Pregnancy-associated plasma protein A \u2013 a new indicator of pulmonary vascular remodeling in chronic thromboembolic pulmonary hypertension?

Steffen D Kriechbaum,Christian W Hamm,Felix Rudolph,Till Keller,Lisa Mielzarek,Eckhard Mayer,Christoph B Wiedenroth,Moritz Haas,Stefan Guth,Christoph Liebetrau

doi:10.1186/s12931-020-01472-3

Abstract

BackgroundIn chronic thromboembolic pulmonary hypertension (CTEPH) impaired pulmonary hemodynamics lead to right heart failure. Natriuretic peptides reflect hemodynamic disease severity. Pregnancy-associated plasma protein-A (PAPP-A) might address another aspect of CTEPH - chronic tissue injury and inflammation. This study assessed dynamics of PAPP-A in CTEPH patients who undergo therapy with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA).MethodsThe study included a total of 125 CTEPH patients scheduled for treatment (55 PEA/ 70 BPA) and a control group of 58 patients with pulmonary hypertension other than CTEPH. Biomarker measurement was performed at baseline and follow-up in the CTEPH cohort, prior to each BPA in the BPA cohort and once in the control group.ResultsThe median PAPP-A level was slightly higher (p = 0.05) in CTEPH patients [13.8 (11.0–18.6) mU/L], than in the control group [12.6 (8.6–16.5) mU/L], without a difference between the BPA and PEA group (p = 0.437) and without a correlation to mean pulmonary artery pressure (p = 0.188), pulmonary vascular resistance (p = 0.893), cardiac index (p = 0.821) and right atrial pressure (p = 0.596). PEA and BPA therapy decreased the mean pulmonary artery pressure (p < 0.001) and pulmonary vascular resistance (p < 0.001) and improved the WHO-functional-class (baseline: I:0/II:25/III:80/IV:20 vs. follow-up: I:55/II:58/III:10/IV:2). PAPP-A levels decreased after PEA [13.5 (9.5–17.5) vs. 11.3 (9.8–13.6) mU/L; p = 0.003) and BPA treatment [14.3 (11.2–18.9) vs. 11.1 (9.7–13.3) mU/L; p < 0.001). The decrease of PAPP-A levels is delayed in comparison to N-terminal pro-B-type natriuretic peptide.ConclusionPAPP-A is overexpressed in CTEPH and decrease significantly after surgical or interventional therapy, however without association to hemodynamics. Further investigation is needed to define the underlying mechanism of PAPP-A expression and changes after therapy in CTEPH.

Highlights

In chronic thromboembolic pulmonary hypertension (CTEPH) insufficient thrombus resolution and vascular remodeling lead to chronic obstructions of the pulmonary arteries [1]
plasma protein-A (PAPP-A) is overexpressed in CTEPH and decrease significantly after surgical or interventional therapy, without association to hemodynamics
Further investigation is needed to define the underlying mechanism of PAPP-A expression and changes after therapy in CTEPH

Summary

Introduction

In chronic thromboembolic pulmonary hypertension (CTEPH) insufficient thrombus resolution and vascular remodeling lead to chronic obstructions of the pulmonary arteries [1]. Impaired pulmonary hemodynamics in CTEPH correlate with non-invasively measured blood biomarkers such as natriuretic peptides and render such markers as indicators for disease severity and therapy response [2]. Pregnancy-associated plasma protein-A (PAPP-A), clinically established in the pregnancy first-trimesterscreening, was identified as key regulator of insulin-like growth factor (IGF)/IGF-binding-protein pathways via cleaving of IGF-binding-protein [3]. This pathway has been reported in the context of atherosclerosis, coronary artery disease, heart failure and non-cardiac conditions [4]. In chronic thromboembolic pulmonary hypertension (CTEPH) impaired pulmonary hemodynamics lead to right heart failure. This study assessed dynamics of PAPP-A in CTEPH patients who undergo therapy with pulmonary endarterectomy (PEA) or balloon pulmonary angioplasty (BPA)

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Conclusion