Comparative performances of soluble urokinase plasminogen activator receptor and Mid-regional proADM to predict composite death and new heart failure rehospitalisation in acutely breathless patients
Authors: Chew-Harris J , Kuan W S , Ibrahim I , Chan S P , Li Z , Liew O W , Appleby S , Frampton C , Troughton R , Chong J P C , Tan L L , Lin W , Ooi S B S , Richards A M , Pemberton C J 
Published: October 2022

Abstract

Background
Soluble urokinase plasminogen activator receptor (suPAR) is a pleotropic receptor, capable of orchestrating plaque vulnerability and vascular immune dysfunction. Mid-regional pro-adrenomedullin (MR-proADM) is the stable peptide precursor of adrenomedullin, with concentrations reflective of vasodilation and cardiac remodelling. We compared the prognostic performances of suPAR and MR-proADM for the composite clinical endpoint of death and new heart failure (HF) in patients with undifferentiated breathlessness.

Methods
Patients presenting to hospital with the primary complaint of acute dyspnoea were recruited in New Zealand (n=612) and in Singapore (n=483)]. Baseline plasma measurements were undertaken for suPAR (ViroGates) and MR-proADM (Thermo Scientific). Cardiac biomarker levels of NT-proBNP (Roche) was available on all patients. Statistical assessment was made using SPSS v28 (IBM), with all biomarkers treated as continuous variables and presented as median [interquartile range (IQR)]. Prognostic performance of suPAR, MR-proADM and NT-proBNP to predict the composite clinical endpoint of death/new HF at 90-days and 1-yr were assessed using receiver operator curve (ROC) area under the curve (AUC) analysis (Z-scores) and Cox hazard regression analysis (per doubling of biomarker concentrations) after adjustment for traditional risk factors. P-value &lt;0.05 was considered statistically significant.

Results
In the entire acutely breathless cohort [median age: 65 years (IQR: 52.9–76.0), 63.1% males], 343/1095 of patients had the final adjudication of ADHF. suPAR and MR-proADM concentrations were higher with increasing age (Spearmans rho, r&gt;0.46, P&lt;0.0001), lower eGFR (r&gt;0.58, P&lt;0.0001) and in those with ADHF (r&gt;0.40, P&lt;0.0001). During the follow-up period, 122 patients were categorised with death/new HF by 90-days, rising to 281 at 1-year. suPAR and MR-proADM were able to predict death/new HF at 90-days (both ROC-AUC &gt;0.77) and at 1-year (both ROC-AUC ≥0.78) (Table 1). All markers were however less accurate in predicting this endpoint in the presence of ADHF (ROC-AUC &lt;0.71). After adjustment in Cox-regression modelling, suPAR obtained HR &gt;1.35 per doubling of suPAR concentrations (P=0.001) for outcomes at 90-days and at 1-year (Table 2), achieving the highest prognostic performance for this clinical endpoint, followed by NT-proBNP (HR &gt;1.29) (Table 2), whilst MR-proADM was not an independent predictor of death/HF in this cohort. suPAR was also an independent predictor of death/HF for patients with ADHF, obtaining HR &gt;1.35 per doubling of concentrations. Above a cut-off concentration of 3.6 ng/mL, suPAR was associated with a HR of 2.1 (95% CI: 1.55–2.91) for death/HF at 1-year for acutely dyspnoeic patients.

Conclusion
suPAR concentrations is superior than MR-proADM in predicting the clinical end-point of death/HF at 1-year in this cohort. It may aid in risk-stratification strategies for the management of acutely breathless patients.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): National Heart Foundation of New ZealandHealth Research Council of New Zealand