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

The heart regulates the endocrine response to heart failure: cardiac contribution to circulating... Abstract 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. View largeDownload slide View largeDownload slide Heart failure , Natriuretic peptides , BNP , Neprilysin , Total artificial heart , CARMAT Introduction 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 outcome in patients with symptomatic HF with reduced systolic function.8 However, the predominant source of soluble NEP (sNEP) in patients with HF remains unclear. The CARMAT total artificial heart (TAH) is a biventricular pulsatile assist device, implanted via sternotomy after excision of both ventricles, leaving the entire native atria in place and is capable of fully restoring cardiac output in patients with advanced HF.9 In this study, by measuring variations in circulating mediators associated 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 endocrine 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, respectively, with end-stage bi-ventricular HF with left ventricular ejection fraction (LVEF) <20% (Table 1). The implant procedures were uneventful, both patients were rehabilitated and discharged home. Based on body weight, inferior vena cava, left atrial pressure, and inflow pressures, both patients presented features of congestion until hospital discharge (Table 2). Table 1 Baseline characteristics of the patients with reduced cardiac systolic function undergoing total artificial heart implant (n = 2) Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Table 1 Baseline characteristics of the patients with reduced cardiac systolic function undergoing total artificial heart implant (n = 2) Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Table 2 Parameters at baseline and after total artificial heart implant Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Table 2 Parameters at baseline and after total artificial heart implant Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Venous blood samples were collected on the day before the operation and weekly thereafter until post-operative week 6 in tubes containing sodium citrate. Blood samples were immediately centrifuged and stored at −80 °C. BNP, mid-regional-pro-ANP (MR-proANP), pro-BNP T71-glycosylation, furin activity, sNEP concentration and activity, and substance P concentration were measured as previously described.2,3 The study was approved by the competent authorities and ethics committees, and patients gave signed informed consent. Regional differences in circulating soluble neprilysin and cardiac RNA analysis To determine the cardiac contribution of sNEP in patients with advanced HF with reduced cardiac systolic function, we used EDTA plasma samples from three cohorts: Samples simultaneously drawn from the coronary sinus and the cubital vein of 21 patients with advanced HF and reduced cardiac systolic function (NCT01949246).11,12 Samples simultaneously drawn from the pulmonary artery and the left atrium of 16 patients with reduced or preserved cardiac systolic function undergoing cardiac surgery (NCT01723930). Samples drawn from the cardiac coronary sinus, femoral artery, femoral vein, and pulmonary artery from six patients with preserved cardiac systolic function undergoing elective cardiac catheterization remote from any acute event, as previously described.13 Patient characteristics are summarized in Supplementary material online, Tables S1–S3. The cardiac tissue samples from advanced HF patients (n = 17) and controls (n = 8) for RNA analysis have been previously described.14 Total RNA was extracted using the Qiagen RNeasy kit as per manufacturer’s instructions. Variables are expressed as median [interquartile range]. Groups were compared with a Wilcoxon signed-rank or rank-sum test, as appropriate. A two-sided P-value <0.05 was considered significant. Results Circulating mediators in two patients with advanced heart failure undergoing total artificial heart implantation Preoperatively, the NP pathway was markedly activated in both patients (Take home figure, Panels A, B). The following values were obtained at baseline for Patient 1 and 2, respectively: BNP 474 and 695 pg/mL; MR-proANP 778 and 946 pmol/L; furin activity 2.11 and 2.74 pmol/mL/min; percentage of T71-glycosylated proBNP 43.7% and 46.1%; sNEP concentration 358 and 475 pg/mL; sNEP activity 437 and 628 pmol/mL/min. Take home figure View largeDownload slide Circulating mediators in patients with