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Monitoring Biomarkers in Patients Receiving Neprilysin Inhibitors

  • Heart Failure (F Peacock and L Zhang, Section Editors)
  • Published:
Current Emergency and Hospital Medicine Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To understand the role of neprilysin inhibition in the management of chronic heart failure with reduced ejection fraction (HFrEF) and review effects of neprilysin inhibition on concentrations of natriuretic peptides and other biomarkers.

Recent Findings

Neprilysin inhibition improves cardiovascular outcomes in patients with chronic HFrEF. As bioactive natriuretic peptides are degraded by neprilysin, treatment with sacubitril/valsartan results in an increase in concentrations of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). In contrast, neprilysin inhibition led to reduction in concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). Reduction in NT-proBNP to ≤ 1000 pg/mL with neprilysin inhibition improved cardiovascular outcomes in a recent analysis. Other biomarkers may be affected by neprilysin inhibition.

Summary

Neprilysin inhibition results in an increase in ANP, BNP, and CNP with corresponding reduction in NT-proBNP concentrations. Other biomarkers may be similarly affected. Given widespread clinical measurement, more data are needed to better understand potential impact on neprilysin inhibition on ability to interpret BNP.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine. 2014;371(11):993–1004. The largest and first trial in a decade to give us a medication that improved mortality in patients with heart failure with reduced ejection fraction- sacubitril/valsartan. https://doi.org/10.1056/NEJMoa1409077.

    Article  PubMed  Google Scholar 

  2. • Yancy CW, Jessup M, Bozkurt B, Butler J, Casey d Jr, Colvin MM, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA Guideline for the Management of Heart FailureA Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68(13):1476–88. The guideline that incorporated sacubitril/valsartan into the treatment strategy of patients with heart failure with reduced ejection fraction. https://doi.org/10.1016/j.jacc.2016.05.011.

    Article  PubMed  Google Scholar 

  3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey d Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62(16):1495–539. https://doi.org/10.1016/j.jacc.2013.05.020.

    Article  Google Scholar 

  4. Troughton RW, Frampton CM, Brunner-La Rocca H-P, Pfisterer M, Eurlings LWM, Erntell H, et al. Effect of B-type natriuretic peptide-guided treatment of chronic heart failure on total mortality and hospitalization: an individual patient meta-analysis. Eur Heart J. 2014;35(23):1559–67. https://doi.org/10.1093/eurheartj/ehu090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Savarese G, Trimarco B, Dellegrottaglie S, et al. Natriuretic peptide-guided therapy in chronic heart failure: a meta-analysis of 2,686 patients in 12 randomized trials. PLoS One. 2013;8:e58287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Langenickel TH, Dole WP. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure. Drug Discovery Today: Therapeutic Strategies. 2012;9:e131–9.

    Article  Google Scholar 

  7. McMurray JJV. Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances. Eur J Heart Fail. 2015;17(3):242–7. https://doi.org/10.1002/ejhf.250.

    Article  CAS  PubMed  Google Scholar 

  8. Vanneste Y, Michel A, Dimaline R, Najdovski T, Deschodt-Lanckman M. Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site. Biochem J. 1988;254(2):531–7. https://doi.org/10.1042/bj2540531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen Y, Burnett JC. Biochemistry, therapeutics, and biomarker implications of neprilysin in cardiorenal disease. Clin Chem. 2017;63(1):108–15. https://doi.org/10.1373/clinchem.2016.262907.

    Article  CAS  PubMed  Google Scholar 

  10. Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. JACC: Heart Failure. 2014;2:663–70.

    PubMed  Google Scholar 

  11. Ibrahim NE, Januzzi JL. Beyond natriuretic peptides for diagnosis and management of heart failure. Clin Chem. 2017;63(1):211–22. https://doi.org/10.1373/clinchem.2016.259564.

    Article  CAS  PubMed  Google Scholar 

  12. de Bold AJ, de Bold MLK. Determinants of natriuretic peptide production by the heart: basic and clinical implications. J Investig Med: Off Publ Am Fed Clin Res. 2005;53(7):371–7. https://doi.org/10.2310/6650.2005.53710.

    Article  Google Scholar 

  13. Vodovar N, Séronde M-F, Laribi S, Gayat E, Lassus J, Boukef R, et al. Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure. Eur Heart J. 2014;35(48):3434–41. https://doi.org/10.1093/eurheartj/ehu314.

