Childhood and adolescence provide a unique window of opportunity to prevent atherosclerotic cardiovascular disease later in life, especially for pediatric groups at risk. The growing list of pediatric groups at risk includes individuals with chronic inflammatory disorders, organ transplants, familial hypercholesterolemia, endocrine disorders, childhood cancer, chronic kidney diseases, congenital heart diseases, and premature birth, as well as increasing numbers of children and adolescents with traditional risk factors such as obesity, hypertension, hyperlipidemia, and hyperglycemia. Here, we focus on recent advances in cardiovascular risk assessment and management and their implications for pediatric practice. First, hyperlipidemia and hyperglycemia are highly prevalent in the young, with hyperlipidemia occurring in 14.6% and hyperglycemia in 16.4% of children and adolescents with a normal weight. Implementation of nonfasting lipid and glycated hemoglobin screening in youth at risk is emerging as a promising avenue to improve testing compliance and lipid and glucose management. Second, blood pressure, lipid, and glucose management in youth at risk are reviewed in depth. Third, multisite and multimodal assessment of early atherosclerosis is discussed as a way to capture the complexity of atherosclerosis as a systemic disease. In addition to conventional carotid intima-media thickness measurements, the measurement of aortic pulse wave velocity and peripheral arterial tonometry can advance the assessment of early atherosclerosis in pediatrics. Finally, we make a plea for lifetime atherosclerotic cardiovascular disease risk stratification that integrates disease-associated risk factors and traditional risk factors and could facilitate tailored cardiovascular risk management in growing numbers of children and adolescents at risk.

Over the last decades, childhood and adolescence have emerged as an important window of opportunity to prevent atherosclerotic cardiovascular disease later in life, as reviewed in the first part of a review series on cardiovascular risk in pediatrics.1  This is particularly relevant for pediatric groups at risk, such as those with chronic inflammatory disorders, organ transplants, endocrine disorders, childhood cancer, chronic kidney diseases, congenital heart diseases, and premature birth, especially after fetal growth restriction. Here, in the second part of this review series, we discuss recent advances in cardiovascular risk management in the young, focusing on antihypertensive, lipid-lowering, and glucose-lowering strategies for children and adolescents at risk. In addition, we review techniques to assess preclinical atherosclerosis. Currently, these techniques are mainly used for research purposes, yet in the near future, they may also be harnessed for cardiovascular risk assessment in the young. Finally, we make a plea for tailored cardiovascular risk assessment and management in children and adolescents at risk.

Lifestyle factors such as physical activity, diet, and smoking, might explain up to 90% of the attributable risk of coronary heart disease in the general population. A recent study in Tsimane, a forager-horticulturalist population in the Bolivian Amazon, provides a colorful illustration.2  Tsimane live a preindustrial lifestyle of hunting, gathering, fishing, and farming, which coincides with a low prevalence of traditional cardiovascular risk factors such as dyslipidemia, hypertension, hyperglycemia, and obesity. As a result, they have the lowest population levels of coronary artery disease reported to date. At 75 years of age and older, 65% of Tsimane do not show any coronary plaque formation on computed tomography (CT), compared with 19% in a multiethnic control population in the industrialized world.2 

Unfortunately, many young people in the industrialized world have developed an unhealthy lifestyle. The prevalence of childhood overweight and obesity, hypertension, and physical inactivity have all surged over the last decades.3  It is still unclear how this will translate into incident cardiovascular disease later in life, yet the forecast seems somber. Young people with chronic disease, many of whom are at risk for early atherosclerosis, seem disproportionately affected by unhealthy lifestyle trends. Various studies suggest they engage in unhealthy and risky lifestyles at similar or even higher rates than healthy peers.47  Taken together, lifestyle modification seems crucial to improving cardiovascular outcomes of children and adolescents at risk. A comparison of effective lifestyle interventions goes beyond the scope of this review and can be found elsewhere.811  Here, we will focus on antihypertensive, lipid-lowering, and glucose-lowering strategies for children and adolescents at risk.

Hypertension in childhood and adolescence has a prevalence of 3% to 3.6%, up to 14.7% in severely obese youth, and is an established risk factor for the development of atherosclerosis.1214  In multiple studies, hypertension early in life has been associated with increased carotid atherosclerosis, left ventricular hypertrophy, cardiovascular mortality, and overall mortality.1520  The 2017 clinical practice guideline of the American Academy of Pediatrics uses a percentile-based approach for elevated blood pressure and hypertension in children aged 1 to 13 years and applies adult cut point to adolescents 13 years and older (Table 1).21  In children aged 1 to 13 years, elevated blood pressure is defined as 3 auscultatory blood pressure measurements at 3 different visits between the 90th and 94th percentile for age, height, and sex. Hypertension is defined as blood pressure equal to or greater than the 95th percentile, or >130/80 mmHg, whichever is lower. The definitions for adolescents 13 years and older follow the adult guidelines and are sex and height independent. In adolescents, stage 1 hypertension is defined as a blood pressure measurement of 130/80 to 139/89 mmHg, and stage 2 hypertension as a blood pressure measurement >140/90 mmHg. Ambulatory blood pressure monitoring permits measurement in a nonmedical environment to unveil masked hypertension, exclude white-coat hypertension, and study diurnal patterns.22 

TABLE 1

Cardiovascular Risk Factor Definitions: Hypertension

HypertensionaChildren Aged 1–12 yAdolescents Aged >12 y
Normal BP <90th percentile <120/<80 mmHg 
Elevated BP 90th to 95th percentile 120/<80 to 129/<80 mmHg 
120/80 mmHg to 95th percentileb  
Stage 1 HTN 95th to 95th percentile + 12 mmHg 130/80 to 139/89 mmHg 
130/80 to 139/89 mmHgb  
Stage 2 HTN ≥95th percentile + 12 mmHg ≥140/90 mmHg 
≥140/90 mmHgb  
HypertensionaChildren Aged 1–12 yAdolescents Aged >12 y
Normal BP <90th percentile <120/<80 mmHg 
Elevated BP 90th to 95th percentile 120/<80 to 129/<80 mmHg 
120/80 mmHg to 95th percentileb  
Stage 1 HTN 95th to 95th percentile + 12 mmHg 130/80 to 139/89 mmHg 
130/80 to 139/89 mmHgb  
Stage 2 HTN ≥95th percentile + 12 mmHg ≥140/90 mmHg 
≥140/90 mmHgb  

BP, blood pressure; HTN, hypertension

a

Adapted from Flynn et al21 

b

Both definitions apply, to harmonize definitions for older children and adolescents.

