Divergent Inflammatory and Bioenergetic Metabolomic Signatures Distinguish Methamphetamine-Associated From Idiopathic...

Methamphetamine-associated pulmonary arterial hypertension (Meth-APAH) is an increasingly recognized cause of pulmonary arterial hypertension (PAH) and is associated with worse outcomes than idiopathic PAH (IPAH). Although both share histopathologic features of pulmonary vascular remodeling, the molecular basis for their clinical divergence remains unclear, particularly at the metabolic level. We performed high-throughput, non-targeted plasma metabolomic profiling in patients with Meth-APAH and matched IPAH controls enrolled from the Pulmonary Arterial Hypertension Biobank. Multivariate and regression analyses adjusted for demographics, hemodynamic severity, and PAH therapies were used to identify distinguishing metabolites. Among 98 patients (49 Meth-APAH and 49 IPAH), baseline hemodynamics and functional status were similar, although Meth-APAH patients had higher smoking prevalence and lower PAH therapy use. Of 757 metabolites passing quality control, 55 differed significantly between subtypes, including 22 enriched in Meth-APAH. Meth-APAH was characterized by elevations in amino acid-derived metabolites and pro-inflammatory eicosanoids, implicating dysregulation of the kynurenine pathway and arachidonic acid metabolism. IPAH demonstrated relative enrichment of branched-chain amino acids, antioxidant metabolites, and specialized pro-resolving mediators. Exploratory survival analyses identified associations between subtype-discriminating metabolites and outcomes. These findings reveal metabolic heterogeneity across PAH etiologies and support biologically distinct pathobiology in Meth-APAH and IPAH.