Baroreflex Activation Therapy for Resistant Hypertension and Heart Failure

Login or register to view PDF.
Creative Commons Licence
 
Abstract

Hypertension and heart failure are important contributors to global morbidity and mortality. Despite therapeutic lifestyle and pharmacological measures, a significant proportion of people with hypertension do not reach treatment targets. Patients with resistant or poorly controlled hypertension are at significantly increased risk of cardiovascular events, including heart failure. Since dysfunction of the sympathetic nervous system appears to play a key role in the development and progression of both hypertension and heart failure, these patients may benefit from treatment modalities aimed at reducing sympathetic function. The purpose of this paper is to provide an overview of baroreflex activation therapy as a potential treatment strategy in patients with resistant hypertension or heart failure.

Disclosure
MP is on the advisory board for AstraZeneca; and has received speaker’s fees from AstraZeneca, Bayer, and Boehringer Ingelheim. MHO has received a parttime clinical research grant from the Novo Nordisk Foundation. DLB is on the advisory board for Cardax, Cereno Scientific, PhaseBio, Regado Biosciences; the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: Baim Institute for Clinical Research (PORTICO trial, funded by St Jude Medical), Cleveland Clinic (including the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology, Baim Institute for Clinical Research (RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Duke Clinical Research Institute (clinical trial steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications, Society of Cardiovascular Patient Care, WebMD (CME steering committees); Other: Clinical Cardiology, NCDR-ACTION Registry Steering Committee, VA CART Research and Publications Committee; Research funding: Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Site Co-Investigator: Biotronik, Boston Scientific, St Jude Medical, Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, Takeda. The other authors have no conflicts of interest to declare.
Correspondence
Deepak L Bhatt, Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School, 75 Francis St, Boston, MA 02115, US. E: dlbhattmd@post.harvard.edu
Received date
09 April 2019
Accepted date
18 June 2019
Citation
US Cardiology Review 2019;13(2):ePub: 26 September 2019.
DOI
https://doi.org/10.15420/usc.2019.13.2
Open access
This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Hypertension is an important contributor to global morbidity and mortality and is a major burden on healthcare systems.1,2 More than 20% of the world’s population has high blood pressure when defined by conventional criteria: systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg.3,4 Even with therapeutic lifestyle and pharmacological measures, blood pressure remains poorly controlled in a significant proportion of these people.5–10 The European Society of Cardiology/European Society of Hypertension (ESC/ESH) define treatment-resistant hypertension when office blood pressure cannot be reduced to <140/90 mmHg despite optimal doses of appropriate medications (usually three).11 The American College of Cardiology/American Heart Association (ACC/AHA) define resistant hypertension as an office blood pressure ≥130/80 mmHg in patients on ≥3 antihypertensive medications at optimal doses or <130/80 mmHg in patients on ≥4 agents.12,13 Formal diagnosis requires confirmation using out-of-hospital measurements and exclusion of both pseudo-resistant hypertension and secondary hypertension.11–13

Hypertension is significantly associated with subclinical and clinical cardiovascular disease, including left ventricular remodeling and overt heart failure.14–16 This risk is considerably greater among patients with resistant or poorly controlled hypertension, particularly if the condition is persistent.5,6,8,17–20 By extension, many patients with heart failure remain symptomatic and limited in their daily activities despite guideline-recommended drug and device therapy.21,22 Since dysfunction of the sympathetic nervous system appears to play a key role in the development and progression of hypertension and heart failure, treatment modalities aimed at reducing sympathetic function may be beneficial.23–25 Padmanabhan et al. recently published a review of one such intervention, renal denervation.26 Renal denervation may be associated with significant blood pressure reductions compared with sham control, particularly found in trials of second-generation renal denervation systems.27,28 By extension, the purpose of this paper is to provide an overview of baroreflex activation therapy (BAT) as a potential treatment strategy in patients with resistant hypertension or heart failure, respectively.