TABLE 2

Cardiovascular Risk Factor Definitions: Hyperlipidemia

Children and Adolescents
HyperlipidemiaaNormal (mg/dL)Borderline (mg/dL)Abnormal (mg/dL)
Total cholesterol <170 (<4.3 mmol/L) 170–199 (4.3–5.1 mmol/L) ≥200 (≥5.1 mmol/L) 
Triglycerides (0–9 y) <75 (<0.8 mmol/L) 75–99 (0.8–1.1 mmol/L) ≥100 (≥1.1 mmol/L) 
Triglycerides (10–19 y) <90 (<1.0 mmol/L) 90–129 (1.0–1.5 mmol/L) ≥130 (≥1.5 mmol/L) 
HDL-c >45 (>1.2 mmol/L) 40–45 (1.0–1.2 mmol/L) <40 (<1.0 mmol/L) 
LDL-c <110 (<2.8 mmol/L) 110–129 (2.8–3.3 mmol/L) ≥130 (≥3.4 mmol/L) 
Non-HDL-c <120 (<3.1 mmol/L) 120–144 (3.1–3.7 mmol/L) ≥145 (≥3.7 mmol/L) 
Children and Adolescents
HyperlipidemiaaNormal (mg/dL)Borderline (mg/dL)Abnormal (mg/dL)
Total cholesterol <170 (<4.3 mmol/L) 170–199 (4.3–5.1 mmol/L) ≥200 (≥5.1 mmol/L) 
Triglycerides (0–9 y) <75 (<0.8 mmol/L) 75–99 (0.8–1.1 mmol/L) ≥100 (≥1.1 mmol/L) 
Triglycerides (10–19 y) <90 (<1.0 mmol/L) 90–129 (1.0–1.5 mmol/L) ≥130 (≥1.5 mmol/L) 
HDL-c >45 (>1.2 mmol/L) 40–45 (1.0–1.2 mmol/L) <40 (<1.0 mmol/L) 
LDL-c <110 (<2.8 mmol/L) 110–129 (2.8–3.3 mmol/L) ≥130 (≥3.4 mmol/L) 
Non-HDL-c <120 (<3.1 mmol/L) 120–144 (3.1–3.7 mmol/L) ≥145 (≥3.7 mmol/L) 
a

Adapted from De Jesus.26 

*

To convert mg/dL to mmol/L, divide the results for total cholesterol, HDL-c, LDL-c and non-HDL-c by 38.6. For triglycerides, divide by 88.6. The thresholds for borderline and abnormal lipid and lipoprotein levels reflect approximately the 75th and 95th percentile. For HDL-c, thresholds for borderline levels are approximately the 25th to 50th percentile, and less than the 25th percentile for abnormal levels.

TABLE 3

Cardiovascular Risk Factor Definitions: Hyperglycemia

Children and Adolescents
HyperglycemiaaNormalPrediabetesT2D
HbA1c (%) <5.7 (<39 mmol/mol) 5.7–6.4 (39–47 mmol/mol) ≥6.5 (≥48 mmol/mol) 
Fasting glucose (mg/dL) <100 (<5.6 mmol/L) 100–125 (5.6–6.9 mmol/L) ≥126 (≥7 mmol/L) 
2 h glucose (OGTT) (mg/dL) <140 (<7.8 mmol/L) 140–199 (7.8–11.0 mmol/L) ≥200 (≥11.1 mmol/L) 
Children and Adolescents
HyperglycemiaaNormalPrediabetesT2D
HbA1c (%) <5.7 (<39 mmol/mol) 5.7–6.4 (39–47 mmol/mol) ≥6.5 (≥48 mmol/mol) 
Fasting glucose (mg/dL) <100 (<5.6 mmol/L) 100–125 (5.6–6.9 mmol/L) ≥126 (≥7 mmol/L) 
2 h glucose (OGTT) (mg/dL) <140 (<7.8 mmol/L) 140–199 (7.8–11.0 mmol/L) ≥200 (≥11.1 mmol/L) 

OGTT, oral glucose tolerance test.

a

Adapted from Arslanian.39 

*

The OGTT should be performed by using a glucose load of 1.75mg/kg (max 75g). Please note that in the absence of unequivocal hyperglycemia, result should be confirmed by repeat testing.

In children diagnosed with hypertension, nonpharmacologic and pharmacologic therapy is aimed at a reduction of the systolic and diastolic blood pressure less than the 90th percentile and <130/80 mmHg in adolescents.21  Evidence-based nonpharmacological interventions include daily moderate to vigorous physical activity and a diet low in sodium and rich in fruits, vegetables, and low-fat dairy, in accordance with the Dietary Approaches to Stop Hypertension recommendations.23,24  Pharmacological treatment should be initiated when nonpharmacological interventions have failed or more aggressive treatment is needed because of significant hypertension, evidence of end-organ damage (eg, left ventricular hypertrophy), or concurrent risk factors. Although few studies compared the effectiveness of antihypertensive agents in childhood, there is sufficient evidence that antihypertensive agents can effectively decrease blood pressure with minor adverse effects.25  The choice of antihypertensive agent should be tailored to the clinical scenario. As a first line of therapy, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, long-acting calcium channel blockers, and thiazide diuretics are recommended. If the blood pressure is not controlled with a single agent, a thiazide diuretic can be added as a second agent to counteract the salt and water retention that occurs in many antihypertensive regimes.21 

Screening for hyperlipidemia in children and adolescents at risk is recommended in the 2018 multisociety lipid-management guideline by the American Academy of Pediatrics and the 2011 expert panel on cardiovascular risk reduction.26,27  Reference values for lipid and lipoprotein species are shown in Table 2. Adherence to these guidelines seems suboptimal because lipid screening is currently performed in a minority of children and adolescents at risk.28  The lack of lipid screening may be explained by several factors. For one, fasted blood sampling has long been the standard for lipid screening, which limits adherence to lipid testing. A standard lipid screening includes the direct measurement of total cholesterol, high-density lipoprotein cholesterol (HDL-c), and triglycerides. Very low-density lipoprotein cholesterol (VLDL-c) and low-density lipoprotein cholesterol (LDL-c) levels are subsequently calculated by using the Friedewald equation, which approximates VLDL-c levels as a ratio of triglycerides/5 (mg/dL). LDL-c levels are approximated by subtracting HDL-c and VLDL-c levels from the total cholesterol level. Nonfasting estimation of VLDL-c and LDL-c levels by the Friedewald equation was long considered inaccurate on the account of postprandial changes in circulating lipid levels. Recent studies have established, however, that circulating lipids and lipoproteins are only marginally affected by habitual food intake.29 

Over the last few years, nonfasting lipid screening has, therefore, emerged as the novel standard.29,30  Moreover, improved equations have been developed to approximate VLDL-c and LDL-c levels.31,32  These novel recommendations will hopefully promote nonfasting lipid screening in children and adolescents at risk because the prevalence of hyperlipidemia in the young is concerning. In normal-weight children and adolescents 8 to 17 years of age, the prevalence of high total cholesterol levels is ∼ 7.7%, whereas 6.7% have low HDL-c levels and 7.2% show high non-HDL-c levels, which includes VLDL-c and LDL-c.12  The prevalence of all forms of hyperlipidemia in normal-weight children and adolescents is ∼14.6%, and goes up to 39.3% in obesity.12  Hyperlipidemia in children and adolescents may thus be one of the most prevalent risk factors for early atherosclerosis.

Even at a young age, hyperlipidemia acts as an independent predictor for subclinical atherosclerosis.17  Several studies have revealed that hyperlipidemia in the young confers a high lifetime risk of atherosclerotic cardiovascular disease (ASCVD).3335  Early preventive treatment could therefore substantially improve cardiovascular outcomes. Obesity accounts for most cases of hyperlipidemia, yet other secondary causes such as hypothyroidism, diabetes, obstructive liver disease, and renal disease need to be excluded. In addition, hypertriglyceridemia can be induced by triglyceride-raising drugs including sirolimus, tacrolimus, cyclosporine, cyclophosphamide, L-asparaginase, vitamin A derivatives, beta blockers, thiazide diuretics, glucocorticoids, and oral estrogens.27  Next to exclusion of these secondary causes, the evaluation of primary lipid disorders such as familial hypercholesterolemia (FH) might require specialized lipid or genetic testing.

