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Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood

Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood
Literature review current through: Jan 2024.
This topic last updated: Oct 18, 2023.

INTRODUCTION — Atherosclerotic vascular changes can begin in early childhood, setting the stage for atherosclerotic cardiovascular disease (ASCVD) events in adulthood. For most children, atherosclerotic vascular changes can be minimized or even prevented with adherence to a healthy lifestyle. However, in some children, the atherosclerotic process is accelerated because of the presence of identifiable risk factors (table 1).

The evidence linking atherosclerotic changes in childhood to ASCVD later in life will be reviewed here. Related topics include:

(See "Overview of the management of the child or adolescent at risk for atherosclerosis".)

(See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis".)

(See "Dyslipidemia in children and adolescents: Management".)

(See "Familial hypercholesterolemia in children".)

ATHEROSCLEROTIC CHANGES IN CHILDHOOD — Evidence for the development of atherosclerosis in childhood includes autopsy studies showing atherosclerotic changes in the young and noninvasive, indirect data in children and adolescents showing vascular changes that commonly precede adult ASCVD.

In addition, these studies demonstrate an accelerated burden of vascular changes and premature atherosclerosis among children and adolescents with well-established ASCVD risk factors (eg, overweight/obesity, hypertension, dyslipidemia, and smoke exposure). These ASCVD risk factors often track into adulthood.

These data, along with evidence from adult studies, are the basis for promoting healthy behaviors in childhood to prevent and reduce risk factors associated with premature atherosclerosis and, by extension, overt ASCVD. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children" and "Overview of the management of the child or adolescent at risk for atherosclerosis".)

Direct evidence from autopsy studies — Autopsy studies in children and young adults who have died of noncardiovascular causes demonstrate that atherosclerosis can begin in childhood. Findings in these studies included fatty streaks (accumulation of lipid-filled macrophages within the intima of the artery, which are early atherosclerotic changes) and fibrous plaques (a more advanced stage of atherosclerosis).

Examples of these studies include:

In the Bogalusa Heart Study, autopsies performed in 204 young subjects (2 to 39 years of age, mean age 19.6 years) demonstrated fatty streaks in 50 percent of cases between 2 and 15 years of age and in 85 percent of older subjects between 21 and 39 years of age [1]. The prevalence of raised fibrous plaques in the aorta and coronary arteries also increased with age from approximately 20 percent in subjects between 2 and 15 years of age to 70 percent in those between 26 and 39 years of age. The prevalence and the extent of atherosclerosis found in the aorta and coronary arteries were greater with increasing body mass index (BMI), blood pressure measurements, and levels of serum total cholesterol and low-density lipoprotein cholesterol (LDL-C). The degree of atherosclerotic changes increased with worsening severity and greater numbers of risk factors.

The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study examined the right coronary arteries and aortas in autopsies of 2876 individuals between 15 and 34 years of age [2,3]. In subjects who were 15 to 19 years of age, raised fatty streaks were present in 10 percent of coronary arteries and 30 percent of aortas. The extent of fatty streaks increased with increasing age, elevated blood pressure, higher serum LDL-C, and lower serum high-density lipoprotein cholesterol. Female patients lagged by five years behind male patients in the progression of the extent of raised lesions in the right coronary arteries. In a subsequent report, individuals with early and more severe atherosclerotic changes were more likely to have had one or more ASCVD risk factor (including dyslipidemia, obesity, hyperglycemia, hypertension, or smoking) [4]. The prevalence of risk factors among adolescents and young adults in the PDAY study mirror that of population-based data of general pediatric population [5].

A subsequent study examined autopsy reports of 3832 United States military service members who died in combat or due to unintentional injury between 2001 and 2011 [6]. Mean age was 26 (range 18 to 59) years, and 98 percent were male. The presence of any coronary atherosclerosis was noted in 8.5 percent of deceased service members, with 2.3 percent having severe atherosclerosis (defined as ≥50 percent narrowing of one or more vessels). Those with any atherosclerosis had a higher prevalence of dyslipidemia, hypertension, and obesity. Interestingly, smoking did not appear to be a contributor in this study.

Evidence of subclinical atherosclerosis — Studies using noninvasive imagining to evaluate vascular changes in children and adolescents provide indirect evidence for early development of atherosclerosis, which is associated with ASCVD in adulthood [7,8]. These indirect measures include changes in vessel anatomy (ie, increased intima-media thickness [IMT] and coronary calcification), mechanical changes (ie, decreased arterial distensibility or increased stiffness), and physiologic changes (ie, decreased flow mediated vasodilatation) [7].

Carotid IMT (CIMT) – Adults with increased CIMT detected by ultrasonography have a higher likelihood of experiencing an ASCVD event. Among children and adolescents, increased CIMT may be seen in patients with certain high-risk conditions (eg, familial hypercholesterolemia [FH]) and in children with ASCVD risk factors (ie, family history of premature ASCVD, overweight, dyslipidemia, hypertension, diabetes mellitus [DM]) [9-19]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial intima-media thickness'.)

