ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE ESC Heart Failure 2020; 7: 559–566 Published online 115 February 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12607 Neprilysin inhibition, endorphin dynamics, and early symptomatic improvement in heart failure: a pilot study Elena Revuelta-López1,2, Julio Núñez2,3, Paloma Gastelurrutia1,2, Germán Cediel4, James L. Januzzi5, Nasrien E. Ibrahim5, Michele Emdin6, Roland VanKimmenade7, Domingo Pascual-Figal2,8, Eduardo Núñez3, Frank Gommans7, Josep Lupón2,4,9 and Antoni Bayés-Genís2,4,9* 1 Heart Failure and Cardiac Regeneration (ICREC) Research Program, Health Science Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain; 2Centro de Investigación Biomédica en Red Enfermedades Cardiovaculares, (CIBERCV,), Madrid, Spain; 3Cardiology Department, Hospital Clínico Universitario, Universitat de València, INCLIVA, Valencia, Spain; INCLIVA; Universitat de València, Valencia, Spain; 4Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 5 Division of Cardiology, Massachusetts General Hospital and Cardiometabolic Trials, Baim Institute for Clinical Research, Boston, Massachusetts, MA, USA; 6Institute of Life Sciences, Scuola Superiore Sant’Anna, Fondazione Toscana Gabriele Monasterio, Pisa, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy; 7Department of Cardiology, Radboud University Medical Centre, Nijmegen, The Netherlands; 8Cardiology Department, Hospital Virgen de la Arrixaca, Universidad de Murcia, Murcia, Spain; 9 Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain Abstract Aim Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart fail- ure with reduced ejection fraction. Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients’ physical functioning after initiation of sacubitril/valsartan treatment. Methods and results A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin recep- tor blocker was replaced by sacubitril/valsartan because of clinical indication by the responsible physician. By protocol, pa- tients were reevaluated at 30 days after the start of sacubitril/valsartan. Serum levels of α- (α-EP), γ-Endorphin (γ-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient’s functional status. Baseline median levels of circulating α-EP, γ-EP, and sNEP were 582 (160–772), 101 (37–287), and 222 pg/mL (124–820), respectively. There was not a significant increase in α-EP nor γ-EP serum values after sacubitril/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ-EP, and ΔsNEP between 30 days and baseline were 9.3 ( 34 44), 3.0 ( 46.0 18.9), and 0 units ( 16.4 157.0), respectively. In a pre–post sacubitril/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Δα-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. Conclusions These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients’ symptoms improvement. Keywords Heart failure; Neprilysin; Sacubitril/valsartan; Endorphins; α-Endorphin; γ-Endorphin Received: 11 July 2019; Revised: 26 November 2019; Accepted: 9 December 2019 *Correspondence to: Antoni Bayes-Genis, Cardiology Service and Heart Failure Unit, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n 08916, Badalona (Barcelona), Spain. Tel: +34 934973743. Email: abayesgenis@gmail.com © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. 560 E. Revuelta-López et al. Introduction other therapeutic modifications were performed between both visits. Demographic information, medical history, vital Sacubitril/valsartan is a first-in-class angiotensin receptor signs, 12-leads electrocardiogram, standard laboratory data, neprilysin inhibitor developed for the treatment of heart fail- and pharmacological treatments were routinely assessed at ure (HF) with reduced ejection fraction (HFrEF). The visits. A trained cardiologist assessed the NYHA association PARADIGM-HF trial, which tested sacubitril/valsartan for class in the study visits. The estimated glomerular filtration treating HFrEF, showed that it was superior to enalapril in re- rate (eGFR) was estimated by the Modification of Diet in ducing the risk of cardiovascular death and HF hospitalization, Renal Disease Study equation, based on creatinine and as well as improving quality of life of surviving HFrEF pa- other characteristics of the patients. Institutional commit- tients.1,2 The benefits of sacubitril/valsartan are achieved tees of each participating centre approved the study proto- via two mechanisms: (i) the inhibition of neprilysin (NEP) col, local ethics committees approved the study, and