Metabolic abnormalities in pediatric pulmonary arterial hypertension: a narrative review of direct evidence, mechanistic boundaries, and a validation-focused research agenda
Year: 2026
Type: review
Abstract: Background and Objective: 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. Methods: 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. Key Content and Findings: 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. Conclusions: 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.
Source: Translational Pediatrics
Authors: Kexin Sui, Xunan Jia, Shuai Wang, Zhijun Li
Institution: Heilongjiang University of Chinese Medicine
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223313934