Arterial stiffness – Arterial stiffness can be measured with the pulse wave velocity (PWV), which is the speed at which an aortic pulse travels between arteries in the upper body to the lower body (typically measured as the brachial-ankle PWV). In adults, increased arterial stiffness is associated with a higher likelihood of ASCVD. PWV measurements vary among adolescents and young adults based upon sex, age, and ethnicity [20]. A high burden of ASCVD risk factors (ie, high BMI, hypertension, hypertriglyceridemia, glucose intolerance) is associated with higher PWV in adolescents and young adults, even after adjusting for age and sex [20-22]. Increased arterial stiffness can lead to cardiac remodeling and is associated with higher left ventricular mass in adolescents and young adults [23]. In one study of 670 adolescents and young adults (age range 10 to 24 years) stratified into three groups based upon BMI (lean [BMI <85th percentile], overweight and obese [BMI ≥85th percentile], and overweight/obese with type 2 DM), there was a progressive increase in PWV from the lean group to the obese and obese/type 2 DM groups [24]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial stiffness'.)

Flow-mediated dilation – Flow-mediated dilation (FMD) measures the endothelial response to an adverse stimulus (eg, ischemia induced by an inflated blood pressure cuff) by brachial artery ultrasonography (also referred to as brachial artery reactivity). Lower brachial artery reactivity has been identified in children with obesity [14], a family history of premature coronary disease [15], type 1 DM, and Kawasaki disease with aneurysms. (See "Coronary endothelial dysfunction: Clinical aspects", section on 'Noninvasive testing'.)

Numerous longitudinal studies have demonstrated an association between the traditional ASCVD risk factors (ie, dyslipidemia, obesity, hypertension, smoke exposure, and DM) during childhood and evidence of early atherosclerotic changes in adulthood based upon one or more of the above measures (CIMT, PWV, and/or FMD).

Bogalusa study – In a cohort of 486 adults (age range 25 to 37 years), childhood measurements of LDL-C levels and BMI positively predicted CIMT [10].

Muscatine study – In a cohort of 725 adults (age range 33 to 42 years), childhood total cholesterol levels and BMI were predictors of CIMT in adulthood [9].

Cardiovascular Risk in Young Finns study – In a cohort of Finnish patients followed for >25 years, CIMT increased as the number of ASCVD risk factors increased [25]. In particular, elevated childhood levels of LDL-C and insulin, as well as obesity, were predictive of increased CIMT [26]. In subsequent studies, carotid artery elasticity decreased as the number of childhood ASCVD risk factors increased and FMD was lower in male patients who had hypertension during adolescence [27,28]. In this cohort, exposure to ASCVD risk factors over time correlated with the extent of coronary artery calcification by computed tomography [29,30]. In follow-up studies of this cohort at age 34 to 49 years, the number of early life ASCVD risk factors correlated with worse midlife cognitive function [31,32].

Coronary Artery Risk Development in Young Adults (CARDIA) study – In a cohort of patients initially recruited at 18 to 30 years of age and followed for 15 years, baseline ASCVD risk factors (smoking, dyslipidemia, glucose intolerance, hypertension) were associated with increased risk of coronary artery calcification later in life [33,34].

i3C studies (international Childhood Cardiovascular Cohort Consortium) – In an analysis of combined data from the above four prospective studies, the number of childhood ASCVD risk factors (eg, dyslipidemia, hypertension, high BMI) was associated with elevated adult CIMT, even in children as young as nine years of age [13]. A childhood ASCVD risk score that included five variables (BMI, systolic blood pressure, total cholesterol, triglyceride level, and youth smoking) correlated with risk of ASCVD events in midlife [35]. Further studies have shown that dyslipidemia in adolescence was also predictive of increased adult CIMT, even after accounting for sex, obesity, and hypertension [36,37].

RISK STRATIFICATION — As discussed in the previous section, traditional risk factors for atherosclerotic cardiovascular disease (ASCVD) and other specific conditions in children and adolescents are associated with accelerated atherosclerosis and early ASCVD. We agree with the risk stratification schema established by the American Heart Association, which is similar to but slightly modifies the previous schema proposed by an expert panel convened by the National Heart, Lung, and Blood Institute (algorithm 1) [38,39].

