INTRODUCTION — Although cardiovascular disease (CVD) generally presents in adulthood, atherosclerosis begins in childhood. For most children, vascular changes, if present, are mild and can be minimized with adherence to a healthy lifestyle. However, in some children, the process is accelerated because of the presence of identifiable risk factors (eg, obesity and hypertension) and/or specific diseases associated with CVD (eg, types 1 and 2 diabetes mellitus and Kawasaki disease) [1]. Identification of children who are at-risk for atherosclerosis may allow timely intervention to decrease the atherosclerotic process, thereby preventing or delaying CVD [1-3].

The management of the child identified as being at-risk for atherosclerosis will be reviewed here. Identifying the child at-risk for atherosclerosis and assessing his or her risk for CVD is discussed separately. (See "Identifying the child at-risk for atherosclerosis".)

RATIONALE FOR INTERVENTION — The rationale for initiating therapy to reduce the risk of CVD in at-risk pediatric patients is based upon the following observations:

• Indirect evidence supports the association of accelerated atherosclerosis in childhood with future increased risk of CVD as follows:

• - The relationship between atherosclerosis and increased risk CVD is well established in adults. (See "Overview of the risk factors for cardiovascular disease".)
• - Children with high-risk diseases, such as homozygous familial hypercholesterolemia, not only have subclinical premature atherosclerosis, but also can have cardiovascular events in childhood or very early in adult life. (See "Diseases associated with atherosclerosis in childhood", section on 'Familial hypercholesterolemia' and "Primary disorders of LDL-cholesterol metabolism", section on 'Familial hypercholesterolemia'.)

• Identifiable risk factors for CVD in the adult (eg, obesity, hypertension, dyslipidemia, and smoking) accelerate the atherosclerotic process in childhood. In children and young adults, the severity and extent of atherosclerosis is greater as the number of risk factors increases. (See "Identifying the child at-risk for atherosclerosis", section on 'Atherosclerotic changes in childhood'.)

• Many of these identifiable risk factors can be modified by therapeutic lifestyle changes and drug therapies. The modification of these risk factors in adults has resulted in a reduced risk of CVD. (See "Primary prevention of coronary heart disease and stroke".)

• In studies of children with severe dyslipidemia (eg, familial hypercholesterolemia), statin therapy appears to be effective and safe in improving lipid profiles and modifying preclinical vascular findings.
• Identification of specific pediatric disease states associated with an increased risk of CVD allows targeted therapy that may reduce future CVD in affected children [4]. (See "Diseases associated with atherosclerosis in childhood".)

Based upon the above observations, therapeutic interventions should be considered in children with the following modifiable risk factors:

• Dyslipidemia
• Hypertension
• Obesity
• Insulin resistance
• Smoking
• Physical inactivity

In addition, therapeutic interventions to reduce (or prevent) accelerated atherosclerosis and CVD should be initiated in children with high-risk diseases (ie, familial hypercholesterolemia, types 1 and 2 diabetes mellitus, chronic kidney disease, heart transplantation, Kawasaki disease, chronic inflammatory disease, childhood cancer survivors, and some types of congenital heart disease) [4]. (See "Diseases associated with atherosclerosis in childhood".)

DYSLIPIDEMIA — Dyslipidemias are disorders of lipoprotein metabolism. We define pediatric dyslipidemia as one or more of the following serum lipoprotein profile findings:

• Total cholesterol (TC) >200 mg/dL (5.18 mmol/L)
• Low-density lipoprotein cholesterol (LDL-C) >130 mg/dL (3.36 mmol/L)
• High-density lipoprotein cholesterol (HDL-C) <40 to 45 mg/dL (1.0 mmol/L)
• Triglycerides >150 mg/dL (1.7 mmol/L) in adolescents and >130 mg/dL (1.47 mmol/L) in younger children

(See "Identifying the child at-risk for atherosclerosis", section on 'Dyslipidemia'.)

In adults, it is well established that dyslipidemia is associated with atherosclerotic cardiovascular disease. Similar long-term evidence is lacking in children due to the long follow-up and large numbers of patients that would be required to demonstrate such an effect.

The American Heart Association (AHA) in 2007 and the American Academy of Pediatrics (AAP) in 2008 reviewed and updated the National Cholesterol Education Program (NCEP) and AAP 1998 guidelines for treatment of childhood dyslipidemia (table 1) [3,5-7]. The AHA and AAP guidelines include recommendations on patient selection, initiation of therapy, and targeted goals.

In the AAP statement, therapeutic approaches to prevent dyslipidemia are divided into a broad population approach and an individual approach focusing on identified children with dyslipidemia and/or who have other risk factors for atherosclerosis. Therapy on a population basis includes nonpharmacological approaches including environmental and community efforts to increase physical activity and decrease "junk foods" in schools. Therapy for the individual includes nonpharmacologic and pharmacologic interventions, as discussed in the following sections.