advanced heart failure with reduced cardiac systolic function undergoing TAH implantation. BNP, B-type natriuretic peptide; MR-proANP, mid-regional pro-atrial natriuretic peptide; proBNP T71-glycosylation, pro-B-type natriuretic peptide glycosylation at threonine 71; sNEP, soluble neprilysin. Take home figure View largeDownload slide Circulating mediators in patients with advanced heart failure with reduced cardiac systolic function undergoing TAH implantation. BNP, B-type natriuretic peptide; MR-proANP, mid-regional pro-atrial natriuretic peptide; proBNP T71-glycosylation, pro-B-type natriuretic peptide glycosylation at threonine 71; sNEP, soluble neprilysin. The replacement of the failing ventricles with TAH was associated with an immediate drop in circulating NPs (BNP ∼90%, MR-proANP ∼67%), and a nearly total disappearance of T71-glycosylated proBNP (∼1%) and circulating furin activity (∼3%). Replacement of the ventricles was also associated with a marked decrease in both sNEP concentration and activity, and a striking reciprocal increase in circulating substance P. From week 1 onwards, NP plasma levels remained overall unchanged. In contrast, partial recoveries in T71-glycosylated proBNP, furin activity, sNEP activity and concentrations were observed, whereas substance P concentration reciprocally decreased. Regional differences in circulating soluble neprilysin and cardiac RNA analysis To confirm the cardiac contribution of circulating sNEP in patients with advanced HF, we compared concentration and activity of sNEP in the coronary sinus and in other vascular beds in patients with reduced or preserved cardiac systolic function. No difference in sNEP concentration and activity between coronary sinus, femoral artery, femoral vein, and pulmonary artery was seen in six patients with preserved cardiac systolic function (all P > 0.05, see Supplementary material online, Figure S1). By contrast, sNEP concentration and activity were 2.9-fold [1.7–5.8] and 3-fold [1.9–4.7] higher in the blood collected from the coronary sinus than in the blood collected from the cubital vein, respectively, in 21 HF patients with reduced systolic function (all P < 0.0001, see Supplementary material online, Figure S2A and B). These findings were in line with a 1.5-fold increase in NEP mRNA levels in left ventricular samples from patients with reduced systolic function compared with healthy individuals (P = 0.03, see Supplementary material online, Figure S2C). Since this analysis could not exclude a sNEP contribution from the lungs, we measured the trans-pulmonary gradient of sNEP concentration in five patients with reduced cardiac systolic function (LVEF < 45%) and found it neutral (P = 1.0, see Supplementary material online, Figure S2D). Trans-pulmonary gradient of sNEP concentration was slightly positive in 11 patients with preserved cardiac systolic function (P = 0.017, see Supplementary material online, Figure S3). Discussion The replacement of a failing heart by a TAH offered a unique opportunity to show the essential role of the heart as a regulator of the cardiovascular endocrine response in HF. First, our study allowed to distinguish atrial and ventricular contributions to the NP pathway in patients with advanced HF. Our findings confirmed that both ANP and BNP are mainly produced by the ventricles and, to a smaller extent, by the atria.1 It was estimated that ∼90% of circulating BNP and ∼67% of MR-proANP (a surrogate of ANP production) originated from the ventricles, although a reduction in atrial release of NPs after TAH implantation cannot be excluded. Furthermore, this massive drop in plasma NPs was accompanied by an almost complete disappearance of T71-glycosylated proBNP and circulating furin activity. These results confirm that proBNP is glycosylated most preferentially in ventricular cardiomyocytes,15 and strongly suggest that circulating furin activity is mostly derived from ventricular cardiomyocytes. From week 1 onward, proBNP glycosylation was partially restored, suggesting that the remaining atrial cardiomyocytes acquired ventricular features. Second, the removal of the failing ventricles induced a marked decrease in sNEP concentration and activity, both partially recovering afterwards. Of interest, the postoperative decrease in sNEP was associated with an immediate increase in circulating substance P. While the surgery itself may account in part for the increase in substance P concentration, the strong correlation between substance P and sNEP activity in