Urinary cathepsin A as a non-invasive diagnostic biomarker in heart failure

Abstract Background Heart failure (HF) still lacks a simple, repeatable test that can be applied outside specialist centres. Urine collects protein changes linked to disease, but whether urinary lysosomal cathepsin A (CTSA) can help diagnose HF is unknown. We assessed urinary CTSA as a potential diagnostic marker for HF. Methods We enrolled 58 HF patients and 50 age- and sex-matched healthy controls. Urine from 10 patients and 10 controls was analyzed by 4D label-free quantitative (4D-LFQ) proteomics; the remaining samples were used for ELISA confirmation. Differentially expressed proteins were identified and subjected to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) analyses. CTSA abundance was measured by ELISA and evaluated by regression and receiver operating characteristic (ROC) analysis, with adjustment for renal function. Results 4D-LFQ identified 200 differentially expressed proteins (82 up- and 118 downregulated; fold change > 1.5, P < 0.05). Bioinformatic analysis highlighted CTSA, a lysosomal protease in the renin–angiotensin system. ELISA showed that urinary CTSA was higher in HF than in controls (median [IQR] 3055.43 [2498.33–3434.76] vs 2551.4 [2084.76–2785.9] pg/mL; P < 0.0001). The CTSA/eGFR ratio discriminated HF from controls (AUC 0.89, 95% CI 0.83–0.96; sensitivity 85.0%, specificity 81.25%). The association remained positive after adjustment for eGFR (β = 524.098, P = 0.001). PPI analysis placed CTSA at the centre of a cluster of co-expressed lysosomal hydrolases and peptidases. Conclusions Urinary CTSA is increased in HF and, when interpreted with renal function, performs as a non-invasive diagnostic marker. It complements blood-based assays and merits validation in larger cohorts.