Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Mini Review
  • Mini review series: Current topic in Hypertension
  • Published:

Denervation or stimulation? Role of sympatho-vagal imbalance in HFpEF with hypertension

Hypertension Research volume 46, pages 1727–1737 (2023)Cite this article

A Correction to this article was published on 28 April 2023

This article has been updated

Abstract

Heart failure (HF) in the elderly is an increasingly large and complex problem in modern society. Notably, the cause of HF with preserved ejection fraction (HFpEF) is multifactorial and its pathophysiology is not fully understood. Among these, hypertension has emerged as a pivotal factor in the pathophysiology and therapeutic targets of HFpEF. Neuronal elements distributed throughout the cardiac autonomic nervous system, from the level of the central autonomic network including the insular cortex to the intrinsic cardiac nervous system, regulate the human cardiovascular system. Specifically, increased sympathetic nervous system activity due to sympatho-vagal imbalance is suggested to be associated the relationship between hypertension and HFpEF. While several new pharmacological therapies, such as sodium-glucose cotransporter 2 inhibitors, have been shown to be effective in HFpEF, neuromodulatory therapies of renal denervation and vagus nerve stimulation (VNS) have received recent attention. The current review explores the pathophysiology of the brain-heart axis that underlies the relationship between hypertension and HFpEF and the rationale for therapeutic neuromodulation of HFpEF by non-invasive transcutaneous VNS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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

Similar content being viewed by others

Change history

References

  1. Nagai M, Förster CY, Dote K, Shimokawa H. Sex hormones in heart failure revisited? Eur J Heart Fail. 2019;21:308–10.

    Article  PubMed  Google Scholar 

  2. Takami T, Hoshide S, Kario K. Differential impact of antihypertensive drugs on cardiovascular remodeling: a review of findings and perspectives for HFpEF prevention. Hypertens Res. 2022;45:53–60.

    Article  PubMed  Google Scholar 

  3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, et al. ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136:e137–61.

    Article  PubMed  Google Scholar 

  4. Jin CN, Liu M, Sun JP, Fang F, Wen YN, Yu CM, et al. The prevalence and prognosis of resistant hypertension in patients with heart failure. PLoS One. 2014;9:e114958.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Seravalle G, Grassi G. Sympathetic nervous system and hypertension: new evidences. Auton Neurosci. 2022;238:102954.

    Article  PubMed  Google Scholar 

  6. Huynh K. Hypertension: PATHWAY to improving the treatment of drug-resistant hypertension. Nat Rev Cardiol. 2015;12:681.

    Article  CAS  PubMed  Google Scholar 

  7. Nagai M, Dote K. Treatment-resistant hypertension assessed by home blood pressure monitoring: a new target for intervention? Hypertens Res. 2022;45:167–9.

    Article  CAS  PubMed  Google Scholar 

  8. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018;36:1953–2041.

    Article  CAS  PubMed  Google Scholar 

  9. Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison Himmelfarb CR, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension. 2018;72:e53–e90.

    Article  CAS  PubMed  Google Scholar 

  10. Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, et al. Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Circulation. 2007;115:2145–52.

    Article  PubMed  Google Scholar 

  11. Narita K, Hoshide S, Kario K. Association of treatment resistant hypertension defined by home blood pressure monitoring with cardiovascular outcome. Hypertens Res. 2022;45:75–86.

    Article  PubMed  Google Scholar 

  12. Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N. Engl J Med. 2006;355:260–9.

    Article  CAS  PubMed  Google Scholar 

  13. Kostis JB, Davis BR, Cutler J, Grimm RH Jr, Berge KG, et al. Prevention of heart failure by antihypertensive drug treatment in older persons with isolated systolic hypertension. SHEP Cooperative Research Group. JAMA. 1997;278:212–6.

