PMID- 36470771 OWN - NLM STAT- MEDLINE DCOM- 20230117 LR - 20240313 IS - 1557-3117 (Electronic) IS - 1053-2498 (Print) IS - 1053-2498 (Linking) VI - 42 IP - 2 DP - 2023 Feb TI - Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension. PG - 173-182 LID - S1053-2498(22)02206-9 [pii] LID - 10.1016/j.healun.2022.10.026 [doi] AB - BACKGROUND: Subtypes of pulmonary arterial hypertension (PAH) differ in both fundamental disease features and clinical outcomes. Angiogenesis and inflammation represent disease features that may differ across subtypes and are of special interest in connective tissue disease-associated PAH (CTD-PAH). We compared inflammatory and angiogenic biomarker profiles across different etiologies of PAH and related them to clinical outcomes. METHODS: Participants with idiopathic PAH, CTD-PAH, toxin-associated PAH (tox-PAH), or congenital heart disease-associated PAH (CHD-PAH) were enrolled into a prospective observational cohort. Baseline serum concentrations of 33 biomarkers were related to 3-year mortality, echocardiogram, REVEAL score, and 6-minute walk distance (6MWD). Findings were validated using plasma proteomic data from the UK PAH Cohort Study. RESULTS: One hundred twelve patients were enrolled: 45 idiopathic, 27 CTD-PAH, 20 tox-PAH, and 20 CHD-PAH. Angiogenic and inflammatory biomarkers were distinctly elevated within the CTD-PAH cohort. Six biomarkers were associated with mortality within the entire PAH cohort: interleukin-6 (IL-6, HR:1.6, 95% CI:1.18-2.18), soluble fms-like tyrosine kinase 1 (sFlt-1, HR:1.35, 95% CI:1.02-1.80), placental growth factor (PlGF, HR:1.55, 95% CI:1.07-2.25), interferon gamma-induced protein 10 (IP-10, HR:1.44, 95% CI:1.04-1.99), tumor necrosis factor-beta (TNF-beta, HR:1.81, 95% CI:1.11-2.95), and NT-proBNP (HR:2.19, 95% CI:1.52-3.14). Only IL-6 and NT-proBNP remained significant after controlling for multiple comparisons. IL-6, IP-10, and sFlt-1 significantly associated with mortality in CTD-PAH, but not non-CTD-PAH subgroups. In the UK cohort, IP-10, PlGF, TNF-beta, and NT-proBNP significantly associated with 5-year survival. CONCLUSION: Levels of angiogenic and inflammatory biomarkers are elevated in CTD-PAH, compared with other etiologies of PAH, and may correlate with clinical outcomes including mortality. CI - Copyright (c) 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved. FAU - Hirsch, Kellen AU - Hirsch K AD - Department of Medicine, University of Washington, Seattle, Washington. FAU - Nolley, Stephanie AU - Nolley S AD - Department of Medicine, University of Washington, Seattle, Washington. FAU - Ralph, David D AU - Ralph DD AD - Department of Medicine, University of Washington, Seattle, Washington. FAU - Zheng, Ying AU - Zheng Y AD - Department of Bioengineering, University of Washington, Seattle, Washington. FAU - Altemeier, William A AU - Altemeier WA AD - Department of Medicine, University of Washington, Seattle, Washington; Center for Lung Biology, University of Washington, Seattle, Washington. FAU - Rhodes, Christopher J AU - Rhodes CJ AD - National Heart and Lung Institute, Imperial College London, London, United Kingdom. FAU - Morrell, Nicholas W AU - Morrell NW AD - Department of Medicine, University of Cambridge, Cambridge, United Kingdom. FAU - Wilkins, Martin R AU - Wilkins MR AD - National Heart and Lung Institute, Imperial College London, London, United Kingdom. FAU - Leary, Peter J AU - Leary PJ AD - Department of Medicine, University of Washington, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington. FAU - Rayner, Samuel G AU - Rayner SG AD - Department of Medicine, University of Washington, Seattle, Washington; Department of Bioengineering, University of Washington, Seattle, Washington; Center for Lung Biology, University of Washington, Seattle, Washington. Electronic address: srayner@uw.edu. LA - eng GR - FS/15/59/31839/BHF_/British Heart Foundation/United Kingdom GR - RG/19/3/34265/BHF_/British Heart Foundation/United Kingdom GR - KL2 TR002317/TR/NCATS NIH HHS/United States GR - RE/18/4/34215/BHF_/British Heart Foundation/United Kingdom GR - KL2 TR000421/TR/NCATS NIH HHS/United States GR - FS/SBSRF/22/31025/BHF_/British Heart Foundation/United Kingdom PT - Journal Article PT - Observational Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20221107 PL - United States TA - J Heart Lung Transplant JT - The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation JID - 9102703 RN - 0 (Interleukin-6) RN - 0 (Chemokine CXCL10) RN - 0 (Lymphotoxin-alpha) RN - 144589-93-5 (Placenta Growth Factor) RN - 0 (Biomarkers) SB - IM MH - Humans MH - Female MH - *Pulmonary Arterial Hypertension/complications MH - *Hypertension, Pulmonary MH - Cohort Studies MH - Interleukin-6 MH - Chemokine CXCL10 MH - Lymphotoxin-alpha MH - Proteomics MH - Placenta Growth Factor MH - Familial Primary Pulmonary Hypertension MH - Biomarkers MH - Inflammation PMC - PMC9840657 MID - NIHMS1848127 OTO - NOTNLM OT - angiogenesis OT - biomarkers OT - connective tissue disease OT - etiology subtypes OT - inflammation OT - pulmonary arterial hypertension EDAT- 2022/12/06 06:00 MHDA- 2023/01/18 06:00 PMCR- 2024/02/01 CRDT- 2022/12/05 22:14 PHST- 2022/05/01 00:00 [received] PHST- 2022/10/09 00:00 [revised] PHST- 2022/10/31 00:00 [accepted] PHST- 2022/12/06 06:00 [pubmed] PHST- 2023/01/18 06:00 [medline] PHST- 2022/12/05 22:14 [entrez] PHST- 2024/02/01 00:00 [pmc-release] AID - S1053-2498(22)02206-9 [pii] AID - 10.1016/j.healun.2022.10.026 [doi] PST - ppublish SO - J Heart Lung Transplant. 2023 Feb;42(2):173-182. doi: 10.1016/j.healun.2022.10.026. Epub 2022 Nov 7.