Pediatric Preventive Cardiovascular Disease

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Background

Cardiovascular disease (CVD) is the leading cause of death in the US. In children, interventions are available to prevent risk factors (primordial prevention), identify and treat risk factors in childhood (primary prevention), and to address the risk of additional events in those who already have coronary artery disease (secondary prevention).

The AHA’s scientific statement on Cardiovascular Risk Reduction in High-Risk Pediatric Patients was updated in 2019, and offers a wealth of guidance for us on this topic.

CVD Risk Factors

CVD risk factors can be broadly categorized into 4 categories (examples included, but not an exhaustive list by any means):

  1. Traditional CVD risk factors: familial hypercholesterolemia (FH), HTN, HLD from non-genetic causes, T2DM, obesity, tobacco exposure
  2. Structural heart disease and congenital coronary pathology: congenital heart disease (repaired and unrepaired), anomalous origin of coronary artery
  3. Acquired coronary pathology: Kawasaki disease, heart transplant
  4. Chronic medical conditions that accelerate CVD risk: HIV, T1DM, renal disease, cancer and its treatment, systemic inflammatory disorders

The AHA delineates many of these issues in terms of risk severity:

  • High risk: homozygous familial hypercholesterolemia (FH), T2DM, T1DM, ESRD, Kawasaki disease with persistent aneurysms, solid-organ transplant vasculopathy, childhood cancer survivor (stem cell recipient)
  • Moderate risk: severe obesity (BMI ≥120% of the 95th percentile or absolute BMI ≥35), heterozygous FH, confirmed HTN, coarctation, Lp(a), predialysis CKD, aortic stenosis, childhood cancer survivor (chest radiation)
  • At risk: obesity, insulin resistance with comorbidities (dyslipidemia, NAFLD, PCOS), white-coat HTN, HCM and other cardiomyopathies, pulmonary hypertension, chronic inflammatory conditions (JIA, SLE, IBD, HIV), s/p coronary artery translocation for anomalous coronary arteries or TGA, childhood cancer (cardiotoxic chemotherapy only), Kawasaki disease with regressed aneurysms (max z score ≥5)

Following risk stratification by disease process, additional CVD risk factors should be evaluated in all patients (noting specific cut points and treatment goals for certain parameters):

  • Family history of early CAD in expanded 1st-degree pedigree (men ≤55yo, women ≤65yo)
  • Physical activity history
  • Smoking history
  • BP (3 separate occasions), interpreted for age/sex/height
    • Treatment goals: ≤90th percentile for age/sex or 120/70 (whichever is lower) for all risk stratification categories
  • BMI
    • Treatment goals: ≤85th percentile for age/sex if high risk; ≤90th if moderate risk; ≤95th if at risk
  • Fasting glucose
    • Treatment goals: <100 mg/dL (or A1c <7%) for all risk stratification categories
  • Fasting lipid profile
    • Treatment goals: ≤100 mg/dL if high risk; ≤130 if moderate risk; ≤160 if at risk

Next we’ll focus on a few specific CVD risk factors.

Obesity

As a CVD risk factor, the AHA categorizes obesity based on its severity, distinguishing between severe obesity (BMI ≥120% of the 95th percentile or absolute BMI ≥35) and obesity, which are categorized as moderate risk and at risk, respectively.

USPSTF and the AAP recommend screening for obesity on an annual basis, although they disagree on when to initiate screening: ≥6yo per USPSTF and ≥2yo per AAP’s Bright Futures.

