Skip to main content

Advertisement

SpringerLink
Log in

Baroreflex Activation: from Mechanisms to Therapy for Cardiovascular Disease

  • Device-Based Approaches for Hypertension (M Schlaich, Section Editor)
  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Recent technical advances have led to the development of a medical device that can reliably activate the carotid baroreflex with an acceptable degree of safety. Because activation of the sympathetic nervous system plays an important role in the pathogenesis of hypertension and heart failure, the unique ability of this device to chronically suppress central sympathetic outflow in a controlled manner suggests potential value in the treatment of these conditions. This notion is supported by both clinical and experimental animal studies, and the major aim of this article is to elucidate the physiological mechanisms that account for the favorable effects of baroreflex activation therapy in patients with resistant hypertension and heart failure. Illumination of the neurohormonal, renal, and cardiac actions of baroreflex activation is likely to provide the means for better identification of those patients that are most likely to respond favorably to this device-based therapy.

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

Similar content being viewed by others

References

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

  1. Lohmeier TE, Iliescu R. Chronic lowering of blood pressure by carotid baroreflex activation. Mechanisms and potential for hypertension therapy. Hypertension. 2011;57:880–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment. Hypertension. 2008;51:1403–19.

    CAS  PubMed  Google Scholar 

  3. Scheffers IJM, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension. J Am Coll Cardiol. 2010;56:1254–8.

    PubMed  Google Scholar 

  4. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled Rheos Pivotal trial. J Am Coll Cardiol. 2011;58:765–73. The first randomized controlled trial investigating safety and efficacy of baroreflex activation therapy as treatment for resistant hypertension.

    PubMed  Google Scholar 

  5. Bakris GL, Nadim MK, Haller H, et al. Baroreflex activation therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal trial. J Am Soc Hypertens. 2012;6:152–8.

    PubMed  Google Scholar 

  6. Hoppe UC, Brandt M-C, Wachter R, et al. Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial. J Am Soc Hypertens. 2012;6:270–6.

    PubMed  Google Scholar 

  7. Gasser JP, Bisognano JD. Baroreflex activation therapy in hypertension. J Hum Hypertens. 2014;1–6.

  8. Cohn JN, Levine TB, Olivari MT. Plasma norepinephrine as a guide to prognosis in patients with chronic heart failure. N Engl J Med. 1984;311:819–23.

    CAS  PubMed  Google Scholar 

  9. Tordoir JHM, Scheffers I, Schmidli J, Savolainen H, Liebeskind U, Hansky B, et al. An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for treatment of resistant hypertension. Eur J Vasc Endovasc Surg. 2007;33:414–21.

    CAS  PubMed  Google Scholar 

  10. Lohmeier TE, Irwin ED, Rossing MA, et al. Prolonged activation of the baroreflex produces sustained hypotension. Hypertension. 2004;43:306–11.

    CAS  PubMed  Google Scholar 

  11. Lohmeier TE, Dwyer TM, Irwin ED, et al. Prolonged activation of the baroreflex abolishes obesity-induced hypertension. Hypertension. 2007;49:1307–14.

    CAS  PubMed  Google Scholar 

  12. Schmidli J, Savolainen H, Eckstein F, et al. Acute device-based blood pressure reduction: electrical activation of the carotid baroreflex in patients undergoing elective carotid surgery. Vascular. 2007;15:63–9.

    PubMed  Google Scholar 

  13. Lohmeier TE, Drummond HA. The baroreflex in the pathogenesis of hypertension. In: Lip GYH, Hall JE, editors. Comprehensive hypertension. New York: Elsevier; 2007. p. 265–79.

    Google Scholar 

  14. Malpas SC. Sympathetic nervous system activity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90:513–57.

    CAS  PubMed  Google Scholar 

  15. Heusser K, Tank J, Engeli S, et al. Carotid baroreceptor stimulation, sympathetic activity, baroreflex function, and blood pressure in hypertensive patients. Hypertension. 2010;55:619–26.

    CAS  PubMed  Google Scholar 

  16. Lohmeier TE, Iliescu R, Dwyer TM, et al. Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol. 2010;299:H402–9. Shows that chronic baroreflex activation has sustained effects to suppress central sympathetic outflow and lower arterial pressure without activating the renin-angiotensin system.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Lohmeier TE, Hildebrandt DA, Dwyer TM, et al. Prolonged activation of the baroreflex decreases arterial pressure even during chronic adrenergic blockade. Hypertension. 2009;53:833–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lohmeier TE, Iliescu R. Lowering of blood pressure by chronic suppression of central sympathetic outflow: insight from prolonged baroreflex activation. J Appl Physiol. 2012;113:1652–8.

