Pediatric Heart Failure: An Evolving Public Health Concern

The care of children suffering from heart failure presents unique challenges that are inadequately met at the present time. In the pediatric population, a wide variety of disease processes can result in heart failure, including primary cardiomyopathy as well as an expanding population of children with palliated complex congenital heart disease (CHD). Regardless of the underlying etiology of heart failure, pediatric heart failure outcomes remain poor despite growing resource utilization. In addition, given the overlap in symptomatology between heart failure and more common childhood illnesses, the diagnosis of new-onset heart failure in children requires a heightened level of suspicion in combination with early pediatric cardiology consultation. Emerging molecular evidence suggests that pediatric heart failure is distinct from adult heart failure, which may contribute to the limited efficacy of adult heart failure therapies in the children. Significant improvement in pediatric heart failure outcomes will require a shift in the approach to clinical and translation research (including support for pediatric-specific heart failure therapies) as well as widespread implementation of multidisciplinary teams to care for pediatric heart failure in a chronic disease model. Increased awareness among pediatricians, funding agencies, and policymakers regarding the obstacles facing pediatric patients with heart failure is critical to meeting the needs of this complex patient population.

Expanding Population of At-Risk Patients

Heart failure in children results from a myriad of disease processes, including primary cardiomyopathy, CHD, rhythm disorders, and acquired heart diseases (primarily chemotherapy-induced cardiomyopathy, myocarditis, rheumatic heart disease, and Kawasaki disease). These causes of heart failure in children differ substantially from those found in the adult population,¹ where coronary artery disease and myocardial ischemia are significant contributors to heart failure.

Primary cardiomyopathy refers to a disease of the heart muscle that results in abnormal contractility. Primary cardiomyopathies are the principal causes of heart failure in children with structurally normal hearts.^2,3 The annual incidence of cardiomyopathies in children younger than 18 years of age is about 1.1-1.5 per 100 000,^2,3 which is similar to the incidence of non-Hodgkin lymphoma in children and adolescents.⁴ The main types of primary cardiomyopathy include dilated, hypertrophic, and restrictive and the causes of cardiomyopathy in children often include genetic abnormalities of sarcomeric, cytoskeletal, or cell membrane proteins or ion channels. Children with dilated cardiomyopathy (DCM), where the left ventricle is both dilated and poorly functioning, are at greatest risk for heart failure.^2,3

However, in addition to those with heart failure caused by a primary cardiomyopathy, there is a growing population of children with CHD who are currently asymptomatic but considered at-risk for future development of heart failure (American College of Cardiology/American Heart Association Heart Failure Classification stage A or B⁵). Overall, CHD accounts for 60%-70% of heart failure admissions in children and is an independent risk factor for hospital mortality.⁶ Inpatient mortality is higher among children with heart failure and CHD compared with children with heart failure and structurally normal hearts (19% vs 11%).⁶ Although a detailed review of each type of CHD is beyond the scope of this article, about one-third of children with CHD have complex malformations, which often combine both volume and pressure overload and affect both systemic and pulmonary circulations. For example, CHD with single ventricle physiology (SV) encompasses a group of severe abnormalities in cardiac structure where improper development of the fetal heart results in only 1 functional pumping chamber. Because of advancements in medical and surgical care, an increasing number of infants with SV are surviving surgical palliation of their CHD but remain at risk for developing impaired myocardial function later in childhood or adulthood.⁷ This is reflected in the indications for pediatric heart transplantation (which is the only long-term treatment option for children with end-stage heart failure): in the recent era, 57% of children were transplanted for CHD, with failed SV palliation being the predominant indication.⁸

Similarly, more individuals are surviving childhood cancers; nevertheless, successful cancer treatment frequently includes the use of cardiotoxic chemotherapeutic agents (such as anthracyclines). Thus, the incidence of anthracycline-mediated cardiomyopathy is expected to increase.⁹ Improvements in respiratory support for children with neuromuscular disorders and other skeletal myopathies have also resulted in increased survival and a longer lifespan,^10,11 such that those with associated cardiomyopathies have a higher likelihood of experiencing complications related to heart failure. Therefore, the clinical syndrome of heart failure is occurring in a growing number of pediatric patients.

