 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 22. 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 22 provide evidence addressing the key
questions critical to this evidence reviewincluding 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. 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., 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.,
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-HDLC), lower HDL cholesterol (HDLC), 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.,,,
An international study with more limited information on risk factors was consistent
with these findings.
Figure 23, 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.
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 23 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 23. Atherosclerosis Maps of the Right Coronary Artery
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.
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
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.,,
Children with hypertension have increased cIMT, increased LVM, and eccentric
left ventricular geometry.,, 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.,,,, Children and young adults with
a family history of myocardial infarction have increased cIMT, higher prevalence
of coronary calcium, and impaired FMD.,,, Endothelial dysfunction has been
demonstrated by ultrasound and plethysmography in association with cigarette smoking
(passive and active) and obesity.,
,, In several randomized controlled trials,
a change in FMD has been used to assess the response to an exercise
intervention. ,, Left ventricular
hypertrophy at levels associated with excess mortality in adults has been demonstrated
in children with severe obesity and impaired glucose tolerance.
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 adulthoodlow-density lipoprotein cholesterol
(LDLC), non-HDLC and serum apolipoproteins, obesity, hypertension, tobacco
use, and diabeteswith measures of subclinical atherosclerosis in later adulthood.,,,,,,,,
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.,,,, In two of these cohorts, worsening
risk status between the earliest and latest measurements was associated with increased
evidence of the presence of atherosclerosis.,
SUMMARY OF THE EVIDENCE REVIEW LINKING RISK FACTORS IN CHILDHOOD TO CLINICAL CARDIOVASCULAR
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
LDLC 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 LDLC 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., In contrast,
genetic traits associated with low cholesterol are associated with longer life expectancy. In the PDAY
study, every increase in non-HDLC 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. 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. 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.,
In a 25-year followup, the presence of the metabolic syndrome risk factor cluster
in children predicted clinical CVD in adults ages 3048 years. In the PDAY study, there
is a strong relationship between abdominal aortic atherosclerosis and tobacco use., 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 smokingestablished risk factors for CVD in
adultscontribute 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.,, 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 918
years of age, predicting higher levels of physical activity later in life., The second risk factor is HDLC.
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.,,
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).,,,,,,,,,, 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.
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 23,
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
or the development of obesity, which often is associated with insulin resistance
(as opposed to elevated blood sugar in adults), elevated triglycerides, reduced
HDLC, and elevated blood pressure. This latter combination, known as the metabolic
syndrome in adults, has become increasingly prevalent in childhood. ,,,,,,,,,, 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.
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. There is ample evidence from both cross-sectional
and longitudinal studies that obesity-related risk factor clustering exists in childhood
and continues into adulthood. ,,,,,,,,
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,,,,
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.
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.,,,,,,,, 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.,
Tracking data on physical activity are more limited. Physical activity levels do
track but not as strongly as the other risk factors.,,  Because
of tobacco's addictive nature, its use often persists into adulthood, although approximately
50 percent of those who have ever smoked eventually quit. 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. 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.,,,,,,,
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 22). 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.
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 3034 years, absence
of subclinical atherosclerosis as young adults, extended life expectancy, and a
better of quality of life free from CVD.,,,,,
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 22 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 11, questions 914), 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, 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.
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
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.
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 providerspediatricians, family practitioners, nurses
and nurse practitioners, physician assistants, and registered dietitiansare
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
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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
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