Skip to main content
SpringerLink
Log in

Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction

  • Original Paper
  • Published:
Clinical Research in Cardiology Aims and scope Submit manuscript

Abstract

Background

Sacubitril/valsartan reduced the occurrence of sudden cardiac death in the PARADIGM-HF trial. However, limited information is available about the mechanism.

Methods

Heart failure (HF)-patients receiving sacubitril/valsartan for a class-I indication equipped with an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) with remote tele-monitoring were retrospectively analyzed. Device-registered arrhythmic-events were determined [ventricular tachycardia/fibrillation (VT/VF), appropriate therapy, non-sustained VT (NsVT; > 4beats and < 30 s), hourly premature ventricular contraction (PVC)-burden], following sacubitril/valsartan initiation (incident-analysis) and over an equal time period before initiation (antecedent-analysis). Reverse remodeling to sacubitril/valsartan was defined as an improvement of left ventricular ejection fraction of ≥ 5% between baseline and follow-up.

Results

A-total of 151 HF-patients with reduced LVEF (29 ± 9%) were included. Patients were switched from ACE-I or ARB to equal doses of sacubitril/valsartan (expressed as %-target-dose; before = 58 ± 30% vs. after = 56 ± 27%). The mean follow-up of both the incident and antecedent analysis was 364 days. Following the initiation, VT/VF-burden dropped (individual patients with VT/VF pre_n = 19 vs. post_n = 10, total-episodes of VT/VF pre_n = 51 vs. post_n = 14, both p < 0.001), resulting in reduced occurrence of appropriate therapy (pre_n = 16 vs. post_n = 6; p < 0.001). NsVT-burden per patient also dropped (mean episodes pre_n = 7.7 ± 11.8 vs. post_n = 3.7 ± 5.4; p < 0.001). There was no impact on atrial-fibrillation burden. PVC-burden dropped significantly which was associated with an improvement in BiV-pacing in patients with < 90% BiV-pacing at baseline. A higher degree of reverse remodeling was associated with a lower burden of NsVT and PVCs (both p < 0.05).

Conclusion

Initiation of sacubitril/valsartan is associated with a lower degree of VT/VF, resulting in less ICD-interventions. This beneficial effect on ventricular arrhythmias might be related to cardiac reverse remodeling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Shen L, Jhund PS, Petrie MC, Claggett BL, Barlera S, Cleland JGF, Dargie HJ, Granger CB, Kjekshus J, Kober L, Latini R, Maggioni AP, Packer M, Pitt B, Solomon SD, Swedberg K, Tavazzi L, Wikstrand J, Zannad F, Zile MR, McMurray JJV (2017) Declining risk of sudden death in heart failure. N Engl J Med 377(1):41–51

    Article  PubMed  Google Scholar 

  2. McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004

    Article  CAS  Google Scholar 

  3. Virmani R, Burke AP, Farb A (2001) Sudden cardiac death. Cardiovasc Pathol 10(6):275–282

    Article  CAS  PubMed  Google Scholar 

  4. Sinha SK, Crain B, Flickinger K, Calkins H, Rickard J, Cheng A, Berger R, Tomaselli G, Marine JE (2016) Clinical inferences of cardiovascular implantable electronic device analysis at autopsy. J Am Coll Cardiol 68(12):1255–1264

    Article  PubMed  Google Scholar 

  5. Chung MK, Szymkiewicz SJ, Shao M, Zishiri E, Niebauer MJ, Lindsay BD, Tchou PJ (2010) Aggregate national experience with the wearable cardioverter-defibrillator: event rates, compliance, and survival. J Am Coll Cardiol 56(3):194–203

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kober L, Thune JJ, Nielsen JC, Haarbo J, Videbaek L, Korup E, Jensen G, Hildebrandt P, Steffensen FH, Bruun NE, Eiskjaer H, Brandes A, Thogersen AM, Gustafsson F, Egstrup K, Videbaek R, Hassager C, Svendsen JH, Hofsten DE, Torp-Pedersen C, Pehrson S (2016) Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 375(13):1221–1230