Nonpharmacologic therapy — Nonpharmacologic therapy, also referred to as lifestyle modification, includes dietary interventions and increased activity. In general, at least a six month trial of lifestyle modification is implemented before pharmacologic therapy is considered.

Diet — Dietary recommendations have been developed by the AHA/AAP/NCEP for all children (population-based approach) and for those with dyslipidemia (patient-based approach).

• Population-based approach — The AHA/AAP/NCEP guidelines recommend a low-saturated-fat, low-cholesterol diet that has the appropriate number of calories to support growth and development in all healthy children greater than two years of age (table 2) [5-9]. The AHA/AAP/NCEP diet targets the intake of saturated fat to less than 10 percent and total fat to less than 30 percent of the total calories consumed, and the daily intake of dietary cholesterol to less than 300 mg/day (table 2) [5,6,8]. In general, recommendations for caloric intake are based upon the age, sex, and activity level of the child.

In a Special Turku Coronary Risk Factor Intervention Project (STRIP) trial, modest improvements in fasting lipid profiles were seen in children starting at seven months of age whose parents received counseling regarding a low-saturated-fat, low-cholesterol diet compared to those whose parents did not receive any dietary counseling [9-12]. This diet primarily relies on fruit and vegetables, whole grains, low-fat and nonfat dairy products, beans, fish, and lean meat [8]. Recommendations for caloric intake are based upon the age, sex, and activity level of the child.

In 2009, the AHA published implementation strategies for children greater than two years of age that include the following [9]:

• Daily moderate activity of 60 minutes
• Eat vegetables and fruits and limit juice intake
• Use vegetable oils and soft margarines low in saturated fat and trans fatty acid instead of butter or most animal fats
• Eat whole-grain rather than refined-grain bread and cereals
• Reduce intake of sugar-sweetened beverages and foods
• Use non or low-fat milk
• Increase fish consumption, use only lean cuts of meat and reduced-fat meat products, and remove the skin from poultry
• Reduce salt intake
• Teach about a balanced meal, portion size, and caloric contents of snacks
• Encourage eating at home
• Dietary counseling that provides information and focuses on behavior change

Data from a subsequent STRIP study reported that a low-saturated fat, low-cholesterol diet that maintains adequate total fat can be initiated at age seven months, with repeated dietary counseling leading to sustained benefits and no adverse effects on development [13]. At 14 years of age, the group that received repeated dietary counseling had lower saturated fat intakes, serum total cholesterol, and serum LDL-C than the control group. There were no differences between the two groups in the serum HDL-C values, growth, body mass index, pubertal development, or age at menarche for girls. These results suggest that the dietary intervention was both safe and effective when applied from 7 months to 14 years of age.

As a consequence of these findings, the AAP now recommends that children at 12 months of age with risk factors for high cholesterol (family history of high cholesterol, obesity, or early CVD) receive low fat dairy products.

• Patients with dyslipidemia — In children with elevated serum LDL-C, defined as >130 mg/dL (3.36 mmol/L), the AHA/NCEP/AHA guidelines suggest further reduction of saturated fat to less than 7 percent of total calories and cholesterol to less than 200 mg/day [7,8,14]. In our practice, we do not generally add further restriction because adherence is difficult and may foster noncompliance and stress between the child and parents.

In children with severe dyslipidemia (LDL-C >190 mg/dL [4.9 mmol/L]), diet modification alone is rarely sufficient to reach target levels for LDL (ie, minimal target of <130 mg/dL [3.35 mmol/L] and optimal target of <100 mg/dL [2.29 mmol/L]). If targeted lipid values are not reached with nonpharmacologic therapy alone, pharmacologic therapy should be considered and is initiated based upon the severity of dyslipidemia and the presence of other CVD risk factors. (See 'Pharmacologic therapy' below.)

In most children with elevated triglycerides (TG), a diet that is low in carbohydrate intake is recommended [4]. In patients with hyperchylomicronemia related to rare genetic disorders such as lipoprotein lipase deficiency (Frederickson's Type I), fat restriction may be necessary.

Dietary counseling should be tailored to the patient and his/her family. Behavior modification and motivational interviewing techniques may be helpful. Support and lifestyle modification for the whole family is usually necessary for successful change in the child.

Activity — In adults, evidence demonstrates that daily vigorous activity decreases the risk of CVD and improves fasting lipid profiles. Data similar in quality are lacking in children. However, cross-sectional studies demonstrate a positive correlation between the amount of exercise and improved fasting lipoprotein profiles in children and adolescents [15]. In one prospective pediatric study, improvement in the ratio of serum total to HDL cholesterol was associated with an increase in aerobic fitness over a five-year period of time [16]. (See "Exercise and fitness in the prevention of cardiovascular disease" and 'Inactivity' below.)

Dietary supplements — Dietary supplements include fiber and plant stanols, sterols, and omega-3 fatty acids. The following is summary of these supplements, which are discussed in greater detail separately. (See "Lipid lowering with diet or dietary supplements", section on 'Fiber' and "Lipid lowering with diet or dietary supplements", section on 'Plant sterols',(See "Fish oil and marine omega-3 fatty acids".)

