Biomarkers to Predict the Response to Cardiac Resynchronization Therapy

Ward Heggermont; Angelo Auricchio; Marc Vanderheyden


Europace. 2019;21(11):1609-1620. 

In This Article

Cystatin C

Cystatin C (CysC) is a protein encoded by the CST3 gene. All human nucleated cells produce CysC as a chain of 120 amino acids which functions as an intracellular inhibitor of lysosomal proteinases and an extracellular inhibitor of cysteine proteases. The clinical relevance of CysC stems from extensive research in kidney failure, where the marker is of superior accuracy to more conventional, established markers of renal dysfunction e.g. serum creatinine.[48] Moreover, CysC levels have been shown to coincide with worse clinical outcome and the occurrence of clinically relevant events in patients with HF.[49] This observation lead to the hypothesis that CysC might be of interest to predict adverse, or beneficial, outcome in HF patients whom receive resynchronization therapy. The first report on the relevance of CysC levels in predicting outcome in CRT patients was published in 2013.[50] Yamamoto et al. showed that elevated CysC levels were significantly associated with long-term outcome (mortality and cardiovascular events) in 117 patients with a median follow-up time of 3.2 years and an incidence rate of 29.1% for mortality, and 50.4% for cardiovascular events. This finding remained consistent even after multivariate Cox regression analysis. However, there was no superiority of CysC compared to the glomerular filtration rate (eGFR) to predict the response to CRT.[50] A few years later, in the BIOCRT study,[51] CysC levels were measured in 133 patients, both in peripheral venous and coronary sinus (CS) blood samples. Classical serum creatinine levels and eGFR, were measured simultaneously. The three markers (CysC, creatinine, and eGFR) were predictive of major adverse cardiac events (MACEs) during a follow-up term of on average 2 years, but only baseline CysC levels were associated with the identification of adverse clinical outcome after CRT implantation. CysC levels associated with CRT non-response at 6 months with an adjusted OR of 3.6 (P = 0.02). Moreover, the addition of CysC to classical predictive parameters resulted in an improved prediction of CRT non-response (P ≤ 0.003). On top of that, serial measurements of CysC resulting in absolute values of >1 mg/L were associated with a CRT non-response and a reduced 6-min walk distance, as well as 2 years of MACE (P ≤ 0.04).[51] Of note, the measurement of CysC levels in CS blood had no added value with respect to prognostic significance, meaning that peripheral blood-derived CysC levels were sufficient to predict adverse response to CRT, a feature improving the usefulness of CysC as a biomarker. Overall, the importance of CysC in the prediction of the response to CRT relates to the fact that patients with severe kidney failure display worse outcome after device therapy.[52,53]