# Metabolic profiling and comprehensive metabolic pathway mapping: a systems biology approach to cardiovascular failure and organ injury following infant congenital heart disease surgery

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $623,434

## Abstract

Project Summary
Twenty-five percent of children with congenital heart disease (CHD) undergo intervention in the first year of life,
often requiring surgery with cardiopulmonary bypass (CPB). CPB and related techniques including deep
hypothermic circulatory arrest (DHCA) are necessary but contribute to poor postoperative physiology. Mortality
for high risk surgeries remains >10%. Major complications occur in 30% of these complex surgeries and are
key drivers of hospital length of stay (LOS) and costs. Novel diagnostic, mechanistic, and therapeutic
approaches are critically needed to impact this burden on our infants, families, and healthcare system.
Metabolites are the small-molecule end products of the genome that collectively determine minute-to-minute
cellular physiology. Individual metabolites (e.g. lactate) are commonly used in postoperative management, but
the interrelated metabolomic changes induced by infant cardiac surgery remain poorly understood. Recently,
the metabolic profile of infants undergoing CPB was shown to shift markedly during the first 24hrs
postoperatively and metabolites from two related pathways (kynurenine and nicotinamide metabolism) were
associated with mortality and ICU LOS. Evolution of the postoperative metabolic profile beyond 24hrs and
comprehensive changes in circulating/tissue kynurenine and nicotinamide metabolites are unknown.
Overall Hypothesis: Infant cardiac surgery with CPB induces pathologic changes in the circulating metabolome
across multiple key metabolic pathways. These changes directly impact postoperative outcomes and organ
injury through a combination of beneficial metabolite depletion and pathologic metabolite production.
Proposal: The study will use a combined clinical and translational approach. The clinical arm will consist of a
prospective cohort study of infants undergoing CPB, with serial targeted metabolic profiling and pathway
mapping through 72hrs postoperatively. The complementary translational arm will consist of a piglet model of
CPB/DHCA to evaluate and modulate organ-specific flux through kynurenine and nicotinamide metabolism.
Specific Aim 1: Validate the association of the 24hr postoperative metabolic profile with the combined outcome
of death, cardiac arrest, or mechanical circulatory support and determine the evolution of this pathologic
metabolic profile through 72hrs postoperatively.
Specific Aim 2: Perform quantitative mapping of the kynurenine and nicotinamide metabolic pathways in order
to a) quantify individual metabolite abnormalities, b) identify contributing changes in pathway enzymes, and c)
determine the association of specific pathway abnormalities with postoperative outcomes.
Specific Aim 3: In a piglet model of CPB with DHCA, quantify circulating and organ-specific kynurenine and
nicotinamide pathway metabolites and determine the effects of pathway blockade on development of
postoperative acute organ injury using systemic indoleamine 2,3-dioxygenase inhibition.

## Key facts

- **NIH application ID:** 10400930
- **Project number:** 5R01HL156936-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jesse Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $623,434
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400930

## Citation

> US National Institutes of Health, RePORTER application 10400930, Metabolic profiling and comprehensive metabolic pathway mapping: a systems biology approach to cardiovascular failure and organ injury following infant congenital heart disease surgery (5R01HL156936-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400930. Licensed CC0.

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