The Baroflex Activation Therapy System

Open in new tab

Baroflex Activation Therapy Pathway

Open in new tab

Role of the Sympathetic Nervous System in Hypertension and Heart Failure

The pathogenesis of essential hypertension is complex and multifactorial, but the sympathetic nervous system may be particularly and persistently overactive in patients with resistant hypertension, exerting direct effects on not only the heart and vasculature, but also the renin–angiotensin–aldosterone system, glomerular filtration and renal tubular sodium reabsorption.25,29,30 Baroreflex impairment appears to be a crucial component in the dysfunction of the sympathetic nervous system, probably through an abnormally reduced ability to exert sympathoinhibition.29,30

Imbalances in the autonomic nervous system may also result in impaired left ventricular function and clinical heart failure.25,31,32 The compensatory mechanisms that are recruited lead to more inappropriate and excessive activity of the sympathetic nervous system and consequently, adverse cardiac remodeling, heart rate elevation, and salt and water retention.24,25 Indeed, Cohn et al. found lower survival in patients with heart failure who had higher circulating norepinephrine concentrations.33 Baroreflex sensitivity is also independently associated with prognosis in this setting.34

The Concept of Baroreflex Activation Therapy

Carotid BAT consists of leads placed adjacent to the carotid sinus, an implantable pulse generator, and an external programming system (Figure 1).35 Electronic stimulation of the baroreceptors elicit the baroreflex, resulting in reduced sympathetic and increased vagal tone (Figure 2).36,37 Blood pressure reduction and improvements in cardiac structure and function ensue.38 The first experiments in humans were performed more than 60 years ago when Carlsten et al. observed that direct stimulation of the carotid sinus nerve resulted in an acute decline in blood pressure in patients undergoing surgery for neck cancer.39 In 1967, Braunwald et al. extended the possible uses of BAT as they found instantaneous relief of otherwise incapacitating angina pectoris using carotid stimulation.40 Although BAT received little or no attention for decades thereafter, primarily due to successful drug development, an increasing need for alternative treatment approaches for resistant hypertension and heart failure has prompted renewed research in this area.35,41–43

Baroreflex Activation Therapy in Resistant Hypertension

Feasibility studies of the first-generation Rheos® Baroreflex Hypertension Therapy System (CVRx) (Figure 3), such as the non-randomized Device Based Therapy in Hypertension Trial (DEBuT-HT) showed substantial and sustained reductions in both systolic and diastolic blood pressures.36,41,44,45

In the subsequent Rheos Pivotal Trial, patients with office systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥80 mmHg taken after ≥1 month of maximally tolerated therapy with ≥3 antihypertensive drugs underwent device implantation and underwent blinded randomization 2:1 to immediate (1 month after implantation; n=181) or deferred (7 months after implantation; n=84) activation.46 Although lead implantation was bilateral, 75% of patients only required unilateral activation. All participants were followed for an additional 6 months. The investigators tested five co-primary endpoints of which sustained efficacy, BAT safety and device safety were met. However, acute efficacy (≥10 mmHg systolic blood pressure reduction at 6 months with immediate versus deferred activation, 54% versus 46%; p=0.97) and procedural safety endpoints were not met. Blood pressure reductions were maintained beyond the duration of the trial.47,48

Due to these shortcomings, the second-generation, minimally invasive Barostim neo™ system (CVRx) was developed and examined in an open-label trial (Figure 3).35,36 The device was implanted in 30 patients with systolic blood pressure ≥140 mmHg despite taking ≥3 antihypertensive drugs and deemed compliant with their regimen. Only unilateral carotid sinus exposure was required. The primary efficacy endpoint was reduction in office systolic blood pressure compared with baseline. System- and procedure-related complications comprised the primary safety endpoint. At 6 months, average systolic and diastolic blood pressures had decreased by 26 mmHg and 12 mmHg, respectively (p<0.001 for both). Three complications occurred within 30 days after surgery, and beyond this perioperative period, one system-related complication was reported. Interestingly, six of 30 participants in the Barostim neo trial had undergone unsuccessful renal denervation but achieved blood pressure reductions with BAT that were comparable to those who had not undergone renal denervation.

Several observational studies have since examined the Barostim neo device and have consistently shown it to achieve reductions in blood pressure. For example, Halbach et al. included 17 patients in an open-label, single-arm study and found mean systolic and diastolic blood pressure reductions of 32 mmHg and 14 mmHg during on/off testing with unilateral BAT.49 Wallbach et al. demonstrated significant 6-month reductions in 24-hour ambulatory blood pressure (mean systolic blood and diastolic pressure reductions, 8 mmHg and 5 mmHg; p<0.01 for both) in 44 patients with resistant hypertension.50 The specific matter regarding patients with prior renal denervation was assessed by the same group of investigators who reported significant reductions in blood pressure (mean office systolic blood pressure reduction, 19 mmHg; p<0.01) and albuminuria (median reduction, 29%; p=0.02) in 28 people treated with BAT.51 The number of antihypertensive drugs remained unchanged over the course of the study.