Nonpharmacological treatment is the first line of therapy. Dietary modifications can effectively improve lipid and lipoprotein levels and can safely be sustained in actively growing children and adolescents.36  Effective dietary recommendations include reduction of cholesterol, trans fat, and saturated fat intake, stimulation of fruit and vegetable consumption, reduction of the glycemic index, and decreased portion sizes if weight reduction is required.37  Pharmacological treatment is considered as the second line of therapy if dyslipidemia persists after 6 months of lifestyle and dietary modifications. In children <10 years of age, pharmacological treatment is mainly considered for severe primary lipid disorders. In children >10 years of age, guidelines recommend statin therapy for LDL-c levels ≥130mg/dL (3.4mmol/L) in the presence of multiple high-level risk factors such as diabetes and hypertension, for LDL-c levels ≥160mg/dL (4.1mmol/L), and a single high-level risk factor such as a family history of premature heart disease, or with multiple moderate-level risk factors, and for LDL-c levels ≥190mg/dL (4.9mmol/L) without risk factors.26  Statins effectively inhibit endogenous cholesterol synthesis and lower LDL-c by 20% to 50% and randomized controlled trials reveal they are generally well tolerated in children and adolescents.38  Ezetimibe may be used for those not reaching LDL-c goals on statins and lifestyle modification.27 

The balance between insulin secretion from the pancreatic beta-cells and insulin sensitivity in the target tissues is critical for glucose homeostasis. Insulin action decreases hepatic gluconeogenesis, increases glucose uptake in muscle and fat, suppresses lipolysis from adipocytes, and increases lipid accumulation by liver and adipocytes.39  When insulin action is impaired, hyperglycemia will ensue. In type 1 diabetes, insulin secretion by the pancreas is primarily impaired because of beta-cell dysfunction and pancreatic islet autoimmunity.40  In type 2 diabetes (T2D), insulin action is decreased because of insulin resistance in the target tissues. At first, hyperinsulinemia compensates for insulin resistance. When beta-cells cannot compensate anymore because of advancing insulin resistance or deterioration of beta-cell function, progression to hyperglycemia and T2D occurs.41  The development of insulin resistance and T2D is the specter of cardiovascular risk management in the young, for several reasons.

First, insulin resistance and T2D are major risk factors for early atherosclerosis. Younger age at diagnosis of T2D is associated with higher cardiovascular risk.42  In fact, young adults diagnosed with T2D during childhood or adolescence show a higher prevalence of complications and comorbidities, including hypertension and arterial stiffness, than young adults with type 1 diabetes.43  Second, the prevalence of prediabetes in adolescents and young adults is high. In the United States, ∼1 of 5 adolescents and 1 of 4 young adults have prediabetes, as defined by 1 of 3 glucose dysregulation phenotypes, including a glycated hemoglobin A1c (HbA1c) level between 5.7% and 6.4%, a fasting glucose measurement of 100mg/dL to 126mg/dL, or a 2 hour plasma glucose of 140mg/dL to 199mg/dL after a 75 g oral glucose tolerance test.44  T2D is diagnosed when any of the 3 glucose dysregulation phenotypes deteriorates further and has a prevalence in youth of ∼ 0.5% (Table 3).39,45 

Interestingly, the 3 glucose dysregulation phenotypes do not always overlap, partly due to variability in fasting glucose and oral glucose tolerance testing, compared with HbA1c.46  HbA1c-defined (pre)diabetes seems to demonstrate the best risk discrimination for cardiovascular disease and can be assessed in nonfasting blood samples, carrying clear advantages from a cardiovascular risk management perspective.39,47  A third feature of concern is that a substantial amount of insulin resistance and prediabetes goes unnoticed. Screening for T2D is recommended in children and adolescents with obesity, as youth with T2D are characteristically overweight or obese. This approach seems effective because most cases of youth-onset T2D are promptly diagnosed.45  However, the situation is different for prediabetes, as revealed in the 2005 to 2016 United States survey. In adolescents with a normal weight, 16.4% showed prediabetes as characterized by 1 of the 3 glucose dysregulation phenotypes, including 4.8% with increased HbA1c levels.44  Many of these adolescents would not have been screened for prediabetes otherwise, because of their normal weight. Youth with prediabetic levels of HbA1c have a high burden of other cardiometabolic risk factors because hypertension occurs in 14.4% of these adolescents, and hyperlipidemia in more than 26%.45 

Altogether, prediabetes is associated with an increased risk of ASCVD.48  We, therefore, advocate the implementation of prediabetes screening in cardiovascular risk management guidelines for children and adolescents at risk, irrespective of their body mass index, in line with recent recommendations of the Endocrine Society.49  Early diagnosis of prediabetes would enable lifestyle interventions to prevent future diabetes and cardiovascular risk. Over the last few years, several studies indicated that lifestyle and nutritional interventions for prediabetes can reduce diabetes development and cardiovascular mortality.5052  In youth with T2D, pharmacological therapy is recommended in addition to lifestyle and nutritional modifications. Metformin is the initial pharmacological treatment in asymptomatic patients with normal renal function and HbA1c <8.5%. In symptomatic patients with an HbA1c ≥8.5%, insulin therapy is recommended along with metformin.39  Novel oral antidiabetic drugs such as sodium glucose transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists may be introduced in youth with T2D in the near future because their cardioprotective effects are currently emerging in adults with T2D.53,54 

Although the assessment of preclinical atherosclerosis is mainly performed in a research setting, there are rare but important clinical indications for advanced vascular imaging. In addition, knowledge about preclinical atherosclerosis is relevant for pediatricians to increase understanding of the impact of cardiovascular risk factors. First, imaging of the coronary arteries is performed for specific pediatric indications, such as giant aneurysms in Kawasaki disease and coronary abnormalities in congenital heart disease. Second, the assessment of preclinical atherosclerosis is a promising avenue to improve cardiovascular risk assessment for children and adolescents in the near future. In adults, American Heart Association guidelines recommend coronary artery calcium scoring (CAC) to facilitate shared decision making on the initiation of statin therapy in individuals with moderate risk.55  Similarly, aortic pulse wave velocity measurements are known to improve the performance of established cardiovascular risk calculators.56,57  In pediatrics, the assessment of preclinical atherosclerosis might similarly aid cardiovascular risk management in the near future.

In adults with suspected coronary artery disease, CT is traditionally employed to visualize coronary artery atherosclerosis and stenosis with angiography and to assess the burden of calcification with CAC.58  Coronary CT angiography with iodinated contrast enables the visualization of coronary artery stenosis and reveals adverse plaque characteristics such as spotty calcification or a necrotic core. Imaging is timed to ensure peak contrast enhancement of the coronary arteries, and electrocardiogram gating during a single breath hold is used to minimize motion artifacts. Another CT evaluation is to measure CAC, which is performed with noncontrast CT and has prognostic value because a CAC score of 0 in asymptomatic adults is associated with an annual cardiovascular mortality rate of <1% for 15 years, whereas a CAC score >300 Agatston units carries a 4-fold higher risk.59 

Technical advantages of CT include a submillimeter spatial resolution and short scan time. The radiation exposure depends on the scanner and protocol and is currently 1 to 10mSv, compared with 0.1mSv for a single radiograph.58  However, radiation exposure is still a disadvantage for use in pediatrics, as are other disadvantages such as the required breath hold and need to lie still. Moreover, except for coronary pathology as in Kawasaki disease, children and adolescents at risk will generally not show coronary abnormalities on CT because atherogenesis begins in the abdominal aorta, and plaque is usually noncalcified early on.

CAC has limited use in pediatrics and coronary CT angiography is mainly helpful in the setting of giant/large aneurysms from Kawasaki disease, homozygous FH, or congenital heart disease with previous coronary manipulation, or concerns about coronary compression. For most pediatric groups at risk, the value of CT is limited, and alternative vascular measurements such as carotid artery intima-media thickness (cIMT), aortic pulse wave velocity, and endothelial function measurements are more appropriate, as detailed below and illustrated in Figure 1.