    Article  CAS  PubMed  Google Scholar 

  14. Shityakov S, Nagai M, Ergün S, Braunger BM, Förster CY. The protective effects of neurotrophins and microRNA in diabetic retinopathy, nephropathy and heart failure via regulating endothelial function. Biomolecules. 2022;12:1113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ferreira JP, Fitchett D, Ofstad AP, Kraus BJ, Wanner C, Zwiener I, et al. Empagliflozin for patients with presumed resistant hypertension: a post hoc analysis of the EMPA-REG OUTCOME trial. Am J Hypertens. 2020;33:1092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jackson AM, Benson L, Savarese G, Hage C, Jhund PS, Petrie MC, et al. Apparent treatment-resistant hypertension across the spectrum of heart failure phenotypes in the Swedish HF registry. JACC Heart Fail. 2022;10:380–92.

    Article  PubMed  Google Scholar 

  17. Rossignol P, Claggett BL, Liu J, Vardeny O, Pitt B, Zannad F, et al. Spironolactone and resistant hypertension in heart failure with preserved ejection fraction. Am J Hypertens. 2018;31:407–14.

    Article  CAS  PubMed  Google Scholar 

  18. Jackson AM, Jhund PS, Anand IS, Düngen HD, Lam CSP, Lefkowitz MP, et al. Sacubitril-valsartan as a treatment for apparent resistant hypertension in patients with heart failure and preserved ejection fraction. Eur Heart J. 2021;42:3741–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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. Eur Heart J. 2021;42:3599–726.

    Article  CAS  PubMed  Google Scholar 

  20. Wu Y, Quan C, Yang Y, Liang Z, Jiang W, Li X. Renalase improves pressure overload-induced heart failure in rats by regulating extracellular signal-regulated protein kinase 1/2 signaling. Hypertens Res. 2021;44:481–8.

    Article  CAS  PubMed  Google Scholar 

  21. Grabowski K, Herlan L, Witten A, Qadri F, Eisenreich A, Lindner D, et al. Cpxm2 as a novel candidate for cardiac hypertrophy and failure in hypertension. Hypertens Res. 2022;45:292–307.

    Article  CAS  PubMed  Google Scholar 

  22. Kamel H, Rahman AF, O’Neal WT, Lewis CE, Soliman EZ. Effect of intensive blood pressure lowering on left atrial remodeling in the SPRINT. Hypertens Res. 2021;44:1326–31.

    Article  PubMed  Google Scholar 

  23. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Hear J Cardiovasc Imaging. 2015;16:233–71.

    Article  Google Scholar 

  24. Airale L, Paini A, Ianniello E, Mancusi C, Moreo A, Vaudo G, et al. Left atrial volume indexed for height2 is a new sensitive marker for subclinical cardiac organ damage in female hypertensive patients. Hypertens Res. 2021;44:692–9.

    Article  CAS  PubMed  Google Scholar 

  25. Inciardi RM, Claggett B, Minamisawa M, Shin SH, Selvaraj S, Gonçalves A, et al. Association of left atrial structure and function with heart failure in older adults. J Am Coll Cardiol. 2022;79:1549–61.

    Article  PubMed  Google Scholar 

  26. Nagai M, Hoshide S, Kario K. The insular cortex and cardiovascular system: A new insight into the brain-heart axis. J Am Soc Hypertens. 2010;4:174–82.

    Article  PubMed  Google Scholar 

  27. Nagai M, Dote K, Kato M, Sasaki S, Oda N, Kagawa E, et al. The insular cortex and Takotsubo cardiomyopathy. Curr Pharm Des. 2017;23:879–88.

    Article  CAS  PubMed  Google Scholar 

  28. Cardinali DP. Autonomic nervous system: basic and clinical aspects. Springer; 2017.

  29. Ferraro S, Klugah-Brown B, Tench CR, Bazinet V, Bore MC, Nigri A, et al. The central autonomic system revisited - Convergent evidence for a regulatory role of the insular and midcingulate cortex from neuroimaging meta-analyses. Neurosci Biobehav Rev. 2022;142:104915.

    Article  PubMed  Google Scholar 

  30. Hilz MJ, Dutsch M, Perrine K, Nelson PK, Rauhut U, Devinsky O. Hemisphreic influence on autonomic modulation and baroreflex sensitivity. Ann Neurol. 2001;49:575–84.

    Article  CAS  PubMed  Google Scholar 

  31. Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology. 1992;42:1727–32.

