Dataset Information

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

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 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.

SUBMITTER: Lyle MA

PROVIDER: S-EPMC6942207 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

Lyle Melissa A MA Iyer Seethalakshmi R SR Redfield Margaret M MM Reddy Yogesh N V YNV Felker G Michael GM Cappola Thomas P TP Hernandez Adrian F AF Scott Christopher G CG Burnett John C JC Pereira Naveen L NL

JACC. Heart failure 20190807 1

<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>A case-c ...[more]

PMID: 31392960

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Project description:AIMS:Neuregulin1-? (NRG1-?) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1-? is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). METHODS AND RESULTS:Circulating NRG1-? was quantified in 86 stable patients with HFpEF (EF ?45% and N-terminal pro-brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1-? and the composite outcome of all-cause mortality/HF hospitalization in HFpEF and all-cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th-75th percentile) NRG1-? was 6.5 (2.1-11.3) ng/mL; in HFrEF, 3.6 (2.1-7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9-3.6) ng/mL; after HTx 2.1 (1.4-3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1-34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1-? was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04-2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1-? with outcomes was modified by ischaemia (log-rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1-? was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1-? trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48-1.05, P = 0.085). CONCLUSIONS:Neuregulin1-? was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1-? with outcomes in non-ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1-? from microvascular endothelial dysfunction in the former (non-ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Project description:BackgroundInterleukin (IL)-6 is a central inflammatory mediator and potential therapeutic target in heart failure (HF). Prior studies have shown that IL-6 concentrations are elevated in patients with HF, but much fewer data are available in heart failure with preserved ejection fraction (HFpEF).ObjectivesThis study aims to determine how IL-6 relates to changes in cardiac function, congestion, body composition, and exercise tolerance in HFpEF.MethodsClinical, laboratory, body composition, exercise capacity, physiologic and health status data across 4 National Heart, Lung, and Blood Institute-sponsored trials were analyzed according to the tertiles of IL-6.ResultsIL-6 was measured in 374 patients with HFpEF. Patients with highest IL-6 levels had greater body mass index; higher N-terminal pro-B-type natriuretic peptide, C-reactive protein, and tumor necrosis factor-α levels; worse renal function; and lower hemoglobin levels, and were more likely to have diabetes. Although cardiac structure and function measured at rest were similar, patients with HFpEF and highest IL-6 concentrations had more severely impaired peak oxygen consumption (12.3 ± 3.3 mL/kg/min 13.1 ± 3.1 mL/kg/min 14.4 ± 3.9 mL/kg/min, P < 0.0001) as well as 6-minute walk distance (276 ± 107 m vs 332 ± 106 m vs 352 ± 116 m, P < 0.0001), even after accounting for increases in IL-6 related to excess body mass. IL-6 concentrations were associated with increases in total body fat and trunk fat, more severe symptoms during submaximal exercise, and poorer patient-reported health status.ConclusionsIL-6 levels are commonly elevated in HFpEF, and are associated with greater symptom severity, poorer exercise capacity, and more upper body fat accumulation. These findings support testing the hypothesis that therapies that inhibit IL-6 in patients with HFpEF may improve clinical status. (Clinical Trial Registrations: Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure [RELAX], NCT00763867; Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction, NCT02053493; Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF, NCT02742129; Inorganic Nitrite to Enhance Benefits From Exercise Training in Heart Failure With Preserved Ejection Fraction [HFpEF], NCT02713126).

Dataset Information

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

Background

Objectives

Methods

Results

Conclusions

Publications

Circulating Neprilysin in Patients With Heart Failure and Preserved Ejection Fraction.

Similar Datasets

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