• Fiber — Currently available data vary on whether or not increased fiber intake can reduce serum LDL-C [7]. Fiber is thought to bind with cholesterol within bile acids, thus removing it from the enterohepatic circulation. Supplemental fiber is usually required at a calculated dose of the child's age plus 5 g/day, up to a dose of 20 g/day.

It may be difficult for children to consume enough dietary fiber supplements on a regular basis to induce a reduction in serum LDL. In our practice, we prefer that children consume fiber from dietary sources (eg, fruit, vegetables, and whole grains) and generally do not recommend fiber supplements.

• Plant stanols and sterols — In adults, these compounds, which are found in margarine, orange juice, yogurt drinks, cereal bars, and dietary supplements, have been shown to reduce dietary cholesterol by 5 to 10 percent. One study in children showed that an intake of 20 g/day of plant sterol contained in a margarine product reduced serum LDL-C by 8 percent. Although stanols reduce serum LDL levels, there are no data demonstrating that they reduce the risk of early CVD. In general, data are more supportive for the effectiveness and safety for statin than stanol therapy. (See "Lipid lowering with diet or dietary supplements", section on 'Plant sterols'.)

These compounds decrease absorption of fat-soluble vitamins and beta-carotene. Children taking these supplements should take a multivitamin daily.

• Omega-3 fatty acids (ie, fish oil supplements) — Data have demonstrated that dietary and supplemental omega-3 fatty acids lower serum TG levels, in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). (See "Fish oil and marine omega-3 fatty acids", section on 'Effects on cardiovascular risk factors'.)

In our practice, we may recommend omega-3 fatty acid supplements (1 gm) for children who are not eating fish. For children with extremely elevated serum TG (600 to 1000 mg/dL), we may use omega-3 fatty acid supplement (dose of 2 to 4 gms per day) in conjunction with statin or fibrate therapy.

Pharmacologic therapy — In adults, it is well-established that dyslipidemia is associated with atherosclerosis and increases the risk of CVD. Large randomized clinical trials in adult patients with hypercholesterolemia demonstrate that statin therapy lowers low-density lipoprotein cholesterol (LDL-C) and reduces coronary artery (CA) morbidity. (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease".)

In addition, small clinical trials in children with familial hypercholesterolemia show that statin therapy, compared to placebo, decreases serum LDL-C without significant adverse side effects after several years of follow-up [14,17,18]. Duration of follow-up has been insufficient to prove that statin therapy lowers the risk of CVD in individuals started on statins in childhood. Most studies however, suggest that the progression of subclinical atherosclerosis is reduced:

• A follow-up evaluation at a mean of 4.5 years after initiation of statin therapy demonstrated decreased carotid intima media thickness [18].
• Brachial artery reactivity testing improved in children 9 to 18 years old with heterozygous familial hypercholesterolemia who received 28 weeks of statin therapy, achieving reactivity readings similar to control adolescents [19].
• In contrast, one study showed no clear improvement in preclinical disease (ie, carotid intima media thickness and arterial stiffness) after two years of statin therapy in 80 adolescents with heterozygous familial hypercholesterolemia [20].

Studies of patients who have undergone cardiac transplantation also demonstrated that statin therapy was an effective and safe intervention [21,22]. In two studies, the use of statin therapy compared to no statin therapy reduced TC and decreased the incidences of cardiac transplant vasculopathy and mortality. In one study, no significant side effects of statin therapy were noted during the eight-year observation period [22].

Criteria — Based upon the above findings, the use of statin therapy to treat children with dyslipidemia has been advocated. The 2007 AHA and 2008 AAP statements recommend the use of statin therapy if all of the following criteria are met [3,7]:

• Age and sex of the child - In general, boys should be older than 10 years of age, and girls should have started their menses and have regular periods. Female patients should be counseled regarding the potential teratogenic effects of statin therapy and the need for appropriate contraception, if warranted. Therapy can be initiated in patients as young as eight years of age with severe dyslipidemia (eg, familial hypercholesterolemia or type 1 diabetes mellitus) who have failed nonpharmacologic therapy.

For the most part, patients should be at least Tanner stage II, indicating some advancement in pubertal development due to a theoretical risk of derangement in that process by statin-mediated alteration in sex steroid hormone production. Of note, however, no abnormality in pubertal development has been reported in clinical trials to date. Although girls are less often included in statin trials, several trials that included female participants have not detected abnormalities in pubertal development over the study period of one and two years [14,18,23]. In one trial that evaluated post-pubertal girls between 10 and 17 years of age, there were no changes in menses and hormone levels (ie, LH, FSH, estradiol, cortisol, and DHEA), which remained unchanged compared to baseline [24].

In children less than eight years of age, pharmacological therapy should only be considered if serum LDL-C exceeds 500 mg/dL (12.9 mmol/L) [7]. This generally occurs only in patients with homozygous familial hypercholesterolemia, an extremely rare genetic condition associated with myocardial infarction in childhood.