    Article  CAS  PubMed  Google Scholar 

  32. Augustine JR. The insular lobe in primates including humans. Neurol Res. 1985;7:2–10.

    Article  CAS  PubMed  Google Scholar 

  33. Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev. 1996;22:229–44.

    Article  CAS  PubMed  Google Scholar 

  34. Mesulam MM, Mufson EJ. The Insula of Reil in man and monkey: architectonics, connectivity, and function. In: Peters A, Jones EG, editors. Cerebral Cortex. New York: Plenum Press; 1985. pp. 179–226.

  35. Ruggiero DA, Mraovitch S, Granata M, Anwar M, Reis DJ. A role of insular cortex in cardiovascular function. J Comp Neurol. 1987;257:189–207.

    Article  CAS  PubMed  Google Scholar 

  36. Deng H, Xiao X, Yang T, Ritola K, Hantman A, Li Y, et al. A genetically defined insula-brainstem circuit selectively controls motivational vigor. Cell. 2021;184:6344–60.e18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Shipley MT, Sanders MS. Special senses are really special: Evidence for a reciprocal, bilateral pathway between insular cortex and nucleus parabrachialis. Brain Res Bull. 1982;8:493–501.

    Article  CAS  PubMed  Google Scholar 

  38. Gamal-Eltrabily M, Espinosa de Los Monteros-Zúñiga A, Manzano-García A, Martínez-Lorenzana G, Condés-Lara M, González-Hernández A. The rostral agranular insular cortex, a new site of oxytocin to induce antinociception. J Neurosci. 2020;40:5669–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Butcher KS, Cechetto DF. Receptors in lateral hypothalamic area involved in insular cortex sympathetic responses. Am J Physiol. 1998;275:689–96.

    Google Scholar 

  40. Patel KP, Zhang PL, Krukoff TL. Alterations in brain hexokinase activity associated with heart failure in rats. Am J Physiol. 1993;265:R923–8.

    CAS  PubMed  Google Scholar 

  41. Patel KP, Zhang PL, Carmines PK. Neural influences on renal responses to acute volume expansion in rats with heart failure. Am J Physiol. 1996;271:H1441–8.

    CAS  PubMed  Google Scholar 

  42. Patel KP, Katsurada K, Zheng H. Cardiorenal syndrome: the role of neural connections between the heart and the kidneys. Circ Res. 2022;130:1601–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Katsurada K, Shinohara K, Aoki J, Nanto S, Kario K. Renal denervation: basic and clinical evidence. Hypertens Res. 2022;45:198–209.

    Article  PubMed  Google Scholar 

  44. Zheng H, Patel KP. Integration of renal sensory afferents at the level of the paraventricular nucleus dictating sympathetic outflow. Auton Neurosci. 2017;204:57–64.

    Article  PubMed  Google Scholar 

  45. Zhang K, Li YF, Patel KP. Blunted nitric oxide-mediated inhibition of renal nerve discharge within PVN of rats with heart failure. Am J Physiol Heart Circ Physiol. 2001;281:H995–1004.

    Article  CAS  PubMed  Google Scholar 

  46. Zheng H, Katsurada K, Nandi S, Li Y, Patel KP. A critical role for the paraventricular nucleus of the hypothalamus in the regulation of the volume reflex in normal and various cardiovascular disease states. Curr Hypertens Rep. 2022;24:235–46.

    Article  CAS  PubMed  Google Scholar 

  47. Zheng H, Li YF, Wang W, Patel KP. Enhanced angiotensin-mediated excitation of renal sympathetic nerve activity within the paraventricular nucleus of anesthetized rats with heart failure. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1364–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang K, Li YF, Patel KP. Reduced endogenous GABA-mediated inhibition in the PVN on renal nerve discharge in rats with heart failure. Am J Physiol Regul Integr Comp Physiol. 2002;282:R1006–15.

