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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Circulating markers of inflammation and angiogenesis and clinical outcomes across subtypes of pulmonary arterial hypertension

Published:November 06, 2022DOI:https://doi.org/10.1016/j.healun.2022.10.026

      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-β, 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-β, 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.

      Keywords

      Abbreviations:

      6MWD (6-minute walk distance), BMPR2 (Bone morphogenic protein receptor type 2), CHD-PAH (Congenital heart disease-associated PAH), CTD-PAH (Connective tissue disease-associated PAH), IL (Interleukin), IP-10 (Interferon gamma-induced protein 10), IPAH (Idiopathic PAH), mPAP (Mean pulmonary artery pressure), NT-proBNP (N-terminal prohormone of brain natriuretic peptide), PAH (Pulmonary arterial hypertension), PCWP (Pulmonary capillary wedge pressure), PlGF (Placental growth factor), PVR (Pulmonary vascular resistance), RVD (Right ventricular basal diameter), sFlt-1 (Soluble fms-like tyrosine kinase 1), TAPSE (Tricuspid annular plane systolic excursion), TNF (Tumor necrosis factor), Tox-PAH (Toxin-associated PAH), VEGF (Vascular endothelial growth factor)
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      References

        • Thenappan T
        • Shah SJ
        • Rich S
        • Tian L
        • Archer SL
        • Gomberg-Maitland M.
        Survival in pulmonary arterial hypertension: a reappraisal of the NIH risk stratification equation.
        Eur Respir J. 2010; 35: 1079-1087https://doi.org/10.1183/09031936.00072709
        • Simonneau G
        • Montani D
        • Celermajer DS
        • et al.
        Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
        Eur Respir J. 2019; 53https://doi.org/10.1183/13993003.01913-2018
        • Zamanian RT
        • Hedlin H
        • Greuenwald P
        • et al.
        Features and outcomes of methamphetamine-associated pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2018; 197: 788-800https://doi.org/10.1164/rccm.201705-0943OC
        • Fisher MR
        • Mathai SC
        • Champion HC
        • et al.
        Clinical differences between idiopathic and scleroderma-related pulmonary hypertension.
        Arthritis Rheum. 2006; 54: 3043-3050https://doi.org/10.1002/art.22069
        • Benza RL
        • Miller DP
        • Barst RJ
        • Badesch DB
        • Frost AE
        • McGoon MD.
        An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry.
        Chest. 2012; 142: 448-456https://doi.org/10.1378/chest.11-1460
        • Dimopoulos K
        • Wort SJ
        • Gatzoulis MA.
        Pulmonary hypertension related to congenital heart disease: a call for action.
        Eur Heart J. 2014; 35: 691-700https://doi.org/10.1093/eurheartj/eht437
        • Gall H
        • Felix JF
        • Schneck FK
        • et al.
        The Giessen Pulmonary Hypertension Registry: survival in pulmonary hypertension subgroups.
        J Heart Lung Transplant. 2017; 36: 957-967https://doi.org/10.1016/j.healun.2017.02.016
        • Montani D
        • Savale L
        • Natali D
        • et al.
        Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension.
        Eur Heart J. 2010; 31: 1898-1907https://doi.org/10.1093/eurheartj/ehq170
        • Halliday SJ
        • Hemnes AR
        • Robbins IM
        • et al.
        Prognostic value of acute vasodilator response in pulmonary arterial hypertension: beyond the “classic” responders.
        J Heart Lung Transplant. 2015; 34: 312-318https://doi.org/10.1016/j.healun.2014.10.003
        • Limsuwan A
        • Choubtum L
        • Wattanasirichaigoon D.
        5’UTR repeat polymorphisms of the BMPR2 gene in children with pulmonary hypertension associated with congenital heart disease.
        Heart Lung Circ. 2013; 22: 204-210https://doi.org/10.1016/j.hlc.2012.09.004
        • Roberts KE
        • McElroy JJ
        • Wong WPK
        • et al.
        BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease.
        Eur Respir J. 2004; 24: 371-374https://doi.org/10.1183/09031936.04.00018604
        • Morse J
        • Barst R
        • Horn E
        • Cuervo N
        • Deng Z
        • Knowles J.
        Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic protein receptor 2 mutations.