A recent systematic review and meta-analysis of the efficacy and safety of BAT for resistant hypertension found that although device therapy significantly lowered blood pressure, the evidence was limited by a high risk of bias, small sample size, and the fact that only one randomized controlled trial (the Rheos Pivotal Trial) was included in the analysis.52 Indeed, regression towards the mean and placebo effect may, at least in part, have been responsible for the results obtained from observational studies.

Baroreflex Activation Therapy in Heart Failure

Gronda et al. implanted the Barostim neo system in 11 patients who had New York Heart Association (NYHA) class III heart failure, a left ventricular ejection fraction (LVEF) ≤40%, and no indication for cardiac resynchronization therapy.53 The patients’ 6-minute walking distance increased significantly at 6 months, with an average of approximately 50 m (p=0.05). Favorable effects were also seen for LVEF, NYHA class, and quality of life (p<0.05 for all) and were maintained beyond the initial 6-month study period.54,55 However, no significant changes were observed for systolic or diastolic blood pressure.

The Rheos and Barostim Neo Devices

Open in new tab

The larger, controlled, open-label Barostim Hope for Heart Failure (HOPE4HF) study randomized patients with NYHA class III heart failure and LVEF ≤35% to receive either BAT (Barostim neo) plus guideline-directed medical therapy (n=76) or medical therapy alone (n=70) for 6 months.42 The primary safety endpoint, system- and procedure-related major adverse neurological and cardiovascular events, occurred in 2.8% of patients in the BAT group. Changes in NYHA class, quality of life, and 6-minute walk distance comprised the co-primary efficacy endpoints, all of which were significantly improved with BAT (p<0.05) and results were maintained at 12 months.56 The effects of BAT were more prominent in patients without a cardiac resynchronization therapy device, but did not differ between those with or without coronary artery disease.57,58 BAT has also been found to be cost-effective compared with optimal medical treatment in patients with NYHA class III heart failure who are not eligible for cardiac resynchronization therapy.59

Safety Concerns

BAT implantation is generally well tolerated.35,41,42 It is associated with complications similar to those observed with cardiac pacemaker implantations, including device pocket hematoma, pneumothorax, and pain. Complication rates also appear to mimic those seen with permanent pacemaker implantation. In a cohort of 42 patients, Wallbach et al. reported that almost all experienced mild adverse events in the first 6 months after implantation and activation of the Barostim neo apparatus, but most could be resolved by optimization of device parameters, that is, amplitude, impulse width, and stimulation frequency.60 One patient experienced a stroke with recovery and another a contralateral carotid artery stenosis during the perioperative period. One died during the observational period of 12 months. In a separate study, Heusser et al. noted that stimulation intensities had to be lowered in 12 of 18 patients, resulting in lower efficacy.61 As with any other invasive therapy, safety is expected to improve over time. Finally, the pulse generator battery needs to be replaced approximately every 3 years.

Guidelines

Due to the paucity of evidence, contemporary ESC/ESH guidelines do not routinely recommend BAT for the treatment of hypertension (class of recommendation III, level of evidence B).11 The ACC/AHA guidelines also consider device therapy investigational and as such, provide no recommendation.12,13

Ongoing Studies

The double-blind, randomized trial, the Effect of Baroreflex Activation Therapy on Blood Pressure and Sympathetic Function in Patients with Resistant Hypertension (The Nordic BAT Study), aims to recruit about 100 participants and examine whether use of the Barostim neo device reduces 24-hour systolic ambulatory blood pressure compared with pharmacotherapy alone (NCT02572024).62

Additionally, the open-label Baroreflex Activation Therapy for Heart Failure (BeAT-HF) trial (NCT02627196) will randomize patients with NYHA class II or III heart failure and LVEF ≤35% to either BAT with Barostim neo or guideline-directed medical therapy alone and assess the primary endpoint of cardiovascular mortality or heart failure morbidity. A total of 938 participants have been recruited and will be followed until 2021.

Finally, the Economic Evaluation of Baroreceptor STIMulation for the Treatment of Resistant HyperTensioN (ESTIM-rHTN; NCT02364310) is examining the cost-effectiveness of using Barostim neo compared with standard care in patients with resistant hypertension.

