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Clinical research in pediatric cardiology is under-appreciated and under-funded, yet it has enormous implications for cardiovascular health and healthcare over the entire life-course. Renewed interest in federally funded clinical research makes it timely to propose a comprehensive research agenda that, with its associated rationale, will attract public funds for research into child cardiovascular health and disease.
We propose here a comprehensive pediatric cardiology research agenda consisting of 22 topics and associated research questions. We describe the following five topics in more detail: 1) the need for life-course studies of pediatric cardiac disease and epigenetic factors for later onset of cardiovascular effects; 2) the need to study cardiometabolic disease risk in children; 3) recent pediatric cardiology clinical trials and observational studies; 4) the need to explore the role of physical activity in preventing and treating pediatric cardiology patients; and 5) the need to develop and implement evidence-based interventions to manage pediatric cardiovascular problems.
If the field of pediatric cardiology can adopt a comprehensive research agenda that identifies the most-needed studies, then research could be better coordinated, long-term and collaborative studies would be more readily organized and funded, and the overall financial and scientific efficiency of research in pediatric cardiology would be improved. Targeted research efforts are more likely to realize potential breakthroughs in areas such as genetic and epigenetic screening, biomarkers, cardioprotective strategies, life-course studies, long-term monitoring technologies, environmental influences on disease, evidence-based practice guidelines, and more rapid and safer development of drugs.
Children comprise 26% of the US population but are the target of only 9% of research funds. Given this limited share of research funds, it is both desirable and necessary to establish research priorities. In fact, a clear research agenda can help guide not only pediatric cardiology research but public health policy as well; poor cardiac health at birth and during childhood has repercussions throughout life. For example, health status during the perinatal, postnatal, and childhood periods has a major impact on adult health status: poor cardiac health as a child equates to poor health as an adult.
Elsewhere, we have described a proposed pediatric cardiology research agenda [1-3•]. Here, we identify 22 topics and associated research questions that form a comprehensive research agenda (Table 1). We discuss five areas of pediatric cardiology research in detail, describing several advances illustrating the impact that such research can have on health throughout life. These five areas are: 1) life-course studies of cardiovascular disease, including the epigenetic fetal origins of disease as well as late effects and long-term cardiac consequences; 2) risk factors for pediatric cardiometabolic disease; 3) needed clinical trials and observational studies in pediatric cardiology; 4) the value of physical activity in treating cardiac disease in children; and 5) how to study pediatric cardiac problems and to implement evidence-based findings.
New information has recently been published on the late cardiovascular effects of anthracycline chemotherapy in long-term survivors of childhood cancer [4••,5••]. Anthracycline toxicity remains one of the best-studied environmental exposures during early childhood that is associated with pervasive, persistent, and, in many cases, progressive late cardiotoxicity. Despite improvements in dilated cardiomyopathy soon after anthracycline chemotherapy, especially in girls treated at younger ages and receiving higher doses of anthracycline, long-term follow-up of childhood cancer reveals a restrictive cardiomyopathy, the incidence of which increases with time. Cardiovascular-related morbidity and mortality rates are significantly increased in these patients at 20 and even 30 years after exposure. Radiation therapy is also associated with progressive late cardiovascular toxicity [6•].
These studies [4••,5••,6•] illustrate the need for life-course analyses of the relationships between early environmental exposures and late cardiovascular effects (Table 1, Topics 1 through 3, 5 through 10, and 12) in terms of the mechanisms and time course of injury, monitoring issues, screening techniques, epigenetic factors, environmental and genetic susceptibilities, biomarker development, individual and population disparities, and clinical trial designs.
The importance of long-term follow-up of the effects of medications and chronic illnesses for late cardiovascular health and diseases was recently illustrated in a study of HIV-infected children at high risk for cardiovascular diseases in which medications such as antiretroviral therapy and other disease factors markedly increased their risk of these diseases (Table 1, Topics 3, 5, 6, 9, and 11) [7••].
Other clinical situations have shown that otherwise healthy children may be put at risk by maternal exposures in utero. For example, children born to HIV-infected mothers have a persistent and progressive risk for cardiovascular disease, as well as mortality rates that appear to be related to maternal health and exposures, emphasizing the importance of fetal and developmental origins of subsequent disease [8•, 9•, 10•, 11•]. Furthermore, maternal dietary intake may influence the child's subsequent cardiovascular health or risk. Second-trimester maternal calcium intake appears to affect systolic blood pressure during early childhood, for example [12•]. Thus, the fetal and developmental origins of adult cardiovascular disease and the importance of longer follow-up studies are parts of the proposed pediatric cardiology clinical research plan (Table 1, Topics 3 through 6,11,12).