patients at steady state, and the reciprocal kinetics between substance P and sNEP activity in our two patients, both strongly suggest that the variations in sNEP activity after TAH implantation onwards have affected the plasma concentrations of NEP substrates. Of note, we cannot exclude that the drop in sNEP does not also affect circulating NPs, however, BNP is a poor substrate for sNEP5 and MR-proANP is not expected to be a NEP substrate. While the first post-operative sampling was performed 5 days after TAH implantation, the decrease in sNEP concentration may result either from the removal of a major source of sNEP (the heart) or from a global haemodynamic improvement. In the present study, we found similar concentrations of sNEP in the coronary sinus and in other vascular beds, indicating no relevant contribution from the heart in circulating sNEP in patients with preserved cardiac systolic function. By contrast, in patients with reduced cardiac systolic function, we found a three-fold higher sNEP concentration and activity in the coronary sinus compared to cubital vein and a neutral trans-pulmonary gradient, strongly suggesting that the heart is a major source of sNEP in patients with reduced cardiac systolic function. These data are supported by higher NEP mRNA in failing left ventricles, compared with healthy controls. Altogether, these data indicate that in patients with reduced cardiac systolic function the heart becomes a source of sNEP, which will in turn modulate the plasma concentrations of sNEP substrates. Conclusion In conclusion, this study permitted insight into the pivotal role of the heart as a regulator of the endocrine response in patients with HF with reduced cardiac systolic function. The heart not only contributes directly to the release of NPs but it also constitutes a major source of sNEP in patients with reduced cardiac systolic function. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements We are grateful to Marie-Céline Fournier for technical support and to Wendy Gattis Stough for critical review of the manuscript. Funding National Institute of Health (NHLBI K23HL098370 to J.S. and Q.A.T.). Conflict of interest: A.C.S. reports personal fees from Novartis, Servier, Vifor, outside the submitted work. A.C. reports a patent pending. A.M. reports personal fees from Novartis, Orion, Roche, Servier, Cardiorentis, Zs Pharma, grants and personal fees from Adrenomed, grants from MyCartis, Critical diagnostics, outside the submitted work. C.L. reports personal fees from Carmat, outside the submitted work. D.M.S. reports grants and personal fees from Carmat, during the conduct of the study. JPS reports personal fees from Biotronik, Boston Scientific, Medtronic, Impulse Dynamics, Respicardia, Respicardia, grants and personal fees from Abbott, outside the submitted work. J.P. reports grants and personal fees from Medtronic, grants and personal fees from LFB Biomedicaments, grants and personal fees from Pulsion Medical Systems, personal fees from Maquet, grants from Baxter, outside the submitted work. A.M.A. reports he is a recipient of speaker's honoraria, travel support, and research grants from diagnostic companies with an interest in HF markers including Roche Diagnostics, Alere, and Critical Diagnostics. References 1 Yasue H , Yoshimura M , Sumida H , Kikuta K , Kugiyama K , Jougasaki M , Ogawa H , Okumura K , Mukoyama M , Nakao K. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure . Circulation 1994 ; 90 : 195 – 203 . Google Scholar CrossRef Search ADS PubMed 2 Vodovar N , Seronde MF , Laribi S , Gayat E , Lassus J , Boukef R , Nouira S , Manivet P , Samuel JL , Logeart D , Ishihara S , Cohen Solal A , Januzzi JL Jr , Richards AM , Launay JM , Mebazaa A , Network G. Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure . Eur Heart J 2014 ; 35 : 3434 – 3441 . Google Scholar CrossRef Search ADS PubMed 3 Ichiki T , Burnett JC Jr. Post-transcriptional modification of pro-BNP in heart failure: is glycosylation and circulating furin key for cardiovascular homeostasis? Eur Heart J 2014 ; 35 : 3001 – 3003 . Google Scholar CrossRef Search ADS PubMed 4 Vodovar N , Seronde MF , Laribi S , Gayat E , Lassus J , Januzzi JL Jr , Boukef R , Nouira S , Manivet P , Samuel JL , Logeart D , Cohen-Solal A , Richards AM , Launay JM , Mebazaa A , Network G. Elevated plasma B-Type natriuretic peptide concentrations directly inhibit circulating neprilysin activity in heart failure . JACC Heart Fail 2015 ; 3 : 629 – 636 . Google Scholar CrossRef Search