key: cord-0912918-2cwkmj18
authors: Khoury, Michael; Kavey, Rae-Ellen W.; Pierre, Julie St.; McCrindle, Brian W.
title: Incorporating Risk Stratification into the Practice of Pediatric Preventive Cardiology
date: 2020-07-14
journal: Can J Cardiol
DOI: 10.1016/j.cjca.2020.06.025
sha: 4e6e5b734e11a645a21dcad3703e58457c9e0237
doc_id: 912918
cord_uid: 2cwkmj18

Atherosclerosis in its earliest stages is associated with the same traditional cardiovascular disease (CVD) risk factors as are associated with manifest CVD events in adulthood. Clustering of risk factors is associated with exponential increases in atherosclerotic burden from a young age. Some medical conditions and risk behaviors occurring in children can either increase the likelihood of higher levels of risk factors (such as chronic kidney disease) or the presence of risk factor clustering (such as obesity and cardiometabolic syndrome), or are associated with acquired coronary artery pathology (such as Kawasaki disease). This creates a milieu for, or increases the impact of, accelerated atherosclerosis that in turn increases the likelihood of premature CVD. This review highlights the importance of considering the total risk factor and risk condition profile of pediatric patients. An algorithm is provided for stratifying patients into high, moderate and at risk categories, and practical examples are provided as to how the evaluation and management of one risk factor or risk condition might need to be intensified in the context of additional risk factors or risk conditions. For example, for treatment of an adolescent with familial hypercholesterolemia, the target low-density lipoprotein cholesterol level might be lowered by the concomitant presence of low high-density lipoprotein cholesterol or elevated lipoprotein(a) levels. As awareness of cardiovascular risk and atherosclerosis in pediatric patients increases, new at risk conditions that warrant consideration are emerging. The identification and management of high risk individuals is an important part of the overall practice of pediatric preventive cardiology.

Atherosclerosis, evident either at autopsy or from vascular assessment, has been well documented in youth. The rate of atherosclerosis accumulation has been shown to be influenced by traditional cardiovascular risk factors (CVRFs) in a manner similar to adults. An early longitudinal study, the Bogalusa Heart Study, showed that the extent of atherosclerosis at autopsy in youth increased geometrically when multiple CVRFs were present ( Figure 1 ). 1, 2 This observation and others highlight the importance of evaluating and addressing the total risk profile from an early age. They also inform an imperative that the management of a particular CVRF should be intensified when other CVRFs are present.

Pediatric patients at high risk for accelerated atherosclerosis are those with extreme levels and/or lifetime exposure to a single CVRF, such as genetic low-density lipoprotein cholesterol (LDL-C) elevation with familial hypercholesterolemia (FH); clustering of CVRFs often driven by risk behaviors and genetic predispositions, such as cardiometabolic syndrome associated with obesity; and risk conditions associated with acquired structural and functional coronary artery abnormalities, such as Kawasaki disease complicated by coronary artery aneurysms. They also include conditions associated with a pathophysiologic milieu that either directly affects the vessels or leads to a clustering of CVRFs for atherosclerosis, such as diabetes mellitus or inflammatory conditions. This review will focus on surveillance, evaluation and management of CVRFs in youth at increased risk for premature cardiovascular disease ( Figure 2 ). More detailed information regarding the evidence-base for each risk factor and condition is provided in 5 a recent American Heart Association (AHA) Scientific Statement -Cardiovascular Risk Reduction in High-Risk Pediatric Patients. 3 

