Abstract OBJECTIVE: While angiogenesis, the formation of new blood vessels from pre-existing vessels, may be beneficial in restoring the failing myocardium, apoptosis may contribute to progression of heart failure (HF). We investigated the role of pigment epithelium-derived factor (PEDF), a new antiangiogenic factor with additional proapoptotic effects, in patients with advanced HF. METHODS AND RESULTS: We assayed PEDF levels in 351 patients with advanced HF at baseline. During the median follow-up time of 16 months 50% of patients experienced the composite endpoint rehospitalization and/or death. The risk of a clinical event increased with concentrations of the antiangiogenic marker PEDF with a 1.94-fold higher risk in the third tertile compared to the first tertile (95% confidence interval: 1.33-2.84). This association remained significant after adjustment for B-type natriuretic peptide (BNP) and other risk factors in a Cox regression model (P=0.015). Experimental data revealed that PEDF may contribute to progression of HF by inducing apoptosis in human cardiac myocytes and fibroblasts via activation of caspase 3. CONCLUSION: We suggest a role of PEDF in the progression of HF by inducing apoptosis of human cardiac myocytes and fibroblasts. Our clinical data suggest that PEDF concentrations may have the potential to become a valuable marker of the prognosis of HF in addition to BNP.