FIGURE 1

Multimodal and multisite assessment of early atherosclerosis.

This figure provides an overview of key techniques to assess early atherosclerosis in youth at risk. The color boxes indicate the measurement location. Moreover, technical principles, advantages (pro) and disadvantages (con) of the 4 techniques are shown.

FIGURE 1

Multimodal and multisite assessment of early atherosclerosis.

This figure provides an overview of key techniques to assess early atherosclerosis in youth at risk. The color boxes indicate the measurement location. Moreover, technical principles, advantages (pro) and disadvantages (con) of the 4 techniques are shown.

Close modal

Sonographic evaluation of the common cIMT as a preclinical measure of atherosclerosis gained traction in the early 21st century when cIMT was identified as an independent predictor of cardiovascular events in adults, in addition to traditional cardiovascular risk factors, in the Framingham Heart study.60  Although the predictive value of cIMT in children and adolescents has not been confirmed in longitudinal cardiovascular outcome studies, cIMT emerged as a frequently used noninvasive measure of preclinical atherosclerosis in pediatric research. Standardized assessment of cIMT in pediatric studies is safe, inexpensive, feasible, and accurate, with normative values available for children aged 6 years and older.61,62 

Over the last few years, various pediatric studies have revealed increased cIMT in a number of diagnoses, and cIMT measurements are often used to assess the effect of lifestyle intervention programs.61,63  Nonetheless, caution about the use of cIMT as the main preclinical measure of atherosclerosis is warranted. Atherogenesis starts in the iliac arteries and abdominal aorta during childhood, and only later in higher regions of the arterial tree such as the carotids. In addition, recent studies reveal that changes in cIMT at a young age reflect physiologic adaptations of the carotid media in response to higher blood pressure or body mass, rather than atherogenesis in the carotid intima layer.64  Therefore, preclinical measures of atherosclerosis in the aorta seem preferable for the identification of early atherosclerosis. A recent study in adults compared the predictive value of cIMT and aortic ultrasound and revealed that atherogenic changes in the abdominal aorta are superior to cIMT in the prediction of cardiovascular events.65 

Overall, cIMT has practical advantages and value in pediatrics, yet appears to be inferior to aortic measures of preclinical atherosclerosis in predicting cardiovascular events. Several authors have, in fact, advocated a multimodal and multisite approach to cardiovascular risk assessment to overcome the limitations of cIMT and capture the complexity of atherosclerosis as a systemic disease.66  Two of these multimodal measurements are aortic pulse wave velocity and endothelial function tests, as discussed below.

Propagation of the aortic pulse wave after contraction of the left ventricle depends on the elastic properties of the aortic wall. The aortic pulse wave velocity (PWV) is calculated by dividing the distance between the proximal and distal aorta by the transit time of the pressure wave gradient and reflects these aortic wall properties. A stiff aortic wall enhances the propagation of the pulse wave and generates a higher aortic PWV. The aortic PWV naturally increases with age and is also enhanced by hypertension and atherosclerosis.67  In various adult studies, aortic PWV has been established as an independent predictor of cardiovascular events, even after correction for blood pressure.56,6870  Reference values per age decade and blood pressure category are available, which enables clinical implementation of PWV as a measure of aortic stiffness and cardiovascular prognosis in adults.71  In pediatric studies, various groups at risk have enhanced aortic PWV, compared with healthy peers.72,73 

Notwithstanding its value for cardiovascular risk assessment, there are important methodological considerations. Aortic PWV can reliably be assessed by cardiovascular magnetic resonance imaging or invasive measurements. In most studies, however, aortic PWV is estimated by noninvasive assessment of carotid-femoral PWV or brachial-ankle PWV. Validation studies have revealed that carotid-femoral PWV measurements are superior to brachial-ankle PWV measurements in estimating aortic PWV.74  Several techniques are available to map carotid and femoral pulse waves, including transcutaneous tonometry, piezoelectric mechanotransducers, and cuff-based oscillometric devices.75  There are major differences in clinical viability and validation of these techniques, also between suppliers.75  Moreover, few devices have been validated for children and adolescents. International consensus on the best techniques for pediatric studies is, therefore, required to realize successful implementation in pediatric cardiovascular risk assessment.

Over the years, endothelial dysfunction has emerged as another preclinical measure of atherosclerosis. Endothelial dysfunction is induced by cardiovascular risk factors such as hypertension, dyslipidemia, and inflammation. In the coronary and peripheral microcirculation, these factors can lead to the loss of endothelial integrity, increased expression of adhesion molecules, the release of prothrombotic factors and cytokines, and upregulation of antigen-presenting molecules, which altogether characterize endothelial dysfunction and promote atherogenesis.76  The assessment of endothelial function is based on the principle that healthy arteries dilate in response to vasodilators or reactive hyperemia via flow-mediated vasodilatation. In contrast, endothelial dysfunction coincides with impaired endothelial-dependent vasodilatation.76  Endothelial function can be assessed invasively, for example by intracoronary vascular reactivity tests.77  Noninvasive assessment of endothelial function, however, offers clear advantages for cardiovascular risk assessment in pediatrics.

In adults, flow-mediated vasodilatation (FMD) of the brachial artery is commonly used for the noninvasive assessment of endothelial function in research. During a 5 minute supra systolic occlusion of the brachial artery using a blood pressure cuff, shear stress in the upstream brachial artery stimulates the release of nitric oxide and other vasodilators and leads to reactive hyperemia. After release of the blood pressure cuff, FMD is assessed by ultrasound as the increase in brachial artery flow. FMD has successfully been pioneered in pediatric studies in the past.78  Nonetheless, standardized assessment of FMD in pediatrics is complicated by numerous patient, environmental and procedural factors.79 

Moreover, peripheral arterial tonometry (PAT) gained traction as a practical alternative. Finger plethysmography with pneumatic probes on a finger of both hands captures arterial pulse wave amplitudes in response to reactive hyperemia. Similar to FMD, a blood pressure cuff on one arm is used to induce reactive hyperemia. The contralateral arm and finger serve as a control. After release of the blood pressure cuff, a reactive hyperemia index is calculated by comparing pulse wave amplitudes in the fingers of both hands.76  The PAT measurements are observer-independent and show high reproducibility in children, as long as methodological considerations such as diurnal variation and the influence of room conditions, stress, and meals are taken into account.80  PAT measurements do not always correlate with FMD, yet in adults, predict future cardiovascular events with a similar prognostic magnitude.81  Both FMD and PAT are established independent predictors of cardiovascular events and all-cause mortality in adults.8184  In pediatrics, PAT measurements are enhanced in various populations at risk, and PAT is considered a promising addition to the multimodal assessment of cardiovascular risk, although further standardization and validation studies are still needed80  and adaptations need to be made for the smallest children.

In the first part of this review series on cardiovascular risk in pediatrics, we have presented a diverse and growing list of pediatric groups at risk for ASCVD.1  At-risk groups include individuals with chronic inflammatory disorders, organ transplants, familial hypercholesterolemia, endocrine disorders, childhood cancer, chronic kidney diseases, congenital heart diseases, and premature birth (especially after fetal growth restriction), in addition to increasing numbers of children and adolescents with traditional risk factors such as obesity, hypertension, hyperlipidemia, and hyperglycemia. This diverse and growing list underscores that cardiovascular risk assessment and management have solidly entered the realm of general pediatrics.

Some may argue that we should not undertake a large shift toward prevention until the long-term effectiveness of cardiovascular risk management strategies in children and adolescents has been established. Here, we propose a proactive approach to the growing pool of atherosclerotic risk in childhood because recent advances in cardiovascular risk assessment and management offer promising avenues for effective prevention of cardiovascular disease in pediatrics and significant benefits can be derived from heart-healthy habits that do not require pharmacotherapy.