CVRFs, including obesity, dyslipidemia, hypertension, and at-risk behaviors including eating habits, physical inactivity, screen time, and smoking and electronic cigarette use are common in youth (Table 1) . 4 Autopsy studies have demonstrated that the presence and intensity of such CVRFs is associated with atherosclerotic development and burden in childhood and young adulthood. 2, 5 Moreover, modifiable CVRFs such as obesity, dyslipidemia, and hypertension track from childhood to adulthood; for example, an overweight teen has a 75% likelihood of becoming an obese adult. 6 Thus, the timely management of CVRFs in youth has the potential to reduce or delay atherosclerotic cardiovascular disease in adulthood, particularly for youth with conditions predisposing them to increased CV risk. 3 Prospectively evaluating the impact of CVRF management in youth on the occurrence of manifest atherosclerotic cardiovascular disease in adulthood in a randomized controlled manner would be logistically very difficult and likely unethical given the weight of evidence to date. On this basis, the United States Preventive Services Task Force (USPSTF) has indicated that insufficient evidence exists to recommend in favor of or against screening of lipid disorders and blood pressure in youth. 7, 8 Despite this, as outlined below, indirect evidence suggests that the early and effective management of CVRFs can result in improvements in manifest cardiovascular disease in adulthood and non-invasive measures of atherosclerotic burden and vascular dysfunction in youth. For example, 6 early statin initiation in youth with FH has recently been shown to result in significant reductions in cardiovascular disease in adulthood, compared with their FH-affected parents, who had not started statin therapy until adulthood. 9 Obesity is a particularly important CVRF to consider in childhood. Along with insulin resistance, it often provides the metabolic milieu for the development of a specific form of CVRF clustering known as cardiometabolic syndrome. 10, 11 While cardiometabolic syndrome is difficult to diagnose in childhood due in part to natural agerelated fluctuations in body habitus and lipid and blood pressure normative values, 4 the presence of CVRF clustering in youth is associated with endothelial dysfunction 12 and is predictive of future cardiovascular disease in adulthood. 13 Moreover, landmark autopsy studies have demonstrated that increasing CVRF clustering is associated with increased atherosclerotic burden in children and young adults. 2, 14 Since obesity tracks relatively strongly from childhood to adulthood, 15 In the pre-statin era, the median age of first myocardial infarction was significantly earlier in the FH population than the general population, approximately 50 years in males and 60 years in females, 23, 25, 26 with an estimated LDL-C burden in an untreated 35 year-old with FH equivalent to that of a typical 55 year-old. 27, 28 FH serves as a model for not only the impact of severe elevations of isolated CVRFs, but also for the impact of CVRF clustering on youth already at increased risk. For example, a recent systematic review and meta-analysis identified the presence of CVRFs such as hypertension, diabetes mellitus, elevated lipoprotein(a), and smoking as strongly associated with an increased risk of cardiovascular disease events in FH patients. 29 A large pediatric FH study showed that not only were more extreme levels of LDL-C in the affected child associated with more cardiovascular disease events in the family, but that risk of events was further increased if the affected child also had low high-density lipoprotein cholesterol (HDL-C) or high lipoprotein(a). 30 To this end, risk scores to predict cardiovascular disease events in the FH population have been developed, as traditional risk stratifying tools such as the Framingham Risk Score are not applicable to the FH population. 31-33 Fortunately, a number of clinical trials have repeatedly shown that early statin use in the pediatric FH population can slow or even reverse 8 atherosclerotic progression 34-37 and may effectively normalize cardiovascular risk in this high-risk population. 9, 38 Hypertension is another established risk factor for accelerated atherosclerosis.

Pediatric hypertension can either be primary (essential) or secondary to an underlying at-risk disorder. 39 Hypertension in youth is associated with evidence of cardiac (increased left ventricular mass, systolic and diastolic dysfunction) and vascular (endothelial dysfunction, increased vascular stiffness, and increased carotid intima media thickness) target organ damage, that in turn is associated with progression to manifest cardiovascular disease in adulthood. 39, 40 Moreover, blood pressure abnormalities track from childhood to adulthood, 39 

