Baroreceptors are embedded in the walls of the major arteries, veins, and the heart and are activated in response to a rise in blood pressure (BP) and/or volume.¹ Arterial baroreceptors in the carotid sinus and aortic arch are activated mainly by an increase in BP, whereas cardiopulmonary baroreceptors in the thoracic veins and the heart are activated mainly by an increase in blood volume.¹ While activation of both arterial and cardiopulmonary baroreceptors inhibits efferent sympathetic signals to the renal, splanchnic, and skeletal-muscle vessels, resulting in vasodilation, only arterial baroreceptors activation results in activation of the parasympathetic pathway to the sino-atrial (SA) node, thus decreasing the heart rate.¹

Due to its key role in modulating the autonomic nervous system, baroreflex dysregulation can lead to autonomic dysfunction. An autonomic dysfunction characterized by sympathetic overactivation and parasympathetic withdrawal (due to the loss of the ability to exert sympathoinhibition) is a central pathomechanism in the development and progression of several cardiovascular (CV) diseases, such as resistant hypertension and heart failure (HF).^2-4 Therefore, device-based targeting of the baroreflex system was suggested as a novel pathway to address autonomic dysfunction and restore the physiological autonomic balance in certain CV disease.

Baroreflex activation therapy (BAT) is a device-based approach that consists of an implanted pulse generator (implanted in the pectoral region), external programming system, and leads placed adjacent to the carotid sinus to deliver electrical pulses to the carotid baroreceptors.⁵ Electrical stimulation of the carotid baroreceptors results in activation of the baroreflex system with subsequent increase in the parasympathetic outflow and inhibition of the sympathetic activity.⁵

Applications of BAT

Resistant Hypertension

The first application of BAT was in patients with resistant hypertension. The prospective, nonrandomized, feasibility DEBuT-HT (Device Based Therapy in Hypertension trial) study showed that, in patients with resistant hypertension (systolic BP [SBP] ≥160 mmHg or diastolic ≥90 mmHg despite ≥3 antihypertensive medications), BAT therapy using the Rheos® Baroreflex Hypertension Therapy™ (CVRx, Inc.) reduced mean BP by 21/12 mmHg after 3 months of therapy with a favorable safety profile.⁶ In the subsequent Rheos® Pivotal trial, patients with resistant hypertension were randomized to either immediate (1 month after implantation) or deferred (after 6 months of implantation) activation of BAT therapy, and five co-primary endpoints (acute SBP response at 6 months, sustained efficacy at 12 months, procedure safety, BAT safety, and device safety).⁷ While the endpoints of sustained efficacy, BAT safety, and device safety were met, the endpoints of acute response and procedural safety were not met.⁷

To address the shortcomings of the Rheos® System, a second generation, less invasive system for delivering BAT, the Barostim neo™ system (CVRx, Inc.), was developed and tested in a single-arm, open-label study of 30 patients with resistant hypertension.⁸ In this study, BAT with the Barostim neo™ system resulted in a decrease in BP by 26/12 mm Hg at 6 months (p<0.001 for both) with three minor procedure-related complications within 30 days of implant, all of which resolved.⁸ These results provided a reassuring safety profile for this generation. Several subsequent observational studies showed consistent results;⁹ however, given the paucity of large-scale-trial-driven evidence to support the use of BAT in resistant hypertension, the contemporary European and American guidelines do not recommend the routine use of BAT in managing resistant hypertension.^10,11

Heart Failure

In a proof-of-concept study, 11 patients with HF, New York Heart Association (NYHA) class III, and left ventricular ejection fraction (LVEF) of <40% who were ineligible for cardiac resynchronization therapy (CRT) received BAT with Barostim™ neo.¹² At 6 months, BAT resulted in a significant improvement in baroreflex sensitivity, LVEF, NYHA class, Minnesota Living with HF (MLHFQ) score, and 6-minute walk distance (P <0.05 for all) with only one complication during the study period (perioperative anemia).¹² This study was followed by the phase II HOPE4HF (Barostim® Hope of HF Study) trial, which randomized 146 patients with LVEF ≤35% and NYHA functional class III to either medical therapy alone or BAT and medical therapy. Compared to medical therapy alone, BAT with medical therapy resulted in a greater improvement in NYHA functional class, MLHFQ score, and 6-minute walk distance (P <0.05 for all). This study also demonstrated a great safety profile with a freedom from major adverse neurological and CV events of 97.2%.¹³ Subsequently, the randomized, parallel-group pivotal BeAT-HF (Baroreflex Activation Therapy for HF) trial included 408 patients with LVEF ≤35% and NYHA functional class II-III in its expedited initial phase (phase I). At 6 months, BAT resulted in a significant improvement in MLHFQ score and 6-minute walk distance and reduction in the levels of NT-proB-type natriuretic peptide (P <0.05 for all) with a major adverse neurological or CV system or procedure-related event rate of 97%.⁵ Based on these results, the Food and Drug Administration approved the Barostim™ neo system in 2019 in patients with HF and LVEF ≤35%, current NYHA functional class III or recent NYHA functional class III, and NT-proBNP <1,600 pg/mL who are ineligible for CRT. The extended phase (phase II) of BeAT-HF aims to assess the rate of CV mortality and HF morbidity as an endpoint and is still ongoing.

Given that the currently available evidence is insufficient to derive conclusion regarding reduction in mortality of hospitalization for HF with BAT, the contemporary European and American HF guidelines do not provide specific recommendations regarding the use of BAT in patients with HF.^14,15

Future Directions

BAT is an emerging device-based therapy for HF and resistant hypertension; more data from large-scale trials are still needed to establish the efficacy of this therapy on hard CV outcomes. In addition, development of tools and markers to identify patients with a more pronounced baroreflex dysfunction may help identify those who would benefit the most from this therapy.

References

1. Kaufmann H, Norcliffe-Kaufmann L, Palma J-A. Baroreflex dysfunction. N Engl J Med 2020;382:163-78.
2. Bhatt DL, Kristensen AMD, Pareek M, Olsen MH. Baroreflex activation therapy for resistant hypertension and heart failure. US Cardiol Rev 2019;13:83–7.
3. Ferguson DW, Abboud FM, Mark AL. Selective impairment of baroreflex-mediated vasoconstrictor responses in patients with ventricular dysfunction. Circulation 1984;69:451-60.
4. Gassler JP, Bisognano JD. Baroreflex activation therapy in hypertension. J Hum Hypertens 2014;28:469-74.
5. Fudim M, Abraham WT, von Bardeleben RS, et al. Device therapy in chronic heart failure: JACC State-of-the-Art Review. J Am Coll Cardiol 2021;78:931-56.
6. Scheffers IJM, 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;56:1254-58.
7. 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.
8. 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;6:270-76.
9. 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.
10. 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 2018;71:e127-e248.
11. Williams B, Mancia G, Spiering W, 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 (ESC) and the European Society of Hypertension (ESH). Eur Heart J 2018;39:3021-3104.
12. 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.
13. 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;3:487-496.
14. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2021;42:3599-3726.
15. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;145:e895-e1032.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, Acute Heart Failure, Hypertension

Keywords: Baroreflex, Pressoreceptors, Carotid Sinus, Blood Pressure, Heart Rate, Aorta, Thoracic, Vasodilation, Hypertension, Heart Failure, Muscles, Electric Stimulation, Blood Volume, Antihypertensive Agents, Prospective Studies, Feasibility Studies, Equipment Safety, Stroke Volume, Cardiac Resynchronization Therapy, Ventricular Function, Left, United States Food and Drug Administration, Hospitalization, Morbidity, Anemia

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