Lipidomics for diagnosis and prognosis of pulmonary hypertension

Abstract

Pulmonary hypertension (PH) is a severe hemodynamic, progressive condition associated with high morbidity and mortality where early and less invasive diagnostics could crucially improve management. There is a need for biomarkers in PH that are functional, diagnostic, and prognostic. We used a broad metabolomics approach with machine learning analysis and specific free fatty acid (FFA)/lipid-ratios to develop diagnostic and prognostic PH biomarkers. In a training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, we identified diagnostic and prognostic markers that were validated in an independent cohort of 64 subjects. Markers based on lipophilic metabolites were more robust than those based on hydrophilic metabolites. FFA/lipid-ratios provided excellent diagnostic accuracy for PH with an AUC of up to 0.89 and 0.90 in the training and the validation cohorts, respectively. The ratios provided age-independent prognostic information and a combination of a ratio with established clinical scores increased the hazard ratio (HR) for FPHR4p and COMPERA2 from 2.5 to 4.3 and from 3.3 to 5.6, respectively. Pulmonary arteries (PA) of idiopathic PAH (IPAH) lungs show lipid accumulation and altered expression of lipid homeostasis-related genes that may explain this accumulation. Our functional studies in PA endothelial and smooth muscle cells have shown that increased FFA levels caused excessive proliferation and PA endothelial barrier dysfunction, both hallmarks of pulmonary artery hypertension (PAH). In conclusion, lipidomic changes in PH provide novel diagnostic and prognostic biomarkers and may point to new metabolic therapy targets.

Competing Interest Statement

Several authors (NB, CM, AO, BMN, HO) are inventors of the patent: Biomarker for the diagnosis of pulmonary hypertension (PH) WO2017153472A1 (priority date 09.03.2016, granted in US, KR, JP, pending in CA, EP, AU) being jointly held by CBmed Gmbh, Joanneum Research Forschungsgesellschaft mbH, Medical University Graz and Ludwig Boltzmann Gesellschaft GmbH. The authors received no personal financial gain from the patent. During work on this publication NB was partially employed at CBmed GmbH. TP is chief scientific officer (CSO) of CBmed GmbH. EZ and CM were employed at Joanneum Research Forschungsgesellschaft mbH. The employing companies provided support in the form of salaries, materials and reagents but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. VF received honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Chiesi, BMS, and Boehringer Ingelheim and support for attending meetings, and/or travel from Janssen, MSD, and Boehringer Ingelheim outside the submitted work. CN received support for attending meetings, and/or travel from Boehringer Ingelheim and Inventiva pharma outside the submitted work. BAM reports personal fees from Actelion Pharmaceuticals, Tenax and Regeneron, grants from Deerfield Company, NIH (5R01HL139613-03, R01HL163960, R01HL153502, R01HL155096-01), Boston Biomedical Innovation Ceter (BBIC), Brigham IGNITE award, Cardiovascular Medical research Education Foundation outside the submitted work. BAM reports patent PCT/US2019/059890 (pending), PCT/US2020/066886 (pending) and 9,605,047 (granted) not licensed and outside the submitted work. SU received grants from the Swiss National Science Foundation, Zurich and Swiss Lung League, EMDO-Foundation, Orpha-Swiss, Janssen and MSD all unrelated to the present work. SU received consultancy fees and travel support from Orpha-Swiss, Janssen, MSD and Novartis unrelated to the present work. TJL reports grants for his institution from Acceleron Pharma, Gossamer Bio, Janssen-Cilag, and United Therapeutics; personal fees and non-financial support from Acceleron Pharma, AstraZeneca, Boehringer Ingelheim, Gossamer Bio, Ferrer, Janssen-Cilag, MSD, Orphacare, and Pfizer outside the submitted work. KH is a consultant at Medtronic Oesterreich GmbH outside the submitted work. TP reports grants from AstraZeneca, Novo Nordisk, Sanofi paid to the Medical University of Graz outside the submitted work. TP reports personal fees and nonfinancial support from Novo Nordisk and Roche Diagnostics outside the submitted work. HO reports grants from Bayer, Unither, Actelion, Roche, Boehringer Ingelheim, and Pfizer. HO reports personal fees and nonfinancial support from Medupdate and Mondial, AOP, Bayer, Actelion, Pfizer, Ferrer, Novartis, Astra Zeneca, Boehringer Ingelheim, Chiesi, Menarini, MSD, and GSK outside the submitted work. AO received honoraria for presentations and support for attending meetings, and/or travel from MSD outside the submitted work. No conflict of interest, financial or otherwise, are declared by the authors HL and UB.

Funding Statement

NB, TP disclose that part of this work has been carried out with the K1 COMET Competence Center CBmed, which is funded by the Federal Ministry of Transport, Innovation and Technology; the Federal Ministry of Science, Research and Economy; Land Steiermark (Department 12, Business and Innovation); the Styrian Business Promotion Agency; and the Vienna Business Agency. The COMET program is executed by the Oesterreichische Forschungsfoerderungs GmbH FFG. VB is supported by the Austrian Science Foundation (FWF, T1032-B34).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of the Medical University of Graz, Austria gave ethical approval for this work for the cohort GRAPH (Graz Pulmonary Hypertension Registry, identifier: 23-408ex10/11, registered at ClinicalTrials.gov (NCT01607502). The Ethics Committee of the Medical University of Graz, Austria gave ethical approval for this work for the cohort BioPersMed (Biomarkers of Personalised Medicine, identifier: 23-408ex10/11, renewed every year 24-224 ex 11/12). The Ethics Committee of the Regensburg University, Germany gave ethical approval for this work for the validation cohort (identifier 08/090). The cantonal ethical review board Zurich, Switzerland gave ethical approval for this work for the validation cohort (identifier KEK 2010-0129; 2014-0214; 2017-0476).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data Availability

The author declare that all data supporting the findings in this study are available in the online supplementary data 1 and online repositories. Mass spectrometric data have been deposited in https://zenodo.org under doi: 10.5281/zenodo.7857706. Data is provided de-identified and is available immediately after publication with no end for those who wish to access the data for any purpose.

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