The Journal of Physiological Sciences

, Volume 69, Issue 2, pp 295–303 | Cite as

Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated failing heart

  • Meihua Li
  • Can ZhengEmail author
  • Toru Kawada
  • Masashi Inagaki
  • Kazunori Uemura
  • Masaru Sugimachi
Original Paper


Vagal nerve stimulation (VNS) induces bradycardia in chronic heart failure (CHF). We hypothesized that beta-blocker would cover the beneficial effects of VNS on CHF if the anti-beta-adrenergic effect was the main VNS effect. This study investigated the effects of VNS on cardiac remodeling in rats with CHF treated with metoprolol. Two weeks after myocardial infarction, surviving rats were randomly assigned to groups of sham stimulation (SS), sham stimulation with metoprolol (SSM), or VNS with metoprolol (VSM). Compared to the SS group, heart rate was significantly reduced in the SSM and VSM groups. Hemodynamic assessments showed that VSM rats maintained better cardiac pump function and presented higher cardiac index and lower heart weight than SSM rats. VSM was also associated with lower plasma brain natriuretic peptide and norepinephrine levels than SSM. VSM but not SSM improved the 50-day survival rate compared with the SS group. The results suggest that VNS may exert its beneficial effects on the failing heart independently of its anti-beta-adrenergic mechanism.


Vagal nerve stimulation Beta-blocker Myocardial infarction Cardiac remodeling Chronic heart failure 



This study was partly supported by JSPS KAKENHI (Grant Number: C—26461099, 17K09544).

Author contributions

ML, CZ, and MS designed the study. ML and CZ performed the measurements and statistical analysis, and drafted the manuscript. KT, MI, and KU joined in interpreting the data. All authors have read and approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The author(s) declare that they have no competing interests.

Research involving animals

The care of animals and all animal experiments were performed in strict accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996), and the Guiding Principles for the Care and Use of Animals in the Field of Physiological Sciences, which have been approved by the Physiological Society of Japan. All protocols were reviewed and approved by the Animal Subject Committee in the National Cerebral and Cardiovascular Center.


