The Angiotensin Receptor–Neprilysin Inhibitor is Related to Lower Post-transplant Use of Extracorporeal Membrane Oxygenation

Authors

  • Li Yuan Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China https://orcid.org/0000-0003-1073-2080
  • Zhaohua Yang Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Wenrui Ma Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Jie Cui Department of Cardiology, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Junjiang Liu Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Shouguo Yang Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Hongqiang Zhang Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Fanshun Wang Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Huan Liu Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Chunsheng Wang Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China
  • Xiaoning Sun Department of Cardiac Surgery, Zhongshan Hospital Fudan University, 200032 Shanghai, China

DOI:

https://doi.org/10.59958/hsf.8075

Keywords:

heart transplantation, sacubitril/valsartan, extracorporeal membrane oxygenation

Abstract

Background: Extracorporeal membrane oxygenation (ECMO) support after heart transplant is a risk factor for mortality in patients with severe graft dysfunction. Extensive studies have shown that angiotensin receptor–neprilysin inhibitor (ARNI) sacubitril–valsartan has a significant effect on unloading and vascular remodeling in patients with heart failure; however, the impact of ARNIs on heart transplant recipients remains unknown. Methods: This observational, retrospective cohort study included 152 patients who underwent heart transplantation between January 2015 and April 2021. We excluded patients <18 years old and those who underwent re-transplantation or multiple organ transplantation. Patients were divided into two groups based on whether they received an ARNI for at least one month before transplant. The clinical data of recipients and donors from our institutional medical records and the China Organ Transplant Response System were interrogated. Results: In total, 67 patients (mean age, 49.6 years; 81% male) were treated with sacubitril/valsartan before transplant and included in the cohort. The total rate of post-transplant ECMO use was 21.1% (n = 32). Kaplan–Meier survival analysis showed a considerable increase in 6-month mortality in heart transplant recipients supported by ECMO (log-rank p < 0.001). The rate of ECMO use was significantly lower in patients treated with ARNIs than for those who were not (13% vs. 27%; p = 0.041). The multivariate analyses that included three models with different preset covariates demonstrated a lower risk of post-transplant ECMO support in patients receiving the ARNI (all p < 0.05). After propensity score matching, the results also suggested that ARNIs can be a protective factor against post-transplant ECMO support (p = 0.042). Conclusion: Pretransplant use of ARNI agents was associated with a lower risk of ECMO support after HT. Randomized controlled trials are warranted to confirm the effectiveness of ARNIs in improving post-transplant hemodynamics and reducing ECMO use in HT recipients.

References

Bhagra SK, Pettit S, Parameshwar J. Cardiac transplantation: indications, eligibility and current outcomes. Heart (British Cardiac Society). 2019; 105: 252–260. https://doi.org/10.1136/heartjnl-2018-313103.

Kobashigawa J, Zuckermann A, Macdonald P, Leprince P, Esmailian F, Luu M, et al. Report from a consensus conference on primary graft dysfunction after cardiac transplantation. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2014; 33: 327–340. https://doi.org/10.1016/j.healun.2014.02.027.

Segovia J, Cosío MDG, Barceló JM, Bueno MG, Pavía PG, Burgos R, et al. RADIAL: a novel primary graft failure risk score in heart transplantation. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2011; 30: 644–651. https://doi.org/10.1016/j.healun.2011.01.721.

Cosío Carmena MDG, Gómez Bueno M, Almenar L, Delgado JF, Arizón JM, González Vilchez F, et al. Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2013; 32: 1187–1195. https://doi.org/10.1016/j.healun.2013.08.004.

Sabatino M, Vitale G, Manfredini V, Masetti M, Borgese L, Maria Raffa G, et al. Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: Epidemiology, risk factors, and outcomes. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2017; 36: 1217–1225. https://doi.org/10.1016/j.healun.2017.02.014.

Segovia J, Pulpón LA, Sanmartín M, Tejero C, Serrano S, Burgos R, et al. Primary graft failure in heart transplantation: a multivariate analysis. Transplantation Proceedings. 1998; 30: 1932. https://doi.org/10.1016/s0041-1345(98)00485-0.

Yuan L, Ma W, Cui J, Liu J, Yang Z, Yang S, et al. Mildly Elevated Pulmonary Artery Systolic Pressure is Associated with Extracorporeal Membrane Oxygenation Support after Heart Transplantation. Journal of Cardiac Surgery. 2023; 2023: 8877476.