• Failure of nonpharmacologic therapy - After a 6 to 12 month trial of a low-saturated fat and cholesterol diet and activity regimen, the targeted serum LDL-C level remains abnormal. (See 'Nonpharmacologic therapy' above.)

• One of the following four conditions:

• - The LDL-C is greater than or equal to 190 mg/dL (4.9 mmol/L) without other CVD risk factors.

OR

• - The LDL-C is greater than or equal to 160 mg/dL (4.1 mmol/L) but less than 190 mg/dL (4.9 mmol/L) and one of the following three conditions; (1) a family history of premature CVD, (2) two or more other CVD risk factors after vigorous attempts to control CVD risk factors (ie, overweight, hypertension, insulin resistance, or smoke exposure), or (3) a primary disease associated with a moderate or mild increased risk of CVD (table 1). (See "Diseases associated with atherosclerosis in childhood" and 'High-risk diseases' below.)

OR

• - The LDL-C is greater than or equal to 130 mg/dL and the patient has moderate risk underlying disease, such as heterozygous familial hypercholesterolemia, or type II diabetes mellitus (algorithm 1).

OR

• - The LDL-C is greater than or equal to 100 mg/dL and the patient has high risk underlying disease, such as homozygous FH, or diabetes mellitus type I (algorithm 1).

Lipid-altering agents encompass several classes of drugs that include statins, fibric acid derivatives, bile acid sequestrants, nicotinic acid, and cholesterol absorption inhibitors (eg, ezetimibe). These drugs differ with respect to mechanism of action and to the degree and type of lipid lowering.

Based upon these revised guidelines, only a small percentage of children in the United States would require pharmacological treatment. This was illustrated in a study that analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2000 that showed only 0.8 percent of the 7180 adolescents between 12 and 17 years of age met the criteria for pharmacologic therapy [25]. Of these 26 patients, 11 had LDL-C greater than 190 mg/dL, and the remaining 15 had LDL-C greater than 160 mg/dL and at least one risk factor (obesity, diabetes, hypertension, cigarette smoking, and a positive family history). Overall, 6.6 percent of the group had elevated LDL-C levels (defined as >130 mg/dL), and 9.6 had elevated total cholesterol (defined as >200 mg/dL).

The following sections review the use of these drugs in children with dyslipidemia (table 3). A more complete discussion of these drugs in the management of adults with hypercholesterolemia is found separately. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention" and "Treatment of lipids (including hypercholesterolemia) in secondary prevention" and "ATP III guidelines for treatment of high blood cholesterol".)

Statins — Statins are the most commonly used drugs in the treatment of hypercholesterolemia in adults and are the only class of drugs to demonstrate improvements in CVD morbidity and mortality. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention".)

In children with familial hypercholesterolemia, who are at high risk for CVD, clinical trials have shown a consistent 20 to 40 percent reduction of serum LDL-C with the use of statins [14,17,26-29].

In patients with heterozygous hypercholesterolemia, a systematic review of 18 studies (ie, eight randomized control trials, seven prospective case series, two studies with control groups, and one nonrandomized control trial) demonstrated statin therapy lowered LDL-C by 33 percent and TG by 3 percent, and increased HDL-C by 3 percent [30]. There was no difference in adverse reactions between statin and placebo for the study periods that ranged from 6 to 96 weeks.

Although long-term outcome data are not available, studies of preclinical disease suggest that the atherosclerotic process is slowed with statin therapy [18]. Adverse effects in affected children are similar to those seen in adult patients. They include gastrointestinal symptoms, muscle cramps and myopathy, and elevation of liver transaminases.

Several different formulations of statin therapy are available. Currently lovastatin, simvastatin, pravastatin, and atorvastatin are approved by the United States Food and Drug Administration for use in children (table 3). Pravastatin, simvastatin and lovastatin are available in generic forms.

When considering initiation of statin therapy, one needs to balance the extent of risk reduction of CVD against the risk of potential adverse effects from the drug itself [31]. In adults older than 40 years of age, five-year clinical trials have shown statin therapy to be effective in reducing the absolute risk reduction of nonfatal MI or CVD death by 3 percent (from 9.4 to 6.4 percent). Similar long-term data are not available in children who are at a much lower short-term risk for cardiovascular events and may require therapy for several decades to achieve an absolute reduction in cardiovascular mortality and morbidity. In addition, although long-term data have suggested an outstanding safety profile for statins, the long-term safety of statin therapy initiated in childhood is unknown. Ultimately, management decisions must be individualized to the patient's specific circumstances [31]. (See "Clinical trials of cholesterol lowering for primary prevention of coronary heart disease" and "Primary prevention of coronary heart disease and stroke" and 'Our approach' below.)

In our practice, when statin therapy is initiated, we follow the regimen outlined by the AHA statement [3].

