Neuromodulation for Heart Failure: An EP Perspective

Heart failure with reduced ejection fraction (HFrEF) is a major source of human suffering and premature death. Fortunately, there have been major advances in the medical therapy for patients with HF in the past three decades. However, despite these advances, many patients with HFrEF continue to have NYHA Class III symptoms leading to frequent hospitalizations, causing massive healthcare expenditures. Electrophysiologists know this all too well. Patients with heart rhythm disorders commonly have HF. Efforts to tackle cases of refractory atrial fibrillation frequently result in encounters with HF patients who struggle with recurrent hospitalizations for dyspnea and volume overload. Electrophysiologists are often called to implant defibrillators, with or without cardiac resynchronization therapy (CRT), for primary prevention of sudden cardiac death in patients with advanced HF. Physicians and other healthcare providers who care for patients with implantable devices are also often involved in end-of-life decisions and device deactivation for patients with terminal HF.

For these reasons, it is understandable that there are several efforts underway to provide non-pharmacological therapies for patients with advanced HFrEF, and that electrophysiologists are interested. Currently, these alternative options include mechanical support with left ventricular assist devices (LVADs) and cardiac transplantation. These approaches can dramatically help individual patients, but come with significant morbidity and costs. Given the known autonomic dysfunction associated with heart failure, a logical category of therapies that is being pursued for patients with HF involves neuromodulation. Examples of such neuromodulation therapies are vagal nerve stimulation (VNS), spinal cord stimulation (SCS), renal artery denervation (RDN), and baroreceptor stimulation (BRS). Unfortunately, most of these therapies have not demonstrated significant benefit. For example, VNS did not reduce the rate of death or HF events in patients with chronic HF in the INOVATE-HF trial.¹ In addition, VNS as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on cardiac remodeling and functional capacity in patients with symptomatic HF.² Implantable devices that provide SCS also have not panned out. Spinal cord stimulation did not result in a reduction in LVESVi after 6 months of therapy compared to the control arm in 81 patients enrolled in the DEFEAT-HF study.³ Most of the trials investigating the benefits of RDN have been in patients with hypertension, with only a few small trials using RDN for HF, and these have also not shown promise. In one study of 20 patients, investigators found no significant relation between RDN and clinical status, exercise capacity, and hemodynamic parameters in optimally treated patients with HF and a systolic blood pressure over 110 mmHg.⁴

On the other hand, BAT has shown some positive results. The only FDA-approved device that delivers BAROSTIM activation therapy (BAT) is the BAROSTIM NEO System manufactured by CVRx, Inc. The device looks much like a standard pacing system and is typically implanted on the right side. The current version involves a unilateral surgical cutdown over the right carotid body by a vascular surgeon with placement of a stimulation electrode directly to the vessel. This electrode is on the end of a traditional appearing pacing lead that is tunneled over the clavicle and attached to the header of a stimulation generator placed in the subcutaneous prepectoral pocket, much like a pacemaker. Thus, the implanted system lives entirely outside of the vasculature. There is currently ongoing investigational work to develop a device that can be placed percutaneously without a surgical cut down. Early studies of BAT delivered by the BAROSTIM NEO System in patients with HF showed significant reductions in sympathetic activity with parallel increases in parasympathetic activity that persisted for at least six months. Promising results from the HOPE4HF phase 2 trial led to CE Mark approval in Europe and Breakthrough Device Designation by the FDA in 2015. Early in 2016, the first patients were enrolled in the BeAT-HF trial, the pivotal trial for the BAROSTIM NEO System. This trial enrolled patients with Class III symptoms and a LVEF ≤35%, but no indication for CRT. This trial found that BAT was associated with a significant reduction in NT-proBNP and improvements in functional capacity.⁵ The BAROSTIM NEO System received Premarket Approval (PMA) by the FDA in August 2019, and is now commercially available. The device is indicated for the improvement of symptoms of HF for patients who remain symptomatic despite treatment with guideline-directed medical therapy, are NYHA Class III or Class II (who had a recent history of Class III), have a LVEF ≤35%, a NT-proBNP <1600 pg/ml, and no indication for CRT.

So far, the development of devices to provide neuromodulation for patients with advanced systolic HF has yielded only one promising therapy. The delivery of BAT to the carotid body has been shown to improve the functional capacity of patients with advanced HFrEF. This is reminiscent of the early days of CRT 20 years ago. At that time, as with this early-stage therapy, there was biological plausibility as well as early evidence of safety and effectiveness. Since then, CRT has seen significant improvements in delivery systems and leads, the ability to optimize an acute response, and better identification of patients who are most likely to benefit. It will be interesting to see how BAT technology evolves over the next few years. 

Stay safe,

Bradley P. Knight, MD, FACC, FHRS

Editor-in-Chief, EP Lab Digest

@DrBradleyKnight

Disclosures: Dr. Knight reports that he is a consultant, speaker, investigator, and offers fellowship support for Abbott, Baylis Medical, Biosense Webster, Inc., BIOTRONIK, Boston Scientific, Medtronic, and SentreHEART. He has received compensation for serving as a consultant to CVRx, Inc. 

1. Gold MR, Van Veldhuisen DJ, Hauptman PJ, et al. Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial. J Am Coll Cardiol. 2016;68:149-158. doi: 10.1016/j.jacc.2016.03.525
2. Zannad F, De Ferrari GM, Tuinenburg AE, et al. Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial. Eur Heart J. 2015;36(7):425-433.
3. Zipes DP, Neuzil P, Theres H, et al. Determining the feasibility of spinal cord neuromodulation for the treatment of chronic systolic heart failure: the DEFEAT-HF Study [published correction appears in JACC Heart Fail. 2018;6(6):542]. JACC Heart Fail. 2016;4(2):129-136.
4. Drożdż T, Jastrzebski M, Moskal P, et al. Renal denervation in patients with symptomatic chronic heart failure despite resynchronization therapy – a pilot study. Postepy Kardiol Interwencyjnej. 2019;15(2):240-246. doi: 10.5114/aic.2019.8601
5. Zile MR, Lindenfeld J, Weaver FA, et al. Baroreflex activation therapy in patients with heart failure with reduced ejection fraction. J Am Coll Cardiol. 2020;76(1):1-13.