Endotrophin, an extracellular hormone, in combination with neoepitope markers of von Willebrand factor improves prediction of mortality in the ECLIPSE COPD cohort

• Main Authors: Sarah R. Rønnow, Lasse L. Langholm, Morten A. Karsdal, Tina Manon-Jensen, Ruth Tal-Singer, Bruce E. Miller, Jørgen Vestbo, Diana J. Leeming, Jannie M. B. Sand
• Format: Article
• Language: English
• Published: BMC 2020-07-01
• Series: Respiratory Research
• Subjects: COPD; Biomarkers; Extracellular matrix
• Online Access: http://link.springer.com/article/10.1186/s12931-020-01461-6

Abstract Background Lung epithelial damage, activation of the wound healing cascade, and remodeling of the extracellular matrix (ECM) play a major role in chronic obstructive pulmonary disease (COPD). The pro-peptide of type VI collagen has been identified as the hormone endotrophin. Endotrophin has been shown to promote fibrosis and inflammation, whereas von Willebrand factor (VWF) is a crucial part of wound healing initiation. Here, we assessed the released and activated form of VWF and endotrophin, the pro-peptide of type VI collagen, serologically to investigate their association with mortality in COPD subjects alone or in combination. Methods One thousand COPD patients with 3 years of clinical follow-up from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) cohort were included. Serum and heparin plasma were collected at 6 months and 1 year, respectively. Competitive ELISA utilizing specific monoclonal antibodies assessed endotrophin/type VI collagen formation (PRO-C6), VWF release (VWF-N), and activated VWF (VWF-A). Biomarker levels were dichotomized into high and low as defined by receiver operating characteristic (ROC) curves based on mortality data. Kaplan-Meier analysis was used to determine hazard ratios for all-cause mortality for biomarkers alone or in combination. Results High levels of PRO-C6, VWF-A, and VWF-N have previously been shown to be individually associated with a higher risk of mortality with hazard ratios of 5.6 (95% CI 2.4–13.1), 3.7 (1.8–7.6), and 4.6 (2.2–9.6), respectively. The hazard ratios increased when combining the biomarkers: PRO-C6*VWFA 8.8 (2.8–27.7) and PRO-C6*VWFN 13.3 (5.6–32.0). Notably, PRO-C6*VWF-N increased more than 2-fold. Conclusion We demonstrated that by combining two pathological relevant aspects of COPD, tissue remodeling, and wound healing, the predictive value of biomarkers for mortality increased notably.