Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure

Abstract

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve. Achieving autonomic engagement was accompanied by improvement from baseline in six-minute walk duration (6MWD), health-related quality of life, and left ventricular EF (LVEF), over and above those achieved by concomitant guideline-directed medical therapy (GDMT) administered to counteract harmful neurohormonal activation, with relative freedom from deleterious effects. Autonomic engagement and positive directional changes have persisted over time, and an exploratory analysis suggests that improvement in autonomic tone, symptoms, and physical capacity may be independent of baseline NT-proBNP values. Based upon these encouraging observations, prospective, randomized controlled trials examining the effects on symptoms and cardiac function as well as natural history have been warranted. A multi-national, large-scale, randomized, controlled trial is well underway to determine the outcomes associated with ART using autonomic nervous system engagement as a guide for VNS delivery.

Keywords: autonomic nervous system; autonomic regulation therapy; cardiomyopathy; guideline directed medical therapy (GDMT); heart failure; left ventricular ejection fraction; neuromodulation; vagus nerve stimulation.

FIGURE 1

Organization and Function of Autonomic Nervous System for Neuromodulation and Cardiac Control. DRG = Dorsal root ganglia, a group of cell bodies responsible for the transmission of sensory messages from receptors such as thermoreceptors, nociceptors, proprioceptors, and chemoreceptors, to the central nervous system. ICN = intracardiac network, a “little brain” of the heart comprising intracardiac ganglia and interconnecting neurons making adjustments of the cardiac mechanical and electrical activity comprising intracardiac ganglia and interconnecting neurons. From Hanna H, Shivkumar K, and Ardell J. Card Fail Review 2018; 4: 92–98, with permission.

FIGURE 2

VNS system to deliver ART. Adapted from Anand IS, et al. ESC Heart Fail 2020 with permission.

FIGURE 3

VNS intensity encompasses a combination of pulse amplitude (current), pulse frequency, pulse duration, and duty cycle. Adapted from Anand IS, et al. Int J Neurol Neurother 2019 with permission.

FIGURE 4

Mechanisms of action of ART and GDMT. Figure adapted from Konstam MA, et al. Circ Heart Fail 2019 with permission. Additional information is provided in Supplementary Appendix S1, S2

FIGURE 5

Stimulation frequencies used for VNS and associated changes from baseline in symptomatic and functional outcomes in the treatment arms of ANTHEM-HF, INOVATE-HF, and NECTAR-HF. △ = difference; % = percent; bpm = beats per minute; Hz = Hertz; m = meters; ms = milliseconds; other abbreviations as in the text. p-values are two-sided and are based on two-sample t-tests. From Inand AS, et al. ESC Heart Fail 2020; 7: 76–84, with permission.

FIGURE 6

ANTHEM-HFrEF Pivotal Study Design. CVD = Cardiovascular death. HFH = Heart failure hospitalization. Mo = months. N = number. PMA = Pre-Market Application. sPMA = supplementary Pre- Market Application. Dotted lines represent serial interim analyses as appropriate. Other abbreviations as in text. From Konstam MA, et al. Circ Heart Fail 2019; 12: e005879, with permission.