    Article  CAS  PubMed  Google Scholar 

  49. Xu B, Zheng H, Patel KP. Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure. Am J Physiol Heart Circ Physiol. 2012;302:H1700–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Balint B, Jaremek V, Thorburn V, Whitehead SN, Sposato LA. Left atrial microvascular endothelial dysfunction, myocardial inflammation and fibrosis after selective insular cortex ischemic stroke. Int J Cardiol. 2019;292:148–55.

    Article  PubMed  Google Scholar 

  51. Nagai M, Dote K, Kato M. Left atrial fibrosis after ischemic stroke: how the insular cortex-ganglionated plexi axis interacts? Int J Cardiol. 2019;294:16.

    Article  PubMed  Google Scholar 

  52. Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, et al. Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.

    Article  CAS  PubMed  Google Scholar 

  53. Suzuki K, Claggett B, Minamisawa M, Nochioka K, Mitchell GF, Anand IS, et al. Pulse pressure, prognosis, and influence of Sacubitril/Valsartan in heart failure with preserved ejection fraction. Hypertension. 2021;77:546–56.

    Article  CAS  PubMed  Google Scholar 

  54. Kario K, Okada K, Kato M, Nishizawa M, Yoshida T, Asano T, et al. 24-hour blood pressure-lowering effect of an SGLT-2 inhibitor in patients with diabetes and uncontrolled nocturnal hypertension: Results from the randomized, placebo-controlled SACRA Study. Circulation. 2018;139:2089–97.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl J Med. 2021;385:1451–61.

    Article  CAS  PubMed  Google Scholar 

  56. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. DELIVER trial committees and investigators. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl J Med. 2022;387:1089–98.

    Article  PubMed  Google Scholar 

  57. Kario K, Williams B. Nocturnal hypertension and heart failure: Mechanisms, evidence, and new treatments. Hypertension. 2021;78:564–77.

    Article  CAS  PubMed  Google Scholar 

  58. Kario K, Williams B. Angiotensin receptor–neprilysin inhibitors for hypertension-hemodynamic effects and relevance to hypertensive heart disease. Hypertens Res. 2022;45:1097–110.

    Article  CAS  PubMed  Google Scholar 

  59. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373:1275–81.

    Article  PubMed  Google Scholar 

  60. Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Böhm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376:1903–9.

    Article  PubMed  Google Scholar 

  61. Ahmed M, Nudy M, Bussa R, Hajduczok A, Naccarelli GV, Filippone EJ, et al. A systematic review, meta-analysis, and meta regression of the sham controlled renal denervation randomized controlled trials. Trends Cardiovasc Med. 2022 (In press).

  62. Donazzan L, Mahfoud F, Ewen S, Ukena C, Cremers B, Kirsch CM, et al. Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension. Clin Res Cardiol. 2016;105:364–71.

    Article  PubMed  Google Scholar 

  63. Brandt MC, Mahfoud F, Reda S, Schirmer SH, Erdmann E, Böhm M, et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol. 2012;59:901–9.

    Article  PubMed  Google Scholar 

  64. Mahfoud F, Urban D, Teller D, Linz D, Stawowy P, Hassel J-H, et al. Effect of renal denervation on left ventricular mass and function in patients with resistant hypertension: data from a multi-centre cardiovascular magnetic resonance imaging trial. Eur Heart J. 2014;35:2224–31.

    Article  PubMed  Google Scholar 

  65. Schirmer SH, Sayed MMYA, Reil J-C, Lavall D, Ukena C, Linz D, et al. Atrial remodeling following catheter-based renal denervation occurs in a blood pressure- and heart rate-independent manner. JACC Cardiovasc Inter. 2015;8:972–80.

    Article  Google Scholar 

  66. Patel HC, Rosen SD, Hayward C, Vassiliou V, Smith GC, Wage RR, et al. Renal denervation in heart failure with preserved ejection fraction (RDT-PEF): a randomized controlled trial. Eur J Heart Fail. 2016;18:703–12.

    Article  CAS  PubMed  Google Scholar 

  67. Kresoja KP, Rommel KP, Fengler K, von Roeder M, Besler C, Lücke C, et al. Renal sympathetic denervation in patients with heart failure with preserved ejection fraction. Circ Heart Fail. 2021;14:e007421.