all causes an increase in the activity of its substrates, such as na- patients provided written informed consent prior to enrol- triuretic peptides, and (ii) the specific blockade of the angio- ment. This study was conducted in accordance with the tensin receptor AT1 instead of the inhibition of the Declaration of Helsinki. Patients with presence of angiotensin-converting enzyme.3 extracardiac disease with an estimated life expectancy of Neprilysin is an abundant enzyme that can also be found in less than 1 year, treated with narcotic analgesics, with mod- its circulating soluble form, which has emerged as a new bio- erate to severe alcoholism, severe renal (eGFR < 30 marker with promising implications for prognosis and therapy mL/min/1.73 m2) or severe hepatic insufficiency (Child-Pugh in patients with HF.4–6 Its ubiquity allows it to participate in C classification), hyperkalaemia (>5.4 mmol/L), systolic the degradation path of multiple substrates, suggesting many blood pressure < 100 mmHg, prior history of angioedema, multifaceted potential consequences of its inhibition beyond pregnant women, or participating in randomized clinical the natriuretic peptide system.7 Neuropeptides, including trial, were excluded. endorphins (EPs), are also recognized substrates that NEP is capable of degrading. α-Endorphin (α-EP) and γ-Endorphin (γ-EP), well-known endogenous opioid peptides, have Measurement of serum endorphins levels morphinomimetic behaviour, affect several physiologic activ- ities, and are potential antipsychotic and analgesic drugs.8 Blood samples were collected and serum was obtained by EPs are also capable of producing feelings of welfare and tol- centrifugation for 10 min at 3000 rpm and stored at erance to pain.9,10 80°C. All samples were obtained between 09:00 am and In the present work, we aimed to explore the dynamics of 12:00 pm using the same protocol at the first visit and at serum EPs values in patients with HFrEF upon treatment with 30 days. sacubitril/valsartan and its relation to the improvement in α-EP was measured by Human α-Endorphin ELISA kit functional class assessed by New York Heart Association (BlueGene Biotech; Shanghai, China; Code No. E01A3095; (NYHA) class. Lot No. 20161219). Serum aliquots were diluted 1:2 in PBS (pH 7.0–7.2). This assay has high sensitivity and excellent specificity for detecting α-EP, and the manufacturer observed no significant cross-reactivity or interference between α-EP Methods and analogues. The range of the assay is between 0 and 2500 pg/mL. The sensitivity in this assay is 1.0 pg/mL. Study design and participants γ-EP was analysed by a competitive binding enzyme-linked immunosorbent assay technology, Human γ-Endorphin ELISA A prospective, observational, multicentre, international study kit (Abbexa Ltd.; Cambridge Science Park, Cambridge, UK; was conducted between 1 November 2016 and 1 December Code No. abx258229; Lot No. L201701A884). Assay’s range 2017. Patients were eligible if they had stable HF with left is between 12.35 and 1000 pg/mL, and assay’s sensitivity is ventricular ejection fraction ≤40% and were under treatment 5.47 pg/mL. with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (Figure 1). In a first visit, and in agreement with current guide- Measurement of sNEP lines,11,12 treatment with angiotensin-converting enzyme in- hibitor or angiotensin receptor blocker was replaced by Soluble neprilysin was measured by a sandwich immunoassay sacubitril/valsartan because of clinical indication by the re- human neprilysin/CD10 ELISA kit (Aviscera Bioscience; Santa sponsible physician. Doses of sacubitril/valsartan treatment Clara, CA; Code No. SK00724-01; Lot No. 20113187). Serum were individualized. By protocol, patients were reevaluated aliquots were diluted one quarter in dilution buffer provided at 30 days after the start of sacubitril/valsartan, and no by the manufacturer before incubation. Standard range and ESC Heart Failure 2020; 7: 559–566 DOI: 10.1002/ehf2.12607 Neprilysin and endorphins in HF symptoms 561 Figure 1 Patients flow diagram. ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin II receptor blockers; ARNI, angiotensin receptor- neprilysin inhibitor; HF, heart failure; LVEF, left ventricular ejection fraction. sensitivity are between 62.5–8000 and 30 pg/mL, respec- ischaemic heart disease (62.9%). Baseline medians of left ven- tively. Physicians in charge of clinical assessment were tricular ejection fraction, NT-proBNP, and eGFR were 30% blinded to endorphins and sNEP levels. (25–35), 925 ng/L (374–1700), and 64 mL/min/1.73 m2 (50– 82), respectively. The starting dose of sacubitril/valsartan was 24/26 mg in 67 (63.8%) and 49/51 mg in 38 (36.2%) pa- Statistical analysis tients according to their clinical status. Baseline median levels of circulating α-EP, γ-EP, and sNEP Continuous variables were expressed as mean (±standard de- were 582 (160–772), 101 (37–287), and 222 pg/mL (124– viation) or median (interquartile range) as appropriate. Dis- 820), respectively. There was not a significant increase of crete variables were expressed as percentages. The primary α-EP nor γ-EP serum values after sacubitril/valsartan treat- outcome was the association between absolute changes in ment (P value = 0.194 and 0.102, respectively). There were plasma Δα and Δγ-endorphins (visit posttreatment visit no significant differences in sNEP values between 30 days pretreatment) with the NYHA class at 30 days (NYHA30-d and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ- class). Secondary outcome included the association between EP, and ΔsNEP between 30 days and baseline were 9.3 ΔsNEP (visit posttreatment visit pretreatment) and ( 34 44), 3.0 ( 46.0 18.9), and 0 units ( 16.4 NYHA30-d class. The independent association among these 157.0), respectively (Table 1). Baseline NYHA functional class markers and NYHA30-d class was tested with analysis of co- is shown in Table 1. After 30 days treatment with variance. NYHAbaseline class was included as a covariate in all sacubitril/valsartan, a significant improvement in NYHA class models. Other covariates were selected by means of multi- was found (Figure 2), with 36 (34.3%) patients experiencing variable fractional polynomial method, which combines back- improvement by at least one NYHA class category. Before ward elimination with the selection of a fractional polynomial sacubitril/valsartan treatment 8.6% of the patients were in function. This ensures the right match between the functional NYHA class I, while after the treatment the percentage of pa- form of continuous covariates and the outcome. A two-sided tients in NYHA class I was 32.4%. A multivariable analysis re- P value of <0.05 was set as alpha for all analyses. All analyses vealed that NYHAbaseline class (Figure 3A), NT-proBNPbaseline were performed using Stata 14.1. (Figure 3B), and eGFRbaseline (Figure 3C) were significant pre- dictors of NYHA30-d class. After forcing the three markers in the statistical model, Results Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (NYHA30-d class) Baseline characteristics of HF patients treated with (P = 0.014 and P < 0.001, respectively). For Δα-EP, the sacubitril/valsartan are shown in Table 1. A total of 115 pa- association was linear and negative (Figure 4A), where higher tients admitted in six sites in four countries (Spain, Italy, the Δα-EP values are indicative of lower NYHA30-d class. For Netherlands, and United States) were enrolled. However, Δγ-EP, the association was not significant (Figure 4B). On we excluded 10 patients because they did not attend the the other hand, ΔsNEP was positive and linearly associated follow-up visits, or they admitted they did not adhere to with higher NYHA30-d class (Figure 4C). In a sensitivity analy- treatment. The median (IQR) age was 68 years (60–75), and sis, the sacubitril/valsartan dose [(24/26)/(49/51)] was not 81 (77.1%) were male. The most frequent aetiology was significant as predictor of NYHA30-d class, either as main ESC Heart Failure 2020; 7: 559–566 DOI: 10.1002/ehf2.12607 562 E. Revuelta-López et al. Table 1 Baseline characteristics improvement beyond the haemodynamic benefits achieved Age (years) 66.7 ± 11.4 with sacubitril/valsartan. Men, n (%) 81 (77.1) Heart failure is a chronic and progressive disease with Aetiology, n (%) multiple hospital readmissions and worse prognosis. Symp- CM ischaemic 66 (62.9) CM hypertensive 4 (3.8) toms of HF worsen patients’ quality of life substantially. CM dilated 35 (33.3) Thus, changes in one NYHA functional class category lead NYHA functional class, n (%) to positive improvements in patient’s quality of life.13,14 I 9 (8.6) II 77 (73.3) Sacubitril/valsartan has proven to be a superior alternative III 18 (17.1) to angiotensin-converting enzyme inhibitor/angiotensin re- IV 1 (1) ceptor blocker to treat HF, reducing the risk of death and Hypertension, n (%) 72 (68.6) Dyslipidaemia, n (%) 72 (68.6) improving the condition of patients with HErEF.1,2,15 