ADS PubMed 5 Bayes-Genis A , Barallat J , Richards AM. A test in context: neprilysin: function, inhibition, and biomarker . J Am Coll Cardiol 2016 ; 68 : 639 – 653 . Google Scholar CrossRef Search ADS PubMed 6 McKie PM , Burnett JC Jr. Rationale and therapeutic opportunities for natriuretic peptide system augmentation in heart failure . Curr Heart Fail Rep 2015 ; 12 : 7 – 14 . Google Scholar CrossRef Search ADS PubMed 7 Ponikowski P , Voors AA , Anker SD , Bueno H , Cleland JGF , Coats AJS , Falk V , González-Juanatey JR , Harjola V-P , Jankowska EA , Jessup M , Linde C , Nihoyannopoulos P , Parissis JT , Pieske B , Riley JP , Rosano GMC , Ruilope LM , Ruschitzka F , Rutten FH , van der Meer P Authors/Task Force Members . 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC . Eur Heart J 2016 ; 37 : 2129 – 2200 . Google Scholar CrossRef Search ADS PubMed 8 McMurray JJ , Packer M , Desai AS , Gong J , Lefkowitz MP , Rizkala AR , Rouleau JL , Shi VC , Solomon SD , Swedberg K , Zile MR ; PARADIGM-HF Investigators and Committees . Angiotensin-neprilysin inhibition versus enalapril in heart failure . N Engl J Med 2014 ; 371 : 993 – 1004 . Google Scholar CrossRef Search ADS PubMed 9 Carpentier A , Latremouille C , Cholley B , Smadja DM , Roussel JC , Boissier E , Trochu JN , Gueffet JP , Treillot M , Bizouarn P , Meleard D , Boughenou MF , Ponzio O , Grimme M , Capel A , Jansen P , Hagege A , Desnos M , Fabiani JN , Duveau D. First clinical use of a bioprosthetic total artificial heart: report of two cases . Lancet 2015 ; 386 : 1556 – 1563 . Google Scholar CrossRef Search ADS PubMed 10 Smadja DM , Saubaméa B , Susen S , Cholley B , Kindo M , Bruneval P , Jansen P , Latremouille C , Roussel JC , Carpentier A. Bioprosthetic total artificial heart induces a profile of acquired hemocompatibility with membranes recellularization . J Am Coll Cardiol 2017 ; 70 : 404 – 406 . Google Scholar CrossRef Search ADS PubMed 11 Truong QA , Januzzi JL , Szymonifka J , Thai WE , Wai B , Lavender Z , Sharma U , Sandoval RM , Grunau ZS , Basnet S , Babatunde A , Ajijola OA , Min JK , Singh JP. Coronary sinus biomarker sampling compared to peripheral venous blood for predicting outcomes in patients with severe heart failure undergoing cardiac resynchronization therapy: the BIOCRT study . Heart Rhythm 2014 ; 11 : 2167 – 2175 . Google Scholar CrossRef Search ADS PubMed 12 Arrigo M , Truong QA , Onat D , Szymonifka J , Gayat E , Tolppanen H , Sadoune M , Demmer RT , Wong KY , Launay J-M , Samuel J-L , Cohen-Solal A , Januzzi JL , Singh JP , Colombo PC , Mebazaa A . Soluble CD146 is a novel marker of systemic congestion in heart failure patients: an experimental mechanistic and transcardiac clinical study . Clinical Chemistry 2017 ; 63 : 386 – 393 . Google Scholar CrossRef Search ADS PubMed 13 Palmer SC , Yandle TG , Nicholls MG , Frampton CM , Richards AM. Regional clearance of amino-terminal pro-brain natriuretic peptide from human plasma . Eur J Heart Fail 2009 ; 11 : 832 – 839 . Google Scholar CrossRef Search ADS PubMed 14 Mebazaa A , Vanpoucke G , Thomas G , Verleysen K , Cohen-Solal A , Vanderheyden M , Bartunek J , Mueller C , Launay JM , Van Landuyt N , D'Hondt F , Verschuere E , Vanhaute C , Tuytten R , Vanneste L , De Cremer K , Wuyts J , Davies H , Moerman P , Logeart D , Collet C , Lortat-Jacob B , Tavares M , Laroy W , Januzzi JL , Samuel JL , Kas K. Unbiased plasma proteomics for novel diagnostic biomarkers in cardiovascular disease: identification of quiescin Q6 as a candidate biomarker of acutely decompensated heart failure . Eur Heart J 2012 ; 33 : 2317 – 2324 . Google Scholar CrossRef Search ADS PubMed 15 Tonne JM , Campbell JM , Cataliotti A , Ohmine S , Thatava T , Sakuma T , Macheret F , Huntley BK , Burnett JC Jr , Ikeda Y. Secretion of glycosylated pro-B-type natriuretic peptide from normal cardiomyocytes . Clin Chem 2011 ; 57 : 864 – 873 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal Oxford University Press

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Abstract