Stobierska-Dzierzek B, Awad H, Michler RE. The evolving management of acute right-sided heart failure in cardiac transplant recipients. Journal of the American College of Cardiology. 2001; 38: 923–931. https://doi.org/10.1016/s0735-1097(01)01486-3.

Rosendale JD, Kauffman HM, McBride MA, Chabalewski FL, Zaroff JG, Garrity ER, et al. Hormonal resuscitation yields more transplanted hearts, with improved early function. Transplantation. 2003; 75: 1336–1341. https://doi.org/10.1097/01.TP.0000062839.58826.6D.

Meers CM, Wauters S, Verbeken E, Scheers H, Vanaudenaerde B, Verleden GM, et al. Preemptive therapy with steroids but not macrolides improves gas exchange in caustic-injured donor lungs. The Journal of Surgical Research. 2011; 170: e141–e148. https://doi.org/10.1016/j.jss.2011.05.062.

Venkateswaran RV, Patchell VB, Wilson IC, Mascaro JG, Thompson RD, Quinn DW, et al. Early donor management increases the retrieval rate of lungs for transplantation. The Annals of Thoracic Surgery. 2008; 85: 278–286; discussion 286. https://doi.org/10.1016/j.athoracsur.2007.07.092.

Wood KE, Becker BN, McCartney JG, D'Alessandro AM, Coursin DB. Care of the potential organ donor. The New England Journal of Medicine. 2004; 351: 2730–2739. https://doi.org/10.1056/NEJMra013103.

Souter MJ, Eidbo E, Findlay JY, Lebovitz DJ, Moguilevitch M, Neidlinger NA, et al. Organ Donor Management: Part 1. Toward a Consensus to Guide Anesthesia Services During Donation After Brain Death. Seminars in Cardiothoracic and Vascular Anesthesia. 2018; 22: 211–222. https://doi.org/10.1177/1089253217749053.

Kumar TKS, Mathis C, Sathanandam S, Zurakowski D, Subramanian S, Allen J, et al. Effect of thyroid hormone on cardiac function following orthotopic heart transplantation in piglets. Pediatric Transplantation. 2017; 21: 10.1111/petr.13002. https://doi.org/10.1111/petr.13002.

Novitzky D, Mi Z, Collins JF, Cooper DKC. Increased Procurement of Thoracic Donor Organs After Thyroid Hormone Therapy. Seminars in Thoracic and Cardiovascular Surgery. 2015; 27: 123–132. https://doi.org/10.1053/j.semtcvs.2015.06.012.

McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal. 2021; 42: 3599–3726. https://doi.org/10.1093/eurheartj/ehab368.

McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine. 2014; 371: 993–1004. https://doi.org/10.1056/NEJMoa1409077.

Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet (London, England). 2012; 380: 1387–1395. https://doi.org/10.1016/S0140-6736(12)61227-6.

Mentz RJ, Ward JH, Hernandez AF, Lepage S, Morrow DA, Sarwat S, et al. Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure. Journal of the American College of Cardiology. 2023; 82: 1–12. https://doi.org/10.1016/j.jacc.2023.04.019.

DeRoo SC, Takayama H, Nemeth S, Garan AR, Kurlansky P, Restaino S, et al. Extracorporeal membrane oxygenation for primary graft dysfunction after heart transplant. The Journal of Thoracic and Cardiovascular Surgery. 2019; 158: 1576–1584.e3. https://doi.org/10.1016/j.jtcvs.2019.02.065.

Mehra MR, Canter CE, Hannan MM, Semigran MJ, Uber PA, Baran DA, et al. The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update. The Journal of Heart and Lung Transplantation: the Official Publication of the International Society for Heart Transplantation. 2016; 35: 1–23. https://doi.org/10.1016/j.healun.2015.10.023.

Gaies MG, Gurney JG, Yen AH, Napoli ML, Gajarski RJ, Ohye RG, et al. Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatric Critical Care Medicine: a Journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2010; 11: 234–238. https://doi.org/10.1097/PCC.0b013e3181b806fc.

Zern EK, Cheng S, Wolfson AM, Hamilton MA, Zile MR, Solomon SD, et al. Angiotensin Receptor-Neprilysin Inhibitor Therapy Reverses Pulmonary Hypertension in End-Stage Heart Failure Patients Awaiting Transplantation. Circulation. Heart Failure. 2020; 13: e006696. https://doi.org/10.1161/CIRCHEARTFAILURE.119.006696.