Poor Outcomes

A diagnosis of pediatric heart failure, regardless of etiology, is generally progressive and often portends a poor prognosis. Pediatric heart failure is the leading cause of mortality in children with heart disease, with subpopulations of children with severe heart failure (demonstrating other end-organ failure or requiring extracorporeal membrane oxygenation or ventricular assist device support) having a mortality risk as high as 50%-65%.¹² Children hospitalized with end-stage heart failure have among the highest mortality and longest length of stay.^12,13 In the US, there were approximately 14 000 pediatric heart failure-related hospitalizations in 2006,¹² many of which required intensive care management.¹³ As discussed previously, heart failure in the pediatric population may be the result of a number of distinct disease processes, thus, published studies often separate patients based on heart failure etiology. Because of the high risk of developing heart failure, hospital admissions for pediatric patients with heart failure secondary to DCM are well-characterized in the literature. heart failure-related intensive care unit hospitalizations in children with DCM are increasing¹³ and these children experience an in-hospital mortality of 11%, with a 30-day readmission rate after hospital discharge ranging from 13% to 34%.^13,14 Although a minority of patients will have improvement in their ventricular function over time, freedom from death or transplant is only 65%-72% at 1 year^15–18 and 50%-63% at 5 years^16–18 postdiagnosis in children with DCM. Importantly, compared with the marked improvement in adult heart failure outcomes over the past 15 years,¹⁹ there has only been a very modest improvement in survival for children with DCM since 2000.^20,21 The first hospitalization for pediatric patients with DCM is often the beginning of a period of clinical decline, progression to end stage heart failure and the need for cardiac transplantation.

Increasing Resource Utilization

Despite the relatively small number of children affected by heart failure, the costs associated with a heart failure diagnosis are disproportionately high. Both prolonged hospital length of stay and frequent hospital admissions contribute to high resource utilization in the care of patients with pediatric heart failure. In a value-based model assessing the outcome of hospital length of stay and mortality, pediatric cardiomyopathy and heart failure-related hospitalizations were associated with worse outcomes and greater charges compared with adult heart failure hospitalizations.²² The average charge for a single pediatric heart failure hospitalization was $116 000 ± $5700 in 2000-2009,²² and median cost for a pediatric heart failure readmission was $25 500 (IQR $8800-$113 000) with a significant increase from 2004 to 2013.¹⁴ When compared with adults with heart failure, children hospitalized with heart failure have a longer length of stay, experience higher mortality, more frequently suffer from associated respiratory failure and sepsis, more frequently require ventricular assist device (VAD) and extracorporeal membrane oxygenation, and incur, on average, 3 times the cost.²² Notably, infants and small children who require VAD support cannot be discharged from the hospital secondary to limitations of the devices, resulting in hospitalization (often several months) until heart transplantation.

Challenges in the Diagnosis of Heart Failure

Heart failure in children is a complex pathophysiological syndrome, and signs and symptoms (growth failure, respiratory distress, exercise intolerance, gastrointestinal complaints) are fairly characteristic irrespective of the underlying etiology.¹ However, the diagnosis of heart failure in children remains challenging because (1) new-onset heart failure is a relatively uncommon pediatric clinical syndrome; (2) symptoms of pediatric heart failure have significant overlap with symptoms of other common childhood disease processes, such as acute gastroenteritis or bronchiolitis²³; and (3) inferring hemodynamic status based on clinical examination in pediatric patients can be difficult. Recent studies have demonstrated that abdominal complaints such as nausea, vomiting, abdominal pain, decreased appetite, or weight loss (secondary to venous congestion and/or low cardiac output) are common presenting symptoms of heart failure in infants, children, and adolescents,^23–25 whereas classic cardiovascular features of heart failure are more likely to be present in adults. Thus, heart failure should be included in the differential diagnosis of children presenting with gastrointestinal symptoms.²⁵ Assessment of a child’s hemodynamic profile (warm, cold, wet, and dry) can assist with risk stratification in the setting of heart failure, with death or deterioration being highest among children with both congestion and low cardiac output.²⁶ Nevertheless, clinical evaluation of filling pressures in children can be challenging^24,26; the presence of overt pedal or facial edema and ascites are uncommon in patients with pediatric heart failure²⁷ despite the fact that venous congestion (pulmonary capillary wedge pressure >15 mm Hg) is common in children with end-stage heart failure.²⁶ Given the limitations of the pediatric examination in demonstrating classic signs of heart failure, early consultation with a pediatric cardiologist is recommended along with use of complementary testing. Laboratory testing (B-type natriuretic peptide), imaging (echocardiogram, chest radiograph, cardiac magnetic resonance imaging), and invasive testing (cardiac catheterization) may be indicated.

In addition to the clinical challenges of diagnosing new-onset pediatric heart failure, a uniform definition of pediatric heart failure is needed to provide a consistent approach to report and assess outcomes in this population (currently underway).