Abstract 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. View largeDownload slide View largeDownload slide Heart failure , Natriuretic peptides , BNP , Neprilysin , Total artificial heart , CARMAT Introduction 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 outcome in patients with symptomatic HF with reduced systolic function.8 However, the predominant source of soluble NEP (sNEP) in patients with HF remains unclear. The CARMAT total artificial heart (TAH) is a biventricular pulsatile assist device, implanted via sternotomy after excision of both ventricles, leaving the entire native atria in place and is capable of fully restoring cardiac output in patients with advanced HF.9 In this study, by measuring variations in circulating mediators associated 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 endocrine 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, respectively, with end-stage bi-ventricular HF with left ventricular ejection fraction (LVEF) <20% (Table 1). The implant procedures were uneventful, both patients were rehabilitated and discharged home. Based on body weight, inferior vena cava, left atrial pressure, and inflow pressures, both patients presented features of congestion until hospital discharge (Table 2). Table 1 Baseline characteristics of the patients with reduced cardiac systolic function undergoing total artificial heart implant (n = 2) Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Table 1 Baseline characteristics of the patients with reduced cardiac systolic function undergoing total artificial heart implant (n = 2) Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Patient 1 Patient 2 Age (years) 68 73 Left ventricular ejection fraction (%) 15% 17% Aetiology of heart failure Dilated cardiomyopathy Ischaemic heart disease INTERMACS (class) 2 2 Comorbidities Hypertension Atrial fibrillation Dyslipidaemia Peripheral artery disease Discharge (post- operative day) 150 77 Table 2 Parameters at baseline and after total artificial heart implant Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Table 2 Parameters at baseline and after total artificial heart implant Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Parameter Baseline Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Patient 1  Weight (kg) 69 78 75 79 75 76 78  Mean arterial pressure (mmHg) 83 78 74 83 94 98 98  Cardiac output (L/min) 2.5 4.4 4.6 5.2 5.1 5.1 5.1  Left atrial pressure (mmHg) — 8 — — — — —  Left inflow pressure (mmHg) — 19 21 20 18 18 17  Inferior vena cava diameter (mm) 31 28 26 29  Right inflow pressure (mmHg) — 10 13 12 11 11 13  Creatinine (µmol/L) 90 281 97 113 93 84 75 Patient 2  Weight (kg) 59 67 79 82 82 80 80  Mean arterial pressure (mmHg) 69 85 77 92 77 83 76  Cardiac output (L/min) 2.9 5.2 5.5 5.1 5.1 6 6.1  Left atrial pressure (mmHg) — 14 — — — — —  Left inflow pressure (mmHg) — 16 20 25 24 24 22  Inferior vena cava diameter (mm) 35 — 45 — — — 31  Right inflow pressure (mmHg) — 10 16 19 16 19 16  Creatinine (µmol/L) 159 137 74 73 134 129 92 Venous blood samples were collected on the day before the operation and weekly thereafter until post-operative week 6 in tubes containing sodium citrate. Blood samples were immediately centrifuged and stored at −80 °C. BNP, mid-regional-pro-ANP (MR-proANP), pro-BNP T71-glycosylation, furin activity, sNEP concentration and activity, and substance P concentration were measured as previously described.2,3 The study was approved by the competent authorities and ethics committees, and patients gave signed informed consent. Regional differences in circulating soluble neprilysin and cardiac RNA analysis To determine the cardiac contribution of sNEP in patients with advanced HF with reduced cardiac systolic function, we used EDTA plasma samples from three cohorts: Samples simultaneously drawn from the coronary sinus and the cubital vein of 21 patients with advanced HF and reduced cardiac systolic function (NCT01949246).11,12 Samples simultaneously drawn from the pulmonary artery and the left atrium of 16 patients with reduced or preserved cardiac systolic function undergoing cardiac surgery (NCT01723930). Samples drawn from the cardiac coronary sinus, femoral artery, femoral vein, and pulmonary artery from six patients with preserved cardiac systolic function undergoing elective cardiac catheterization remote from any acute event, as previously described.13 Patient characteristics are summarized in Supplementary material online, Tables S1–S3. The cardiac tissue samples from advanced HF patients (n = 17) and controls (n = 8) for RNA analysis have been previously described.14 Total RNA was extracted using the Qiagen RNeasy kit as per manufacturer’s instructions. Variables are expressed as median [interquartile range]. Groups were compared with a Wilcoxon signed-rank or rank-sum test, as appropriate. A two-sided P-value <0.05 was considered significant. Results Circulating mediators in two patients with advanced heart failure undergoing total artificial heart