Lipidomics for diagnosis and prognosis of pulmonary hypertension.

Autor:	Bordag N; Department of Dermatology and Venereology, Medical University of Graz, Graz, Austria.; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria.; BioMedTech, Graz, Austria., Nagy BM; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria., Zügner E; Institute for Biomedical Research and Technologies (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria., Ludwig H; School of Informatics, Communications, and Media, University of Applied Sciences Upper Austria, Hagenberg, Austria., Foris V; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria., Nagaraj C; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; BioMedTech, Graz, Austria., Biasin V; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Physiology, Otto Loewi Research Centre, Medical University of Graz, Graz, Austria., Bodenhofer U; School of Informatics, Communications, and Media, University of Applied Sciences Upper Austria, Hagenberg, Austria., Magnes C; Institute for Biomedical Research and Technologies (HEALTH), Joanneum Research Forschungsgesellschaft m.b.H, Graz, Austria., Maron BA; University of Maryland School of Medicine, Baltimore, MD and The University of Maryland-Institute for Health Computing, Bethesda, MD, USA., Ulrich S; Clinic of Pulmonology, University and University Hospital of Zurich, Zürich, Switzerland., Lange TJ; Department of Internal Medicine II, Pulmonology and Critical Care, Kreisklinik Bad Reichenhall, Bad Reichenhall, Germany.; Faculty of Medicine, University of Regensburg, Regensburg, Germany., Hötzenecker K; Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria., Pieber T; CBmed GmbH, Center for Biomarker Research in Medicine, Graz, Austria.; Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz Austria.; BioMedTech, Graz, Austria., Olschewski H; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.; BioMedTech, Graz, Austria., Olschewski A; Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria.; Experimental Anaesthesiology, Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria.; BioMedTech, Graz, Austria.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2023 Nov 29. Date of Electronic Publication: 2023 Nov 29.
DOI:	10.1101/2023.05.17.23289772
Abstrakt:	Background: Pulmonary hypertension (PH) poses a significant health threat with high morbidity and mortality, necessitating improved diagnostic tools for enhanced management. Current biomarkers for PH lack functionality and comprehensive diagnostic and prognostic capabilities. Therefore, there is a critical need to develop biomarkers that address these gaps in PH diagnostics and prognosis. Methods: To address this need, we employed a comprehensive metabolomics analysis in 233 blood based samples coupled with machine learning analysis. For functional insights, human pulmonary arteries (PA) of idiopathic pulmonary arterial hypertension (PAH) lungs were investigated and the effect of extrinsic FFAs on human PA endothelial and smooth muscle cells was tested in vitro . Results: PA of idiopathic PAH lungs showed lipid accumulation and altered expression of lipid homeostasis-related genes. In PA smooth muscle cells, extrinsic FFAs caused excessive proliferation and endothelial barrier dysfunction in PA endothelial cells, both hallmarks of PAH.In the training cohort of 74 PH patients, 30 disease controls without PH, and 65 healthy controls, diagnostic and prognostic markers were identified and subsequently validated in an independent cohort. Exploratory analysis showed a highly impacted metabolome in PH patients and machine learning confirmed a high diagnostic potential. Fully explainable specific free fatty acid (FFA)/lipid-ratios were derived, providing exceptional diagnostic accuracy with an area under the curve (AUC) of 0.89 in the training and 0.90 in the validation cohort, outperforming machine learning results. These ratios were also prognostic and complemented established clinical prognostic PAH scores (FPHR4p and COMPERA2.0), significantly increasing their hazard ratios (HR) from 2.5 and 3.4 to 4.2 and 6.1, respectively. Conclusion: In conclusion, our research confirms the significance of lipidomic alterations in PH, introducing innovative diagnostic and prognostic biomarkers. These findings may have the potential to reshape PH management strategies. Competing Interests: Competing interests 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 Center (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, Zürich 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 Österreich 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 non-financial support from Medupdate and Mondial, AOP, Astra Zeneca, Bayer, Boehringer Ingelheim, Chiesi, Ferrer, Menarini, MSD, and GSK, Iqvia, Janssen, Novartis, and Pfizer 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.
Databáze:	MEDLINE
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