• Treatment is initiated at the lowest dose, which is given once a day, usually at bedtime, because most LDL-C synthesis occurs during nighttime hours.
• Initial choice of agent is generally based on price and patient preference.
• The patient is assessed four weeks after the start of therapy to determine the efficacy of the treatment and whether there are any adverse effects. At this visit, laboratory evaluations include fasting lipoprotein profile, and measurements of serum creatinine kinase, alanine aminotransferase, and aspartate aminotransferase are performed.

The targeted values of LDL-C depend on the presence of associated risk factors, but are generally as follows:

• - Minimal, less than 130 mg/dL (3.35 mmol/L)
• - Optimal, less than 110 mg/dL (2.85 mmol/L)
• - Less than 100 mg/dL for patients with high risks due to co-existing disease

• If the targeted value is met and there are no laboratory abnormalities, therapy is continued at the same dose. Reassessment after four and eight weeks of therapy to confirm dosing, and then every six months thereafter.
• If the targeted value is not met, the dose is increased. Reassessment is performed in four weeks. If treatment is well tolerated but goals are not yet met, the dose of statin may be doubled, or another drug (eg, ezetimibe) may be added until the target or the maximum dose is reached or there is evidence of toxicity. Laboratory testing is reassessed again eight weeks after the dose change to ensure dosing is correct and there are no detectable side effects. (See 'Other agents' below.)

• If there are laboratory abnormalities, the drug is stopped for two weeks and the laboratory testing is repeated. When the abnormalities resolve, the drug may be restarted with close monitoring. For patients with adverse symptoms possibly related to the drug, it is most helpful to obtain laboratory testing while the symptoms are ongoing. This can help the practitioner to decipher if they are in fact drug-related, in which case, the drug should then be stopped for two weeks before retesting and re-evaluating.
• Once a dosing regimen has been established, ongoing monitoring of growth, fasting lipoprotein profile, and laboratory evaluation for toxicity should be performed every six months.
• Adolescent females should be counseled about the possibility of teratogenicity and should be counseled regarding appropriate contraceptive methods while receiving statin therapy. (See "Lipid lowering with statins", section on 'Use in pregnancy'.)

Children and adolescents generally are not treated with more than one class of lipid-lowering agents, aside from the combination of statin with ezetimibe, because of the increased risk of side effects, particularly muscle toxicity. Side effects are also more commonly seen in patients on other medications, such as cyclosporine. Statins should be used with caution in patients with renal insufficiency and doses should be lower when used in these circumstances.

Fibric acid derivatives — Fibric acid derivatives raise HDL-C and lower TG. Although data are limited on the use of fibric acid derivatives in children [32], it is recommended by the AHA as the preferred class of drugs in treating children with elevated TG [33]. In one report from a tertiary center that reviewed its management of 76 children with hypertriglyceridemia (53 patients with primary and 13 with adiposity-related hypertriglyceridemia), triglyceride levels decreased with the use of fibrates, did not change with the use of statins, and increased with the use of bile acid-binding resins [34].

In our experience fibric acid derivatives have been well tolerated if given as monotherapy (eg, not combined with a statin). Generally, fibric acid medications are reserved for the rare child with severe triglyceride elevations (considered at levels >600 to 1000 mg/dL, usually prescribed for levels >1000 mg/dL) and are most often used in older adolescents. The risk of myopathy and rhabdomyolysis is increased when they are used in conjunction with statins or in patients with renal insufficiency. The simultaneous use of both statin and fibrate is rare in clinical practice and they should be administered under the supervision of a clinician with expertise in treating children with dyslipidemia.

Other agents — Bile acid sequestrants are not as effective as statins and have adverse side effects that result in poor compliance (eg, constipation and bloating). For these reasons, bile acid sequestrants are used relatively infrequently. The sequestrants are, however, extremely safe, as they are not absorbed systemically but remain in the gut and are excreted along with the bile containing cholesterol. For pre-pubertal patients with severe LDL-C elevations (heterozygous familial hypercholesterolemia) who are able to be very compliant and do not experience bloating or constipation, the sequestrants can effectively lower LDL-C as much as 10 to 20 percent. They can be used until puberty is farther advanced, at which time statin therapy can be initiated.

Cholesterol absorption inhibitors (eg, ezetimibe) are a new class of lipid-lowering agents that prevent intestinal absorption of cholesterol and plant sterols. In adults, in combination with statins, ezetimibe further lowers serum LDL but may not further lower CVD risk. Data are limited on the use of these agents in children. In one observational study, ezetimibe therapy (10 mg per day) was associated with a decrease in TC and LDL-C in children suspected of having familial hypercholesterolemia or familial combined hyperlipidemia, who failed to adequately response to diet therapy or developed adverse effects with statin therapy [35]. There were no significant changes in TG or HDL-C. The mean duration of ezetimibe therapy was 105 days, and no adverse effects were reported. Further studies are needed to see if ezetimibe is a safe and effective therapy for the treatment of dyslipidemia in children. (See "Lipid lowering with drugs other than statins and fibrates", section on 'Ezetimibe'.)

