Metabolic abnormalities in pediatric pulmonary arterial hypertension: a narrative review of direct evidence, mechanistic boundaries, and a validation-focused research agenda.
- 1Department of Pediatrics, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China.
- 2Department of Cardiology, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China.
- 3School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, China.
Abstract
Metabolic reprogramming has been proposed as a major mechanism of pulmonary arterial hypertension (PAH), but evidence from adult patients, experimental models, and children is uneven. This distinction is especially important in pediatric disease because congenital heart disease (CHD), developmental syndromes, identifiable genetic disorders, and treatable metabolic conditions are more prominent than in adult-onset PAH. This narrative review evaluates what has been measured directly in children, defines the boundaries of extrapolation from adult and experimental studies, and identifies priorities for pediatric validation. PubMed-indexed literature and reference lists were searched from database inception through July 2026 using terms related to pediatric PAH, metabolomics, proteomics, biomarkers, mitochondria, glycolysis, pyruvate dehydrogenase, right-ventricular metabolism, CHD, genetics, and cobalamin C deficiency. Priority was given to original pediatric cohorts and biospecimen studies, followed by adult human mechanistic studies with perturbation or rescue and experimental studies that directly measured metabolic function. Direct pediatric studies document severe and heterogeneous disease, a substantial burden of genetic diagnoses, clinically informative but mechanistically nonspecific circulating biomarkers, and exploratory serum and bronchoalveolar-lavage metabolomic signatures in CHD-associated PAH. These studies do not establish a shared pulmonary vascular metabolic mechanism. Cobalamin C (cblC) deficiency provides the clearest evidence that a defined metabolic disorder can cause severe pediatric pulmonary hypertension and that targeted biochemical treatment can normalize pulmonary pressure in many affected children. Adult human and experimental studies support candidate roles for pyruvate dehydrogenase regulation, mitochondrial redox signaling and fission, endothelial and fibroblast glycolysis, inflammation, and right-ventricular lipid handling, but these pathways remain candidates for pediatric testing rather than established pediatric targets. No metabolism-directed therapy has demonstrated efficacy and long-term safety in children with idiopathic, heritable, or CHD-associated PAH. Clinical practice should prioritize phenotype-directed screening for defined metabolic or nutritional disorders. Research should use pediatric subgroup-specific sampling, direct flux measurements, causal perturbation and rescue, independent replication, and prospective linkage to clinical outcomes.
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BibTeX
@article{sui2026metabolic,
title = {{Metabolic abnormalities in pediatric pulmonary arterial hypertension: a narrative review of direct evidence, mechanistic boundaries, and a validation-focused research agenda.}},
author = {Kexin Sui and Xunan Jia and Shuai Wang and Zhijun Li},
journal = {Translational pediatrics},
year = {2026},
month = sep,
doi = {10.21037/tp-2026-0781},
url = {https://europepmc.org/article/MED/42996402},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Metabolic abnormalities in pediatric pulmonary arterial hypertension: a narrative review of direct evidence, mechanistic boundaries, and a validation-focused research agenda.
AU - Kexin Sui
AU - Xunan Jia
AU - Shuai Wang
AU - Zhijun Li
PY - 2026
DA - 2026/09/30
JO - Translational pediatrics
DO - 10.21037/tp-2026-0781
UR - https://europepmc.org/article/MED/42996402
AB - Metabolic reprogramming has been proposed as a major mechanism of pulmonary arterial hypertension (PAH), but evidence from adult patients, experimental models, and children is uneven. This distinction is especially important in pediatric disease because congenital heart disease (CHD), developmental syndromes, identifiable genetic disorders, and treatable metabolic conditions are more prominent than in adult-onset PAH. This narrative review evaluates what has been measured directly in children, defines the boundaries of extrapolation from adult and experimental studies, and identifies priorities for pediatric validation. PubMed-indexed literature and reference lists were searched from database inception through July 2026 using terms related to pediatric PAH, metabolomics, proteomics, biomarkers, mitochondria, glycolysis, pyruvate dehydrogenase, right-ventricular metabolism, CHD, genetics, and cobalamin C deficiency. Priority was given to original pediatric cohorts and biospecimen studies, followed by adult human mechanistic studies with perturbation or rescue and experimental studies that directly measured metabolic function. Direct pediatric studies document severe and heterogeneous disease, a substantial burden of genetic diagnoses, clinically informative but mechanistically nonspecific circulating biomarkers, and exploratory serum and bronchoalveolar-lavage metabolomic signatures in CHD-associated PAH. These studies do not establish a shared pulmonary vascular metabolic mechanism. Cobalamin C (cblC) deficiency provides the clearest evidence that a defined metabolic disorder can cause severe pediatric pulmonary hypertension and that targeted biochemical treatment can normalize pulmonary pressure in many affected children. Adult human and experimental studies support candidate roles for pyruvate dehydrogenase regulation, mitochondrial redox signaling and fission, endothelial and fibroblast glycolysis, inflammation, and right-ventricular lipid handling, but these pathways remain candidates for pediatric testing rather than established pediatric targets. No metabolism-directed therapy has demonstrated efficacy and long-term safety in children with idiopathic, heritable, or CHD-associated PAH. Clinical practice should prioritize phenotype-directed screening for defined metabolic or nutritional disorders. Research should use pediatric subgroup-specific sampling, direct flux measurements, causal perturbation and rescue, independent replication, and prospective linkage to clinical outcomes.
SN - 2224-4336
SN - 2224-4344
ER -