Soluble Transferrin Receptor-1 in Pulmonary Hypertension Associated with COPD

Purpose: The pulmonary vascular involvement of COPD ranges from severe airway obstruction without pulmonary hypertension (PH) to mild airway obstruction with severe PH. Iron-dependent molecular regulators like hypoxia-inducible factor-2 (HIF-2) may contribute to these phenotypic variations. We explored the role of soluble transferrin receptor-1 (sTfR1) for diagnosis and prognosis of PH associated with COPD. Methods: We analyzed COPD outpatients who underwent right heart catheterization and performed unsupervised clustering analysis based on sTfR1 levels and non-invasive clinical parameters to identify specific COPD phenotypes. Additionally, we examined explanted end-stage COPD lungs for TfR1 expression and iron deposition. Results: sTfR1 was associated with mean pulmonary artery pressure (mPAP) (r = 0.45, p < 0.001), pulmonary vascular resistance (PVR) (r = 0.395, p < 0.001) and poor survival. sTfR1 predicted severe PH (AUROC [95% CI], 0.72 [0.61–0.83]), and AUROC was further improved based on a combination of sTfR1 and low hemoglobin (0.82 [0.73–0.92]). sTfR1-based cluster analysis distinguished three COPD phenotypes with significantly different survival. One of the two clusters with poor survival was characterized by moderate airway obstruction and moderate PH but elevated sTfR1, anemia and inflammation. In explanted COPD lungs, TfR1-positive and iron-laden cells, most likely, consisted of macrophages, and iron-loaded cell density was negatively correlated with mPAP in patients with moderate/severe PH (r = − 0.681, p = 0.015). Conclusions: Elevated sTfR1 predicts poor prognosis in patients with COPD and, particularly in combination with low hemoglobin, may serve as a biomarker for severe PH in COPD, identifying a distinct phenotype with systemic inflammation, anemia and iron deficiency.