Investigations of a closely related, even less invasive, concept are also ongoing.63 The endovascular baroreceptor amplification device (carotid bulb expansion device), MobiusHD™ (Vascular Dynamics) was evaluated in the Controlling and Lowering Blood Pressure With the MOBIUSHD (CALM-FIM_EUR) study, including 30 patients with office systolic blood pressure ≥160 mmHg despite ≥3 antihypertensive drugs.64 Mean office blood pressure was reduced by 24/12 mmHg at 6 months (p<0.001 for both systolic and diastolic blood pressure), with a total of five safety events. The US arm of the study, Controlling and Lowering Blood Pressure with the MOBIUSHD™ (CALM-FIM_US) (NCT01831895), is currently ongoing. The related Controlling and Lowering Blood Pressure with the MobiusHD™ (CALM-2) study (NCT03179800) aims to examine the safety and efficacy of the MobiusHD device in a prospective, randomized, double-blind, sham-controlled fashion.

Conclusion

BAT is a potential treatment modality for patients with resistant hypertension and heart failure. However, long-term follow-up from larger randomized, sham-controlled, blinded studies is needed to properly assess its efficacy and safety.

References
  1. Olsen MH, Angell SY, Asma S, et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension. Lancet 2016;388:2665–2712.
    Crossref | PubMed
  2. GBD 2017 Risk Factor Collaborators. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018;392:1923–94.
    Crossref | PubMed
  3. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based measurement studies with 19.1 million participants. Lancet 2017;389:37–55.
    Crossref | PubMed
  4. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics – 2018 Update: A Report from the American Heart Association. Circulation 2018;137:e67–e492.
    Crossref | PubMed
  5. Daugherty SL, Powers JD, Magid DJ, et al. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation 2012;125:1635–42.
    Crossref | PubMed
  6. Kumbhani DJ, Steg PG, Cannon CP, et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J 2013;34:1204–14.
    Crossref | PubMed
  7. Sim JJ, Bhandari SK, Shi J, et al. Characteristics of resistant hypertension in a large, ethnically diverse hypertension population of an integrated health system. Mayo Clin Proc 2013;88:1099–1107.
    Crossref | PubMed
  8. Hung CY, Wang KY, Wu TJ, et al. Resistant hypertension, patient characteristics, and risk of stroke. PLoS One 2014;9:e104362.
    Crossref | PubMed
  9. Sinnott SJ, Smeeth L, Williamson E, et al. Trends for prevalence and incidence of resistant hypertension: population based cohort study in the UK 1995–2015. BMJ 2017;358:j3984.
    Crossref | PubMed
  10. Carey RM, Sakhuja S, Calhoun DA, et al. Prevalence of apparent treatment-resistant hypertension in the United States. Hypertension 2019;73:424–31.
    Crossref | PubMed
  11. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–104.
    Crossref | PubMed
  12. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;138:e426–83.
    Crossref | PubMed
  13. Carey RM, Calhoun DA, Bakris GL, et al. Resistant hypertension: detection, evaluation, and management: a scientific statement from the American Heart Association. Hypertension 2018;72:e53–e90.
    Crossref | PubMed
  14. Cuspidi C, Mancia G, Ambrosioni E, et al. Left ventricular and carotid structure in untreated, uncomplicated essential hypertension: results from the Assessment Prognostic Risk Observational Survey (APROS). J Hum Hypertens 2004;18:891–6.
    Crossref | PubMed
  15. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903–13.
    Crossref | PubMed
  16. Forouzanfar MH, Liu P, Roth GA, et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115mmHg, 1990–2015. JAMA 2017;317:165–82.
  17. Iyer AS, Ahmed MI, Filippatos GS, et al. Uncontrolled hypertension and increased risk for incident heart failure in older adults with hypertension: findings from a propensity-matched prospective population study. J Am Soc Hypertens 2010;4:22–31.
    Crossref | PubMed
  18. Muntner P, Davis BR, Cushman WC, et al. Treatment-resistant hypertension and the incidence of cardiovascular disease and end-stage renal disease: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertension 2014;64:1012–21.