ASCVD risk conditions are categorized as follows:

High-risk conditions include:

Homozygous familial hypercholesterolemia (FH) (see 'Dyslipidemia' below and 'Familial hypercholesterolemia' below)

Diabetes mellitus (DM; type 1 or type 2) (see 'Diabetes mellitus' below)

End-stage kidney disease (see 'Chronic kidney disease' below)

Kawasaki disease with persistent coronary aneurysms (see 'Kawasaki disease' below)

Solid-organ transplant vasculopathy (see 'Transplant vasculopathy' below)

Childhood cancer survivor following stem cell transplantation (see 'Childhood cancer' below)

Moderate-risk conditions include:

Severe obesity (body mass index [BMI] ≥99th percentile or a BMI ≥35 kg/m2) (see 'Obesity' below)

Confirmed hypertension (blood pressure >95th percentile or ≥130/80 mmHg on three separate occasions) (see 'Hypertension' below)

Heterozygous FH (see 'Dyslipidemia' below and 'Familial hypercholesterolemia' below)

Predialysis chronic kidney disease (CKD) (see 'Chronic kidney disease' below)

Aortic stenosis or coarctation (see 'Congenital heart disease' below)

Childhood cancer survivor with exposure to chest irradiation (see 'Childhood cancer' below)

At-risk conditions include:

Obesity that is not severe (BMI ≥95th to <99th percentile) (see 'Obesity' below)

Insulin resistance with comorbidities (eg, nonalcoholic fatty liver disease, polycystic ovary syndrome) (see 'Diabetes mellitus' below)

White-coat hypertension (elevated blood pressure measurements in the office with normal values outside of the office setting) (see 'Hypertension' below)

Chronic inflammatory disease (eg, systemic lupus erythematosus [SLE], juvenile idiopathic arthritis) (see 'Chronic inflammatory diseases' below)

HIV infection (see 'HIV infection' below)

Kawasaki disease with regressed coronary aneurysms (see 'Kawasaki disease' below)

Cardiomyopathy (eg, hypertrophic cardiomyopathy) (see "Hypertrophic cardiomyopathy in children: Clinical manifestations and diagnosis")

Surgically repaired congenital heart disease (CHD) involving coronary artery translocation (eg, transposition of the great arteries repair) (see 'Congenital heart disease' below)

Childhood cancer survivor with cardiotoxic chemotherapy only (see 'Childhood cancer' below)

Adolescent depressive and bipolar disorders (see 'Depressive and bipolar disorders' below)

Children initially placed in the moderate-risk or at-risk tier based on their primary diagnosis should be moved to a higher tier if they have additional risk factors (algorithm 1). (See 'Traditional ASCVD risk factors' below.)

TRADITIONAL ASCVD RISK FACTORS

Background — In adults, several large prospective population-based studies have shown that multiple risk factors (eg, increased body mass index [BMI], hypertension, dyslipidemia, diabetes mellitus [DM], and family history of ASCVD) are associated with higher risk of ASCVD. (See "Overview of established risk factors for cardiovascular disease".)

These ASCVD risk factors are common in the pediatric population. In studies using data from the United States National Health and Nutrition Examination Survey (NHANES), the reported prevalence of ASCVD risk factors in children and adolescents age 8 to 19 years were [40-43]:

Dyslipidemia – 20 to 30 percent

Prediabetes/DM – 15 percent

Blood pressure (BP) in the hypertensive range – 8 to 14 percent

While data linking these risk factors in childhood to cardiovascular events are limited, these risk factors are associated with acceleration of atherosclerosis in children based on autopsy data and measures of subclinical atherosclerosis based on noninvasive imaging (see 'Atherosclerotic changes in childhood' above). In addition, longitudinal studies demonstrate a reasonably strong correlation between childhood blood pressure, serum lipid levels, and BMI with analogous values measured in middle age [44]. Thus, children with ASCVD risk factors are more likely to be at-risk adults.

Children with specific disease states (eg, familial hypercholesterolemia [FH], DM, and chronic kidney disease) also are more likely to develop atherosclerosis and ASCVD at an earlier age. In extreme cases, patients may experience cardiovascular events during childhood or adolescence. (See 'Other conditions' below.)

A study using NHANES data of adolescents and young adults (12 to 39 years of age) enrolled from 1988 to 1994 demonstrated that DM (eg, high hemoglobin A1c levels), central obesity (weight-to-height ratio ≥0.65), and smoking were associated with an increased risk for death before 55 years of age after accounting for age, sex, and race/ethnicity [45]. Because there were relatively few deaths, it was not possible to determine whether these factors were associated with specific causes of death (eg, cardiovascular deaths).

Risk factors and diseases associated with premature atherosclerosis generally do not occur in isolation but often cluster and the risk of premature ASCVD rises as the number of risk factors increases [1,13,25,42]. As an example, in one of the above NHANES studies, the risk of one or more additional ASCVD risk factors rose with increasing BMI as follows (37 percent for adolescents with normal BMI, 49 percent for those with overweight BMI, and 61 percent for those with obesity) [42]. Among adolescents with obesity, 8 percent had ≥3 additional ASCVD risk factors. These data highlight the high prevalence of ASCVD risk factors in adolescents in the United States, especially among individuals with obesity.

The association between elevated BMI on other ASCVD risk factors was described in a meta-analysis of 63 observational studies, including >49,000 children [46]. Compared with children with healthy weight, those with obesity had higher systolic BP (mean difference 7.5 mmHg), higher total cholesterol (mean difference 6 mg/dL [0.15 mmol/L]), higher triglyceride levels (mean difference 23 mg/dL [0.26 mmol/L]), and increased left ventricular size.

Dyslipidemia — Dyslipidemias are disorders of lipoprotein metabolism that result in at least one of the following abnormalities (table 2) [38]:

High total cholesterol

High low-density lipoprotein cholesterol (LDL-C)

Low high-density lipoprotein cholesterol

High triglycerides

Dyslipidemia is a well-established risk factor for ASCVD in adults. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

Evidence linking pediatric dyslipidemia with risk of premature ASCVD includes the following:

Studies involving children with monogenic causes of dyslipidemia such as familial hypercholesterolemia (FH), which are discussed separately. (See "Familial hypercholesterolemia in children", section on 'Benefits of statin therapy'.)

An analysis of data from i3C (international Childhood Cardiovascular Cohort) consortium showed the risk of cardiovascular events increased 1.3 fold for each unit increase in childhood cholesterol levels [35].

Studies demonstrating associations between pediatric dyslipidemia and preclinical atherosclerosis (eg, carotid intima-media thickness [CIMT]) in adulthood or atherosclerotic lesions on autopsy. These studies are discussed above. (See 'Atherosclerotic changes in childhood' above.)

The evaluation and management of children with abnormal lipid profiles are discussed separately. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis" and "Dyslipidemia in children and adolescents: Management".)

Obesity — In the previously discussed autopsy studies, BMI was positively correlated with more extensive atherosclerotic changes in the aorta and coronary arteries during childhood. (See 'Direct evidence from autopsy studies' above.)

There is also evidence demonstrating that higher BMI during childhood is associated with increased risk of ASCVD in adulthood. This was illustrated by a large prospective cohort study of 276,835 Danish children who were born from 1930 to 1976 for whom childhood BMI measurements were available from mandatory school examinations [47]. Ischemic coronary events (eg, angina pectoris, acute myocardial infarction, other ischemic heart disease) were determined for each subject through a national registry that was established in 1968. There was a positive linear association between increasing BMI at every age from 7 to 13 years and the number of events in adulthood, with stronger associations in males as compared with females. The effect of excess weight on the risk of an event rose with increasing age. Relatively small increases in weight in childhood were associated with increased ASCVD risk in adulthood.

Other studies have shown that children or adolescents who are overweight (defined as BMI ≥85th percentile) or obese (defined as BMI percentile >95th percentile), compared with normal-weight children, are more likely to be hypertensive, have dyslipidemia, develop insulin resistance and type 2 DM, and develop ASCVD as they age [48,49]. The cardiovascular comorbidities and complications of obesity in childhood are discussed in greater detail separately. (See "Overview of the health consequences of obesity in children and adolescents", section on 'Cardiovascular'.)

As mentioned previously, studies that have assessed indirect measures of atherosclerosis (eg, CIMT, flow-mediated dilation) have found evidence of subclinical atherosclerosis among overweight and obese youth [14,18,24]. Overweight children are also more likely to be inactive, have obstructive sleep apnea, and have increased left ventricular mass, all of which are associated with ASCVD in adults. (See "Definition, epidemiology, and etiology of obesity in children and adolescents", section on 'Persistence into adulthood' and "Overweight and obesity in adults: Health consequences".)

Diabetes mellitus — Insulin resistance, hyperinsulinemia, and elevated blood glucose are associated with ASCVD. In addition, children with DM compared with those without DM are at increased risk for other ASCVD risk factors, such as hypertension and dyslipidemia. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus" and "Overview of established risk factors for cardiovascular disease", section on 'Diabetes mellitus'.)

Type 1 DM – In adolescents with type 1 DM, accelerated atherosclerotic changes have been described at autopsy and in studies demonstrating preclinical markers of atherosclerosis (eg, increased CIMT), abnormal arterial stiffness, and impaired endothelial function [50]. There have also been reports of myocardial infarctions in young adults with type 1 DM.

Type 2 DM – In adolescents with type 2 DM, cardiovascular abnormalities, such as increased left ventricular wall thickness and increased arterial stiffness, have been reported. Children with type 2 DM often have comorbid obesity and are at increased risk of developing metabolic syndrome (also referred to as syndrome X or insulin resistance syndrome), a condition of multiple ASCVD risk factors (ie, dyslipidemia, hypertension, type 2 DM, and obesity). (See 'Metabolic syndrome' below and "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

The management of types 1 and 2 DM, including screening and prevention of ASCVD, are discussed separately. (See "Complications and screening in children and adolescents with type 1 diabetes mellitus", section on 'Cardiovascular disease' and "Chronic complications and screening in children and adolescents with type 2 diabetes mellitus", section on 'Other microvascular complications'.)

Metabolic syndrome — The constellation of ASCVD risk factors that includes type 2 DM, abdominal obesity, hyperglycemia, dyslipidemia, and hypertension is referred to as metabolic syndrome. In adults, metabolic syndrome is associated with an increased risk of ASCVD and all-cause mortality.

In a report using data from the National Heart, Lung, and Blood Institute Lipid Research Clinics Princeton Prevalence Study and the Princeton Follow-up Study, children between the ages of 6 to 19 years who were identified as meeting criteria for metabolic syndrome had a >10-fold higher risk of ASCVD at 25-year follow-up compared with the general school-age population (odds ratio 14.6, 95% CI 4.8-45.3) [51]. They also were more likely to have metabolic syndrome in adulthood (odds ratio 6.2, 95% CI 2.8-13.8).

The concept of metabolic syndrome in childhood is primarily used in research; it is not used in routine clinical care, because the relationship between childhood metabolic syndrome and ASCVD events is not well characterized and there is no consensus on the pediatric definition [52]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Children and adolescents'.)

Hypertension — In adults, hypertension is a well-established risk factor for ASCVD. (See "Cardiovascular risks of hypertension".)

In children, data directly linking hypertension with ASCVD are lacking. However, hypertension is associated with preclinical evidence of accelerated atherosclerosis (ie, increased CIMT and arterial stiffness). (See 'Atherosclerotic changes in childhood' above.)

In addition, patients with elevated blood pressure in childhood are more likely to have hypertension in adulthood.

The evaluation and treatment of hypertension in children and adolescents are discussed separately. (See "Definition and diagnosis of hypertension in children and adolescents" and "Nonemergent treatment of hypertension in children and adolescents".)

Family history — Individuals with first-degree relatives (parent or sibling) who have experienced premature ASCVD are at increased risk of ASCVD. Premature ASCVD in this context is generally defined as myocardial infarction, treated angina, interventions for coronary artery disease, sudden cardiac death, or ischemic stroke before age 55 (males) or 65 (females). (See "Overview of established risk factors for cardiovascular disease", section on 'Family history'.)

In children, subclinical vascular abnormalities can be seen among offspring of individuals with premature ASCVD. Evidence of accelerated atherosclerosis (eg, lower brachial arterial reactivity and greater CIMT) is more commonly detected in adolescent offspring of individuals with premature myocardial infarction compared with controls without a family history of premature ASCVD [15]. However, the sensitivity of a positive family history for detection of ASCVD or dyslipidemia appears to be relatively low. Several studies have shown that a positive family history fails to detect 30 to 60 percent of children with dyslipidemia [53] and that the risk of dyslipidemia may be independent of a family history of ASCVD [54]. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Rationale for lipid screening'.)

Nevertheless, individuals with a family history positive for early ASCVD disease have twice the risk of ASCVD as those without, even after adjusting for conventional risk factors [55]. The impact of a positive family history upon ASCVD is more fully discussed separately. (See "Overview of established risk factors for cardiovascular disease", section on 'Family history' and "Coronary artery disease and myocardial infarction in young people", section on 'Family history'.)

Nicotine exposure — Smoke exposure, including secondhand cigarette smoke, increases the risk of ASCVD [56]. Because of its addictive nature, pediatric tobacco use increases the risk of persistent adult smoking. The risk of CVD due to smoke exposure is discussed separately. (See "Cardiovascular risk of smoking and benefits of smoking cessation" and "Secondhand smoke exposure: Effects in children", section on 'Atherogenesis'.)

There is also evidence that the use of electronic nicotine delivery systems also may increase the risk of hypertension and ASCVD [57]. (See "Vaping and e-cigarettes", section on 'Adverse health effects'.)

MODIFIABLE HEALTH BEHAVIORS — The following health behaviors, while not considered independent risk factors for ASCVD per se, are nevertheless important aspects of promoting a heart-healthy lifestyle. These behaviors often contribute to some of the risk factors discussed above (eg, obesity, type 2 diabetes, dyslipidemia, hypertension). (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children".)

Diet — For all children, health care providers should promoting a heart-healthy diet that is rich in vegetables, fruits, and whole grains; low in saturated fat; and devoid of trans fats (table 3). (See "Dietary recommendations for toddlers and preschool and school-age children".)

Physical activity — Evidence from both adult and pediatric studies demonstrates that daily vigorous activity and reduction in sedentary behavior improves cardiovascular health and decreases the risk of ASCVD in adulthood. The American Academy of Pediatrics and the National Heart, Lung, and Blood Institute expert panels recommend age-based daily activity for all children as summarized in the table (table 4) [38]. (See "Pediatric prevention of adult cardiovascular disease: Promoting a healthy lifestyle and identifying at-risk children", section on 'Physical activity' and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease".)

Sleep habits — In adults, abnormal sleep duration (both too little and too much) and sleep disordered breathing (eg, obstructive sleep apnea) have been linked to increased risk of ASCVD. These associations are discussed elsewhere. (See "Insufficient sleep: Definition, epidemiology, and adverse outcomes", section on 'Cardiovascular morbidity' and "Obstructive sleep apnea and cardiovascular disease in adults".)

There are fewer data establishing a link between sleep problems in childhood and risk of premature ASCVD. Nevertheless, establishing healthy sleep habits (table 5A-B), including appropriate duration of sleep (figure 1), is generally considered part of a heart-healthy lifestyle. (See "Assessment of sleep disorders in children".)

OTHER CONDITIONS — In addition to the risk factors listed above, other conditions that are associated with accelerated atherosclerosis and premature ASCVD include the following (algorithm 1 and table 1) [38,39,58].

Familial hypercholesterolemia — Familial hypercholesterolemia (FH) is an autosomal codominant genetic disease. The clinical syndrome (phenotype) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) level from birth, xanthomata in untreated adults and patients with homozygous FH, and a propensity to early-onset ASCVD. FH is inherited with a gene-dosing effect, in which homozygotes are more adversely affected than heterozygotes (figure 2). Heterozygous FH is fairly common (estimated to occur in approximately 1 in 200 to 300 individuals), whereas homozygous FH is a rare disorder.

The diagnosis and treatment of FH are discussed separately. (See "Familial hypercholesterolemia in children" and "Familial hypercholesterolemia in children", section on 'Management'.)

Children with other monogenetic defects or with a high abundance of polygenic contributions can have a phenotype similar to FH. (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

Chronic kidney disease — Children with chronic kidney disease (CKD) are at increased risk for developing ASCVD. Accelerated atherosclerosis has been demonstrated in iliac artery samples at the time of renal transplantation and at autopsy [59,60].

Children with CKD often have additional ASCVD risk factors, including hypertension and dyslipidemia. Studies have demonstrated evidence of preclinical atherosclerosis (eg, coronary artery calcification, abnormal flow-mediated dilation [FMD], increased carotid intima-medial thickness [CIMT], increased aortic stiffness) and left ventricular hypertrophy in pediatric patients with CKD [60-65]. These abnormalities seem to be, in part, related to the degree of uremia. In addition, some medications used to prevent renal transplant rejection are associated with ASCVD risk factors (eg, cyclosporine is associated with hypertension; rapamycin is associated with dyslipidemia; corticosteroids are associated with hypertriglyceridemia, hypertension, and diabetes mellitus [DM]). (See "Chronic kidney disease in children: Complications", section on 'Risk for cardiovascular disease'.)

Individuals with childhood-onset nephrotic syndrome are at increased risk for early atherosclerosis in part due to hyperlipidemia, which is a characteristic feature of nephrotic syndrome. Other factors that may play a role include chronic inflammation, hypercoagulability, and the effects of corticosteroid therapy. Studies have demonstrated evidence of preclinical atherosclerosis (increased CIMT, abnormal FMD]) in patients with childhood-onset nephrotic syndrome [66-68]. Complications of pediatric nephrotic syndrome and clinical implications of lipid abnormalities in nephrotic syndrome are discussed separately. (See "Complications of nephrotic syndrome in children" and "Lipid abnormalities in nephrotic syndrome", section on 'Clinical implications'.)

Kawasaki disease — Kawasaki disease (also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood and is associated with the development of coronary artery aneurysms, which can lead to myocardial ischemia or infarction (movie 1 and movie 2). In developed countries, Kawasaki disease has surpassed rheumatic fever as the leading cause of acquired cardiovascular disease in childhood.

The risk of ASCVD in patients with a history of Kawasaki disease depends upon initial aneurysm size, occurrence of coronary thrombosis, and degree and nature of remodeling of the arterial wall over time. This is discussed in detail separately (See "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Accelerated atherosclerosis'.)

Childhood cancer — As life expectancy for pediatric cancer survivors has improved, it has become increasingly apparent that these patients are at risk for premature ASCVD [69-71]. The increased risk in this population is likely due to a combination of damaged myocardium and direct vascular effect from chemotherapeutic agents, particularly anthracyclines [72]. Radiation therapy, particularly to the mediastinum, is also associated with premature atherosclerosis [73]. In addition, survivors of childhood cancer are more likely to have other ASCVD risk factors including obesity, insulin resistance, and dyslipidemia [74-79]. Issues related to cancer survivorship are discussed in greater detail separately. (See "Cancer survivorship: Cardiovascular and respiratory issues" and "Overview of cancer survivorship in adolescents and young adults".)

Transplant vasculopathy — In children who undergo cardiac transplantation, transplant vasculopathy is a significant long-term complication and cause of death [80]. A multicenter autopsy study demonstrated severe coronary stenosis in 28 of 36 children deceased after cardiac transplant [80]. Approximately three-quarters of children with cardiac transplantation have evidence of coronary artery abnormalities detected by angiography and intracoronary ultrasonography [81,82].

Cardiac transplant vasculopathy leads to the development of vessel narrowing secondary to thickening of the intimal and medial layers of the coronary. It appears to be multifactorial in origin, with both immunologic and nonimmunologic factors being implicated. Among the factors associated with vasculopathy are cellular and vascular rejection, anti-human leukocyte antigen antibody production, and cytomegalovirus infection. Patients with cardiac transplants are likely to have other ASCVD risk factors, such as dyslipidemia, hypertension, elevated body mass index (BMI), DM, and deconditioning. Similar to children who undergo renal transplantation, these additional risk factors may be associated with medications used to prevent rejection. (See "Heart transplantation in adults: Cardiac allograft vasculopathy pathogenesis and risk factors".)

The management of patients with cardiac transplantation to prevent and treat cardiac transplant vasculopathy, as well as to screen and treat dyslipidemia, is discussed separately. (See "Heart Transplantation: Prevention and treatment of cardiac allograft vasculopathy" and "Heart transplantation: Hyperlipidemia after transplantation".)

Congenital heart disease — Congenital heart disease (CHD) occurs in approximately 1 percent of live births. Because of improvements in surgical, transcatheter, and perioperative management, many more children with CHD are surviving to adulthood in the contemporary era compared with previous eras. As a result, there is increasing evidence that some CHD defects are associated with an increased risk for premature ASCVD.

Risk of ASCVD is likely to be greatest in those with coronary artery abnormalities or left-sided obstructive lesions.

Coronary artery abnormalities – In patients with coronary artery anomalies, premature atherosclerosis of the coronary artery has been demonstrated in autopsies [83] and detected by coronary artery angiography [84]. In addition, surgical manipulation of the coronary arteries, especially associated with the arterial switch operation for transposition of the great arteries, is associated with increased risk for coronary artery stenosis, premature atherosclerosis, and coronary artery dysfunction [85-87]. (See "D-transposition of the great arteries (D-TGA): Management and outcome", section on 'Early atherosclerotic coronary artery disease'.)

Left-sided obstructive lesions – Cardiac lesions that obstruct the left ventricle or aorta, such as aortic stenosis and coarctation, are associated with an increased risk of ASCVD in adulthood. In children with coarctation of the aorta, the aorta is less compliant and reactive and the CIMT and femoral IMT is increased [88]. Hypertension is common in patients with coarctation, even years after apparently successful repair. (See "Valvar aortic stenosis in children" and "Clinical manifestations and diagnosis of coarctation of the aorta".)

Comorbid obesity – Children with CHD are not immune to the obesity epidemic. Observational data suggest the prevalence of overweight and obesity in children with CHD is similar to that of the general population [89,90]. However, the physiologic consequences of obesity may be greater in the CHD population.

Chronic inflammatory diseases — It is well established that the prevalence of ASCVD is increased in adults with chronic inflammatory illnesses, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Increasing evidence suggests that children and adolescents affected by these disorders often have increased ASCVD risk factors [58], with nearly three-quarters reported to have accelerated atherosclerosis associated with dyslipidemia, and a higher risk of premature ASCVD [91]. Children and adolescents with SLE have increased CIMT compared with healthy controls [92]. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Cardiac' and "Coronary artery disease in systemic lupus erythematosus".)

It is unclear if patients with coronavirus disease 2019 (COVID-19)-associated multisystem inflammatory syndrome in children (MIS-C) are at increased risk for premature ASCVD since long-term follow-up data are not available. Cardiac involvement is common in MIS-C, but the frequency of coronary involvement may be less than in Kawasaki disease. Follow-up in patients with MIS-C is discussed separately. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome", section on 'Follow-up'.)

HIV infection — Considerable progress has been made in the treatment and prevention of pediatric HIV infection, and life expectancy for HIV-infected children has improved considerably in the era of potent antiretroviral therapy. However, in children infected with HIV early in life, prolonged exposure to HIV and antiretroviral therapy is associated with a number of long-term complications, including dyslipidemia, DM, lipodystrophy, and hypertension [93]. For instance, patients with perinatally acquired HIV infection have been found to have indirect evidence of subclinical coronary vascular disease (ie, increased coronary artery wall thickness) [94,95]. ASCVD risk in youth with perinatal HIV infection is likely multifactorial. In addition to traditional ASCVD risk factors, chronic inflammation, abnormal immune function, side effects of antiretroviral therapy, and direct HIV viral effects may contribute. Long-term morbidities in HIV-infected children are discussed in greater detail separately. (See "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Long-term morbidities'.)

Depressive and bipolar disorders — Growing evidence suggests that major depressive disorder and bipolar disorder in adolescence may be associated with premature ASCVD. The mechanism appears to be multifactorial and multiple systemic processes have been implicated, including inflammation, oxidative stress, and autonomic dysfunction [96]. The association between depressive and bipolar disorders, particularly major depression, and ASCVD in adults is well established. (See "Psychosocial factors in acute coronary syndrome", section on 'Depression' and "Psychosocial factors in coronary and cerebral vascular disease".)

Depressive and bipolar disorders that begin in childhood or adolescence can persist into adulthood. In addition, many traditional ASCVD risk factors (eg, DM, obesity, sedentary lifestyle, smoking) are more prevalent among adolescents with major depressive disorder and bipolar disorder compared with the general pediatric population [96]. In observational studies of adolescents and young adults, the relationship between major depressive disorder and bipolar disorder and indirect measures of atherosclerosis (ie, CIMT, ultrasound-determined brachial artery flow-mediated dilation, or digital pulse-wave amplitude) is inconsistent [96]. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis" and "Pediatric bipolar disorder: Clinical manifestations and course of illness".)

PRENATAL FACTORS — There is emerging evidence that prenatal factors impact offspring cardiovascular health in adulthood. These include fetal growth restriction; gestational and pregestational diabetes mellitus; and maternal factors such as hypertension, hyperlipidemia, prenatal smoking, and excessive weight gain during pregnancy [97-99]. Studies have demonstrated that fetal growth restriction is associated with an increased risk of insulin resistance, ASCVD risk factors (eg, dyslipidemia, hypertension, and elevated C-reactive protein), and vascular dysfunction [100,101]. However, additional research is needed to determine the relative contribution of fetal factors compared with the known contributions of the postnatal risk factors, as discussed above.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in children".)

SUMMARY AND RECOMMENDATIONS

Atherosclerotic changes in childhood – Although atherosclerotic cardiovascular disease (ASCVD) generally manifests clinically in adulthood, there is that atherosclerosis can begin in childhood. A childhood origin of ASCVD is supported by direct evidence from autopsy studies and indirect data showing subclinical vascular changes. (See 'Atherosclerotic changes in childhood' above.)

Traditional risk factors – Traditional ASCVD risk factors include (table 1) (see 'Traditional ASCVD risk factors' above):

Dyslipidemia (see 'Dyslipidemia' above and "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis")

Overweight/obesity (see 'Obesity' above and "Definition, epidemiology, and etiology of obesity in children and adolescents")

Diabetes mellitus (DM; type 1 or 2) (see 'Diabetes mellitus' above)

Hypertension (see 'Hypertension' above and "Epidemiology, risk factors, and etiology of hypertension in children and adolescents")

Family history of premature ASCVD (see 'Family history' above)

Smoking/nicotine exposure (see 'Nicotine exposure' above and "Secondhand smoke exposure: Effects in children" and "Prevention of smoking and vaping initiation in children and adolescents")

Other conditions – Other conditions associated with increased risk of premature CVD include (table 1) (see 'Other conditions' above):

Familial hypercholesterolemia (FH) (see 'Familial hypercholesterolemia' above and "Familial hypercholesterolemia in children")

Chronic kidney disease (CKD) (see 'Chronic kidney disease' above and "Chronic kidney disease in children: Complications", section on 'Risk for cardiovascular disease')

Kawasaki disease (see 'Kawasaki disease' above and "Cardiovascular sequelae of Kawasaki disease: Clinical features and evaluation", section on 'Accelerated atherosclerosis')

Childhood cancer (See 'Childhood cancer' above and "Cancer survivorship: Cardiovascular and respiratory issues".)

Transplant vasculopathy (see 'Transplant vasculopathy' above)

Certain congenital heart disease (CHD) defects and cardiomyopathies (see 'Congenital heart disease' above)

Chronic inflammatory disease (eg, systemic lupus erythematosus [SLE]) (see 'Chronic inflammatory diseases' above and "Coronary artery disease in systemic lupus erythematosus")

HIV (see 'HIV infection' above and "Pediatric HIV infection: Classification, clinical manifestations, and outcome", section on 'Long-term morbidities')

Adolescent mood disorders (see 'Depressive and bipolar disorders' above and "Psychosocial factors in coronary and cerebral vascular disease")

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jane Newburger, MD, MPH, and Michael Mendelson, MD, ScM, who contributed to an earlier version of this topic review.

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Topic 5781 Version 47.0

References

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