Chronic vagal nerve stimulation exerts additional beneficial effects on the beta-blocker-treated failing heart
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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.
KeywordsVagal nerve stimulation Beta-blocker Myocardial infarction Cardiac remodeling Chronic heart failure
This study was partly supported by JSPS KAKENHI (Grant Number: C—26461099, 17K09544).
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.
- 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
- 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
- 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.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.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
- 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
- 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
- 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
- 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