Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients

Antoni Bayés-Genís, Jaume Barallat, Amparo Galán, Marta De Antonio, Mar Domingo, Elisabet Zamora, Agustín Urrutia, Josep Lupón

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112 Citations (Scopus)


© 2015 American College of Cardiology Foundation. Background Neprilysin is a membrane-bound enzyme that breaks down natriuretic peptides. The PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial showed that patients with heart failure (HF) treated with an angiotensin receptor neprilysin inhibitor lived longer without being hospitalized for HF than those receiving standard care with enalapril. Objectives This study sought to assess the presence of circulating soluble neprilysin in a real-life cohort of HF patients and correlate neprilysin levels with outcomes. Methods Circulating soluble neprilysin was measured with a modified sandwich immunoassay in consecutive ambulatory patients with HF who were followed up for 4.1 years. Associations between neprilysin level and a composite endpoint that included cardiovascular death or HF hospitalization were explored. Results Median neprilysin concentration in 1,069 patients was 0.642 ng/ml (median quartile 1 to 3: 0.385 to 1.219). Neprilysin weakly but significantly correlated with age (rho = 0.16; p < 0.001). In age-adjusted Cox regression analyses, neprilysin concentrations were significantly associated with the composite endpoint (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.06 to 1.29; p = 0.001) and cardiovascular death (HR: 1.19; 95% CI: 1.06 to 1.32; p = 0.002). In comprehensive multivariable analyses, soluble neprilysin remained significantly associated with both the composite endpoint (HR: 1.18; 95% CI: 1.07 to 1.31; p = 0.001) and cardiovascular death (HR: 1.18; 95% CI: 1.05 to 1.32; p = 0.006). Conclusions Identification of circulating neprilysin in HF patients and the positive association of neprilysin with cardiovascular mortality and morbidity further support the importance of NEP inhibition for augmenting natriuretic peptides as a therapeutic target.
Original languageEnglish
Pages (from-to)657-665
JournalJournal of the American College of Cardiology
Issue number7
Publication statusPublished - 1 Jan 2015


  • B-type natriuretic peptide
  • prognosis
  • survival


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