Pulmonary Vascular Growth in Infants with Single Ventricle Heart Disease: Deep Phenotyping and Biomarker Development

Doctor's Name: 
Jesse Davidson
Hospital/Institution: 
University of Colorado Denver

Collaboratively awarded through the CHF and AHA Congenital Heart Defect Research Awards (Total Grant Amount $216,000; CHF portion = $108,000)

SUMMARY: Single ventricle heart disease (SVHD) is a common and severe form of congenital heart disease. No cure exists, but life can be prolonged into adulthood through a series of three palliative surgeries that reroute blood into the lungs without assistance from the heart. Despite these surgeries, transplant-free survival in the first year is <70%. Survivors suffer a lifetime of complications often due to pathologic pulmonary blood flow. Better diagnostic and therapeutic strategies are desperately needed to improve pulmonary vascular development and blood flow in this high risk population. We propose a hypothesis driven study of endothelin-1 (ET-1; a potent pulmonary vasoconstrictor) combined with unbiased metabolomic and proteomic analysis in infants undergoing stage 2 palliation (superior cavopulmonary anastomosis-SCPA or Glenn shunt). The overall study aim is to identify novel biomarkers and biologic pathways associated with poor early pulmonary vascular development and post-operative hypoxemia. Aims--In infants undergoing SCPA: 1) Measure the association between ET1 concentration, pulmonary vascular development, and post-operative hypoxemia 2) Identify metabolic alterations associated with poor pulmonary vascular development and hypoxemia 3) Perform preliminary protein pathway assessment in infants with poor pulmonary vascular development and hypoxemia Innovation: 1) First evaluation in SVHD of ET-1 and early pulmonary vascular development 2) Novel application of metabolomic and proteomic assays to assess the molecular phenotype of this population 3) Development of the first pediatric cardiology deep phenotype dataset to be made available to researchers world-wide through the AHA Precision Medicine Platform Approach: Prospective cohort study of 50 infants undergoing SCPA and 50 healthy controls. Serum samples will be collected at pre-SCPA cardiac catheterization and 1, 24, and 48 hours post-operation. Control samples will be collected during elective surgeries. Impact: 1) Form the foundation for development of ET-1 as a clinical diagnostic test followed by biomarker-directed clinical trials of ET-1 receptor antagonists in high risk patients 2) Accelerate the development of biomarker panels and the identification of novel therapeutic targets in high risk SVHD patients 3) Stimulate broad ongoing research in this critical population through open source data-sharing of this pediatric cardiology deep phenotype dataset.

Award Date 1: 
2018
Award Amount 1: 
$108,000