implantation Preoperatively, the NP pathway was markedly activated in both patients (Take home figure, Panels A, B). The following values were obtained at baseline for Patient 1 and 2, respectively: BNP 474 and 695 pg/mL; MR-proANP 778 and 946 pmol/L; furin activity 2.11 and 2.74 pmol/mL/min; percentage of T71-glycosylated proBNP 43.7% and 46.1%; sNEP concentration 358 and 475 pg/mL; sNEP activity 437 and 628 pmol/mL/min. Take home figure View largeDownload slide Circulating mediators in patients with advanced heart failure with reduced cardiac systolic function undergoing TAH implantation. BNP, B-type natriuretic peptide; MR-proANP, mid-regional pro-atrial natriuretic peptide; proBNP T71-glycosylation, pro-B-type natriuretic peptide glycosylation at threonine 71; sNEP, soluble neprilysin. Take home figure View largeDownload slide Circulating mediators in patients with advanced heart failure with reduced cardiac systolic function undergoing TAH implantation. BNP, B-type natriuretic peptide; MR-proANP, mid-regional pro-atrial natriuretic peptide; proBNP T71-glycosylation, pro-B-type natriuretic peptide glycosylation at threonine 71; sNEP, soluble neprilysin. The replacement of the failing ventricles with TAH was associated with an immediate drop in circulating NPs (BNP ∼90%, MR-proANP ∼67%), and a nearly total disappearance of T71-glycosylated proBNP (∼1%) and circulating furin activity (∼3%). Replacement of the ventricles was also associated with a marked decrease in both sNEP concentration and activity, and a striking reciprocal increase in circulating substance P. From week 1 onwards, NP plasma levels remained overall unchanged. In contrast, partial recoveries in T71-glycosylated proBNP, furin activity, sNEP activity and concentrations were observed, whereas substance P concentration reciprocally decreased. Regional differences in circulating soluble neprilysin and cardiac RNA analysis To confirm the cardiac contribution of circulating sNEP in patients with advanced HF, we compared concentration and activity of sNEP in the coronary sinus and in other vascular beds in patients with reduced or preserved cardiac systolic function. No difference in sNEP concentration and activity between coronary sinus, femoral artery, femoral vein, and pulmonary artery was seen in six patients with preserved cardiac systolic function (all P > 0.05, see Supplementary material online, Figure S1). By contrast, sNEP concentration and activity were 2.9-fold [1.7–5.8] and 3-fold [1.9–4.7] higher in the blood collected from the coronary sinus than in the blood collected from the cubital vein, respectively, in 21 HF patients with reduced systolic function (all P < 0.0001, see Supplementary material online, Figure S2A and B). These findings were in line with a 1.5-fold increase in NEP mRNA levels in left ventricular samples from patients with reduced systolic function compared with healthy individuals (P = 0.03, see Supplementary material online, Figure S2C). Since this analysis could not exclude a sNEP contribution from the lungs, we measured the trans-pulmonary gradient of sNEP concentration in five patients with reduced cardiac systolic function (LVEF < 45%) and found it neutral (P = 1.0, see Supplementary material online, Figure S2D). Trans-pulmonary gradient of sNEP concentration was slightly positive in 11 patients with preserved cardiac systolic function (P = 0.017, see Supplementary material online, Figure S3). Discussion The replacement of a failing heart by a TAH offered a unique opportunity to show the essential role of the heart as a regulator of the cardiovascular endocrine response in HF. First, our study allowed to distinguish atrial and ventricular contributions to the NP pathway in patients with advanced HF. Our findings confirmed that both ANP and BNP are mainly produced by the ventricles and, to a smaller extent, by the atria.1 It was estimated that ∼90% of circulating BNP and ∼67% of MR-proANP (a surrogate of ANP production) originated from the ventricles, although a reduction in atrial release of NPs after TAH implantation cannot be excluded. Furthermore, this massive drop in plasma NPs was accompanied by an almost complete disappearance of T71-glycosylated proBNP and circulating furin activity. These results confirm that proBNP is glycosylated most preferentially in ventricular cardiomyocytes,15 and strongly suggest that circulating furin activity is mostly derived from ventricular cardiomyocytes. From week 1 onward, proBNP glycosylation was partially restored, suggesting