Neuromodulation devices for heart failure

Abstract

Autonomic imbalance with a sympathetic dominance is acknowledged to be a critical determinant of the pathophysiology of chronic heart failure with reduced ejection fraction (HFrEF), regardless of the etiology. Consequently, therapeutic interventions directly targeting the cardiac autonomic nervous system, generally referred to as neuromodulation strategies, have gained increasing interest and have been intensively studied at both the pre-clinical level and the clinical level. This review will focus on device-based neuromodulation in the setting of HFrEF. It will first provide some general principles about electrical neuromodulation and discuss specifically the complex issue of dose-response with this therapeutic approach. The paper will thereafter summarize the rationale, the pre-clinical and the clinical data, as well as the future prospectives of the three most studied form of device-based neuromodulation in HFrEF. These include cervical vagal nerve stimulation (cVNS), baroreflex activation therapy (BAT), and spinal cord stimulation (SCS). BAT has been approved by the Food and Drug Administration for use in patients with HfrEF, while the other two approaches are still considered investigational; VNS is currently being investigated in a large phase III Study.

Keywords: Autonomic imbalance; Autonomic regulation therapy; Device-therapy; Neuromodulation; Sympathetic nervous system.

Figure 1

Device-based autonomic modulation (electroceutical) therapy for heart failure and a reduced ejection fraction. RCTs, randomized clinical trials.

Figure 2

Summary of results from the INOVATE-HF study using vagal nerve stimulation. (A) Schematic showing the proposed neuromodulation pathways and the stimulation device design. (B) Kaplan–Meier curves plotting the time to first HF event or all-cause death in the control and treatment groups. Vagal nerve stimulation did not have a statistically significant effect. (C) Data examining change from baseline to 12 months in control group vs. treatment group. There was a significant treatment based increase in 6-min hall walk distance and Kansas city quality of life score but no significant change in left ventricular end-systolic volume index. LVESVi, left ventricular end-systolic volume index, KCCQ, Kansas city quality of life score; 6MHW, 6-min hall walk.

Figure 3

Schematic representation of the baroreceptor activation therapy device components and the mechanisms of action of baroreceptor activation therapy and their effects on advanced heart failure with a reduced ejection fraction–associated changes in autonomic function.

Figure 4

Baroreflex Activation Therapy for Heart Failure trial design. Baroreflex Activation Therapy for Heart Failure was designed in collaboration with the FDA breakthrough device programme and was divided into two phases: pre-market phase and post-market phase. The details and status of the Baroreflex Activation Therapy for Heart Failure study are represented. MANCE, major adverse neurological and cardiovascular events; MLWHF, Minnesota living with heart failure; 6MHW, 6 minutes hallwalk; PMA, premarket approval.

Figure 5

Primary efficacy endpoints in the Baroreflex Activation Therapy for Heart Failure trial pre-market phase. There were significant improvements in quality of life score using the Minnesota living with heart failure questionnaire, exercise capacity measured using the 6-min hall walk test, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide levels. MLWHF, Minnesota living with heart failure questionnaire; 6MHW, 6-min hall walk.

Figure 6

The effects of baroreceptor activation therapy across all baseline covariates examined in the Baroreflex Activation Therapy for Heart Failure study were very consistent for all four primary endpoints: quality of life score using the Minnesota living with heart failure questionnaire, exercise capacity measured using the 6-min hall walk test, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide levels. MLWHF, Minnesota living with heart failure questionnaire; 6MHW, 6-min hall walk.

Figure 6

The effects of baroreceptor activation therapy across all baseline covariates examined in the Baroreflex Activation Therapy for Heart Failure study were very consistent for all four primary endpoints: quality of life score using the Minnesota living with heart failure questionnaire, exercise capacity measured using the 6-min hall walk test, New York Heart Association class, and N-terminal pro-B-type natriuretic peptide levels. MLWHF, Minnesota living with heart failure questionnaire; 6MHW, 6-min hall walk.