Pediatric medical conditions identified as increased risk are categorized by the underlying disease profile and the degree of associated risk in Table 2 . To demonstrate an approach to evaluation in clinical settings like these in childhood, the factors which confer added risk in two conditions, a medical diagnosis (diabetes mellitus) and a coronary artery diagnosis (Kawasaki disease) are described. In addition to these established diagnoses which are extensively reviewed in the AHA Scientific Statement referenced above, 3 there are other recognized conditions in which evidence of 9 associated accelerated atherosclerosis in childhood or very early adult life is emerging or under-recognized. One of these is the association between psychiatric disorders, specifically major depressive disorders and bipolar disorder, and increased pediatric cardiovascular risk. 50 Another risk condition is cystic fibrosis, and the emerging evidence for accelerated atherosclerosis in that population is described as an introduction to integrating CV risk assessment into management of these complex young patients. Clinicians and researchers must consider the long-term cardiovascular risk implications of various pediatric chronic diseases, as their treatments and long-term prognosis continue to improve. This is particularly important and relevant for youth who have developed the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)associated pediatric inflammatory multisystem syndrome. The long-term vascular implications and similarities to Kawasaki disease, discussed below, remains to be determined. 51

High risk medical diagnosis: Diabetes mellitus -type 1 and type 2. Type 1 diabetes (T1DM) is a condition of absolute, lifelong insulin deficiency caused by T-cellmediated autoimmune destruction of pancreatic β-cells. This predominant form of diabetes mellites diagnosed in childhood and early adolescence leads to chronic, recurrent hyperglycemia even with insulin replacement therapy. Overall, the ageadjusted relative risk for atherosclerotic cardiovascular disease in T1DM is 10 times that of the general population. 52 Subclinical vascular abnormalities are present in T1DM youth, even in the first decade after diagnosis. 3 When T1DM is diagnosed in childhood, cardiovascular disease is the leading cause of death beginning at age 20, at rates >3%/yr. 52 10 Cardiovascular disease in T1DM individuals is the result of an accelerated atherosclerotic process. Hyperglycemia is the primary mediator and intensive glycemic control reduces cardiovascular disease events in adults and improves vascular abnormalities in adolescents. 53, 54 Nephropathy complicates 30% of T1DM cases and accelerates atherosclerosis through chronic inflammation and uremia-related factors. 55 Traditional CVRFs are prevalent with elevated total and LDL-C levels inversely correlated with glycemic control and significantly elevated apolipoprotein B and small, dense LDL particle levels, regardless of glycemic control. 56 Hypertension is also common, found in 6% of T1DM youth. 52 Obesity is increasingly prevalent, present in ~40% of children with T1DM. 52 Risk clustering mediates a profoundly atherogenic state and 14%-45% of children with T1DM have two or more major CVRFs. 52 By contrast with T1DM, type 2 diabetes mellitus (T2DM) is a condition of insulin resistance secondary to excessive weight gain as visceral fat, with the resultant inability of skeletal muscle, liver and fat to respond to normal insulin levels. T2DM is increasingly diagnosed in youth, in parallel with rising obesity rates: >85% of T2DM adolescents are obese. In Canada, T2DM incidence in youth ranges from 1.54 to 12.5/100,000 per year, compared with a mean of 11.8/100,000 per year in American teenagers. 57 There is a strong genetic component: in adolescents who develop T2DM, 45-80% have at least one parent with T2DM. 58 Native American and Canadian indigenous people plus South Asians, Pacific Islanders and Latinos are at increased risk for development of T2DM. 59 In adults, both T1DM and T2DM are powerful predictors of future cardiovascular disease, equivalent to a history of prior coronary events. 60 In youth, T2DM is associated 11 with anatomic and histologic vascular changes at autopsy, structural and functional vascular changes in vivo, and early cardiovascular disease events. 52 Multiple CVRFs accelerate the atherosclerotic process in T2DM youth. Of primary importance is diabetic nephropathy, often present at the time of T2DM diagnosis. 61 Hyperglycemia increases cardiovascular disease risk with an 18% increase in events per 1% increase in hemoglobin A1c in adults. 62 Up to 40% of Canadian and American adolescents with T2DM have elevated triglycerides and low HDL-C, the atherogenic pattern of combined dyslipidemia. 63, 64 Over a four-year follow-up, one-third of T2DM youth in a long-term observational study developed hypertension. 65 The cardiometabolic syndrome cluster of CVRFs described in the previous section is highly prevalent: its detection at a mean age of 12 years is an independent predictor of CV disease before 50 years of age. 13 In adults with diabetes mellitus, CVRF management definitively reduces cardiovascular disease events. An approach to CVRF reduction in youth with high risk conditions (such as T1DM and T2DM) is outlined in Table 3 and in the treatment algorithm ( Figure 2 ), as well as in the current Canadian guidelines. 66 In morbidly obese T2DM adolescents, gastric bypass has been shown to significantly reduce metabolic and cardiac abnormalities. 67 High risk coronary artery condition: Kawasaki disease (KD). This acute, selflimited arteritis of unknown etiology occurs primarily in children <5 years of age. The incidence is highest in the Japanese, Asians and Pacific Islanders. The incidence in Canada and the United States is similar at 25-30 per 100,000 children < 5 years of age per year, compared with >250 per 100,000 in Japan. 68, 69 The acute illness is marked by 12 dramatic inflammation of all medium-sized arteries, multiple organs and tissues leading to a range of striking signs and symptoms. The critical problem is development of coronary artery (CA) aneurysms in 20 to 25% of untreated patients. The incidence of CA involvement is significantly lower at <5% for children treated with intravenous immunoglobulin in the acute stage. 69 The CA pathology involves a 3 stage arteriopathy: (1) acute necrotizing arteritis; followed by (2) chronic inflammation and vasculitis; and (3) luminal myofibroblastic proliferation. 70 Outcomes depend on the severity of CA involvement, which ranges from none to dilation to aneurysms of different sizes and characteristics. Myocardial infarctions occur because of acute thrombosis of aneurysms, or stenoses caused by progressive luminal occlusion from myofibroblastic proliferation. CA aneurysms from KD account for 5% of acute CA syndromes in adults <40 years of age. 69 Children with CA aneurysms require specific long-term thromboprophylaxis beginning in the acute stage when large aneurysms are at highest risk for thrombosis and later with the concomitant development of stenoses. CA thrombosis with actual or impending lumen occlusion is an acute emergency requiring immediate thrombolysis.

