Autopsy studies have demonstrated that atherosclerosis, the pathologic basis for coronary artery disease and cerebrovascular events, begins in childhood and is associated with the presence of modifiable and nonmodifiable cardiovascular risk factors (CVRFs) such as obesity, dyslipidemia, and hypertension ( Fig. 25.1 ). These risk factors track into adulthood, and their presence in childhood is associated with subclinical adverse vascular changes that are precursors of overt atherosclerosis that predict cardiovascular (CV) events in adulthood. Thus the reduction of CVRFs in youth may reduce atherosclerotic cardiovascular disease (CVD) burden in adulthood. To this end, longitudinal studies have demonstrated that preservation of low levels of CV risk is associated with less subclinical atherosclerosis in adulthood. Therefore early identification and intervention for increased cardiovascular risk in childhood are essential, especially in high-risk conditions where accelerated atherosclerotic progression may occur, such as diabetes, chronic kidney disease, solid organ transplant, and Kawasaki disease. Fortunately, early intervention in childhood has led to improvements in CVRFs and noninvasive measures of atherosclerotic burden.
This chapter summarizes cardiovascular risk assessments in the pediatric population with a focus on primordial prevention (prevention of the acquisition of CVRFs), primary prevention (treatment of elevated CVRFs when identified), and secondary prevention (intensification of treatment of CVRFs in high-risk or symptomatic youth). The chapter concludes with a summary of invasive and noninvasive modalities used to detect atherosclerotic burden in children.
Cardiovascular Risk Factors
In 2011, the National Heart, Lung, and Blood Institute (NHLBI) provided integrated guidelines for comprehensive assessment and management of cardiovascular risk in children and adolescents, including a summary document with an age-specific CV health assessment screening schedule ( Table 25.1 ). The full guidelines can be found online at https://www-nhlbi-nih-gov.easyaccess1.lib.cuhk.edu.hk/health-pro/guidelines/current/cardiovascular-health-pediatric-guidelines/summary .
Risk Factor | Birth–1 Year | 1–4 Years | 5–9 Years | 9–11 Years | 12–17 Years | 18–21 Years |
---|---|---|---|---|---|---|
Family history | Evaluate fhx for early CVD a | Update | Update | Update | Update | |
Smoking | Anti-smoking in household | Same | Same—begin smoking history assessment in child | Same | Same | Same |
Diet | Support breastfeeding | Low-fat (2%) milk to age 2 years; fat-free milk >2 years, ≤4 oz/day juice | <30% of total calories from fat, <10% from saturated fat, avoid trans fat | Same | Same | Same |
Physical activity | Parents as model; no screen time <2 years | Active play, 2 h/day screen time | MVPA >1 h/day; screen time <2 h/day | Same. Obtain activity history | Same | Enforce lifelong activity |
Growth, overweight, obesity | Obtain fhx for obesity; discuss healthy weight/height, healthy diet | Calculate BMI starting at age 2 years | Calculate BMI; if overweight (>85th percentile) or obese (>95th percentile), manage as per algorithms | Same | Same | Same |
Lipids | No routine screening | Selective screening b | Selective screening b | Universal lipid screening c | Selective screening b | Repeat universal screening c |
Blood pressure | Measure in high-risk infants d | Annual measurement starting at 3 years; chart for age/sex/height; manage as per algorithm | Same | Same | Same | Same |
Type 2 diabetes | None | None | None | Fasting glucose | Same | Same |
a Parents, grandparents, aunts/uncles, men <55 years old, women <65 years old.
b Selective screening warranted if positive family history for premature CVD, parent has dyslipidemia, child has any other risk factors or high-risk conditions.
c Lipid screening may be either nonfasting non-HDL-C or a fasting lipid profile.
d High risk infants: infants with renal/urologic/cardiac abnormalities or history of neonatal ICU stay.
CVRFs can be classified as modifiable and nonmodifiable. Nonmodifiable CVRFs include family history, race and ethnicity, and sex. Modifiable CVRFs include traditional risk factors such as tobacco exposure, dyslipidemia, hypertension, diabetes, and overweight/obesity, as well as CVRFs secondary to pediatric conditions, such as perinatal factors, inflammatory disorders, renal disorders, and postoperative conditions.
Family History
The NHLBI Expert Panel Guidelines recommend a detailed family history assessment be taken at the initial encounter and/or at 3 years of age, followed by repeat assessments at 9 to 11 years and 18 years. If there is a positive family history, the patient should be evaluated for other CVRFs. Furthermore, if a positive family history is present or the child has positive CVRFs, other family members should be evaluated (“reverse cascade screening”). Finally, the family history should be reviewed at each nonurgent health encounter.