that the remaining atrial cardiomyocytes acquired ventricular features. Second, the removal of the failing ventricles induced a marked decrease in sNEP concentration and activity, both partially recovering afterwards. Of interest, the postoperative decrease in sNEP was associated with an immediate increase in circulating substance P. While the surgery itself may account in part for the increase in substance P concentration, the strong correlation between substance P and sNEP activity in patients at steady state, and the reciprocal kinetics between substance P and sNEP activity in our two patients, both strongly suggest that the variations in sNEP activity after TAH implantation onwards have affected the plasma concentrations of NEP substrates. Of note, we cannot exclude that the drop in sNEP does not also affect circulating NPs, however, BNP is a poor substrate for sNEP5 and MR-proANP is not expected to be a NEP substrate. While the first post-operative sampling was performed 5 days after TAH implantation, the decrease in sNEP concentration may result either from the removal of a major source of sNEP (the heart) or from a global haemodynamic improvement. In the present study, we found similar concentrations of sNEP in the coronary sinus and in other vascular beds, indicating no relevant contribution from the heart in circulating sNEP in patients with preserved cardiac systolic function. By contrast, in patients with reduced cardiac systolic function, we found a three-fold higher sNEP concentration and activity in the coronary sinus compared to cubital vein and a neutral trans-pulmonary gradient, strongly suggesting that the heart is a major source of sNEP in patients with reduced cardiac systolic function. These data are supported by higher NEP mRNA in failing left ventricles, compared with healthy controls. Altogether, these data indicate that in patients with reduced cardiac systolic function the heart becomes a source of sNEP, which will in turn modulate the plasma concentrations of sNEP substrates. Conclusion In conclusion, this study permitted insight into the pivotal role of the heart as a regulator of the endocrine response in patients with HF with reduced cardiac systolic function. The heart not only contributes directly to the release of NPs but it also constitutes a major source of sNEP in patients with reduced cardiac systolic function. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements We are grateful to Marie-Céline Fournier for technical support and to Wendy Gattis Stough for critical review of the manuscript. Funding National Institute of Health (NHLBI K23HL098370 to J.S. and Q.A.T.). Conflict of interest: A.C.S. reports personal fees from Novartis, Servier, Vifor, outside the submitted work. A.C. reports a patent pending. A.M. reports personal fees from Novartis, Orion, Roche, Servier, Cardiorentis, Zs Pharma, grants and personal fees from Adrenomed, grants from MyCartis, Critical diagnostics, outside the submitted work. C.L. reports personal fees from Carmat, outside the submitted work. D.M.S. reports grants and personal fees from Carmat, during the conduct of the study. JPS reports personal fees from Biotronik, Boston Scientific, Medtronic, Impulse Dynamics, Respicardia, Respicardia, grants and personal fees from Abbott, outside the submitted work. J.P. reports grants and personal fees from Medtronic, grants and personal fees from LFB Biomedicaments, grants and personal fees from Pulsion Medical Systems, personal fees from Maquet, grants from Baxter, outside the submitted work. A.M.A. reports he is a recipient of speaker's honoraria, travel support, and research grants from diagnostic companies with an interest in HF markers including Roche Diagnostics, Alere, and Critical Diagnostics. References 1 Yasue H , Yoshimura M , Sumida H , Kikuta K , Kugiyama K , Jougasaki M , Ogawa H , Okumura K , Mukoyama M , Nakao K. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure . Circulation 1994 ; 90 : 195 – 203 . Google Scholar CrossRef Search ADS PubMed 2 Vodovar N , Seronde MF , Laribi S , Gayat E , Lassus J , Boukef R , Nouira S , Manivet P , Samuel JL , Logeart D , Ishihara S , Cohen Solal A , Januzzi JL Jr , Richards AM , Launay JM , Mebazaa A , Network G. Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure . Eur Heart J 2014 ; 35 : 3434 – 3441 . 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European Heart JournalOxford University Press

Published: Dec 13, 2017

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