The role of cathepsin D in the pathophysiology of heart failure and its potentially beneficial properties: a translational approach

AIMS: Cathepsin D is a ubiquitous lysosomal protease that is primarily secreted due to oxidative stress. The role of circulating cathepsin D in heart failure (HF) is unknown. The aim of this study is to determine the association between circulating cathepsin D levels and clinical outcomes in patients with HF and to investigate the biological settings that induce the release of cathepsin D in HF. METHODS AND RESULTS: Cathepsin D levels were studied in 2174 patients with HF from the BIOSTAT‐CHF index study. Results were validated in 1700 HF patients from the BIOSTAT‐CHF validation cohort. The primary combined outcome was all‐cause mortality and/or HF hospitalizations. Human pluripotent stem cell‐derived cardiomyocytes were subjected to hypoxic, pro‐inflammatory signalling and stretch conditions. Additionally, cathepsin D expression was inhibited by targeted short hairpin RNAs (shRNA). Higher levels of cathepsin D were independently associated with diabetes mellitus, renal failure and higher levels of interleukin‐6 and N‐terminal pro‐B‐type natriuretic peptide (P < 0.001 for all). Cathepsin D levels were independently associated with the primary combined outcome [hazard ratio (HR) per standard deviation (SD): 1.12; 95% confidence interval (CI) 1.02–1.23], which was validated in an independent cohort (HR per SD: 1.23, 95% CI 1.09–1.40). In vitro experiments demonstrated that human stem cell‐derived cardiomyocytes released cathepsin D and troponin T in response to mechanical stretch. ShRNA‐mediated silencing of cathepsin D resulted in increased necrosis, abrogated autophagy, increased stress‐induced metabolism, and increased release of troponin T from human stem cell‐derived cardiomyocytes under stress. CONCLUSIONS: Circulating cathepsin D levels are associated with HF severity and poorer outcome, and reduced levels of cathepsin D may have detrimental effects with therapeutic potential in HF.