Mona Alotaibi, Junzhe Shao, Michael W. Pauciulo, William C. Nichols, Anna R. Hemnes, Atul Malhotra, Nick H. Kim, Jason X-J Yuan, Timothy Fernandes, Kim M. Kerr, Laith Alshawabkeh, Ankit A. Desai, Andreea M. Bujor, Robert Lafyatis, Jeramie D. Waltrous, Tao Long, Susan Cheng, Stephen Y. Chan, Mihit Jain
University of California San Diego. Peking University. University of Cincinnati and Cincinnati Children’s Hospital Medical Center. Vanderbilt University Medical Center. Indiana University. Boston University Medical Center. University of Pittsburgh Medical Center. Cedars-Sinai Medical Center.
United States and China
Chest
Chest 2023; 163: 204-215
DOI: 10.1016/j.chest.2022.08.2230
Abstract
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.
Category
Class I. Pulmonary Hypertension Associated with Connective Tissue Disease
Class I. Idiopathic Pulmonary Hypertension
Acquired Patient Factors Associated with Pulmonary Vascular Disease
Potential Biomarkers Associated with Pulmonary Vascular Disease
Age Focus: Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
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