  1. 1.
    Pfeffer MA (1995) Left ventricular remodeling after acute myocardial infarction. Annu Rev Med 46:455–466CrossRefGoogle Scholar
  2. 2.
    Hammermeister KE, DeRouen TA, Dodge HT (1979) Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations. Circulation 59:421–430CrossRefGoogle Scholar
  3. 3.
    Likoff MJ, Chandler SL, Kay HR (1987) Clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol 59:634–638CrossRefGoogle Scholar
  4. 4.
    Vaughan DE, Pfeffer MA (1994) Angiotensin converting enzyme inhibitors and cardiovascular remodelling. Cardiovasc Res 28:159–165CrossRefGoogle Scholar
  5. 5.
    Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH (1996) The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med 334:1349–1355CrossRefGoogle Scholar
  6. 6.
    Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL (2001) Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658CrossRefGoogle Scholar
  7. 7.
    La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ (1998) Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 351:478–484CrossRefGoogle Scholar
  8. 8.
    Lechat P, Hulot JS, Escolano S, Mallet A, Leizorovicz A, Werhlen-Grandjean M, Pochmalicki G, Dargie H (2001) Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation 103:1428–1433CrossRefGoogle Scholar
  9. 9.
    Li M, Zheng C, Sato T, Kawada T, Sugimachi M, Sunagawa K (2004) Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation 109:120–124CrossRefGoogle Scholar
  10. 10.
    De Ferrari GM, Stolen C, Tuinenburg AE, Wright DJ, Brugada J, Butter C, Klein H, Neuzil P, Botman C, Castel MA, D’Onofrio A, de Borst GJ, Solomon S, Stein KM, Schubert B, Stalsberg K, Wold N, Ruble S, Zannad F (2017) Long-term vagal stimulation for heart failure: eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial. Int J Cardiol 244:229–234CrossRefGoogle Scholar
  11. 11.
    Gold MR, Van Veldhuisen DJ, Hauptman PJ, Borggrefe M, Kubo SH, Lieberman RA, Milasinovic G, Berman BJ, Djordjevic S, Neelagaru S, Schwartz PJ, Starling RC, Mann DL (2016) Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol 68:149–158CrossRefGoogle Scholar
  12. 12.
    Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, DiCarlo LA, Ardell JL, Rector TS, Amurthur B, KenKnight BH, Anand IS (2014) Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial. J Card Fail 20:808–816CrossRefGoogle Scholar
  13. 13.
    Gronda E, Vanoli E (2016) Autonomic modulation with baroreflex activation therapy in heart failure. Curr Heart Fail Rep 13:273–280CrossRefGoogle Scholar
  14. 14.
    Sabbah HN, Imai M, Zaretsky A, Rastogi S, Wang M, Jiang A, Zaca V (2007) 509 Therapy with vagus nerve electrical stimulation combined with beta-blockade improves left ventricular systolic function in dogs with heart failure beyond that seen with beta-blockade alone. European Journal of Heart Failure Supplements 6:114CrossRefGoogle Scholar
  15. 15.
    Li M, Zheng C, Kawada T, Inagaki M, Uemura K, Shishido T, Sugimachi M (2013) Donepezil markedly improves long-term survival in rats with chronic heart failure after extensive myocardial infarction. Circ J 77:2519–2525CrossRefGoogle Scholar
  16. 16.
    Li M, Zheng C, Inagaki M, Kawada T, Sunagawa K, Sugimachi M (2005) Chronic vagal stimulation decreased vasopressin secretion and sodium ingestion in heart failure rats after myocardial infarction. Conf Proc IEEE Eng Med Biol Soc 4:3962–3965Google Scholar
  17. 17.
    Li M, Zheng C, Kawada T, Inagaki M, Uemura K, Sugimachi M (2014) Adding the acetylcholinesterase inhibitor, donepezil, to losartan treatment markedly improves long-term survival in rats with chronic heart failure. Eur J Heart Fail 16:1056–1065CrossRefGoogle Scholar
  18. 18.
    Komajda M, Isnard R, Cohen-Solal A, Metra M, Pieske B, Ponikowski P, Voors AA, Dominjon F, Henon-Goburdhun C, Pannaux M, Bohm M, prEserve DlvefchFwisI (2017) Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur J Heart Fail 19:1495–1503CrossRefGoogle Scholar
  19. 19.
    Kawada T, Li M, Zheng C, Shimizu S, Uemura K, Turner MJ, Yamamoto H, Sugimachi M (2014) Chronic vagal nerve stimulation improves baroreflex neural arc function in heart failure rats. J Appl Physiol (1985) 116:1308–1314CrossRefGoogle Scholar
  20. 20.
    Kawada T, Shimizu S, Uemura K, Hayama Y, Yamamoto H, Shishido T, Nishikawa T, Sugimachi M (2018) Ivabradine preserves dynamic sympathetic control of heart rate despite inducing significant bradycardia in rats. J Physiol Sci. Google Scholar
  21. 21.
    Guth BD, Heusch G, Seitelberger R, Ross J Jr (1987) Mechanism of beneficial effect of beta-adrenergic blockade on exercise-induced myocardial ischemia in conscious dogs. Circ Res 60:738–746CrossRefGoogle Scholar
  22. 22.
    Vaseghi M, Shivkumar K (2008) The role of the autonomic nervous system in sudden cardiac death. Prog Cardiovasc Dis 50:404–419CrossRefGoogle Scholar
