Prognostic and reclassification value of serum cathepsin S over the GRACE risk score in patients with non-ST-segment elevation acute coronary syndrome

Abstract

Abstract Background Cathepsin S is an extracellular matrix degradation enzyme that plays an important role in atherosclerotic cardiovascular disease by inducing vasa vasorum development and atherosclerotic plaque rupture. Purpose To determine the prognostic and reclassification value of baseline serum cathepsin S after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is a clinical guideline recommended risk score in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods Serum cathepsin S was measured by ELISA in 1,129 consecutive patients presenting with acute symptoms to the emergency department for whom a final adjudicated diagnosis of NSTE-ACS was made. All-cause mortality or all-cause death/non-fatal myocardial infarction (MI) after a median follow-up of 21 months were evaluated as the primary or secondary study endpoint, respectively. The Net Reclassification Index (NRI) estimated the reclassification predictive value for risk of each end-point of cathepsin S over the GRACE score. Results After a median follow-up of 21 months 101 (8.95%) deaths were reported. The combined endpoint of death or non-fatal MI occurred in 176 (15.6%) patients. Dose-response curve analysis adjusted for the effect of age, gender, diabetes mellitus, high-sensitivity-cardiac troponin T, high-sensitivity C-reactive protein, revascularization and index diagnosis revealed a non-linear association of continuous cathepsin S with all-cause death (P=0.036 for non-linearity; adjusted HR=1.60 for 80th vs. 20th percentiles, P=0.038) or with the combined endpoint (P=0.008 for non-linearity, adjusted HR=1.53 for 80th vs. 20th percentiles, P=0.011). Serum cathepsin S maintained its predictive value for all-cause death (adjusted HR=1.70 highest vs. lowest tertile, 95% CI 1.03–2.82, P=0.039) after adjusting for the GRACE Score. Similarly, cathepsin S predicted the combined endpoint of all-cause death or non-fatal MI (adjusted HR=1.67 highest vs. lowest tertile, 95% CI 1.15–2.42, P=0.007) independently of the GRACE Score. When cathepsin S was added over the GRACE Score it correctly reclassified risk for all-cause death in 20% of the population (P=0.004). Similarly, serum Cathepsin S conferred a significant reclassification value over the GRACE score for all-cause death or non-fatal MI in 15.9% of the population. Conclusions Serum cathepsin S is a predictor of mortality and improves risk stratification over the GRACE score in patients with NSTE-ACS. The clinical application of cathepsin S as a novel biomarker in NSTE-ACS should be further explored and validated. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Heart Foundation