Abstract
There are growing numbers of infants and children living with single-ventricle congenital heart disease (SV). However, cardiac dysfunction and, ultimately, heart failure (HF) are common in the SV population and the ability to predict the progression to HF in SV patients has been limited, primarily due to an incomplete understanding of the disease pathogenesis. Here, we tested the hypothesis that non-invasive circulating metabolomic profiles can serve as novel biomarkers in the SV population. We performed systematic metabolomic and pathway analyses on a subset of pediatric SV non-failing (SVNF) and failing (SVHF) serum samples, compared with samples from biventricular non-failing (BVNF) controls. We determined that serum metabolite panels were sufficient to discriminate SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects. Many of the identified significantly dysregulated metabolites were amino acids, energetic intermediates and nucleotides. Specifically, we identified pyruvate, palmitoylcarnitine, 2-oxoglutarate and GTP as promising circulating biomarkers that could be used for SV risk stratification, monitoring response to therapy and even as novel targets of therapeutic intervention in a population with few other options.
Highlights
Due to enhanced surgical interventions, better long-term care and improved treatment of late sequelae, the population of children and young adults living with congenital heart disease (CHD) is on the rise
There were no significant differences in age in the biventricular non-failing (BVNF) vs. the SVHF groups (p > 0.99) or the SV non-failing (SVNF) vs. the SVHF groups (p = 0.15); the SVNF patients were significantly younger than the BVNF cohort (p = 0.02)
Our metabolomic analysis revealed that serum circulating metabolite profiles and pathways differentiated SVHF subjects from BVNF subjects, as well as SVHF subjects from SVNF subjects, including pathways related to specific amino acids, energetic intermediates and nucleotides
Summary
Due to enhanced surgical interventions, better long-term care and improved treatment of late sequelae, the population of children and young adults living with congenital heart disease (CHD) is on the rise. The survival benefit is most striking in patients with complex lesions, such as those with single-ventricle congenital heart disease (SV), and it is estimated that there are about 1.6 per 10,000 children and young adults living with SV physiology today [1]. The increased survival of infants and children with SV results in a growing number of patients at risk for this atypical form of heart failure (HF) and prototypical pharmacological HF therapies have been largely ineffective in mitigating the need for cardiac transplantation [1,2,3,4]. There is an unmet need to identify predictive and prognostic biomarkers that can provide both a rational basis for treatment and a better understanding of risk stratification and HF progression in the SV population
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