    Article  CAS  PubMed  Google Scholar 

  68. Katsurada K, Nandi SS, Sharma NM, Patel KP. Enhanced expression and function of renal SGLT2 (Sodium-Glucose Cotransporter 2) in heart failure: Role of renal nerves. Circ Heart Fail. 2021;14:e008365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Patel KP, Xu B, Liu X, Sharma NM, Zheng H. Renal denervation improves exaggerated sympathoexcitation in rats with heart failure: A role for neuronal nitric oxide synthase in the paraventricular nucleus. Hypertension. 2016;68:175–84.

    Article  CAS  PubMed  Google Scholar 

  70. Persu A, Jin Y, Lengelé JP, Jacobs L, Renkin J, Staessen JA. Con: renal denervation for all resistant hypertensive patients: the Emperor’s new clothes. Nephrol Dial Transpl. 2014;29:1116–9.

    Article  Google Scholar 

  71. Kjeldsen SE, Narkiewicz K, Burnier M, Oparil S. The five RADIANCE-HTN and SPYRAL-HTN randomised studies suggest that the BP lowering effect of RDN corresponds to the effect of one antihypertensive drug. Blood Press. 2021;30:327–31.

    Article  PubMed  Google Scholar 

  72. Fengler K, Reimann P, Rommel KP, Kresoja KP, Blazek S, Unterhuber M, et al. Comparison of long-term outcomes for responders versus non-responders following renal denervation in resistant hypertension. J Am Heart Assoc. 2021;10:e022429.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Fontes MAP, Marzano LAS, Silva CC, Silva ACS. Renal sympathetic denervation for resistant hypertension: where do we stand after more than a decade. J Bras Nefrol. 2020;42:67–76.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, et al. 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. 2014;20:808–16.

    Article  PubMed  Google Scholar 

  75. Hadaya J, Ardell JL. Autonomic modulation for cardiovascular disease. Front Physiol. 2020;11:617459.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Olshansky B, Sabbah HN, Hauptman PJ, Colucci WS. Parasympathetic nervous system and heart failure: pathophysiology and potential implications for therapy. Circulation. 2008;118:863–71.

    Article  PubMed  Google Scholar 

  77. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, et al. 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. 2014;20:808–16.

    Article  PubMed  Google Scholar 

  78. Premchand RK, Sharma K, Mittal S, Monteiro R, Dixit S, Libbus I, et al. Extended follow-up of patients with heart failure receiving autonomic regulation therapy in the ANTHEM‐HF study. J Card Fail. 2016;22:639–42.

    Article  PubMed  Google Scholar 

  79. Clarke BM, Upton AR, Griffin H, Fitzpatrick D, DeNardis M. Chronic stimulation of the left vagus nerve in epilepsy: balance effects. Can J Neurol Sci. 1997;24:230–4.

    Article  CAS  PubMed  Google Scholar 

  80. Ventureyra ECG. Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept. Child’s Nerv Syst. 2000;16:101–2.

    Article  CAS  Google Scholar 

  81. Lim SH. Use of acupunture in the treatment of epilepsy (abstract). Second Congress of Asian Oceanian Epilepsy Organization, Taipei, Taiwan, November 1998, p 142.

  82. Shen EY. The concept and mechanisms of acupuncture in seizure control (abstract). 2nd Congress of Asian Oceanian Epilepsy Organization, Taipei, Taiwan, November 1998, p 142.

  83. Fallgatter AJ, Neuhauser B, Herrmann MJ, Ehlis AC, Wagener A, Scheuerpflug P, et al. Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J Neural Transm (Vienna). 2003;110:1437–43.

    Article  CAS  PubMed  Google Scholar 

  84. Deuchars SA, Lall VK, Clancy J, Mahadi M, Murray A, Peers L, et al. Mechanisms underpinning sympathetic nervous activity and its modulation using transcutaneous vagus nerve stimulation. Exp Physiol. 2018;103:326–31.