Pediatric Heart Failure is Distinct from Adult Heart Failure

Detailed investigations of the molecular alterations associated with heart failure in adults have been ongoing for several decades, resulting in progress in medical management and dramatically improved survival. In contrast, focused investigations of the molecular mechanisms underlying pediatric heart failure have started only relatively recently and provide a growing body of evidence suggesting that heart failure in children is unique from that in adults, which may, in part, account for the limited efficacy of medical therapies extrapolated from the adult heart failure experience.^17,21,28,29 Specifically, pediatric hearts that have failed secondary to DCM demonstrate unique β-adrenergic receptor adaptation, with downregulation of both β₁ and β₂ adrenergic receptors, and only β₁ adrenergic receptors are downregulated in adults with DCM.³⁰ In addition, the myocardium in pediatric DCM demonstrates increased cyclic adenosine monophosphate and phospholamban phosphorylation in response to chronic phosphodiesterase 3 inhibition, which is not seen in adult hearts with DCM.³¹ Similarly, unique gene expression profiles of adenylyl cyclase isoforms and phosphosdiesterase families support differential molecular adaptation to heart failure in children compared with adults.³² Fibrosis appears to play a less prominent role in the progression of heart failure in children with DCM compared with their adult counterparts.^33,34 Circulating factors that may influence disease progression are also likely to be unique to the pediatric age group.^35,36 Furthermore, pediatric patients with heart failure secondary to SV CHD demonstrate unique β-adrenergic adaptation,³⁷ phosphodiesterase expression³² and activity,³⁸ and fibrotic gene expression profiles.³⁹

Limitations of Medical Therapies and Future Directions

The aforementioned molecular differences between adult and pediatric heart failure may contribute to the limited success of adult heart failure therapies in children with heart failure.^20,29 Treatment options tailored specifically to pediatric heart failure do not currently exist. Current adult heart failure guidelines recommend use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, and aldosterone receptor antagonists for patients with heart failure with reduced ejection fraction, all with class of recommendation I and level of evidence A.⁵ Conversely, large, multicenter, randomized-controlled trials in pediatric heart failure are rare, and the vast majority of treatment recommendations are level of evidence C.^27,40

Significant improvements in pediatric heart failure outcomes require a shift in the traditional clinical and translational research model. First, appropriate therapeutic drug targets identified at the bench should progress toward drug development specifically for children. Currently, pharmaceutical companies are deterred by the relatively narrow indication of pediatric heart failure (particularly in comparison with the large number of adult patients with heart failure), precluding development of medications that may be effective in children but not adults. Second, conclusions from traditional clinical trials utilizing frequentist statistical design are often limited by the small patient populations common to many pediatric diseases. Applying Bayesian statistical methods to pediatric clinical trial design allows for incorporation of prior information and adaptive trial design,⁴¹ in the hopes of obtaining meaningful and significant results from a limited sample size. Greater utilization of comparative effectiveness research in pediatric heart failure may better assess the role of health care delivery and public health interventions on health-related outcomes. The National Heart, Blood, and Lung Institute has proposed creation of new paradigms for pediatric heart failure, focusing research on molecular mechanisms relevant to pediatric heart failure, development of relevant surrogate endpoints, expansion of existing registries, and encouraging collaboration within the pediatric heart failure community.⁴² In addition, the National Heart, Blood, and Lung Institute established the Pediatric Circulatory Support Program to fund the development of novel circulatory support devices for children with medically refractory heart failure,⁴³ with the goal of miniaturized VADs appropriate for pediatric-sized patients providing the opportunity to transition to the outpatient realm. Lastly, notable progress in the care of pediatric heart failure patients may arise from robust, systematic quality improvement efforts such as ongoing projects through the Advance Cardiac Therapies Improving Outcomes Network, a learning health network.

Heart Failure as a Chronic Disease

Given the sheer number of affected individuals and societal cost of caring for adult patients with heart failure, substantial effort has been invested in improving the chronic clinical care of these patients. Review of 29 randomized trials demonstrated that adult heart failure management programs that involve specialized follow-up by multidisciplinary teams decrease both mortality and hospitalizations.⁴⁴ This multidisciplinary infrastructure is thought to better address the complex interplay between medical, psychosocial, and behavioral factors facing patients with heart failure and their families, and the beneficial effects of these multidisciplinary strategies are comparable in magnitude to those afforded by pharmacologic treatment, such as angiotensin converting enzyme inhibitors.⁴⁴ Three key components to an effective multidisciplinary heart failure program include a nurse specifically trained in heart failure, patient heart failure education (including precipitating factors, medication adherence, and nutritional guidance), and accessible heart failure clinicians.⁴⁴ Although currently rarely implemented in the pediatric population, development of programmatic infrastructure to address the psychosocial, financial, and comorbid disease states associated with pediatric heart failure may be similarly effective in improving quality of life and decreasing hospital re-admission rates in children with heart failure. Support from policymakers and hospital administration will be key to the implementation of multidisciplinary teams that bridge inpatient and outpatient heart failure care for children.

Conclusions

Pediatric heart failure remains a devastating diagnosis for many children and their families, and represents a significant health care cost burden. Improvements in both outcomes and resource utilization may be achieved through (1) improving our ability to diagnose heart failure in a timely manner, (2) supporting pediatric-specific heart failure investigations in order to develop tailored, efficacious therapies, and (3) advocating for multidisciplinary, integrated care models to support pediatric heart failure as a chronic disease.

Glossary

CHD

Congenital heart disease

DCM

Dilated cardiomyopathy

SV

Single ventricle physiology

VAD

Ventricular assist device