        J Rheumatol. 2002; 29: 2379-2381
        • Rhee RL
        • Gabler NB
        • Sangani S
        • Praestgaard A
        • Merkel PA
        • Kawut SM.
        Comparison of treatment response in idiopathic and connective tissue disease-associated pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2015; 192: 1111-1117https://doi.org/10.1164/rccm.201507-1456OC
        • Sanchez O
        • Sitbon O
        • Jaï’S X
        • Simonneau G
        • Humbert M
        Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension.
        Chest. 2006; 130: 182-189https://doi.org/10.1378/chest.130.1.182
        • Newman JH
        • Rich S
        • Abman SH
        • et al.
        Enhancing insights into pulmonary vascular disease through a precision medicine approach. A joint NHLBI-Cardiovascular medical research and education fund workshop report.
        Am J Respir Crit Care Med. 2017; 195: 1661-1670https://doi.org/10.1164/rccm.201701-0150WS
        • Dweik RA
        • Rounds S
        • Erzurum SC
        • et al.
        An official American Thoracic Society Statement: pulmonary hypertension phenotypes.
        Am J Respir Crit Care Med. 2014; 189: 345-355https://doi.org/10.1164/rccm.201311-1954ST
        • Galiè N
        • Humbert M
        • Vachiery J-L
        • et al.
        2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endor.
        Eur Heart J. 2016; 37: 67-119https://doi.org/10.1093/eurheartj/ehv317
        • Humbert M
        • Farber HW
        • Ghofrani HA
        • et al.
        Risk assessment in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
        Eur Respir J. 2019; 53https://doi.org/10.1183/13993003.02004-2018
        • Halliday SJ
        • Hemnes AR.
        Identifying “super responders” in pulmonary arterial hypertension.
        Pulm Circ. 2017; 7: 300-311https://doi.org/10.1177/2045893217697708
        • Humbert M
        • Guignabert C
        • Bonnet S
        • et al.
        Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.
        Eur Respir J. 2019; 53https://doi.org/10.1183/13993003.01887-2018
        • Säleby J
        • Bouzina H
        • Lundgren J
        • Rådegran G.
        Angiogenic and inflammatory biomarkers in the differentiation of pulmonary hypertension.
        Scand Cardiovasc J. 2017; 51: 261-270https://doi.org/10.1080/14017431.2017.1359419
        • Al-Naamani N
        • Palevsky HI
        • Lederer DJ
        • et al.
        Prognostic significance of biomarkers in pulmonary arterial hypertension.
        Ann Am Thorac Soc. 2016; 13: 25-30https://doi.org/10.1513/AnnalsATS.201508-543OC
        • Malhotra R
        • Paskin-Flerlage S
        • Zamanian RT
        • et al.
        Circulating angiogenic modulatory factors predict survival and functional class in pulmonary arterial hypertension.
        Pulm Circ. 2013; 3: 369-380https://doi.org/10.4103/2045-8932.110445
        • Heresi GA
        • Aytekin M
        • Newman J
        • Dweik RA.
        CXC-chemokine ligand 10 in idiopathic pulmonary arterial hypertension: marker of improved survival.
        Lung. 2010; 188: 191-197https://doi.org/10.1007/s00408-010-9232-9
        • Soon E
        • Holmes AM
        • Treacy CM
        • et al.
        Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension.
        Circulation. 2010; 122: 920-927https://doi.org/10.1161/CIRCULATIONAHA.109.933762
        • Tiede SL
        • Gall H
        • Dörr O
        • et al.
        New potential diagnostic biomarkers for pulmonary hypertension.
        Eur Respir J. 2015; 46: 1390-1396https://doi.org/10.1183/13993003.00187-2015
        • Hoeper MM
        • Bogaard HJ
        • Condliffe R
        • et al.
        Definitions and diagnosis of pulmonary hypertension.
        J Am Coll Cardiol. 2013; 62 (Suppl): D42-D50https://doi.org/10.1016/j.jacc.2013.10.032
        • Benza RL
        • Gomberg-Maitland M
        • Elliott CG
        • et al.
        Predicting survival in patients with pulmonary arterial hypertension: The REVEAL Risk Score Calculator 2.0 and comparison with ESC/ERS-Based Risk Assessment Strategies.
        Chest. 2019; 156: 323-337https://doi.org/10.1016/j.chest.2019.02.004
        • Bild DE
        • Bluemke DA
        • Burke GL
        • et al.
        Multi-Ethnic Study of Atherosclerosis: objectives and design.
