Cathepsin S levels predict survival in NSTE-ACS patients

Circulating cathepsin S (CTSS) is significantly associated with long-term mortality and may be used to enhance risk stratification of patients with non–ST-segment elevation acute coronary syndrome (NSTE-ACS) over the Global Registry of Acute Coronary Events (GRACE) risk score, suggests a study.

“Herein, we report that increased circulating levels of CTSS in NSTE-ACS patients, measured during the acute phase of the syndrome, are associated with an adverse risk profile at presentation and confer independent long-term prognostic value,” said the researchers, led by Kimon Stamatelopoulus from the Kapodistrian University of Athens Medical School, Athens, Greece.

“Importantly, combined with the GRACE score, a reliable prognostic tool in ACS, CTSS improved risk stratification in terms of reclassification and discrimination,” they added.

Stamatelopoulus and colleagues conducted this single-centre cohort study and recruited 1,112 consecutive patients with adjudicated NSTE-ACS from the emergency department of an academic hospital. The researchers then measured CTSS in serum using enzyme-linked immunosorbent assay.

A total of 367 (33.0 percent) deaths occurred during the study period. CTSS predicted an increased risk of all-cause mortality (hazard ratio [HR] for highest vs lowest quarter of CTSS, 1.89, 95 percent confidence interval [CI], 1.34‒2.66; p<0.001) and cardiovascular (CV) death (HR, 2.58, 95 percent 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). [J Am Coll Cardiol 2022;80:998-1010]

GRACE score

The addition of CTSS to the GRACE score resulted in significant discrimination and reclassification value for all-cause mortality (Delta Harrell’s C, 0.03, 95 percent CI, 0.012‒0.047; p=0.001; net reclassification improvement, 0.202; p=0.003) and CV death (area under curve, 0.056, 95 percent CI, 0.017‒0.095; p=0.005; net classification improvement, 0.390; p=0.001) even after further consideration of high-sensitivity troponin-T and left ventricular ejection fraction.

GRACE is an established risk score widely recommended for treatment decisions of patients with NSTE-ACS and with good long-term prognostic ability. [Eur Heart J 2010;31:2755-2764; BMJ Open 2014;4:e004425]

“Although the GRACE score had initially shown good performance for long-term prognosis in post-ACS patients, its prognostic value was lower than expected in some validation cohorts,” the researchers said. [J Am Coll Cardiol Intv 2012;5:1108-1116]

“Thus, further refinement of accurate risk stratification of NSTE-ACS patients by additionally assessing such biomarkers would possibly improve the accurate recognition of patients in need of aggressive secondary prevention and minimize unaddressed residual risk,” they added.

Therapeutic implications

In ACS patients, targeting an atherosclerosis-specific inflammatory pathway by canakinumab, an interleukin (IL)-1b‒neutralizing monoclonal antibody, substantially reduced systemic inflammation and major adverse CV events. [Eur Heart J 2020;41:2153-2163; N Engl J Med 2017;377:1119-1131]

However, despite the benefits provided by canakinumab in ACS patients, a substantial residual risk remains in those treated with the drug. Such risk was potentially driven by high levels of other inflammatory molecules such as those of IL-6 and IL-18. [Eur Heart J 2020;41:2153-2163]

“Thus, assessment of different inflammatory pathways may confer additive prognostic effects, and individually targeting them might incrementally improve CV outcomes,” the researchers said.

In this regard, a clinical assay for CTSS measurement must be developed to identify patients eligible for anti-CTSS immunotherapy, which would lead to the assessment of CTSS as a potential therapeutic target in those with NSTE-ACS.

“Whether other cathepsins also confer an incremental value of GRACE risk score in the prediction of survival in patients with NSTE-ACS remains unknown,” the researchers said. “Future studies are warranted to evaluate the prognostic value of other cathepsins in comparison to CTSS in these patients.”