Abstract BACKGROUND Soluble CD146 (sCD146), is an endothelial marker with similar diagnostic power as natriuretic peptides in decompensated heart failure (HF). While natriuretic peptides are released by the failing heart, sCD146 may be released by veins in response to stretch induced by systemic congestion in HF. This study investigated the source, effects of vascular stress on release and prognostic properties of sCD146 in HF. METHODS In a peripheral venous stress study, plasma concentrations of sCD146 and N-terminal probrain natriuretic-peptide (NT-proBNP) were measured in 44 HF patients at baseline and after 90 min of unilateral forearm venous congestion. In addition, sCD146 and NT-proBNP were measured in peripheral vein (PV) and coronary sinus (CS) blood samples of 137 HF patients and the transcardiac gradient was calculated. Those patients were followed for major adverse cardiovascular events (MACE) during 2 years. RESULTS The induction of venous stress was associated with a pronounced increase in circulating concentrations of sCD146 in the congested arm (+60 μg/L) compared to the control arm (+16 μg/L, P = 0.025), while no difference in NT-proBNP concentrations was seen. In contrast to positive transcardiac gradient for NT-proBNP, median sCD146 concentrations were lower in CS than in PV (396 vs 434, P < 0.001), indicating a predominantly extracardiac source of sCD146. Finally, increased PV concentrations of sCD146 were associated with higher risk of MACE at 2 years. CONCLUSIONS Soluble CD146 is released from the peripheral vasculature in response to venous stretch and may reflect systemic congestion in chronic HF patients.