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Big data biochemistry research, also known as omics, involves measuring biochemical molecules ranging from hundreds to hundreds of thousands. This approach allows investigators to understand data on a much larger and different scope and scale, in contrast to traditional biomarker strategies that focus on single molecules or small panels.
Areas of research categorized as omics include genomics (DNA), transcriptomics (RNA), proteomics (proteins) and metabolomics (metabolites).
Omics research begins with inductive reasoning, identifying unanticipated patterns in the data, followed by hypothesis-driven science. It can transform a basic profiling study into an exploration of deeper realms, with the potential to directly impact patient care.
Applications for omics research include a thorough exploration of the biological systems affected in complex diseases, identification of candidate molecules and pathways for subsequent study of disease mechanisms and translation to clinical care through the development of novel biomarkers and medical therapies.
Congenital heart disease, characterized by abnormalities in the structure of the heart that affect how it functions and circulates blood, is an optimal application for an omics approach for several reasons:
- Disease complexity
- Longitudinal nature
- Repeated physiological derangement (disturbance of normal bodily function), including:
- Direct surgical trauma
- Ischemia‐reperfusion injury
- Systemic inflammation
- Low blood flow to vital organs
- Chronic cyanosis (low blood oxygen levels)
- Potential for interventions needed (i.e., pediatric heart surgery, cardiac catheterization, heart transplant)
Around 40,000 babies born each year in the U.S. are affected by congenital heart disease, and approximately 25% require intervention within the first year of life. More than 10% of infants won’t survive high-risk surgery, and 30% to 40% of infants who do survive surgery will face complications.
Published omics research in congenital heart disease
Two physician scientists at the Children’s Hospital Colorado Heart Institute have spent several years conducting omics-based research to better understand why infants with congenital heart disease who undergo complex cardiac surgery are at an elevated risk for poor outcomes.
Jesse Davidson, MD, MPH, associate medical director of the Child Health Research Enterprise, and Benjamin Frank, MD, published their first omics-focused paper in 2018, where they sought to characterize metabolomic changes caused by surgery in these patients. The pair, along with research collaborators at Children’s Colorado and University of Colorado School of Medicine, have since conducted several additional, related multi-omics studies.
Presentations of preliminary research findings
Drs. Davidson and Frank, along with their research colleagues, have many ongoing studies that continue to edge them closer to discovering new approaches for clinical care and treatment to improve outcomes for patients with congenital heart disease.
In August of 2023, team members presented the preliminary findings of several studies at the World Congress of Pediatric Cardiology and Cardiac Surgery in Washington, DC.
A 2023 prospective observational cohort study is the first to report mapping of the arginine metabolism pathway in patients with single ventricle heart disease undergoing stage 2 palliation. Study authors hypothesized interstage single ventricle heart disease infants would have decreased circulating levels of arginine pathway intermediates compared to control infants who underwent non-cardiac surgery.
The study population included 75 infants with single ventricle heart disease undergoing stage 2 palliation and 76 similar age infants undergoing non-cardiac surgery.
Data collection and analysis
- Venous samples collected preoperative and 2-, 24- and 48-hours postoperatively
- O2 saturation in the first 48 postoperative hours and arginine metabolite concentrations
- Multivariable analysis controlling for key clinical factors
Findings
- Six of nine metabolites analyzed differed between cases and controls, including decreased arginine and increased asymmetric dimethyl arginine levels.
- Pathway changes, including decreased arginine and citrulline levels, persisted through 48 hours.
- Increased asymmetric dimethyl arginine levels at 24 hours were associated with greater postoperative hypoxemia burden.
- A longer postoperative length of stay was linked to lower preoperative and 2-hour postoperative concentrations of several metabolites, including arginine and citrulline.
Conclusions
Arginine metabolism mapping could inform a biomarker-directed, personalized medicine approach to identify the single ventricle heart disease patients most likely to benefit from pulmonary vascular interventions.
Patients with single ventricle heart disease experience significant neurologic injury, particularly damage to white matter, causing lifelong neurodevelopmental abnormalities, yet there are no clinically available biomarkers of either. This study, presented at the Pediatric Cardiac Intensive Care Society Annual International Meeting in December 2022, sought to identify new predictors of neurologic injury to risk-stratify patients using precision medicine.
Study participants included 33 patients with single ventricle heart disease and 24 healthy controls.
Data collection and analysis
- Expanded analysis of 1,500 proteins in infants undergoing stage 2 palliation
- Patients with single ventricle heart disease followed for 36 months
- 13 patients underwent neurodevelopmental testing, compared by secondary analysis
- Eight had abnormal Motor Composite Scores
- Six had abnormal Cognitive Composite Scores
Findings
- 568 proteins circulating in the blood differed between patients with single ventricle heart disease and controls
- Distinguishing proteins included proteins inducing inflammatory cascades in brain, heart, liver, vasculature
- Proteomic profiling sufficiently distinguished normal versus abnormal scores of motor and cognitive developments in sub-cohort
Conclusions
Preliminary data from this study identified promising proteins with biologic plausibility as markers of neurologic injury or impaired neurodevelopment warranting further investigation.
