Pulmonary Vascular Development in Single Ventricle Heart Disease: A Longitudinal Biomarker Approach

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Project Summary/Abstract Background: Children with single ventricle heart disease (SVHD) experience significant morbidity due to inadequate pulmonary blood flow from insufficient pulmonary vascular development. Options to diagnose and treat this pathologic pulmonary vascular development remain limited. Endothelin-1 (ET1) and both arginine/nitric oxide (NO) and tryptophan metabolites have been linked to pathologic pulmonary vascular development. Preliminary data from our group demonstrate alterations in circulating ET1, arginine metabolites, and tryptophan metabolites at the time of Stage 2 palliation. Persistence of these pathway abnormalities between Stage 2 and Stage 3 palliation and their association with outcomes have not been studied. Hypothesis: Increased ET1 and dysregulation of the arginine/NO and tryptophan pathways in SVHD patients undergoing staged palliation disrupts pulmonary vascular development, leading to decreased pulmonary blood flow, worsened hypoxemia, and cardiorespiratory morbidities during the critical pre-Stage 3 growth years, the immediate post-operative period, and throughout childhood. Aims: Quantify serum concentrations of ET1, arginine/NO metabolites, and tryptophan metabolites in SVHD subjects immediately prior to and following both Stage 2 and Stage 3 palliation, and at the time of post-Fontan cardiac MRI to: 1) determine the association between biomarker abnormalities at Stage 2, persistent pathway changes at Stage 3, and pulmonary vascular growth by Stage 3, 2) evaluate the association between biomarker abnormalities at Stage 3, pulmonary vascular adequacy for the Stage 3 operation, and post-operative complications, and 3) determine the relationship between a pro-angiogenic metabolic signature, changes in aorto-pulmonary collateral burden, and altered pulmonary arterial flow dynamics before and after Stage 3. Methods: Longitudinal, prospective cohort study in children undergoing staged SVHD palliation combined with a cross-sectional study of older SVHD patients. Impact: 1) First longitudinal study of ET1 exposure early in SVHD palliation to support future development of ET1 as a clinical diagnostic test and biomarker-directed clinical trials of ET1 receptor antagonist. 2) First comprehensive pathway mapping of arginine/NO and tryptophan metabolism as markers of pathologic pulmonary vascular development in CHD. 3) Novel metabolomic approach to understanding AP collateral phenotype and identification of new markers of disease/potential therapeutic targets. Career Development: The proposed study will allow me to gain the data, skills, experience, and publications needed to support my transition to independent research. I will augment this with a Master of Science degree in the Clinical Sciences (MSCS) specifically targeting advanced data analysis and clinical trial design. Combined, these development aims will position me to achieve my goal of becoming an R01 funded expert in pulmonary vascular development in children with congenital heart disease.