A positive family history for premature CVD is defined as the presence of CVD (myocardial infarction, treated angina, percutaneous coronary catheter interventional procedure, or coronary artery bypass surgery), stroke, or sudden cardiac death in a parent or sibling, in males younger than 55 years old and females younger than 65 years old. As the parents and siblings of children and adolescents undergoing assessment are often quite young themselves, the Expert Panel expanded this definition to include premature CVD occurring in grandparents and aunts and uncles.
In longitudinal epidemiologic studies of CV risk, a family history of premature CVD is associated with increased risk of CVD in adulthood. In infants, a positive family history in grandparents is associated with relative coronary artery luminal narrowing at autopsy compared with infants without positive family histories. Noninvasive assessments have also demonstrated increased carotid intima media thickness (cIMT) and reduced endothelial function (brachial flow-mediated dilation [FMD]) in children and young adults with a strong history of premature CVD. Family history of CVD is associated with the elevation of CVRFs in the children. These findings suggest that family history is an important consideration in the cardiovascular risk assessment of children and adolescents. However, family history may be inaccurate and incomplete, owing to factors such as divorce, geographical separation, and other social circumstances.
Tobacco
Tobacco use among family members should be assessed at each well-child visit. Among its countless adverse effects, cigarette smoking is a potent CVRF, promoting atherosclerotic development even in young individuals. Several studies have also linked secondhand smoke exposure to CV risk in youth, and in-utero secondhand smoke exposure appears to have an obesogenic effect. In addition, exposure to secondhand smoke is a risk factor for future cigarette use. Fortunately, exposure to secondhand smoke and trends in cigarette use among youth have been decreasing in recent decades.
While trends in cigarette use have been declining, the use of electronic cigarettes is increasing in popularity among youth. Though most adults use these devices for smoking cessation, youth who experiment with them are typically smoking-naïve and are motivated by new, appealing features of electronic cigarettes. Therefore while further study is required to understand the safety, or otherwise, of these devices themselves, concern exists that electronic cigarette use may be a risk factor for future cigarette use in youth.
Given the impact of both cigarette smoking and exposure to secondhand smoke, interventions should target both parents and children/adolescents. It should be recognized, however, that public health measures, rather than individual counseling assessments, have been the most successful to prevent and limit tobacco use. This includes taxation of tobacco products, clean indoor air legislation, and advertising against tobacco products. Individualized interventions designed to reduce smoke exposure in children and tobacco initiation and reduction in adolescents have generally had mixed results. Despite this, given the importance of communicating the message of risk associated with tobacco use and the lack of harm associated with such interventions, routine identification and intervention of patients and families who smoke is imperative. Patients and families should be informed of the addictive and adverse effects of tobacco. The five “A questions” (Ask, Advise, Assess, Assist, and Arrange) can help physicians assess the readiness for quitting. From this, appropriate resources may be provided. While pharmacotherapies such as nicotine replacement have been shown to be effective in promoting smoking cessation in adults, studies in young smokers, to date, have yielded mixed results.
Nutrition and Diet
Dietary intake assessments should take place at each scheduled health visit. Consultation with a registered dietician may be necessary to ensure that adequate caloric intake is achieved within a healthy eating pattern. To optimize adoption of recommended changes, it is imperative to consider cultural practices and unique food preferences for each family.
In the first 6 months of life, human milk is the preferred source of complete nutrition for healthy term newborns, with continued breastfeeding recommended up to 12 months. Breastfeeding may potentially be protective against obesity, is associated with lower adulthood levels of total cholesterol (TC) and decreased cIMT, and is associated with a decreased risk of type 2 diabetes later in life. After the first 12 months, children should be transitioned to reduced-fat (2% to fat-free) milk.