    PubMed  PubMed Central  Google Scholar 

  19. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev. 1997;77:75–197.

    CAS  PubMed  Google Scholar 

  20. Ehmke H, Persson PB, Fischer S, et al. Resetting of pressure-dependent renin release by intrarenal α1-adrenoceptors in conscious dogs. Pflugers Arch. 1989;413:261–6.

    CAS  PubMed  Google Scholar 

  21. Yang HM, Lohmeier TE, Kivlighn SD, et al. Sustained increases in plasma epinephrine concentration do not modulate renin release. Am J Physiol. 1989;257:E57–64.

    CAS  PubMed  Google Scholar 

  22. Lohmeier TE, Iliescu R, Liu B, et al. Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension. 2012;59:331–8. Provides insight into the mechanisms that account for abolition of hypertension and suppression of renin secretion and GFR during chronic activation of the baroreflex in dogs with obesity-induced hypertension.

    CAS  PubMed  Google Scholar 

  23. Lohmeier TE, Dwyer TM, Hildebrandt DA, et al. Influence of prolonged baroreflex activation on arterial pressure in angiotensin hypertension. Hypertension. 2005;46:1194–200.

    CAS  PubMed  Google Scholar 

  24. Lohmeier TE, Liu B, Georgakopoulos D, et al. Cardiovascular responses to chronic baroreflex activation in aldosterone hypertension. Hypertension. 2013;62:A354.

    Google Scholar 

  25. Alnima T, de Leeuw PW, Tan ES, et al. Renal responses to long-term carotid baroreflex activation therapy in patients with drug-resistant hypertension. Hypertension. 2013;61:1334–9. This study reports an initial modest non-progressive decrease in eGFR in association with the antihypertensive response to 12 months of baroreflex activation therapy in patients with resistant hypertension. There were no changes in eGFR during baroreflex activation in patients in the lowest baseline eGFR category (<60 mL/min).

    CAS  PubMed  Google Scholar 

  26. Iliescu R, Irwin ED, Georgakopoulos D, Irwin ED, et al. Renal responses to chronic suppression of central sympathetic outflow. Hypertension. 2012;60:749–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular hyperfiltration. Am J Physiol Renal Physiol. 2004;286:F8–15.

    CAS  PubMed  Google Scholar 

  28. Hall JE, Brands MW, Henegar JR. Angiotensin II and long-term arterial pressure regulation: the overriding dominance of the kidney. J Am Soc Nephrol. 1999;10:S258–65.

    CAS  PubMed  Google Scholar 

  29. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685–93.

    CAS  PubMed  Google Scholar 

  30. Wustmann K, Kucera JP, Scheffers I, et al. Effects of chronic baroreceptor stimulation on the autonomic cardiovascular regulation in patients with drug-resistant arterial hypertension. Hypertension. 2009;54:530–6.

    CAS  PubMed  Google Scholar 

  31. Schwartz PJ, De Ferrari GM. Sympathetic-parasympathetic interaction in health and disease: abnormalities and relevance in heart failure. Heart Fail Rev. 2011;16:101–7.

    PubMed  Google Scholar 

  32. Hildreth CM. Prognostic indicators of cardiovascular risk in renal disease. Front Physiol. 2012;2:1–6.

    Google Scholar 

  33. Tsuji H, Venditti FJ, Manders ES, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994;90:878–83.

    CAS  PubMed  Google Scholar 

  34. Reed MJ, Robertson CE, Addison PS. Heart rate variability measurements and the prediction of ventricular arrhythmias. Quart J Med. 2005;98:87–95.

    CAS  Google Scholar 

  35. Beske S, Alvarez GE, Ballard TP, et al. Reduced cardiovagal gain in visceral obesity: implications for the metabolic syndrome. Am J Physiol Heart Circ Physiol. 2002;282:H630–5.

    CAS  PubMed  Google Scholar 

  36. Grassi G, Seravalle G, Dell’Oro R, et al. Adrenergic and reflex abnormalities in obesity-related hypertension. Hypertension. 2000;36:538–42.