        Am J Epidemiol. 2002; 156: 871-881https://doi.org/10.1093/aje/kwf113
        • Rhodes CJ
        • Wharton J
        • Swietlik EM
        • et al.
        Using the plasma proteome for risk stratifying patients with pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2022; 205: 1102-1111https://doi.org/10.1164/rccm.202105-1118OC
        • Harbaum L
        • Rhodes CJ
        • Wharton J
        • et al.
        Mining the plasma proteome for insights into the molecular pathology of pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2022; 205: 1449-1460https://doi.org/10.1164/rccm.202109-2106OC
        • Humbert M
        • Monti G
        • Brenot F
        • et al.
        Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.
        Am J Respir Crit Care Med. 1995; 151: 1628-1631https://doi.org/10.1164/ajrccm.151.5.7735624
        • Hemnes A
        • Rothman AMK
        • Swift AJ
        • Zisman LS.
        Role of biomarkers in evaluation, treatment and clinical studies of pulmonary arterial hypertension.
        Pulm Circ. 2020; 102045894020957234https://doi.org/10.1177/2045894020957234
        • Simpson CE
        • Chen JY
        • Damico RL
        • et al.
        Cellular sources of interleukin-6 and associations with clinical phenotypes and outcomes in pulmonary arterial hypertension.
        Eur Respir J. 2020; 55https://doi.org/10.1183/13993003.01761-2019
        • Wienke J
        • Mertens JS
        • Garcia S
        • et al.
        Biomarker profiles of endothelial activation and dysfunction in rare systemic autoimmune diseases: implications for cardiovascular risk.
        Rheumatology (Oxford). 2021; 60: 785-801https://doi.org/10.1093/rheumatology/keaa270
        • Kolstad KD
        • Khatri A
        • Donato M
        • et al.
        Cytokine signatures differentiate systemic sclerosis patients at high versus low risk for pulmonary arterial hypertension.
        Arthritis Res Ther. 2022; 24: 39https://doi.org/10.1186/s13075-022-02734-9
        • Toshner M
        • Rothman AMK.
        IL-6 in pulmonary hypertension: Why novel is not always best.
        Eur Respir J. 2020; 55https://doi.org/10.1183/13993003.00314-2020
        • Khurana R
        • Moons L
        • Shafi S
        • et al.
        Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation.
        Circulation. 2005; 111: 2828-2836https://doi.org/10.1161/CIRCULATIONAHA.104.495887
        • Levine RJ
        • Maynard SE
        • Qian C
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683https://doi.org/10.1056/NEJMoa031884
        • Luttun A
        • Tjwa M
        • Moons L
        • et al.
        Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1.
        Nat Med. 2002; 8: 831-840https://doi.org/10.1038/nm731
        • Chen P-Y
        • Qin L
        • Li G
        • et al.
        Endothelial TGF-β signalling drives vascular inflammation and atherosclerosis.
        Nat Metab. 2019; 1: 912-926https://doi.org/10.1038/s42255-019-0102-3
        • Lim SY
        • Lee JH
        • Welsh SJ
        • et al.
        Evaluation of two high-throughput proteomic technologies for plasma biomarker discovery in immunotherapy-treated melanoma patients.
        Biomark Res. 2017; 5: 32https://doi.org/10.1186/s40364-017-0112-9
        • Rhodes CJ
        • Wharton J
        • Ghataorhe P
        • et al.
        Plasma proteome analysis in patients with pulmonary arterial hypertension: an observational cohort study.
        Lancet Respir Med. 2017; 5: 717-726https://doi.org/10.1016/S2213-2600(17)30161-3
        • Jais X
        • Launay D
        • Yaici A
        • et al.
        Immunosuppressive therapy in lupus- and mixed connective tissue disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases.
        Arthritis Rheum. 2008; 58: 521-531https://doi.org/10.1002/art.23303
        • Sweatt AJ
        • Hedlin HK
        • Balasubramanian V
        • et al.
        Discovery of distinct immune phenotypes using machine learning in pulmonary arterial hypertension.
        Circ Res. 2019; 124: 904-919https://doi.org/10.1161/CIRCRESAHA.118.313911
        • Aguinis H
        • Vassar M
        • Wayant C.
        On reporting and interpreting statistical significance and p values in medical research.
        BMJ evidence-based Med. 2021; 26: 39-42https://doi.org/10.1136/bmjebm-2019-111264