Nutrient-dense food choices throughout childhood may have significant health benefits and decrease future risk of CVD. Higher fruit and vegetable intake has been associated with decreased adiposity, lower blood pressure, and reduced cholesterol levels. Conversely, sedentary children who frequently consume energy-dense and nutrient-deplete foods are at risk of developing overweight/obesity. Therefore added sugars and saturated and trans fats should be considered “discretionary” calories. The 2015–20 Dietary Guidelines for Americans (DGA) recommends consumption of a healthy eating pattern that accounts for all foods and beverages within an age-, sex- and activity-appropriate calorie level. This includes a variety of vegetables, fruits, grains, fat-free/low-fat dairy, a variety of protein-containing foods (seafood, lean meats and poultry, eggs, legumes, nuts, seeds, and soy proteins), and oils and limiting added sodium and sugar. Limiting total fat content less than 30% of daily calories has been shown to result in lower TC and low-density lipoprotein cholesterol (LDL-C). Furthermore, they recommend limiting saturated (<10% calories/day) and trans-fats, with the remaining 20% of fat intake coming from monounsaturated and polyunsaturated fats. Sugar-sweetened beverages and other foods with added sugar may be obesogenic and therefore should be avoided (<10% calories/day). With respect to natural, unsweetened, fruit juice the American Academy of Pediatrics recommends children aged 6 months to 6 years of age limit intake to 1 serving (4 to 6 ounces) per day and 2 servings per day for children 7 to 18 years old.
Physical Activity and Sedentary Behavior
Physical activity and screen time (TV, computer, cellphone) levels should be assessed at each well-child visit. Parents should be instructed that they must act as role models, creating an environment that promotes and models physical activity.
Physical inactivity is an independent risk factor for coronary artery disease. In recent decades, there has been a decrease in physical activity levels and increase in sedentary activities such that total screen time in children now ranges from 2.7 to 4.3 hours/day. These changes in physical activity patterns are associated with worsened lipid profiles, increases in systolic blood pressure, and increased levels of obesity, insulin resistance, and type 2 diabetes. Optimal cardiovascular risk profiles are seen in those who are consistently physically active.
The Expert Panel, in accordance with the 2008 Physical Activity Guidelines for Americans , recommends at least 1 hour of moderate to vigorous physical activity (comparable to walking briskly or jogging) per day with vigorous intense physical activity (comparable with running, playing soccer, or playing singles tennis) at least 3 days/week. The AAP recommends no screen time for children less than 18 months, high-quality programming only between 18 and 24 months supervised by a parent, and limiting screen time to 1 hour/day for children 2 to 5 years old, with appropriate parental limits set for screen time for children older than 6 years of age. Setting good physical activity patterns early in life is essential as childhood habits track fairly well into adolescence and adulthood. Furthermore, physical activity patterns (ideal or adverse) cluster with dietary choices, and smoking patterns.
Overweight and Obesity
Starting at age 2 years, body mass index (BMI, kg/m 2 ) should be routinely calculated at all visits and compared to age- and sex-specific percentiles from the Centers for Disease Control and Prevention (CDC). A BMI between the 85th and less than 95th percentile is classified as overweight and greater than or equal to 95th percentile as obese. Although a recent study demonstrated a downward trend in the prevalence of obesity among 2- to 5-year-old children, there have been no overall changes in prevalence of obesity in youth between 2003 and 2012, with obesity rates in children 2 to 19 years old remaining at approximately 17%. Children at risk for developing obesity include those who are currently overweight, have a positive family history of obesity in one or both of the parents, experience more rapid increases in weight than height, have excessive increases in weight during adolescence, and who have increased sedentary time. Due to the association of obesity with elevations in other CVRFs, the presence of obesity should prompt evaluation for CVRF clustering, including assessments of blood pressure, lipids, insulin resistance and risk for type 2 diabetes, liver function abnormalities, left ventricular hypertrophy, and sleep apnea. Addressing the childhood obesity epidemic is imperative as obesity is associated with atherosclerotic burden at autopsy, tracks strongly into adulthood, and its presence in childhood is significantly associated with coronary heart disease events in adulthood. Improvements in weight status are associated with improvements in various modifiable CVRFs, including blood pressure, TC, LDL-C, triglycerides (TG), and insulin resistance. Overweight and obesity are also associated with subclinical markers of vascular dysfunction, and exercise and weight loss are associated with improvements in these measures.
In addition to guidelines for healthy diet and exercise for all children, practitioners should be aware of additional recommendations for treatment of overweight and obesity (see below). While trials of community-based programs have yielded mixed results, comprehensive multidisciplinary lifestyle weight-loss programs have resulted in greater success in children older than 6 years. Medications such as orlistat and metformin may be prescribed for obese children and adolescents who have seen no improvements in obesity despite compliance with a dedicated obesity program. The Expert Panel recommendations for obesity management are as follows :
Ages 2 to 5 years old: For overweight children, parents should be counseled with a focus on an energy-balanced diet and a reinforcement of physical activity recommendations. If no improvements are noted after 6 months, further counseling with a registered dietician is warranted. Obese children should undergo assessment of comorbidities (hypertension, insulin resistance, and dyslipidemia) and family-based weight-gain prevention initiated with counseling from a registered dietician and a prescription for moderate-to-vigorous physical activity and limited screen time. Follow-up should be arranged for 3 months.
