Published online before print November 27, 2006, doi: 10.1161/CIRCULATIONAHA.106.179568
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(Circulation. 2006;114:2710-2738.)
© 2006 American Heart Association, Inc.
AHA Scientific Statements |
Cardiovascular Risk Reduction in High-Risk Pediatric Patients
A Scientific Statement From the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: Endorsed by the American Academy of Pediatrics
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Abstract |
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Abstract
IntroductionAlthough for most children the process of atherosclerosis is subclinical, dramatically accelerated atherosclerosis occurs in some pediatric disease states, with clinical coronary events occurring in childhood and very early adult life. As with most scientific statements about children and the future risk for cardiovascular disease, there are no randomized trials documenting the effects of risk reduction on hard clinical outcomes. A growing body of literature, however, identifies the importance of premature cardiovascular disease in the course of certain pediatric diagnoses and addresses the response to risk factor reduction. For this scientific statement, a panel of experts reviewed what is known about very premature cardiovascular disease in 8 high-risk pediatric diagnoses and, from the science base, developed practical recommendations for management of cardiovascular risk.
Key Words: AHA Scientific Statements • atherosclerosis • cardiovascular diseases • risk factors • prevention • pediatrics
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Introduction |
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The atherosclerotic process begins in childhood, with progression clearly shown to be mediated by the presence of identified risk factors. Pathological studies in children and young adults demonstrate that the extent of atherosclerotic vascular change is associated with both the number of premortem risk factors and their intensity.1–6 In vivo noninvasive studies relate each of the known risk factors measured in childhood to abnormalities of vascular structure and function.7–19 Finally, a decrease in number or intensity of risk factors is associated with improvement in the vascular abnormalities.20–24
For most children, the degree of vascular involvement is minor, the rate of progression is slow, and the appropriate therapeutic approach is preventive, with an emphasis on healthy lifestyles and behavior modification.25,26 By contrast, certain pediatric disease states are associated with dramatically accelerated atherosclerosis, with clinical coronary events occurring in childhood or very early in adult life. A classic example is homozygous hypercholesterolemia, in which markedly elevated low-density lipoprotein (LDL) cholesterol levels are associated with coronary disease in the first decade of life.27 Another is Kawasaki disease, in which coronary pathology developed as part of the acute disease process predisposes patients to very early coronary events.28 For children with diagnoses like these, intensive cardiovascular risk reduction is of critical importance. However, awareness of the risk for premature atherosclerosis is often limited when the main focus of medical care is the complex primary diagnosis. The goal of this statement is to summarize the evidence for accelerated atherosclerosis in high-risk pediatric settings and to present guidelines for cardiovascular risk management. The recommendations are directed toward both the pediatric care providers and the subspecialists who manage the primary disease process in these complex young patients.
The statement was developed by a writing group convened under the joint direction of the American Heart Association’s Expert Panel on Population and Prevention Science and the Council for Cardiovascular Disease in the Young, cosponsored by the Councils on Epidemiology and Prevention, Nutrition, Physical Activity, and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Cardiovascular Disease and by the Quality of Care and Outcomes Research Working Group. Members were nominated by 
1 of these scientific councils and are each recognized experts in premature atherosclerosis beginning in childhood. The group selected 8 pediatric disease settings for inclusion: (1) familial hypercholesterolemia; (2) diabetes mellitus, type 1 and type 2; (3) chronic kidney disease; (4) heart transplantation; (5) Kawasaki disease; (6) congenital heart disease; (7) chronic inflammatory disease; and (8) childhood cancer. For each, the evidence for early coronary disease was reviewed by an expert in the area. On the basis of the risk of manifest coronary disease in childhood and very early adult life, a stratification protocol was established, and each disease was classified as follows (Table 1):
- Tier I: Pathological and/or clinical evidence for manifest coronary disease before 30 years of age
- Tier II: Pathophysiological evidence for arterial dysfunction indicative of accelerated atherosclerosis before 30 years of age
- Tier III: Increased cardiovascular risk factors with epidemiological evidence for manifest coronary disease with or without arterial dysfunction early in adult life but after 30 years of age
- Tier II: Pathophysiological evidence for arterial dysfunction indicative of accelerated atherosclerosis before 30 years of age
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Recommendations for cardiovascular risk identification and reduction specific to each disease setting were developed as a consensus of the group, and an algorithm was developed outlining the risk factor evaluation and management strategy by disease tier (Figure). As in current risk-reduction recommendations for adults and for children with type 1 diabetes, critical levels for intervention and goals for risk reduction have been tailored to the risk intensity (Table 2).29,30 For children with diagnoses in tier I, complete risk factor assessment is recommended, and therapy is instituted essentially at the time of diagnosis, aimed at maximally decreasing risk factor levels; the intervention strategy for tier I patients regards the diagnosis as a "coronary heart disease equivalent," with recommendations similar to the secondary prevention guidelines for adults with established coronary disease (Table 3). For children in tier II, complete assessment of all risk factors is recommended, with defined therapeutic goals. For children in tier III, complete risk factor assessment is recommended, with therapeutic goals as recommended for children in general.