    Article  CAS  PubMed  Google Scholar 

  14. Ibrahim N, Januzzi JL. The potential role of natriuretic peptides and other biomarkers in heart failure diagnosis, prognosis and management. Expert Rev Cardiovasc Ther. 2015:1–14.

  15. Ichiki T, Huntley BK, Sangaralingham SJ, Burnett JC. Pro-atrial natriuretic peptide: a novel guanylyl cyclase-A receptor activator which goes beyond atrial and B-type natriuretic peptides JACC heart failure 2015;3:715–723.

  16. D'Elia E, Iacovoni A, Vaduganathan M, Lorini FL, Perlini S, Senni M. Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides. European Journal of Heart Failure 2017:n/a-n/a.

  17. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular effects of angiotensin-converting enzyme inhibitors in humans. Circulation. 1997;95(5):1115–8. https://doi.org/10.1161/01.CIR.95.5.1115.

    Article  CAS  PubMed  Google Scholar 

  18. Craig TJ, Bernstein JA, Farkas H, Bouillet L, Boccon-Gibod I. Diagnosis and treatment of bradykinin-mediated angioedema: outcomes from an angioedema expert consensus meeting. Int Arch Allergy Immunol. 2014;165(2):119–27. https://doi.org/10.1159/000368404.

    Article  CAS  PubMed  Google Scholar 

  19. O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance P in inflammatory disease. J Cell Physiol. 2004;201(2):167–80. https://doi.org/10.1002/jcp.20061.

    Article  PubMed  Google Scholar 

  20. Kato J, Tsuruda T, Kita T, Kitamura K, Eto T. Adrenomedullin. A protective factor for blood vessels 2005;25:2480–2487.

  21. Taubman MB. Angiotensin II. A vasoactive hormone with ever-increasing biological roles 2003;92:9–11.

  22. Januzzi JL Jr, Ibrahim NE. Renin-angiotensin system blockade in heart failure: more to the picture than meets the eye∗. J Am Coll Cardiol. 2017;69(7):820–2. https://doi.org/10.1016/j.jacc.2016.10.083.

    Article  PubMed  Google Scholar 

  23. van Kimmenade RRJ, Januzzi JL. Emerging biomarkers in heart failure. Clin Chem. 2012;58(1):127–38. https://doi.org/10.1373/clinchem.2011.165720.

    Article  PubMed  Google Scholar 

  24. Böhm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76(1):8–18. https://doi.org/10.1016/j.cardiores.2007.06.004.

    Article  PubMed  Google Scholar 

  25. Bayes-Genis A, Barallat J, de Antonio M, Domingo M, Zamora E, Vila J, et al. Bloodstream amyloid-beta (1-40) peptide, cognition, and outcomes in heart failure. Revista Española de Cardiología (English Edition). 2017;70(11):924–32. https://doi.org/10.1016/j.rec.2017.02.021.

    Article  Google Scholar 

  26. Langenickel TH, Tsubouchi C, Ayalasomayajula S, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 2016;81:878–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Northridge D, Alabaster C, Connell JC, et al. Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet. 1989;334:591–3.

    Article  Google Scholar 

  28. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure. The Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). 2002;106:920–6.

  29. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial*. Am J Hypertens. 2004;17(2):103–11. https://doi.org/10.1016/j.amjhyper.2003.09.014.

    Article  CAS  PubMed  Google Scholar 

  30. Campbell DJ, Krum H, Esler MD. Losartan increases bradykinin levels in hypertensive humans. Circulation. 2005;111(3):315–20. https://doi.org/10.1161/01.CIR.0000153269.07762.3B.

    Article  CAS  PubMed  Google Scholar 

  31. Claggett B, Packer M, McMurray JJV, et al. Estimating the long-term treatment benefits of sacubitril–valsartan. N Engl J Med. 2015;373:2289–90.

    Article  PubMed  Google Scholar 

  32. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–95.

    Article  CAS  PubMed  Google Scholar 

  33. Karlström P, Alehagen U, Boman K, Dahlström U, on behalf of the U-sg. Brain natriuretic peptide-guided treatment does not improve morbidity and mortality in extensively treated patients with chronic heart failure: responders to treatment have a significantly better outcome. Eur J Heart Fail. 2011;13(10):1096–103. https://doi.org/10.1093/eurjhf/hfr078.

    Article  PubMed  Google Scholar 

  34. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients. The International Collaborative of NT-proBNP Study. Eur Heart J. 2006;27:330–7.

