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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Curr Opin Pediatr. Author manuscript; available in PMC 2010 October 1.
Published in final edited form as:
PMCID: PMC2892901
NIHMSID: NIHMS202862

Clinical Research Directions In Pediatric Cardiology

Abstract

Purpose of review

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.

Recent findings

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.

Summary

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.

Keywords: cardiology, epigenetics, clinical trials, late effects, pediatric, child

Introduction

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.

Table 1
Essential Topics and Research Questions of a Comprehensive Clinical Research Agenda in Pediatric Cardiology

1. Life-course Studies of Pediatric Cardiovascular Disease

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••].

2. Risk Factors for Cardiometabolic Disease in Children

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.

3. Recent Clinical Trials and Observational Studies in Pediatric Cardiology

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 [24]. Although a 2007 report suggested that dexrazoxane increased the incidence of secondary malignancies in children with Hodgkin's disease [25], 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••].

4. The Role of Physical Activity in Preventing and Treating Cardiac Disease in Children

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 [32]. Massin et al. outlines the atherosclerotic cardiovascular risk of children with congenital heart disease [32]. Up to 25% of children with congenital or acquired heart disease are overweight [33]. 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) [34].

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 [37], but some patients showed improvements only in ventilation [38]. 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 [41]. 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 [42], renal disease [43], and HIV infection [44], 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 [44].

As discussed in other sections of this article, the prevalence of childhood obesity and its metabolic consequences are now out of control [45]. 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 [45]. Metabolic syndrome, in turn, is associated with reduced cardiorespiratory fitness, low physical activity, and living in an urban environment [46]. 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 [49].

5. How to Study Pediatric Cardiac Problems and to Implement Evidence-based Findings

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.

Conclusions

We conclude the following:

  • Clinical research in pediatric cardiology must accelerate rapidly in the near future if we are to reduce cardiovascular morbidity and mortality for the entire population.
  • Epigenetic cardiovascular factors clearly affect development.
  • We need a greater understanding of the timeframe over which cardiovascular risk remains modifiable.
  • We need to identify validated biomarkers as surrogate endpoints for clinically important cardiovascular disease.
  • Multi-disciplinary, multiple-site life-course study groups are essential for accurately determining the risk of exposures and to identify vulnerable sub-populations. Such study groups would also inform future clinical studies and trials.
  • Local infrastructure [50••] and expertise in pediatric cardiology clinical research is highly variable and must be strengthened to increase the discovery of both incremental and break-through advances in care.

Acknowledgments

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.

Abbreviations

BNP
brain natriuretic peptide
cTnT
serum cardiac troponin T
DNA
deoxynucleic acid
HIV
human immunodeficiency virus
NT-proBNP
N terminal-prohormone brain natriuretic peptide

Footnotes

Disclosures: No conflicts of interest or sponsorships are noted.

References and recommended reading

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).