Niacin is particularly effective in raising HDL cholesterol, increasing levels by 20 to 30 percent [36]. However, compliance is difficult due to frequent side effects (eg, rash, flushing, and headaches). As a result, niacin is rarely used. Niacin comes in several different formulations, including various over the counter preparations, so care should be taken with dosing. The prescription formulation is the most convenient for use.

The remainder of this discussion is presented separately.

Our approach — In our practice, treatment of dyslipidemia is based upon the estimation of the child's risk for premature CVD.

We initiate non-pharmacologic therapy including counseling promoting healthy lifestyle changes of a low-saturated-fat, low-cholesterol diet and an exercise regimen that provides daily vigorous activity. In the very young patient, life-style management is the mainstay of therapy. We also recommend low fat dairy products in children after the age of 12 months. (See 'Diet' above and 'Activity' above.)

If non-pharmacologic therapy fails to reach the targeted goal by six months, statin therapy is considered in the older child. The potential absolute benefit of reduced CVD risk versus the unknown risk of long-term statin therapy is discussed with the family. The decision to start pharmacologic therapy is based upon the severity of the child's dyslipidemia, the presence of other co-morbid conditions, the severity of family history of premature CVD, and the preferences of the child and family.

In patients with severe dyslipidemia who are known to have an increased risk of premature cardiovascular events before 30 years of age because of an underlying high-risk disease (algorithm 1), such as homozygous familial hypercholesterolemia, statin therapy is initiated. In these patients, the absolute risk reduction of CVD provided by statin therapy outweighs its potential side effects. The target LDL for these very high risk patients is <100 mg/dL. In addition, lifestyle behavior modifications are emphasized.

As noted above, statins are not generally prescribed before 10 years of age, except in the highest-risk circumstances such as heart transplant patients or children with homozygous familial hypercholesterolemia. In our practice, pharmacologic therapy is considered in a child as young as eight years of age with a very averse lipid profile despite optimal nonpharmacologic management (ie, diet, weight, and activity) and a family history of early CVD. In those with homozygous familial hyperlipidemia, pharmacological therapy, even at high doses, almost never sufficiently lowers cholesterol values, and LDL-C apheresis every several weeks is usually required to achieve acceptable lipid levels. For the vast majority of children, the main focus of management to prevent or slow the progression of atherosclerosis is lifestyle modification.

HYPERTENSION — In 2004, the National High Blood Pressure Education Program Working Group (NHBPEP) revised guidelines for the treatment of hypertension. These included the following recommendations:

• The targeted goal for blood pressure (BP) is less than the 95th percentile based upon age and gender (table 4A-B and table 5A-B). The age- and height-specific blood pressure percentiles may be determined using calculators for boys (calculator 1) or for girls (calculator 2).
• If there are comorbid risk factors (eg, obesity and diabetes mellitus), and/or evidence of target-organ damage (ie, left ventricular hypertrophy, renal scarring, or retinopathy), or diseases with high risk of early atherosclerosis (Tier 1), the BP targeted goal is lowered to the <90th percentile for age and gender.
• Children who are pre-hypertensive (BP >90th percentile and <95th percentile) and do not fall into the category above should be treated with nonpharmacologic therapy (eg, diet and exercise) to reduce their BP to below the 90th percentile.

Treatment for hypertension includes both nonpharmacologic and pharmacologic interventions. Management decisions are dependent upon the severity of hypertension, the underlying cause, and the presence of other CVD risk factors.

Our approach — In our practice, we use the NHBPEP guidelines for initiating treatment as follows:

• We begin pharmacologic therapy in children with severe hypertension (defined as BP levels that are 5 mmHg greater than the 99th percentile for age and gender), those with hypertensive target-organ damage (eg, left ventricular hypertrophy) or high risk diseases (algorithm 1) with a BP above the 95th percentile for age and gender.
• In the remaining patients with BP above the targeted goal, nonpharmacologic therapy, including diet and activity, is initiated.
• If the BP persists above the targeted goal despite nonpharmacologic therapy, an antihypertensive medication is started. The targeted BP goal is lower in patients who have an additional comorbid condition or risk factor.

Drug selection is usually left to the discretion of the clinician, who should consider the clinical setting and whether a particular class of drug may be more beneficial or cause more adverse effects. As an example, in children who have insulin resistance or diabetes mellitus, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) are preferred over other classes of antihypertensive because of their established benefit in reducing microalbuminuria and preserving renal function. Once daily dosing increases compliance, particularly in the hypertensive adolescent.

The treatment of hypertension in children and adolescents is discussed separately in greater detail. (See "Treatment of hypertension in children and adolescents".)

OBESITY — Overweight and obesity are associated with accelerated atherosclerosis in childhood and increased risk of CVD in adults. Treatment for obesity in childhood is difficult and involves lifestyle changes at many levels. A multidisciplinary approach involving nutritional modification, behavioral counseling, and increased physical activity appears to increase the success rate of weight reduction [37]. The targeted body mass index (BMI) is ideally less than the 85th percentile for age and gender, with slightly higher BMI percentiles allowed for children with less severe risk factors (algorithm 1). (See "Comorbidities and complications of obesity in children and adolescents" and "Overview of therapy for obesity in adults".)

