An Explorative Metabolomic Analysis of the Endothelium in Pulmonary Hypertension

Pulmonary hypertension (PH) is classified into five clinical diagnostic groups, including group 1 [idiopathic pulmonary arterial hypertension (IPAH) and connective tissue disease-associated PAH (CTD-aPAH)] and group 4 (chronic thromboembolic pulmonary hypertension (CTEPH)). PH is a progressive, life-threatening, incurable disease. The pathological mechanisms underlying PH remain elusive; recent evidence has revealed that abnormal metabolic activities in the endothelium may play a crucial role. This research introduces a novel approach for studying PH endothelial function, building on the genome-scale metabolic reconstruction of the endothelial cell (EC) to investigate intracellular metabolism. We demonstrate that the intracellular metabolic activities of ECs in PH patients cluster into four phenotypes independent of the PH diagnosis. Notably, the disease severity differs significantly between the metabolic phenotypes, suggesting their clinical relevance. The significant metabolic differences between the PH phenotypes indicate that they may require different therapeutic interventions. In addition, diagnostic capabilities enabling their identification is warranted to investigate whether this opens a novel avenue of precision medicine.