First, hyperlipidemia confers a high lifetime risk of ASCVD and is highly prevalent in the young because it occurs in 14.6% of children and adolescents with a normal weight, up to 39.3% of children and adolescents with obesity in the United States. Despite national recommendations, however, lipid screening is only performed in a minority of children and adolescents at risk.28  Additional implementation of nonfasting lipid screening might improve testing compliance and lipid management in pediatrics. Second, screening for T2D is routinely performed in children and adolescents with obesity, but not in youth with a normal weight. Because up to 16.4% of adolescents with a normal weight show prediabetes, we would advocate HbA1c screening in all children and adolescents at risk, irrespective of their body mass index. Early diagnosis of prediabetes enables lifestyle and nutritional interventions to avert the development of T2D and its cardiovascular sequelae. Third, multisite and multimodal assessment of early atherosclerosis emerges as a way to capture the complexity of atherosclerosis as a systemic disease.

To date, cIMT measurements have been used in childhood as the main noninvasive measure of preclinical atherosclerosis. Recent studies, however, reveal that several cIMT changes at a young age likely reflect physiologic adaptations of the carotid media layer, rather than atherogenesis of the carotid intima layer. The implementation of additional measures of preclinical atherosclerosis, such as aortic PWV measurements and PAT, could improve the assessment of early atherosclerosis in pediatrics. Fourth, cardiovascular risk stratification in adults is based on 10-year ASCVD risk, and there is no established alternative for risk stratification in pediatrics yet. Longitudinal studies in children and adolescents at risk are still in process and will hopefully facilitate lifetime ASCVD risk stratification in pediatrics in the near future.

The assessment of preclinical atherosclerosis using cIMT, PWV, and PAT measurements is a promising avenue to improve cardiovascular risk estimations in pediatrics, just like PWV measurements are known to improve the performance of established cardiovascular risk calculators in adults.56,57  Finally, risk management in pediatrics faces ethical dilemmas, such as shared decision-making on lifelong preventive medication. Which lifetime cardiovascular risk would justify lifelong preventive treatment? These and other outstanding questions in the field have been summarized in Table 4.

TABLE 4

Outstanding Questions in the Field

Assessment of Early Atherosclerosis 
 What is the relative predictive value of aortic PWV, PAT, and cIMT measurements, with respect to cardiovascular outcomes? 
 How can multimodal and multisite assessment of atherosclerosis be implemented in pediatric cardiovascular risk assessment? 
 Can we develop a lifetime ASCVD risk calculator for children and adolescents? Can cIMT, PWV, and PAT measurements improve the accuracy of a lifetime ASCVD risk calculator in pediatrics? 
Cardiovascular Risk Management 
 How could we implement lifetime ASCVD risk stratification for children and adolescents at risk? 
 Can we harness the pediatric “window of opportunity” to improve cardiovascular outcomes in youth at risk? 
 What is the best strategy to tailor early prevention to the needs of individual children and adolescents at risk? 
 How can youth at risk be involved in lifelong prevention, for example by shared decision making? 
Specific Aspects of Risk Management 
 Lifestyle: What are effective and sustainable lifestyle and nutritional interventions in youth at risk? 
 Wt management: In normal physiology, adipocyte numbers increase until adolescence.85,86  Are the increased adipocyte numbers in obesity rooted in childhood adipose tissue development? What are the implications for obesity prevention? 
 Blood pressure management: What is the impact of specific hypertension categories, such as masked hypertension and isolated systolic hypertension, on ASCVD development in the young? What is the most effective first and second line of pharmacological therapy for cardiovascular outcomes in children and adolescents with persistent hypertension? 
 Lipid management: Which cut-off levels for hyperlipidemia should be implemented to start lipid-lowering medication in youth at risk? 
 Glucose management: What is the impact of prediabetes screening in youth at risk on early lifestyle interventions and cardiovascular outcomes? 
Assessment of Early Atherosclerosis 
 What is the relative predictive value of aortic PWV, PAT, and cIMT measurements, with respect to cardiovascular outcomes? 
 How can multimodal and multisite assessment of atherosclerosis be implemented in pediatric cardiovascular risk assessment? 
 Can we develop a lifetime ASCVD risk calculator for children and adolescents? Can cIMT, PWV, and PAT measurements improve the accuracy of a lifetime ASCVD risk calculator in pediatrics? 
Cardiovascular Risk Management 
 How could we implement lifetime ASCVD risk stratification for children and adolescents at risk? 
 Can we harness the pediatric “window of opportunity” to improve cardiovascular outcomes in youth at risk? 
 What is the best strategy to tailor early prevention to the needs of individual children and adolescents at risk? 
 How can youth at risk be involved in lifelong prevention, for example by shared decision making? 
Specific Aspects of Risk Management 
 Lifestyle: What are effective and sustainable lifestyle and nutritional interventions in youth at risk? 
 Wt management: In normal physiology, adipocyte numbers increase until adolescence.85,86  Are the increased adipocyte numbers in obesity rooted in childhood adipose tissue development? What are the implications for obesity prevention? 
 Blood pressure management: What is the impact of specific hypertension categories, such as masked hypertension and isolated systolic hypertension, on ASCVD development in the young? What is the most effective first and second line of pharmacological therapy for cardiovascular outcomes in children and adolescents with persistent hypertension? 
 Lipid management: Which cut-off levels for hyperlipidemia should be implemented to start lipid-lowering medication in youth at risk? 
 Glucose management: What is the impact of prediabetes screening in youth at risk on early lifestyle interventions and cardiovascular outcomes? 

Cardiovascular risk assessment and management have entered the realm of general pediatrics and provide a unique opportunity to improve cardiovascular outcomes in growing numbers of children and adolescents at risk. Considering the fact that pediatricians coordinate the follow-up of many children and adolescents at risk, they could fulfill a pivotal role in tailored blood pressure, lipid, and glucose management in pediatric populations at risk. As an example, Fig 2 illustrates how cardiovascular risk management of pediatric populations at risk could be implemented in general pediatrics. Much progress has been made, but more work needs to be done. Meanwhile, with this review, we aim to provide some practical guidance.

FIGURE 2

Implementation of cardiovascular risk management (CVRM) in general pediatrics, an example.

The flowchart illustrates how CVRM could be implemented in the follow-up of children and adolescents at risk for early ASCVD, who are not routinely subjected to CVRM yet. Please note that the flowchart does not replace current CVRM guidelines in specific populations at risk, such as FH.

a Please see Schipper and de Ferranti1  for an overview of pediatric populations at risk.

b Consider referral to a pediatric endocrinologist, nephrologist, lipid expert, or cardiologist if suspected primary disease.

c BP, lipid and glucose reference values are provided in Tables 13. Ambulatory BP reference values are provided in Wühl et al.22 

d Effective lifestyle interventions are reviewed in Bleich et al, Styne et al, Robinson et al, and Steinbeck et al.811 

e High risk conditions, such as homozygous FH, benefit from implementation of advanced CVRM early in the disease. At risk and moderate risk conditions may allow for stepwise implementation of advanced CVRM, depending on the risk factors. Tailoring of CVRM to the needs of individual children and adolescents is an important outstanding question in the field (Table 4).

FIGURE 2

Implementation of cardiovascular risk management (CVRM) in general pediatrics, an example.