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In this era of evidence-based medicine, most scientific statements require positive results from multiple randomized trials to recommend any intervention. To date, no randomized trials beginning in childhood have demonstrated an improvement in hard clinical cardiac end points in response to risk factor reduction; given the major cost and time limitations, the potential for such trials in the near future seems low. There is, however, a large and growing knowledge base in pediatric populations with regard to the presence of accelerated atherosclerosis, the relationship of the atherosclerotic process to the presence and intensity of risk factors, and the response to risk factor change at the vascular level. The present scientific statement is not intended to preclude or inhibit the design and execution of future randomized treatment trials. Rather, we hope to assist physicians in learning what is already known about increased risk for premature atherosclerosis in children with these diagnoses, as well as the range of approaches to risk assessment and treatment. Until evidence-based data are available, the present statement provides practical interim recommendations based on a consensus of the group after a careful review of the available science for each diagnosis, including all published guidelines. Typical statements about level of evidence and the strength of each recommendation are not included. For easy access, references for each section of the report are grouped together.
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Familial Hypercholesterolemia |
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Introduction
Aggressive management of hyperlipidemia in adults, particularly directed toward lowering LDL cholesterol levels, has led to major reductions in cardiovascular morbidity and mortality. In children and adolescents, hyperlipidemia may be secondary to associated conditions such as medications or obesity, but extreme LDL elevations are more commonly associated with primary or genetic hyperlipidemias.47 Both types of lipid abnormalities have been shown to be associated with vascular pathology in youth: a greater extent of vascular involvement, with fatty streaks and fibrous plaques at autopsy; higher presence of coronary artery calcium by electron-beam computed tomography; and increased carotid intima-media thickness, reduced arterial distensibility and compliance, and endothelial dysfunction by ultrasound.7,48,49 Increasing evidence indicates that appropriate therapy can reverse these changes.20,21 Of the primary hyperlipidemias, familial hypercholesterolemia (FH) is the most common and the most clearly documented to have important cardiovascular consequences beginning in childhood.49–52 Therefore, the identification and management of FH in children is of great consequence.53
Pathophysiology
FH is an autosomal dominant monogenetic condition. Homozygous hypercholesterolemia is rare, with an occurrence of 1:1 000 000 individuals, but the heterozygous state exists in the general population with an incidence of 1:500. It is the most common monogenetic disorder in North America and Europe. Certain populations have a higher frequency and greater concentrations of specific mutations.
The genetic defect is characterized by various mutations that affect the production and processing of cell-surface LDL receptors.54–56 Defectiveness or deficiency of these receptors results in impaired hepatic clearance of circulating LDL particles, which leads to their accumulation in the bloodstream. A similar phenotype can be produced by mutations in the receptor that recognizes apolipoprotein B100 protein on the surface of LDL particles, known as familial defective apolipoprotein B100.57,58
The elevated levels of LDL contribute to accelerated atherosclerosis, with manifest cardiovascular disease within the first 2 decades of life for homozygotes59 and beginning in early to mid-adulthood for heterozygotes.60 Elevated LDL levels are evident before birth61 and persist throughout the lifespan.
Homozygous FH can be distinguished from heterozygous FH clinically by the much more extreme elevations in LDL and can be confirmed by either genetic characterization of the LDL receptor mutations (from leukocytes) or by quantification of LDL receptor activity (from skin fibroblasts). Children with homozygous FH have more severe and earlier functional and structural vascular abnormalities, including clinical coronary artery disease (CAD), aortic valve disease, and aortic disease, beginning in the first decade of life.59
Children with heterozygous FH have been shown to have abnormalities on noninvasive vascular assessments, including greater carotid-intima media thickness and abnormal arterial endothelial function.11,13,49,62–64 Effective lipid-lowering therapy has been shown to improve these abnormalities.20,21
Identification
Children with homozygous FH usually present within the first decade of life, most commonly after investigation of physical findings related to cholesterol deposition, such as tendon xanthomata, cutaneous xanthelasma, or corneal arcus, or with clinical manifestations of atherosclerotic cardiovascular disease.59 Children and adolescents with heterozygous FH are asymptomatic, with no findings on physical examination related to their hypercholesterolemia.65 Often, they present with either elevated LDL levels noted on blood screening or after investigation prompted by a family history of premature cardiovascular disease or hyperlipidemia.
The lipid profile abnormalities are strikingly abnormal in homozygous patients. Although LDL levels vary between individuals, they are often in the 15- to 25-mmol/L (500- to 1000-mg/dL) range, with high-density lipoprotein (HDL) levels reduced between 0.5 and 1.0 mmol/L (20 to 40 mg/dL). Both parents will have lipoprotein profiles consistent with heterozygous FH. Although not necessary for clinical management, determination of an LDL receptor mutation on skin biopsy or leukocyte culture confirms the diagnosis.
In heterozygous FH, fasting lipoprotein profile characteristics include LDL levels well above the 95th percentile for age and gender, often associated with low HDL and normal triglyceride levels. Additional criteria include the presence of a parent with a similar profile in a family with a history of premature cardiovascular disease in conjunction with tendon xanthomata.66 Determination of an LDL receptor mutation is not routinely performed.
A Dutch study of 1034 children with heterozygous FH showed that an LDL level >3.5 mmol/L (135 mg/dL) had a 98% posttest probability of the presence of an LDL receptor mutation.65 Mean LDL levels were 5.8 mmol/L (225 mg/dL) for girls and 5.42 mmol/L (210 mg/dL) for boys. A positive family history of premature cardiovascular disease in a first-degree relative was present for 31% of children. Children of a parent with FH and premature cardiovascular disease had higher LDL, lower HDL, and higher lipoprotein(a) levels. Children with lower HDL levels were heavier and had higher triglyceride levels. LDL levels appeared to be independent of lifestyle or anthropometric characteristics.