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Consensus recommendations on pediatric cardiomyopathy clinical research future directions from an NIH-sponsored international workshop.
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Overview of anthracycline cardiotoxicity in childhood cancer survivors.
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Assessment of risk factors for late cardiovascular disease and health in HIV-infected children. Children infected with HIV had adverse cardiac risk profiles compared with NHANES controls. Antiretroviral therapy had a significant influence on these factors.
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Risk factors and history of cardiometabolic disease in children with HIV.
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Myocardial infarction and cardiomyopathy increased risks in HIV patients.
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State of the science evidence-based recommendations for treating HIV cardiovascular disease.
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Effects of antiretroviral therapy and HIV in the development of cardiomyopathy and vasculopathy.
12. Bakker R, Rifas-Shiman SL, Kleinman KP, Lipshultz SE, Gillman MW. Maternal calcium intake during pregnancy and blood pressure in the offspring at age 3 years: A follow-up analysis of the Project Viva cohort. Am J Epidemiol. 2008;168(12):1374–80. [PMC free article] [PubMed]
An important birth cohort that has illustrated the importance of prenatal factors on postnatal cardiovascular risk.
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An example of how cardiac biomarker development occurs that illustrates the mechanisms and reversibility of isoproterenol cardiotoxicity.
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The importance of developing chronic care comprehensive care programs for many pediatric cardiology patients and their families.
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The challenges of implementing clinical practice guidelines in pediatric cardiology.
16. Messiah SE, Arheart KL, Lipshultz SE, Miller TL. Body mass index, waist circumference, and cardiovascular risk factors in adolescents. J Pediatr. 2008;153(6):845–50. [PubMed]••
The importance of simple measurements in assessing the risk of premature cardiovascular disease.
17. Steinberger J, Daniels SR, Eckel RH, et al. Progress and Challenges in Metabolic Syndrome in Children and Adolescents A Scientific Statement From the American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee of the Council on Cardiovascular Disease in the Young; Council on Cardiovascular Nursing; and Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2009;119:628–47. [PubMed]••
A comprehensive overview of the literature (more than 300 references) summarizing the current state of the field as of early 2009
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This article compares the utility of four most commonly referenced definitions of pediatric metabolic syndrome.
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A comprehensive analysis of NHANES 1999-2002 identifying multiple risk factors for metabolic syndrome in US children and adolescents. For the first time, the prevalence of metabolic syndrome was ascertained in children as young as 8 years old. Up to 10% of overweight 8- to 11-year olds and 44% of overweight 12- to 14-year-olds met the criteria for metabolic syndrome.
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This prospective study of 143 children with Duchenne (128) or Becker (15) muscular dystrophy found similar mean ages at diagnosis of cardiomyopathy (14 years), prevalence of congestive heart failure (30% to 33%), and depressed left ventricular function. However at 5 years, only 57% of the Duchenne group were alive whereas 100% of the Becker group were alive; 4 had received heart transplants. Cardiac disease is an important source of morbidity and mortality in muscular dystrophy patients. Careful cardiac monitoring may identify patients who could benefit from specific cardiac therapies.
24. Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351(2):145–53. [PubMed]
25. Tebbi CK, London WB, Friedman D, et al. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007;25(5):493–500. [PubMed]
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This recent report found an increase risk of acute myeloid leukemia in children with Hodgkin's disease treated with dexrazoxane, a free-radical scavenger. The results from this large randomized clinical trial of 205 children with acute lymphoblastic leukemia, median follow-up 6.2 years, found no secondary malignancies in the dexrazoxane group, and one melanoma, outside the radiation field in the untreated group. The authors recommend continued use and study of dexrazoxane in doxorubicin-containing chemotherapy regimens.
27. Lipshultz SE, Simbre VC, 2nd, Hart S, et al. Frequency of elevations in markers of cardiomyocyte damage in otherwise healthy newborns. Am J Cardiol. 2008;102(6):761–6. [PMC free article] [PubMed]••
Elevated troponin T, a marker of myocardial injury, was found in 16 of 17 apparently normal infants; 2 children had troponin T levels consistent with myocardial infarction. Elevated levels were more likely to be found with low birth weight, maternal infection and non-White race. None of these children had cardiac symptoms. Whether this response is pathologic or has long-term consequences is yet to be determined.
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B-type natriuretic peptide (BNP) was markedly elevated in 33 children with structural or acquired heart disease admitted to the emergency department. A control group of 70 children showed no such elevation. The authors conclude that serum BNP levels are useful in recognizing acute heart disease in children.
30. Ratnasamy C, Kinnamon DD, Lipshultz SE, Rusconi P. Associations between neurohormonal and inflammatory activation and heart failure in children. Am Heart J. 2008;155(3):527–33. [PubMed]••
This study of 19 children with heart failure found that elevated levels of various neuroendocrine and inflammatory biomarkers were associated with the severity of symptoms and degree of ventricular dysfunction. Measurements of these biomarkers could be used clinically to objectively assess the degree of heart failure, particularly in the young patients in whom symptom severity is difficult to assess.