With large CA aneurysms, sustained thromboprophylaxis with anticoagulation is recommended; with small CA aneurysms, only a single or dual antiplatelet agent is recommended. Children with no CA involvement are felt to have no ongoing sequelae and are typically discharged from cardiology care. 69 Atherosclerosis is not thought to be part of the specific vasculopathic process associated with KD, but CVRF optimization is recommended empirically in all children who have had CA aneurysms of any size. 3 Statins are being evaluated in acute KD and 13 in children with CA aneurysms in the convalescent stage. With persistent CA aneurysms, statin therapy is recommended for empiric use for its presumed pleotropic effects, specifically its anti-inflammatory properties. 3

At risk condition --emerging evidence: Cystic fibrosis (CF). CF is the most common autosomal recessive disease seen in the Caucasian population. A mutation in the CF transmembrane conductance regulator gene disrupts regulation of chloride and sodium ions across epithelial cell membranes, resulting in buildup of thick mucus throughout the body. Although CF is a multiorgan disease, its effects on the pulmonary system are the leading cause of patient morbidity and mortality. Decreased right ventricular function paralleling the presence of pulmonary hypertension is a wellestablished late complication but with increasing survival, there is emerging concern about cardiovascular disease. 71 Certainly, known CVRFs for accelerated atherosclerosis are common in the CF population, including chronic inflammation, dyslipidemia (primarily low HDL-C) and nephropathy. 72, 73 CF-related diabetes is the most common comorbidity, occurring in ∼20% of adolescents and 40-50% of adults. 74 Although studies of left ventricular function in CF patients have been inconclusive, recent echocardiographic strain analysis revealed significant bi-atrial enlargement, impaired left atrial conduit and reservoir functions and abnormal atrial volume indexes which were significant predictors of mortality. 75 Evaluation of arterial flow-mediated dilation has revealed both microvascular and conduit artery endothelial dysfunction in patients with CF, potentially secondary to oxidative stress. 76 By contrast, coronary angiography performed in preparation for lung transplantation in a small series of middle-aged Canadian CF patients revealed no evidence of luminal narrowing or focal 14 stenosis despite the presence of diabetes in 64% and dyslipidemia in 78% of these patients. 77 Clearly, further prospective evaluation is needed as life expectancy continues to increase for this important group of patients.

