Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes

Stamatelopoulos, Kimon and Mueller-Hennessen, Matthias and Georgiopoulos, Georgios and Lopez-Ayala, Pedro and Sachse, Marco and Vlachogiannis, Nikolaos I and Sopova, Kateryna and Delialis, Dimitrios and Bonini, Francesca and Patras, Raphael and Ciliberti, Giorgia and Vafaie, Mehrshad and Biener, Moritz and Boeddinghaus, Jasper and Nestelberger, Thomas and Koechlin, Luca and Tual-Chalot, Simon and Kanakakis, Ioannis and Gatsiou, Aikaterini and Katus, Hugo and Spyridopoulos, Ioakim and Mueller, Christian and Giannitsis, Evangelos and Stellos, Konstantinos (2022) Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes. Journal of the American College of Cardiology, 80 (10). pp. 998-1010. ISSN 1558-3597

Abstract

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture. OBJECTIVES: The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score. METHODS: This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint. RESULTS: In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction. CONCLUSIONS: Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score.