NEUROMODULATION OF THE FAILING HEART: LOST IN TRANSLATION?

Abstract

Sympathovagal imbalance contributes to progressive worsening of HF (HF) and is associated with untoward clinical outcomes. Based on compelling pre-clinical studies which supported the role of autonomic modulation in HF models, a series of clinical studies were initiated using spinal cord stimulation (SCS), vagus nerve stimulation (VNS) and baroreceptor activation therapy (BAT) in patients with HF with a reduced ejection fraction (HFrEF). While the phase II studies with BAT remain encouraging, the larger clinical studies with SCS and VNS have yielded disappointing results. Here we will focus on the pre-clinical studies that supported the role of neuromodulation in the failing heart, as well provide a critical review of the recent clinical trials that have sought to modulate autonomic tone in HF patients. This review will conclude with an analysis of some of the difficulties in translating device-based modulation of the autonomic nervous from pre-clinical models into successful clinical trials, as well as provide suggestions for how to move the field of neuromodulation forward.

Figure 1

The Autonomic Nervous System Diagram of pre-ganglionic and post-ganglionic sympathetic and parasympathetic fibers.

Figure 2

Schematic Demonstrating the Location and Stimulation Sites for Device-Based Neuromodulation Modality (A) Vagus nerve stimulator placed in right subpectoral region with standard transvenous pacing/sensing lead placed in right ventricular (closed loop) and vagus nerve stimulating lead (dotted white lines) tunneled to cervical vagus region. (B) Vagus nerve stimulator placed in right subpectoral region with vagus nerve stimulating lead (dotted white line) tunneled to cervical vagus region (open loop). (C) The spinal cord stimulation (SCS) generator is implanted in abdomen or paraspinous region with stimulation lead (blue line) placed in dorsal epidural space at thoracic level 4. (D) Baroreflex stimulation generator placed in right subpectoral region with bilateral stimulation leads tunneled to the carotid baroreceptor region. Modified and adapted with permission from Lopshire and Zipes . BAT = baroreceptor activation therapy; SCS = spinal cord stimulation; VNS = vagus nerve stimulation.

Figure 3

Results of the CardioFit System Pilot Trial (A) Change in New York Heart Association (NYHA) classification at 3 and 6 months after vagus nerve stimulation. (B) Change in left ventricular end-systolic volume index at 3 and 6 months.

Figure 4

Primary Clinical Endpoint of the ANTHEM-HF Trial Mean and 95% confidence intervals of echocardiographic changes after 6 months of autonomic regulation therapy (overall, left-side treatment, and right-side treatment). Reproduced with permission from Premchand RK et al. . ANTHEM-HF = Autonomic Regulation Therapy via Left or Right Cervical Vagus Nerve Stimulation in Patients With Chronic Heart Failure; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; LVESD = left ventricular end-systolic diameter.

Figure 5

Primary Efficacy Endpoint of the INOVATE-HF Trial There was no significant difference in the primary composite outcome of death from any cause or a worsening heart failure event in the vagus nerve stimulation (VNS) treatment arm when compared with the control group (hazard ratio: 1.14; 95% confidence interval: 0.86 to 1.53; p = 0.37). Reproduced with permission from Gold et al. . INOVATE-HF = INcrease of VAgal TonE in Heart Failure.

Figure 6

Primary Efficacy Endpoint of the DEFEAT-HF Trial There was no significant difference in the change in left ventricular end-systolic volume index (LVESVi) over 6 months between the spinal cord stimulation and control groups (p = 0.30). The bottom line of the box equals the 25th percentile, the top line equals the 75th percentile and the line within the box equals the median. The dots represent patient values that exceed the 75th percentile. Reproduced with permission from Zipes et al. . DEFEAT-HF = Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure.