Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction

Melissa A. Lyle, Seethalakshmi R. Iyer, Margaret M. Redfield, Yogesh N.V. Reddy, G. Michael Felker, Thomas P. Cappola, Adrian F. Hernandez, Christopher G. Scott, John C Jr. Burnett, Naveen Luke Pereira

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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 HFpEF patients with normal controls. Methods: A case-control study was performed in 242 symptomatic HFpEF patients 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.

Original languageEnglish (US)
JournalJACC: Heart Failure
DOIs
StateAccepted/In press - Jan 1 2019

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Neprilysin
Heart Failure
Confidence Intervals
Body Mass Index
Smoking
History
Type 5 Cyclic Nucleotide Phosphodiesterases
Left Ventricular Dysfunction
Nitrates
Echocardiography
Case-Control Studies

Keywords

  • diastolic dysfunction
  • heart failure
  • neprilysin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Lyle, M. A., Iyer, S. R., Redfield, M. M., Reddy, Y. N. V., Felker, G. M., Cappola, T. P., ... Pereira, N. L. (Accepted/In press). Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction. JACC: Heart Failure. https://doi.org/10.1016/j.jchf.2019.07.005

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction. / Lyle, Melissa A.; Iyer, Seethalakshmi R.; Redfield, Margaret M.; Reddy, Yogesh N.V.; Felker, G. Michael; Cappola, Thomas P.; Hernandez, Adrian F.; Scott, Christopher G.; Burnett, John C Jr.; Pereira, Naveen Luke.

In: JACC: Heart Failure, 01.01.2019.

Research output: Contribution to journalArticle

Lyle, Melissa A. ; Iyer, Seethalakshmi R. ; Redfield, Margaret M. ; Reddy, Yogesh N.V. ; Felker, G. Michael ; Cappola, Thomas P. ; Hernandez, Adrian F. ; Scott, Christopher G. ; Burnett, John C Jr. ; Pereira, Naveen Luke. / Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction. In: JACC: Heart Failure. 2019.
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abstract = "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 HFpEF patients with normal controls. Methods: A case-control study was performed in 242 symptomatic HFpEF patients 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.",
keywords = "diastolic dysfunction, heart failure, neprilysin",
author = "Lyle, {Melissa A.} and Iyer, {Seethalakshmi R.} and Redfield, {Margaret M.} and Reddy, {Yogesh N.V.} and Felker, {G. Michael} and Cappola, {Thomas P.} and Hernandez, {Adrian F.} and Scott, {Christopher G.} and Burnett, {John C Jr.} and Pereira, {Naveen Luke}",
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AU - Lyle, Melissa A.

AU - Iyer, Seethalakshmi R.

AU - Redfield, Margaret M.

AU - Reddy, Yogesh N.V.

AU - Felker, G. Michael

AU - Cappola, Thomas P.

AU - Hernandez, Adrian F.

AU - Scott, Christopher G.

AU - Burnett, John C Jr.

AU - Pereira, Naveen Luke

PY - 2019/1/1

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N2 - 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 HFpEF patients with normal controls. Methods: A case-control study was performed in 242 symptomatic HFpEF patients 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.

AB - 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 HFpEF patients with normal controls. Methods: A case-control study was performed in 242 symptomatic HFpEF patients 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.

KW - diastolic dysfunction

KW - heart failure

KW - neprilysin

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