The goal for detecting, evaluating and managing high-risk youth is to achieve primordial and primary prevention of cardiovascular disease. To accomplish this, the clinician must ensure that any of the underlying risk conditions (Table 2 ) are optimally managed and that other contributing CVRFs (Table 1) The initial physical examination should be complete and systematic to evaluate both for secondary causes and complications of the CVRFs and conditions in question.

The height, weight, body mass index (BMI), and blood pressure should be measured in a standardized manner and then converted to age-and sex-(for height, weight, and BMI) or age-, sex-, and height-specific normative values (for blood pressure) to allow for appropriate categorization. 4, 39 Waist circumference, particularly when indexed to height (waist-to-height ratio) is a useful additional measure that is more indicative of central adiposity and associated with CVRF clustering. 82 Table 2 . Assessment of all CVRFs allows further stratification: if >2 RFs are identified, the patient is reclassified into the next highest tier (Figure 2 ). Tier-specific goals for CVRFs are indicated in step 3 with defined lower thresholds for initiating pharmacotherapy and more aggressive treatment targets in patients with higher cardiovascular risk categories (Table 3) . Rigorous, age-appropriate education in diet, activity and smoking cessation is indicated for all risk tiers. For high risk children, intensive therapeutic lifestyle change (TLC) like this is combined with condition-specific management, as described below. For children in the moderate risk category, intensive TLC alone is indicated prior to initiating pharmacotherapy for up to six months. Children in at risk categories are managed expectantly with standard guidelines.

For high risk conditions, specific therapy is indicated to achieve blood pressure, LDL-C, glucose and hemoglobin A1c goals. Management of the underlying condition should be optimized in conjunction with the managing pediatric subspecialist. As an example, in patients with T1DM, hyperglycemia should be minimized with frequent glucose checks and assessment of HbA1c and insulin levels per pediatric endocrinology. The management of dyslipidemia and the indications for pharmacotherapy are based on the patient's risk category (Table 3) . 3, 4 In high-risk patients with an LDL-C >3.4 mmol/L, consideration of concurrent statin therapy at the onset of lifestyle changes is warranted. 3 Otherwise, the timing and thresholds for statin initiation depend on the patient's underlying cardiovascular risk categorization ( Table 3 ).

The management of hypertriglyceridemia is typically reserved for those with marked elevations in triglyceride levels in an effort to reduce the risk for pancreatitis. 4 Lifestyle modifications, including reduced intake of simple carbohydrates and added sugars, and increased moderate-vigorous physical activity (>5 hours per week), with weight loss counseling as appropriate, should be undertaken. 3 He has no other health issues, is on no medications or supplements, and his past medical history is unremarkable. Review of systems was remarkable for snoring. His family history is remarkable in that his father is obese, and is on medication for hypertension, dyslipidemia and T2DM, and he had a myocardial infarction at age 43 years. The paternal grand-father had a stroke at age 72 years. The mother is obese and is on medication for T2DM, but her family history is negative for cardiovascular disease.

The patient has a younger brother age 10 years who has a normal BMI, and is described as healthy and very active. The family history thus demonstrates the presence of premature cardiovascular disease on the paternal side and CVRFs on both the paternal and maternal side. Physical examination showed his height to be at the 50 th percentile, weight above the 95 th percentile, with BMI above 120% of the 95 th percentile. 84 His waist-to-height ratio was 0.65 (elevated). His blood pressure by auscultation was 142/94 mmHg, confirmed on repeated assessments. Acanthosis At first glance, this patient has several CVRF likely related to his severe obesity.