Prior admission for acute heart failure, n (%) 54 (51.4) However, because of the large variety of substrates de- Left ventricular ejection fraction (%) 30 (25–35) (25–35) graded by NEP, its pharmacological inhibition could lead to Heart rate (bpm) 65 (60–73) Systolic blood pressure (mmHg) 115 (107–130) a significant increase in its substrates deriving in unknown Diastolic blood pressure (mmHg) 70 (62–78) effects. Urea (mg/dL) 45 (32–64)) Endogenous opioid peptides play an important role in the Creatinine, mg/dL (IQR) 1.15 (0.95–1.38) Sodium, mmol/L (IQR) 139 (137–141) management of pain and several physiological activities.16,17 Haemoglobin, g/dl (IQR) 13.8 (12.4–14.8) They are known to be released with states of pleasure includ- NT-proBNP, ng/L (IQR) 925 (374–1700) 2 ing emotions brought upon by laughter, love, sex, and sports. eGFR, m/min/m (IQR) 64 (50–82) α-EP, pg/mL (IQR) 582 (160–772) They are also involved in the development of cardiovascular γ-EP, pg/mL (IQR) 101 (37–287) diseases such as hypertension and congestive HF, although sNEP, pg/mL (IQR) 222 (124–820) the mechanisms of action are not completely known.18,19 En- Δα-EP, units (IQR) 9.3 ( 34–44) Δγ-EP, units (IQR) 3 ( 46–18.9) dogenous opioid peptides may modulate cardiac function at ΔsNEP, units (IQR) 0 ( 16.4–157) the hormonal level via coupling to mu opiate receptors, Treatments which have impact in the heart’s performance and the vascu- Furosemide, n (%) 67 (63.8) Torasemide, n (%) 15 (14.3) lature.20 Endorphins such as α-EP and γ-EP act as functionally Antialdosteronic, n (%) 91 (86.7) antagonistic neuropeptides in the brain, and their balanced Beta blockers, n (%) 101 (96.2) expression is very important for behavioural homeostasis.21 Digoxin, n (%) 13 (12.4) Statin, n (%) 71 (67.6) Its implication in diverse physiological activities determines Acetylsalicylic acid, n (%) 55 (52.4) its importance to maintain a correct balance between them. Nitrates, n (%) 15 (14.3) α-EP and γ-EP are both originated from the same precur- Anticoagulants, n (%) 55 (52.4) Initial daily dose Sac/Val 24/26 mg, n (%) 67 (63.8) sor22,23; the proteolytic activity cleaves β-EP into γ-EP and Initial daily dose Sac/Val 49/51 mg, n (%) 38 (36.2) convert it into α-EP.24 However, our results show that an in- Values are expressed as mean ± SE or median (IQR). crease in α-EP was associated with an early clinical improve- CM, cardiomyopathy; EP, endorphin; eGFR, glomerular filtration ment as determined by NYHA functional class. In spite that rate; NEP, neprilysin; NT-proBNP, N-terminal pro-brain natriuretic α-EP and γ-EP are equivalent substrates for NEP,25 they seem peptides; NYHA, New York Heart Association; sNEP, soluble neprilysin. to evolve differently. The baseline values of α-EP were higher than the basal values of γ-EP (582 vs. 101 pg/mL). This differ- ence may be one of the reasons why there is an association between NYHA class and α-EP and not with γ-EP. Serum values of β-EP are well known in congestive26 and acute27 effect or as interacting with any of the markers (P value for HF, but α-EP and γ-EP pathways are little studied in HF interactions for α-EP, γ-EP, and sNEP were 0.201, 0.808, and patients. 0.233, respectively). Opioid peptides are susceptible to rapid enzymatic degra- dation,28 and it is known that a lot of peptidases are involved in their degradation, such as aminopeptidases, angiotensin- converting enzyme, insulin-degrading enzyme, and dipeptidyl Discussion peptidases, among others.29–31 Previous studies reported a significant decrease in NHYA class after sacubitril/valsartan In this contemporary cohort of patients with HFrEF, we found treatment,31 and our data provide preliminary evidence of an important association between Δα-EP and the early clinical the association between Δα-EP and the early clinical improve- improvement after the start of sacubitril/valsartan. These ment after sacubitril/valsartan treatment. findings suggest that the altered cleavage of endorphin pep- We did not find significant differences between baseline tides by NEP inhibition may participate in patients’ symptoms and posttreatment α-EP levels in the whole sample. However, ESC Heart Failure 2020; 7: 559–566 DOI: 10.1002/ehf2.12607 Neprilysin and endorphins in HF symptoms 563 Figure 2 NYHA class changes after sacubitril/valsartan initiation. NYHA, New York Hear Association. Figure 3 NYHAbaseline class (A), NT-proBNPbaseline (B), and eGFRbaseline (C) were significantly predictors of the