    Crossref | PubMed
  19. Irvin MR, Booth JN 3rd, Shimbo D, et al. Apparent treatment-resistant hypertension and risk for stroke, coronary heart disease, and all-cause mortality. J Am Soc Hypertens 2014;8:405–13.
    Crossref | PubMed
  20. Tsioufis C, Kasiakogias A, Kordalis A, et al. Dynamic resistant hypertension patterns as predictors of cardiovascular morbidity: a 4-year prospective study. J Hypertens 2014;32:415–22.
    Crossref | PubMed
  21. Ponikowski P, Voors AA, Anker SD, et al. 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 2016;37:2129–200.
    Crossref | PubMed
  22. Yancy CW, Jessup M, Bozkurt B, et al. 2017 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. J Am Coll Cardiol 2017;70:776–803.
    Crossref | PubMed
  23. Seravalle G, Mancia G, Grassi G. Role of the sympathetic nervous system in hypertension and hypertension-related cardiovascular disease. High Blood Press Cardiovasc Prev 2014;21:89–105.
    Crossref | PubMed
  24. Grassi G, Seravalle G, Mancia G. Sympathetic activation in cardiovascular disease: evidence, clinical impact and therapeutic implications. Eur J Clin Invest 2015;45:1367–75.
    Crossref | PubMed
  25. Goldsmith SR, Bart BA, Pin AIL. Neurohormonal imbalance: a neglected problem and potential therapeutic target in acute heart failure. Curr Probl Cardiol 2018;43:294–304.
    Crossref | PubMed
  26. Padmanabhan D, Isath A, Gersh B. Renal denervation: Paradise lost? Paradise regained? US Cardiology Review 2018;12:78–86.
    Crossref
  27. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393–1401.
    Crossref | PubMed
  28. Sardar P, Bhatt DL, Kirtane AJ, et al. Sham-controlled randomized trials of catheter-based renal denervation in patients with hypertension. J Am Coll Cardiol 2019;73:1633–42.
    Crossref | PubMed
  29. Grassi G, Seravalle G, Brambilla G, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol 2014;177:1020–5.
    Crossref | PubMed
  30. Seravalle G, Lonati L, Buzzi S, et al. Sympathetic nerve traffic and baroreflex function in optimal, normal, and high-normal blood pressure states. J Hypertens 2015;33:1411–7.
    Crossref | PubMed
  31. Grassi G, Seravalle G, Cattaneo BM, et al. Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure. Circulation 1995;92:3206–11.
    Crossref | PubMed
  32. Grassi G, Seravalle G, Quarti-Trevano F, et al. Sympathetic and baroreflex cardiovascular control in hypertension-related left ventricular dysfunction. Hypertension 2009;53:205–9.
    Crossref | PubMed
  33. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819–23.
    Crossref | PubMed
  34. Osterziel KJ, Hanlein D, Willenbrock R, et al. Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure. Br Heart J 1995;73:517–22.
    Crossref | PubMed
  35. Hoppe UC, Brandt MC, 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.
    Crossref | PubMed
  36. Gassler JP, Bisognano JD. Baroreflex activation therapy in hypertension. J Hum Hypertens 2014;28:469–74.
    Crossref | PubMed
  37. Victor RG. Carotid baroreflex activation therapy for resistant hypertension. Nat Rev Cardiol 2015;12:451–63.
    Crossref | PubMed
  38. Gronda E, Francis D, Zannad F, et al. Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction. J Cardiovasc Med (Hagerstown) 2017;18:641–9.
    Crossref | PubMed
  39. Carlsten A, Folkow B, Grimby G, et al. Cardiovascular effects of direct stimulation of the carotid sinus nerve in man. Acta Physiol Scand 1958;44:138–45.
    Crossref | PubMed
  40. Braunwald E, Epstein SE, Glick G, et al. Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves. N Engl J Med 1967;277:1278–83.
    Crossref | PubMed
  41. Scheffers IJ, Kroon AA, Schmidli J, et al. Novel baroreflex activation therapy in resistant hypertension: results of a European multi-center feasibility study. J Am Coll Cardiol 2010;56:1254–8.
    Crossref | PubMed
  42. Abraham WT, Zile MR, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction. JACC Heart Fail 2015;3:487–96.
    Crossref | PubMed
  43. Lohmeier TE, Hall JE. Device-based neuromodulation for resistant hypertension therapy. Circ Res 2019;124:1071–93.
    Crossref | PubMed
