Higher circulating cathepsin D levels were independently associated with an increased risk of all-cause mortality or heart failure hospitalizations (HR per SD 1.12; 95% CI 1.02-1.23).
Cohort (n=3,874)
Are circulating cathepsin D levels associated with clinical outcomes in patients with heart failure?
Higher circulating cathepsin D levels are associated with increased mortality and heart failure hospitalizations, while in vitro silencing suggests reduced levels may have detrimental cellular effects.
Hazard Ratio: 1.12 (95% CI 1.02–1.23)
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.
Hoes et al. (Tue,) conducted a cohort in Heart failure (n=3,874). Circulating cathepsin D levels vs. Lower levels was evaluated on All-cause mortality and/or HF hospitalizations (HR 1.12, 95% CI 1.02-1.23). Higher circulating cathepsin D levels were independently associated with an increased risk of all-cause mortality or heart failure hospitalizations (HR per SD 1.12; 95% CI 1.02-1.23).