Ages 6 to 11 years old: In this age range, recommendations for overweight and obese children are the same as for younger children (above) with more aggressive dietary management and an emphasis on negative-energy balance if obese. If there are no improvements in BMI percentile, referral to a comprehensive multidisciplinary lifestyle weight-loss program should be made. Children with comorbidities at the initial assessment, a BMI greater than 97th percentile, or if with progressive rise in BMI despite therapy, should be promptly referred to a more intensive, comprehensive multidisciplinary lifestyle weight-loss program rather than an office-based plan.
Ages 12 to 21 years old: For overweight and obese adolescents without comorbidities, an office-based strategy including counseling from a dietician regarding balancing energy intake and physical activity is the initial approach. If BMI does not improve in the obese patient, referral to a comprehensive multidisciplinary lifestyle weight-loss program should be made. For obese adolescents with comorbidities, or for those with a BMI greater than 35 kg/m 2 , immediate referral should be made to a comprehensive multidisciplinary lifestyle weight-loss program. If there are no improvements despite compliance with such a program for 6 to 12 months, orlistat may be considered under the care of an experienced clinician. If the BMI remains far above 35 kg/m 2 with comorbidities despite lifestyle therapy for over 1 year, referral to a center with experience in pediatric bariatric surgery may be considered.
Hypertension
This section focuses on the diagnosis, prevention, and treatment of hypertension to lower CV risk in children and adolescents.
Blood pressure should be measured annually beginning at age 3 years or at every health care encounter if the child is obese; takes medications known to increase blood pressure; or has renal disease, a history of aortic arch obstruction or coarctation, or diabetes. Oscillometric devices may be used for blood pressure screening in children and adolescents, but if BP is elevated, confirmation should be made with auscultatory readings. For children younger than 3 years, blood pressure should be measured in infants at risk for hypertension, such as those with renal disease or urologic malformations, congenital heart disease, prematurity, a history of umbilical arterial access, or treatment with medications that raise blood pressure. The mean of replicate measures of blood pressure should be obtained using an appropriate blood pressure cuff (an inflatable bladder length that is 80% to 100% of the upper arm circumference and a bladder width that is at least 40% of the arm circumference). For children younger than 13 years, the mean blood pressure level should be evaluated using age-, sex- and height-specific blood pressures percentiles from the recently published American Academy of Pediatrics Clinical Practice Guideline on pediatric blood pressure assessments ( Fig. 25.2 ). For youth 13 and older, a single cut-point is used ( Table 25.2 ). Further details regarding ideal assessment of blood pressure are provided in the “Nursing Implications” section below.
Children Aged 1–13 Years a | Children Aged ≥13 Years | |
---|---|---|
Normal BP | <90th percentile b | <120/<80 mm Hg |
Elevated BP | ≥90th to <95th percentile | 120/<80 to 129/<80 mm Hg |
Stage 1 HTN | ≥95th to <95th percentile + 12 mm Hg | 130/80 to 139/89 mm Hg |
Stage 2 HTN | ≥95th percentile + 12 mm Hg | ≥140/90 mm Hg |
a If blood pressure values exceed criteria used for children aged ≥13 then those corresponding cutoffs are used.
Elevated and hypertensive blood pressure measurements must be confirmed on repeated visits before the diagnosis of hypertension can be made ( Table 25.3 ). Ambulatory blood pressure monitoring can be useful in the confirmation of hypertension prior to the initiation of pharmacotherapy and is often employed at the third visit for those with elevated blood pressure or stage 1 hypertensive measurements or at the first or second visit for those with stage 2 hypertensive measurements. Ambulatory blood pressure monitors are also useful in helping the clinician evaluate for white coat hypertension, masked hypertension, and nocturnal hypertension. Patients with stage 2 hypertension measurements may require a more prompt evaluation and initiation of therapy, along with subspecialty referral. Symptomatic patients require immediate initiation of treatment and consultation with pediatric hypertension experts.
