Urinary Proteomic Signature in Acute Decompensated Heart Failure: Advances into Molecular Pathophysiology

Abstract

Acute decompensated heart failure (ADHF) is a life-threatening clinical syndrome involving multi-organ function deterioration. ADHF results from multifaceted, dysregulated pathways that remain poorly understood. Better characterization of proteins associated with heart failure decompensation is needed to gain understanding of the disease pathophysiology and support a more accurate disease phenotyping. In this study, we used an untargeted mass spectrometry (MS) proteomic approach to identify the differential urine protein signature in ADHF patients and examine its pathophysiological link to disease evolution. Urine samples were collected at hospital admission and compared with a group of healthy subjects by two-dimensional electrophoresis coupled to MALDI-TOF/TOF mass spectrometry. A differential pattern of 26 proteins (>1.5-fold change, p < 0.005), mostly of hepatic origin, was identified. The top four biological pathways (p < 0.0001; in silico analysis) were associated to the differential ADHF proteome including retinol metabolism and transport, immune response/inflammation, extracellular matrix organization, and platelet degranulation. Transthyretin (TTR) was the protein most widely represented among them. Quantitative analysis by ELISA of TTR and its binding protein, retinol-binding protein 4 (RBP4), validated the proteomic results. ROC analysis evidenced that combining RBP4 and TTR urine levels highly discriminated ADHF patients with renal dysfunction (AUC: 0.826, p < 0.001) and significantly predicted poor disease evolution over 18-month follow-up. In conclusion, the MS proteomic approach enabled identification of a specific urine protein signature in ADHF at hospitalization, highlighting changes in hepatic proteins such as TTR and RBP4.