    Article  PubMed  Google Scholar 

  7. Brignole M, Auricchio A, Baron-Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE (2013) 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy: the task force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Europace 15(8):1070–1118

    Article  PubMed  Google Scholar 

  8. Martens P, Verbrugge FH, Nijst P, Dupont M, Nuyens D, Herendael HV, Rivero-Ayerza M, Tang WH, Mullens W (2017) Incremental benefit of cardiac resynchronisation therapy with versus without a defibrillator. Heart 103(24):1977–1984

    CAS  PubMed  Google Scholar 

  9. Wilkoff BL, Fauchier L, Stiles MK, Morillo CA, Al-Khatib SM, Almendral J, Aguinaga L, Berger RD, Cuesta A, Daubert JP, Dubner S, Ellenbogen KA, Mark Estes NA, Fenelon G, Garcia FC, Gasparini M, Haines DE, Healey JS, Hurtwitz JL, Keegan R, Kolb C, Kuck KH, Marinskis G, Martinelli M, McGuire M, Molina LG, Okumura K, Proclemer A, Russo AM, Singh JP, Swerdlow CD, Teo WS, Uribe W, Viskin S, Wang CC, Zhang S (2016) 2015 HRS/EHRA/APHRS/SOLAECE expert consensus statement on optimal implantable cardioverter-defibrillator programming and testing. Heart Rhythm 13(2):e50–e86

    Article  PubMed  Google Scholar 

  10. Martens P, Verbrugge FH, Nijst P, Bertrand PB, Dupont M, Tang WH, Mullens W (2017) Feasibility and association of neurohumoral blocker up-titration after cardiac resynchronization therapy. J Card Fail 23(8):597–605

    Article  CAS  PubMed  Google Scholar 

  11. Martens P, Belien H, Dupont M, Vandervoort P, Mullens W (2018) The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction. Cardiovasc Ther 36:e12435. https://doi.org/10.1111/1755-5922.12435

    Article  CAS  PubMed  Google Scholar 

  12. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 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 37(27):2129–2200

    Article  Google Scholar 

  13. Mullens W, Martens P (2018) Exploiting the natriuretic peptide pathway to preserve glomerular filtration in heart failure. JACC Heart Fail 6(6):499–502

    Article  PubMed  Google Scholar 

  14. Landstrom AP, Dobrev D, Wehrens XHT (2017) Calcium signaling and cardiac arrhythmias. Circ Res 120(12):1969–1993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zile MR, Claggett BL, Prescott MF, McMurray JJ, Packer M, Rouleau JL, Swedberg K, Desai AS, Gong J, Shi VC, Solomon SD (2016) Prognostic implications of changes in N-terminal Pro-B-type natriuretic peptide in patients with heart failure. J Am Coll Cardiol 68(22):2425–2436

    Article  CAS  PubMed  Google Scholar 

  16. Levine YC, Rosenberg MA, Mittleman M, Samuel M, Methachittiphan N, Link M, Josephson ME, Buxton AE (2014) B-type natriuretic peptide is a major predictor of ventricular tachyarrhythmias. Heart Rhythm 11(7):1109–1116

    Article  PubMed  Google Scholar 

  17. Wang Z, Taylor LK, Denney WD, Hansen DE (1994) Initiation of ventricular extrasystoles by myocardial stretch in chronically dilated and failing canine left ventricle. Circulation 90(4):2022–2031

    Article  CAS  PubMed  Google Scholar 

  18. de C Diego, L Gonzalez-Torres, Nunez JM, Centurion IR, Martin-Langerwerf DA, Sangio AD, Chochowski P, Casasnovas P, Blazquez JC, Almendral J (2018) Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm 15(3):395–402

    Article  PubMed  Google Scholar 

  19. Chin KL, Collier T, Pocock S, Pitt B, McMurray JJV, van Veldhuisen DJ, Swedberg K, Vincent J, Zannad F, Liew D (2019) Impact of eplerenone on major cardiovascular outcomes in patients with systolic heart failure according to baseline heart rate. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1410-4

