Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) may experience more extreme lipid dysregulation than patients with idiopathic PAH (IPAH), according to a new study published in Arthritis & Rheumatology.

The study’s authors believe that such extreme metabolic dysregulation observed in CTD-PAH may account for shorter survival and unfavorable therapeutic responses in patients with CTD-PAH.

“Findings such as ours lay a groundwork for investigation of tailored approaches to therapy selection that may eventually replace the “one size fits all” paradigm currently employed across PAH subgroups,” the authors wrote.

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The results demonstrated that patients with CTD-PAH exhibited lower levels of sex steroid hormones and higher levels of free fatty acids (FA) and FA intermediates compared with patients with IPAH.

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Moreover, right ventricular-pulmonary vascular circulation in CTD-PAH showed an uptake of acylcholines and a release of free FAs and acylcarnitines.

These alterations may imply a reduced capacity for mitochondrial beta oxidation within the diseased pulmonary circulation, suggesting a change in the way patients with CTD-PAH use metabolic substrates for energy production.

Dysregulated lipid metabolites were associated with hemodynamic and right ventricular measurements, as well as with transplant-free survival, in both types of PAH.

The researchers performed a comprehensive analysis of clinical data and plasma samples from a multicenter cohort of adult subjects with CTD-PAH (n=141) and IPAH (n=165) enrolled in the Pulmonary Vascular Disease Phenomics (PVDOMICS) study.

The study used supervised and unsupervised machine learning algorithms, as well as regression models, to compare the metabolomic profiles of CTD-PAH and IPAH patients and investigate the associations and interactions between metabolites and clinical phenotypes.

In addition, the researchers assessed metabolic gradients across the pulmonary circulation using paired mixed venous and wedged samples in a subset of subjects.


Simpson CE, Hemnes AR, Griffiths M, et al. Metabolomic differences in connective tissue disease-associated versus idiopathic pulmonary arterial hypertension in the PVDOMICS cohort. Arthritis Rheumatol. Published online June 19, 2023. doi:10.1002/art.42632