Risk Factors/Comorbidities
A study of 2400 heterozygous FH Dutch adults showed that during 112 943 person-years of follow-up, 33% had at least 1 atherosclerotic cardiovascular event, predominantly clinical CAD.66 Male gender, smoking, hypertension, diabetes mellitus, low HDL, and elevated lipoprotein(a) levels were shown to independently contribute to the development of cardiovascular disease.
Treatment Recommendations for Children With FH
Children With Homozygous FH Who Are at High Risk for Very Early Cardiovascular Disease (Tier I)
- Complete cardiovascular assessment is necessary at diagnosis, because important subclinical cardiovascular disease requiring intervention may already be present.59
- Treatment should be instituted as soon as possible.41,67,68 The cornerstone of therapy in the majority of patients is weekly or biweekly plasmapheresis, preferably LDL apheresis.67,69 Although the majority of lipid-lowering drugs lower LDL primarily by feedback mechanisms that upregulate LDL receptor activity, patients with homozygous FH may still benefit.68,70 Use of high-dose statins is therefore recommended, in combination with a cholesterol absorption inhibitor.
- Low-dose anticoagulation may also be indicated. Ongoing surveillance for cardiovascular disease is essential.
- The presence of homozygous FH mandates intensive therapy aimed at reducing LDL levels. Interventions to prevent or reduce associated risk factors are important, but the critical therapy is lipid lowering.
Children With Heterozygous FH Who Are at Moderate Risk for Premature Cardiovascular Disease (Tier II)
- Routine cardiovascular assessment is not generally indicated, although referral to a lipid specialist is recommended.
- The presence of heterozygous FH merits therapy focused primarily at reducing LDL levels.71,72 Lifestyle interventions are important to prevent or reduce associated risk factors but are insufficient for lipid lowering.73–76
- There is uniform consensus that lipid-lowering drug therapy is the cornerstone of management in adults, but considerable controversy exists over when to initiate pharmacological treatment in children.77 Randomized clinical trial results indicating a decline in future atherosclerotic disease in response to lipid-lowering therapy begun in childhood are not available. However, extrapolation from adult studies suggests that lipid-lowering therapy should be considered when LDL cholesterol levels are severely elevated. The only existing guideline, from 1991, recommends consideration of drug therapy after 10 years of age in children with specific LDL cutpoints.36 We are in general agreement with this recommendation, but we also recommend tailoring therapy to each child, considering actual LDL levels, sex, presence of other risk factors, and important family history of premature disease. The wishes of the family with regard to drug therapy also need to be taken into account. Thus, there is room for discretion and clinical judgment.
- When the decision is made to begin drug treatment, initial therapy with a statin is recommended, because bile-acid binding resins78–81 and cholesterol absorption inhibitors (not yet studied in children) are usually inadequate alone to achieve sufficient LDL reduction.52,82 Several recent studies of statins in children have shown similar safety and efficacy as in adults.21,83–87
- Statin therapy is recommended at age 10 years in males and after the onset of menses in females.77 In selected patients with extremely high LDL levels, associated lipid abnormalities or other risk factors, or the presence of a particularly worrisome family history, statin therapy may be initiated at a younger age. Appropriate safety monitoring and surveillance of growth and development is recommended.77 The use of bile-acid binding resins and the cholesterol absorption inhibitors should be considered important adjunctive therapy in combination with a statin.
- Some evidence suggests that consumption of plant sterol esters may be a useful adjunct to therapy.88–91 Other therapies, such as antioxidant vitamins92,93 and docosahexanoic acid,94 are more controversial, and some other complementary therapies have been shown to have no therapeutic effect.95
- Identification and treatment of comorbidities have been shown to be effective. Specific management is outlined in the algorithm shown in the Figure and in Tables 2 and 3
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Diabetes Mellitus |
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Introduction
Diabetes mellitus, a metabolic disease characterized by hyperglycemia that results from defects in insulin secretion (type 1) and insulin action (type 2), is associated with accelerated development of vascular disease. Diabetic vascular disease in children and adolescents with type 1 diabetes mellitus is represented mainly by microangiopathy that involves the eye and kidney. In adults with diabetes, microangiopathy persists and is responsible for the high incidence of renal failure; however, a major cause of morbidity and early mortality is macroangiopathy, characterized by clinical cardiovascular, cerebrovascular, and peripheral vascular disease.96–98
Because insulin is the only significant hypoglycemic hormone, hyperglycemia is the result of impaired secretion of insulin; resistance to the effect of insulin in liver, muscle, and fat cells; or a combination of these pathophysiological situations. Insulin resistance is very frequently seen in association with obesity, particularly abdominal obesity.
The most recent criteria for diagnosis of diabetes recommended by the American Diabetes Association are as follows99:
- Symptoms of diabetes (polyuria, polydipsia, or unexplained weight loss) plus casual plasma glucose concentration 200 mg/dL (11.1 mmol/L). ("Casual" means any time of day, without regard to time since last meal.) OR
- Fasting plasma glucose concentration 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours. OR
- Two-hour plasma glucose concentration 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test. The test should be performed as described by the World Health Organization with a glucose load that contains the equivalent of 75 g of anhydrous glucose dissolved in water.
