Your activity: 28 p.v.
< Back
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

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
Authors:
Jacob C Hartz, MD, MPH
Sarah D de Ferranti, MD, MPH
Section Editor:
David R Fulton, MD
Deputy Editor:
Carrie Armsby, MD, MPH
Literature review current through: Nov 2022. | This topic last updated: May 07, 2021.

INTRODUCTION — Atherosclerotic vascular changes can begin in early childhood, setting the stage for cardiovascular disease (CVD) events in adulthood [1]. For most children, atherosclerotic vascular changes are minor and can be minimized or even prevented with adherence to a healthy lifestyle. However, in some children, the process is accelerated because of the presence of identifiable risk factors (eg, obesity, dyslipidemia, hypertension) or specific diseases that are associated with premature CVD (eg, diabetes mellitus [DM]) [1-3].

The evidence linking atherosclerotic changes in childhood to CVD later in life will be reviewed here. In addition, risk factors in childhood that are associated with early atherosclerosis and CVD will also be discussed (table 1).

Pediatric interventions to reduce or minimize atherosclerosis and management of the child at risk for atherosclerosis are discussed separately. (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".)

ATHEROSCLEROTIC CHANGES IN CHILDHOOD

Overview — 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 CVD.

In addition, these studies demonstrate an accelerated burden of vascular changes and premature atherosclerosis among children and adolescents with well-established CVD risk factors (eg, overweight/obesity, hypertension, dyslipidemia, and smoke exposure). These CVD 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 CVD. (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 develop in childhood, with findings of fatty streaks (accumulation of lipid-filled macrophages within the intima of the artery, which are early atherosclerotic changes) and fibrous plaque (a more advanced stage of atherosclerosis), as illustrated by the following:

●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 [4]. 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 [5,6]. 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 CVD risk factor (including dyslipidemia, obesity, hyperglycemia, hypertension, or smoking) [7]. The prevalence of risk factors among adolescents and young adults in the PDAY study mirror that of population-based data of general pediatric population [8].

●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 [9]. 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 CVD in adulthood [10,11]. 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) [10].

●Carotid IMT (CIMT) – Adults with increased CIMT detected by ultrasonography have a higher likelihood of a CVD event (ie, myocardial infarction and stroke). Among children and adolescents, increased CIMT may be seen in patients with certain high-risk conditions (eg, familial hypercholesterolemia [FH]) and in children with CVD risk factors (ie, family history of premature CVD, overweight, dyslipidemia, hypertension, diabetes mellitus [DM]) [12-20]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial intima-media thickness'.)

●Arterial stiffness – Arterial stiffness is measured as the speed at which an aortic pulse travels between two major arteries, one of which is located in the upper body (ie, carotid or brachial artery) and the other in the lower body (ie, femoral or ankle). In adults, increased arterial stiffness is associated with a higher likelihood of CVD. Arterial stiffness normally varies among adolescents and young adults based upon sex, age, and ethnicity [21]. After adjusting for age and sex, a higher burden of CVD risk factors (ie, increased BMI, hypertension, elevated serum triglycerides, and fasting insulin concentrations) are linked to worsening arterial stiffness in adolescents and young adult [21-23]. Increased arterial stiffness can lead to cardiac remodeling and is associated with higher left ventricular mass in adolescents and young adults [24]. 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 arterial stiffness from the lean group to the obese and obese/type 2 DM groups [25,26]. After adjusting for other CVD risk factors, central obesity remained an independent predictor for increased arterial stiffness. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial stiffness'.)

●Flow-mediated dilation – Flow-mediated dilation 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 [17], a family history of premature coronary disease [18], 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 presence of established risk factors for CVD (ie, dyslipidemia, obesity, hypertension, smoke exposure, and DM) during childhood and evidence of early atherosclerotic changes in adulthood based on the above measures that detect vascular changes.

●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 [13].

●Muscatine study – In a cohort of 725 adults (age range 33 to 42 years), childhood total cholesterol levels positively predicted CIMT, and in women, childhood BMI was also a significant predictor of IMT [12].

●Cardiovascular Risk in Young Finns study – In a cohort of Finnish patients followed for 27 years, IMT increased as the number of CVD risk factors increased [27]. In particular, elevated childhood levels of LDL-C and insulin, as well as obesity, were predictive of increased IMT [28]. In subsequent studies, carotid artery elasticity decreased as the number of childhood CVD risk factors increased and flow-mediated dilation was lower in male patients who had elevated blood pressure during adolescence [29,30]. In this cohort, exposure to CVD risk factors over time correlated with the extent of coronary artery calcification by computed tomography [31,32], a measure of atherosclerosis predictive of CVD events [33].

●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 CVD risk factors (smoking and higher LDL-C, glucose, and systolic blood pressure) were associated with increased risk of coronary artery calcium later in life [34,35].

●i3C studies (international Childhood Cardiovascular Cohort Consortium) – In a meta-analysis that combined data from the above four prospective studies, the number of abnormal childhood CVD risk factors (eg, cholesterol, triglycerides, blood pressure, and BMI) was predictive of elevated adult CIMT, even in children as young as nine years of age, with progressive strengthening of the association through adolescence [16]. 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 cardiovascular risk factors and other specific conditions in children and adolescents are associated with accelerated atherosclerosis and early CVD. 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) [1,3].

CVD 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 cardiovascular disease risk factors presenting in childhood' below.)

TRADITIONAL CARDIOVASCULAR DISEASE RISK FACTORS PRESENTING IN CHILDHOOD

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 CVD) are associated with higher risk of CVD. (See "Overview of established risk factors for cardiovascular disease".)