Other topics in pediatric cardiology research are also of emerging interest. These topics include developing biomarkers and understanding the mechanisms of reversible and irreversible myocardial injury during early childhood that may be related to chronic adrenergic stimulation, as might occur in a child on inotropic therapy in a cardiac critical care unit (Table 1, Topics 1 through 3, 6, and 9) [13•]. Additionally, research into models of comprehensive long-term care of pediatric cardiology patients with chronic illnesses is now available (Table 1, Topics 3, 10, 11, 12, and 21) [14••]. Finally, studies comparing real-world clinical management of pediatric cardiology patients with clinical practice guidelines indicate that new implementation strategies are needed because clinical practice in this field does not conform to known standards (Table 1, Topics 12, 14) [15••].
The importance of waist circumference and body mass index as predictors of the long-term risk of premature cardiovascular disease has also been recognized (Table 1, Topics 3 and 9 through 12 [16••]. More than 17% of children in the United States aged 2 to 19 years are obese, and another 34% are overweight and at risk for becoming obese [17••]. In the proposed research plan, childhood obesity and its complications are thus a top priority.
Recent studies have reported an association between childhood obesity and the development of a cluster of cardiometabolic disease risk factors characterized by variable combinations of insulin resistance, dyslipidemia, and hypertension, which some authors have termed “metabolic syndrome” [17, 18••]. In turn, this clustering is associated with the onset of type 2 diabetes and long-term atherosclerotic cardiovascular complications in both childhood and adulthood [19,20].
Nearly one million adolescents aged 12 to 19 years in the US, or about 4% of the population in this age range, have signs and symptoms of metabolic syndrome [18••]. Among overweight adolescents, the prevalence is nearly 30%. Among 8- to 11-year-olds, national prevalence estimates of metabolic syndrome risk factors ranged from 2% to 9%, using two age-, sex-, and ethnicity-adjusted definitions [21••].
Identifying individual children and adolescents who either are at risk for or who have metabolic syndrome has remained more elusive and controversial. Much of the controversy surrounding metabolic syndrome in children is in its definition [18••, 22]. Definitions of pathological processes are typically based on endpoints. The difficulty in defining these predictors of cardiovascular risk in childhood is that most children have not experienced the endpoint of interest (atherosclerotic cardiovascular disease). Thus, there is technically no single, established operational definition of metabolic syndrome in children [17••]. The challenge is to set an appropriate cut-point for each risk factor that takes into account age and sex, as well as continuous growth, the onset of puberty, and perhaps ethnic background and setting these cut-points should be a research priority as such. One approach has been to use age- and sex-adjusted percentiles as the cut-points for these risk factors, which raises the issues of which percentiles maximize both the sensitivity and specificity of the prediction and on what cohort these cut-points are determined: an historical cohort from before the current obesity epidemic, perhaps as far back as the first or second National Health and Nutrition Examination Surveys, or a more current cohort that may potentially be skewed toward higher risk.
The American Heart Association has stated that further research is necessary to define pediatric metabolic syndrome. Specific areas of inquiry include the need to: 1) assess large-scale observational and outcome studies to determine stability and predictive power of future chronic disease (e.g. diabetes and cardiovascular disease); 2) clarify the molecular basis of metabolic syndrome; 3) establish the importance of environmental exposures or toxins in the development of metabolic syndrome; 4) determine the appropriate use of medical management in treating insulin resistance, pre-hypertension, early vascular changes, elevated triglyceride levels, and low high density lipoprotein cholesterol levels; 5) identify the pathways linking insulin resistance and obesity with other metabolic syndrome components beginning early in life; 6) better understand leptin biology and the mechanisms of weight regulation; 7) assess any genetic predisposition and prenatal and neonatal factors that promote the development of insulin resistance and metabolic syndrome; and 8) determine whether the mechanisms and pathways of metabolic syndrome vary among racial or ethic groups [17••].
