Lower neprilysin levels in HFpEF
Circulating Neprilysin in Patients with Heart Failure with Preserved Ejection Fraction
Introduction and methods
Abnormalities in active relaxation and passive stiffness of the heart can result in heart failure with preserved ejection fraction (HFpEF) . Atrial natriuretic peptide (ANP) and natriuretic peptides (NPs) affect these processes under normal conditions [2-4]. In addition, NPs directly reduce vascular resistance and affect natriuresis [5-7]. Neprilysin (NEP), a membrane bound metalloendopeptidase, is responsible for removal of at least 50% of NPs and inhibition of NEP results in increase in ANP and reduction in intra-cardiac filling pressures . The angiotensin receptor-NEP inhibitor (ARNI) sacubitril/valsartan is currently being evaluated as treatment for HFpEF in the PARAGON-HF trial comparted to valsartan alone.
NEP can be released for the cell surface and circulating soluble NEP (sNEP) were significantly associated with CV death or HF hospitalization in patients with reduced ejection fraction (HFrEF) . A study in HFpEF patients showed that sNEP levels were not associated with NYHA class, 6-minute walk test of cardiac hospitalization and death .
In this study, it was examined whether sNEP is a biomarker in HFpEF and levels of sNEP in 242 HFpEF patients (previously enrolled in RELAX and NEAT-HFpEF clinical trials [11,12]) were compared with 891 asymptomatic controls without HF or diastolic dysfunction (previously enrolled in PAVD study from Olmsted County [13,14]).
- When HFpEF patients were divided into tertiles based on sNEP levels, there was a higher prevalence of patients with NYHA class III/IV in the highest tertile vs. lowest tertile, but no association with sNEP levels and NT pro-BNP levels, echocardiographic measurements, or prior HF hospitalization.
- Mean sNEP levels were lower in HFpEF patients compared with controls (3.5 ng/mL [95%CI:2.5-4.8] vs. 8.5 ng/mL [95%CI: 7.2-10.0], P<0.001)
- After adjusting for age, gender, BMI, smoking history and hypertension, sNEP levels remained lower in HFpEF patients compared with controls (4.2 ng/mL [95%CI:2.8-6.4] vs. 8.0 ng/mL [95%CI:6.7-9.6], P=0.01).
- After propensity matching for age, BMI, diabetes, hypertension, smoking history and renal function, median sNEP levels remained lower in HFpEF patients compared with controls (2.4 ng/mL [IQR:0.6-27.7] vs. 4.9 ng/mL [IQR: 1.2-54.2], P=0.02) in a group of 111 subjects.
Levels of sNEP were lower in HFpEF patients compared to asymptomatic controls, also after multivariable adjustment and propensity matching. There was no association between sNEP levels and NPs levels, CV remodeling and HF hospitalizations in HFpEF patients.
The authors write: ‘ These data fundamentally question our simplistic assumptions of sNEP as a potential biomarker in HFpEF, contrary to its recent importance in HFrEF.’
To note, according to the authors it is important to recognize the complexity of the interaction between NEP and NPs. NEP is very non-specific in terms of substrate selection and levels of sNEP may depend on the complex interplay of various substrates. Also, circulating sNEP levels may not correlate with biologically active tissue levels.
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