Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan;163(1):204-215.
doi: 10.1016/j.chest.2022.08.2230. Epub 2022 Sep 7.

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

Mona Alotaibi  1 , Junzhe Shao  2 , Michael W Pauciulo  3 , William C Nichols  3 , Anna R Hemnes  4 , Atul Malhotra  1 , Nick H Kim  1 , Jason X-J Yuan  1 , Timothy Fernandes  1 , Kim M Kerr  1 , Laith Alshawabkeh  5 , Ankit A Desai  6 , Andreea M Bujor  7 , Robert Lafyatis  8 , Jeramie D Watrous  9 , Tao Long  9 , Susan Cheng  10 , Stephen Y Chan  11 , Mohit Jain  9
Affiliations

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

Mona Alotaibi et al. Chest. 2023 Jan.

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.

Keywords: biomarkers; metabolomics; pulmonary hypertension; scleroderma.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Study overview. Summary of study workflow and data analysis plan. 6MWT = 6-min walk test; IPAH = idiopathic pulmonary arterial hypertension; SSc-PAH = systemic sclerosis-associated pulmonary arterial hypertension; SSc-no PH = systemic sclerosis without associated pulmonary arterial hypertension.
Figure 2
Figure 2
Bioactive metabolite analysis of SSc-PAH vs IPAH. A, Volcano plot of metabolites distinguishing SSc-PAH from IPAH in the discovery and validation cohorts. ORs and P values are derived from multivariable regression analyses. Red dots indicate metabolites significant in both discovery and validation cohorts; black dots indicate metabolites significant only in the discovery cohort; and gray dots indicate all metabolites measured in the discovery and validation cohorts. B, Waterfall plot of significant metabolites distinguishing SSc-PAH from IPAH. Values are plotted as log2 fold change of metabolite levels in SSc-PAH relative to IPAH. FAHFA = fatty acyl esters of hydroxy fatty acid; Eic = eicosanoid; IPAH = idiopathic pulmonary arterial hypertension; LTB4 = leukotriene B4; PGF2α = prostaglandin F2α; SSc-PAH = systemic sclerosis-associated pulmonary arterial hypertension.
Figure 3
Figure 3
Receiver-operating characteristic curves show the performance of the model in distinguishing idiopathic pulmonary arterial hypertension from systemic sclerosis-associated pulmonary arterial hypertension using nine metabolites. The blue curve represents the training set, and the red curve represents the testing set. AUC = area under the curve.
Figure 4
Figure 4
Metabolite levels in SSc-no PH vs SSc-PAH. Violin plots of nervonic acid, lignoceric acid, FHAFA, 17β estradiol, novel eicosanoid, PGF2α, and LTB4 levels in SSc-no PH vs SSc-PAH. All displayed metabolites had a P value < .05. FAHFA = fatty acyl esters of hydroxy fatty acid; LTB4 = leukotriene B4; PGF2α = prostaglandin F2α; SSc-PAH = systemic sclerosis-associated pulmonary arterial hypertension; SSc-no PH = systemic sclerosis without associated pulmonary arterial hypertension.
Figure 5
Figure 5
Forest plots of metabolites association with markers of disease severity. Forest plots display the relative effect sizes and 95% CIs of significant metabolites and 6MWD, functional class, right atrial pressure, and Fick cardiac index. P values and effect sizes were derived from linear regression analysis for 6MWD, right atrial pressure, and cardiac index, and from logistic regression analysis for functional class. 6MWD = 6-minute walk distance; FAHFA = fatty acyl esters of hydroxy fatty acid; Eic = eicosanoid; IPAH = idiopathic pulmonary arterial hypertension; PGF2α = prostaglandin F2α; SSc-PAH = systemic sclerosis-associated pulmonary arterial hypertension; SSc-no PH = systemic sclerosis without associated pulmonary arterial hypertension.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Badesch D.B., Raskob G.E., Elliott C.G., et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376–387. - PubMed
    1. Allanore Y., Simms R., Distler O., et al. Systemic sclerosis. Nat Rev Dis Primers. 2015;1:15002. - PubMed
    1. Fisher M.R., Mathai S.C., Champion H.C., et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54(9):3043–3050. - PubMed
    1. Chung L., Liu J., Parsons L., et al. Characterization of connective tissue disease-associated pulmonary arterial hypertension from REVEAL: identifying systemic sclerosis as a unique phenotype. Chest. 2010;138(6):1383–1394. - PMC - PubMed
    1. Ahmed S., Palevsky H.I. Pulmonary arterial hypertension related to connective tissue disease: a review. Rheum Dis Clin North Am. 2014;40(1):103–124. - PubMed

Publication types

MeSH terms

-