Vagus Nerve Stimulation for the Treatment of Heart Failure: Investigational Approach Takes Aim at the Drivers of HF Progression

Randy Lieberman, MD
Director of Electrophysiology
Harper University Hospital: Cardiovascular Institute
Detroit Medical Center
Detroit, Michigan

Randy Lieberman, MD
Director of Electrophysiology
Harper University Hospital: Cardiovascular Institute
Detroit Medical Center
Detroit, Michigan


Congestive heart failure (CHF) is a major worldwide problem, and the incidence is increasing. Chronic heart failure symptoms with reduced ejection fraction, despite optimal drug therapy, are a significant cause of hospitalization and mortality.

HF is characterized by a dysfunction of the immune response and autonomic imbalance of the parasympathetic and sympathetic systems. The degree of immune activation and autonomic imbalance is related to CHF severity, disease progression, and death. There is growing evidence that these two phenomena might be closely related to decreased parasympathetic function. Restoration or augmentation of parasympathetic tone could be a therapeutic approach to CHF. Over the past several years, pre-clinical and early clinical research has been conducted in the EP lab to explore the value of parasympathetic (vagal nerve) stimulation for the treatment of CHF. Further, a multi-center pivotal clinical trial is currently evaluating the potential of vagal nerve stimulation (VNS) to reduce hospitalization and death among patients with CHF.

HF Progression

Heart failure begins with myocardial damage, which may be caused by myocardial infarction, longstanding hypertension, or in some cases, idiopathic cardiomyopathy. In response, the autonomic sympathetic nervous system is activated. The sympathetic nervous system activation increases circulating epinephrine and norepinephrine. These elevated catecholamines force more calcium into the cells to make the heart pump harder and create an environment in which it can function in a super strong state. At the same time, the renin-angiotensin system is activated to manage decreased blood flow and increased fluid in the body. These neurohormonal responses are effective compensation mechanisms short term, but ultimately they contribute to the vicious cycle of CHF progression. These maladaptive responses lead to apoptosis, arrhythmias and sudden death, additional fibrosis, heart remodeling, and further HF deterioration.

VNS and Vagal Tone: Targeting the Weak Link in HF Therapy

Researchers have known for more than 30 years that there is a companion part to the activation of the sympathetic nervous system in heart failure, namely the early withdrawal or reduced activity of the parasympathetic nervous system. Minimal left ventricular (LV) damage, stretch or ischemia triggers signals to the brain (afferent), which results in decreased parasympathetic function, termed “parasympathetic withdrawal.” This autonomic activation to parasympathetic withdrawal precedes sympathetic activation and CHF symptoms. Decreased parasympathetic vagal stimulation is associated with increased immune-inflammatory response, as measured by cytokine markers (e.g., TNF-α and IL-6). At the early stage, these immune cytokines may be necessary for healing or protecting the heart, but chronically they are maladaptive and lead to autoimmune LV remodeling and progressive CHF.

More specifically, clinical and experimental data support the association between TNF-α and CHF mortality. Experimental vagotomy is associated with increased TNF-α, while TNF-α decreases with vagal stimulation. IL-6 is clinically associated with autonomic imbalance, as measured by heart rate variability (HRV). HRV, which measures parasympathetic withdrawal, has also been shown to be a strong marker for mortality. As demonstrated in the MERIT-HF trial, the use of beta blockers alone does not alter the immune markers, nor does it impact HRV.1

Furthermore, data from multiple publications on canine CHF have demonstrated that vagal nerve stimulation turns off the immune/inflammatory response, improves LV function, and positively affects other key drivers of HF progression, including nitric oxide expression. These effects appear to be independent of beta blockers, or heart rate reductions.2 When VNS was applied to HF-induced canines under a high-rate pacing model, the data showed improvements in the neuroimmune reflex even with the artificially maintained heart rate.3 These results confirm that heart rate reduction alone does not appear to be a major component in the mechanism of action of VNS for HF. Rather, it is just another measure of increased vagal tone.

