Cathepsin S and Survival in NSTE-ACS Patients

Aug 31, 2022
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Authors:
Stamatelopoulos K, Mueller-Hennessen M, Georgiopoulos G, et al.
Citation:
Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 2022;80:998-1010.
Summary By:
Salim Hayek, MD, FACC

Quick Takes

  • Cathepsin S (CTSS) is an extracellular matrix degradation enzyme thought to have a role in atherogenesis and which levels in serum have previously been found to be associated with long-term mortality.
  • This observational cohort study examines the predictive value of CTSS in a cohort of 1,112 patients admitted for suspected non–ST-segment elevation myocardial infarction.
  • Higher levels of CTSS were associated with an increased risk of all-cause death at 8 years of follow-up, with modest improvement in risk discrimination when combined with the GRACE score. Clinical implications are unclear given the lack of therapies targeting CTSS or changes in management that would be triggered by high levels.

Study Questions:

Is cathepsin S (CTSS) associated with long-term mortality in patients hospitalized for non–ST-segment elevation myocardial infarction (NSTEMI)?

Methods:

This is a single-center prospective cohort study recruiting patients with suspected NSTEMI, in whom serum samples were collected for measurement of CTSS. At the time of the analysis, CTSS was measured in a subset of 1,112 participants (of 2,702). It is unclear whether patients were limited to type I NSTEMI or including both type I or type II. A time to survival analysis was performed with all-cause mortality at 8 years (median follow-up) as the primary endpoint, and cardiovascular mortality as a secondary endpoint.

Results:

The cohort consisted of older patients (mean age 67 years), and a majority of men (68%). There were 367 (33.0%) deaths recorded at the time of the analysis for this study. Higher CTSS levels were associated with diabetes mellitus, but not the number of diseased coronary arteries. The cathepsin level was associated with increased mortality (hazard ratio [HR] for highest vs. lowest quarter of CTSS, 1.89; 95% confidence interval [CI], 1.34-2.66; p < 0.001) and cardiovascular death (HR, 2.58; 95% CI, 1.15-5.77; p = 0.021) after adjusting for traditional cardiovascular risk factors, high-sensitivity C-reactive protein (hs-CRP), left ventricular ejection fraction (LVEF), high-sensitivity troponin T (hs-TnT), revascularization, and index diagnosis. Addition of CTSS to the GRACE score, hs-TnT, and LVEF conferred a modest improvement in risk discrimination for all-cause death (∆AUC 0.008) and cardiovascular death (∆AUC 0.014).

Conclusions:

Serum CTSS levels in patients admitted for NSTEMI are associated with long-term mortality and modestly improve risk stratification of these patients.

Perspective:

CTSS is an extracellular matrix degradation enzyme with both elastolytic and collagenolytic properties thought to have a role in atherogenesis. Levels have previously been shown to predict outcomes in non–acute coronary syndrome (ACS) cohorts. The authors investigated the predictive value of serum levels of CTSS in patients suspected of NSTEMI and found an association with long-term mortality. The improvement in risk discrimination was only modest when considering available data. There was no strong association between CTSS and burden of atherosclerosis, despite associations with other markers of disease, including inflammation or hs-CRP. It would have been of value to compare the predictive value of CTSS to hs-CRP rather than the GRACE score which was not meant to predict long-term mortality. While preclinical animal experiments show promise with regard to CTSS’s role in atherogenesis, there is no other evidence of causal involvement such as mendelian randomization or clinical interventions. Thus, clinical implications are limited at this time, pending studies showing how levels of CTSS or targeting CTSS can impact patient management.

Clinical Topics: Acute Coronary Syndromes, Cardiovascular Care Team, Prevention, Stable Ischemic Heart Disease, Vascular Medicine, ACS and Cardiac Biomarkers, Chronic Angina

Keywords: Acute Coronary Syndrome, Atherosclerosis, Cathepsins, C-Reactive Protein, Diabetes Mellitus, Extracellular Matrix, Heart Disease Risk Factors, Inflammation, Myocardial Infarction, Non-ST Elevated Myocardial Infarction, Risk Assessment, Risk Factors, Secondary Prevention, Stroke Volume, Survival Analysis, Troponin T, Ventricular Function, Left


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