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

In chronic thromboembolic pulmonary hypertension (CTEPH) insufficient thrombus resolution and vascular remodeling lead to chronic obstructions of the pulmonary arteries [1]. The corresponding impaired pulmonary hemodynamics burden the right heart, cause right heart remodeling and ultimately failure [1]. Pulmonary endarterectomy (PEA), medical treatment targeting pulmonary hypertension (PH) and balloon pulmonary angioplasty (BPA) are specific treatment modalities [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]. Considering the multifaceted pathophysiology of CTEPH, biomarkers not primarily reflecting hemodynamics might further provide information about individual disease mechanisms facilitating treatment decisions. Pregnancy-associated plasma protein-A (PAPP-A), clinically established in the pregnancy first-trimester-screening, 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]. Its role in PH, especially CTEPH, has not been investigated so far.

The current study aimed to evaluate PAPP-A levels in CTEPH and to explore the potential modification of PAPP-A levels by PEA or BPA treatment.

We analyzed 125 consecutive patients with CTEPH and 58 controls (Patients with PH and suspected CTEPH that was excluded after diagnostic workup). Standardized diagnostic and therapeutic work-up of CTEPH patients has been published earlier [2]. The CTEPH group of the study included 55 patients that underwent PEA and 70 in whom BPA was performed. In PEA patients, biospecimen were obtained at baseline and 12 months after surgery (12-MFU), in BPA at baseline, before each staged procedure and 6 months after the final procedure (6-MFU). In control patients, biomaterial was obtained at enrollment. The biomaterial included venous blood samples that were aliquoted and frozen at − 80 °C. The study was approved by the respective local ethics committee and each patient gave written informed consent. PAPP-A was measured in frozen serum samples using an automated immunofluorescence assay on the Kryptor compact plus instrument (PAPP-A Thermo Scientific, BRAHMS GmbH, Henningsdorf, Germany).

Variables are expressed as median (IQR), mean ± SD or number (%) as appropriate. Comparative analyses used the Student t-test, Mann-Whitney-U-test, Wilcoxon signed-rank test, X²-test and Fisher-Yates test. Bivariate Pearson correlation assessed associations of PAPP-A with pulmonary hemodynamics and other biomarkers. All p-values are seen as descriptive. Statistical analyses were performed with R3.5.1 software package (R Foundation for Statistical Computing, Vienna, Austria).

The comparative analysis of hemodynamic findings revealed a higher pulmonary artery pressure (meanPAP; 43.1 ± 9.7 vs. 39.9 ± 10.9 mmHg; p = 0.041) and pulmonary vascular resistance (PVR; 6.76(5.27–9.61) vs. 4.63(3.15–10.3) WU; p = 0.006) in CTEPH patients compared to the PH control group at baseline. A comprehensive illustration of baseline characteristics of the CTEPH cohort and the control group is provided in Table 1.

PAPP-A levels at baseline were comparable in CTEPH patients [13.8(IQR 11.0–18.6) mU/L] and PH controls [12.6(IQR 8.6–16.5) mU/L] (p = 0.051). No relevant correlation between PAPP-A and hemodynamic parameters such as meanPAP (r = 0.120; p = 0.188), pulmonary vascular resistance (PVR) (r = 0.013; p = 0.893) or NT-proBNP (r = 0.128; p = 0.169) was observed in CTEPH patients. Nevertheless, PAPP-A correlated with C-reactive protein (r = 0.259; p = 0.004).

Surgical and interventional treatment led to an improvement of pulmonary hemodynamics and a decrease of natriuretic peptides, which is illustrated in Table 2.

The PAPP-A levels did not differ between the PEA and BPA treatment group (13.7 (10.4–17.6) vs. 14.5 (11.2–18.9) mU/L; p = 0.437) at baseline (Fig. 1, left panel). PAPP-A levels decreased significantly after treatment from 13.7 (10.4–17.6) to 11.4 (9.9–14.6) mU/L (p = 0.003) after PEA and 14.5 (11.2–18.9) to 11.1 (9.8–12.9) mU/L (p < 0.001) after BPA therapy (Fig. 1, left panel).

BPA is a staged procedure (median 6 procedures/patient) with only a limited number of pulmonary segments treated per session. PAPP-A levels decreased continuously reaching a significant change after 4 procedures in contrast to the hemodynamic marker NT-proBNP as a comparator that was significantly lowered already after the first procedure (Fig. 1, right panel).

Key findings of this study are: (1) PAPP-A levels might be associated with CTEPH and decrease after interventional or surgical treatment. (2) The PAPP-A treatment response shows a slow and continuous lowering in marker levels in contrast to the rapid improvement in hemodynamics reflected by biomarkers such as NT-proBNP.

The PAPP-A levels in CTEPH patients, which are modifiable by treatment. Seem not to be mediated by hemodynamics and their improvement after treatment raising the question about the origin and role of PAPP-A in CTEPH.

Acute pulmonary embolism impairs pulmonary vascular homeostasis. The mechanisms leading to development of CTEPH in a subset of PE patients are not fully understood. Endothelial damage, dysfunction and inflammation are known to be involved in vascular remodeling. The IGF-I/IGF-receptor signaling promotes inflammation, anti-apoptosis and proliferation in various cell types such as endothelial and smooth muscle cells [5, 6]. Yang et al. reported a key role of the IGF-I/IGF-receptor signaling in neonatal PH, revealing an upregulation of IGF-I expression in pulmonary endothelial and smooth muscle cells under experimental hypoxia [7, 8]. Further, Harrington et al. identified PAPP-A as a promotor of atherosclerotic plaque progression and plaque vulnerability. This processes seemed to be driven by PAPP-A-mediated proinflammatory effects of macrophage cytokines and a consecutive upregulation of the IGF-I/IGF-receptor axis [9].

One might hypothesize, that an overexpression of PAPP-A might thus reflect chronic vascular remodeling in CTEPH. The potential use as a biomarker indicating disease mechanisms other than hemodynamics is further supported by the availability of robust automated measurement technology due to the routine use in the context of pregnancy. Further, as the IGF pathway plays a relevant role in certain cancer entities, PAPP-A has already been discussed as treatment target that led to e.g. development of monoclonal PAPP-A antibodies [10].

The present clinical study is based on relatively small cohort and therefore the results only allow to hypothesize about the potential role of PAPP-A. However, it is the first analysis showing an association of PAPP-A with CTEPH. Especially the modification of PAPP-A levels by treatment not primary mediated via hemodynamic improvement should stimulate further investigations to confirm the present results from a small cohort and further analyze the specific role of PAPP-A in the pathophysiology of CTEPH and a potential clinical use as biomarker or even treatment target.