BP Category | Screening Timeline | Lifestyle Counseling a | Upper and Lower Limb BP | ABPM | Diagnostic Evaluation b | Pharmacologic Treatment | Consider Subspecialty Referral c |
---|---|---|---|---|---|---|---|
Normal | Annual | X | – | – | – | – | – |
Elevated BP | Initial measurement | X | – | – | – | – | – |
Second measurement in 6 mo | X | X | – | – | – | – | |
Third measurement in 6 mo | X | – | X | X | – | X | |
Stage 1 HTN | Initial measurement | X | – | – | – | – | – |
Second measurement in 1-2 wk | X | X | – | – | – | – | |
Third measurement in 3 mo | X | – | X | X | X | X | |
Stage 2 HTN | Initial measurement | X | X | ||||
Second measurement within 1 wk with concurrent referral to subspecialty care | X | X | X | X | X |
a Lifestyle counseling: nutrition (DASH diet), physical activity (3–-5 times per week, 30–60 minutes per session), and weight management when appropriate.
b See text for further details.
c Much of the evaluation and management strategy may have been completed prior to subspecialty referral for hypertension.
Blood pressure levels in children and adolescents increased from 1988 to 1999 and plateaued or even decreased slightly in the decade that followed. The general increase in population blood pressure levels paralleled trends in obesity prevalence, a finding that is not surprising as multiple studies have demonstrated associations between obesity and blood pressure. Frequent evaluation of blood pressure across the lifespan is essential because elevated blood pressure may progress to sustained hypertension. Using data from cohorts combined in the Fourth Report (the previous pediatric hypertension guidelines), Falkner and colleagues found that 14% of boys and 12% of girls with elevated blood pressure (previously termed prehypertension) progressed to sustained hypertension 2 years later. Baseline blood pressure and baseline and follow-up BMI were independent determinants of subsequent blood pressure, consistent with data demonstrating significant (though imperfect) tracking of blood pressure levels and anthropometric measures from childhood to adulthood.
The relationship between elevated blood pressure levels and target organ damage is well documented. Autopsy studies demonstrated greater histologic evidence of atherosclerosis in those with elevated blood pressure. In addition, adverse vascular changes associated with elevations in blood pressure have been found in cross-sectional studies in childhood. Higher systolic blood pressure is correlated with increased cIMT and arterial stiffness. Given that arterial compromise (higher cIMT and stiffness ) is associated with left ventricular mass (LVM), it comes as little surprise that hypertension itself, when present in childhood, leads to elevated LVM childhood and adulthood. Elevated LVM is a risk factor for the occurrence of CVD events in hypertensive adults. Therefore echocardiographic LVM should be evaluated in youth with stage 2 or persistent stage 1 hypertension (at the time of consideration of pharmacotherapy) to assess for hypertensive target organ disease.
Fortunately, regression in left ventricular hypertrophy/LVM with effective pharmacologic treatment of hypertension has been demonstrated in adults. Small studies in children demonstrate similar improvements. In addition, the reduction in LVM appears to be correlated with the degree in blood pressure reduction with treatment ( Fig. 25.3 ).
Lifestyle modification is the initial therapy for youth with elevated blood pressure and stage 2 hypertension without LVH. In infants and children, modest reductions in salt intake yield significant reductions in blood pressure. A randomized trial of the Dietary Approaches to Stop Hypertension (DASH) diet in adolescents with elevated blood pressure resulted in higher intakes of fruits, vegetables, and low-fat dairy products and lower intake of total fat, resulting in significant decreases in systolic blood pressure. There is strong evidence in adults that increased physical activity promotes reductions in blood pressure, with some suggestions of similar but weaker independent associations in children. In addition, physical activity promotion and reduction in sedentary activities are lifestyle recommendations for overweight and obesity in children. Therefore increasing physical activity should be included in the recommended lifestyle modifications for children with elevated blood pressure or hypertension. Pharmacologic therapy is indicated for children who remain hypertensive despite lifestyle therapy, those who have symptomatic hypertension, those with stage 2 hypertension, and in those with hypertension at any stage with chronic kidney disease or diabetes mellitus. First-line medications include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, long-acting calcium channel blockers, and thiazide diuretics. At present, the literature does not support the preferential use of any one class of antihypertensives in children. In addition, long-term safety data are not available.