The flowchart illustrates how CVRM could be implemented in the follow-up of children and adolescents at risk for early ASCVD, who are not routinely subjected to CVRM yet. Please note that the flowchart does not replace current CVRM guidelines in specific populations at risk, such as FH.

a Please see Schipper and de Ferranti1  for an overview of pediatric populations at risk.

b Consider referral to a pediatric endocrinologist, nephrologist, lipid expert, or cardiologist if suspected primary disease.

c BP, lipid and glucose reference values are provided in Tables 13. Ambulatory BP reference values are provided in Wühl et al.22 

d Effective lifestyle interventions are reviewed in Bleich et al, Styne et al, Robinson et al, and Steinbeck et al.811 

e High risk conditions, such as homozygous FH, benefit from implementation of advanced CVRM early in the disease. At risk and moderate risk conditions may allow for stepwise implementation of advanced CVRM, depending on the risk factors. Tailoring of CVRM to the needs of individual children and adolescents is an important outstanding question in the field (Table 4).

Close modal

The guidelines/recommendations in this article are not American Academy of Pediatrics policy, and publication herein does not imply endorsement.

Dr Schipper conceptualized the study and drafted the initial manuscript; Dr de Ferranti reviewed and revised the manuscript; and both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest relevant to this article to disclose.

ASCVD

atherosclerotic cardiovascular disease

CAC

coronary artery calcium scoring

cIMT

carotid intima-media thickness

CT

computed tomography

FH

familial hypercholesterolemia

FMD

flow-mediated vasodilatation

HbA1c

hemoglobin A1c, glycated hemoglobin

HDL-c

high-density lipoprotein cholesterol

LDL-c

low-density lipoprotein cholesterol

PAT

peripheral arterial tonometry

PWV

pulse wave velocity

T2D

type 2 diabetes

VLDL-c

very low-density lipoprotein cholesterol

1
Schipper
HS
,
de Ferranti
SD
.
Atherosclerotic cardiovascular risk as an emerging priority in pediatrics
.
Pediatrics
.
2022
;
150
(
5
):
e2022057956
2
Kaplan
H
,
Thompson
RC
,
Trumble
BC
, et al
.
Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study
.
Lancet
.
2017
;
389
(
10080
):
1730
1739
3
Andersson
C
,
Vasan
RS
.
Epidemiology of cardiovascular disease in young individuals
.
Nat Rev Cardiol
.
2018
;
15
(
4
):
230
240
4
Sawyer
SM
,
Drew
S
,
Yeo
MS
,
Britto
MT
.
Adolescents with a chronic condition: challenges living, challenges treating
.
Lancet
.
2007
;
369
(
9571
):
1481
1489
5
Lui
GK
,
Rogers
IS
,
Ding
VY
, et al
.
Risk estimates for atherosclerotic cardiovascular disease in adults with congenital heart disease
.
Am J Cardiol
.
2017
;
119
(
1
):
112
118
6
Maahs
DM
,
Daniels
SR
,
de Ferranti
SD
, et al;
American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council for High Blood Pressure Research, and Council on Lifestyle and Cardiometabolic Health
.
Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association
.
Circulation
.
2014
;
130
(
17
):
1532
1558
7
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
(
13
):
e603
e634
8
Bleich
SN
,
Vercammen
KA
,
Zatz
LY
,
Frelier
JM
,
Ebbeling
CB
,
Peeters
A
.
Interventions to prevent global childhood overweight and obesity: a systematic review
.
Lancet Diabetes Endocrinol
.
2018
;
6
(
4
):
332
346
9
Styne
DM
,
Arslanian
SA
,
Connor
EL
, et al
.
Pediatric obesity-assessment, treatment, and prevention: an endocrine society clinical practice guideline
.
J Clin Endocrinol Metab
.
2017
;
102
(
3
):
709
757
10
Robinson
TN
,
Banda
JA
,
Hale
L
, et al
.
Screen media exposure and obesity in children and adolescents
.
Pediatrics
.
2017
;
140
(
Suppl 2
):
S97
S101
11
Steinbeck
KS
,
Lister
NB
,
Gow
ML
,
Baur
LA
.
Treatment of adolescent obesity
.
Nat Rev Endocrinol
.
2018
;
14
(
6
):
331
344
12
Kit
BK
,
Kuklina
E
,
Carroll
MD
,
Ostchega
Y
,
Freedman
DS
,
Ogden
CL
.
Prevalence of and trends in dyslipidemia and blood pressure among US children and adolescents, 1999-2012
.
JAMA Pediatr
.
2015
;
169
(
3
):
272
279
13
Hansen
ML
,
Gunn
PW
,
Kaelber
DC
.
Underdiagnosis of hypertension in children and adolescents
.
JAMA
.
2007
;
298
(
8
):
874
879
14
Jackson
SL
,
Zhang
Z
,
Wiltz
JL
, et al
.
Hypertension among youths - United States, 2001-2016
.
MMWR Morb Mortal Wkly Rep
.
2018
;
67
(
27
):
758
762
15
Koskinen
JS
,
Kytö
V
,
Juonala
M
, et al
.
Childhood risk factors and carotid atherosclerotic plaque in adulthood: the Cardiovascular Risk in Young Finns Study
.
Atherosclerosis
.
2020
;
293
(
293
):
18
25
16
Juhola
J
,
Magnussen
CG
,
Berenson
GS
, et al
.
Combined effects of child and adult elevated blood pressure on subclinical atherosclerosis: the International Childhood Cardiovascular Cohort Consortium
.
Circulation
.
2013
;
128
(
3
):
217
224
17
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
(
12
):
1246
1255
18
Lai
C-C
,
Sun
D
,
Cen
R
, et al
.
Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa Heart Study
.
J Am Coll Cardiol
.
2014
;
64
(
15
):
1580
1587
19
Sundstrom
J
,
Neovius
M
,
Tynelius
P
, %
Rasmussen
F
.
Association of blood pressure in late adolescence with subsequent mortality: cohort study of Swedish male conscripts
.
BMJ
.
2011
;
342
:
d643
20
Gray
L
,
Lee
IM
,
Sesso
HD
,
Batty
GD
.
Blood pressure in early adulthood, hypertension in middle age, and future cardiovascular disease mortality: HAHS (Harvard Alumni Health Study)
.
J Am Coll Cardiol
.
2011
;
58
(
23
):
2396
2403
21
Flynn
JT
,
Kaelber
DC
,
Baker-Smith
CM
, et al;
Subcommittee on Screening and Management of High Blood Pressure in Children
.
Clinical practice guideline for screening and management of high blood pressure in children and adolescents
.
Pediatrics
.
2017
;
140
(
3
):
e20171904
22
Wühl
E
,
Witte
K
,
Soergel
M
,
Mehls
O
,
Schaefer
F
;
German Working Group on Pediatric Hypertension
.
Distribution of 24-h ambulatory blood pressure in children: normalized reference values and role of body dimensions
.
J Hypertens
.
2002
;
20
(
10
):
1995
2007
23
Hansen
HS
,
Froberg
K
,
Hyldebrandt
N
,
Nielsen
JR
.
A controlled study of eight months of physical training and reduction of blood pressure in children: the Odense Schoolchild Study
.
BMJ
.
1991
;
303
(
6804
):
682
