New Mechanistic and Therapeutic Targets for Pediatric Heart Failure

Challenges and Opportunities in Pediatric Heart Failure and Transplantation 79 P ediatric heart failure (HF) is the inability of the heart of an infant, child, or adolescent to meet the body's metabolic demands.It involves circulatory, neurohumoral, and molecular abnormalities that manifest as edema, respiratory distress, growth failure, and exercise intolerance.The myriad causes include inherited and acquired myocardial anomalies (cardiomyopathy [CM]), volume overload (intracardiac shunts, valvular regurgitation), and the unique hemodynamics predicated by a functional single ventricle (palliated complex congenital heart disease [CHD]).Although the societal and financial costs of adult HF are well known, the burden of pediatric HF is less familiar, but no less onerous.New-onset HF requiring hospital admission occurs in 0.87 per 100 000 children, 1 yet that does not include the growing population with CHD-related HF.In 2006, there were nearly 14 000 pediatric hospitalizations for HF from all causes in the United States. 2 The rate of HF-related admissions was nearly 18 per 100 000 children, 2 which is comparable to severe sepsis.3 The mortality for pediatric HF hospitalizations is significant.The 7% overall hospital mortality rate exceeds the 4% mortality of adult HF admissions 4 and represents a 20-fold increase over children without HF. 2 With comorbidities like renal failure, sepsis, or stroke, hospital mortality in pediatric HF can exceed 20%, 2 yet the risk does not end with discharge.After an initial HF hospitalization, only 21% of children in 1 study avoided readmission, death, or transplantation.5 Pediatric HF treatment is resource intensive.Although the total healthcare costs for pediatric HF are lower than for adults, per-patient costs are higher.The estimated hospital charge per pediatric HF admission in 2006 was >$135 000, with aggregate charges exceeding $1.8 billion.6 Certain subpopulations of pediatric HF incurred disproportionally higher costs.For example, single-ventricle CHD averaged >$200 000 per hospitalization, 7 whereas adult HF admissions averaged <$25 000.8 These data do not account for the full burden of pediatric HF.There are no national cost estimates for outpatient pediatric HF management, and, because long-term survival rates are higher in children, the lifetime costs of HF in children are likely to be much higher than in adults.Few HF therapies are developed specifically for children, and drugs that benefit adults have not clearly demonstrated clinical effectiveness in pediatric HF. 9 In fact, pediatric HF therapy has not improved survival significantly over the past 30 years.10 Consequently, we need to understand the mechanisms unique to pediatric HF to inform the development of appropriate therapies. Working GroupIn April 2013, the National Heart, Lung, and Blood Institute convened a Working Group (WG) of experts in pediatric and adult cardiology, HF, CM, cardiomyocyte proliferation, genomics, pediatric cardiac surgery, gene therapy, and imaging.Although the WG acknowledged the need to improve clinical care and quality of life for children with HF, its purpose was to identify promising research targets, or mechanistic areas related to the unique pathogenesis of pediatric HF with possible therapeutic potential.

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