Additional points from the AHA guideline:

  • Obesity has been shown to be a prominent correlate of aortic and coronary fatty streaks or other atherosclerotic lesions (see McGill et al 2000, Berenson et al 2001)
  • Youth with severe obesity (BMI ≥120% of the 95th percentile or absolute BMI ≥35) are generally viewed as being at the highest level of risk because of the high number and magnitude of CVD risk factors, the presence of endothelial activation and subclinical atherosclerosis (see Kelly et al 2010, Shah et al 2015, Urbina et al 2009), and the strong tracking of adiposity from childhood into adulthood (see Freedman et al 2007)
  • The magnitude of weight loss necessary to elicit meaningful improvements in CVD risk factors among youth with obesity has not been fully determined; a BMI reduction of 5% to 10% or 0.25 to 0.5 in BMI standard deviation score could be required (see Abrams et al 2013, de Ferranti et al 2015, Reinehr et al 2016)
  • Therapeutic lifestyle change modification therapy, including counseling on diet and physical activity, is the cornerstone of pediatric obesity treatment; however, its effectiveness is limited in severe obesity because of small effect size and difficulty with sustainability (see Danielsson et al 2012, Kalarchian et al 2009)

More broadly, obesity is an incredibly complex topic, for which the AAP released its first clinical practice guideline in 2023.

Hypertension

The AHA categorizes confirmed HTN as a moderate risk factor for CVD.

In children, USPSTF and the AAP differ on screening recommendations. As of 2020, USPSTF says that the current evidence is insufficient to assess the balance of benefits and harms of screening for high BP in children and adolescents. In contrast, AAP’s Bright Futures recommends annual BP measurement starting at 3yo in all children (in keeping with the AAP’s 2017 clinical practice guideline on the topic), but to perform risk assessment at all prior preventive care visits starting at the newborn visit. Risk assessment implies that BP measurement should occur in infants and children with specific risk conditions at visits before age 3 years:

  • History of prematurity <32 week’s gestation or small for gestational age, very low birth weight, other neonatal complications requiring intensive care, umbilical artery line
  • Congenital heart disease (repaired or unrepaired)
  • Recurrent UTIs, hematuria, or proteinuria
  • Known renal disease or urologic malformations
  • Family history of congenital renal disease
  • Solid-organ transplant
  • Malignancy or bone marrow transplant
  • Treatment with drugs known to raise BP
  • Other systemic illnesses associated with HTN (neurofibromatosis, tuberous sclerosis, sickle cell disease, etc)
  • Evidence of elevated intracranial pressure

HTN can be primary (aka essential) or secondary, although guidance for investigating the latter is a point of contrast in pediatric and adult guidelines. For instance, per the AAP’s clinical practice guideline, “Primary HTN is now the predominant diagnosis for hypertensive children and adolescents seen in referral centers in the United States.” The guideline also notes the following recommendation (evidence quality C, moderate strength): “Children and adolescents ≥6 years of age do not require an extensive evaluation for secondary causes of HTN if they have a positive family history of HTN, are overweight or obese, and/or do not have history or physical examination findings suggestive of a secondary cause of HTN.” Somewhat in contrast, the AHA’s adult guideline states, “Although secondary hypertension should be suspected in younger patients (<30 years of age) with elevated BP, it is not uncommon for primary hypertension to manifest at a younger age, especially in blacks, and some forms of secondary hypertension, such as renovascular disease, are more common at older age.”

Additional points from the AHA pediatric guideline:

  • Two longitudinal cohort studies demonstrated that elevated blood pressure in childhood predicts increased central large artery stiffness in adulthood, denoting a worsening of arterial function (see Juonala et al 2005, Pletcher et al 2010)
  • Another demonstrated that elevated blood pressure predicts worse cIMT, itself a summary structural marker of accumulated arterial insults (see Raitakari et al 2003)
  • Data from >1 million people (mostly males) entering mandatory military service at a mean age of 18 years in Sweden demonstrated a similar continuous relationship between young adult blood pressure and CVD mortality over the rest of the life course (see Sundstrom et al 2011)
  • Both therapeutic lifestyle change modification and pharmacotherapy aim to lower blood pressure to below 90% of the age-sex-height–referenced norm or <130/80 mm Hg, whichever is lower.
  • Therapeutic lifestyle change modification counseling to improve both diet and physical activity should always be offered and likely provides other preventive benefits in addition to blood pressure lowering (see Flynn et al 2017, Saneei et al 2013)

Diabetes

The AHA categorizes T2DM and T1DM as high risk for CVD.