685
24
Couch
SC
,
Saelens
BE
,
Levin
L
,
Dart
K
, %
Falciglia
G
,
Daniels
SR
.
The efficacy of a clinic-based behavioral nutrition intervention emphasizing a DASH-type diet for adolescents with elevated blood pressure
.
J Pediatr
.
2008
;
152
(
4
):
494
501
25
Chaturvedi
S
,
Lipszyc
DH
,
Licht
C
,
Craig
JC
,
Parekh
RS
.
Cochrane in context: pharmacological interventions for hypertension in children
.
Evid Based Child Health
.
2014
;
9
(
3
):
581
583
26
De Jesus
JM
;
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
S256
27
Grundy
SM
,
Stone
NJ
,
Bailey
AL
, et al
.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines
.
Circulation
.
2019
;
139
(
25
):
e1082
e1143
28
Berger
JH
,
Chen
F
,
Faerber
JA
,
O’Byrne
ML
,
Brothers
JA
.
Adherence with lipid screening guidelines in standard- and high-risk children and adolescents
.
Am Heart J
.
2021
;
232
:
39
46
29
Nordestgaard
BG
,
Langsted
A
,
Mora
S
, et al.
European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) joint consensus initiative
.
Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine
.
Eur Heart J
.
2016
;
37
(
25
):
1944
1958
30
Farukhi
Z
,
Mora
S
.
The future of low-density lipoprotein cholesterol in an era of nonfasting lipid testing and potent low-density lipoprotein lowering
.
Circulation
.
2018
;
137
(
1
):
20
23
31
Martin
SS
,
Blaha
MJ
,
Elshazly
MB
, et al
.
Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile
.
JAMA
.
2013
;
310
(
19
):
2061
2068
32
Sathiyakumar
V
,
Park
J
,
Golozar
A
, et al
.
Fasting versus nonfasting and low-density lipoprotein cholesterol accuracy
.
Circulation
.
2018
;
137
(
1
):
10
19
33
McGill
HC
Jr
,
McMahan
CA
,
Gidding
SS
.
Preventing heart disease in the 21st century: implications of the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study
.
Circulation
.
2008
;
117
(
9
):
1216
1227
34
Lloyd-Jones
DM
,
Wilson
PWF
,
Larson
MG
, et al
.
Lifetime risk of coronary heart disease by cholesterol levels at selected ages
.
Arch Intern Med
.
2003
;
163
(
16
):
1966
1972
35
Jacobs
DR
Jr
,
Woo
JG
,
Sinaiko
AR
, et al
.
Childhood cardiovascular risk factors and adult cardiovascular events
.
N Engl J Med
.
2022
;
386
(
20
):
1877
1888
36
Obarzanek
E
,
Kimm
SYS
,
Barton
BA
, et al;
DISC Collaborative Research Group
.
Long-term safety and efficacy of a cholesterol-lowering diet in children with elevated low-density lipoprotein cholesterol: seven-year results of the Dietary Intervention Study in Children (DISC)
.
Pediatrics
.
2001
;
107
(
2
):
256
264
37
Zachariah
JP
,
Chan
J
,
Mendelson
MM
, et al
.
Adolescent dyslipidemia and standardized lifestyle modification: benchmarking real-world practice
.
J Am Coll Cardiol
.
2016
;
68
(
19
):
2122
2123
38
Vuorio
A
,
Kuoppala
J
,
Kovanen
PT
, et al
.
Statins for children with familial hypercholesterolemia
.
Cochrane Database Syst Rev
.
2019
;
2019
(
11
):
CD006401
39
Arslanian
S
,
Bacha
F
,
Grey
M
,
Marcus
MD
,
White
NH
,
Zeitler
P
.
Evaluation and management of youth-onset type 2 diabetes: a position statement by the American Diabetes Association
.
Diabetes Care
.
2018
;
41
(
12
):
2648
2668
40
Roep
BO
,
Thomaidou
S
,
van Tienhoven
R
,
Zaldumbide
A
.
Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?)
.
Nat Rev Endocrinol
.
2021
;
17
(
3
):
150
161
41
James
DE
,
Stöckli
J
,
Birnbaum
MJ
.
The aetiology and molecular landscape of insulin resistance
.
Nat Rev Mol Cell Biol
.
2021
;
22
(
11
):
751
771
42
Zoungas
S
,
Woodward
M
,
Li
Q
, et al;
ADVANCE Collaborative group
.
Impact of age, age at diagnosis and duration of diabetes on the risk of macrovascular and microvascular complications and death in type 2 diabetes
.
Diabetologia
.
2014
;
57
(
12
):
2465
2474
43
Dabelea
D
,
Stafford
JM
,
Mayer-Davis
EJ
, et al;
SEARCH for Diabetes in Youth Research Group
.
Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood
.
JAMA
.
2017
;
317
(
8
):
825
835
44
Andes
LJ
,
Cheng
YJ
,
Rolka
DB
,
Gregg
EW
,
Imperatore
G
.
Prevalence of prediabetes among adolescents and young adults in the United States, 2005-2016
.
JAMA Pediatr
.
2020
;
174
(
2
):
e194498
45
Wallace
AS
,
Wang
D
,
Shin
J-I
,
Selvin
E
.
Screening and diagnosis of prediabetes and diabetes in US children and adolescents
.
Pediatrics
.
2020
;
146
(
3
):
e20200265
46
Selvin
E
,
Crainiceanu
CM
,
Brancati
FL
,
Coresh
J
.
Short-term variability in measures of glycemia and implications for the classification of diabetes
.
Arch Intern Med
.
2007
;
167
(
14
):
1545
1551
47
Warren
B
,
Pankow
JS
,
Matsushita
K
, et al
.
Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study
.
Lancet Diabetes Endocrinol
.
2017
;
5
(
1
):
34
42
48
Schlesinger
S
,
Neuenschwander
M
, %
Barbaresko
J
, et al
.
Prediabetes and risk of mortality, diabetes-related complications and comorbidities: umbrella review of meta-analyses of prospective studies
.
Diabetologia
.
2022
;
65
(
2
):
275
285
49
Rosenzweig
JL
,
Bakris
GL
,
Berglund
LF
, et al
.
Primary prevention of ASCVD and T2DM in patients at metabolic risk: an endocrine society* clinical practice guideline
.
J Clin Endocrinol Metab
.
2019
;
104
(
9
):
3939
3985
50
Gong
Q
,
Zhang
P
,
Wang
J
, et al;
Da Qing Diabetes Prevention Study Group
.
Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study
.
Lancet Diabetes Endocrinol
.
2019
;
7
(
6
):
452
461
51
Nathan
DM
,
Bennett
PH
,
Crandall
JP
, et al;
Research Group
.
Does diabetes prevention translate into reduced long-term vascular complications of diabetes?
Diabetologia
.
2019
;
62
(
8
):
1319
1328
52
Kahleova
H
,
Salas-Salvadó
J
,
Rahelić
D
,
Kendall
CWC
,
Rembert
E
,
Sievenpiper
JL
.
Dietary patterns and cardiometabolic outcomes in diabetes: a summary of systematic reviews and meta-analyses
.
Nutrients
.
2019
;
11
(
9
):
2209
53
Zaccardi
F
,
Khunti
K
,
Marx
N
,
Davies
MJ
.
First-line treatment for type 2 diabetes: is it too early to abandon metformin?
Lancet
.
2020
;
396
(
10264
):
1705
1707
54
Ghouse
J
,
Blanche
P
,
Skov
MW
, et al
.
Early glycaemic changes after initiation of oral antidiabetic medication and risk of major adverse cardiovascular events: results from a large primary care population of patients with type 2 diabetes
.
Eur Heart J Cardiovasc Pharmacother
.
2021
;
7
(
6
):
486
495
55
Taron
J
,
Lyass
A
,
Mahoney
TF
, et al
.
