R01HL156936

Metabolic Profiling and Comprehensive Metabolic Pathway Mapping: A Systems Biology Approach to Cardiovascular Failure and Organ Injury Following Infant Congenital Heart Disease Surgery - 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 24 hours 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 24 hours 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 72 hours 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 24-hour 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 72 hours 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 the development of postoperative acute organ injury using systemic indoleamine 2,3-dioxygenase inhibition.

The Regents Of The Univ. Of Colorado

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Aurora, Colorado 800457106 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 445% from $561,992 to $3,061,754.