  23. 23.
    Cohen-Solal A, Jacobson AF, Pina IL (2017) Beta blocker dose and markers of sympathetic activation in heart failure patients: interrelationships and prognostic significance. ESC Heart Fail 4:499–506CrossRefGoogle Scholar
  24. 24.
    Vanoli E, De Ferrari GM, Stramba-Badiale M, Hull SS Jr, Foreman RD, Schwartz PJ (1991) Vagal stimulation and prevention of sudden death in conscious dogs with a healed myocardial infarction. Circ Res 68:1471–1481CrossRefGoogle Scholar
  25. 25.
    Qing KY, Wasilczuk KM, Ward MP, Phillips EH, Vlachos PP, Goergen CJ, Irazoqui PP (2018) B fibers are the best predictors of cardiac activity during vagus nerve stimulation. Bioelectron Med 4:5CrossRefGoogle Scholar
  26. 26.
    Nishizaki A, Sakamoto K, Saku K, Hosokawa K, Sakamoto T, Oga Y, Akashi T, Murayama Y, Kishi T, Ide T, Sunagawa K (2016) Optimal titration is important to maximize the beneficial effects of vagal nerve stimulation in chronic heart failure. J Card Fail 22:631–638CrossRefGoogle Scholar
  27. 27.
    Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A (2008) Long-term vagal stimulation in patients with advanced heart failure: first experience in man. Eur J Heart Fail 10:884–891CrossRefGoogle Scholar
  28. 28.
    Saku K, Kishi T, Sakamoto K, Hosokawa K, Sakamoto T, Murayama Y, Kakino T, Ikeda M, Ide T, Sunagawa K (2014) Afferent vagal nerve stimulation resets baroreflex neural arc and inhibits sympathetic nerve activity. Physiol Rep 2:e12136CrossRefGoogle Scholar
  29. 29.
    Smith BN, Dou P, Barber WD, Dudek FE (1998) Vagally evoked synaptic currents in the immature rat nucleus tractus solitarii in an intact in vitro preparation. J Physiol 512(Pt 1):149–162CrossRefGoogle Scholar
  30. 30.
    Tracey KJ (2002) The inflammatory reflex. Nature 420:853–859CrossRefGoogle Scholar
  31. 31.
    Kiss A, Tratsiakovich Y, Mahdi A, Yang J, Gonon AT, Podesser BK, Pernow J (2017) Vagal nerve stimulation reduces infarct size via a mechanism involving the alpha-7 nicotinic acetylcholine receptor and downregulation of cardiac and vascular arginase. Acta Physiol (Oxf) 221:174–181CrossRefGoogle Scholar
  32. 32.
    Hamann JJ, Ruble SB, Stolen C, Wang M, Gupta RC, Rastogi S, Sabbah HN (2013) Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure. Eur J Heart Fail 15:1319–1326CrossRefGoogle Scholar
  33. 33.
    Morita H, Manders WT, Skelton MM, Cowley AW Jr, Vatner SF (1986) Vagal regulation of arginine vasopressin in conscious dogs. Am J Physiol 251:H19–H23Google Scholar
  34. 34.
    Thames MD, Schmid PG (1981) Interaction between carotid and cardiopulmonary baroreflexes in control of plasma ADH. Am J Physiol 241:H431–H434Google Scholar
  35. 35.
    Goldsmith SR (1992) Baroreflex loading maneuvers do not suppress increased plasma arginine vasopressin in patients with congestive heart failure. J Am Coll Cardiol 19:1180–1184CrossRefGoogle Scholar
  36. 36.
    Goldsmith SR, Francis GS, Levine TB, Cowley JAW, Cohn JN (1983) Impaired response of plasma vasopressin to orthostatic stress in patients with congestive heart failure. J Am Coll Cardiol 2:1080–1083CrossRefGoogle Scholar
  37. 37.
    Wu MY, Chang NC, Su CL, Hsu YH, Chen TW, Lin YF, Wu CH, Tam KW (2014) Loop diuretic strategies in patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials. J Crit Care 29:2–9CrossRefGoogle Scholar
  38. 38.
    Felker GM, O’Connor CM, Braunwald E, Heart Failure Clinical Research Network I (2009) Loop diuretics in acute decompensated heart failure: necessary? Evil? A necessary evil? Circ Heart Fail 2:56–62CrossRefGoogle Scholar
  39. 39.
    Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, Udelson JE, Zannad F, Cook T, Ouyang J, Zimmer C, Orlandi C, Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan I (2007) Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA 297:1319–1331CrossRefGoogle Scholar
  40. 40.
    Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole-Wilson P (1987) Untreated heart failure: clinical and neuroendocrine effects of introducing diuretics. Br Heart J 57:17–22CrossRefGoogle Scholar
  41. 41.
    Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN (1985) Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 103:1–6CrossRefGoogle Scholar
  42. 42.
    DiCarlo LA, Libbus I, Kumar HU, Mittal S, Premchand RK, Amurthur B, KenKnight BH, Ardell JL, Anand IS (2018) Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study. ESC Heart Fail 5:95–100CrossRefGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Meihua Li
    • 1
  • Can Zheng
    • 1
    Email author
  • Toru Kawada
    • 1
  • Masashi Inagaki
    • 1
  • Kazunori Uemura
    • 1
  • Masaru Sugimachi
    • 1
  1. 1.Department of Cardiovascular DynamicsNational Cerebral and Cardiovascular CenterSuitaJapan

Personalised recommendations