Targeting BMPR2 Signaling to Improve Right Ventricular Function in Congenital Heart Disease
Abstract
Congenital heart disease (CHD), meaning a heart defect present at birth, is the most common class of birth defects (1 in 120 newborns) and is one of the leading causes of death of children below the age of 1. Despite major advances in surgical techniques, the repair of these congenital defects is often imperfect and repetitive surgeries are required in many children until adulthood. Certain defects affect more the right side of the heart ? examples would be defects such as tetralogy of Fallot and a transposition of the great arteries. Children and adults with these types of heart defect often develop right-sided heart failure, which affects their quality of life and survival. No therapy currently exists that could strengthen the right heart in particular. Medications that are used to treat left heart failure either do not work or are even harmful in right heart failure. We propose to study a specific signaling pathway in right heart failure ? the Bone Morphogenetic Protein receptor 2 (BMPR2) pathway. We have evidence that this pathway is downregulated in right heart failure and that low BMPR2 contributes to scarring and reduced blood supply to the right heart. In our previous work, we have screened over 3600 Food and Drug Administration-approved drugs to find a drug that could activate the BMPR2 pathway and have identified one drug that has been in clinical use for over 20 years ? the immunosuppressive drug FK506 (Tacrolimus). FK506 is able to activate BMPR2 at very low, sub-immunosuppressive doses and is therefore very safe. While we have used FK506 already for a different disease that is characterized by low BMPR2 signaling, pulmonary hypertension, and shown that it improved experimental pulmonary hypertension and furthermore started a clinical trial, the potential effect of FK506 on the right heart has not been studied. In this proposal, we will first study the effect of BMPR2 signaling and FK506 on cells involved in right heart scarring and reduced blood supply. We will then use animal models of chronic right heart failure to test whether we can prevent the development of right heart failure and scarring by increasing BMPR2 signaling. Lastly, we will develop a non-invasive blood biomarker to assess which patients with CHD are deficient in BMPR2 and might benefit from a ?BMPR2- activating? therapy with FK506. Our research is highly significant for patients with CHD and will benefit the civilian population as well as address a military need. For children and adults with repairs of their CHD who achieve excellent levels of physical activity (e.g., the Olympic champion Shaun White) and who would like to enlist in military service, it will be very valuable to be able prevent the development of late right ventricle failure. For children with CHD lesions that cannot be totally repaired and who require multi-stage palliation surgery over several years a ?right heart supportive? therapy might delay surgery and improve quality of life and survival. For military personnel, whose dependents are born with severe CHD, who often require long absences from their assigned duties, are distracted due to worry about a child?s condition, and in many cases require reassignment so that the Service member can live closer to a center of excellence for pediatric cardiovascular care, a therapy that would improve the outcome of their children would present a major breakthrough.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710327
Entities
People
- Edda Spiekerkoetter
Organizations
- Stanford University
- United States Army