Coronary artery calcium score-directed primary prevention with statins on the basis of the 2018 American College of Cardiology/American Heart Association/Multisociety cholesterol guidelines
.
J Am Heart Assoc
.
2021
;
10
(
1
):
e018342
56
Ben-Shlomo
Y
,
Spears
M
,
Boustred
C
, et al
.
Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects
.
J Am Coll Cardiol
.
2014
;
63
(
7
):
636
646
57
Valencia-Hernández
CA
,
Lindbohm
JV
,
Shipley
MJ
, et al
.
Aortic pulse wave velocity as adjunct risk marker for assessing cardiovascular disease risk: prospective study
.
Hypertension
.
2022
;
79
(
4
):
836
843
58
Dweck
MR
,
Williams
MC
,
Moss
AJ
,
Newby
DE
,
Fayad
ZA
.
Computed tomography and cardiac magnetic resonance in ischemic heart disease
.
J Am Coll Cardiol
.
2016
;
68
(
20
):
2201
2216
59
Valenti
V
,
Ó Hartaigh
B
,
Heo
R
, et al
.
A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9,715 individuals
.
JACC Cardiovasc Imaging
.
2015
;
8
(
8
):
900
909
60
Polak
JF
,
Pencina
MJ
,
Pencina
KM
, %
O’Donnell
CJ
,
Wolf
PA
,
D’Agostino
RB
Sr
.
Carotid-wall intima-media thickness and cardiovascular events
.
N Engl J Med
.
2011
;
365
(
3
):
213
221
61
Dalla Pozza
R
,
Ehringer-Schetitska
D
,
Fritsch
P
,
Jokinen
E
,
Petropoulos
A
, %
Oberhoffer
R
;
Association for European Paediatric Cardiology Working Group Cardiovascular Prevention
.
Intima media thickness measurement in children: a statement from the Association for European Paediatric Cardiology (AEPC) Working Group on Cardiovascular Prevention endorsed by the Association for European Paediatric Cardiology
.
Atherosclerosis
.
2015
;
238
(
2
):
380
387
62
Drole Torkar
A
,
Plesnik
E
,
Groselj
U
, %
Battelino
T
,
Kotnik
P
.
Carotid intima-media thickness in healthy children and adolescents: normative data and systematic literature review
.
Front Cardiovasc Med
.
2020
;
7
(
November
):
597768
63
Meyer
AA
,
Kundt
G
,
Lenschow
U
, %
Schuff-Werner
P
,
Kienast
W
.
Improvement of early vascular changes and cardiovascular risk factors in obese children after a six-month exercise program
.
J Am Coll Cardiol
.
2006
;
48
(
9
):
1865
1870
64
Chiesa
ST
,
Charakida
M
,
Georgiopoulos
G
, et al
.
Determinants of intima-media thickness in the young: the ALSPAC study
.
JACC Cardiovasc Imaging
.
2021
;
14
(
2
):
468
478
65
Parkkila
K
,
Kiviniemi
A
,
Tulppo
M
, %
Perkiömäki
J
,
Kesäniemi
YA
,
Ukkola
O
.
Abdominal aorta plaques are better in predicting future cardiovascular events compared to carotid intima-media thickness: a 20-year prospective study
.
Atherosclerosis
.
2021
;
330
(
February
):
36
42
66
Blaha
MJ
.
The future of CV risk prediction: multisite imaging to predict multiple outcomes
.
JACC Cardiovasc Imaging
.
2014
;
7
(
10
):
1054
1056
67
Kim
H-L
,
Kim
S-H
.
Pulse wave velocity in atherosclerosis
.
Front Cardiovasc Med
.
2019
;
6
(
April
):
41
68
Ohyama
Y
,
Ambale-Venkatesh
B
,
Noda
C
, et al
.
Aortic arch pulse wave velocity assessed by magnetic resonance imaging as a predictor of incident cardiovascular events: the MESA (Multi-Ethnic Study of Atherosclerosis)
.
Hypertension
.
2017
;
70
(
3
):
524
530
69
Voges
I
,
Kees
J
,
Jerosch-Herold
M
, et al
.
Aortic stiffening and its impact on left atrial volumes and function in patients after successful coarctation repair: a multiparametric cardiovascular magnetic resonance study
.
J Cardiovasc Magn Reson
.
2016
;
18
(
1
):
56
70
Vlachopoulos
C
,
Aznaouridis
K
,
Stefanadis
C
.
Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis
.
J Am Coll Cardiol
.
2010
;
55
(
13
):
1318
1327
71
Vermeersch
SJ
,
Dynamics
B
,
Society
L
;
Reference Values for Arterial Stiffness’ Collaboration
.
Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’
.
Eur Heart J
.
2010
;
31
(
19
):
2338
2350
72
Panchangam
C
,
Merrill
ED
,
Raghuveer
G
.
Utility of arterial stiffness assessment in children
.
Cardiol Young
.
2018
;
28
(
3
):
362
376
73
Ververs
FA
,
Eikendal
ALM
,
Kofink
D
, et al
.
Preclinical aortic atherosclerosis in adolescents with chronic disease
.
J Am Heart Assoc
.
2022
;
11
(
14
):
e024675
74
Salvi
P
,
Scalise
F
,
Rovina
M
, et al
.
Noninvasive estimation of aortic stiffness through different approaches
.
Hypertension
.
2019
;
74
(
1
):
117
129
75
Milan
A
,
Zocaro
G
,
Leone
D
, et al
.
Current assessment of pulse wave velocity: comprehensive review of validation studies
.
J Hypertens
.
2019
;
37
(
8
):
1547
1557
76
Alexander
Y
,
Osto
E
,
Schmidt-Trucksäss
A
, et al
.
Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis
.
Cardiovasc Res
.
2021
;
117
(
1
):
29
42
77
Masi
S
,
Rizzoni
D
,
Taddei
S
, et al
.
Assessment and pathophysiology of microvascular disease: recent progress and clinical implications
.
Eur Heart J
.
2021
;
42
(
26
):
2590
2604
78
Donald
AE
,
Charakida
M
,
Falaschetti
E
, et al
.
Determinants of vascular phenotype in a large childhood population: the Avon Longitudinal Study of Parents and Children (ALSPAC)
.
Eur Heart J
.
2010
;
31
(
12
):
1502
1510
79
Flammer
AJ
,
Anderson
T
,
Celermajer
DS
, et al
.
The assessment of endothelial function: from research into clinical practice
.
Circulation
.
2012
;
126
(
6
):
753
767
80
Bruyndonckx
L
,
Radtke
T
,
Eser
P
, et al
.
Methodological considerations and practical recommendations for the application of peripheral arterial tonometry in children and adolescents
.
Int J Cardiol
.
2013
;
168
(
4
):
3183
3190
81
Matsuzawa
Y
,
Kwon
TG
,
Lennon
RJ
, %
Lerman
LO
,
Lerman
A
.
Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis
.
J Am Heart Assoc
.
2015
;
4
(
11
):
1
15
82
Rubinshtein
R
,
Kuvin
JT
,
Soffler
M
, et al
.
Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events
.
Eur Heart J
.
2010
;
31
(
9
):
1142
1148
83
Xu
Y
,
Arora
RC
,
Hiebert
BM
, et al
.
Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis
.
Eur Heart J Cardiovasc Imaging
.
2014
;
15
(
7
):
736
746
84
Young
A
,
Garcia
M
,
Sullivan
SM
, et al
.
Impaired peripheral microvascular function and risk of major adverse cardiovascular events in patients with coronary artery disease
.
Arterioscler Thromb Vasc Biol
.
2021
;
41
(
5
):
1801
1809
85
Spalding
KL
,
Arner
E
,
Westermark
PO
, et al
.
Dynamics of fat cell turnover in humans
.
Nature
.
2008
;
453
(
7196
):
783
787
86
Arner
P
,
Bernard
S
,
Salehpour
M
, et al
.
Dynamics of human adipose lipid turnover in health and metabolic disease
.
Nature
.
2011
;
478
(
7367
):
110
113