Soluble Receptor for Advanced Glycation End Products Is a Sensitive Biomarker in Human Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury and associated with inflammation, cell proliferation, and migration in PAH, and may be a novel PAH biomarker.

Method: Adult cohort: We recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH), and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. Pediatric cohort (n = 20): during cardiac catheterization, EDTA blood was collected near simultaneously at three anatomic blood draw sites, together with pressure recordings and blood gas analysis (SpO₂): superior vena cava (SVC), pulmonary artery (PA), and ascending aorta (AAO). Study patients consisted of PH patients and non-PH controls (n = 10 per group). Patients with any intra- or extracardiac shunt were excluded. For qPCR, Western blotting, immunohistochemistry, and human lung tissue were obtained from IPAH patients, HPAH patients, and controls (LuTx donor lungs).

Results: The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3,044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3,332 ± 321.6 pg/mL) versus controls (1,766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II + III PAH versus controls (p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults but were similar in PH and non-PH controls

Conclusion: Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

Publikationsverlauf

Artikel online veröffentlicht:
12. Februar 2022