outcome. (A) Analysis adjusted by baseline values of eGFR-MDRD method, and NT-proBNP, and α-endorphin, -Log--endorphin, and -sNEP. (B) Analysis adjusted by baseline values of NYHA class and eGFR-MDRD method, and α-endorphin, -Log--endorphin, and -sNEP. (C) Analysis adjusted by baseline values of NYHA class, and NT-proBNP, and α- endorphin, -Log--endorphin, and -sNEP. eGFR, estimated glomerular filtration index; NT-proBNP, N-terminal pro-brain natriuretic peptides; NYHA, New York Heart Association; sNEP, soluble neprilysin; , 30-day minus baseline. ESC Heart Failure 2020; 7: 559–566 DOI: 10.1002/ehf2.12607 564 E. Revuelta-López et al. Figure 4 (A) α-endorphin dynamics and NYHA class at 30 days; (B) -endorphin dynamics and NYHA class at 30 days; (C) sNEP dynamics and NYHA class at 30 days. *All estimates adjusted by NYHA class, eGFR, NT-proBNP, α-endorphin, -endorphin, and -sNEP. eGFR, estimated glomerular filtration index; NYHA, New York Heart Association; sNEP, soluble neprilysin; , 30-day minus baseline. we found a significant relationship between Δα-EP and NYHA inhibition may have autocrine, paracrine, or endocrine func- improvement. These findings suggest a heterogeneous and tions; however, the duration and effects of endorphin eleva- idiosyncratic endorphins response to sacubitril/valsartan that tion with sacubitril/valsartan is unclear. Our data suggest that may partially explain the short-term clinical improvement beyond the haemodynamic benefits achieved with found in some patients.31–35 The absence of increased α-EP sacubitril/valsartan, the altered cleavage of endorphin pep- and γ-EP after treatment with sacubitril/valsartan in all pa- tides by NEP inhibition may participate in patients’ symptoms tients may be due to the existence of these degradation path- improvement. ways, because of the importance of maintaining its equilibrium for behavioural homeostasis. This study has several limitations. The NYHA is based on the subjective assessment made by the physician and a Acknowledgements more objective determination of the patients’ functional status may be of interest. However, we should point out We would like to acknowledge the work of the HF units that NYHA evaluation was blinded to clinicians. In addition, nurses in collecting the data and their invaluable patient care. because of the importance of the balance between α-EP And we are very grateful to the patients who decided to par- and γ-EP, the homeostatic mechanisms for this maintenance ticipate in this study. could be the reason for not finding significant increases of these substrates after the treatment with sacubitril/ valsartan; however, to corroborate this theory, further stud- ies are necessary. Conflict of interest In conclusion, from an HF standpoint, endorphins and their effects and interactions are yet partially understood and The authors have no other funding, financial relationships, or studied. It is likely that endorphin elevation after NEP conflicts of interest to disclose. ESC Heart Failure 2020; 7: 559–566 DOI: 10.1002/ehf2.12607 Neprilysin and endorphins in HF symptoms 565 Funding TerCel (RD16/00111/0006), CIBER Cardiovascular (CB16/11/ 00403) projects, as a part of the Plan Nacional de I + D + This work was supported in part by Fundació La Marató de I, and it was cofunded by ISCIII-Subdirección General de TV3 (201516-10, 201502-30), Generalitat de Catalunya Evaluación y el Fondo Europeo de Desarrollo Regional (Departament de Salut) PERIS Acció Instrumental de (FEDER). This work has been developed in the context of Programes de Recerca Orientats (SLT002/16/00234) and CERCA Programme (Generalitat de Catalunya) and AGAUR (2017-SGR-483), Societat Catalana de Cardiologia, AdvanceCat with the support of ACCIÓ (Catalonia Trade & “la Caixa” Banking Foundation, grants from the Spanish Min- Investment; Generalitat de Catalunya) under the Catalan istry of Economy and Competitiveness-MINECO (SAF2017- ERDF operational program (European Regional Development 84324-C2-1-R), Instituto de Salud Carlos III (PI17/01487, Fund) 2014–2020. PI18/00256, and PIC18/00014), Red de Terapia Celular- References 1. McMurray JJV, Packer M, Desai AS, acute heart failure: a pilot study. JACC ACC/AHA/HFSA Focused Update of the Gong J, Lefkowitz MP, Rizkala AR, Rou- Heart Fail 2015; 3: 641–644. 2013 ACCF/AHA Guideline for the man- leau JL, Shi VC, Solomon SD, Swedberg 6. Bayés-Genís A, Barallat J, Galán A, de agement of heart failure. 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