- Current American Diabetes Association guidelines recommend 100 mg/dL as the upper limit of normal for fasting glucose in adults.
- In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. An oral glucose tolerance test is not recommended for routine clinical testing.
The progression from insulin resistance and impaired carbohydrate metabolism to type 2 diabetes mellitus has been documented in adults100,101 and children.102,103 In adults, weight loss has been shown to reverse this, with frank diabetes regressing to insulin resistance.104 Patients with impaired fasting glucose and/or impaired glucose tolerance are referred to as "prediabetic," which acknowledges the relatively high risk for development of frank diabetes.105 With the current obesity epidemic and its metabolic consequences, the identification of children with early prediabetes is very important, because appropriate management may decrease the progression to overt diabetes. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus defines impaired fasting glucose as >100 mg/dL (5.6 mmol/L) but <126 mg/dL (7.0 mmol/L) and impaired glucose tolerance as 2-hour oral glucose tolerance test values >140 mg/dL (7.8 mmol/L).99,106 Specific guidelines have been defined for screening for type 2 diabetes mellitus in obese children, particularly those from high-risk racial/ethnic groups (Native American, Hispanic-American, black, Asian, and Pacific Islander), those with a positive family history of type 2 diabetes mellitus, and those with physical signs of insulin resistance.37
Epidemiology: Type 1 Diabetes Mellitus
Epidemiological data from the Third National Health and Nutrition Examination Survey (NHANES III) reveal that the prevalence of type 1 diabetes mellitus in adolescents is 1.7/1000. Although limited, data show a significant increase in atherosclerosis in adolescents and young adults with diabetes relative to nondiabetics.107–109
Adolescents with type 1 diabetes mellitus have increased levels of subclinical atherosclerosis as measured by carotid intima-media thickness and by radial tonometry.110–112 In children, type 1 diabetes mellitus is independently associated with oxidative modification of LDL cholesterol.113
Pathogenesis of Premature Atherosclerosis: Type 1 Diabetes Mellitus
Hyperglycemia is the primary mediator of atherosclerosis in type 1 diabetes mellitus; insulin therapy to control this should be under the direction of endocrinology specialists. Hyperglycemia causes raised levels of atherogenic, cholesterol-enriched, apolipoprotein B–containing remnant particles by reducing the expression of heparin sulfate.114
Autopsy studies in young adults with fatal myocardial infarction and type 1 diabetes mellitus showed that the atherosclerotic plaque in these patients was more dense in fibrous tissue than the more calcific plaques of nondiabetic individuals; this may influence the timing and severity of clinical disease in these patients.115 In addition, microalbuminuria is a predictor of increased risk for vascular complications.116
In defining risk for adults, the presence of type 1 diabetes mellitus is considered the equivalent of a history of coronary disease.98 The intensity of lipid-lowering therapy is correspondingly increased in this setting.
Epidemiology: Type 2 Diabetes Mellitus
In 2003, the US Centers for Disease Control and Prevention reported that 40% (5.2 million) of all diabetic individuals >35 years of age had been diagnosed with cardiovascular disease. Although it was previously considered a disease of adults, in the past decade, type 2 diabetes mellitus has become a far more common occurrence in the pediatric population. Depending on the ethnic composition of the population, between 8% and 50% of newly diagnosed adolescent diabetic patients have type 2 diabetes mellitus.117,118 Data from NHANES III reveal that the prevalence of type 2 diabetes mellitus in adolescents is 4.1/1000. These increases coincide with increasing rates of overweight and physical inactivity in children.119
Because type 2 diabetes mellitus is a relatively recent problem in adolescents, few long-term follow-up data exist. One study of Pima Indians followed a cohort of 36 individuals for a mean of 10 years to a median age of 26 years. At baseline (age 5 to 19 years), 85% were obese, and 14% had hypertension, whereas 30% had total cholesterol >200 mg/dL, and 55% had triglyceride concentrations >200 mg/dL. Fifty-eight percent of the patients had microalbuminuria, and 16% had a urinary albumin/creatinine ratio >300 mg/g, which indicates that the renal effects of diabetes were already present at diagnosis. After 10 years of follow-up, the number of patients with increased urinary albumin excretion was increased significantly, as was the magnitude of albuminuria, which is evidence of increased cardiovascular risk over that relatively short period of time.120
In adults, the metabolic syndrome is now an extremely common diagnosis. This cluster of findings (abdominal obesity, insulin resistance, dyslipidemia, and hypertension) frequently appears together and has been shown to predict future overt diabetes and early cardiovascular disease.121 There is no current definition for metabolic syndrome in children, but the components of this diagnosis are known to cluster together as they do in adults.122 Presence of the components of the metabolic syndrome in adolescence has been shown to predict early cardiovascular disease.123 Although no current guidelines address management of the metabolic syndrome in children, it is important to identify and address the individual elements of the syndrome whenever a child presents with obesity.