Dyslipidemia
The Expert Panel universally recommends a nonfasting non-high-density lipoprotein cholesterol (non-HDL-C) assessment for all children between ages 9 and 11 years old and again between 17 and 21 years old. Non-HDL-C (non-HDL-C = TC – HDL) measures the TC content of all atherogenic apoB-containing lipoproteins and can be obtained in the nonfasting state. Childhood non-HDL-C appears to be superior to LDL-C in predicting adult dyslipidemia and nonlipid CVD risk factors. If a nonfasting HDL-C is not available, cut-points for additional action for elevated levels of nonfasting TC are also provided in the guidelines. Additional screening, in the form of two averaged fasting lipid profiles, should be performed between 2 and 8 years old and between 12 and 16 years old in children with a family history of premature CVD in a parent, grandparent, aunt/uncle, or sibling; a parent with a TC greater than 240 mg/dL or known dyslipidemia; if the patient has diabetes, hypertension, is overweight (for 12- to 16-year-old screening) or obese (for 2- to 8-year-old screening); if the patient smokes cigarettes; or if the patient has a moderate- or high-risk medical condition ( Table 25.4 ).
Moderate Risk | High Risk |
---|---|
Kawasaki disease with regressed coronary aneurysms | Type 1 or type 2 diabetes |
Chronic inflammatory disease (systemic lupus erythematosus, juvenile rheumatoid arthritis) | Chronic kidney disease/end-stage renal disease/postrenal transplant |
HIV infection | Postorthotopic heart transplant |
Nephrotic syndrome | Kawasaki disease with current aneurysms |
The rationale for screening at around age 10 years is that lipid lipoprotein levels at birth are very low and increase slowly in the first 2 years of life. Levels thereafter are stable in late childhood until adolescence, where, during puberty, TC and LDL-C levels decrease before rising in late-teen years. Racial differences exist as well, with higher TC and HDL-C and lower levels of very LDL-C and TG seen in black children and adolescents. Lipoprotein level cut-off points are shown in Tables 25.5 and 25.6 .
Category | Acceptable (mg/dL) | Borderline (mg/dL) | Abnormal (mg/dL) |
---|---|---|---|
Total cholesterol | <170 | 170–199 | ≥200 |
LDL cholesterol | <110 | 110–129 | ≥130 |
Non-HDL cholesterol | <120 | 120–144 | ≥145 |
Apolipoprotein B | <90 | 90–109 | ≥110 |
Triglycerides | |||
0–9 years | <75 | 75–99 | ≥100 |
10–19 years | <90 | 90–129 | ≥130 |
HDL cholesterol | >45 | 40–44 | <40 |
Apolipoprotein A-1 | >120 | 115–120 | <115 |
Category | Acceptable (mg/dL) | Borderline (mg/dL) | Abnormal (mg/dL) |
---|---|---|---|
Total cholesterol | <190 | 190–224 | ≥225 |
LDL cholesterol | <120 | 120–159 | ≥160 |
Non-HDL cholesterol | <150 | 150–189 | ≥190 |
Triglycerides | <115 | 115–149 | ≥150 |
HDL cholesterol | >45 | 40–44 | <40 |
The previous 1992 Expert Panel Guidelines recommended selective screening for dyslipidemia based on the presence of a family history of premature CVD. However, family history may be inaccurate and incomplete for numerous reasons. A systematic review by the U.S. Preventive Services Task Force (USPSTF) concluded that relying on family history for selective screening would miss the majority of children with inherited dyslipidemias, including approximately 50% of those with familial hypercholesterolemia (FH). Therefore while a positive family history may be associated with increased CVRF and future CVD, a negative family history does not rule out dyslipidemia in children.
As mentioned above, key autopsy studies have demonstrated a clear correlation between dyslipidemia and the onset and severity of atherosclerosis in children, adolescents, and young adults. In recent decades, the dyslipidemic patterns observed in children have evolved. Historically, the predominant dyslipidemia evaluated in preventative cardiology clinics was elevated levels of LDL-C, due to FH. In recent decades, however, a dyslipidemic pattern associated with obesity has been observed with increasing frequency in children, consisting of moderate to severe elevations in TG, normal to mild elevations in LDL-C, and reduced HDL-C. The incidence of this form of dyslipidemia is increasing as the incidence of overweight/obesity and insulin resistance increases. Unfortunately, both of these patterns have been associated with atherosclerotic lesions and dyslipidemias have also been associated with endothelial dysfunction and increased cIMT. Therefore it is important to address dyslipidemia early in life since numerous studies have demonstrated that dyslipidemia tracks from childhood to adulthood. Approximately half of children with lipid levels above the 75th percentile will have dyslipidemia as adults. Lipid values are associated with other CVRFs, including obesity and fasting insulin levels. Moreover, young adults with a TC level greater than 200 mg/dL have a five times increased risk of having a CVD event 40 years later compared with individuals with TC less than 172 mg/dL.
