Author + information
- Received May 15, 2019
- Revision received June 21, 2019
- Accepted July 15, 2019
- Published online December 30, 2019.
- Melissa A. Lyle, MDa,∗,
- Seethalakshmi R. Iyer, MSa,∗,
- Margaret M. Redfield, MDa,
- Yogesh N.V. Reddy, MD, MSca,
- G. Michael Felker, MD, MHSb,
- Thomas P. Cappola, MDc,
- Adrian F. Hernandez, MDb,
- Christopher G. Scott, MSd,
- John C. Burnett Jr., MDa and
- Naveen L. Pereira, MDa,e,∗ ()
- aDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
- bDivision of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
- cDivision of Cardiovascular Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- dDivision of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
- eDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
- ↵∗Address for correspondence:
Dr Naveen L Pereira, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905.
Background 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.
Objectives 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 patients with HFpEF with normal controls.
Methods A case-control study was performed in 242 symptomatic patients with HFpEF previously enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) and Nitrates’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection (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 enzyme-linked immunosorbent assay (ELISA) in all subjects.
Results Overall, sNEP levels were lower in HFpEF compared with controls (3.5 ng/ml; confidence interval [CI]: 2.5 to 4.8 vs. 8.5 ng/ml; CI: 7.2 to 10.0; p < 0.001). After adjusting for age, gender, body mass index (BMI), and smoking history, mean sNEP levels were also lower in HFpEF compared with controls (4.0 ng/ml [CI: 2.7 to 5.4] vs. 8.2 ng/ml [CI: 6.8 to 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 [interquartile range: 0.6 to 27.7] vs. 4.9 ng/ml [interquartile range: 1.2 to 42.2]; p = 0.02).
Conclusions Patients with HFpEF on average have significantly lower circulating sNEP levels compared with controls. These findings challenge our current understanding of the complex biology of circulating sNEP in HFpEF.
↵∗ Drs. Lyle and Iyer have contributed equally to this work.
Dr Felker has received research grants from NHLBI, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics; served as a consultant to Novartis, Amgen, Bristol-Myers Squibb, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems, Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, and SC Pharma. Dr Pereira is supported by National Institute on Aging Grant R21AG53512. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received May 15, 2019.
- Revision received June 21, 2019.
- Accepted July 15, 2019.
- 2020 American College of Cardiology Foundation
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