Guglin M, Zucker MJ, Bazan VM, Bozkurt B, El Banayosy A, Estep JD, et al. Venoarterial ECMO for Adults: JACC Scientific Expert Panel. Journal of the American College of Cardiology. 2019; 73: 698–716. https://doi.org/10.1016/j.jacc.2018.11.038.

Menendez JT. The Mechanism of Action of LCZ696. Cardiac Failure Review. 2016; 2: 40–46. https://doi.org/10.15420/cfr.2016:1:1.

Andersen S, Axelsen JB, Ringgaard S, Nyengaard JR, Hyldebrandt JA, Bogaard HJ, et al. Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure. International Journal of Cardiology. 2019; 293: 203–210. https://doi.org/10.1016/j.ijcard.2019.06.065.

Hobbs AJ, Moyes AJ, Baliga RS, Ghedia D, Ochiel R, Sylvestre Y, et al. Neprilysin inhibition for pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled, proof-of-concept trial. British Journal of Pharmacology. 2019; 176: 1251–1267. https://doi.org/10.1111/bph.14621.

Desai AS, Heywood JT, Rathman L, Abraham WT, Adamson P, Brett ME, et al. Early Reduction in Ambulatory Pulmonary Artery Pressures After Initiation of Sacubitril/Valsartan. Circulation. Heart Failure. 2021; 14: e008212. https://doi.org/10.1161/CIRCHEARTFAILURE.120.008212.

Cacciatore F, Amarelli C, Maiello C, Mattucci I, Salerno G, Di Maio M, et al. Sacubitril/valsartan in patients listed for heart transplantation: effect on physical frailty. ESC Heart Failure. 2020; 7: 757–762. https://doi.org/10.1002/ehf2.12610.

Gentile P, Cantone R, Perna E, Ammirati E, Varrenti M, D'Angelo L, et al. Haemodynamic effects of sacubitril/valsartan in advanced heart failure. ESC Heart Failure. 2022; 9: 894–904. https://doi.org/10.1002/ehf2.13755.

Nesterov SV, Räty J, Nammas W, Maaniitty T, Galloo X, Stassen J, et al. Short-term effects of sacubitril/valsartan therapy on myocardial oxygen consumption and energetic efficiency of cardiac work in heart failure with reduced ejection fraction: A randomized controlled study. European Journal of Heart Failure. 2024; 26: 117–126. https://doi.org/10.1002/ejhf.3072.

Baliga RS, Zhao L, Madhani M, Lopez-Torondel B, Visintin C, Selwood D, et al. Synergy between natriuretic peptides and phosphodiesterase 5 inhibitors ameliorates pulmonary arterial hypertension. American Journal of Respiratory and Critical Care Medicine. 2008; 178: 861–869. https://doi.org/10.1164/rccm.200801-121OC.

Chang PC, Wo HT, Lee HL, Lin SF, Chu Y, Wen MS, et al. Sacubitril/Valsartan Therapy Ameliorates Ventricular Tachyarrhythmia Inducibility in a Rabbit Myocardial Infarction Model. Journal of Cardiac Failure. 2020; 26: 527–537. https://doi.org/10.1016/j.cardfail.2020.03.007.

Ge Q, Zhao L, Ren XM, Ye P, Hu ZY. LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis. Experimental Biology and Medicine (Maywood, N.J.). 2019; 244: 1028–1039. https://doi.org/10.1177/1535370219861283.

Pascual-Figal D, Bayés-Genis A, Beltrán-Troncoso P, Caravaca-Pérez P, Conde-Martel A, Crespo-Leiro MG, et al. Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review. Frontiers in Cardiovascular Medicine. 2021; 8: 754499. https://doi.org/10.3389/fcvm.2021.754499.

Published

2025-01-16

How to Cite

Yuan, L., Yang, Z., Ma, W., Cui, J., Liu, J., Yang, S., Zhang, H., Wang, F., Liu, H., Wang, C., & Sun, X. (2025). The Angiotensin Receptor–Neprilysin Inhibitor is Related to Lower Post-transplant Use of Extracorporeal Membrane Oxygenation. The Heart Surgery Forum, 28(1), E010-E018. https://doi.org/10.59958/hsf.8075

Issue

Vol. 28 No. 1 (2025)

Section

Article

Copyright (c) 2025 The Author(s)

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Author Disclosure & Copyright Agreement