    CAS  PubMed  Google Scholar 

  37. Pietrasik G, Goldenberg I, McNitt S, Moss AJ, Zareba W. Obesity as a risk factor for sustained ventricular tachyarrhythmias in MADIT II patients. J Cardiovasc Electrophysiol. 2007;18:87–95.

    Google Scholar 

  38. Wanahita N, Messerli FH, Bangalore S, Gami AS, Somers VK, Steinberg JS. Atrial fibrillation and obesity—results of meta-analysis. Am Heart J. 2008;155:310–5.

    PubMed  Google Scholar 

  39. Wang TJ, Parise H, Levy D, D’Agostino Sr RB, Wolf PA, Vasan RS, et al. Obesity and the risk of new-onset atrial fibrillation. J Am Med Assoc. 2004;292:2471–7.

    CAS  Google Scholar 

  40. Iliescu R, Tudorancea I, Irwin ED. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol. 2013;305:H1080–8. Based on continuous 24-hour recordings of spontaneous fluctuations in arterial pressure and heart rate, this study shows that chronic baroreflex activation restores impaired cardiac baroreflex sensitivity and heart rate variability in obesity hypertension.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of left ventricular dysfunction (SOLVD). Circulation. 1990;82:1724–9.

    CAS  PubMed  Google Scholar 

  42. The SOLVD. investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.

    Google Scholar 

  43. Cibis II. Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBUS II). Lancet. 1999;353:9–13.

    Google Scholar 

  44. Lechat P. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II trial. Circulation. 2001;103:1428–33.

    CAS  PubMed  Google Scholar 

  45. Sabbah HN, Ilsar I, Zaretsky A, et al. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev. 2011;16:171–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhang Y, Popovic ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail. 2009;2:692–9.

    CAS  PubMed  Google Scholar 

  47. Li M, Zheng C, Sato T, et al. Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats. Circulation. 2004;109:120–4.

    PubMed  Google Scholar 

  48. Zucker IH, Hackley JF, Cornish KG, et al. Chronic baroreceptor activation enhances survival in dogs with pacing-induced heart failure. Hypertension. 2007;50:904–10.

    CAS  PubMed  Google Scholar 

  49. Sabbah HN, Gupta RC, Imai M, et al. Chronic electrical stimulation of the carotid sinus baroreflex improves left ventricular function and promotes reversal of ventricular remodeling in dogs with advanced heart failure. Circ Heart Fail. 2011;4:65–70. Shows that chronic baroreflex activation improves left ventricular function and partially reverses left ventricular remodeling both globally and at the cellular and molecular levels, and increases the threshold for lethal ventricular arrhythmias in dogs with advanced heart failure.

    PubMed  Google Scholar 

  50. Bisognano JD, Kaufmann CL, Bach DS. Improved cardiac structure and function with chronic treatment using an inflatable device in resistant hypertension. J Am Col Cardiol. 2011;57:1787–8.

    Google Scholar 

  51. Gronda E, Seravalle G, Brambilla G. Chronic baroreflex activation reduces sympathetic tone and improves clinical outcomes in reduced-ejection fraction heart failure. Circulation. 2013;128, A16137.

    Google Scholar 

Download references

Acknowledgements

The authors’ studies cited in this report were funded by National Heart, Lung, and Blood Institute Grant HL-51971.

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA

    Radu Iliescu & Thomas E. Lohmeier

  2. Department of Physiology, University of Medicine and Pharmacy, “Gr. T. Popa,” Iasi, 16, University St., Iasi, Romania

    Radu Iliescu & Ionut Tudorancea

Authors
  1. Radu Iliescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ionut Tudorancea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas E. Lohmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas E. Lohmeier.

Ethics declarations

Conflict of Interest Radu Iliescu and Ionut Tudorancea declare that they have no conflict of interest.

Thomas E. Lohmeier has received consulting fees from CVRx, Inc., and research support from National Institutes of Health.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Device-Based Approaches for Hypertension

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iliescu, R., Tudorancea, I. & Lohmeier, T.E. Baroreflex Activation: from Mechanisms to Therapy for Cardiovascular Disease. Curr Hypertens Rep 16, 453 (2014). https://doi.org/10.1007/s11906-014-0453-9

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11906-014-0453-9

Keywords

Search

Navigation