These CVD risk factors are common in the pediatric population. In studies using data from the United States National Health and Nutrition Examination Survey (NHANES), the prevalence of CVD risk factors in children and adolescents age 8 to 19 years are [38-41]:

●Prehypertension/hypertension – 8 to 14 percent

●Dyslipidemia – 20 to 30 percent

●Prediabetes/DM – 15 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 [42]. Thus, children with CVD risk factors are more likely to be at-risk adults.

Children with specific disease states (eg, familial hypercholesterolemia [FH], DM, and renal failure) also are more likely to develop atherosclerosis and CVD at an earlier age, with some patients experiencing 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 CVD risk factors of DM (eg, high hemoglobin A1c levels), central obesity, and smoking were associated with an increased risk for death before 55 years of age after accounting for age, sex, and race/ethnicity [43]. 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. The risk of premature atherosclerosis and CVD rises as the number of risk factors increases [4,16,27,40]. As an example, in one of the above NHANES studies, the risk of any CVD risk factor rose with increasing BMI as follows: 37, 49, and 61 percent for normal-weight, overweight, and obese adolescents, respectively [40]. In addition, the risk of having three or more CVD risk factors rose with increasing BMI as follows: 1, 2, and 8 percent for normal-weight, overweight, and obese adolescents, respectively. These data highlight the high prevalence of CVD risk factors in adolescents in the United States, especially among overweight or obese individuals.

Similar results showing the effect of elevated BMI on other CVD risk factors were seen in a meta-analysis of 63 studies of 49,220 children, as follows [44]:

●Systolic blood pressure was higher in overweight (4.54 mmHg, 95% CI 2.44-6.64) and obese children (7.5 mmHg, 95% CI 3.4-11.6) compared with normal-weight children.

●Total cholesterol (6 mg/dL, 95% CI 2-10 [0.15 mmol/L, 95% CI 0.04-0.25]) and triglycerides (23 mg/dL, 95% CI 12-25 [0.26 mmol/L, 95% CI 0.13-0.39]) were higher in obese compared with normal-weight children.

●Left ventricular mass was also increased in obese versus normal-weight children (19.1 g, 95% CI 12.7-25.6).

The following sections discuss the recognized risk factors and disease processes associated with accelerated atherosclerosis and CVD in children and adolescents (table 1).

Dyslipidemia — Dyslipidemias are disorders of lipoprotein metabolism that result in at least one of the following abnormalities (table 2) [1]:

●High total cholesterol

●High low-density lipoprotein cholesterol (LDL-C)

●Low high-density lipoprotein cholesterol

●High triglycerides

Although dyslipidemia is an established risk factor for CVD in adults, no long-term studies directly link dyslipidemia in childhood with subsequent CVD events, with the exception of children with monogenic causes of dyslipidemia such as FH [45]. (See "Lipoprotein classification, metabolism, and role in atherosclerosis".)

However, dyslipidemia in childhood is associated with increased risks of atherosclerotic lesions in autopsy studies, increased carotid intima-media thickness (CIMT) in adulthood, and persistent adult dyslipidemia. (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.

There is also evidence demonstrating that higher BMI during childhood is associated with increased risk of CVD 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 [46]. 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 CVD 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 CVD as they age [47,48]. 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 [17,25,26]. 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 CVD in adults. In addition, most obese adolescents remain obese as 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 atherosclerotic CVD. In addition, children with DM compared with those without DM are at increased risk for other atherogenic 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). Other noninvasive tests of vascular function, including arterial stiffness and endothelial function, are abnormal in patients with type 1 DM [49]. There have also been reports of myocardial infarctions in young adults with type 1 DM.

In a small randomized, crossover study in children with type 1 DM comparing atorvastatin (20 mg daily) with placebo, LDL levels predictably improved despite not being excessively elevated at baseline; however, there was no improvement in measures of arterial stiffness or endothelial function [50].

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

The management of types 1 and 2 DM, including screening and prevention of CVD, 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 CVD 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 CVD events and all-cause mortality.

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 CVD events is not well characterized and there is no consensus on the pediatric definition [51]. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)", section on 'Children and adolescents'.)

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 using a definition modified from Adult Treatment Panel (ATP) III had an increased risk of CVD at 25-year follow-up compared with the general school population (odds ratio 14.6, 95% CI 4.8-45.3) [52]. They also were more likely to have metabolic syndrome in adulthood (odds ratio 6.2, 95% CI 2.8-13.8).

Hypertension — In adults, hypertension is a well-established risk factor for adverse cardiovascular outcomes (ie, myocardial infarction and stroke). Epidemiologic studies have shown that the risk of CVD in adult patients increases progressively with incremental increases in blood pressure above 115/75 mmHg. (See "Cardiovascular risks of hypertension".)

In children, data directly linking hypertension with CVD are lacking. However, although similar direct evidence linking elevated blood pressure with CVD events is lacking, hypertension is associated with preclinical evidence of accelerated atherosclerosis (ie, increased CIMT and arterial stiffness). 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 — In adults, a family history of CVD is an important independent risk factor for cardiovascular events. A positive family history of premature CVD is generally defined as myocardial infarction, unstable angina, interventions for coronary artery disease, sudden cardiac death, transient ischemic attack, or stroke in a first- or second-degree relative 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 with a parental history of premature CVD. 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 CVD [18]. However, the sensitivity of a positive family history for detection of CVD 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 CVD [54]. Nevertheless, individuals with a family history positive for early CVD disease have twice the risk of CVD as those without, even after adjusting for conventional risk factors [55]. The impact of a positive family history upon CVD 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 CVD [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 CVD [57]. (See "Vaping and e-cigarettes", section on 'Adverse health effects'.)

OTHER CONDITIONS — In addition to the conditions listed above, other conditions that are associated with accelerated atherosclerosis and premature CVD include (algorithm 1 and table 1) [1,3,58]:

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 atherosclerotic CVD. FH is inherited with a gene-dosing effect, in which homozygotes are more adversely affected than heterozygotes (figure 1). 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 CVD. One-quarter of deaths in children with advanced CKD are due to CVD. 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 CVD risk factors, including hypertension and dyslipidemia. They may have myocardial abnormalities (eg, left ventricular hypertrophy) [61] and evidence of early atherosclerosis, including coronary artery calcification [60], abnormal flow mediated dilation [62], increased carotid intima-medial thickness (CIMT) [63], and increased aortic stiffness [64,65]. 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 CVD 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 and coronary heart disease" and "Chronic kidney disease in children: Overview of management" and "Lipid management in patients with nondialysis chronic kidney disease" and "Kidney transplantation in adults: Lipid abnormalities after kidney transplantation".)

Children with 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. Adult patients with nephrotic syndrome are at increased risk of cardiovascular mortality [66,67]. In a study of adolescents and young adults who had nephrotic syndrome in childhood, CIMT increased with increasing number of relapses. 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'.)

Treatment is directed at reduction of CVD risk factors such as hypertension and dyslipidemia. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines for controlling the epidemic of CVD in CKD, as well as other KDOQI guidelines, can be accessed through the National Kidney Foundation's website.

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 CVD in childhood.

The risk of atherosclerotic CVD in patients with a history of Kawasaki disease is dependent 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 the long-term survival rate improves for pediatric cancer, it has become increasingly apparent that these patients are at risk for premature CVD [68,69]. The combination of damaged myocardium from chemotherapeutic agents and acquired atherosclerotic disease has resulted in an eightfold increase in deaths due to cardiac disease among survivors of childhood cancer beyond five years of diagnosis as compared with the general population and a five- to sixfold increase as compared with siblings [68]. Mediastinal radiation therapy is also associated with premature atherosclerosis, with the highest relative risk estimates in patients treated as children [70].

In addition, survivors of childhood cancer are more likely to have other CVD risk factors including obesity, insulin resistance, dyslipidemia, growth hormone deficiency, and deconditioning [71-76].

In a study of 201 long-term survivors of pediatric cancer, the prevalence of CVD risk factors was increased compared with their healthy siblings [75]. The cancer survivors were also affected by reduced left ventricular mass due to late chemotherapy toxicity.

In another study of 319 childhood cancer survivors in remission ≥5 years (mean age 14.5 years), the cancer survivor group were more likely to have CVD risk factors, including dyslipidemia, insulin resistance, and altered body composition with greater adiposity and less lean body mass, as compared with their siblings [76].

The Children's Oncology Group has developed guidelines for monitoring of CVD risk in childhood cancer survivors after completion of their oncologic therapy [70]. The guidelines include the following recommendations:

●Assessment of an individual's risk for CVD based upon his/her treatment regimen regarding chemotherapeutic agents and his/her cumulative dose as well as the use and dose of mediastinal radiation therapy.

●At each clinical encounter, a complete history and physical should be performed. It should include screening for cardiac symptoms (eg, dyspnea, chest pain, palpitations, and effort intolerance) and transient neurologic symptoms (eg, loss of sensation, paresthesias, weakness, or visual or auditory changes), which may represent cardiac dysfunction.

●Screen for other cardiovascular risk factors; in patients who received mediastinal radiation, the guidelines suggest obtaining a fasting glucose and lipid profile every three to five years due to their increased risk for premature CVD.

●In patients who were exposed to cardiotoxic drugs or mediastinal radiation therapy, baseline echocardiogram and electrocardiogram should be obtained for comparison with subsequent studies. The approach to risk assessment and monitoring of such patients is discussed in greater detail separately. (See "Risk and prevention of anthracycline cardiotoxicity".)

Issues related to cancer survivorship are discussed in greater detail separately. (See "Cancer survivorship: Cardiovascular and respiratory issues" and "Long-term care of the adult hematopoietic cell transplantation survivor" 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 [77]. A multicenter autopsy study demonstrated severe coronary stenosis in 28 of 36 children deceased after cardiac transplant [77]. Approximately three-quarters of children with cardiac transplantation have evidence of coronary artery abnormalities detected by angiography and intracoronary ultrasonography [78,79].

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 CVD 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 atherosclerosis and premature CVD.

Risk of atherosclerotic CVD 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 [80] and detected by coronary artery angiography [81]. 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 [82-84]. (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 CVD in adulthood. In children with coarctation of the aorta, the aorta is less compliant and reactive and the CIMT and femoral IMT is increased [85]. Hypertension is common in patients with coarctation, even years after apparently successful repair. Children with left-sided lesions often have left ventricular hypertrophy, a CVD risk factor in adults. (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 [86,87]. However, the physiologic consequences of obesity may be greater in the CHD population.

Chronic inflammatory diseases — It is well established that the prevalence of CVD 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 CVD risk factors [58], with nearly three-quarters reported to have accelerated atherosclerosis associated with dyslipidemia, and a higher risk of premature cardiovascular events [88]. Children and adolescents with SLE have increased CIMT compared with controls [89], and there are case reports of myocardial infarctions and abnormalities in coronary perfusion detected by myocardial perfusion scanning in pediatric patients with SLE. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Cardiac'.)

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 atherosclerotic CVD 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 [90]. 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) [91,92]. The etiology of CVD risk in youth with perinatal HIV infection is likely multifactorial. In addition to traditional CVD 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 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 atherosclerosis and CVD. The mechanism appears to be multifactorial and multiple systemic processes have been implicated, including inflammation, oxidative stress, and autonomic dysfunction [93]. The association between depressive and bipolar disorders, particularly major depression, and CVD 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 CVD risk factors (eg, DM, obesity, sedentary lifestyle, tobacco smoking) are more prevalent among adolescents with major depressive disorder and bipolar disorder compared with the general pediatric population [93]. 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 [93]. (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 intrauterine growth retardation; gestational diabetes mellitus (DM); and maternal factors such as hypertension, hyperlipidemia, prenatal smoking, and excessive weight gain during pregnancy [94-96]. Studies have demonstrated that intrauterine growth retardation is associated with an increased risk of insulin resistance, CVD risk factors (eg, dyslipidemia, hypertension, and elevated C-reactive protein), and vascular dysfunction [97,98]. 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

●Although cardiovascular disease (CVD) is generally manifest in adulthood, there is both direct evidence based on autopsy studies and indirect data on subclinical vascular changes demonstrating that atherosclerosis can develop early in childhood. (See 'Atherosclerotic changes in childhood' above.)

●In children, indirect evidence for early development of atherosclerosis is based on noninvasive imaging of vascular changes, which are associated with atherosclerosis and CVD in adults. 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). (See 'Evidence of subclinical atherosclerosis' above.)

●Traditional risk factors and other specific conditions are associated with accelerated atherosclerosis and early CVD (algorithm 1 and table 1). The presence of multiple risk factors increases the likelihood of accelerated atherosclerosis. (See 'Risk stratification' above.)

●Traditional CVD risk factors include (see 'Traditional cardiovascular disease risk factors presenting in childhood' above):

•Dyslipidemia (see 'Dyslipidemia' above)

•Overweight/obesity (see 'Obesity' above)

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

•Hypertension (see 'Hypertension' above)

•Family history of premature CVD (see 'Family history' above)

•Nicotine exposure (see 'Nicotine exposure' above)

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

•Familial hypercholesterolemia (FH) (see 'Familial hypercholesterolemia' above)

•Chronic kidney disease (CKD) (see 'Chronic kidney disease' above)

•Kawasaki disease (see 'Kawasaki disease' above)

•Childhood cancer (see 'Childhood cancer' above)

•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])

•HIV (see 'HIV infection' above)

•Adolescent mood disorders (see 'Depressive and bipolar disorders' above)

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.

  1. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents, National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 2011; 128 Suppl 5:S213.
  2. American Academy of Pediatrics. Cardiovascular risk reduction in high-risk pediatric populations. Pediatrics 2007; 119:618.
  3. de Ferranti SD, Steinberger J, Ameduri R, et al. Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association. Circulation 2019; 139:e603.
  4. Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med 1998; 338:1650.
  5. McGill HC Jr, McMahan CA, Zieske AW, et al. Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc Biol 2000; 20:1998.
  6. McGill HC Jr, McMahan CA. Determinants of atherosclerosis in the young. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Am J Cardiol 1998; 82:30T.
  7. McMahan CA, Gidding SS, Malcom GT, et al. Pathobiological determinants of atherosclerosis in youth risk scores are associated with early and advanced atherosclerosis. Pediatrics 2006; 118:1447.
  8. McMahan CA, Gidding SS, Malcom GT, et al. Comparison of coronary heart disease risk factors in autopsied young adults from the PDAY Study with living young adults from the CARDIA study. Cardiovasc Pathol 2007; 16:151.
  9. Webber BJ, Seguin PG, Burnett DG, et al. Prevalence of and risk factors for autopsy-determined atherosclerosis among US service members, 2001-2011. JAMA 2012; 308:2577.
  10. Groner JA, Joshi M, Bauer JA. Pediatric precursors of adult cardiovascular disease: noninvasive assessment of early vascular changes in children and adolescents. Pediatrics 2006; 118:1683.
  11. Aggoun Y, Szezepanski I, Bonnet D. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children. Pediatr Res 2005; 58:173.
  12. Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study. Circulation 2001; 104:2815.
  13. Li S, Chen W, Srinivasan SR, et al. Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study. JAMA 2003; 290:2271.
  14. Raitakari OT, Juonala M, Kähönen M, et al. Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study. JAMA 2003; 290:2277.
  15. Dawson JD, Sonka M, Blecha MB, et al. Risk factors associated with aortic and carotid intima-media thickness in adolescents and young adults: the Muscatine Offspring Study. J Am Coll Cardiol 2009; 53:2273.
  16. Juonala M, Magnussen CG, Venn A, et al. Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium. Circulation 2010; 122:2514.
  17. Ryder JR, Dengel DR, Jacobs DR Jr, et al. Relations among Adiposity and Insulin Resistance with Flow-Mediated Dilation, Carotid Intima-Media Thickness, and Arterial Stiffness in Children. J Pediatr 2016; 168:205.
  18. Gaeta G, De Michele M, Cuomo S, et al. Arterial abnormalities in the offspring of patients with premature myocardial infarction. N Engl J Med 2000; 343:840.
  19. Kusters DM, Wiegman A, Kastelein JJ, Hutten BA. Carotid intima-media thickness in children with familial hypercholesterolemia. Circ Res 2014; 114:307.
  20. Atabek ME, Kurtoglu S, Pirgon O, Baykara M. Arterial wall thickening and stiffening in children and adolescents with type 1 diabetes. Diabetes Res Clin Pract 2006; 74:33.
  21. Alpert BS, Collins RT. Assessment of vascular function: pulse wave velocity. J Pediatr 2007; 150:219.
  22. Im JA, Lee JW, Shim JY, et al. Association between brachial-ankle pulse wave velocity and cardiovascular risk factors in healthy adolescents. J Pediatr 2007; 150:247.
  23. Li S, Chen W, Srinivasan SR, Berenson GS. Childhood blood pressure as a predictor of arterial stiffness in young adults: the bogalusa heart study. Hypertension 2004; 43:541.
  24. Urbina EM, Dolan LM, McCoy CE, et al. Relationship between elevated arterial stiffness and increased left ventricular mass in adolescents and young adults. J Pediatr 2011; 158:715.
  25. Urbina EM, Kimball TR, Khoury PR, et al. Increased arterial stiffness is found in adolescents with obesity or obesity-related type 2 diabetes mellitus. J Hypertens 2010; 28:1692.
  26. Urbina EM, Kimball TR, McCoy CE, et al. Youth with obesity and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and function. Circulation 2009; 119:2913.
  27. Juonala M, Viikari JS, Kähönen M, et al. Life-time risk factors and progression of carotid atherosclerosis in young adults: the Cardiovascular Risk in Young Finns study. Eur Heart J 2010; 31:1745.
  28. Koskinen J, Kähönen M, Viikari JS, et al. Conventional cardiovascular risk factors and metabolic syndrome in predicting carotid intima-media thickness progression in young adults: the cardiovascular risk in young Finns study. Circulation 2009; 120:229.
  29. Juonala M, Järvisalo MJ, Mäki-Torkko N, et al. Risk factors identified in childhood and decreased carotid artery elasticity in adulthood: the Cardiovascular Risk in Young Finns Study. Circulation 2005; 112:1486.
  30. Juonala M, Viikari JS, Rönnemaa T, et al. Elevated blood pressure in adolescent boys predicts endothelial dysfunction: the cardiovascular risk in young Finns study. Hypertension 2006; 48:424.
  31. Hartiala O, Magnussen CG, Kajander S, et al. Adolescence risk factors are predictive of coronary artery calcification at middle age: the cardiovascular risk in young Finns study. J Am Coll Cardiol 2012; 60:1364.
  32. Hartiala O, Kajander S, Knuuti J, et al. Life-course risk factor levels and coronary artery calcification. The Cardiovascular Risk in Young Finns Study. Int J Cardiol 2016; 225:23.
  33. Kondos GT, Hoff JA, Sevrukov A, et al. Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults. Circulation 2003; 107:2571.
  34. Wilkins JT, Li RC, Sniderman A, et al. Discordance Between Apolipoprotein B and LDL-Cholesterol in Young Adults Predicts Coronary Artery Calcification: The CARDIA Study. J Am Coll Cardiol 2016; 67:193.
  35. Loria CM, Liu K, Lewis CE, et al. Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study. J Am Coll Cardiol 2007; 49:2013.
  36. Magnussen CG, Venn A, Thomson R, et al. The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study. J Am Coll Cardiol 2009; 53:860.
  37. Koskinen J, Juonala M, Dwyer T, et al. Impact of Lipid Measurements in Youth in Addition to Conventional Clinic-Based Risk Factors on Predicting Preclinical Atherosclerosis in Adulthood: International Childhood Cardiovascular Cohort Consortium. Circulation 2018; 137:1246.
  38. Jackson SL, Zhang Z, Wiltz JL, et al. Hypertension Among Youths - United States, 2001-2016. MMWR Morb Mortal Wkly Rep 2018; 67:758.
  39. Kit BK, Kuklina E, Carroll MD, et al. Prevalence of and trends in dyslipidemia and blood pressure among US children and adolescents, 1999-2012. JAMA Pediatr 2015; 169:272.
  40. May AL, Kuklina EV, Yoon PW. Prevalence of cardiovascular disease risk factors among US adolescents, 1999-2008. Pediatrics 2012; 129:1035.
  41. Perak AM, Ning H, Kit BK, et al. Trends in Levels of Lipids and Apolipoprotein B in US Youths Aged 6 to 19 Years, 1999-2016. JAMA 2019; 321:1895.
  42. Juhola J, Magnussen CG, Viikari JS, et al. Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study. J Pediatr 2011; 159:584.
  43. Saydah S, Bullard KM, Imperatore G, et al. Cardiometabolic risk factors among US adolescents and young adults and risk of early mortality. Pediatrics 2013; 131:e679.
  44. Friedemann C, Heneghan C, Mahtani K, et al. Cardiovascular disease risk in healthy children and its association with body mass index: systematic review and meta-analysis. BMJ 2012; 345:e4759.
  45. Al-Shaikh AM, Abdullah MH, Barclay A, et al. Impact of the characteristics of patients and their clinical management on outcomes in children with homozygous familial hypercholesterolemia. Cardiol Young 2002; 12:105.
  46. Baker JL, Olsen LW, Sørensen TI. Childhood body-mass index and the risk of coronary heart disease in adulthood. N Engl J Med 2007; 357:2329.
  47. Batty GD, Calvin CM, Brett CE, et al. Childhood Body Weight in Relation to Cause-Specific Mortality: 67 Year Follow-up of Participants in the 1947 Scottish Mental Survey. Medicine (Baltimore) 2016; 95:e2263.
  48. Skinner AC, Perrin EM, Moss LA, Skelton JA. Cardiometabolic Risks and Severity of Obesity in Children and Young Adults. N Engl J Med 2015; 373:1307.
  49. Haller MJ, Stein J, Shuster J, et al. Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes. Pediatr Diabetes 2007; 8:193.
  50. Haller MJ, Stein JM, Shuster JJ, et al. Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 2009; 22:65.
  51. Steinberger J, Daniels SR, Eckel RH, et al. Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation 2009; 119:628.
  52. Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics 2007; 120:340.
  53. Haney EM, Huffman LH, Bougatsos C, et al. Screening and treatment for lipid disorders in children and adolescents: systematic evidence review for the US Preventive Services Task Force. Pediatrics 2007; 120:e189.
  54. Ritchie SK, Murphy EC, Ice C, et al. Universal versus targeted blood cholesterol screening among youth: The CARDIAC project. Pediatrics 2010; 126:260.
  55. Lloyd-Jones DM, Nam BH, D'Agostino RB Sr, et al. Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring. JAMA 2004; 291:2204.
  56. Raghuveer G, White DA, Hayman LL, et al. Cardiovascular Consequences of Childhood Secondhand Tobacco Smoke Exposure: Prevailing Evidence, Burden, and Racial and Socioeconomic Disparities: A Scientific Statement From the American Heart Association. Circulation 2016; 134:e336.
  57. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019; 140:e596.
  58. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation 2006; 114:2710.
  59. Nayir A, Bilge I, Kiliçaslan I, et al. Arterial changes in paediatric haemodialysis patients undergoing renal transplantation. Nephrol Dial Transplant 2001; 16:2041.
  60. Litwin M, Grenda R, Prokurat S, et al. Patient survival and causes of death on hemodialysis and peritoneal dialysis--single-center study. Pediatr Nephrol 2001; 16:996.
  61. Mitsnefes MM, Kimball TR, Witt SA, et al. Left ventricular mass and systolic performance in pediatric patients with chronic renal failure. Circulation 2003; 107:864.
  62. Hussein G, Bughdady Y, Kandil ME, et al. Doppler assessment of brachial artery flow as a measure of endothelial dysfunction in pediatric chronic renal failure. Pediatr Nephrol 2008; 23:2025.
  63. Litwin M, Wühl E, Jourdan C, et al. Evolution of large-vessel arteriopathy in paediatric patients with chronic kidney disease. Nephrol Dial Transplant 2008; 23:2552.
  64. Covic A, Mardare N, Gusbeth-Tatomir P, et al. Increased arterial stiffness in children on haemodialysis. Nephrol Dial Transplant 2006; 21:729.
  65. Bakiler AR, Yavascan O, Harputluoglu N, et al. Evaluation of aortic stiffness in children with chronic renal failure. Pediatr Nephrol 2007; 22:1911.
  66. Ordoñez JD, Hiatt RA, Killebrew EJ, Fireman BH. The increased risk of coronary heart disease associated with nephrotic syndrome. Kidney Int 1993; 44:638.
  67. Radhakrishnan J, Appel AS, Valeri A, Appel GB. The nephrotic syndrome, lipids, and risk factors for cardiovascular disease. Am J Kidney Dis 1993; 22:135.
  68. Mulrooney DA, Yeazel MW, Kawashima T, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 2009; 339:b4606.
  69. Haddy N, Diallo S, El-Fayech C, et al. Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study. Circulation 2016; 133:31.
  70. Shankar SM, Marina N, Hudson MM, et al. Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group. Pediatrics 2008; 121:e387.
  71. Neville KA, Cohn RJ, Steinbeck KS, et al. Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors. J Clin Endocrinol Metab 2006; 91:4401.
  72. Green DM, Hyland A, Chung CS, et al. Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence. J Clin Oncol 1999; 17:3207.
  73. Oeffinger KC, Mertens AC, Sklar CA, et al. Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2003; 21:1359.
  74. Birkebaek NH, Fisker S, Clausen N, et al. Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood. Med Pediatr Oncol 1998; 30:351.
  75. Lipshultz SE, Lipsitz SR, Hinkle AS, et al. Cardiovascular status, subsequent risk, and associated factors in long-term survivors of childhood cancer in a population-based study. Circulation 2005; 112 (Suppl 2):476.
  76. Steinberger J, Sinaiko AR, Kelly AS, et al. Cardiovascular risk and insulin resistance in childhood cancer survivors. J Pediatr 2012; 160:494.
  77. Pahl E, Zales VR, Fricker FJ, Addonizio LJ. Posttransplant coronary artery disease in children. A multicenter national survey. Circulation 1994; 90:II56.
  78. Dent CL, Canter CE, Hirsch R, Balzer DT. Transplant coronary artery disease in pediatric heart transplant recipients. J Heart Lung Transplant 2000; 19:240.
  79. Kuhn MA, Jutzy KR, Deming DD, et al. The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation. J Am Coll Cardiol 2000; 36:250.
  80. Roberts WC. Major anomalies of coronary arterial origin seen in adulthood. Am Heart J 1986; 111:941.
  81. Click RL, Holmes DR Jr, Vlietstra RE, et al. Anomalous coronary arteries: location, degree of atherosclerosis and effect on survival--a report from the Coronary Artery Surgery Study. J Am Coll Cardiol 1989; 13:531.
  82. Ou P, Mousseaux E, Azarine A, et al. Detection of coronary complications after the arterial switch operation for transposition of the great arteries: first experience with multislice computed tomography in children. J Thorac Cardiovasc Surg 2006; 131:639.
  83. Pedra SR, Pedra CA, Abizaid AA, et al. Intracoronary ultrasound assessment late after the arterial switch operation for transposition of the great arteries. J Am Coll Cardiol 2005; 45:2061.
  84. Gagliardi MG, Adorisio R, Crea F, et al. Abnormal vasomotor function of the epicardial coronary arteries in children five to eight years after arterial switch operation: an angiographic and intracoronary Doppler flow wire study. J Am Coll Cardiol 2005; 46:1565.
  85. Vriend JW, de Groot E, de Waal TT, et al. Increased carotid and femoral intima-media thickness in patients after repair of aortic coarctation: influence of early repair. Am Heart J 2006; 151:242.
  86. Pinto NM, Marino BS, Wernovsky G, et al. Obesity is a common comorbidity in children with congenital and acquired heart disease. Pediatrics 2007; 120:e1157.
  87. Pasquali SK, Marino BS, Pudusseri A, et al. Risk factors and comorbidities associated with obesity in children and adolescents after the arterial switch operation and Ross procedure. Am Heart J 2009; 158:473.
  88. Ilowite NT, Copperman N, Leicht T, et al. Effects of dietary modification and fish oil supplementation on dyslipoproteinemia in pediatric systemic lupus erythematosus. J Rheumatol 1995; 22:1347.
  89. Schanberg LE, Sandborg C, Barnhart HX, et al. Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum 2009; 60:1496.
  90. Patel K, Wang J, Jacobson DL, et al. Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus. Circulation 2014; 129:1204.
  91. Abd-Elmoniem KZ, Unsal AB, Eshera S, et al. Increased coronary vessel wall thickness in HIV-infected young adults. Clin Infect Dis 2014; 59:1779.
  92. Idris NS, Grobbee DE, Burgner D, et al. Effects of paediatric HIV infection on childhood vasculature. Eur Heart J 2016; 37:3610.
  93. Goldstein BI, Carnethon MR, Matthews KA, et al. Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation 2015; 132:965.
  94. Mendelson MM, Lyass A, O'Donnell CJ, et al. Association of Maternal Prepregnancy Dyslipidemia With Adult Offspring Dyslipidemia in Excess of Anthropometric, Lifestyle, and Genetic Factors in the Framingham Heart Study. JAMA Cardiol 2016; 1:26.
  95. Gaillard R. Maternal obesity during pregnancy and cardiovascular development and disease in the offspring. Eur J Epidemiol 2015; 30:1141.
  96. Ramakrishnan A, Lee LJ, Mitchell LE, Agopian AJ. Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis. Pediatr Cardiol 2015; 36:1442.
  97. Skilton MR, Viikari JS, Juonala M, et al. Fetal growth and preterm birth influence cardiovascular risk factors and arterial health in young adults: the Cardiovascular Risk in Young Finns Study. Arterioscler Thromb Vasc Biol 2011; 31:2975.
  98. Thompson JA, Regnault TR. In utero origins of adult insulin resistance and vascular dysfunction. Semin Reprod Med 2011; 29:211.
Topic 5781 Version 45.0

References

1 : Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report.

2 : Cardiovascular risk reduction in high-risk pediatric populations.

3 : Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association.

4 : Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study.

5 : Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

6 : Determinants of atherosclerosis in the young. Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group.

7 : Pathobiological determinants of atherosclerosis in youth risk scores are associated with early and advanced atherosclerosis.

8 : Comparison of coronary heart disease risk factors in autopsied young adults from the PDAY Study with living young adults from the CARDIA study.

9 : Prevalence of and risk factors for autopsy-determined atherosclerosis among US service members, 2001-2011.

10 : Pediatric precursors of adult cardiovascular disease: noninvasive assessment of early vascular changes in children and adolescents.

11 : Noninvasive assessment of arterial stiffness and risk of atherosclerotic events in children.

12 : Carotid intimal-medial thickness is related to cardiovascular risk factors measured from childhood through middle age: The Muscatine Study.

13 : Childhood cardiovascular risk factors and carotid vascular changes in adulthood: the Bogalusa Heart Study.

14 : Cardiovascular risk factors in childhood and carotid artery intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study.

15 : Risk factors associated with aortic and carotid intima-media thickness in adolescents and young adults: the Muscatine Offspring Study.

16 : Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium.

17 : Relations among Adiposity and Insulin Resistance with Flow-Mediated Dilation, Carotid Intima-Media Thickness, and Arterial Stiffness in Children.

18 : Arterial abnormalities in the offspring of patients with premature myocardial infarction.

19 : Carotid intima-media thickness in children with familial hypercholesterolemia.

20 : Arterial wall thickening and stiffening in children and adolescents with type 1 diabetes.

21 : Assessment of vascular function: pulse wave velocity.

22 : Association between brachial-ankle pulse wave velocity and cardiovascular risk factors in healthy adolescents.

23 : Childhood blood pressure as a predictor of arterial stiffness in young adults: the bogalusa heart study.

24 : Relationship between elevated arterial stiffness and increased left ventricular mass in adolescents and young adults.

25 : Increased arterial stiffness is found in adolescents with obesity or obesity-related type 2 diabetes mellitus.

26 : Youth with obesity and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and function.

27 : Life-time risk factors and progression of carotid atherosclerosis in young adults: the Cardiovascular Risk in Young Finns study.

28 : Conventional cardiovascular risk factors and metabolic syndrome in predicting carotid intima-media thickness progression in young adults: the cardiovascular risk in young Finns study.

29 : Risk factors identified in childhood and decreased carotid artery elasticity in adulthood: the Cardiovascular Risk in Young Finns Study.

30 : Elevated blood pressure in adolescent boys predicts endothelial dysfunction: the cardiovascular risk in young Finns study.

31 : Adolescence risk factors are predictive of coronary artery calcification at middle age: the cardiovascular risk in young Finns study.

32 : Life-course risk factor levels and coronary artery calcification. The Cardiovascular Risk in Young Finns Study.

33 : Electron-beam tomography coronary artery calcium and cardiac events: a 37-month follow-up of 5635 initially asymptomatic low- to intermediate-risk adults.

34 : Discordance Between Apolipoprotein B and LDL-Cholesterol in Young Adults Predicts Coronary Artery Calcification: The CARDIA Study.

35 : Early adult risk factor levels and subsequent coronary artery calcification: the CARDIA Study.

36 : The association of pediatric low- and high-density lipoprotein cholesterol dyslipidemia classifications and change in dyslipidemia status with carotid intima-media thickness in adulthood evidence from the cardiovascular risk in Young Finns study, the Bogalusa Heart study, and the CDAH (Childhood Determinants of Adult Health) study.

37 : Impact of Lipid Measurements in Youth in Addition to Conventional Clinic-Based Risk Factors on Predicting Preclinical Atherosclerosis in Adulthood: International Childhood Cardiovascular Cohort Consortium.

38 : Hypertension Among Youths - United States, 2001-2016.

39 : Prevalence of and trends in dyslipidemia and blood pressure among US children and adolescents, 1999-2012.

40 : Prevalence of cardiovascular disease risk factors among US adolescents, 1999-2008.

41 : Trends in Levels of Lipids and Apolipoprotein B in US Youths Aged 6 to 19 Years, 1999-2016.

42 : Tracking of serum lipid levels, blood pressure, and body mass index from childhood to adulthood: the Cardiovascular Risk in Young Finns Study.

43 : Cardiometabolic risk factors among US adolescents and young adults and risk of early mortality.

44 : Cardiovascular disease risk in healthy children and its association with body mass index: systematic review and meta-analysis.

45 : Impact of the characteristics of patients and their clinical management on outcomes in children with homozygous familial hypercholesterolemia.

46 : Childhood body-mass index and the risk of coronary heart disease in adulthood.

47 : Childhood Body Weight in Relation to Cause-Specific Mortality: 67 Year Follow-up of Participants in the 1947 Scottish Mental Survey.

48 : Cardiometabolic Risks and Severity of Obesity in Children and Young Adults.

49 : Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes.

50 : Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus.

51 : Progress and challenges in metabolic syndrome in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism.

52 : Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study.

53 : Screening and treatment for lipid disorders in children and adolescents: systematic evidence review for the US Preventive Services Task Force.

54 : Universal versus targeted blood cholesterol screening among youth: The CARDIAC project.

55 : Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults: a prospective study of parents and offspring.

56 : Cardiovascular Consequences of Childhood Secondhand Tobacco Smoke Exposure: Prevailing Evidence, Burden, and Racial and Socioeconomic Disparities: A Scientific Statement From the American Heart Association.

57 : 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

58 : Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics.

59 : Arterial changes in paediatric haemodialysis patients undergoing renal transplantation.

60 : Patient survival and causes of death on hemodialysis and peritoneal dialysis--single-center study.

61 : Left ventricular mass and systolic performance in pediatric patients with chronic renal failure.

62 : Doppler assessment of brachial artery flow as a measure of endothelial dysfunction in pediatric chronic renal failure.

63 : Evolution of large-vessel arteriopathy in paediatric patients with chronic kidney disease.

64 : Increased arterial stiffness in children on haemodialysis.

65 : Evaluation of aortic stiffness in children with chronic renal failure.

66 : The increased risk of coronary heart disease associated with nephrotic syndrome.

67 : The nephrotic syndrome, lipids, and risk factors for cardiovascular disease.

68 : Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort.

69 : Cardiac Diseases Following Childhood Cancer Treatment: Cohort Study.

70 : Monitoring for cardiovascular disease in survivors of childhood cancer: report from the Cardiovascular Disease Task Force of the Children's Oncology Group.

71 : Hyperinsulinemia, impaired glucose tolerance, and diabetes mellitus in survivors of childhood cancer: prevalence and risk factors.

72 : Cancer and cardiac mortality among 15-year survivors of cancer diagnosed during childhood or adolescence.

73 : Obesity in adult survivors of childhood acute lymphoblastic leukemia: a report from the Childhood Cancer Survivor Study.

74 : Growth and endocrinological disorders up to 21 years after treatment for acute lymphoblastic leukemia in childhood.

75 : Cardiovascular status, subsequent risk, and associated factors in long-term survivors of childhood cancer in a population-based study

76 : Cardiovascular risk and insulin resistance in childhood cancer survivors.

77 : Posttransplant coronary artery disease in children. A multicenter national survey.

78 : Transplant coronary artery disease in pediatric heart transplant recipients.

79 : The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation.

80 : Major anomalies of coronary arterial origin seen in adulthood.

81 : Anomalous coronary arteries: location, degree of atherosclerosis and effect on survival--a report from the Coronary Artery Surgery Study.

82 : Detection of coronary complications after the arterial switch operation for transposition of the great arteries: first experience with multislice computed tomography in children.

83 : Intracoronary ultrasound assessment late after the arterial switch operation for transposition of the great arteries.

84 : Abnormal vasomotor function of the epicardial coronary arteries in children five to eight years after arterial switch operation: an angiographic and intracoronary Doppler flow wire study.

85 : Increased carotid and femoral intima-media thickness in patients after repair of aortic coarctation: influence of early repair.

86 : Obesity is a common comorbidity in children with congenital and acquired heart disease.

87 : Risk factors and comorbidities associated with obesity in children and adolescents after the arterial switch operation and Ross procedure.

88 : Effects of dietary modification and fish oil supplementation on dyslipoproteinemia in pediatric systemic lupus erythematosus.

89 : Premature atherosclerosis in pediatric systemic lupus erythematosus: risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort.

90 : Aggregate risk of cardiovascular disease among adolescents perinatally infected with the human immunodeficiency virus.

91 : Increased coronary vessel wall thickness in HIV-infected young adults.

92 : Effects of paediatric HIV infection on childhood vasculature.

93 : Major Depressive Disorder and Bipolar Disorder Predispose Youth to Accelerated Atherosclerosis and Early Cardiovascular Disease: A Scientific Statement From the American Heart Association.

94 : Association of Maternal Prepregnancy Dyslipidemia With Adult Offspring Dyslipidemia in Excess of Anthropometric, Lifestyle, and Genetic Factors in the Framingham Heart Study.

95 : Maternal obesity during pregnancy and cardiovascular development and disease in the offspring.

96 : Maternal Hypertension During Pregnancy and the Risk of Congenital Heart Defects in Offspring: A Systematic Review and Meta-analysis.

97 : Fetal growth and preterm birth influence cardiovascular risk factors and arterial health in young adults: the Cardiovascular Risk in Young Finns Study.

98 : In utero origins of adult insulin resistance and vascular dysfunction.