    Article  PubMed  Google Scholar 

  85. Elkholey K, Niewiadomska M, Morris L, Whyte S, Houser J, Humphrey MB, et al. Transcutaneous vagus nerve stimulation ameliorates the phenotype of heart failure with preserved ejection fraction through its anti-inflammatory effects. Circ Heart Fail. 2022;15:e009288.

    Article  CAS  PubMed  Google Scholar 

  86. Clancy JA, Mary DA, Witte KK, Greenwood JP, Deuchars SA, Deuchars J. Non-invasive vagus nerve stimulation in healthy humans reduces sympathetic nerve activity. Brain Stimul. 2014;7:871–7.

    Article  PubMed  Google Scholar 

  87. Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, et al. Low-level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. 2015;65:867–75.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Stavrakis S, Stoner JA, Humphrey MB, Morris L, Filiberti A, Reynolds JC, et al. TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): a randomized clinical trial. JACC Clin Electrophysiol. 2020;6:282–91.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Yu L, Scherlag BJ, Li S, Sheng X, Lu Z, Nakagawa H, et al. Low-level vagosympathetic nerve stimulation inhibits atrial fibrillation inducibility: direct evidence by neural recordings from intrinsic cardiac ganglia. J Cardiovasc Electrophysiol. 2011;22:455–63.

    Article  PubMed  Google Scholar 

  90. Zhou L, Filiberti A, Humphrey MB, Fleming CD, Scherlag BJ, Po SS, et al. Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction. Exp Physiol. 2019;104:28–38.

    Article  CAS  PubMed  Google Scholar 

  91. Tran N, Asad Z, Elkholey K, Scherlag BJ, Po SS, Stavrakis S. Autonomic neuromodulation acutely ameliorates left ventricular strain in humans. J Cardiovasc Transl Res. 2019;12:221–30.

    Article  PubMed  Google Scholar 

  92. Stavrakis S, Elkholey K, Morris L, Niewiadomska M, Asad ZUA, Humphrey MB. Neuromodulation of inflammation to treat heart failure with preserved ejection fraction: a pilot randomized clinical trial. J Am Heart Assoc. 2022;11:e023582.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Nagai M, Dote K, Kato M, Sasaki S, Oda N, Förster CY. Case report: SGLT2i, transcutaneous vagus nerve stimulation, and their effects on intrarenal venous flow pattern in HFpEF. Front Neurosci. 2022;16:999831.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Yuan H, Silberstein SD. Vagus nerve and vagus nerve stimulation, a comprehensive review: Part II. Headache. 2016;56:259–66.

    Article  PubMed  Google Scholar 

  95. Kraus T, Hösl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J Neural Transm (Vienna). 2007;114:1485–93.

    Article  CAS  PubMed  Google Scholar 

  96. Kraus T, Kiess O, Hösl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. Brain Stimul. 2013;6:798–804.

    Article  PubMed  Google Scholar 

  97. Mogi M, Maruhashi T, Higashi Y, Masuda T, Nagata D, Nagai M, et al. Update on hypertension research in 2021. Hypertens Res. 2022;45:1276–97.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the grant DFG_FO 315/5-1 from Deutsche Forschungsgemeinschaft to CYF.

Author information

Authors and Affiliations

  1. Department of Cardiology, Hiroshima City Asa Hospital, Hiroshima, Japan

    Michiaki Nagai & Keigo Dote

  2. University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg, Germany

    Carola Yvette Förster

Authors
  1. Michiaki Nagai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Keigo Dote
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carola Yvette Förster
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michiaki Nagai.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The original online version of this article was revised: In this article the affiliation details for Author CYF were incorrectly given as ‘Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg, Germany’ but should have been ‘University Hospital Würzburg, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, Würzburg, Germany’. In the Acknowledgements section of this article the grant number for CYF was incorrectly given as ‘FO 315-5-1’ and should have been ‘FO 315/5-1’.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nagai, M., Dote, K. & Förster, C.Y. Denervation or stimulation? Role of sympatho-vagal imbalance in HFpEF with hypertension. Hypertens Res 46, 1727–1737 (2023). https://doi.org/10.1038/s41440-023-01272-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-023-01272-4

Keywords

This article is cited by

Search

Advanced search

Quick links