Screening recommendations for T2DM differ among societies, but it’s important to read the fine print:

  • USPSTF: In asymptomatic children and adolescents younger than 18 years, “the USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in children and adolescents.”
  • ADA: “Risk-based screening for prediabetes and/or type 2 diabetes should be considered after the onset of puberty or ≥10 years of age, whichever occurs earlier, in youth with overweight (BMI ≥85th percentile) or obesity (BMI ≥95th percentile) and who have one or more additional risk factors for diabetes.”
    • Risk factors for diabetes: maternal history of diabetes or GDM during the child’s gestation; family history of T2DM in first- or second-degree relative; race and ethnicity (e.g., Native American, African American, Latino, Asian American, Pacific Islander); signs of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, HTN, dyslipidemia, PCOS, or small-for-gestational-age birth weight)

Additional points from the AHA guideline:

  • Once diagnosed, youth with diabetes mellitus should be screened yearly for additional CVD risk factors (see Maahs et al 2014) because of their high prevalence in both types of diabetes mellitus, especially in the presence of obesity (see Kimball et al 1994) or insulin resistance (see Levitt Katz et al 2015)
  • Reducing cardiovascular risk in youth with diabetes mellitus should take a 2- pronged approach, both optimizing glycemic control and reducing additional CVD risk.
  • Unfortunately, as many as half of all children with T2DM are not adequately treated with a single agent, a rate higher than that observed in adults, as shown in the TODAY study (see TODAY Study Group 2012)
  • The TODAY 2 study (Treatment Options for Type 2 Diabetes in Adolescents and Youth Phase II Study) found only 55.9% of youth with T2DM were treated to an ideal LDL level (see TODAY Study Group 2013)

Dyslipidemia

Dyslipidemia is a broad term encompassing a range of lipoprotein disorders involving abnormal cholesterol levels.

AAP’s Bright Futures recommends cholesterol screening in all patients aged 9-11 years and again at 17-21 years of age. (The reason 12-16 years of age is missing here is because cholesterol levels actually drop during puberty!) Interestingly, recent evidence from Nuotio et al 2024 (and its accompanying editorial) calls into question the value of universal lipid screening in adolescents, finding that the addition of lipids (total cholesterol and triglycerides) to a nonlaboratory model (age, sex, BP, BMI, and smoking) did not improve discrimination in predicting CV events.

Additionally, the AAP recommends we perform risk assessment at preventive care visits starting at age 2 years, primarily to target children at risk for FH.

Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a group of genetic defects resulting in severe hypercholesterolemia, leading to increased risk of premature CAD.

FH has 2 forms: heterozygous (inherited from one parent; incidence of 1 in 300-500) and homozygous (inherited from both parents; incidence 1 in 1,000,000). Total cholesterol concentrations are typically in the range of 350-550 mg/dL in heterozygous FH patients and 650-1000 mg/dL in homozygous FH patients.

Unfortunately, FH is both underdiagnosed and undertreated, particularly among children. Heterozygous FH should be considered in the presence of an LDL level ≥160 mg/dL associated with a family history of elevated LDL or premature CVD in first- or second-degree relatives. Homozygous FH should be considered in the presence of an LDL level >400 mg/dL and one or both parents having clinically diagnosed FH, xanthomata in childhood, supravalvar aortic stenosis, or positive genetic testing for an LDL-raising genetic mutation.

Lipoprotein (a)

Lp(a) is an LDL-like particle containing apolipoprotein that promotes inflammation and atherosclerosis by multiple mechanisms. It is a causal and independent risk factor for CVD in adults, but also highly heritable and becomes stable within the first 2 years of life.

There is no uniform recommendation on Lp(a) screening:

Blog post based on Med-Peds Forum talk by Athena Manatis-Lornell, PGY2, and Anu Goel, PGY4

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