He likely has at least stage 1 hypertension, a significant combined dyslipidemia, a positive family history for premature cardiovascular disease, and is at risk for the development of T2DM, non-alcoholic fatty liver disease, and obstructive sleep apnea.

Given that his hypertension is likely related to his obesity, a limited evaluation for secondary causes was performed and was negative. Ambulatory blood pressure monitoring confirmed a diagnosis of sustained hypertension, showing mean day-and night-time systolic and diastolic blood pressures above the 95 th percentile, the majority of measures above the 95 th percentile, and abnormal nighttime dipping (percentage 20 drop from the mean daytime to mean nighttime levels. Less than 10% is considered abnormal and indicates abnormal circadian variation in blood pressure 85 ). An echocardiogram showed normal anatomy and ventricular function, but evidence of increased left ventricular mass secondary to his obesity and hypertension. A sleep study showed evidence of obstructive sleep apnea. A repeat fasting lipid profile showed similar findings to the values from referral, and it was felt that while his combined dyslipidemia was primarily related to his obesity, given the higher than expected LDL-C, there was likely also a familial component. His fasting glucose and hemoglobin A1c levels were borderline high, so an oral glucose tolerance test was performed which suggested insulin resistance but not T2DM. A liver ultrasound confirmed the presence of non-alcoholic steatohepatitis. Hence, the evaluation confirmed the presence of multiple CVRFs in the context of a positive family history. While severe obesity placed the patient at baseline in a moderate risk category (Table 2) , the presence of multiple CVRFs escalated his risk status to high risk ( Figure 2, Step 2).

Decision-making regarding coordinated management of his multiple CVRFs started with an aggressive focus on improving his risk behaviors. He was referred to an exercise medicine program for evaluation and implementation of exercise prescription with targets of achieving an accumulation of 60 minutes of moderate-vigorous physical activity per day, while cutting screen time to no more than an hour per day (Figure 2, Step 4). Working with them, he developed a planned exercise program: 30 minutes per day after school using an exercise bike already in the home, walking the family dog for 15-20 minutes each day, walking to school, and using an exercise app each day for 15 minutes with body-weight strength-training exercises. His mother agreed to participate 21 with him and to encourage him. A dietician worked with the family to eliminate sugarsweetened beverages and limit junk food and eating out to no more than once a week, and to emphasize selection of healthier food choices in every setting. He was to limit his intake of refined carbohydrates (white bread was his preferred snack food) and to increase his intake of vegetables. He would start preparing a healthier lunch to take to school, rather than his preferred lunch of cafeteria French fries.

Given that he had evidence of target organ damage secondary to hypertension, a decision was made to start him on an ACEi, and he achieved target blood pressure control, with improvements noted in subsequent ambulatory blood pressure monitoring From the Bogalusa Heart Study of cardiovascular risk factors measured in youth and autopsy assessment of the extent of atherosclerosis. Values shown are the percentages of the intimal surface covered with lesions in subjects with 0, 1, 2, and 3 or 4 risk factors. Risk factors were elevated values for body-mass index, systolic blood pressure, and serum triglyceride and LDL cholesterol concentrations, defined as values above the 75 th percentile for the study group (specific for study period, race, sex, and age). 

Relation of serum lipoprotein levels and systolic blood pressure to early atherosclerosis. The Bogalusa Heart Study

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

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Cardiovascular risk factors and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study

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

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Defined as a parent, grandparent, aunt/uncle, or sibling with myocardial infarction, angina, stroke, coronary artery bypass graft/stent/angioplasty at <55 years in men and <65 years in women

HbA1C >7% in patients with diabetes mellitus CV: cardiovascular; CAD: coronary artery disease; BMI: body mass index; BP: blood pressure; LDL-C: low-density lipoprotein cholesterol; FG: fasting glucose

Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the

Step 4.

Step 5.

If goals not met, consider medication - Table 3