Pathogenesis of Premature Atherosclerosis: Type 2 Diabetes Mellitus
Both hyperglycemia and insulin resistance are implicated in endothelial dysfunction, to a greater degree in type 2 diabetes mellitus than in type 1.124 Microalbuminuria is a predictor of increased risk for vascular complications.116
Insulin resistance has been implicated in the development of dyslipidemia by enhancing hepatic synthesis of very-low-density lipoprotein (VLDL), which results in increased plasma triglyceride and LDL cholesterol levels.125 Resistance to the action of insulin on lipoprotein lipase in peripheral tissues may also contribute to elevated triglyceride and LDL cholesterol levels.126,127 Insulin resistance may also be responsible for the reduced levels of HDL cholesterol observed in type 2 diabetes mellitus, and this is accounted for by an increase in the rate of apolipoprotein A1/HDL cholesterol degradation, which exceeds the rate of its synthesis.128 The increase of triglyceride-rich lipoproteins due to both exaggerated postprandial lipemia and VLDL overproduction in the face of low lipoprotein lipase activity results in long residence time of these particles in circulation and the formation of small, dense LDL.
Insulin resistance is also associated with hypertension through urinary sodium retention, increased sympathetic nervous system activity,129 and stimulation of vascular smooth muscle growth.130 Insulin levels have been found to be significantly higher in adult patients with essential hypertension131–133 and borderline hypertension134 than in normotensive control patients. In addition hyperinsulinemia is known to directly stimulate the formation of the atherogenic plaque by promoting smooth muscle proliferation, connective tissue formation, and LDL deposition in the plaque.
Other intrinsic metabolic factors such as apolipoproteins, lipoprotein(a), and homocysteine are known to influence the development of cardiovascular disease; their potential relationship to insulin resistance remains to be clarified. Free fatty acids may also stimulate, either independently or in concert with hyperglycemia, the production of reactive oxygen species (oxidative stress),135 which has been associated with target-organ damage such as that related to diabetes and atherosclerotic cardiovascular disease.136 Finally, oxidative stress is associated with an increase in insulin resistance.137
Risk Factors/Comorbidities
Patients with type 2 diabetes mellitus often have other risk factors for cardiovascular disease. It is believed that obesity leads to insulin resistance and increased circulating insulin concentrations over time. At some point, a loss of control of blood glucose begins to emerge, resulting in dietary glucose intolerance and ultimately in type 2 diabetes mellitus. Obese individuals develop different degrees of insulin resistance, and not all those with obesity develop glucose intolerance. Obesity-associated insulin resistance varies significantly with genetic background. Black children are more insulin resistant than age-, sex-, and body mass index (BMI)–matched white children.138 The factors that make some individuals more likely to progress to type 2 diabetes mellitus are not well understood at the present time.139 A strong family predisposition is known to exist, and parental history is therefore important in risk assessment. In the future, genetic markers may help identify those offspring of diabetic parents who are at greatest risk of developing diabetes. Children with type 2 diabetes mellitus are usually diagnosed after 10 years of age and are almost always obese. The mean BMI in clinical series has ranged from 26 to 38 kg/m2.117,118 Current American Diabetes Association guidelines recommend routine glucose testing in obese children >10 years of age with 2 additional risk factors for type 2 diabetes mellitus.37
The prevalence of hypertriglyceridemia has ranged from 4% to 32%.113,114 Weight control improves glucose tolerance, with a recommended weight loss in adults of 10% to 15%.
The prevalence of hypertension has ranged from 17% to 32%. Essential hypertension is known to be associated with diabetes in adults,139 and it is estimated that the cardiovascular risk doubles when hypertension and diabetes coexist. Prevalence data are not available for hypertension in children with diabetes.
Exercise training improves insulin sensitivity and endothelial vascular function beyond the benefits of glycemic control and blood pressure reduction in children and adults.140,141 Agents such as metformin and thiazolidinediones have been used effectively in adolescents with type 2 diabetes mellitus and have been shown to decrease BMI and improve glucose tolerance.142,143
Recommendations in Children With Diabetes Mellitus
Children With Type I Diabetes Mellitus Who Are at High Risk for Early Cardiovascular Disease (Tier I)
Optimal management of hyperglycemia will modify this risk, but aggressive management of related risk factors has been shown to improve outcome and is recommended. Specific management recommendations are presented in the algorithm (Figure) and accompanying tables.
Children With Type 2 Diabetes Mellitus Who Are at Moderate Risk for Cardiovascular Disease (Tier II)
The differences between type 1 and type 2 diabetes mellitus are significant: Age at presentation for type 1 diabetes mellitus is younger, with 25% of patients diagnosed between 5 and 10 years of age and another 40% between 10 and 15 years of age; typically, the degree of hyperglycemia in type 1 diabetes mellitus is severe, and patients are very symptomatic. By contrast, type 2 diabetes mellitus diagnosed in childhood usually presents asymptomatically, with mild to moderate hyperglycemia in adolescence in combination with obesity, signs of insulin resistance, and other components of the metabolic syndrome. When type 2 diabetes mellitus begins in childhood, the risk for accelerated atherosclerosis is increased beyond that seen in those who develop this diagnosis as adults, but less than when type 1 diabetes mellitus is diagnosed in a child. Specific recommendations for management are contained in the algorithm (Figure) and accompanying tables; using the treatment algorithm, patients with type 2 diabetes mellitus are defined as being at moderate risk but will almost always be managed as "high risk" because of associated comorbidities.
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Pediatric Chronic Kidney Disease |
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Introduction
Success with renal replacement therapy has lengthened the life expectancy of children with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Now, morbidity and mortality in children with CKD/ESRD are not only related to chronic renal failure and renal replacement therapy but also to cardiovascular disease as a result of prolonged exposure to cardiovascular risk factors.
