Author + information
- †Department of Cardiology, University Hospital Jean Minjoz, Besancon, France
- ‡Département Hospitalo-Universitaire Neurovasc, Paris, France
- §Department of Anaesthesiology and Intensive Care, Lariboisière Hospital, Paris, France
- ‖Unité Mixte de Recherche en Santé 942 Inserm, Paris, France
- ¶Paris Diderot University, Sorbonne Paris Cité, Paris, France
- ↵∗Reprint requests and correspondence:
Dr. Alexandre Mebazaa, Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France.
Neprilysin (NEP) is a membrane-bound enzyme with a large extracellular component that hydrolyzes atrial natriuretic peptide (ANP), but less so brain natriuretic peptide (BNP), and degrades various very important endogenous vasoactive peptides, including adrenomedullin and bradykinin for the vasodilators and angiotensin I and II and endothelin-1 for the vasoconstrictors and substance P (1).
Neprilysin was unknown by the cardiology world until the press release in March 2014 announcing the early closure of the PARADIGM-HF (Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial and the publication a few months later of its results in the New England Journal of Medicine (2). LCZ696 was the studied drug, first in a new class of drugs that act simultaneously as angiotensin receptor blockers and neprilysin inhibitors; drugs whose dual actions share the acronym ARNi (i.e., angiotensin receptor neprilysin inhibitor). In the PARADIGM-HF trial, LCZ696 was compared with the angiotensin-converting enzyme inhibitor enalapril in 8,442 patients with heart failure (HF) with reduced ejection fraction. The hazard ratio for cardiovascular death or rehospitalization (primary endpoint) was 0.80. Although PARADIGM-HF demonstrated that NEP is an important biotarget in HF, the mechanism of the beneficial action of LCZ696 needs to be clarified. A study by Packer et al. (3) showed that LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal prohormone of BNP [NT-proBNP] and troponin) compared with enalapril, whereas circulating BNP increased.
Previous studies have shown that NEP, like many other membrane-bound metalloproteases, can be released from the cell surface, producing a non–membrane-associated form. In a very recent paper, Bayes-Genis et al. (4) showed that a median concentration of the soluble form of neprilysin (sNEP) was 0.642 ng/ml (interquartile range [IQR]: 0.385 to 1.219 ng/ml) in 1,069 patients with stable chronic heart failure. Plasma concentration of sNEP is associated with short- and long-term outcomes, independent of NTproBNP.
In the paper published by Bayes-Genis et al. (5) in this issue of JACC: Heart Failure, median sNEP concentrations at admission were 0.67 ng/ml (IQR: 0.37 to 1.29 ng/ml) in a pilot multicenter study of acute heart failure (AHF) patients (5). It is interesting that those levels were similar to the levels found in patients with stable chronic heart failure by the same group and confirm those concentrations recently described in AHF by Vodovar et al. (6) (i.e., 0.305 ng/ml in AHF patients with high circulating BNP). Furthermore, no relationship was found between concentrations of sNEP and BNP or NT-proBNP levels (4–6). However, Bayes-Genis et al. (5) show an association between cardiovascular death or heart failure rehospitalization at short-term and long-term in AHF.
Circulating NEP is active and retains catalytic activity. Vodovar et al. (6) showed that NEP activity varies in AHF and chronic HF as a function of circulating BNP levels. The higher the circulating BNP (>916 pg/ml), the lower the activity of circulating NEP and vice versa. This suggests that BNP, 1 of the substrates of NEP, may act as an endogenous inhibitor of circulating NEP.
The growing data for NEP are of a great importance when LCZ696 will be used in our patients. Long-lasting therapies are not optimally given in chronic HF patients. Biomarker (mostly NT-proBNP)-guided strategies have been suggested as a way of monitoring the optimization of those agents. Further studies should assess the “dual” role of the circulating concentration of sNEP as a marker of severity of HF or, even better, NEP activity to assess the degree of response to LCZ696.
A modern way of managing HF patients is to apply biomarker-guided therapy. Hence, natriuretic peptides are known to be overproduced in HF patients. It was even recently demonstrated that increased plasma concentrations of NT-proBNP in hospitalized HF patients was at least partially related to post-transcriptional regulation. Both the drop in NT-proBNP glycosylation and the increase in furin activity accelerates NT-proBNP production and its release into the plasma. Accordingly, plasma levels of NPs reflect heart condition and may be used to titrate HF medications during hospitalization and later during outpatient visits.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Mebazaa has received speaker honoraria from The Medicines Company, Novartis, Orion, Servier, and Vifor Pharma; and fees as a member of the advisory boards and Steering Committee from Cardiorentis of The Medicines Company, Adrenomed, and Critical Diagnostics. Dr. Seronde has reported that she has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
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