31. Sakuragi S, Abhayaratna K, Gravenmaker KJ, et al. Influence of adiposity and physical activity on arterial stiffness in healthy children: the lifestyle of our kids study. Hypertension. 2009;53(4):611–6. [PubMed]••
This comprehensive assessment measured arterial stiffness by carotid-femoral pulse wave velocity in 573 school-aged children. Cardio-respiratory fitness, body mass index, and adiposity were significantly associated with arterial stiffness, an atherosclerotic cardiovascular risk factor.
32. Massin MM, Hövels-Gürich H, Seghaye MC. Atherosclerosis lifestyle risk factors in children with congenital heart disease. Eur J Cardiovasc Prev Rehabil. 2007;14(2):349–51. [PubMed]
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35. Jenkins PC, Chinnock RE, Jenkins KJ, et al. Decreased exercise performance with age in children with hypoplastic left heart syndrome. J Pediatr. 2008;152(4):507–12. [PubMed]••
This is a large and comprehensive report of 42 children with hypoplastic left heart syndrome who underwent serial assessment of exercise testing in 4 centers across the US. The significant age-related decline in exercise test results regardless of surgical strategy suggests that exercise programs may be warranted in this population to prevent this decline.
36. Binkhorst M, van de Belt T, de Hoog M, et al. Exercise capacity and participation of children with a ventricular septal defect. Am J Cardiol. 2008;102(8):1079–84. [PubMed]
In this Dutch study, 42 children from the Netherlands with either patent or surgically repaired ventricular septal defects had relatively normal exercise test results and considered themselves to be healthy. However, children with ventricular septal defects participated in sports to a lesser extent.
37. Mays WA, Border WL, Knecht SK, et al. Exercise capacity improves after transcatheter closure of the Fontan fenestration in children. Congenit Heart Dis. 2008;3(4):254–61. [PubMed]
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39. Paridon SM, Mitchell PD, Colan SD, et al. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol. 2008;52(2):99–107. [PubMed]••
A study of 411 children who had a Fontan procedure and who were part of the Pediatric Heart Network found that boys and adolescents were at the greatest risk for decreased exercise performance.
40. Somarriba G, Extein J, Miller TL. Exercise rehabilitation in pediatric cardiomyopathy. Prog Pediatr Cardiol. 2008;25(1):91–102. [PMC free article] [PubMed]••
A review of the approach behind a comprehensive assessment of exercise capacity in children with cardiomyopathy. Case studies are reported of two children with idiopathic dilated cardiomyopathy and their response to a structured exercise program.
41. Patel JN, Kavey RE, Pophal SG, et al. Improved exercise performance in pediatric heart transplant recipients after home exercise training. Pediatr Transplant. 2008;12(3):336–40. [PubMed]
42. Courneya KS, Katzmarzyk PT, Bacon E. Physical activity and obesity in Canadian cancer survivors: population-based estimates from the 2005 Canadian Community Health Survey. Cancer. 2008;112(11):2475–82. [PubMed]
43. Pattaragarn A, Warady BA, Sabath RJ. Exercise capacity in pediatric patients with end-stage renal disease. Perit Dial Int. 2004;24(3):274–80. [PubMed]
44. Miller TL. A hospital-based exercise program to improve body composition, strength, and abdominal adiposity in 2 HIV-infected children. AIDS Read. 2007;17(9):450–2. 455–458. [PubMed]
45. Pan Y, Pratt CA. Metabolic syndrome and its association with diet and physical activity in US adolescents. J Am Diet Assoc. 2008;108(2):276–86. discussion 286. [PubMed]
46. Kriemler S, Manser-Wenger S, Zahner L, et al. Reduced cardiorespiratory fitness, low physical activity and an urban environment are independently associated with increased cardiovascular risk in children. Diabetologia. 2008;51(8):1408–15. [PubMed]
47. Benson AC, Torode ME, Fiatarone Singh MA. The effect of high-intensity progressive resistance training on adiposity in children: a randomized controlled trial. Int J Obes (Lond) 2008;32(6):1016–27. [PubMed]••
One of the first randomized trials of a high-intensity, progressive-resistance training program in children. The study found that the training improved cardiometabolic endpoints and muscle strength in normal and overweight children.
48. Dobbins M, De Corby K, Robeson P, et al. School-based physical activity programs for promoting physical activity and fitness in children and adolescents aged 6-18. Cochrane Database Syst Rev. 2009;(1) CD007651. [PubMed]
A systematic review of the literature in an explosive field of school-based nutrition and physical activity intervention programs.
49. Walther C, Adams V, Bothur I, et al. Increasing physical education in high school students: effects on concentration of circulating endothelial progenitor cells. Eur J Cardiovasc Prev Rehabil. 2008;15(4):416–22. [PubMed]
50. Miller TL, Lipshultz SE. Building a pediatric clinical research division. J Pediatr. 2008;152(1):1–2. 2.e1–2.e2. [PubMed]••
Demonstration project for a successful local clinical research infrastructure.
51. Wilkinson JD, Sleeper LA, Alvarez JA, Bublik N, Lipshultz SE. for the Pediatric Cardiomyopathy Study Group. The pediatric cardiomyopathy registry: 1995-2007. Prog Pediatr Cardiol. 2008;25(1):31–6. [PMC free article] [PubMed]••
Overview of a successful pediatric cardiology registry platform for clinical research.
52. Garber AM, Tunis SR. Does comparative-effectiveness research threaten personalized medicine? N Engl J Med. 2009;360:1925–7. [PubMed]
The contrasting issues of these two approaches are reviewed.
53. Avorn J. Debate about funding comparative-effectiveness research. N Engl J Med. 2009;360:1927–9. [PubMed]
Further information on clinical research approaches in the current era.
54. Naik AD, Petersen LA. The neglected purpose of comparative-effectiveness research. N Engl J Med. 2009;360:1929–31. [PMC free article] [PubMed]
Discussion on current needs in clinical research.
55. Lipsitz SR, Fitzmaurice GM, Ibrahim JG, et al. Joint generalized estimating equations for multivariate longitudinal binary outcomes with missing data: an application to acquired immune deficiency syndrome data. J Royal Stat Soc: Series A (Statistics in Society) 2009;172(1):3–20. [PMC free article] [PubMed]
Methodological issues of missing data common to long-term follow-up studies.