    Article  PubMed  Google Scholar 

  20. Kobayashi M, Rossignol P, Ferreira JP, Aragao I, Paku Y, Iwasaki Y, Watanabe M, Fudim M, Duarte K, Zannad F, Girerd N (2018) Prognostic value of estimated plasma volume in acute heart failure in three cohort studies. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1385-1

    Article  PubMed  Google Scholar 

  21. Rossello X, Ariti C, Pocock SJ, Ferreira JP, Girerd N, McMurray JJV, van Veldhuisen DJ, Pitt B, Zannad F (2018) Impact of mineralocorticoid receptor antagonists on the risk of sudden cardiac death in patients with heart failure and left-ventricular systolic dysfunction: an individual patient-level meta-analysis of three randomized-controlled trials. Clin Res Cardiol. https://doi.org/10.1007/s00392-018-1378-0

    Article  PubMed  Google Scholar 

  22. Mogensen UM, Jhund PS, Abraham WT, Desai AS, Dickstein K, Packer M, Rouleau JL, Solomon SD, Swedberg K, Zile MR, Kober L, McMurray JJV (2017) Type of atrial fibrillation and outcomes in patients with heart failure and reduced ejection fraction. J Am Coll Cardiol 70(20):2490–2500

    Article  PubMed  Google Scholar 

  23. Lakkireddy D, Di BL, Ryschon K, Biria M, Swarup V, Reddy YM, Verma A, Bommana S, Burkhardt D, Dendi R, Dello RA, Casella M, Carbucicchio C, Tondo C, Dawn B, Natale A (2012) Radiofrequency ablation of premature ventricular ectopy improves the efficacy of cardiac resynchronization therapy in nonresponders. J Am Coll Cardiol 60(16):1531–1539

    Article  PubMed  Google Scholar 

  24. Boveda S, Marijon E, Jacob S, Defaye P, Winter JB, Bulava A, Gras D, Albenque JP, Combes N, Pavin D, Delarche N, Teubl A, Lambiez M, Chevalier P (2009) Incidence and prognostic significance of sustained ventricular tachycardias in heart failure patients implanted with biventricular pacemakers without a back-up defibrillator: results from the prospective, multicentre, Mona Lisa cohort study. Eur Heart J 30(10):1237–1244

    Article  PubMed  Google Scholar 

  25. Gracieux J, Sanders GD, Pokorney SD, Lopes RD, Thomas K, Al-Khatib SM (2014) Incidence and predictors of appropriate therapies delivered by the implantable cardioverter defibrillator in patients with ischemic cardiomyopathy: a systematic review. Int J Cardiol 177(3):990–994

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Pieter Martens is supported by a doctoral fellowship by the Research Foundation—Flanders (FWO, Grant number: 1127917N). Pieter Martens and Wilfried Mullens are researchers for the Limburg Clinical Research Program (LCRP) UHasselt-ZOL-Jessa, supported by the foundation Limburg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-Limburg and Jessa Hospital.

Author information

Authors and Affiliations

  1. Department of Cardiology, Ziekenhuis Oost-Limburg, Schiepse Bos 6, 3600, Genk, Belgium

    Pieter Martens, Dieter Nuyens, Maximo Rivero-Ayerza, Hugo Van Herendael, Jan Vercammen, Wendy Ceyssens, Evert Luwel, Matthias Dupont & Wilfried Mullens

  2. Doctoral School for Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium

    Pieter Martens

  3. Biomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt University, Diepenbeek, Belgium

    Wilfried Mullens

Authors
  1. Pieter Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dieter Nuyens
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maximo Rivero-Ayerza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo Van Herendael
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jan Vercammen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wendy Ceyssens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Evert Luwel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matthias Dupont
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wilfried Mullens
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pieter Martens.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martens, P., Nuyens, D., Rivero-Ayerza, M. et al. Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction. Clin Res Cardiol 108, 1074–1082 (2019). https://doi.org/10.1007/s00392-019-01440-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00392-019-01440-y

Keywords

Search

Navigation