  44. Illig KA, Levy M, Sanchez L, et al. An implantable carotid sinus stimulator for drug-resistant hypertension: surgical technique and short-term outcome from the multicenter phase II Rheos feasibility trial. J Vasc Surg 2006;44:121–38.
    Crossref | PubMed
  45. Tordoir JH, Scheffers I, Schmidli J, et al. An implantable carotid sinus baroreflex activating system: surgical technique and short-term outcome from a multi-center feasibility trial for the treatment of resistant hypertension. Eur J Vasc Endovasc Surg 2007;33:414–21.
    Crossref | PubMed
  46. 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.
    Crossref | PubMed
  47. 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.
    Crossref | PubMed
  48. de Leeuw PW, Bisognano JD, Bakris GL, et al. Sustained reduction of blood pressure with baroreceptor activation therapy: results of the 6-year open follow-up. Hypertension 2017;69:836–43.
    Crossref | PubMed
  49. Halbach M, Hickethier T, Madershahian N, et al. Acute on/off effects and chronic blood pressure reduction after long-term baroreflex activation therapy in resistant hypertension. J Hypertens 2015;33:1697–703.
    Crossref | PubMed
  50. Wallbach M, Lehnig LY, Schroer C, et al. Effects of baroreflex activation therapy on ambulatory blood pressure in patients with resistant hypertension. Hypertension 2016;67:701–9.
    Crossref | PubMed
  51. Wallbach M, Halbach M, Reuter H, et al. Baroreflex activation therapy in patients with prior renal denervation. J Hypertens 2016;34:1630–8.
    Crossref | PubMed
  52. Chunbin W, Fu S, Jing H. Efficacy and safety of baroreflex activation therapy for treatment of resistant hypertension: a systematic review and meta-analysis. Clin Exp Hypertens 2018;40:501–8.
    Crossref | PubMed
  53. Gronda E, Seravalle G, Brambilla G, et al. Chronic baroreflex activation effects on sympathetic nerve traffic, baroreflex function, and cardiac haemodynamics in heart failure: a proof-of-concept study. Eur J Heart Fail 2014;16:977–83.
    Crossref | PubMed
  54. Gronda E, Seravalle G, Trevano FQ, et al. Long-term chronic baroreflex activation: persistent efficacy in patients with heart failure and reduced ejection fraction. J Hypertens 2015;33:1704–8.
    Crossref | PubMed
  55. Dell’Oro R, Gronda E, Seravalle G, et al. Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report. J Hypertens 2017;35:2532–6.
    Crossref | PubMed
  56. Weaver FA, Abraham WT, Little WC, et al. Surgical experience and long-term results of baroreflex activation therapy for heart failure with reduced ejection fraction. Semin Thorac Cardiovasc Surg 2016;28:320–8.
    Crossref | PubMed
  57. Zile MR, Abraham WT, Weaver FA, et al. Baroreflex activation therapy for the treatment of heart failure with a reduced ejection fraction: safety and efficacy in patients with and without cardiac resynchronization therapy. Eur J Heart Fail 2015;17:1066–74.
    Crossref | PubMed
  58. Halbach M, Abraham WT, Butter C, et al. Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease. Int J Cardiol 2018;266:187–92.
    Crossref | PubMed
  59. Borisenko O, Muller-Ehmsen J, Lindenfeld J, et al. An early analysis of cost-utility of baroreflex activation therapy in advanced chronic heart failure in Germany. BMC Cardiovasc Disord 2018;18:163-018-0898-x.
    Crossref | PubMed
  60. Wallbach M, Bohning E, Lehnig LY, et al. Safety profile of baroreflex activation therapy (NEO) in patients with resistant hypertension. J Hypertens 2018;36:1762–9.
    Crossref | PubMed
  61. Heusser K, Tank J, Brinkmann J, et al. Acute response to unilateral unipolar electrical carotid sinus stimulation in patients with resistant arterial hypertension. Hypertension 2016;67:585–91.
    Crossref | PubMed
  62. Gordin D, Fadl Elmula FEM, Andersson B, et al. The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. Blood Press 2017;26:294–302.
    Crossref | PubMed
  63. van Kleef MEAM, Bates MC, Spiering W. Endovascular baroreflex amplification for resistant hypertension. Curr Hypertens Rep 2018;20:46.
    Crossref | PubMed
  64. Spiering W, Williams B, Van der Heyden J, et al. Endovascular baroreflex amplification for resistant hypertension: a safety and proof-of-principle clinical study. Lancet 2017;390:2655–61.
    Crossref | PubMed