The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin.

Mattia Arrigo1,2, Nicolas Vodovar1, Hélène Nougue 1,3, Malha Sadoune1, Chris J. Pemberton4, Pamela Ballan5, Pierre-Olivier Ludes5, Nicolas Gendron6,7,8, Alain Carpentier6,9, Bernard Cholley6,10, Philippe Bizouarn11, Alain Cohen-Solal1,12,13, Jagmeet P. Singh14, Jackie Szymonifka15, Christian Latremouille6,9, Jane-Lise Samuel1, Jean-Marie Launay1,16, Julien Pottecher5,17, A. Mark Richards4,18, Quynh A. Truong15, David M. Smadja6,7,8, and Alexandre Mebazaa1,3,12*

Aims : Heart failure (HF) is accompanied by major neuroendocrine changes including the activation of the natriuretic peptide (NP) pathway. Using the unique model of patients undergoing implantation of the CARMAT total artificial heart and investigating regional differences in soluble neprilysin (sNEP) in patients with reduced or preserved systolic function, we studied the regulation of the NP pathway in HF.

Methods and results : Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart were collected before implantation and weekly thereafter until post-operative week 6. The ventricular removal was associated with an immediate drop in circulating NPs, a nearly total disappearance of circulating glycosylated proBNP and furin activity and a marked decrease in sNEP. From post-operative week 1 onwards, NP concentrations remained overall unchanged. In contrast, partial recoveries in glycosylated proBNP, furin activity, and sNEP were observed. Furthermore, while in patients with preserved systolic function (n=6), sNEP concentrations in the coronary sinus and systemic vessels were similar (all P>0.05), in patients with reduced left-ventricular systolic function, sNEP concentration, and activity were three-fold higher in coronary sinus compared to systemic vessels (n=21, all P<0.0001), while the trans-pulmonary gradient was neutral (n=5,P=1.0).

Conclusion : The heart plays a pivotal role as a regulator of the endocrine response in systolic dysfunction, not only by directly releasing NPs but also by contributing to circulating sNEP, which in turn determines the bioavailability of other numerous vasoactive peptides.

Keywords Heart failure • Natriuretic peptides • BNP • Neprilysin • Total artificial heart • CARMAT

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin.

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