There are many different causes and modifiers of dyslipidemia, including genetic and environmental factors, nutrition, and physical activity, among others. Secondary causes of dyslipidemia are listed in Table 25.7 , adapted from the Expert Panel Guidelines. Inherited dyslipidemias are responsible for a significant proportion of pediatric dyslipidemia. They occur due to either single-gene or oligogenic defects involving several genes. FH, the most common inherited disorder, results in significant elevations in LDL-C, with the more rare homozygous form producing dramatic increases in LDL-C. FH is an autosomal dominant disorder, involving gene mutations either in the LDL receptor (most commonly), apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9). Over 500 mutations have been identified related to FH resulting in a wide range of effects, from null alleles that block LDL-C receptor formation to defects resulting in defective receptors with limited function. Heterozygous FH should be suspected in youth with an LDL-C greater than 160 mg/dL with at least one first-degree relative with similar LDL-C elevations, a history of premature CVD events, or positive genetic testing for an FH-associated gene defect. Children with heterozygous FH typically have LDL-C elevations sufficient to warrant pharmacologic treatment. While homozygous FH is very rare (approximately 1:1 million prevalence), heterozygous FH is far more prevalent. In fact, recent estimates of incidence suggest heterozygous FH to be present in approximately 1:250 individuals. A higher prevalence is found in certain ethnic groups (e.g., French Canadians, Lebanese, South Africans). If left untreated, the median age of onset for first myocardial infarction is approximately 50 years in males and 60 years in women.
Exogenous | Endocrine/Metabolic | Renal | Infectious |
---|---|---|---|
Alcohol | Hypothyroidism/hypopituitarism | Chronic renal disease | Acute viral/bacterial infection a |
Drug therapy | T1DM and T2DM | Hemolytic uremic syndrome | HIV |
Corticosteroids | Pregnancy | Nephrotic syndrome | Hepatitis |
Isoretinoin | Polycystic ovary syndrome | ||
β-Blockers | Lipodystrophy | ||
Some oral contraceptives | Acute intermittent porphyria | ||
Select chemotherapeutic agents | |||
Select antiretroviral agents | |||
Hepatic | Inflammatory Disease | Storage Disease | Other |
Obstructive liver disease/cholestatic conditions | Systemic lupus erythematosus | Glycogen-storage disease | Kawasaki disease |
Biliary cirrhosis | Juvenile rheumatoid arthritis | Gaucher disease | Anorexia nervosa |
Alagille syndrome | Cystine storage disease | Post–solid organ transplantation | |
Juvenile Tay-Sachs disease | Childhood cancer survivor | ||
Niemann-Pick disease | Progeria | ||
Idiopathic hypercalcemia | |||
Klinefelter syndrome | |||
Werner syndrome |
a Measurement should be delayed until at least 3 weeks following the infection.
Homozygous FH is typically associated with LDL-C values exceeding 400 mg/dL and is frequently associated with acquired aortic valve disease developing under the age of 20. CVD events typically occur in the second decade of life. Children with homozygous FH often present with physical manifestations in infancy and early childhood. This often consists of cutaneous xanthomata that may be located between fingers and toes and over the buttocks, elbows, and knees, and tendinous xanthomata, typically most prominent in the Achilles tendon ( Fig. 25.4 ). Complete cardiac investigation is indicated at the time of diagnosis since important atherosclerotic development may have already taken place. Despite severely reduced or absent LDL-C receptor function, these patients may show some response to high doses of statin and cholesterol absorption inhibitors. However, the majority of patients will require further treatments, including the use of LDL apheresis to clear circulating LDL, typically performed biweekly.
Management of Pediatric Dyslipidemia
With the exception of children with severe elevations in LDL-C or TG, the initial management of children with dyslipidemia begins with dietary counseling with a referral to a registered dietician. For children and young adults between 2 and 21 years old with elevations in LDL-C or TG, a diet where 25% to 30% of total calories come from fat, with less than or equal to 7% of total calories coming from saturated fat (with avoidance of trans fats whenever possible), approximately 10% from monounsaturated fats, and less than 200 mg/day of cholesterol is recommended. For children with elevations in LDL-C, plant sterol esters and/or plant stanol esters (which are found in some foods such as margarines) may be used (up to 2 g/day) as replacement for other fat sources in children greater than 2 years old with FH. The water-soluble fiber psyllium may be added to the diet, at a dose of 6 g/day for children 2 to 12 years old and 12 g/day for children greater than or equal to 12 years old. For children with elevations in TG, families and children/adolescents should be counseled toward decreased sugar intake, avoidance of sugar-sweetened beverages, and replacing simple carbohydrates with complex ones. In addition, for obese children with elevations in TG, nutrition counseling should include caloric restriction and increased activity as described above. Dietary fish intake may be increased to increase omega-3 fatty acid intake, as it has been shown to lower TG levels.