Only systematic, long-term follow-up of well characterized pediatric cohorts into adulthood will provide the information needed to define appropriate age-, sex-, and race or ethnicity-specific cardiovascular risks in childhood. Such studies should allow earlier and more aggressive lifestyle interventions as well as more appropriate pharmacologic treatment of these children.
Results from the Pediatric Cardiomyopathy Registry (a study funded by the National Heart Lung and Blood Institute since 1995) indicate that children with Duchenne or Becker muscular dystrophy in addition to cardiomyopathy are at greater risk of premature mortality than are children with other causes of cardiomyopathy [23••]. As a result, regular cardiac evaluations can now be recommended for children with muscular dystrophy early in their presentation to optimize the application of potentially beneficial cardiac therapies.
In 2004, Lipshultz et al. reported the results of a randomized clinical trial in which dexrazoxane, a free radical scavenger, prevented or reduced the cardiac injury associated with doxorubicin treatment for childhood acute lymphoblastic leukemia . Although a 2007 report suggested that dexrazoxane increased the incidence of secondary malignancies in children with Hodgkin's disease , a follow-up analysis of the 2004 study of high-risk children with acute lymphoblastic leukemia found that dexrazoxane was not associated with an increased risk of secondary malignant neoplasms [26••]. The authors of the 2004 study concluded that given the potential importance of dexrazoxane as a cardioprotectant, it should continue to be used and studied in doxorubicin-containing pediatric cancer treatment regimens.
Interest in the use of cardiac biomarkers to evaluate cardiac status in children is increasing (Table 1, Topic 9). Cardiac troponin T (cTnT) is a serum biomarker associated with myocardial injury from a variety of causes. In a study of 32 healthy newborns, cTnT levels were elevated in both cord (24 or 76%) and peripheral blood (30 or 94%) and were high enough to be associated with myocardial infarction in 2 (0.6%) of these infants [27••]. Other biomarkers associated with cardiac disease or dysfunction were also found in smaller proportions of this sample. The authors concluded that subclinical myocardial injury occurs in apparently healthy newborns, but whether this injury is pathologic or a response to the stress of the immediate perinatal period or to other prenatal factors remains to be determined.
Another biomarker used to assess cardiac status is N-terminal pro-hormone brain natriuretic peptide (NT-proBNP), which is secreted by myocytes in the cardiac ventricle. This biomarker is elevated in patients with both asymptomatic and symptomatic ventricular dysfunction, including congestive heart failure. Mangat et al. found that elevated and rising brain natriuretic peptide (BNP) levels, the active hormone, were associated with both abnormal echocardiographic measurements of left ventricular dysfunction as well as with clinical assessments of cardiac-related disability using either the New York Heart Association or the Ross (for non-ambulatory infants) classifications [28•]. In children with congestive heart failure, a serum BNP level greater than 290 pg/mL was associated with death, transplantation, or listing for transplantation [28•].
Maher et al. found that BNP was useful in identifying heart disease in children admitted to emergency departments. The mean BNP level was 3290 pg/mL in children with acute presentations of congenital or acquired heart disease and 17 pg/mL in children with respiratory or other infections [29••]. Another recent report found that neuroendocrine (NT-proBNP levels) and inflammatory activation (levels of C-reactive protein, tumor necrosis factor-alpha or soluble tumor necrosis factor receptor II) were associated with more severe symptoms and dilated cardiomyopathy in children with heart failure [30••].
The benefits of a healthy life style in health and sickness are well documented [21••]. Substantial evidence currently indicates that among children with chronic disease that can lead to, or is a result of, cardiac dysfunction, structured exercise programs can improve some clinical endpoints and are safe in the right environment.
In light of the rapidly increasing rates of childhood obesity, interest is now even greater in ascertaining its cardiovascular effects in children with and without chronic illness (Table 1, Topic 11) [31••]. Children with chronic disease, especially those with cardiac dysfunction, are at risk for sedentary lifestyles and poor nutrition that can lead to overweight and exacerbate or promote cardiac dysfunction . Massin et al. outlines the atherosclerotic cardiovascular risk of children with congenital heart disease . Up to 25% of children with congenital or acquired heart disease are overweight . Emerging evidence suggests that children with congenital heart disease, cardiomyopathy (congenital or acquired), cardiac transplantation, or metabolic cardiac risk (secondary to obesity) can benefit from increased physical activity and improved nutrition (Table 1, Topic 12) .
