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Observational Study
. 2023 Feb;42(2):173-182.
doi: 10.1016/j.healun.2022.10.026. Epub 2022 Nov 7.

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

Kellen Hirsch  1 , Stephanie Nolley  1 , David D Ralph  1 , Ying Zheng  2 , William A Altemeier  3 , Christopher J Rhodes  4 , Nicholas W Morrell  5 , Martin R Wilkins  4 , Peter J Leary  6 , Samuel G Rayner  7
Affiliations
Observational Study

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

Kellen Hirsch et al. J Heart Lung Transplant. 2023 Feb.

Abstract

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: angiogenesis; biomarkers; connective tissue disease; etiology subtypes; inflammation; pulmonary arterial hypertension.

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Figures

Figure 1:
Figure 1:. Heatmap of biomarker concentrations by PAH subtype.
Heatmap displays row Z scores for serum markers of angiogenesis and inflammation across subtypes of pulmonary arterial hypertension. Asterisks denote biomarkers that significantly differ across subtype: * p≤0.05, ** p≤0.01. PAH: pulmonary arterial hypertension; IPAH: idiopathic PAH; CTD-PAH: connective tissue disease-associated PAH; Tox-PAH: toxin-associated PAH; CHD-PAH: congenital heart disease-associated PAH.
Figure 2:
Figure 2:. Biomarker associations with mortality in the pooled PAH cohort.
Cox proportional hazards models adjusted for age, sex, and pulmonary arterial hypertension etiology were run evaluating biomarker associations with mortality. The hazard ratio for a one-standard-deviation change in biomarker level against mortality is shown. Definition of abbreviations: IL-6: interleukin-6; IP-10: interferon gamma-induced protein 10; TNF-β: tumor necrosis factor-beta; sFlt-1: soluble fms-like tyrosine kinase 1; PlGF: placental growth factor; NT-proBNP: N-terminal pro-brain natriuretic peptide.
Figure 3:
Figure 3:. Biomarker association with mortality across different subgroups.
Cox proportional hazards models adjusted for age, sex, and pulmonary arterial hypertension etiology were performed separately for the CTD-PAH and non-CTD-PAH subgroups. The non-CTD-PAH subgroup includes patients with idiopathic, congenital heart disease-associated, and toxin-associated PAH. Definition of abbreviations: PAH: pulmonary arterial hypertension; CTD-PAH: connective tissue disease-associated PAH; IL-6: interleukin-6; IP-10: interferon gamma-induced protein 10; TNF-β: tumor necrosis factor-beta; sFlt-1: soluble fms-like tyrosine kinase 1; PlGF: placental growth factor; NT-proBNP: N-terminal pro-brain natriuretic peptide.
Figure 4:
Figure 4:. Biomarker associations with echocardiographic and clinical outcomes.
Linear regression models were run on biomarker associations with REVEAL 2.0 score, right ventricle (RV) diameter, tricuspid annular plane systolic excursion (TAPSE), and 6-minute walk distance (6MWD). Models were adjusted for age, sex, etiology, and height. Graphs display the difference in REVEAL score, RV diameter, TAPSE, or 6MWD associated with a standard deviation change in biomarker concentration (* p≤0.05; ** p≤0.01; *** p≤0.001).
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References

    1. 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(5):1079–1087. doi:10.1183/09031936.00072709 - DOI - PMC - PubMed
    1. Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J. 2019;53(1). doi:10.1183/13993003.01913-2018 - DOI - PMC - PubMed
    1. 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(6):788–800. doi:10.1164/rccm.201705-0943OC - DOI - PMC - PubMed
    1. Fisher MR, Mathai SC, Champion HC, et al. Clinical differences between idiopathic and scleroderma-related pulmonary hypertension. Arthritis Rheum. 2006;54(9):3043–3050. doi:10.1002/art.22069 - DOI - PubMed
    1. 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(2):448–456. doi:10.1378/chest.11-1460 - DOI - PubMed

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