Catherine E. Simpson, Anna R. Hemnes, Megan Griffiths, Gabriele Grunig, W. H. Wison Tang, Joe G. N. Garcia, John Barnard, Suzy A. Comhair, Rachel L. Damico, Stephen C. Mathai, Paul M. Hassoun, the PVDOMICS Study Group
Johns Hopkins University. Vanderbilt University. University of Texas Southwestern Medical Center. New York University Grossman School of Medicine. Cleveland Clinic. University of Arizona College of Medicine.
United States
Arthritis and Rheumatology
Arthritis Rheumatol 2023;
DOI: 10.1002/art.42632
Abstract
Objective: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) experience worse survival and derive less benefit from pulmonary vasodilator therapies than patients with idiopathic PAH (IPAH). We sought to identify differential metabolism in CTD-PAH versus IPAH patients that might underlie these observed clinical differences.
Methods: Adult subjects with CTD-PAH (n=141) and IPAH (n=165) from the PVDOMICS (Pulmonary Vascular Disease Phenomics) Study were included. Detailed clinical phenotyping was performed at cohort enrollment, including broad-based global metabolomic profiling of plasma samples. Subjects were followed prospectively for ascertainment of outcomes. Supervised and unsupervised machine learning algorithms and regression models were used to compare CTD-PAH versus IPAH metabolomic profiles and to measure metabolite-phenotype associations and interactions. Gradients across the pulmonary circulation were assessed using paired mixed venous and wedged samples in a subset of 115 subjects.
Results: Metabolomic profiles distinguished CTD-PAH from IPAH, with CTD-PAH patients demonstrating aberrant lipid metabolism, with lower circulating levels of sex steroid hormones and higher free fatty acids (FA) and FA intermediates in CTD-PAH. Acylcholines were taken up by the right ventricular-pulmonary vascular circulation, particularly in CTD-PAH, while free FAs and acylcarnitines were released. In both PAH subtypes, dysregulated lipid metabolites, among others, were associated with hemodynamic and right ventricular measurements and with transplant-free survival.
Conclusions: CTD-PAH is characterized by aberrant lipid metabolism that may signal shifted metabolic substrate utilization. Abnormalities in RV-pulmonary vascular FA metabolism may imply reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation.
Category
Class I. Pulmonary Hypertension Associated with Connective Tissue Disease
Class I. Idiopathic Pulmonary Hypertension
Vascular Cell Biology and Mechanisms of 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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