How tryptophan is metabolized through the kynurenine pathway plays a key role in how the body’s immune system responds to physiological stress. Infants with congenital heart disease that undergo cardiac surgery with cardiopulmonary bypass experience a general upward shift in kynurenine pathway activity, and at least one of these intermediates can increase post-surgical death.
This study sought to determine if changes in kynurenine pathway metabolite levels were associated with length of stay and vasoactive inotropic score.
Study participants included 96 infants under 6 months old with congenital heart disease undergoing cardiopulmonary bypass.
Data collection and analysis
- Recorded perioperative changes in kynurenine pathway metabolites
- Measured key circulating pathway enzyme levels
- Cross-sectional analysis performed to associate metabolite levels at each timepoint with vasoactive inotropic score at 48 hours and length of stay
Findings
- All kynurenine pathway metabolites and pathway enzymes significantly altered at some point during the postoperative period
- Changes in pathway enzyme levels demonstrate potential rate limiting steps within the kynurenine pathway
- Vasoactive inotropic score linked to significant baseline elevations in kynurenic acid and picolinic acid, 2- and 24-hour postoperative decline in kynurenine, 24-and 48-hour postoperative decline in anthranilic acid
- Length of stay linked to elevated circulating kynurenic acid and picolinic acid at all time points
Conclusions
Kynurenic acid and picolinic acid serum concentration throughout the perioperative period could be powerful predictors of clinical outcomes and may help clinicians develop a personalized approach when treating infants undergoing cardiopulmonary bypass.
Little is known about amino profiles of infants prior to cardiopulmonary bypass surgery and the preoperative factors that affect those levels or the effect of preoperative nutrition on perioperative amino acid levels.
This study evaluated the trend of serum levels of circulating amino acids in patients undergoing congenital heart disease surgery with cardiopulmonary bypass and the impact of key preoperative factors on perioperative circulating amino acid levels.
Study participants included 83 infants under 120 days old undergoing congenital heart disease surgery.
Data collection and analysis
- Secondary analysis of 19 previously collected and measured circulating amino acid levels
- Evaluation of 58 samples collected preoperatively during rewarming from cardiopulmonary bypass and 24 hours after admission to the cardiac intensive care unit
Findings
- 16 amino acids exhibited significantly decreased serum levels at rewarming
- 11 of the 16 continued to decrease through 24 hours into cardiac intensive care unit admission
- Age, weight, ductal dependence and route of preoperative nutrition impacted preoperative amino acid levels
- Key amino acid levels significantly higher in infants receiving preoperative enteral nutrition than in infants exclusively receiving parenteral nutrition at pre-bypass, rewarming and 24 hours after bypass
Conclusions
The administration of enteral nutrition preoperatively may prevent or lessen the decrease in amino acid levels after cardiopulmonary bypass. More research is needed to determine if low amino levels affect outcomes and if this population should receive additional perioperative amino acid supplementation.
Cardiopulmonary bypass with deep hypothermic circulatory arrest is known to cause
systemic inflammation, ischemia-reperfusion injury and significant disruptions to the circulating metabolome and proteome. This study aimed to define the poorly understood organ-specific transcriptome response of a model of cardiopulmonary bypass with deep hypothermic circulatory arrest compared to mechanically ventilated control models.
Study participants included 7 models and 8 control models.
Data collection and analysis
- 6 hours of critical care after separated from bypass
- Samples of lung, liver, kidney, heart, ileum
- Whole transcriptome sequencing performed
- Analysis of differentially expressed gene and pathway/network
Findings
Cardiopulmonary bypass with deep hypothermic circulatory arrest altered transcription in all organs analyzed.
- Largest changes found (most to least) in liver, heart, lung, kidneys
- Response different among all organs
- Only 15% overlap in differentially expressed genes
- Upregulations:
- Protein synthesis and mitochondrial gene expression in liver
- Wound repair/regeneration and detoxification in kidney
- Protein synthesis in cardiac muscle
- Fluid/electrolyte transport, metal ion detoxification in liver
- Cellular response to cardiovascular peptide hormones in ileum
- Downregulations:
- Shared immune response in the heart, liver, kidney
- Mainly adaptive immune pathways
Conclusions
Individual organs likely contribute differently to the systemic postoperative response. Differentially expressed gene patterns could inform the investigation of targeted therapies for the prevention and treatment of organ injury after cardiac surgery.
Featured researchers
Jesse Davidson, MD, MPH
Cardiologist, associate medical director
Child Health Research Enterprise
Children’s Hospital Colorado
Associate professor
Pediatrics-Cardiology
University of Colorado School of Medicine
Benjamin Frank, MD
Cardiologist
The Heart Institute
Children’s Hospital Colorado
Assistant professor
Pediatrics-Cardiology
University of Colorado School of Medicine