In short, these comprehensive pre-clinical studies suggested that VNS could have important effects on many of the key pathophysiologic mechanisms that contribute to the progressive downhill course that characterizes HF.

VNS for CHF: Human Data

Following the pre-clinical studies, a multi-center pilot study was conducted in Germany, Italy, the Netherlands, and Serbia to test the safety and efficacy of VNS in patients with HF. This study investigated treatment with an implantable VNS system (CardioFit®, BioControl Medical, Yehud, Israel; Figure 1) in 32 patients with NYHA Class II–IV and left ventricular ejection fraction (LVEF) ≤35%. At six-month follow-up, the data showed that patients experienced significant improvement across key clinical measures including left ventricular function and structure, heart rate variability, quality of life (Minnesota Living with Heart Failure Questionnaire), and six-minute hall walk tests (Figure 2). The study also showed that VNS was safe and well tolerated. There were two implant-related adverse events: pulmonary edema, which was resolved with standard therapy, and a set screw that required tightening.4

Longer term follow-up from the pilot study also showed that treatment effects were durable. Twenty-three patients had extended follow-up to 12 months. The improvements in LVEF, quality of life, six-minute hall walk tests, and NYHA classifications were all maintained at 12 months (Figure 3). Two-year data on treatment durability has been submitted for presentation at the 2012 AHA Scientific Sessions. 

Current Clinical Study: INOVATE-HF

In October 2010, the U.S. Food and Drug Administration (FDA) approved a global, multi-center investigational device exemption (IDE) clinical study to determine the safety and effectiveness of the CardioFit implantable VNS system for the treatment of HF (Figure 1). Called INOVATE-HF (INcrease Of VAgal TonE in Heart Failure), the prospective, randomized, controlled study is designed to evaluate the system’s potential to reduce hospitalization and death among patients with HF.

The VNS system has three components, including a cuff electrode placed around the vagus nerve, a standard RV sensing lead and a generator. The implant procedure is straightforward and averages about 60 minutes done in an EP lab or hybrid suite.

A growing number of EP labs around the world are now participating in INOVATE-HF. The study is enrolling up to 650 patients at up to 80 centers in the United States and Europe. Study enrollees are randomized on a 3:2 basis with the implantable VNS system and optimal medical therapy or optimal medical therapy alone. The primary efficacy endpoint is time to first occurrence of unplanned HF hospitalization or all-cause death. The primary safety endpoints are system-related complications within 90 days of implantation and non-inferiority to optimal medical therapy beyond 90 days. Secondary endpoints include the rate of unplanned HF hospitalization as well as the change from baseline to 12 months in HF symptoms as well as functional and structural cardiovascular status.

Final results of the INOVATE-HF study, which are expected in 2015, will be used to support a Premarket Approval Application (PMA) to the FDA for approval of the implantable VNS system for the treatment of HF.


The early clinical data supporting VNS for the treatment of HF is compelling and has led to a pivotal, randomized study to gain further evidence on the therapy’s safety and effectiveness. If the results of the broader clinical study mirror those from the pilot trial, VNS may prove to be a very important option in the armamentarium of HF therapy.


  1. The MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353:2001–2007.
  2. Sabbah HN, Ilsar I, Zaretsky A, et al. Vagus nerve stimulation in experimental heart failure. Heart Fail Rev 2011;16:171–178.
  3. Zhang Y, Popovic ZB, Bibevski S, et al. Chronic vagus nerve stimulation improves autonomic control and attenuates systemic inflammation and heart failure progression in a canine high-rate pacing model. Circ Heart Fail 2009;2:692–699.
  4. De Ferrari GM, Crijns HJ, Borggrefe M, et al. Chronic vagus nerve stimulation: A new and promising therapeutic approach for chronic heart failure. Eur Heart J 2010;32:847–855. doi:10.1093/eurheartj/ehq391