Epidemiology
Cardiovascular disease now accounts for the majority of deaths in adults with ESRD and approximately one fourth of pediatric ESRD deaths.144–146 The cardiac abnormalities associated with ESRD include pericardial disease, arrhythmias, abnormalities of left ventricular function, and CAD.144,145 Twenty percent of hospitalizations in pediatric ESRD patients enrolled in Medicare are reported to be due to arrhythmias, 10% to cardiomyopathy, and 3% to a cardiac arrest.147 The incidence of cardiomyopathy reported among pediatric ESRD patients doubled over the 6-year period from 1991 to 1996.147
Pathogenesis
The mechanisms that lead to cardiovascular disease in CKD primarily originate with vascular or myocardial injury from a multitude of highly prevalent cardiovascular risk factors in renal failure, and perhaps uremia itself. Damage to the vascular endothelium and left ventricle manifests as accelerated CAD and cardiomyopathy and has been described extensively in adults undergoing dialysis or after kidney transplantation. In children with CKD, subclinical manifestations of vascular disease have been reported.
Subclinical evidence of atherosclerosis with intimal plaque has been reported in pediatric ESRD. In a series of children with iliac artery biopsy at the time of transplantation, atherosclerosis in the uropathy group was also associated with increased serum calcium and longer duration of dialysis.148
Medial vessel calcification and arteriosclerosis or Mönckeberg’s arteriosclerosis has also been reported in the pediatric ESRD population, with vascular calcification in the coronary arteries, aorta, peripheral vessels, and aortic valve. An autopsy series of subjects with CKD revealed soft tissue calcification in 60% of the pediatric patients, half of whom were undergoing dialysis at the time of death.149 In a small autopsy series, 4 of 8 had evidence of arteriosclerosis, diffuse vascular calcification, and calcified valves.150
There is evidence of significant left ventricular hypertrophy in children with CKD and ESRD.151 Depending on the setting and the classification system used, hypertrophy is reported in 40% to 75% of the pediatric ESRD population.152–156 At initiation of dialysis, 69% of subjects 4 to 18 years of age had evidence of left ventricular hypertrophy.152 Postmortem studies have shown >50% of children with ESRD have evidence of left ventricular hypertrophy.150
Decreased arterial wall compliance is also common among dialysis patients, coincident with worsening left ventricular hypertrophy.157 Stiffness of the aorta has been shown to be higher in children undergoing dialysis than in healthy control subjects.157 Carotid artery compliance has been shown to be significantly lower in children undergoing dialysis, with the decrease correlating significantly with age and blood pressure.157
Risk Factors/Comorbidities
Most risk factors for the development of cardiovascular disease are highly prevalent in CKD. Hypertension is seen in 49% of children with CKD158 and 50% to 60% of patients undergoing dialysis.159 Hypertension is even more common in the transplant population, with 65% to 80% of patients being treated.159 In the young adult population, 18 to 35 years of age, systolic hypertension occurs in 51% and diastolic hypertension in 35% of the dialysis population.160
Approximately 29% to 87% of pediatric peritoneal dialysis patients have elevated cholesterol levels, with LDL >100 mg/dL (>2.29 mmol/L).44 Similarly, 72% to 84% of pediatric kidney transplant recipients had LDL >100 mg/dL (>2.29 mmol/L).44 In ESRD, triglycerides are consistently elevated, with average triglyceride levels >150 mg/dL and HDL cholesterol levels reduced. Lipoprotein(a), a lipoprotein associated with a mild increase in cardiovascular risk in the general population, is significantly elevated in ESRD, although the contribution to increased risk is unclear. Lipoprotein(a) is primarily genetically regulated, but increasing levels are also related to worsening renal function.162,163
Homocysteine levels also increase with worsening renal function, because metabolism of homocysteine may require intrarenal metabolism.164 Homocysteine has been shown to be elevated in 65% of children with CKD.165 Interestingly, the level only increases after 7 years of age and appears to be independent of renal function.165,166 The higher the homocysteine levels in children with CKD, the lower the vitamin B12 and folate levels.165,166
C-reactive protein levels are elevated 3-fold in pediatric ESRD patients undergoing dialysis and 2-fold in renal transplant recipients compared with healthy control subjects.167 C-reactive protein is highly correlated with coronary calcium, especially in patients who also have an elevated parathyroid hormone level. An elevated C-reactive protein level may reflect chronic inflammation from many sources, including overt or occult infectious processes, comorbid conditions such as access complications, and factors associated with the dialysis procedure per se, including bioincompatible membrane and possibly dialysate leak in the membrane.168
Coronary calcium burden is increased, as measured by coronary computed tomography with either helical or electron-beam computed tomography. In young adults with a history of pediatric ESRD, higher calcium scores are associated with longer dialysis duration and elevated C-reactive protein levels.167,169 It is not known to what extent this represents a dramatic acceleration of atherosclerosis in ESRD or an increased propensity for calcium to accumulate in the medial wall of the coronary vessel owing to altered calcium phosphorus metabolism in ESRD.