    Article  CAS  PubMed  Google Scholar 

  35. Salah K, Kok WE, Eurlings LW, Bettencourt P, Pimenta JM, Metra M, et al. A novel discharge risk model for patients hospitalised for acute decompensated heart failure incorporating N-terminal pro-B-type natriuretic peptide levels: a European coLlaboration on Acute decompeNsated Heart Failure: ÉLAN-HF Score. Heart. 2014;100(2):115–25. https://doi.org/10.1136/heartjnl-2013-303632.

    Article  CAS  PubMed  Google Scholar 

  36. Masson S, Latini R, Anand IS, et al. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in a large population of patients with chronic and symptomatic heart failure: the Valsartan Heart Failure (Val-HeFT) data. Clin Chem. 2006;52:1528–38.

    Article  CAS  PubMed  Google Scholar 

  37. •• Zile MR, Claggett BL, Prescott MF, McMurray JJV, Packer M, Rouleau JL, et al. Prognostic implications of changes in N-terminal pro-B-type natriuretic peptide in patients with heart failure. Journal of the American College of Cardiology. 2016;68(22):2425–36. This study demonstrated that a reduction in NT-proBNP concentrations during treatment with sacubitril/valsartan was associated with better outcomes. https://doi.org/10.1016/j.jacc.2016.09.931.

    Article  CAS  PubMed  Google Scholar 

  38. Norman JA, Little D, Bolgar M, Di Donato G. Degradation of brain natriuretic peptide by neutral endopeptidase: species specific sites of proteolysis determined by mass spectrometry. Biochem Biophys Res Commun. 1991;175(1):22–30. https://doi.org/10.1016/S0006-291X(05)81194-5.

    Article  CAS  PubMed  Google Scholar 

  39. Januzzi JL. B-type natriuretic peptide testing in the era of neprilysin inhibition: are the winds of change blowing? Clin Chem. 2016;62(5):663–5. https://doi.org/10.1373/clinchem.2016.255455.

    Article  CAS  PubMed  Google Scholar 

  40. Semenov AG, Katrukha AG. Different susceptibility of B-type natriuretic peptide (BNP) and BNP precursor (proBNP) to cleavage by neprilysin: the N-terminal part does matter. Clin Chem. 2016;62(4):617–22. https://doi.org/10.1373/clinchem.2016.254524.

    Article  CAS  PubMed  Google Scholar 

  41. Jaffe AS. Unwinding the interaction of natriuretic peptides and neprilysin∗. J Am Coll Cardiol. 2015;65(7):666–7. https://doi.org/10.1016/j.jacc.2014.12.011.

    Article  PubMed  Google Scholar 

  42. Ky B, French B, McCloskey K et al. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circulation: Heart Failure 2011;4:180–187.

  43. O’Meara E, Prescott MF, Rouleau JL, et al. Association between sST2 levels and cardiovascular outcomes and effect of sacubitril/valsartan on sST2 levels: results from the PARADIGM-HF trial. J Card Fail. 2016;22(8):S29–30. https://doi.org/10.1016/j.cardfail.2016.06.094.

    Article  Google Scholar 

  44. Pascual-Figal DA, Casas T, Ordonez-Llanos J, et al. Highly sensitive troponin T for risk stratification of acutely destabilized heart failure. Am Heart J. 2012;163:1002–10.

    Article  CAS  PubMed  Google Scholar 

  45. Packer M, McMurray JJV, Desai AS, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2014;

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Funding Sources

Dr. Ibrahim is supported in part by the Dennis and Marilyn Barry Fellowship in Cardiology. Dr. Januzzi is supported in part by the Hutter Family Professorship in Cardiology.

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Correspondence to James L. Januzzi Jr.

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Conflict of Interest

Dr. Januzzi has received grant support from Siemens, Singulex and Prevencio, consulting income from Roche Diagnostics, Critical Diagnostics, Philips, and Novartis, and participates in clinical endpoint committees/data safety monitoring boards for Amgen, Janssen, Abbvie, Pfizer, and Boehringer Ingelheim. Dr. Ibrahim has nothing to disclose.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Heart Failure

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Ibrahim, N.E., Januzzi, J.L. Monitoring Biomarkers in Patients Receiving Neprilysin Inhibitors. Curr Emerg Hosp Med Rep 6, 8–16 (2018). https://doi.org/10.1007/s40138-018-0149-6

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  • DOI: https://doi.org/10.1007/s40138-018-0149-6

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