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

Author: Marvin A Konstam1, Douglas L Mann2, John James E Udelson1, Jeffrey L Ardell3, Gaetano M De Ferrari4, Martin R Cowie5, Helmut U Klein6, Douglas D Gregory7, Joseph M Massaro8, Imad Libbus9, Lorenzo A DiCarlo9, Javed Butler10, John D Parker11, John R Teerlink12
1 The CardioVascular Center at Tufts Medical Center, Boston, MA, United States.
2 Center for Cardiovascular Research, Washington University School of Medicine, Saint Louis, MO, United States.
3 UCLA Neurocardiology Program of Excellence, University of California, Los Angeles, Los Angeles, CA, United States.
4 Cardiology, Department of Medical Sciences, University of Torino, Turin, Italy.
5 School of Cardiovascular Medicine and Sciences, King's College London, London, United Kingdom.
6 Division of Cardiology, University of Rochester Medical Center, Rochester, NY, United States.
7 Clinical Cardiovascular Science Foundation, Boston, MA, United States.
8 Department of Biostatistics, School of Public Health, Boston University, Boston, MA, United States.
9 LivaNova USA Incorporated, Houston, TX, United States.
10 Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States.
11 University of Toronto, University Health Network, Toronto, ON, Canada.
12 Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco, CA, United States.
Conference/Journal: Front Physiol
Date published: 2022 Apr 21
Other: Volume ID: 13 , Pages: 857538 , Special Notes: doi: 10.3389/fphys.2022.857538. , Word Count: 299

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.

PMID: 35530511 PMCID: PMC9068946 DOI: 10.3389/fphys.2022.857538