Metabolic signatures of transpulmonary gradients in atrial septal defect associated with pulmonary arterial hypertension
X Qian, Y Deng, T Guo, X Huang, X Gao, Y Wu, S Hu, J Tan, S Zhu, L Chong, J Cao, X Wang, L HuaAbstract
Introduction
Understanding the metabolic evolution of transpulmonary gradients in atrial septal defect associated with pulmonary arterial hypertension (ASD-PAH) helps elucidate the underlying pathobiology and reveal disease-specific biomarkers. However, the metabolic profile of pulmonary circulation in ASD-PAH remains poorly recognized.
Purpose
This study aimed to unveil metabolic signatures of transpulmonary gradients in patients with ASD-PAH.
Methods
Patients diagnosed with ASD, ASD-unclassified pulmonary hypertension (PH), and ASD-PAH were enrolled. Blood samples were collected from superior vena cava (SVC) and pulmonary vein (PV) through the defect when performing right cardiac catheterization. UHPLC-MS/MS-based non-targeted metabolomics analysis was utilized to generate metabolic signatures of transpulmonary gradients by comparing metabolite changes from SVC to PV in each group. Subsequently, unique metabolite gradients of pulmonary vascular bed was identified through between-group comparisons.
Results
1060 metabolites were detected in these blood samples from 16 ASD, 15 ASD-unclassified PH, and 39 ASD-PAH patients. A total of 61 differential metabolites in ASD, 109 in ASD-unclassified PH, and 49 in ASD-PAH were identified based on screening criteria after flowing through the lung. Afterwards, comparative analysis between groups (ASD vs ASD-unclassified PH) revealed that long-chain phospholipids and fatty acids, amino acids and their derivatives (methionine, N2-acetyl-L-ornithine, N-formylkynurenine, etc.), nucleotides (AICA ribonucleotide, guanosine, uridine, etc.), bases and their derivatives (xanthine, 7-methylguanine, paraxanthine, etc.) metabolism involved the process from ASD to ASD-unclassified PH. Similar metabolic shifts were also observed in the progression from ASD-unclassified PH to ASD-PAH.
Conclusion
Our study defines distinct metabolic signatures of transpulmonary gradients indicating towards a metabolic pathogenesis of developing from ASD to ASD-PAH, emphasizing the importance of these metabolites in promoting pulmonary vascular remodeling and devising therapeutic strategies.