The heart regulates the endocrine response to heart failure: cardiac

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Keywords. Heart failure • Natriuretic peptides • BNP • Neprilysin • Total artificial heart • CARMAT ..... NT-proBNP and BNP production in acute decompensated heart failure. Eur ... Angiotensin-neprilysin inhibition versus enalapril in heart failure.
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European Heart Journal (2018) 39, 1794–1798 doi:10.1093/eurheartj/ehx679

Pathophysiology

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating neprilysin Mattia Arrigo1,2†, Nicolas Vodovar1†, He´le`ne 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* 1 Inserm UMR-S 942, Hoˆpital Lariboisie`re, Paris, France; 2Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland; 3Department of Anaesthesiology and Intensive Care, Lariboisie`re Hospital, Paris, France; 4University of Otago, Christchurch, New Zealand; 5Department of Anaesthesiology and Intensive Care, Hoˆpitaux Universitaires de Strasbourg, Hoˆpital de Hautepierre, Strasbourg, France; 6Universite´ Paris Descartes-Sorbonne Paris Cite´, Paris, France; 7Inserm UMR-S 1140, Faculte´ de Pharmacie, Paris, France; 8Department of Haematology, Georges Pompidou European Hospital, Paris, France; 9Department of Cardiovascular Surgery, Georges Pompidou European Hospital, Paris, France; 10Department of Anaesthesiology and Intensive Care, Georges Pompidou European Hospital, Paris, France; 11Department of Anaesthesiology and Intensive Care, CHU Nantes, France; 12Universite´ Paris Diderot-Sorbonne Paris Cite´, Paris, France; 13Department of Cardiology, Lariboisie`re Hospital, Paris, France; 14 Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 15Department of Radiology and Division of Cardiology, New York-Presbyterian Hospital and Weill Cornell Medicine, New York, NY, USA; 16Centre for Biological Resources BB-0033-00064, Lariboisie`re Hospital, Paris, France; 17Universite´ de Strasbourg, Faculte´ de Me´decine, Fe´de´ration de Me´decine Translationnelle de Strasbourg (FMTS), Strasbourg, France; and 18National University Health System, Singapore, Singapore

Received 13 May 2017; revised 22 August 2017; editorial decision 1 November 2017; accepted 1 November 2017; online publish-ahead-of-print 13 December 2017

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 Venous blood samples from two patients undergoing replacement of the failing ventricles with a total artificial heart and results 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. 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏 䊏

Keywords

Heart failure



Natriuretic peptides



BNP



Neprilysin



Total artificial heart



CARMAT

This paper was guest edited by Prof. Anthony DeMaria. * Corresponding author. Tel: þ33 1 4995 8071, Fax: þ33 1 4995 8073, Email: [email protected]

The first two authors contributed equally to this work.

C The Author 2017. For permissions, please email: [email protected]. Published on behalf of the European Society of Cardiology. All rights reserved. V

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Heart regulates the endocrine response to heart failure

.. .. .. . Heart failure (HF) is accompanied by the activation of the natriuretic .. . peptide (NP) pathway. Increased intra-cardiac pressures promote .. . the release of the NPs from cardiomyocytes into the bloodstream. .. . While atrial NP (ANP) is released mainly by the atria and brain NP .. . (BNP) mainly by the ventricles in normal individuals, ANP and BNP .. . are both produced at a larger extent by the ventricles in patients with .. . reduced systolic function.1 Circulating NPs may undergo post- .. . translational modifications such as threonine 71 (T71)-glycosylation ... of proBNP, cleavage by the circulating proBNP-convertase furin, and ... breakdown by neprilysin (NEP), amongst others.2,3,4 Neprilysin also ... .. degrades numerous other vasoactive peptides (e.g. substance P).5 .. Given the major role of the NP pathway in HF, several attempts .. . have been made to potentiate their beneficial effects.6,7 Inhibition of .. . NEP activity by sacubitril/valsartan was shown to improve the out- .. . come in patients with symptomatic HF with reduced systolic func- .. . 8 tion. However, the predominant source of soluble NEP (sNEP) in .. .. patients with HF remains unclear. .. The CARMAT total artificial heart (TAH) is a biventricular pul- .. . satile assist device, implanted via sternotomy after excision of .. . both ventricles, leaving the entire native atria in place and is capa- .. .. 9 ble of fully restoring cardiac output in patients with advanced HF. .. In this study, by measuring variations in circulating mediators asso- ... ciated with the replacement of the failing ventricles with a TAH ... and by investigating potential regional differences of sNEP in ... . patients with reduced or preserved cardiac systolic function, we .. . aimed at a better understanding of the pathophysiology of HF, in .. . particular the cardiac contribution to the regulation of the endo- .. .. crine response. .. .. .. .. .. Methods .. .. Patients with advanced heart failure .. . undergoing total artificial heart implantation ... Patients 1 and 2 undergoing TAH implantation have been described .. . elsewhere.9,10 Briefly, both were men, aged 68 and 73 years, respec- .. . tively, with end-stage bi-ventricular HF with left ventricular ejection .. fraction (LVEF)