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

> **NIH NIH K23** · UNIVERSITY OF COLORADO DENVER · 2024 · $186,859

## Abstract

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 childre...

## Key facts

- **NIH application ID:** 10756572
- **Project number:** 5K23HL163490-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Benjamin S Frank
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $186,859
- **Award type:** 5
- **Project period:** 2023-01-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756572

## Citation

> US National Institutes of Health, RePORTER application 10756572, Pulmonary Vascular Development in Single Ventricle Heart Disease: A Longitudinal Biomarker Approach (5K23HL163490-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10756572. Licensed CC0.

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