Neprilysin Is a Predictor of Mortality and Morbidity in Heart Failure | Journal Scan

Study Questions:

Is circulating neprilysin (NEP) a predictor of outcomes in heart failure (HF)?


The study investigators measured circulating soluble NEP in a cohort of 1,069 systolic HF patients from an ambulatory setting in Barcelona, Spain. They followed the cohort for 4.1 ± 2.4 years. They used a modified sandwich immunoassay to measure NEP levels. The median NEP level was 0.642 ng/ml (median quartile 1-3: 0.385-1.219), and the intra-assay coefficient of variation at this median value was 6.5%. They evaluated the association between NEP levels and the composite endpoint that included HF hospitalization or cardiovascular (CV) mortality.


The study authors found a significant correlation between NEP levels and age (rho 0.16; p < 0.001). As a result, they conducted an age-adjusted Cox regression analysis. This analysis found that NEP levels correlated significantly with the composite endpoint (hazard ratio [HR], 1.17; 95% confidence interval [CI], 1.06-1.29; p = 0.001) and CV mortality (HR, 1.19; 95% CI, 1.06-1.32; p = 0.002). They also utilized a comprehensive multivariable analysis (that included age, gender, ischemic etiology, New York Heart Association class, diabetes mellitus, estimated glomerular filtration rate, left ventricular ejection fraction, serum sodium, hemoglobin, N-terminal pro–B-type natriuretic peptide [NT-proBNP], angiotensin-converting enzyme inhibitor therapy, and beta-blocker treatment). This analysis also found that NEP correlated significantly with both the composite endpoint (HR, 1.18; 95% CI, 1.07-1.31; p = 0.001) and CV mortality (HR, 1.18; 95% CI, 1.05-1.32; p = 0.006). When the study authors utilized a multimarker approach to include NEP, NT-proBNP, ST2, and high-sensitivity troponin T, NEP remained significantly associated with the composite primary endpoint (HR, 1.15; 95% CI, 1.03-1.28; p = 0.02) and CV mortality (HR, 1.17; 95% CI, 1.03-1.32; p = 0.02). The likelihood ratios also significantly improved in the model when NEP was included (p = 0.02 for the composite endpoint and p = 0.04 for CV mortality, respectively).


The study authors concluded that their findings of positive association of circulating NEP with CV mortality and morbidity reinforce the importance of NEP inhibition as a treatment option.


This is an important study because it provides a better understanding of NEP inhibition in HF patients given that the PARADIGM-HF trial showed that NEP inhibition in systolic HF improved survival when compared to enalapril. The findings of this study should provide impetus to develop circulating NEP assays that can be utilized for daily clinical use.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Chronic Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Neprilysin, Heart Failure, Heart Failure, Systolic, Biological Markers, Hemoglobins, Hospitalization, Morbidity, Mortality, Adrenergic beta-Antagonists, Angiotensin-Converting Enzyme Inhibitors, Glomerular Filtration Rate, Natriuretic Peptide, Brain, Troponin T, Sodium, Regression Analysis

< Back to Listings