Portal de Periódicos da CAPES

Metabolomic Profiles Differentiate Scleroderma-PAH From Idiopathic PAH and Correspond With Worsened Functional Capacity

2022; Elsevier BV; Volume: 163; Issue: 1 Linguagem: Inglês

10.1016/j.chest.2022.08.2230

1931-3543

Mona Alotaibi, Junzhe Shao, Michael W. Pauciulo, William C. Nichols, Anna R. Hemnes, Atul Malhotra, Nick H. Kim, Jason X.‐J. Yuan, Timothy M. Fernandes, Kim M. Kerr, Laith Alshawabkeh, Ankit A. Desai, Andreea M. Bujor, Robert Lafyatis, Jeramie D. Watrous, Tao Long, Susan Cheng, Stephen Y. Chan, Mohit Jain,

Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis

Background The prognosis and therapeutic responses are worse for pulmonary arterial hypertension associated with systemic sclerosis (SSc-PAH) compared with idiopathic pulmonary arterial hypertension (IPAH). This discrepancy could be driven by divergence in underlying metabolic determinants of disease. Research Question Are circulating bioactive metabolites differentially altered in SSc-PAH vs IPAH, and can this alteration explain clinical disparity between these PAH subgroups? Study Design and Methods Plasma biosamples from 400 patients with SSc-PAH and 1,082 patients with IPAH were included in the study. Another cohort of 100 patients with scleroderma with no PH and 44 patients with scleroderma with PH was included for external validation. More than 700 bioactive lipid metabolites, representing a range of vasoactive and immune-inflammatory pathways, were assayed in plasma samples from independent discovery and validation cohorts using liquid chromatography/high-resolution mass spectrometry-based approaches. Regression analyses were used to identify metabolites that exhibited differential levels between SSc-PAH and IPAH and associated with disease severity. Results From hundreds of circulating bioactive lipid molecules, five metabolites were found to distinguish between SSc-PAH and IPAH, as well as associate with markers of disease severity. Relative to IPAH, patients with SSc-PAH carried increased levels of fatty acid metabolites, including lignoceric acid and nervonic acid, as well as eicosanoids/oxylipins and sex hormone metabolites. Interpretation Patients with SSc-PAH are characterized by an unfavorable bioactive metabolic profile that may explain the poor and limited response to therapy. These data provide important metabolic insights into the molecular heterogeneity underlying differences between subgroups of PAH.