Endothelial dysfunction assessed by brachial artery reactivity in CKD is independent of lipid levels and hypertension but is correlated with left ventricular hypertrophy expressed as left ventricular mass index.166,170 In 25 children with CKD, a double-blind, placebo-controlled, randomized crossover trial of folic acid for 8 weeks showed statistically significant improvement in endothelium-dependent dilatation with lowering of homocysteine levels.171
Treatment Recommendations for Children With CKD
Children With CKD Who Are at High Risk for Cardiovascular Disease (Tier I)
- The origins of cardiovascular morbidity and mortality are in childhood, when the cardiovascular risk milieu is established. Recommendations are directed toward children with CKD stage 5 (estimated glomerular filtration rate <15 mL · min–1 · 1.73 m–2), children undergoing dialysis, and renal transplant recipients.
- The risk of cardiovascular disease can be reduced by modifying traditional cardiovascular risk factors and monitoring for end-organ injury through the use of echocardiography to estimate left ventricular mass172 and, in young adults, computed tomography studies for coronary calcium. Chronic cardiovascular risk factor reduction, begun early in the course of CKD, should be an essential part of clinical management.
- Specific guidelines for cardiovascular risk factor management in children with advanced CKD or ESRD are available from the National Kidney Foundation–Kidney Dialysis Outcomes and Quality Initiative. The guidelines include recommendations for management of cardiovascular disease in dialysis patients and for treatment of hypertension and dyslipidemias in CKD.44,172,173
These recommendations were considered in development of the algorithm shown in the Figure and the treatment guidelines described in Tables 2 and 3.
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Pediatric Heart Transplantation |
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Introduction/Epidemiology
Orthotopic heart transplantation (OHT) in children continues to increase in frequency, with
400 transplantations performed annually in children in the United States.174 After heart transplantation, transplant CAD is the most important cause of mortality beyond the first year after surgery in adults.175 In pediatric survivors of OHT, transplant CAD has been found to be the primary cause of late mortality in 20% to 30% of cases.176,177 On the basis of combined angiographic and intracoronary ultrasound imaging, 74% of pediatric heart transplant patients have evidence of transplant CAD.178 In a recent pathology series, 94% of pediatric OHT specimens showed evidence of cardiac allograft vasculopathy.179
Pathology/Natural History
The histopathology of transplant CAD is the same in children as it is in adults and differs markedly from the typical atherosclerotic process. Histologically, monocyte and T-cell accumulation plus concurrent smooth muscle proliferation comprise the intimal hyperplasia of the coronary arteries.180 Some degree of coronary intimal thickening is seen in virtually every heart transplant recipient beginning in the first year after transplantation.181
Angiographically, affected coronary vessels demonstrate diffuse concentric narrowing along their entire length. With intravascular ultrasound, the pathological process is characterized by concentric intimal thickening.182
When stenosis is diagnosed in the context of transplant CAD, both surgical and catheter revascularization techniques have been used with initial procedural success rate. However, over a very short period of time, the restenosis rate is high, and the long-term outcome is poor.183 The only other option is retransplantation, with known limitations on organ procurement and potential development of coronary vasculopathy in the retransplanted heart.184
Pathogenesis
The pathogenesis of transplant CAD is complex and is still not completely understood. The underlying mechanism has been shown to involve multiple factors including those mechanisms discussed below.
Rejection
Development and progression of transplant CAD have been shown to correlate with evidence of increased rejection.185 Noncompliance with immune-suppressive regimens correlates significantly with increased transplant CAD in children186 and adults.187 Conversely, regression of transplant CAD has been demonstrated with improved immunosuppression in adults.188
In children, late rejection is an independent predictor of transplant CAD, and increased immune suppression has been shown to correlate with a decreased incidence of transplant CAD.189,190 Introduction of novel proliferation signal inhibitors such as sirolimus as part of immunosuppressive therapy has been associated with a decrease in transplant CAD in adults; this type of drug is now being used in children.191
Donor Status
In adults, older donor age, donor atherosclerotic disease, donor hypertension, and male sex of either donor or recipient have been shown to correlate with transplant CAD.192 Donor hearts from patients who suffered explosive brain death have also been shown to have earlier onset of transplant CAD.193
Cytomegalovirus Infection
In adults and in children, cytomegalovirus infection has been associated with accelerated coronary vasculopathy after OHT.194,195 Preemptive treatment with ganciclovir and cytomegalovirus hyperimmune globulin has reduced the incidence and delayed the progression of transplant CAD.196
Risk Factors/Comorbidities
Hyperlipidemia
After transplantation, the combination of immunosuppressive therapy, obesity, and an underlying genetic predisposition to hyperlipidemia promotes combined hyperlipidemia, with elevated total and LDL cholesterol, high triglycerides, and reduced HDL cholesterol.197,198 Hyperlipidemia is present in 60% of adults and at least 40% of children in the first year after transplantation.198,199
Elevated levels of triglycerides have been shown to correlate directly with increased prevalence of transplant CAD in adults.200 In adults, a greater increase in LDL cholesterol in the first year after transplantation has been associated with increased severity of transplant vasculopathy.201 Lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) has led to lower total and LDL cholesterol levels and a significantly lower incidence of transplant vasculopathy in both adults and children.201,202 Benefits have been maximized when lipid therapy has been initiated immediately after transplantation.