INSULIN RESISTANCE AND DIABETES MELLITUS — Insulin resistance, hyperinsulinemia, and elevated blood glucose are associated with atherosclerotic cardiovascular disease. In addition, children with diabetes mellitus are at increased risk for other atherogenic risk factors, such as hypertension and dyslipidemia.

In adults and adolescents with type 1 diabetes mellitus, randomized trials have conclusively established that poor glycemic control is causally associated with long-term vascular sequelae. In addition, adult and adolescent clinical trials demonstrate that intensive insulin therapy resulting in strict glycemic control (hemoglobin A1C levels below 7) decreases the incidence of cardiovascular disease. As a result, strict glycemic control is recommended for children and adolescents with type 1 diabetes. Similar recommendations are made for children with type 2 diabetes, particularly as these children are more commonly overweight. (See "Management of type 1 diabetes mellitus in children and adolescents" and "Complications and screening in children and adolescents with type 1 diabetes mellitus" and "Management of type 2 diabetes mellitus in children and adolescents".)

Because both type 1 and type 2 diabetes mellitus are associated with dyslipidemia, diabetic patients should be screened with a fasting lipid profile. LDL-C targeted goals are less than 100 mg/dL (2.5 mmol/L) in patients with either type 1 or 2 disease.

For patients with elevated LDL-C, initial therapy begins with lifestyle changes affecting diet and level of activity. Statin therapy is recommended when the LDL-C values remains above 100 mg/dL (2.5 mmol/L) despite nonpharmacologic intervention. (See 'Dyslipidemia' above and "Complications and screening in children and adolescents with type 1 diabetes mellitus" and "Comorbidities and complications of type 2 diabetes mellitus in children and adolescents".)

SMOKE EXPOSURE — Because smoke exposure, including second-hand smoke, increases the risk of CVD, all patients and their close contacts who smoke should be counseled on a regular basis to quit smoking. A number of approaches, including behavioral therapy, nicotine replacement therapy, and other pharmacologic therapies are available. (See "Management of smoking cessation".)

INACTIVITY — In adults, a number of observational studies have shown a strong inverse relationship between leisure time activity and energy expenditure, habitual exercise, and fitness and the risk of coronary disease and death. Similar data in children are lacking. One study of 13 year-old children from the Special Turku Coronary Risk Factor Intervention Project (STRIP) trial reported that increased activity was associated with improved brachial artery flow-mediated endothelial function measured by Doppler ultrasound in adolescent boys [38]. In addition, as previously discussed, there is evidence from cross-sectional studies of a positive correlation between the amount of exercise and improved fasting lipoprotein profile. (See 'Dyslipidemia' above.)

Although there are limited data on the effect of exercise on atherosclerosis and dyslipidemia in children, it is reasonable to increase physical activity as recommended by the AHA, especially in children who are sedentary. Sedentary behavior, as distinguished from inadequate activity, is correlated with childhood obesity (Ref Anderson RE et al 1998) and therefore deserves attention as a target for risk reduction. The AAP recommends limiting screen time to 2 hours or less per day [33].

In our practice, we recommend 30 to 60 minutes of exercise, four to six times a week, with the following end points that indicate an adequate degree of exertion [39]:

• Breathlessness
• Fatigue
• Sweating

In a child who has been inactive, we generally start at a lower intensity and frequency than the ultimate target. The exercise regimen is increased week by week to avoid setting unattainable goals. Directions on the expected exercise goals should be specific and clear to both the patient and his/her family.

A more detailed description of the role of exercise in preventing CVD is found separately. (See "Exercise and fitness in the prevention of cardiovascular disease".)

HIGH-RISK DISEASES — Specific pediatric diseases are associated with a high-risk of CVD. In 2006, the American Heart Association (AHA) identified eight of these diseases and classified their risk for CVD based upon a three-tier stratification schema as follows (algorithm 1) [2,4]:

• High risk — Pathologic or clinical evidence of CAD before 30 years of age. Diseases in this category include homozygous familial hypercholesterolemia, type 1 diabetes mellitus, chronic kidney disease, heart transplantation, and Kawasaki disease with current coronary aneurysms.
• Moderate risk — Pathophysiologic evidence for accelerated atherosclerosis before 30 years of life. Diseases in this category include Kawasaki disease with regressed coronary aneurysms, type 2 diabetes mellitus, and chronic inflammatory disease.
• At risk — Epidemiologic evidence for CAD early in adult life but after 30 years of age. Patients in this category include cancer survivors, and those with congenital heart disease or Kawasaki disease without detected coronary involvement.

Management of these patients is divided into treatment of the underlying primary disease and of any comorbid condition. The initiation and the nature of intervention is dependent upon the assessment of the degree of CVD risk for the individual child based upon his/her underlying disease and the presence of comorbid conditions such as hypertension, dyslipidemia, overweight, and hyperglycemia. (See "Diseases associated with atherosclerosis in childhood".)