Statin Therapy
Statins inhibit hydroxymethylglutaryl coenzyme A reductase, the rate-limiting enzyme involved in the endogenous cholesterol synthesis pathway. The subsequent reduction in intracellular cholesterol levels signals an up-regulation in LDL-C receptor synthesis, resulting in increased clearance of circulating LDL-C. In adults with elevated LDL-C levels but no CVD, statin therapy may significantly reduce the future incidence of CVD events. Randomized clinical trials and meta-analysis have demonstrated short- and medium-term safety and efficacy of statins in lowering LDL-C in youth. Combination therapy has also proven effective in pediatric FH patients such that administration of ezetimibe, a cholesterol absorption inhibitor, in combination with simvastatin resulted in significantly greater reductions in LDL-C than simvastatin alone. In children, logistical challenges prevent the existence of randomized clinical trials addressing whether treating dyslipidemias in childhood reduce CVD events later in life. However, a number of studies have demonstrated improvements in noninvasive surrogate markers of atherosclerosis with statin treatment in children with FH. For example, a placebo-controlled randomized trial demonstrated a trend toward regression in cIMT in pravastatin-treated FH subjects, whereas the placebo group demonstrated a trend towards progression over the course of 2 years ( Fig. 25.5 ). A follow-up assessment of this study population demonstrated that earlier initiation of pravastatin was an independent predictor of cIMT at follow-up. Another placebo-controlled randomized trial of children with FH demonstrated improvements in FMD with simvastatin treatment, with FMD levels in the treatment group improving to a level similar to a normal control group. In addition, a recent study demonstrated a slowing of progression of cIMT in children with FH treated with rosuvastatin for two years, such that their cIMT after 2 years was not significantly different from their unaffected siblings.
Adverse effects resulting from statin use are rare but include myopathy and hepatic enzyme elevation. Rhabdomyolysis is an extremely rare occurrence in adults on statin therapy, with an incidence reported at 3 per 100,000 person-years. However, rhabdomyolysis has not occurred in the pediatric trials to date. In adults, muscle complaints are frequently reported but newer analyses suggest these effects occur with no more frequency in the drug group versus the placebo group when subjects are adequately blinded to treatment group. Furthermore there has not been any demonstrated impact on growth, development, or sexual maturation identified. A systematic review of statin use in children with FH found no difference between statin-treated and placebo-treated children regarding adverse events, sexual development, or muscle and liver toxicity.
Statin therapy is the first line medication to be used in patients with sufficiently elevated LDL-C or non-HDL-C levels. An LDL-C greater than or equal to 190 mg/dL on at least two occasions in a child with no history of early CVD who has not responded sufficiently to lifestyle modification meets the recommendation for initiation of pharmacologic therapy. Higher risk youth qualify for intensification of treatment at a lower LDL-C level. Cholesterol-binding resins may also be used although adherence is poor due to lack of palatability (grainy powders) or large pills requiring multiple doses in a day.
A modified version of the proposed treatment algorithm for the treatment of elevated LDL-C, adapted from the Expert Panel Guidelines, is shown in Fig. 25.6 . Of note, to confirm elevated fasting lipid levels, two measurements should be taken more than 2 weeks apart but no more than 3 months apart. Statin therapy should not be initiated until a 6-month trial of lifestyle management has been undertaken, as summarized above. Initiation thresholds vary based on the presence of moderate- and high-level risk factors ( Box 25.1 ). While children younger than 10 years old should not typically be treated, consideration may be made if they have a severe primary hyperlipidemia (e.g., homozygous FH with LDL-C ≥400 mg/dL), a very high-risk family history, high-risk conditions, or multiple risk factors. Children with LDL-C levels of 250 mg/dL or higher or TG of 500 mg/dL or higher should be referred directly to a lipid specialist. Statin therapy should be given once daily, at the lowest available dose. Currently, choice of statins is a matter of preference. A typical initial regimen may include 5 to 10 mg of atorvastatin once daily unless the family/patient prefers a different medication (e.g., if one/both of the parents are taking a different statin).