Obesity
After transplantation, progressive obesity is common in both children and adults, correlating with the intensity and duration of steroid treatment.203,204 In adults and children, pretransplantation and posttransplantation BMI have been shown to be strong predictors of transplant CAD.204 The association of obesity and the metabolic syndrome confers additional risk for transplant CAD and for progression of donor atherosclerosis.205
Hypertension
Cyclosporine therapy, a mainstay of immune suppression after heart transplantation, is associated with hypertension and with renal dysfunction. By 3 years after transplantation, 35% of pediatric heart transplant patients are undergoing chronic antihypertensive therapy; however, in cyclosporine-treated children, 83% of long-term survivors required antihypertensive therapy.174,176
Both hypertension and renal failure are predictors of progressive atherosclerotic disease and of transplant CAD.185 Treatment with angiotensin-converting enzyme inhibitors and calcium channel blockers is associated with a reduction in transplant CAD in adults.206,207
Use of the antioxidant L-arginine has been shown to reverse endothelial dysfunction and attenuate hypertension after transplantation.208 Use of omega-3 fatty acids has also been shown to reduce the rise in blood pressure after heart transplantation.209 Immune suppression with proliferation signal inhibitors, such as everolimus, has resulted in a decrease in cyclosporine dose and in renal dysfunction in adults.210
Insulin Resistance/Diabetes Mellitus
Both chronic hyperglycemia as evidenced by elevated hemoglobin A1C and overt diabetes are prevalent in adult patients after heart transplantation.205,211 Approximately 2% of pediatric heart transplant recipients develop diabetes.212 In adults, higher glucose and insulin levels and elevated levels of hemoglobin A1C are associated with increased evidence of transplant CAD.205,211
Deconditioning
In both children and adults, exercise performance, expressed as measured maximum oxygen uptake, improves from pretransplantation levels but remains significantly reduced compared with normal subjects. This has been attributed in part to chronotropic incompetence caused by cardiac denervation, but deconditioning is also common.213,214
In children and adults, exercise training programs result in increased exercise capacity and in decreased resting heart rate and blood pressure, improved endothelial function, and increased lean body mass, all known factors in the pathogenesis of allograft vasculopathy.215,216 With serial exercise testing, exercise performance deteriorates as transplant CAD develops.
Hyperhomocysteinemia
In adults and children, elevated homocysteine levels are common after OHT.217,218 In adult subjects with evidence of transplant CAD, homocysteine levels have been shown to be significantly higher than in those without evidence of vasculopathy.217 Folate supplementation in adults and children after OHT normalized homocysteine levels, with no evidence to date of any impact on development of transplant CAD.219
Treatment Recommendations After Pediatric Heart Transplantation
After Pediatric Heart Transplantation, Children Are at High Risk for Very Early Cardiovascular Disease (Tier I)
- Please see the algorithm in the Figure and Tables 2 and 3 for specific treatment guidelines.
- Although the process appears to be primarily mediated by chronic rejection, modification of traditional risk factors, particularly reduction in LDL cholesterol, has significantly affected the disease process in children and adults.
- Risk factor identification and intensive modification are indicated beginning in the early posttransplantation period.184 Although there are no guidelines for lipid management after heart transplantation in children, usual care in the United States includes initiation of lipid-lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A enzyme inhibitors in the early posttransplantation period.220
- Optimization of immunosuppression, improved compliance, and preemptive treatment of cytomegalovirus are all critical factors in the pathogenesis of transplant CAD that are being addressed by transplantation cardiologists.
- Specific screening for evidence of transplant CAD is recommended every 6 to 12 months with angiography, with optional intravascular coronary ultrasound.221 Dobutamine stress echocardiography or stress perfusion imaging may be helpful in risk stratification.222
- Patients who develop any evidence of graft dysfunction should be screened specifically for transplant CAD.
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Kawasaki Disease |
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Kawasaki disease is an acute, self-limited vasculitis of unknown origin that occurs predominantly in infants and young children. First described in 1967 in Japan, the disease is now known to occur throughout the world in children of all races.223 Kawasaki disease is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy. The cause of Kawasaki disease remains unknown, and no specific diagnostic test or pathognomonic clinical feature can confirm the diagnosis early in the illness. Kawasaki disease is likely to be caused by an infectious agent(s) that produces clinically apparent disease in genetically predisposed individuals.224 Coronary artery aneurysms or ectasia develops in approximately 15% to 25% of untreated children with the disease and may lead to myocardial infarction, sudden death, or ischemic heart disease.225,226 Kawasaki disease has now surpassed acute rheumatic fever as the leading cause of acquired heart disease in children227; >4000 hospitalizations associated with Kawasaki disease occurred in the United States in 2000.228 Therapy of Kawasaki disease in the acute phase is aimed at reducing inflammation in the coronary artery wall and preventing coronary thrombosis. Long-term management is guided by stratification of patients according to the severity of their CAD and consequent risk of myocardial ischemia. Although coronary artery aneurysms produce the most serious sequelae of Kawasaki disease, vascular inflammation during the acute stage of the illness is diffuse. Children with coronary aneurysms, and even those in whom coronary dilatation was never detected, appear to be at increased risk for future atherosclerotic CAD on the basis of abnormalities in arterial stiffness and endothelial function.
Pathology
Kawasaki disease is a generalized systemic vasculitis that involves blood vessels throughout the body. Aneurysms affect medium-sized extraparenchymal arteries and result from segmental destruction of the vessel wall in sites strikingly similar to those affected by atherosclerosis.229 Although aneurysms in the coronary arteries