APPROACH TO THERAPY — The decision of when to initiate therapy for an individual child to reduce the risk of CVD should be based upon an estimate of the absolute risk reduction for that child and the potential risk of significant side effects of the therapeutic intervention. Unfortunately, long-term outcome data to guide decisions are not currently available. However, evidence supporting the value of preventing early atherosclerosis does exist, both in the pediatric and adult literature. Therapeutic choices are based upon indirect evidence, the preference of patients and their family, and the medical judgment of care providers based upon the best available data. (See "Identifying the child at-risk for atherosclerosis".)

Therapy includes nonpharmacologic and pharmacologic interventions. The initiation and aggressiveness of the therapy are generally based upon the number of risk factors and their severity (ie, dyslipidemia, hypertension, and overweight).

Our management approach includes the following:

• Counseling for weight reduction in overweight patients. (See 'Obesity' above.)

• Counseling for smoking cessation for adolescents or family members who smoke. (See "Management of smoking cessation".)

• In patients with an underlying disease associated with an increased risk of CVD, treatment of the primary disease. (See "Diseases associated with atherosclerosis in childhood".)

• Management of modifiable risk factors such as overweight, dyslipidemia, inactivity, and hypertension as discussed in the above sections, with the strength of the intervention based upon the severity of the child's condition and the existence of other comorbid conditions. (See 'Dyslipidemia' above and 'Hypertension' above.)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Children and heart disease (atherosclerosis)".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

Rationale — The rationale that identifying children who are at-risk for atherosclerosis will allow timely intervention to decrease the atherosclerotic process, thereby preventing or delaying cardiovascular disease, is based upon the following:

• Indirect evidence from clinical trials in adults and children with homozygous familial hypercholesterolemia.
• Evidence that modifiable risk factors (ie, dyslipidemia, hypertension, overweight, diabetes mellitus, and smoke exposure) are associated with accelerated atherosclerosis in children and CVD in adults. Improvement of these risk factors has resulted in a reduction of incidence of CVD in adults.

(See 'Rationale for intervention' above.)

Management approach — Our approach is as follows:

• We recommend weight reduction in overweight patients with a targeted goal of a body mass index (BMI) less than or equal to 85th percentile for age and gender (Grade 1B).
• We recommend smoking cessation for any patient or close contact who smokes (Grade 1A).
• In patients with homozygous familial hypercholesterolemia, we recommend statin therapy (Grade 1B). Nonpharmacologic therapy with a low-saturated-fat, low-cholesterol diet and a daily vigorous exercise regimen is also initiated. In addition, apheresis for LDL-C removal is used as necessary to lower LDL-C. (See 'Dyslipidemia' above and "Primary disorders of LDL-cholesterol metabolism", section on 'Familial hypercholesterolemia'.)

• In children with dyslipidemia, excluding those with severe genetic or high-risk diseases, we recommend an initial trial of nonpharmacologic therapy (Grade 1B). This includes an appropriate diet beginning at 12 months of age (eg, a low-saturated-fat, low-cholesterol diet in patients with elevated LDL-C) (table 2) and an exercise regimen that provides daily vigorous activity as appropriate for age (table 1). (See 'Dyslipidemia' above.)

• We suggest statin therapy in older children (greater than 10 years of age, or 8 years of age in those who are severely affected) who have persistent dyslipidemia despite a 6 to 12 month trial of nonpharmacologic therapy (table 1) (Grade 2C). Because long-term outcome data for statin therapy are lacking in these patients, it remains unknown whether statin therapy started in childhood has either significant long-term benefits or risks. As a result, the decision to start pharmacologic therapy is based upon the severity of the child's dyslipidemia, the presence of other comorbid conditions, and the preferences of the child and family. (See 'Dyslipidemia' above.)

• When we initiate statin therapy, we follow the AHA recommended guidelines. (See 'Statins' above.)

• In children who have elevated blood pressure (BP), we suggest using the National High Blood Pressure Education Program Working Group guidelines for initiating treatment as follows (Grade 2B):

• - Pharmacologic therapy is started in children with severe hypertension (defined as BP levels that are 5 mmHg greater than the 99th percentile for age and gender), those who have hypertensive target-organ damage (eg, left ventricular hypertrophy), and those with diseases that are associated with a high risk of CVD (algorithm 1) and a blood pressure above the 95th percentile for age and gender.
• - In the remaining patients with BP greater than the 90th percentile but less than the 95th percentile, nonpharmacologic therapy including diet and activity is initiated.
• - If the BP persists above the targeted goal despite nonpharmacologic therapy, an antihypertensive medication is started. The targeted BP is lower in children with comorbid conditions such as obesity or dyslipidemia.

The age- and height-specific blood pressure percentiles may be determined using calculators for boys (calculator 1) or for girls (calculator 2).

Drug selection is usually left to the discretion of the clinician, who should consider the clinical setting and whether a particular class of drug may be more beneficial or cause more adverse effects. (See "Treatment of hypertension in children and adolescents".)