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NHLBI Working Group: New Targets for Pediatric Heart Failure

Executive Summary

April 18 and 19, 2013, Rockville, MD

Purpose:

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group meeting on April 18-19, 2013 in Rockville, MD to assess the current state of science and to identify new targets for research in pediatric heart failure. The Working Group consisted of experts in pediatric and adult cardiology, heart failure, cardiomyopathy, cardiomyocyte proliferation, genomics, pediatric cardiac surgery, myocellular signaling, inherited myopathies, gene therapy, and cardiac imaging. The working group supports Goal 1 of the NHLBI Strategic Mission.

Discussion:
Unlike adult heart failure, which results from myocardial damage, heart failure in children comes in several varieties. The final common pathway involves circulatory, neurohormonal and molecular abnormalities and manifests with symptoms of edema, respiratory distress, growth failure, and exercise intolerance. However, the myriad underlying etiologies of pediatric heart failure include not only myocardial insults (e.g., dilated cardiomyopathy), but also volume overload (e.g., left to right shunts and valvular regurgitation), obstruction to flow (e.g. aortic stenosis), elevated systemic venous pressure, and reliance on a right ventricle that was not designed to pump against systemic afterload (e.g., palliated complex congenital heart disease).

The burden of pediatric heart failure has been underappreciated and constitutes an important pediatric public health problem in the United States. Children with heart failure require frequent hospitalizations and suffer significant morbidity. The number of hospitalizations for pediatric heart failure is comparable to pediatric sepsis, and the number of hospitalizations in individuals with congenital heart disease increases with age. Advances in outcomes for children with heart failure have not kept pace with advances in adult heart failure. Mortality rates remain unacceptably high, and length of stay and charges are increasing over time.

Very few of the clinical guidelines for management of heart failure in children are based on data from clinical trials. Moreover, pediatric heart failure trials have demonstrated that medications known to be successful in treating adult heart failure are not effective in children. The largest and most recent of these two trials, the Pediatric Heart Network’s Infant Single Ventricle Trial, provides further evidence that extrapolation of data from adult studies may not be appropriate for pediatric conditions.

Therefore, there is an important need to understand the cellular and genetic mechanisms that are unique to pediatric heart failure to properly inform the development of appropriate therapies. Recent advances in genomics, regenerative medicine, stem cell biology, and imaging make this an ideal time to evaluate how these fields/techniques can be applied to facilitate understanding of pediatric heart failure.

The working group acknowledged the significance of the problem and agreed that pediatric heart failure is a viable research area with many avenues for potential impact.

Recommendations:
The group outlined the following research recommendations to move the field of pediatric heart failure forward:

  1. Create new paradigms for pediatric heart failure. Understanding pediatric heart failure requires new approaches that:
    • Recognize the interdependence of the cardiac ventricles,
    • Avoid hand-me down dogma from adult research and apply a bottom-up approach, and
    • Acknowledge that one size does not fit all; that personalized approaches are imperative to effectively understand and treat the heterogeneous population of children with heart failure.
  2. Focus research on molecular mechanisms of specific relevance to pediatric heart failure:
    • Myocardial architecture/ventricular interactions
    • Fibrosis
    • MicroRNA
    • Cell cycling, regeneration, induced pluripotent stem cells
    • Cytoskeleton, sarcomere, Z-disk
    • Devices - with an emphasis on recovery
    • Genetics
    • Viral myocarditis
  3. Encourage collaboration in the pediatric heart failure community, with the goal of bringing together and augmenting existing resources:
    • Conduct multicenter collaborative trials.
    • Leverage existing resources such as the Pediatric Cardiac Genomics Consortium, the Pediatric Heart Network, the Cell Therapy Network, the Pediatric Cardiomyopathy Registry and the Pediatric Cardiomyopathy Specimen Repository.
    • Develop a national pediatric heart failure registry. Conducting large-scale randomized clinical trials poses significant challenges in this population. In the absence of such trials, a national heart failure registry could provide a wealth of meaningful data. For example, a registry could help to identify subpopulations that may benefit from targeted therapies and may provide a means of linking phenotypic and genotypic data. It may also identify high performing centers with model practices that can be shared with other centers.
  4. Expand existing phenotype registries/databases. There is potential to significantly increase our understanding of mechanisms, outcomes, and responses to therapy if existing databases and registries were expanded to include genomic data, increased granularity, and systematically-collected longitudinal data.
  5. Develop surrogate systems and endpoints that are relevant to the pediatric heart failure population. The ability to translate basic research to improve patient care will rely on appropriate models for pediatric heart failure and meaningful, measurable endpoints for study.
  6. Create industry partnerships. Despite traditional misconceptions, there are enough children with heart failure and an increasing financial burden to garner industry support for research efforts in pediatric heart failure. Partnerships should focus on novel areas specific to children, including partial extracardiac support, ventricular assist devices, biological therapeutics for rare diseases, and drug repurposing. Specific regulatory opportunities, such as the Orphan Disease Program and patent extensions for pediatric indications, should be leveraged to facilitate such partnerships.

Publication Plans:
The group plans to prepare a manuscript delineating these recommendations for publication in a peer-reviewed journal.

NHLBI Contact:

Kristin M. Burns, M.D.
Kristin.burns@nih.gov

Working Group Members:

Co-Chairs:

  • Andrew N. Redington, M.D., The Hospital for Sick Children, Toronto
  • Jeffrey A. Towbin, M.D., Cincinnati Children’s Hospital Medical Center

Members:

  • Barry J. Byrne, M.D., Ph.D., University of Florida
  • Bruce D. Gelb, M.D., Icahn School of Medicine at Mount Sinai, New York
  • Bernhard Kühn, M.D., Boston Children’s Hospital
  • Leslie A. Leinwand, Ph.D., BioFrontiers Institute, University of Colorado, Boulder
  • Seema Mital, M.D., The Hospital for Sick Children, Toronto
  • Mark Rodefeld, M.D., Indiana University School of Medicine
  • Joseph W. Rossano, M.D., The Children’s Hospital of Philadelphia
  • Brian Stauffer, M.D., University of Colorado School of Medicine
  • Michael D. Taylor, M.D., Ph.D., Cincinnati Children’s Hospital Medical Center

NHLBI Staff:

  • Kristin M. Burns, M.D.
  • Denis Buxton, Ph.D.
  • Jonathan R. Kaltman, M.D.
  • Michele Olive, Ph.D.
  • Gail D. Pearson, M.D., Sc.D.
  • Ellen R. Rosenberg, R.N.
  • Charlene A. Schramm, Ph.D.
  • Monica R. Shah, M.D.
  • Jane Scott, Sc.D., M.S.N.
  • Jacqueline G. Weinberg, M.D.
  • Kimberly Wood

Last Updated: May 2013

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