Children with congenital heart disease can show baseline de-conditioning, regardless of previous surgical repair. Children with hypoplastic left heart syndrome had a progressive age-related decline in exercise performance regardless of surgical strategy with children aged 13 to 17 years achieving only 60% of predicted maximum oxygen uptake [35••]. However, children with ventricular septal defects, repaired or not, had normal physical activity levels and fully participated in exercise [36•]. Other studies have shown that repair of the Fontan fenestration improves aerobic and exercise capacity , but some patients showed improvements only in ventilation . Paridon et al. [39••] showed that although maximal aerobic capacity was reduced, higher oxygen saturation was associated with better exercise performance; boys and adolescents were particularly affected.
Similarly, it appears that children with congenital or acquired cardiomyopathy and those who have undergone cardiac transplantation benefit from a structured and supervised exercise rehabilitation program [34,40••]. Two children with idiopathic dilated cardiomyopathy completed a 3-month, hospital-based circuit-training program where their strength, body composition, quality of life and overall activity level improved over baseline [40••]. Another recent study showed that heart transplant recipients benefited from a home-based exercise rehabilitation program: endurance, peak oxygen consumption, and strength all improved . Both studies showed the programs were safe and feasible in these populations. The potential for de-conditioning, along with increased metabolic risk and the likelihood that exercise programs can be beneficial, should also be considered in children with cardiac dysfunction as a result of cancer treatments , renal disease , and HIV infection , to name a few. Miller et al. outlines the response to a structured exercise program in children with HIV, a disease that presents metabolic and cardiomyopathic risk .
As discussed in other sections of this article, the prevalence of childhood obesity and its metabolic consequences are now out of control . The risk of atherosclerotic disease in childhood is a real concern. Physical activity and nutrition are key components of any obesity intervention program, and recent studies have shown that those children with metabolic syndrome had a lower Healthy Eating Index and lower physical activity levels . Metabolic syndrome, in turn, is associated with reduced cardiorespiratory fitness, low physical activity, and living in an urban environment . A high-intensity, progressive, resistance training program improved central and whole body adiposity in overweight children, suggesting a conferred risk reduction for cardiometabolic sequelae [47••]. A Cochrane Review of 26 school-based physical activity programs showed that these programs increased the duration of physical activity and maximum oxygen uptake and reduced television viewing and cholesterol levels [48•]. Participation in school sports programs substantially increased the number of endothelial progenitor cells, which in turn correlates with improved vascular function and that may protect against cardiovascular disease .
Several recent papers have described models for conducting and improving pediatric cardiac clinical research, such as establishing a clinical research division and conducting registry-based research, both of which have provided infrastructures that have lead to investigator successes [50••, 51••]. Having a formal clinical research infrastructure improves both the planning and conducting of research by refining hypotheses; better controlling error, confounding, and bias; improving the accuracy of data collection and processing; and providing quality checks for analyzing and interpreting data.
The need for more and improved research is driven by the fact that prescribing medications to children in the absence of formal pediatric clinical trails can result in substantial risks to their health; an unfortunate but common occurrence in pediatric cardiology. Pediatric medications must be tested in an ethical and safe environment that is supported by scientific excellence (Table 1, Topics 3,12,15 through 17). In particular, we need to determine whether comparative trials, in which groups of patients are compared to determine the effectiveness of interventions, threaten the application of personalized medicine in pediatric cardiology, in which patient characteristics and individual genomic information are used to craft individual management strategies (Table 1, Topics 3 through 22) [52•, 53•, 54•]. The specialized statistical methods needed to analyze long-term follow-up studies with missing data illustrate the requirements for this kind of research [55•]. The components needed to develop a comprehensive research agenda, some research priorities, and some proposed directions in research for pediatric cardiology are detailed in Table 1.
We conclude the following:
Supported by the NIH (HL072705, HL078522, HL053392, CA127642, CA068484, HD052104, AI50274, CA068484, HD052102, HL087708, HL079233, HL004537, HL087000, HL007188, HL094100, HL095127, HD80002), the Children's Cardiomyopathy Foundation, the Women's Cancer Association, the Thrasher Foundation, and the STOP Children's Cancer Foundation.
Disclosures: No conflicts of interest or sponsorships are noted.
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp.xx-xx).