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JACC Heart Fail. 2019 Jul 31. pii: S2213-1779(19)30549-9. doi: 10.1016/j.jchf.2019.07.005. [Epub ahead of print]

Circulating Neprilysin in Patients with Heart Failure with Preserved Ejection Fraction.

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The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Division of Cardiology, Duke Clinical Research Institute, Durham, North Carolina, USA.
Division of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
The Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. Electronic address:



In heart failure with reduced ejection fraction (HFrEF), elevated soluble neprilysin (sNEP) levels are associated with an increased risk of cardiovascular death, and its inhibition with sacubitril/valsartan has improved survival.


This study sought to determine the relevance of sNEP as a biomarker in heart failure with preserved ejection fraction (HFpEF) and to compare circulating sNEP levels in HFpEF patients with normal controls.


A case-control study was performed in 242 symptomatic HFpEF patients previously enrolled in the RELAX and NEAT-HFpEF clinical trials, and 891 asymptomatic subjects without HF or diastolic dysfunction (confirmed by NT-proBNP levels <200 pg/ml and echocardiography), who were enrolled in the Prevalence of Asymptomatic Left Ventricular Dysfunction study. sNEP was measured using a sandwich ELISA assay in all subjects.


Overall, sNEP levels were lower in HFpEF compared to controls (3.5 ng/ml [CI 2.5, 4.8] vs 8.5 ng/ml [CI 7.2, 10.0], p<0.001). After adjusting for age, gender, BMI and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI 2.7,5.4] vs 8.2 ng/ml [CI 6.8, 9.7], p 0.002). The cohorts were propensity matched based on age, BMI, diabetes, hypertension, smoking history and renal function, and sNEP levels remained lower in HFpEF compared with controls (median 2.4 ng/ml [IQR 0.6, 27.7] vs 4.9 ng/ml [IQR 1.2, 42.2], p=0.02).


HFpEF patients on average have significantly lower circulating sNEP levels compared to controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF.


diastolic dysfunction; heart failure; neprilysin


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